Methods and devices for deep brain stimulation

Abstract

To provide a method of treatment performed on a subject's brain.SOLUTION: A method includes a step of applying one or more neuromodulation signals to the lateral habenular nucleus and the posterior commissure. The method further includes applying one or more neuromodulation signals to one or more additional targets in the subject's brain. The one or more additional targets include the dorsomedial nucleus of the thalamus. A first neuromodulation signal having a first frequency is applied to the dorsomedial nucleus, and one or more second neuromodulation signals are applied to the lateral habenular nucleus and the posterior commissure, where each of the one or more second neuromodulation signals has a frequency lower than the first frequency.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to methods and devices for deep brain stimulation (DBS). [Background technology]

[0002] 2. Background of the Invention Deep brain stimulation (DBS) is a neurosurgical procedure introduced in 1987 that involves the implantation of electrodes into specific targets in the brain. A medical device known as a neurostimulator (sometimes called a "brain pacemaker") is used to apply neurostimulation signals in the form of electrical impulses via the electrodes to targets in the brain in order to modify brain circuitry for the treatment of movement disorders and neuropsychiatric disorders.

[0003] This technique is currently being used to target brain circuits involved in Parkinson's disease, dystonia and tremors and has been shown to be highly effective in controlling symptoms. Deep brain stimulation of some brain regions also provides therapeutic benefits for otherwise treatment-resistant disorders such as chronic pain, major depression, addiction, epilepsy, Tourette's disease and obsessive-compulsive disorder.

[0004] Despite DBS's long history, its underlying principles and mechanisms remain unclear. Electrical stimulation is widely believed to control the excitability of neurons in the immediate vicinity of the implanted electrodes. Stimulation frequency is widely used to excite (e.g., below 50 Hertz) or inhibit (e.g., above 100 Hertz) neurons, and stimulation amplitude and pulse width are used to control the amount of charge applied to reach and empirically define threshold responses. The threshold response is also determined by the physical proximity of the electrode contacts to the brain target of interest.

[0005] Typically, electrodes used for DBS are in the form of either circumferential (e.g., cylindrical) or directional contacts distributed along a lead connected to an implantable pulse generator (IPG), which can allow for either a monopolar stimulation configuration (where the IPG acts as the anode) or a bipolar stimulation configuration (between the contacts).

[0006] In U.S. Patent Application Publication No. 2016 / 0367809, which is incorporated herein by reference, the inventors disclose a therapeutic method involving neurostimulation of the periaqueductal gray (PAG) to increase cerebral perfusion, thereby allowing the treatment of various conditions associated with impaired cerebral blood flow. U.S. Patent Application Publication No. 2016 / 0367809 also describes a therapeutic method involving combined neurostimulation of the PAG and the dorsomedial thalamic nucleus. Summary of the Invention [Problem to be solved by the invention]

[0007] Summary of the Invention The present invention builds on the inventors' work in US Patent Publication No. 2016 / 0367809 and is based on the discovery that combined neurostimulation of multiple targets in the brain can result in improved responses to treatment. In particular, the inventors have found that the response to neurostimulation of various targets in the brain can be improved by additional neurostimulation of the lateral habenula (LH) and posterior commissure (PC). [Means for solving the problem]

[0008] Thus, most generally, the invention provides a method of treatment performed on a subject's brain, which involves applying one or more neuromodulatory signals to the LH and PC.

[0009] According to a first aspect of the present invention, there is provided a therapeutic method performed on a subject's brain, the method comprising the step of applying one or more neuromodulatory signals to the lateral habenula (LH) and the posterior commissure (PC).

[0010] The LH and PC can be stimulated via the same (single) neuromodulation signal. Alternatively, separate (different) neuromodulation signals may be applied to each of the LH and PC, respectively.

[0011] Stimulation of the LH and PC can affect the adjacent medial thalamus, and / or periventricular gray matter, and / or periaqueductal gray matter, and / or their respective projections, and can affect the pineal gland and / or contralateral hemisphere projections, via the LH and PC. Thus, applying one or more neuromodulatory signals to the LH and PC can include directly or indirectly applying one or more neuromodulatory signals to the adjacent medial thalamus, and / or periventricular gray matter, and / or periaqueductal gray matter, and / or their respective projections, and can include affecting one or both of the projections of the pineal gland and the contralateral hemisphere projections, via the LH and PC.

[0012] The neuromodulation signal can be an electrical signal that is applied to a target in the brain. For example, the neuromodulation signal can be a pulsed electrical signal. The parameters of the neuromodulation signal, such as frequency, pulse width and pulse amplitude, can be adjusted according to the specific requirements of the treatment. The neuromodulation signal can be applied continuously or in bursts or cycles.

[0013] The present inventors have discovered that neural stimulation of LH and PC in subjects can enhance cerebral blood flow, which can enable various conditions associated with reduced cerebral blood flow to be treated.

[0014] The lateral habenula is part of the habenula complex, which includes the medial and lateral nuclei. Via the stria medullaris, the medial habenula receives fibers from the medial septum-diagonal band complex. The medial habenula also receives fibers from the periaqueductal gray, serotonergic projections from the mesencephalic raphe nuclei, and adrenergic innervation from the superior cervical ganglion. The efferents of the medial habenula terminate only in the interpeduncular nucleus, which projects extensively to the dorsal raphe nucleus and the supramedianal nucleus. The lateral habenula receives afferents mainly from the nuclei of the diagonal band, the lateral preoptic hypothalamic area, the substantia innominata, and the internal pallidum, while the ventral tegmental area, as well as the mesencephalic raphe nucleus and the ventral part of the periaqueductal gray, give rise to ascending inputs to this nucleus. Efferent fibers from the lateral habenula descend in the retroflex fasciculus and terminate in various midbrain centers, including the substantia nigra pars compacta, the ventral part of the periaqueductal gray, the dorsal raphe, and the supracentral nucleus and midbrain ciliary body. Although the functional role of the habenula has not been fully elucidated, their fiber connections suggest that they represent processing stations for a variety of biological functions, such as pain processing, emotion, reproduction, nutrition, stress responses, sleep-wake cycles, and learning.

[0015] The posterior commissure is a round band of white fibers that crosses the midline dorsal to the rostral end of the aqueduct. Most fibers originate from the nucleus of the posterior commissure in the periaqueductal gray matter at the rostral end of the aqueduct, anterior to the oculomotor nuclei, while other fibers are thought to originate from the posterior part of the thalamus, superior colliculus, and medial longitudinal fasciculus. Based on clinical observations, the nucleus of the posterior commissure is suspected to be involved in the generation and premotor control of upward eye movements of the upper eyelid. The nucleus projects to contralateral thalamus, internal capsule, and midbrain locations. The nucleus is interconnected with the adjacent central midbrain ciliary body, which receives input from the cerebellar fastigial nucleus, which has been shown to garner neuroprotection in stroke when stimulated.

[0016] The ventral PC is closely associated with the subhabenular nucleus, the retroflex tractus (habenular projection to the midbrain) and the medial parathalamic nucleus. Thus, applying a neuromodulatory signal to the PC may include directly or indirectly applying a neuromodulatory signal to one or more of the subhabenular nucleus, the retroflex tractus (habenular projection to the midbrain) and the medial parathalamic nucleus.

[0017] The method may further comprise applying one or more neuromodulation signals to one or more additional targets in the brain of the subject.Thus, one or more neuromodulation signals can be applied to LH and PC in combination with one or more additional targets in the brain of the subject.The inventors have found that combining the neurostimulation of brain targets with the neurostimulation of LH and PC can improve the response of targets to neurostimulation.

[0018] The same (single) neuromodulation signal can be applied to each of the LH and PC and one or more additional targets in the subject's brain. Alternatively, different neuromodulation signals can be applied to each or a subset (group) of the LH and PC and one or more additional targets in the subject's brain.

[0019] The one or more additional targets may include the dorsomedial thalamic nucleus (DMN). Thus, according to one embodiment, the method includes applying one or more neuromodulatory signals to each of the DMN, the LH, and the PC.

[0020] The present inventors have found that the response of a subject to the neurostimulation of DMN can be improved by combining the neurostimulation of DMN with the neurostimulation of LH and PC.Therefore, the method of the first aspect may improve the response of a subject to the neurostimulation of DMN, which may lead to improved results of the treatment that includes the neurostimulation of DMN.

[0021] The DMN has extensive and reciprocal connections with the prefrontal cortex, as well as limbic structures, including the limbic cortex, hippocampus, and basolateral amygdala. The DMN is involved in higher cognitive functions, such as spatial working memory and emotional processes. The DMN is also involved in pain processing. In schizophrenia, the volume and number of neurons in the DMN are reduced. The DMN also plays a major role in amygdalohippocampal seizures and controls limbic seizures. The DMN is closely associated with the median parafascicular complex. The DMN and the median parafascicular complex are embedded in different basal ganglia, namely the thalamocortical loop that integrates cognitive and affective aspects of human behavior. The parvocellular sector of the DMN is involved in memory retrieval. The magnocellular sector in monkeys is necessary for new learning, and specific damage in humans is associated with both retrograde and anterograde amnesia. Acute isolated time disorientation can occur with thalamic small artery disease involving the DMN.

[0022] Neurostimulation can be used, for example, to alter emotional responses and memory. For example, high-frequency neurostimulation of the DMN can play a role in improving memory formation. Thus, neurostimulation of the DMN can enable the treatment of a variety of conditions (see Mavridis I "Human Mediodorsal Thalamic Nucleus as a Potential Target for Deep Brain Stimulation" (Review of the Literature and Anatomical Considerations. OA Anatomy 2014 January 12;2(1)-1)).

[0023] One or more additional targets may include the posterior hypothalamic nucleus.According to one embodiment, the method thus comprises applying one or more neuromodulation signals to each of the posterior hypothalamic nucleus, LH and PC (and optionally DMN).The inventors have found that the stimulation of the posterior hypothalamic nucleus can lead to an increase in cerebral blood flow and cerebral blood volume, and reduce the mean transit time of blood through the brain.The stimulation of the posterior hypothalamic nucleus can be used to treat cluster headache.

[0024] The one or more neuromodulation signals may include multiple neuromodulation signals. For example, the one or more neuromodulation signals may include a first neuromodulation signal applied to the DMN, a second neuromodulation signal applied to the LH, and a third neuromodulation signal applied to the PC. In other cases, the same neuromodulation signal may be applied to multiple targets. For example, a first neuromodulation signal may be applied to the DMN, while a second neuromodulation signal may be applied to the LH and the PC.

[0025] Neuromodulation signals can be applied to the LH and PC, as well as any additional targets in the brain, via electrode leads implanted in the subject's brain. The electrode leads can have multiple electrodes configured to apply neuromodulation signals to each of the LH and PC, as well as any additional targets (e.g., DMN). For example, the electrode leads can include a first electrode configured to apply a neuromodulation signal to the DMN, a second electrode configured to apply a neuromodulation signal to the LH, and a third electrode configured to apply a neuromodulation signal to the PC. The same or different neuromodulation signals can be applied to each of the LH and PC, as well as any additional targets in the brain. The electrode leads can be configured such that a separate neuromodulation signal can be applied via each electrode. In this manner, multiple different targets can be stimulated individually. In some cases, multiple targets may be stimulated via the same electrode.

[0026] Different targets (eg, LH, PC, DMN) may be stimulated simultaneously or sequentially.

[0027] In some embodiments, a first neuromodulation signal having a first frequency can be applied to the dorsomedial nucleus and one or more second neuromodulation signals can be applied to the lateral habenular nucleus and the posterior commissure, where each of the one or more second neuromodulation signals has a frequency lower than the first frequency.

[0028] High frequency neuromodulation signals applied to the DMN can serve to inhibit neurons in the DMN, while low frequency neuromodulation signals applied to the LH and PC can serve to enhance the subject's response to the treatment. The first neuromodulation signal and the second neuromodulation signal can be applied via different electrode sets on the electrode lead. The first neuromodulation signal can correspond to a first pulse train having a first frequency, while the second neuromodulation signal can correspond to a second pulse train having a second frequency.

[0029] The same second neuromodulation signal may be applied to both the LH and the PC. Alternatively, different second neuromodulation signals, for example having different frequencies, may be applied to each of the LH and PC, respectively.

[0030] The first neuromodulation signal applied to the DMN can have a frequency within the upper limit of the gamma range (30-100 Hz) or above.

[0031] The second neuromodulatory signal applied to the LH may be in the theta (4-8 Hz), alpha (8-14 Hz), and beta (14-30 Hz) frequency ranges. Stimulation of the LH may also incorporate the habenular commissure, and the pineal commissure with transmission of stimulation to the pineal gland. Stimulation of the LH may be altered to regulate and synchronize with the circadian rhythm.

[0032] The second neuromodulation signal applied to the PC may be in the theta (4-8 Hz) and alpha (8-14 Hz) frequency ranges, and optionally 30-40 Hz.

[0033] In one example, the first frequency may be greater than 70 Hz and each of the one or more second neuromodulation signals may have a frequency between 4 and 50 Hz. In some examples, the same neuromodulation signal may be applied to the LH and PC, while in other examples, separate / different neuromodulation signals may be applied to the LH and PC.

[0034] Stimuli applied at different frequencies may be interlaced, and while stimulation can be applied continuously, variations can be programmed to provide stimulation with burst frequencies or with appropriate on / off periods and can be established from algorithms interpreted from mathematical interpretations of normal and pathological local field potentials, as well as brain rhythm coherence as seen across circadian rhythms.

[0035] In some embodiments, the one or more additional targets may include the ventrolateral periaqueductal gray (VL-PAG).Accordingly, according to one embodiment, the method includes applying one or more neuromodulatory signals to each of the LH, PC, and VL-PAG (and optionally the DMN).

[0036] In this way, compound neural stimulation of the DMN, VL-PAG, LH and PC can be performed. In US Patent Application Publication No. 2016 / 0367809, the inventors disclosed that compound neural stimulation of the DMN and VL-PAG can play a role in increasing the perfusion of the hippocampus and other structures involved in cognition and memory. As a result, compound neural stimulation of the DMN and VL-PAG can enable the treatment of various conditions such as Alzheimer's disease, hypertension and epilepsy. The inventors further found that the subject's response to compound neural stimulation of the DMN and VL-PAG can be improved by additionally applying neural stimulation signals to the LH and PC.

[0037] The neuromodulation signal applied to the VL-PAG may be one of the one or more second neuromodulation signals discussed above. In this manner, a first higher frequency neuromodulation signal may be applied to the DMN, while a lower frequency neuromodulation signal(s) may be applied to the LH, PC and VL-PAG. The neuromodulation signal applied to the VL-PAG may be the same as the neuromodulation signal applied to the LH and / or PC, or may be different from the neuromodulation signal applied to the LH and / or PC.

[0038] The neuromodulation signal applied to the VL-PAG may be in the theta (4-8 Hz) and alpha (8-14 Hz) frequency ranges, and optionally 30-40 Hz.

[0039] In one example, the neuromodulation signal applied to the VL-PAG may have a frequency of 5-50 Hz. Low frequency (e.g., 5-50 Hz) stimulation of the VL-PAG can result in a global increase in cerebral blood flow and volume, as well as a decrease in mean blood transit time.

[0040] The periventricular gray (PVG) and periaqueductal gray (PAG) have been recognized as targets of brain stimulation in the treatment of intractable pain since 1977. The PAG resides within the midbrain and its role in autonomic function has been extensively studied in animal models, where it has been found to be crucially involved in mediating defensive responses to perceived or present danger. Perceived, avoidable fear induces a fight-or-flight response, whereas in contrast, perceived, inescapable fear, which is advantageous to remain undetected, provokes the opposite response pattern: rigidity. Both responses are mediated from the PAG, but from distinct sites, with the dorsal PAG generating the fight-or-flight response, whereas the ventral portion (VL-PAG) generates the rigidity response.

[0041] The tonic response, consisting of hypotension, bradycardia, and hyperventilation, is often combined with analgesia and is mediated by the VL-PAG, which also has dense projections to known sites of cardiovascular integration within the central nervous system (CNS), including the medulla and hypothalamic nuclei, in addition to those involved in motor control and analgesia. The VL-PAG also receives projections from regions involved in somatosensory feedback and autonomic regulation, including forebrain cortical structures, the limbic system, spinal afferents, and hypothalamic nuclei.

[0042] In some embodiments, the method may further include identifying a trajectory in the subject's brain, the trajectory connecting the dorsomedial nucleus over the lateral habenula and posterior commissure with the VL-PAG, and implanting an electrode lead into the subject's brain along the identified trajectory, the electrode lead including multiple electrodes for applying one or more neuromodulation signals. In this manner, the neuromodulation signals may be applied using a single electrode lead that spans the trajectory connecting the DMN, LH, PC, and VL-PAG. This may facilitate neurostimulation of the DMN, LH, PC, and VL-PAG, and may eliminate the need to use multiple electrode leads to stimulate these different targets. Furthermore, having an electrode lead that spans such a trajectory may allow multiple different combinations of neuromodulation signals to be applied to one or more of the DMN, LH, PC, and VL-PAG. This may allow the neurostimulation therapy to be tailored according to the needs of the subject. The trajectory may be transventricular, i.e., the trajectory may pass through the lateral ventricles.

[0043] The phrase "spanning the lateral habenular nucleus and the posterior commissure" may mean that the trajectory passes from one side of the lateral habenular nucleus and the posterior commissure to the other side of the lateral habenular nucleus and the posterior commissure. Usually, the trajectory is spaced away from the lateral habenular nucleus and the posterior commissure and passes adjacent to the lateral habenular nucleus and the posterior commissure.

[0044] The trajectory may be identified, for example, by obtaining an image of the subject's brain (e.g., via computed tomography and / or magnetic resonance imaging) prior to implantation of the electrode lead and plotting the trajectory on the subject's brain. The electrode lead may be implanted in the subject's brain along the identified trajectory, for example, using a stereotactic frame and / or a stereotactic robot.

[0045] After implantation, the electrode lead can follow a substantially straight trajectory passing through the lateral ventricle, bypassing the third ventricle, entering the DMN adjacent to the LH and PC, and entering the VL-PAG. Preferably, the electrode lead trajectory passes adjacent to the LH and PC without contacting the LH or PC to avoid damage to the LH and PC.

[0046] The orbit may further include the anterior thalamic nucleus, such that neuromodulatory signals may be applied to the anterior thalamic nucleus, neurostimulation of which may allow for the treatment of epilepsy.

[0047] The orbit may also further encompass the centromedian and / or parafascicular nuclei of the thalamus, so that neuromodulatory signals may be applied to these thalamic portions.

[0048] The multiple electrodes on the electrode lead may be configured such that, after implantation of the electrode lead, a neuromodulation signal may be applied to each of the DMN, LH, PC, and VL-PAG via an electrode in the multiple electrodes. In some cases, each of the DMN, LH, PC, and VL-PAG may be stimulated via a respective electrode in the multiple electrodes. The electrodes on the electrode lead may be separated from one another such that each target may be stimulated individually.

[0049] The electrodes on the electrode lead may be regularly (equally) spaced apart along the portion of the electrode lead that spans from the DMN to the VL-PAG. This may allow the neuromodulatory signal to be applied to the target along the entire length of the trajectory between the DMN and the VL-PAG. For example, the electrodes may span a length of 20-30 mm on the electrode lead, such as on the distal portion of the electrode lead. In one example, the electrodes may include eight electrodes each having a length of about 1.5 mm with a spacing of 1.5 mm between adjacent electrodes. In another example, the electrodes may include twelve electrodes each having a length of about 1.5 mm with a spacing of 0.5 mm between adjacent electrodes.

[0050] The electrode leads can be implanted unilaterally in one hemisphere of the brain, preferably in the non-dominant hemisphere of the brain. The non-dominant hemisphere is usually the right side, contralateral to the side that primarily controls speech processing. Implanting the electrode leads unilaterally in one hemisphere can minimize the surgical time and risk of complications such as bleeding. However, in some cases, applying neuromodulatory signals to targets in both hemispheres can improve clinical outcomes. In such cases, the electrode leads can be implanted in both hemispheres.

[0051] The right primarily non-dominant hemisphere has been shown to have greater lateralization for cognitive and emotional processing, as well as behavioral expression, and may be preferable to target, allowing for the acquisition of more optimal responses. Thus, electrode leads may be implanted unilaterally in the right hemisphere of the brain.

[0052] Implantation of the electrode lead involves first implanting a guide tube into the user's brain and then inserting the electrode lead through the guide tube.

[0053] The trajectory may be configured such that the spacing between the electrode lead and the lateral habenula is less than 5 mm, and / or the spacing between the electrode lead and the posterior commissure is less than 5 mm. A spacing of 5 mm or less between the electrode lead and the LH and PC can ensure that the LH and PC can be reliably stimulated via the electrodes on the electrode lead. In particular, the electrodes used to apply neuromodulation signals to the LH may be less than 5 mm from the LH, and the electrodes used to apply neuromodulation signals to the PC may be less than 5 mm from the PC. The inventors have found that spacing greater than 5 mm may prevent effective stimulation of the LH and PC, thereby reducing the overall effectiveness of the treatment. For example, the spacing between the electrode lead and the LH may preferably be 4 mm, 3 mm, 2 mm, or 1 mm, or less than any of these values. Similarly, the spacing between the electrode lead and the PC may preferably be 4 mm, 3 mm, 2 mm, or 1 mm, or less than any of these values. Preferably, the spacing between the electrode lead and the lateral habenula is less than 2mm and / or the spacing between the electrode lead and the posterior commissure is less than 2mm.

[0054] In some embodiments, the method can further comprise applying neuromodulation signals to the dorsal anterior cingulate cortex (DACC) and / or corpus callosum (CC).The inventors have found that in some cases, the response to treatment can be improved by additional neurostimulation of DACC and / or CC.Thus, the neurostimulation of one or more of DMN, LH, PC and VL-PAG can be augmented by the combined neurostimulation of DACC and / or CC.DACC and CC can be stimulated via the same electrode or different electrodes.

[0055] The inventors have found that stimulation of DACC and / or CC in combination with LH and PC can further improve a patient's response to neurostimulation.

[0056] In one test subject, we found that bilateral stimulation of DACC combined with LH, PC and VL-PAG results in the subject's positive response to neurostimulation.In addition, applying neuromodulation signals to DMN can further stimulate limbic circuits.Applying neuromodulation signals (e.g. unilaterally) to CC can allow further commissure spreading, which can enhance cerebral blood flow bilaterally.

[0057] The neuromodulation signals applied to the DACC and / or CC may have frequencies within the gamma band (e.g., 30-100 Hz).

[0058] The neuromodulation signal applied to the DACC and / or CC may have a high frequency, for example a frequency greater than 70 Hz.

[0059] In one approach, a single electrode lead can be used to apply neuromodulation signals to one or more of the DACC, CC, DMN, LH, PC and VL-PAG. In such an approach, the trajectory can further pass adjacent to the dorsal anterior cingulate cortex, and the electrode lead can include an electrode configured to apply neuromodulation signals to the dorsal anterior cingulate cortex, and / or the trajectory can further pass adjacent to the corpus callosum, and the electrode lead can include an electrode configured to apply neuromodulation signals to the corpus callosum. If both the DACC and CC are stimulated, the trajectory can pass adjacent to both the DACC and CC, and the same electrode can be used to apply neuromodulation signals to both the DACC and CC. In some cases, separate electrodes may be used to stimulate the DACC and CC. By using a single electrode lead to stimulate multiple targets, surgery time can be minimized and the number of implants required for a subject can be reduced. Preferably, the trajectory can pass no more than 5 mm from the DACC and / or CC to ensure that the DACC and CC can be effectively stimulated via the electrode lead.

[0060] In another approach, separate electrode leads can be used to stimulate the DACC and / or the CC. Thus, the method can further include implanting a second electrode lead into the subject's brain, the second electrode lead including an electrode configured to apply a neuromodulation signal to the dorsal anterior cingulate cortex.

[0061] If it is deemed that the transventricular trajectory connecting the DMN, LH, PC, and VL-PAG cannot safely incorporate the DACC and / or CC without affecting the intraventricular vasculature or sagittal sinus, separate electrode leads targeting the DACC and / or CC can be used.

[0062] In one example, a separate electrode lead may have a single electrode (e.g., a cylindrical electrode) on the electrode lead that extends across the DACC and into the CC. Alternatively, a separate electrode lead may be used that has multiple electrodes configured to stimulate the DACC and CC separately.

[0063] In some embodiments, the method may further include detecting a physiological parameter of the subject and adjusting at least one of the one or more neuromodulation signals based on the detected physiological parameter. In this manner, the physiological parameter may be used as feedback to adjust the neuromodulation signal. This may allow for more accurate and effective neurostimulation of the brain, since the neuromodulation signal may be adjusted based on the subject's response to the signal.

[0064] For example, the physiological parameters may include one or more of the subject's blood pressure, blood flow, cerebral blood flow, and intracranial pressure.

[0065] Physiological parameters may be monitored via one or more sensors placed on or implanted within the subject's body.

[0066] When a neuromodulation signal is applied to the VL-PAG, DACC and / or CC, the neuromodulation signal applied to the VL-PAG, DACC and / or CC can be adjusted based on the detected physiological parameter.

[0067] When the one or more neuromodulation signals are applied in bursts, the neuromodulation signals can be based on measurements of a physiological parameter obtained between the one or more bursts of the neuromodulation signals.

[0068] Adjusting the neuromodulation signal may include adjusting one or more parameters of the neuromodulation signal, such as frequency, pulse width, and pulse amplitude. In some cases, a set point can be associated with a physiological parameter, and the neuromodulation signal can be adjusted until the set point is reached.

[0069] When multiple neuromodulation signals are applied, one, more, or all of the neuromodulation signals can be adjusted based on the detected physiological parameter.

[0070] In some embodiments, the method may further include adjusting at least one of the one or more neuromodulation signals based on the subject's circadian rhythm.

[0071] For example, one or more parameters (eg, frequency, pulse width, and pulse amplitude) of one or more neuromodulation signals can be adjusted or regulated depending on the time of the subject's circadian rhythm.

[0072] In particular, the one or more neuromodulation signals can be adjusted to reflect a circadian rhythm with reduced nighttime activity. This can serve to ensure that the application of the neuromodulation signals does not disrupt the subject's circadian rhythm. This can also serve to maintain and / or re-establish the subject's circadian rhythm.

[0073] When a neuromodulation signal is applied to the VL-PAG, DACC and / or CC, the neuromodulation signal applied to the VL-PAG, DACC and / or CC can be adjusted based on the subject's circadian rhythm.

[0074] To re-establish a subject's circadian rhythm, the stimulation prescription (i.e., stimulation schedule) of one or more neuromodulatory signals can be adjusted to reflect the circadian rhythm and coincide with the fluctuating tonic firing, e.g., as commonly found within circuits and circadian neurons.

[0075] For example, in one embodiment, the method may include applying low-frequency stimulation (e.g., 5-50 Hz) to the LH and PC during the day, and then applying both low-frequency stimulation (e.g., 5-50 Hz) to the LH and PC and high-frequency stimulation (e.g., frequencies above 70 Hz) to the DMN during the night. Alternatively, both low-frequency stimulation (e.g., 5-50 Hz) to the LH and PC and high-frequency stimulation (e.g., frequencies above 70 Hz) to the DMN may be applied during the day and at night, with the current amplitude of the high-frequency stimulation to the DMN being reduced during the day, and conversely, the current amplitude of the high-frequency stimulation to the DMN being increased during the night. Alternatively, both low-frequency stimulation (e.g., 5-50 Hz) to the LH and PC and high-frequency stimulation to the DMN may be applied during the day and at night, with the current amplitude of the high-frequency stimulation (e.g., 50-70 Hz) to the DMN being reduced during the day, and conversely, the current amplitude of the high-frequency stimulation (e.g., above 70 Hz) to the DMN being increased during the night. Alternatively, during the night, high frequency stimulation signals may be applied to the DMN and LH, and low frequency stimulation signals may be applied to the PC.

[0076] Adjusting one or more neuromodulation signals based on the subject's circadian rhythm involves monitoring the subject's physiological parameters (e.g., blood pressure, heart rate, heart rate variability, pulse wave variability, muscle sympathetic nerve activity, changes in body position, brain EEG, brain slow wave activity) to determine the subject's circadian rhythm. The one or more neuromodulation signals can then be adjusted based on the determined circadian rhythm. In fact, the subject's blood pressure and heart rate may vary with the circadian rhythm, resulting in higher blood pressure and heart rate during the day and lower blood pressure and heart rate during the night. In this manner, the circadian variation of blood pressure and / or heart rate can be monitored to determine the subject's circadian rhythm.

[0077] In some cases, the method may include detecting a disruption of the subject's circadian rhythm, for example, by recording the diurnal variation of the subject's physiological parameters (e.g., blood pressure and / or heart rate) and comparing the recorded diurnal variation with a model variation corresponding to an undisturbed circadian rhythm.

[0078] The method may further include adjusting at least one of the one or more neuromodulation signals to attempt to correct the detected disruption of the subject's circadian rhythm.

[0079] Disruption of a subject's circadian rhythm can be detected based on a correlation between the subject's disrupted sleep / wake cycle and local field potentials recorded in one or more targets in the subject's brain (e.g., one or more of the LH, PC, DMN, VL-PAG, DACC, CC).

[0080] Circadian rhythms in blood pressure are associated with high spans during waking periods and low spans during sleeping periods. Cardiovascular events may occur more frequently in the early morning when blood pressure and heart rate rise rapidly. Patients with excessive early morning blood pressure rise and lacking normal nocturnal blood pressure decline (so-called "non-dippers") have been shown to have disproportionately high incidence of stroke, heart failure, and other cardiovascular events. There are many physiological mechanisms underlying abnormalities in 24-h blood pressure profiles, including abnormal and sympathetic nervous system activity, salt-volume balance, and activation of the renin-angiotensin-aldosterone system, but for many patients the mechanisms remain unclear. In normal circadian rhythms in blood pressure, blood pressure declines by 15-25% at night compared to waking values. However, non-dipper patterns are present in 25-40% of patients with hypertension. Clinical studies in patients with hypertension have found that increased adrenergic activity and decreased vagus nerve activity during sleep reduce nocturnal blood pressure slowing.

[0081] The parameters of the one or more neuromodulation signals can be determined, for example, by recording local field potentials across one or more targets in the brain (e.g., one or more of the DMN, LH, PC, VL-PAG, DACC, CC). An analysis of the recorded field potentials can then be performed to determine appropriate stimulation parameters, for example, to enhance cerebral perfusion and / or to re-establish normal circadian rhythm. The neuromodulation signals can also be adjusted based on detection of a disturbed rhythm (e.g., circadian rhythm).

[0082] Local field potentials can be recorded using electrodes on electrode leads implanted in the subject's brain.

[0083] Local field potentials across one or more targets in the brain can be recorded in normal and disease states, using animal models to generate computational and mathematical models. Local field potentials recorded in human disease states can be used to further refine etiological and individualized stimulation parameters, for example, in anticipation of re-establishing normal circadian rhythms and re-adjusting autonomic imbalances.

[0084] The method may further include applying a stimulation signal to the carotid body and / or carotid baroreceptors of the subject. Such a method may be considered an independent aspect of the present invention. More generally, in such an independent aspect, one or more neuromodulation signals may be applied to one or more targets in the brain of the subject, without necessarily being limited to the targets mentioned above. Thus, an independent aspect of the present invention may provide a method of treatment performed on a subject, the method including applying one or more neuromodulation signals to one or more targets in the brain of the subject and applying a stimulation signal to the carotid body and / or carotid baroreceptors of the subject.

[0085] The inventors have found that the neurostimulation of a target in a subject's brain combined with the stimulation of the carotid body and / or carotid baroreceptor of the subject can result in enhanced cerebral blood flow and allow for more precise control of cerebral blood flow.Indeed, since the carotid body and carotid baroreceptor are involved in regulating blood flow and blood pressure, the combined stimulation of a target in a subject's brain and the carotid body and / or carotid baroreceptor can have a synergistic effect on enhancing and controlling cerebral perfusion.One or more targets in a subject's brain to which a neuromodulation signal is applied can be selected to cause an increase in cerebral perfusion.

[0086] Stimulation of the carotid body and / or carotid baroreceptors can be performed simultaneously with neural stimulation of targets in the brain, which may enhance responses both via retrograde peripheral reflex signaling from the carotid body to the brain and anterograde from brain stimulation to the periphery, resulting in enhanced cerebral blood flow.

[0087] One or more neuromodulation signals can be applied via electrode leads implanted in the subject's brain, for example as described above.Thus, neuromodulation signals can be applied to LH and PC, optionally VL-PAG and / or DMN, and optionally DACC and / or CC.As discussed above, stimulation of these targets can result in improved cerebral perfusion, allowing treatment of a wide variety of conditions.

[0088] In one embodiment, stimulation of the carotid body and / or carotid baroreceptors may be combined with simultaneous neural stimulation of the LH, PC, DMN and VL-PAG.

[0089] The stimulation signal can be applied to the carotid body and / or carotid baroreceptors via one or more stimulation electrodes implanted in and / or placed in contact with the subject. The stimulation signal can be applied to the carotid body and / or carotid baroreceptors according to the methods described in our previous application, U.S. Patent Application Publication No. 2015 / 0112359, which is incorporated herein by reference. For example, the stimulation signal can be a pulsed radio frequency (RF) electrical signal applied to the carotid body and / or carotid baroreceptors via electrodes implanted in the subject.

[0090] Electrical stimulation (e.g., with a pulsed RF signal) can modify the function of one or more carotid bodies, resulting in attenuation or elimination of neural signals from those bodies. The effect can be a reduction in mean arterial blood pressure for days, weeks, or months following treatment.

[0091] Carotid baroreceptors are nerve endings in the wall of the aortic arch and in the carotid sinus that detect changes in arterial pressure through stretching of the vessel wall. Baroreceptors are stimulated by stretch and their firing rate increases with pressure. Below a mean pressure of about 60 mmHg, the action potential frequency reaches a minimum, and above about 160 mmHg, baroreceptors reach a maximum firing rate, so that further increases in pressure do not increase the firing rate. Denervation of baroreceptors in humans results in a long-term increase in mean arterial pressure and an increase in heart rate. Conversely, blood pressure can be reduced for a long period of time by stimulating baroreceptors using an electrical pulse generator.

[0092] Carotid baroreceptors may be located in the carotid sinus and the aortic arch. Thus, for example, the carotid baroreceptors may be stimulated via a stimulating electrode implanted in close proximity to the carotid sinus and / or the aortic arch. The carotid body may be stimulated via an electrode implanted at or near the carotid body. In some cases, multiple stimulating electrodes may be used to allow stimulation of multiple targets.

[0093] The method of the present invention can be for treating one or more of hypertension, traumatic brain injury, cerebral vasospasm, cerebral infarction, brain tumor, brain glioma, Parkinson's disease, Alzheimer's disease, vascular dementia, frontotemporal dementia, other dementia, amyotrophic lateral sclerosis, motor neuron disease, Huntington's disease, multiple system atrophy, multiple sclerosis, addiction, depression, post-traumatic stress disorder, schizophrenia, obesity, renal failure, epilepsy and attention deficit hyperactivity disorder.However, the method of the present invention can also be used to treat other conditions, particularly those related to reduced cerebral blood flow.

[0094] Neurostimulation for various conditions can be based on established computational mathematical modeling based on local field potential recording along targets in the brain. Detection of one or more physiological parameters (as discussed above) can be combined with simultaneous adjustment of one or more neuromodulation signals during one or more bursts of neuromodulation signals. One or more neuromodulation signals can be adjusted based on one or more of transcranial brain activity, cerebral blood flow, and sympathetic monitoring to optimize one or more neuromodulation signals, for example, in anticipation of cerebral blood flow, re-establishment of circadian rhythm, and correction of autonomic imbalance.

[0095] The above symptoms can be associated with one or more of the following: reduced cerebral blood flow, autonomic imbalance, circadian disturbance, altered cerebral coherence, cortical spreading depolarization, and cerebral rhythm desynchronization.The inventors have found that neurostimulation of LH and PC, optionally in combination with DMN and / or VL-PAG, and optionally DACC and / or CC, can enhance cerebral blood flow, thereby restoring autonomic imbalance and re-establishing circadian rhythm.As a result, the method of the present invention can be used to treat one or more of the above symptoms.The particular combination of neuromodulation signals used can be tailored to the subject and symptoms being treated.

[0096] According to a second aspect of the present invention, there is provided an apparatus for administering therapy to a subject's brain, the apparatus comprising an electrode lead configured for insertion into the subject's brain, a distal portion of the electrode lead having a plurality of electrodes configured to apply one or more neuromodulation signals to the lateral habenula and the posterior commissure, and a controller configured to generate the one or more neuromodulation signals applied by the plurality of electrodes.

[0097] The apparatus may be used to carry out the method according to the first aspect of the invention. Thus, features of the first aspect of the invention may be shared with the second aspect of the invention.

[0098] The electrode lead can be inserted into the subject's brain for applying neuromodulation signals to targets within the subject's brain via multiple electrodes on a distal portion of the electrode lead.

[0099] Multiple electrodes can be sized and positioned on the electrode lead such that each of the LH and PC can be stimulated via multiple electrodes.

[0100] For example, the positioning and / or individual lengths and / or spacing and / or overall length of the multiple electrodes can be configured, for example, so that electrodes of the multiple electrodes can be positioned proximal to each of the DMN, LH, and PC, such that each of the LH and PC can be stimulated via the multiple electrodes.

[0101] The multiple electrodes can be further configured to apply one or more neuromodulation signals to one or more additional targets in the subject's brain. In this manner, neurostimulation of the LH and PC can be combined with neurostimulation of additional targets in the brain.

[0102] The one or more additional targets can include the dorsomedial thalamic nucleus. In other words, the multiple electrodes can be configured to apply one or more neuromodulatory signals to each of the DMN, the LH, and the PC.

[0103] The multiple electrodes may include two or more electrodes. For example, the multiple electrodes may include a first electrode for stimulating the DMN, a second electrode for stimulating the LH, and a third electrode for stimulating the PC. In some cases, a single electrode can be used to stimulate both the LH and the PC, for example, when the electrode has a sufficient length to apply a neuromodulation signal to both targets. The electrodes of the multiple electrodes can be electrically isolated from each other so that different targets can be stimulated individually.

[0104] The one or more additional targets can include the VL-PAG. Thus, the plurality of electrodes can be further configured to apply a neuromodulation signal to the VL-PAG. In this manner, the neuromodulation signal can be applied to each of the LH and the PC, and optionally to the VL-PAG and / or the DMN. For example, the plurality of electrodes can include an electrode configured (e.g., positioned and dimensioned) to apply a neuromodulation signal to the VL-PAG.

[0105] The electrode lead can be sized to be inserted into the brain of a user. For example, the electrode lead can have an outer diameter of about 1.3 mm or less. The electrode lead can be configured to be implanted along a linear trajectory spanning the LH and PC to the DMN and VL-PAG as described in connection with the first aspect of the present invention.

[0106] The electrode lead may be in the form of an elongated cable having a generally cylindrical shape. The cable may include a set of wires extending through and connected to multiple electrodes such that electrical signals (e.g., neuromodulatory signals) can be transmitted to the electrodes.

[0107] Each of the wires can be electrically coupled to a controller at the proximal end of the electrode lead such that neuromodulation signals generated by the controller can be transmitted via the wires to the electrodes.

[0108] The electrode lead can include an outer protective sheath configured to electrically insulate the electrode lead and to protect the electrode lead from the environment.

[0109] A number of electrodes can be exposed on a surface of the electrode lead for contacting brain tissue to apply neuromodulation signals to the brain tissue.

[0110] An electrode of the plurality of electrodes can have a ring or cylindrical shape, i.e., the electrode can extend around the circumference of the electrode lead, in this manner applying a neuromodulation signal substantially uniformly around the longitudinal axis of the electrode lead.

[0111] Alternatively, an electrode of the plurality of electrodes can be configured to apply a neuromodulation signal in a particular direction, for example, the electrode can extend around only a portion of the circumference of the electrode lead.

[0112] The electrodes of the plurality of electrodes may all be identical, or they may have different shapes, sizes, and orientations (e.g., depending on the particular target they are intended to stimulate).

[0113] In one embodiment, a combination of directional (eg, extending around only a portion of the circumference of the electrode lead) and non-directional (eg, cylindrical electrodes) electrodes can be provided.

[0114] In other embodiments, all of the electrodes may be non-directional (e.g., cylindrical electrodes) or all of the electrodes may be directional (e.g., extending around only a portion of the circumference of the electrode lead).

[0115] The controller is configured to generate one or more neuromodulation signals to be applied by the multiple electrodes. Thus, the controller can include appropriate electronic circuitry for generating one or more neuromodulation signals. As described above, the multiple electrodes can be connected to the controller via a set of wires in an electrode lead configured to transmit the neuromodulation signals to the electrodes.

[0116] The controller can be configured to apply different neuromodulation signals via different electrodes of the plurality of electrodes.

[0117] For example, the controller can be configured to apply a first neuromodulation signal having a first, higher frequency (e.g., greater than 70 Hz) to the DMN via a first electrode and a second neuromodulation signal having a second, lower frequency (e.g., 5-50 Hz) to the LH and PC via a second electrode and a third electrode.

[0118] The controller may be configured to apply the neuromodulation signal in accordance with the method of the first aspect of the invention.

[0119] In some cases, two or more of the plurality of electrodes can be configured in pairs, for example, such that a first electrode of the pair can act as an anode and a second electrode of the pair can act as a cathode, which can allow for bipolar stimulation of brain tissue between the pair of electrodes.

[0120] In some cases, one or more of the multiple electrodes can be configured for monopolar stimulation. For example, an electrode on an electrode lead can act as the cathode, where the guide tube or the case of the controller acts as the anode.

[0121] The controller may be in the form of an implantable pulse generator (IPG), which may be configured to be implanted within the subject's skull, for example, within a pocket formed within the subject's skull.

[0122] In some embodiments, the multiple electrodes may be equally spaced longitudinally along the length of the distal portion of the electrode lead. In other words, the multiple electrodes may include a linear array of equally spaced electrodes arranged along the length of the distal portion of the electrode lead. This may allow targets to be stimulated along substantially the entire length of the distal portion of the electrode lead. The distance between targets in the brain (e.g., DMN, LH, PC, VL-PAG) may vary from subject to subject. Such variations may be accommodated by using a linear array of equally spaced electrodes, since depending on the specific location of the target in the subject's brain, the target may be stimulated using different electrodes in the linear array.

[0123] The number of equally spaced electrodes and their spacing can be selected based on the target to be stimulated and the desired spatial resolution for application of the neuromodulation signal For example, a large number of closely spaced electrodes can allow for more precise stimulation of a target by selecting the electrodes closest to the target.

[0124] Multiple equally spaced electrodes can span a length between 20-25 mm. In this way, multiple electrodes can span the distance between the DMN and the VL-PAG. This can allow targets that are on the trajectory between the DMN and the VL-PAG to be stimulated with the electrodes. In particular, when the electrode leads are implanted along a straight trajectory that spans the LH and PC and connects the DMN and the VL-PAG, it can allow treatment of the LH and PC.

[0125] As a first example, the plurality of equally spaced electrodes may include eight electrodes, each having a length of about 1.5 mm and with a spacing of about 1.5 mm between adjacent electrodes. As a second example, the plurality of equally spaced electrodes may include twelve electrodes, each having a length of about 1.5 mm and with a spacing of about 0.5 mm between adjacent electrodes. Of course, other examples with different numbers and dimensions of electrodes are possible. The second example may provide a higher spatial resolution than the first example due to the increased number of electrodes per unit length.

[0126] The device may further include a proximal electrode (which may also be referred to as an additional electrode) configured to apply a neuromodulation signal to the DACC and / or the CC. In this manner, the neuromodulation signal may be applied to the DACC and / or the CC.

[0127] The length and position of the proximal electrode can determine whether the electrode can apply neuromodulation signals to either or both of the DACC and CC.

[0128] In some embodiments, the proximal electrode may be provided separately from the electrode lead, for example, the proximal electrode may be on a further electrode lead or on a guide tube of the device.

[0129] In some embodiments, the proximal electrode may be disposed on the electrode lead. In this manner, a neuromodulation signal may be applied to the DACC and / or CC via the electrode lead. Thus, the electrode lead may enable compound neurostimulation of one or more of the DMN, LH, PC, VL-PAG, DACC, and CC.

[0130] The proximal electrode may be similar to the electrodes in the plurality of electrodes described above, for example, the proximal electrode may be a ring (eg, cylindrical) or may be a directional electrode.

[0131] The proximal electrode can be longitudinally spaced apart from the plurality of electrodes, e.g., such that the proximal electrode can be positioned adjacent to the DACC and / or CC when the electrode lead is implanted in the subject's brain. In particular, the proximal electrode can be positioned closer to the proximal end of the electrode lead than the plurality of electrodes at the distal portion of the electrode lead.

[0132] The proximal electrode can be longitudinally spaced from the plurality of electrodes by a distance of about 5-15 mm.

[0133] A spacer, for example made from an electrically insulating material, may be disposed between the proximal electrode and the plurality of electrodes.

[0134] The spacer can have a length of about 5-15 mm, i.e., the distance between the proximal electrode and the multiple electrodes can be 5-15 mm. The exact location and dimensions of the proximal electrode can be set based on the location of the DACC and / or CC in the subject's brain to ensure that the DACC and / or CC can be effectively stimulated.

[0135] Each electrode of the plurality of electrodes can have a first length, and the proximal electrode can have a second, longer length. Thus, the proximal electrode can be longer than the other electrodes. This can facilitate applying neuromodulation signals to the DACC. Because the inventors have found that the distance across the lateral ventricle between the DACC and the DMN can vary from subject to subject. Thus, by making the proximal electrode longer, the variation in the location of the DACC from subject to subject can be compensated for, so that the DACC and / or CC can be effectively stimulated using the proximal electrode.

[0136] The length of an electrode of the plurality of electrodes, ie, the first length, may be preferably about 1.5 mm, as discussed above.

[0137] The second length may be 10-30 mm. Such a length of the proximal electrode may ensure that the DACC and / or CC can be effectively stimulated via the proximal electrode despite the variation in the distance spanning the lateral ventricle between subjects. In particular, the inventors have found that the distance spanning the lateral ventricle may be 9-20 mm for different subjects. Thus, by providing the proximal electrode with a length of 10-30 mm, it may be possible to stimulate the DACC and / or CC in different subjects. Preferably, the second length may be 20-30 mm.

[0138] In some embodiments, the device may further include a guide tube for insertion into the patient's brain, the guide tube comprising a hollow tube defining a longitudinal channel capable of receiving the electrode lead therein.

[0139] The length of the hollow tube can be configured such that when the electrode lead is received in the longitudinal channel, a distal portion of the electrode lead protrudes from a distal opening of the hollow tube.

[0140] The guide tube can serve to facilitate implantation of the electrode lead into the subject's brain by ensuring that the electrode lead follows the correct trajectory during insertion. In particular, the guide tube can facilitate transventricular implantation of the electrode lead, i.e., implantation of the electrode lead via the lateral ventricle.

[0141] The hollow tube may be generally cylindrical, with a longitudinal channel extending along the length of the hollow tube.

[0142] The longitudinal channel may be sized to receive the electrode lead, for example, the diameter of the longitudinal channel may be slightly larger than the outer diameter of the electrode lead.

[0143] The hollow tube may be made from any suitable insulating biocompatible material, such as, for example, a biocompatible plastic material (e.g., polycarbonate urethane). Preferably, the material of the hollow tube is rigid to facilitate insertion of the hollow tube into the subject's brain and to prevent movement of the guide tube after insertion into the subject's brain.

[0144] The guide tube can be inserted into the subject's brain by first introducing a guide rod into the subject's brain along a desired trajectory and then sliding the hollow tube over the guide rod. The guide rod can then be withdrawn from the hollow tube and the electrode lead can be inserted through the guide tube into the subject's brain to a desired depth, i.e., so that a distal portion of the electrode lead can reach a target location within the subject's brain.

[0145] The guide rod may typically be fabricated from a radiopaque material to facilitate visualization of the guide rod under computed tomography (CT) or magnetic resonance imaging (MRI).

[0146] The length of the hollow tube can be shorter than the length of the electrode lead such that when the electrode lead is inserted into the guide tube, a distal portion of the electrode lead protrudes from a distal opening of the hollow tube. In this manner, insertion of the electrode lead into the guide tube can expose multiple electrodes on the distal portion of the electrode lead such that the electrodes can apply neuromodulation signals to target brain tissue.

[0147] The length of the hollow tube can be configured to span the distance between the subject's skull and slightly below the lateral ventricle (e.g., a few millimeters below the lateral ventricle). Prior to insertion into the subject's brain, the hollow tube can be cut to a desired length, e.g., based on measurements of the subject's brain.

[0148] If the electrode lead includes a proximal electrode, the guide tube can be configured to enable transmission of neuromodulation signals from the proximal electrode to the outside of the hollow tube when the electrode lead is received within the longitudinal channel of the hollow tube.

[0149] Once the electrode lead is received within the longitudinal channel, the proximal electrode can be positioned within the longitudinal channel. Thus, the hollow tube can allow the neuromodulation signal to be applied to the DACC and / or CC by allowing the neuromodulation signal to be transmitted from the proximal electrode to the outside of the hollow tube. In this manner, there is no need for shortening of the hollow tube to expose the proximal electrode, which may impair the ability of the guide tube to guide the electrode lead along a desired trajectory. Thus, the guide tube can serve to precisely guide the electrode lead along a desired trajectory while allowing the DACC and / or CC to be stimulated via the proximal electrode on the electrode lead.

[0150] In some embodiments, the guide tube can include a window formed in a sidewall of the hollow tube that is configured to expose the proximal electrode to the outside of the hollow tube when the electrode lead is received within the longitudinal channel of the hollow tube. Thus, the window in the sidewall of the hollow tube can allow for transmission of neuromodulation signals from the proximal electrode to the outside of the hollow tube.

[0151] When the electrode lead is inserted into the hollow tube, the proximal electrode can be exposed through the window so that it can be used to apply neuromodulation signals to the DACC and / or CC. Providing a window in the sidewall of the hollow tube for the proximal electrode can allow the proximal electrode to be exposed without having to shorten the length of the hollow tube. As a result, the guide tube can allow for precise placement of the distal portion of the electrode lead while exposing the proximal electrode through the window. The window can be configured to expose all or a portion of the proximal electrode.

[0152] The length of the window in the sidewall of the hollow tube can be shorter than the length of the proximal electrode (e.g., the second length described above). As a result, only a portion of the proximal electrode can be exposed through the window. The length and position of the window can be determined based on the location of the DACC in the subject's brain. As a result, the portion of the proximal electrode exposed through the window can be proximal to the DACC so that a neuromodulation signal can be applied to the DACC and / or CC through the proximal electrode.

[0153] The proximal electrode can be relatively long (e.g., 10-25 mm), and it may be beneficial to expose only a shorter portion of the proximal electrode to avoid stimulating areas distant from the DACC by the proximal electrode.

[0154] The window may, for example, be cut in a sidewall of the hollow tube (e.g., by laser cutting) or may be integrally formed as part of the hollow tube (e.g., via a molding or 3D printing process).

[0155] The window may, for example, have a length of 10 to 25 mm. The guide tube may include a marker to indicate the direction in which the window is facing, ie, to indicate the orientation of the window.

[0156] The markers may be placed on the guide tube so that they are visible when the guide tube is inserted into the subject's brain.

[0157] The marker can serve to inform a user (e.g., a surgeon) which direction the window is facing so that the user can insert the guide tube in the correct orientation, e.g., with the window facing the DACC and / or CC. For example, the marker can be placed on the cap of the guide tube so that it is visible to the user while the guide tube is being inserted into the user's brain.

[0158] When the guide tube is inserted into the subject's brain, the window can be configured to face toward the DACC and / or CC, which can serve to direct neuromodulatory signals from the proximal electrode toward the DACC to ensure effective stimulation of the DACC.

[0159] The window can be formed on a side of the hollow tube such that it is positioned to face the DACC in use. In other words, the window can cover only a portion of the circumference of the hollow tube, i.e., the window does not extend completely around the circumference of the hollow tube. For example, the window can have an opening angle of 10° to 90° about the longitudinal axis of the hollow tube.

[0160] In some examples, the window can include two or more openings formed in the hollow tube. Forming the window as two or more openings (e.g., as opposed to a single larger opening) can serve to improve the stiffness of the hollow tube, thereby facilitating the insertion of the guide tube into the subject's brain. For example, the window can be formed by an array of longitudinally spaced openings in the sidewall of the hollow tube.

[0161] In some embodiments, the guide tube can include an outer electrode on the outer surface of the hollow tube. The outer electrode can be used to apply neuromodulation signals to the target brain tissue. In this manner, neuromodulation signals can be applied to the target brain tissue via the outer electrode of the guide tube. Thus, neuromodulation signals can be applied via both the electrode lead and the guide tube.

[0162] An outer electrode is disposed on the exterior surface of the hollow tube so as to be in contact with the target brain tissue.

[0163] The outer electrode may be made from a conductive material such as, for example, platinum-iridium. The outer electrode can be configured to apply a neuromodulation signal to the DACC and / or the CC.

[0164] As an example, the outer electrode may include a mesh electrode on the outer surface of the hollow tube, which may be in the form of, for example, a meshed metal sleeve disposed on the outer surface of the hollow tube.

[0165] As another example, the outer electrode may include an electrode embedded in a material (e.g., a plastic material) forming a sidewall of a hollow tube, the sidewall of the hollow tube including a window formed therein to expose a portion of the electrode.

[0166] In some cases, the outer electrode can extend around the circumference of the guide tube and can have, for example, a generally cylindrical shape. In other cases, the outer electrode can be configured to provide directional stimulation, for example, when exposed through a window in the material forming the sidewall of the hollow tube. In such cases, the guide tube can include an indicator to indicate the direction in which the outer electrode faces. For example, the indicator can be on the cap of the guide tube.

[0167] The outer electrode can be electrically connected to the controller via a connecting lead extending through the hollow tube. In this way, neuromodulation signals generated by the controller can be transmitted directly to the outer electrode on the guide tube via the connecting lead. Thus, it may not be necessary to provide a proximal electrode on the electrode lead. For example, the connecting lead may be in the form of a thin wire embedded in the material forming the hollow tube. Alternatively, the connecting lead may be disposed within a longitudinal channel of the hollow tube.

[0168] If the electrode lead includes a proximal electrode, the outer electrode can be configured for electrical connection to the proximal electrode when the electrode lead is received within the longitudinal channel of the hollow tube. The proximal electrode on the electrode lead can then be electrically connected to the outer electrode on the guide tube when the electrode lead is received within the longitudinal channel in the hollow tube. As a result, a neuromodulation signal applied to the proximal electrode can be transmitted to the outer electrode, which can then apply the neuromodulation signal to the surrounding target tissue, such as the DACC. Thus, the outer electrode can be used as a substitute for a window to apply a neuromodulation signal to the DACC when using a guide tube.

[0169] By providing an outer electrode on the guide tube that is configured for electrical connection to the proximal electrode, it may be possible to reduce the length of the proximal electrode, since the proximal electrode only needs to be long enough to provide a reliable connection to the outer electrode when the electrode lead is received within the longitudinal channel of the hollow tube.

[0170] When the electrode lead is received within the longitudinal channel of the hollow tube, various mechanisms can be used to electrically connect the outer electrode to the proximal electrode. For example, the connection portion of the outer electrode can be disposed (e.g., exposed) within the longitudinal channel such that the proximal electrode can contact the connection portion of the outer electrode when the electrode lead is received within the longitudinal channel.

[0171] The connecting portion of the outer electrode can be configured to form a slidable electrical connection with the proximal electrode to allow the electrode to be inserted through the longitudinal channel.

[0172] The outer electrode may be a ring electrode, ie, extending around the circumference of the hollow tube.

[0173] Alternatively, the outer electrode can be configured to apply the neuromodulation signal in a particular direction, for example, the outer electrode can extend around only a portion of the circumference of the hollow tube, and in particular, the outer electrode can be configured to face toward the DACC when inserted into the subject's brain.

[0174] In such cases, the guide tube may include a marker (e.g., on the cap of the guide tube) that indicates the direction that the outer electrode is pointing in. In this way, the user can ensure that the outer electrode is correctly oriented to enable stimulation of the DACC.

[0175] The guide tube can include a cap that can be secured to a hole (e.g., a burr hole). The cap can thus serve to secure the guide tube to the subject's skull. For example, the cap can include a threaded exterior so that it can be screwed into a hole in the subject's skull. This can also facilitate removal of the guide tube at a later date.

[0176] In some embodiments, a cap can be secured to the proximal end of the hollow tube, in which case the cap can include an inlet for inserting an electrode lead into the longitudinal channel of the hollow tube.

[0177] In other embodiments, the cap can be separate from the hollow tube. The cap can include a passageway through which the hollow tube can be inserted, for example, the hollow tube can be slidably insertable through the passageway. In other words, when the hollow tube is inserted into the passageway in the cap, the cap can be movable relative to the hollow tube along the length of the hollow tube.

[0178] In this manner, the hollow tube can be inserted into the subject's brain through the passage in the cap. The position of the hollow tube relative to the cap can be adjustable, for example, by inserting a desired length of hollow tube through the passage in the cap. This can allow a user to adjust the length of hollow tube that is inserted into the subject's brain.

[0179] The passageway in the cap can be configured to form a sliding seal around the hollow tube when the hollow tube is inserted through the passageway to prevent leakage through the cap.

[0180] Being able to adjust the length of the hollow tube inserted through the passageway of the cap can be particularly beneficial if the hollow tube includes a window or outer electrode, as it allows a user (e.g., a surgeon) to ensure that the window or outer electrode is at an appropriate depth within the subject's brain. In particular, it can enable a user to ensure that the window or outer electrode is positioned to allow application of a neuromodulation signal to the DACC and / or CC.

[0181] The guide tube may include an indicator, for example in the form of step lines along the side of the hollow tube, to indicate the length of the hollow tube inserted through the passage in the cap. The indicator may be configured to indicate the distance between the cap and the window or the outer electrode.

[0182] Additionally or alternatively, the hollow tube may include an indicator to indicate the orientation of the window or outer electrode.

[0183] The guide tube may further comprise a first limiter, the first limiter being fixed to a proximal portion of the hollow tube and configured to abut the cap when a predetermined length of the hollow tube is inserted through the passage. The first limiter may serve to ensure that only a predetermined length of the hollow tube is inserted through the passage in the cap into the subject's brain. In this manner, it may be possible to ensure that the hollow tube is inserted to a desired depth into the subject's brain. The predetermined length may be determined by the location at which the first limiter is fixed to the proximal portion of the hollow tube. In use, the distal portion of the hollow tube may be inserted through the passage in the cap until the first limiter on the proximal portion of the hollow tube abuts the cap, thus preventing the hollow tube from being further inserted through the passage in the cap.

[0184] The position of the first limiter on the proximal portion of the hollow tube may be adjustable to set a predetermined length of the hollow tube. The first limiter may be provided separately from the guide tube, i.e., may be securable to the proximal portion of the hollow tube. In some cases, the first limiter may be removably securable to the proximal portion of the hollow tube.

[0185] The device may further include a second limiter secured to a proximal portion of the electrode lead and configured to abut the proximal end of the guide tube when a predetermined length of the electrode lead protrudes from the distal opening of the hollow tube.

[0186] The second limiter can serve to ensure that only a predetermined length of the electrode lead protrudes from the distal opening of the hollow tube. In this way, it may be possible to ensure that the electrode lead is inserted to a desired depth into the subject's brain, for example, such that the distal portion of the electrode lead is properly positioned to apply one or more neuromodulation signals.

[0187] The predetermined length can be determined by the location where the second limiter is secured to the proximal portion of the electrode lead.

[0188] In use, the distal portion of the electrode lead can be inserted through the longitudinal channel of the hollow tube until the second limiter on the proximal portion of the electrode lead abuts the cap, thus preventing the electrode lead from being inserted further through the hollow tube.

[0189] The position of the second limiter on the proximal portion of the electrode lead may be adjustable to set a predetermined length of the electrode lead. The first limiter may be provided separately from the electrode lead, i.e., may be securable to the proximal portion of the hollow tube. In some cases, the first limiter may be removably securable to the proximal portion of the hollow tube.

[0190] In some embodiments, the device may further comprise a sensor configured to detect a physiological parameter of the subject and generate an output signal related to the detected physiological parameter, and the controller is configured to adjust at least one of the one or more neuromodulation signals based on the output signal from the sensor.

[0191] In this way, the physiological parameters can be used as feedback to adjust the neuromodulation signals based on the subject's response to the signals, allowing for more precise and effective neurostimulation of the brain.

[0192] For example, the physiological parameters may include one or more of the subject's blood pressure, blood flow, cerebral blood flow, and intracranial pressure.

[0193] When a neuromodulation signal is applied to the VL-PAG, DACC and / or CC, the neuromodulation signal applied to the VL-PAG, DACC and / or CC can be adjusted based on the detected physiological parameter.

[0194] Adjusting the neuromodulation signal may include adjusting one or more parameters of the neuromodulation signal, such as frequency, pulse width, and pulse amplitude. In some cases, a set point can be associated with a physiological parameter, and the neuromodulation signal can be adjusted until the set point is reached.

[0195] Various types of sensors can be used to detect blood pressure and / or blood flow. Since the effect of neurostimulation of the subject's brain can be to enhance cerebral perfusion, changes in blood pressure and / or blood flow can serve as an indicator of the effectiveness of the treatment.

[0196] For example, the sensor may include a wearable sensor configured to measure blood pressure and / or blood flow. The wearable sensor may take the form of a sensor that can be worn on a user's wrist (e.g., as a watch).

[0197] In some cases, the sensor may include an implantable sensor configured to detect blood pressure and / or blood flow. For example, the implantable sensor may be configured to be implanted in the carotid bifurcation, the carotid sinus, or the aortic arch.

[0198] Where the physiological parameter is intracranial pressure, the sensor may take the form of a pressure sensor implanted beneath the subject's skull.

[0199] In some cases, a pressure sensor can be incorporated into the electrode lead or into the guide tube, which may eliminate the need to implant a sensor separately from the electrode lead and guide tube. Similar to blood pressure and / or blood flow, intracranial pressure can serve as an indicator of the effectiveness of treatment.

[0200] In some cases, sensors may be incorporated into the generator: the device's accelerometer, which typically serves to detect changes in individual position and movement, may be optimized to sense changes in the surrounding skull or underlying dura movement secondary to brain pulses, may be calibrated to cerebral blood flow, and may also detect changes in heart rate.

[0201] The sensor can be communicatively coupled to the controller, for example, via a wired or wireless connection, such that an output signal from the sensor can be transmitted to the controller. Upon receiving the output signal from the sensor, the controller can compare the detected physiological parameter to a predetermined set point for the physiological parameter and adjust at least one of the one or more neuromodulation signals, for example, to attempt to change the detected physiological parameter to a value less than, the same as, or greater than the set point.

[0202] In some embodiments, the device may further comprise an external power source, the external power source including a transmitter for wirelessly transmitting power to the controller. In this way, no wired connection is required between the external power source and the controller. Thus, during use, the external power source may be worn by the subject in close proximity to the controller. Then, after use, the external power source may be easily removed. This may facilitate charging the external power source and improve the comfort of the user when the device is not in use, since the external power source may be removed. This may be particularly beneficial when the neurostimulation is performed only during short intervals. The external power source may include a power source such as a battery (e.g., a rechargeable battery).

[0203] Power can be transmitted from a transmitter of the external power source to the controller via inductive coupling between the transmitter and the controller, for example, the transmitter can include a transmitting coil and the controller can include a receiving coil, the transmitting coil and the receiving coil being inductively coupleable such that power can be transferred from the transmitter to the controller.

[0204] The device may further include a wearable cap configured to hold the transmitter in proximity to the controller, such that a subject can wear the cap to hold the transmitter in proximity to the controller and provide power to the controller.

[0205] The cap can include a pocket configured to hold the transmitter. The cap can be configured to hold the transmitter above the controller, which can ensure effective power transmission from the transmitter to the controller.

[0206] The device may further include one or more stimulation electrodes for applying one or more stimulation signals to the subject's carotid body and / or carotid baroreceptors.

[0207] Such a device can be considered an independent aspect of the present invention. More generally, in such an independent aspect, without necessarily being limited to the above targets, the device can include an electrode lead for applying one or more neuromodulation signals to one or more targets in the brain of a subject. Thus, an independent aspect of the present invention can provide a system comprising a device for applying one or more neuromodulation signals to one or more targets in the brain of a subject, and a stimulation electrode for applying a stimulation signal to the carotid body and / or carotid baroreceptors of the subject.

[0208] The one or more stimulation electrodes can be configured to apply a stimulation signal to one or more carotid bodies and / or carotid baroreceptors.

[0209] The one or more stimulation electrodes can be disposed on an implantable lead configured to be implanted in the subject, for example, as described in U.S. Patent Application Publication No. 2015 / 0112359. The stimulation signal applied via the stimulation electrodes can be a pulsed RF signal. The pulsed RF signal can serve to stimulate the carotid body and / or carotid baroreceptors without heating the tissue to ablation temperatures.

[0210] The controller can be configured to generate one or more stimulation signals applied via one or more stimulation electrodes. In this manner, the controller can be configured to generate one or more neuromodulation signals applied by multiple electrodes on the electrode lead, and one or more stimulation signals applied by the one or more stimulation electrodes.

[0211] In such a case, the stimulation electrode or electrodes may be connected to a controller, for example via connecting wires.

[0212] If one or more electrodes are disposed on an implanted lead, the implanted lead can be connected to a controller such that one or more stimulation signals can be sent to the one or more stimulation electrodes.

[0213] Generating both the neuromodulation and stimulation signals with a single controller can facilitate coordination of the application of the neuromodulation and stimulation signals to their respective targets, which can also reduce the number of components in the device.

[0214] Alternatively, a separate signal generator may be provided to generate the one or more stimulation signals. In such a case, the controller and the signal generator may be in wired or wireless communication with each other. This may allow the application of the one or more neuromodulation signals and the one or more stimulation signals to be coordinated.

[0215] The guide tube described as part of the second aspect of the invention may form an independent aspect of the invention.

[0216] Thus, according to a third aspect of the present invention there is provided a guide tube for insertion into a subject's brain, the guide tube comprising a hollow tube defining a longitudinal channel capable of receiving an electrode lead, the guide tube including a window formed in a side wall of the hollow tube, the window being configured to expose a proximal electrode on the electrode lead to an exterior of the hollow tube when the electrode lead is received in the longitudinal channel of the hollow tube.

[0217] Features of the guide tube described in relation to the second aspect of the invention may be shared with the guide tube of the third aspect of the invention and therefore will not be repeated.

[0218] The guide tube can include a window formed in a side wall of the hollow tube, the window configured to expose the proximal electrode to the outside of the hollow tube when the electrode lead is received within the longitudinal channel of the hollow tube.

[0219] The length of the window may be less than the length of the proximal electrode. The guide tube may include a marker to indicate the direction in which the window is facing.

[0220] The window may include two or more openings in the sidewall of the hollow tube. According to a fourth aspect of the present invention there is provided a guide tube for insertion into a subject's brain, the guide tube including a hollow tube defining a longitudinal channel capable of receiving an electrode lead, the guide tube including an outer electrode on an outer surface of the hollow tube.

[0221] Features of the guide tube described in relation to the second aspect of the invention may be shared with the guide tube of the third aspect of the invention and therefore will not be repeated.

[0222] In some embodiments, the guide tube may further comprise a connecting lead extending through the hollow tube for connecting the outer electrode to a controller.

[0223] In other embodiments, when an electrode lead is received within the longitudinal channel of the hollow tube, the outer electrode can be configured for electrical connection to a proximal electrode on the electrode lead.

[0224] The guide tube of the third or fourth aspect of the present invention may further comprise a cap that can be fixed to a hole in the subject's skull, the cap including a passageway through which the hollow tube can be inserted for inserting the hollow tube into the subject's brain.

[0225] The guide tube of the third or fourth aspect of the invention may further comprise a first limiter secured to a proximal portion of the hollow tube, the first limiter configured to abut the cap when a predetermined length of the hollow tube is inserted through the passage.

[0226] As used herein, the term "distal" can refer to the end or portion of a component (e.g., an electrode lead or guide tube) that is located deeper within the subject's brain during use. For example, the distal portion of an electrode lead can be the portion of the electrode lead that is deepest in the subject's brain after the electrode lead is implanted in the subject's brain.

[0227] As used herein, the term "proximal" can refer to the end or portion of a component (e.g., an electrode lead or guide tube) that is closer to the controller, i.e., closer to the patient's skull within the subject's brain, during use.

[0228] As used herein, the "length" of a component (eg, of an electrode) may refer to the length of that component along the longitudinal axis of the hollow tube of an electrode lead or guide tube.

[0229] Embodiments of the present invention are discussed below with reference to the accompanying drawings. [Brief description of the drawings]

[0230] [Figure 1] FIG. 2 is a schematic diagram of an electrode lead that may form part of a device according to an embodiment of the present invention. [Figure 2a] 2 is a schematic diagram of a guide tube according to one embodiment of the present invention. [Figure 2b] 2b is a schematic diagram showing how the electrode lead of FIG. 1 is received in the guide tube of FIG. 2a; [Figure 3a] 2 is a schematic diagram of a guide tube according to one embodiment of the present invention. [Figure 3b] 1 is a schematic diagram of an apparatus according to one embodiment of the present invention; [Figure 4a] 2 is a schematic diagram of a guide tube according to one embodiment of the present invention. [Figure 4b] FIG. 4b is an enlarged cross-sectional view of a portion of the guide tube of FIG. 4a. [Diagram 5] 1 is a schematic diagram of an apparatus according to one embodiment of the present invention; [Figure 6a] 1 is a schematic diagram of an apparatus according to one embodiment of the present invention; [Figure 6b] FIG. 6b is a cross-sectional view of a portion of the device of FIG. 6a. [Figure 6c] FIG. 6b is a top view of a portion of the apparatus of FIG. 6a. [Figure 7a] 1 is a cross-sectional view of an apparatus according to one embodiment of the present invention. [Figure 7b] FIG. 7b is a schematic diagram of the apparatus of FIG. 7a. [Figure 8] FIG. 1 is a schematic diagram showing an apparatus according to an embodiment of the present invention being used on a subject. [Figure 9] FIG. 1 is a schematic diagram showing an apparatus according to an embodiment of the present invention being used on a subject. [Figure 10a] 1 is a cross-sectional view of a subject's head showing an apparatus according to an embodiment of the present invention being used on the subject; [Figure 10b] FIG. 10b is a side view of a subject's head showing a section line corresponding to the section shown in FIG. 10a. [Figure 11]1 is an image of a subject's brain showing trajectories for implanting electrode leads into the subject's brain, according to one embodiment of the present invention. [Figure 12a] FIG. 1 is a pictorial representation of a guide tube implanted in a subject's brain along a preferred trajectory. [Figure 12b] FIG. 1 is a pictorial representation of a guide tube implanted in a subject's brain along a preferred trajectory. [Figure 13] FIG. 1 is an image of a subject's brain showing deviations from the preferred trajectory of implanted electrode leads. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0231] Detailed Description; Further Options and Preferences FIG. 1 is a schematic diagram of an electrode lead 100 that may form part of a device according to an embodiment of the present invention. The electrode lead 100 is configured for insertion into a subject's brain along a trajectory spanning the lateral habenula (LH) and posterior commissure (PC) to connect the dorsomedial nucleus (DMN) and the ventrolateral periaqueductal gray (VL-PAG). The electrode lead 100 is configured to apply one or more neuromodulatory signals to targets along the electrode lead's implantation trajectory, including the DMN, LH, PC, and VL-PAG. Additionally, the electrode lead 100 is configured to apply neuromodulatory signals to the dorsal anterior cingulate cortex (DACC) and / or the corpus callosum (CC). A preferred implantation trajectory of the electrode lead 100 into a subject's brain is described below in conjunction with FIGS. 10-13.

[0232] The electrode lead 100 is in the form of an elongated cylindrical cable having a plurality of electrodes 102 at a distal portion of the electrode lead 100. The plurality of electrodes 102 includes seven equally spaced electrodes. Each electrode 102 is cylindrical and has a length of about 1.7 mm, with a spacing between adjacent electrodes of about 1.7 mm. Thus, the total length spanned by the plurality of electrodes 102 is about 23 mm. Thus, the plurality of electrodes 102 can enable the DMN and VL-PAG, as well as targets located between the DMN and VL-PAG (e.g., LH and PC) to be stimulated via the electrodes 102. By providing the plurality of electrodes as an array of regularly spaced electrodes, it may be possible to accommodate variations in distance between targets in different subjects.

[0233] In other examples, the plurality of electrodes 102 may include a different number of electrodes, and the electrodes 102 may have different dimensions depending, for example, on the particular target being treated. In general, the plurality of electrodes 102 may range in length between 20-30 mm, to accommodate the typical distance between the DMN and the VL-PAG in most subjects.

[0234] The electrode lead 100 further includes a proximal electrode 104 spaced apart from the plurality of electrodes 102. The proximal electrode 104 is spaced apart from the plurality of electrodes 102 by a distance of about 10 mm such that the proximal electrode is located closer to the proximal end of the electrode lead 100 than the plurality of electrodes 102.

[0235] In another example, the proximal electrode 104 may be spaced apart from the plurality of electrodes 102 by a distance of about 5-15 mm.

[0236] A spacer 106 may be provided between the proximal electrode 104 and the plurality of electrodes 102 . The proximal electrode 104 is cylindrical and has a length of approximately 20 mm. In other examples, the proximal electrode 104 may have a length between 15 and 30 mm.

[0237] The proximal electrode 104 is configured to apply a neuromodulation signal to the DACC and / or the CC. The length of the proximal electrode 104 can serve to compensate for variability in the location of the DACC between subjects to ensure that the neuromodulation signal can be applied to the DACC and / or the CC.

[0238] The electrode lead 100 includes a plurality of wires 108 extending therein. Each of the plurality of electrodes 102 and the proximal electrodes 104 is electrically connected to a respective one of the plurality of wires 108. In this manner, a neuromodulation signal may be applied to each of the electrodes 102 and the proximal electrodes 104 via a corresponding wire. Each of the electrodes 102 and the proximal electrodes may be electrically isolated from one another such that separate neuromodulation signals may be applied to each individual electrode. In this manner, multiple targets may be individually stimulated by the electrode lead 100.

[0239] Each of the electrodes 102 and the proximal electrode 104 are exposed on the outer surface of the electrode lead 100 so as to be able to contact target brain tissue when the electrode lead 100 is inserted into the brain.

[0240] The multiple wires 108 may be wound around or carried by the inner core 110 of the electrode lead 100. The inner core 110 may be made from a rigid material to provide rigidity to the electrode lead 100 and facilitate insertion of the electrode lead into the subject's brain.

[0241] The proximal ends of the electrode leads can be connected to a controller (not shown), which is configured to generate one or more neuromodulation signals that are applied by the multiple electrodes 102 and the proximal electrode 104.

[0242] In particular, the wires 108 can be electrically connected to the controller such that neuromodulation signals generated by the controller can be transmitted via the wires 108 to the electrodes 102 and the proximal electrode 104 .

[0243] Each of the multiple wires 108 can be connected to a respective channel in the controller such that a separate neuromodulation signal can be applied via each of the multiple electrodes 102 and the proximal electrode 104.

[0244] The controller may be in the form of, for example, an implantable pulse generator (IPG). Figure 2a shows a schematic diagram of a guide tube 200 according to an embodiment of the invention, which may form part of a device according to an embodiment of the invention.

[0245] The guide tube 200 includes a hollow tube 204 that defines a longitudinal channel extending therethrough and is capable of receiving an electrode lead (e.g., electrode lead 100). The guide tube 200 includes a cap 204 disposed at a proximal end of the hollow tube 202.

[0246] The cap 204 may be secured to the proximal end of the hollow tube 202 . The cap 204 includes an entrance for inserting the electrode lead into a longitudinal channel in the hollow tube 202. Thus, the electrode lead 100 can be inserted into the subject's brain via the guide tube 200. The hollow tube 202 can serve to guide the electrode lead 100 along a desired trajectory within the subject's brain to facilitate implantation of the electrode lead 100.

[0247] The cap 204 further includes a threaded exterior surface 206 such that it can be threaded into an insertion hole (e.g., a burr hole) formed in the subject's skull. In this manner, the guide tube 200 can be inserted into the subject's brain via the insertion hole in the skull and secured to the skull via the threaded exterior surface 206. The hollow tube 202 can be made from a rigid plastic material to facilitate insertion of the hollow tube 202 into the subject's brain.

[0248] The length of the hollow tube 202 (shown as X in FIG. 2a) is configured such that when the electrode lead 100 is inserted into the longitudinal channel of the hollow tube 202, a distal portion of the electrode lead, including the multiple electrodes 102, protrudes from a distal opening 208 of the hollow tube 202. In this manner, when the electrode lead 100 is received in the longitudinal channel of the hollow tube 202, the multiple electrodes 102 on the electrode lead 100 are exposed such that neuromodulation signals can be applied to the surrounding brain tissue via the multiple electrodes 102.

[0249] The hollow tube 202 can be cut to an appropriate length prior to insertion into the subject's brain, for example based on the measured dimensions of the subject's brain. In particular, the length X of the hollow tube 202 can correspond to the distance between the subject's skull and a few millimeters below the lateral ventricle. This can facilitate transventricular implantation of the electrode lead. For example, the length X can be 45-65 mm.

[0250] The guide tube 200 includes a window 210 formed in a sidewall of the hollow tube 202. The window 210 is configured such that a portion of the proximal electrode 104 is exposed through the window 210 when the electrode lead 100 is received in the longitudinal channel of the hollow tube.

[0251] The length of the window 210 (shown as Z in FIG. 2a) is shorter than the length of the proximal electrode 104 such that the portion of the proximal electrode 104 exposed through the window 210 is shorter than the length of the proximal electrode 104. Thus, in the example of FIG. 1 where the proximal electrode has a length of about 20 mm, the window 210 can have a length less than 20 mm, such as 10 mm or 5 mm. By making the window 210 shorter than the proximal electrode 104, it is possible to ensure that the proximal electrode 104 applies neuromodulation signals only to brain tissue in the target region around the window 210, and not along the entire length of the proximal electrode 104. This can avoid stimulating brain tissue away from the target region.

[0252] As noted above, the window 210 may have a length of, for example, 10 to 25 mm. A window 210 in the hollow tube 202 is positioned to be aligned with the DACC when the guide tube is inserted into the subject's brain. In this manner, the portion of the proximal electrode 104 exposed through the window 210 can be used to apply neuromodulation signals to the DACC and / or CC.

[0253] In particular, the distance between the cap 204 and the window 210 (shown as Y in FIG. 2a) can be set such that the window 210 is positioned adjacent to the DACC. Guide tubes having different values ​​of Y can be provided to accommodate anatomical differences between subjects.

[0254] For example, the distance between the cap 204 and the window 210 (shown as Y in FIG. 2a) may be between 20 and 35 mm.

[0255] The window 210 is formed in the sidewall of the hollow tube 202 so as to face in a radial direction. In this way, when the electrode lead 100 is placed in the longitudinal channel of the hollow tube 202, the orientation of the hollow tube 202 relative to the electrode lead 100 can determine the direction in which the proximal electrode 104 can apply a neuromodulation signal. The cap 204 of the guide tube 200 includes a marker 212 (or indicator) in the form of an arrow to indicate the direction in which the window 210 is facing. In this way, a user (e.g., a surgeon) can ensure that the window is oriented in the correct direction when inserting the guide tube 200 into the subject's brain. In particular, the marker 212 can serve to ensure that the window 210 faces toward the DACC when the guide tube is inserted into the subject's brain.

[0256] 2b illustrates a configuration in which the electrode lead 100 is received in a longitudinal channel of the hollow tube 202 of the guide tube 200. As seen in FIG. 2b, in this configuration, a distal portion of the electrode lead 100 including the multiple electrodes 102 protrudes from a distal opening 208 of the hollow tube 202. Additionally, a portion of the proximal electrode 104 is exposed through a window 210 in the sidewall of the hollow tube 202. The proximal end of the electrode lead 100 may extend through an entrance in the cap 204 of the guide tube 200 so that the electrode lead 100 may be connected to a controller (not shown).

[0257] Figure 3a shows a schematic diagram of a guide tube 300 according to another embodiment of the invention. The guide tube 300 may form part of a device according to an embodiment of the invention. The guide tube 300 is similar to the guide tube 200 described above, but with a different window configuration. Therefore, features of the guide tube 300 that correspond to those described in relation to the guide tube 200 are indicated in Figure 3a by the same reference numerals as in Figure 2a and will not be described again.

[0258] The guide tube 300 includes a window 310 formed in a sidewall of the hollow tube 202. The window 310 comprises three openings 312, 314, 316 formed in the sidewall of the hollow tube 202. The openings 312, 314, 316 are equally spaced apart along the length of the hollow tube 202. The three openings together span a length Z, which is similar to the length Z of the window 210 of the guide tube 200. The window 310 is configured such that a portion of the proximal electrode 104 is exposed through the openings 312, 314, 316 when the electrode lead 100 is received in the longitudinal channel of the hollow tube 202. Thus, the window 310 functions similarly to the window 210 of the guide tube 200.

[0259] The inventors have found that by forming the window 310 as a series of smaller openings, it may be possible to increase the stiffness of the hollow tube 202, which may facilitate easier insertion of the hollow tube 202 into the patient's brain. In the example shown, the window 310 includes three openings. However, in other examples, a different number of openings may be used, such as, for example, two, four, five or six openings, and the size and / or spacing of the openings may differ from that discussed above.

[0260] FIG. 3b is a schematic diagram illustrating a device according to an embodiment of the present invention, including a guide tube 300 and an electrode lead 100. FIG. 3b illustrates a configuration in which the electrode lead 100 is received in a longitudinal channel of the hollow tube 202 of the guide tube 300. As seen in FIG. 3b, in this configuration, a distal portion of the electrode lead 100 including the plurality of electrodes 102 protrudes from the distal opening 208 of the hollow tube 202. Additionally, a portion of the proximal electrode 104 is exposed through the openings 312, 314, 316 of the window 310. The proximal end of the electrode lead 100 extends through an entrance in the cap 204 of the guide tube 200 and is connected to a controller 318 in the form of an IPG. The controller is configured to generate a neuromodulation signal that is applied by the proximal electrode 104 and the plurality of electrodes 102.

[0261] FIG. 4a shows a schematic diagram of a guide tube 400 according to another embodiment of the invention. The guide tube 400 can form part of a device according to an embodiment of the invention. The guide tube 400 is similar to the guide tube 200 described above, but does not include a window. Therefore, features of the guide tube 400 that correspond to those described in relation to the guide tube 200 are indicated in FIG. 4a by the same reference numerals as in FIG. 2a and will not be described again. In the example shown in FIG. 4a, the electrode lead 100 is received in a hollow channel within the hollow tube 202 of the guide tube 400.

[0262] The guide tube 400 includes an outer electrode 402 exposed on an exterior surface of the hollow tube 202 of the guide tube 400. The outer electrode 402 is generally cylindrical and forms a portion of the sidewall of the hollow tube 202. The outer electrode 402 is made from a conductive material, such as, for example, platinum-iridium. When the electrode lead is received within the longitudinal channel of the hollow tube 202, the outer electrode 402 is configured for electrical connection to a proximal electrode on an electrode lead, such as, for example, the proximal electrode 104 on the electrode lead 100. FIG. 4b shows an enlarged cross-sectional view of the hollow tube 202 along section AA shown in FIG. 4a, where the electrode lead 100 is received in the longitudinal channel of the hollow tube 202.

[0263] The outer electrode 402 includes a recess 404 formed therein and configured to contact the proximal electrode 104 when the electrode lead is received in the longitudinal channel of the hollow tube 202. In particular, the recess 404 passes through a sidewall of the hollow tube 202 to contact the proximal electrode 104 disposed inside the hollow tube 202. The recess 404 is configured to form a sliding contact with the proximal electrode 104 to enable insertion of the electrode lead 100 through the longitudinal channel of the hollow tube 202. Thus, when the electrode lead 100 is received in the longitudinal channel of the hollow tube 202, the outer electrode 402 is electrically connected to the proximal electrode 104 via the recess 404 of the outer electrode 402. In this manner, a neuromodulation signal applied to the proximal electrode 104 can be transmitted to the outer electrode 402, which can apply the neuromodulation signal to the surrounding target tissue.

[0264] Alternatively, the recess 404 may be referred to as a protrusion that protrudes into the hollow tube 202 and contacts the proximal electrode 104 .

[0265] Mechanisms other than the recess 404 can be used to electrically connect the outer electrode 402 to the proximal electrode 104. For example, instead of the recess 404, a connector can be provided that extends between the outer electrode 402 and the longitudinal channel of the hollow tube 202 through the sidewall of the hollow tube.

[0266] The outer electrode 402 is positioned to allow for neurostimulation of the DACC and / or CC. Thus, the outer electrode 402 can provide an alternative to the windows 210 and 310 discussed above for applying neuromodulation signals to the DACC and / or CC via the proximal electrode 104. For example, the distance Y (shown in FIG. 4a) between the cap 204 and the outer electrode 402 can correspond to the distance between the subject's skull and the DACC. Guide tubes having different distances Y can be provided to accommodate anatomical variations between subjects.

[0267] The hollow tube 202 of the guide tube 400 can typically be made from a plastic material such as polycarbonate urethane. One method of forming the hollow tube 202 of the guide tube 400 includes forming two thin-walled (e.g., 0.2 mm) concentric extrusion tubes of appropriate diameter. A window can then be formed in the inner tube to receive the recess 404 (or connector). The outer electrode 402 and outer tube can then be mounted onto the inner tube, and the plastic forming the tube can be reflowed at high temperature over a mandrel to form a bond and contact between the inner and outer tubes without introducing adhesive.

[0268] 5 illustrates a device 500 according to one embodiment of the present invention. The device includes an electrode lead 502 having a similar configuration to the electrode lead 100 described above. In particular, the electrode lead includes multiple electrodes 504 on a distal portion of the electrode lead 504. However, unlike the electrode lead 100, the electrode lead 502 does not have a proximal electrode. The proximal end of the electrode lead 502 is connected to a controller 506 that is configured to generate neuromodulation signals that are applied by the multiple electrodes 504.

[0269] The apparatus 500 further includes a guide tube 508. The guide tube 508 is similar to the guide tube 200 described above, but does not include a window. Accordingly, features of the guide tube 508 that correspond to those described in relation to the guide tube 200 are indicated in Figure 5 by the same reference numerals as in Figure 2a and will not be described again.

[0270] 5, the electrode lead 502 is received in a hollow channel within the hollow tube 202 of the guide tube 508. A proximal end of the electrode lead 502 may protrude from an entrance within the cap 204 of the guide tube 508 such that it may be connected to a controller 506. A distal portion of the electrode lead 504 protrudes from a distal opening 208 of the hollow tube 202 such that the multiple electrodes 504 are exposed.

[0271] Guide tube 508 includes an outer electrode in the form of a mesh electrode 510 disposed on the exterior surface of hollow tube 202. Mesh electrode 510 is formed from a metallic mesh material that is affixed to or otherwise incorporated into the exterior surface of hollow tube 202.

[0272] The mesh electrode 510 is electrically connected to the controller 506 via a connecting lead 512 extending from the cap 204 of the guide tube 508. Inside the hollow tube 202, the connecting lead 512 is in the form of a thin connecting wire extending between the cap 204 and the mesh electrode 510. The thin connecting wire may be disposed within a longitudinal channel of the hollow tube 202 or may be embedded in the material forming the hollow tube 202. In this manner, neuromodulation signals generated by the controller 506 can be transmitted to the mesh electrode 510, which can then apply the neuromodulation signals to the surrounding brain tissue.

[0273] The mesh electrode 510 is positioned to apply a neuromodulation signal to the DACC and / or CC. For example, the distance between the cap 204 and the mesh electrode 508 can correspond to the distance between the skull and the DACC. In this manner, neuromodulation signals can be applied to the DACC and / or CC via the mesh electrode without the need to include a proximal electrode on the electrode lead 504.

[0274] Of course, in other embodiments, electrodes of different configurations may be used in place of mesh electrode 510. For example, a cylindrical electrode may be used in place of mesh electrode 510.

[0275] 6a, 6b and 6c show a device 600 according to an embodiment of the present invention. The device 600 includes the electrode lead 100 described above. The proximal end of the electrode lead 100 can be connected to a controller (not shown) to generate a neuromodulation signal applied by the multiple electrodes 102 and the proximal electrode 104. The device 600 further includes a guide tube 602. The guide tube 602 includes a hollow tube 604 defining a longitudinal channel capable of receiving the electrode lead 100. The hollow tube 604 includes windows 606 in the form of three openings in a side wall of the hollow tube 604. The windows 606 serve to expose the proximal electrode 104 of the electrode lead 100 to the outside of the hollow tube 604 when the electrode lead 100 is received in the hollow tube 604.

[0276] The guide tube 602 further includes a cap 608. The cap 608 is fixable to a bore in the subject's skull via a threaded exterior surface 610 on the cap 608. The cap 608 includes a passage 612 (see FIG. 6b) through which the hollow tube 604 can be inserted to insert the hollow tube 604 into the subject's brain. Thus, when the cap 608 is fixed to a bore in the subject's skull, the hollow tube 604 can be inserted into the subject's brain via the passage 612 in the cap 608. The cap 608 is separate from the hollow tube 604, i.e., the cap 608 is not fixed relative to the hollow tube 604, such that the position of the hollow tube 604 relative to the cap 608 can be adjusted. The passage 612 in the cap can be configured to form a sliding seal around the hollow tube 604 to prevent leakage through the cap 608.

[0277] The hollow tube 604 includes a gradation line 614 that indicates the orientation of the window 606, i.e., the direction that the window 606 faces. The gradation line 614 also includes a distance marker to indicate the distance between the cap 608 and the window 606 when the hollow tube 604 is inserted through the passageway 612 of the cap 608. In this manner, a user can ensure that the window 606 is inserted at the correct depth and orientation into the subject's brain.

[0278] The hollow tube 604 can be supplied straight to facilitate insertion of the hollow tube through the passage 612 in the cap. Prior to insertion, the distal end 616 of the hollow tube 604 can be cut to an appropriate length, for example, so that the distal end 616 of the hollow tube 604, when inserted, can extend several millimeters below the lateral ventricle.

[0279] The guide tube 602 includes a first limiter 618 fixed near the proximal end 617 of the hollow tube 604, the first limiter 618 being configured to abut against a dome 620 of the cap when a predetermined length of the hollow tube 604 is inserted through the passage.

[0280] The first limiter 618 can be positioned on the proximal portion of the hollow tube 604 such that when the first limiter 618 abuts the dome 620 of the cap 608, the window 606 and distal end 616 of the hollow tube 604 are at the required depth. In particular, the predetermined length can be configured such that the window 606 is adjacent to the DACC (so that neuromodulation signals can be applied to the DACC and / or CC via the proximal electrodes) and the distal end 616 of the hollow tube is several millimeters below the lateral ventricle. The ability to adjust the position of the hollow tube 604 relative to the cap 608 can allow the guide tube 602 to be adapted to the particular anatomy of the subject.

[0281] The position of the first limiter 618 on the proximal portion of the hollow tube 604 can be set, for example, based on the markings of the gradation line 614 .

[0282] The first limiter 618 may be secured to the hollow tube 604 using any suitable means, such as, for example, sutures, adhesive, or a clamping mechanism.

[0283] The proximal end 617 of the hollow tube 604 can be cut to provide a sufficient length to secure the first limiter 618 to the hollow tube 604 .

[0284] In practice, the hollow tube 604 can be introduced into the subject's brain via the passage 612 in the cap 608 over a straight guide rod aligned along a desired trajectory, for example using a stereotactic frame or a stereotactic robot. Once the hollow tube is inserted to the correct depth, i.e., when the first limiter 618 abuts against the dome 620 of the cap 608, the guide rod can be withdrawn. The electrode lead 100 can then be inserted into the subject's brain via the longitudinal passage of the hollow tube 604 and into the canal formed in the subject's brain by the guide rod.

[0285] A second limiter 622 is secured to a proximal portion of the electrode lead 100. The second limiter 622 is positioned on the electrode lead 100 such that when a predetermined length of the electrode lead 100 protrudes through the opening in the distal end 616 of the hollow tube 604, the second limiter 622 abuts the proximal end 617 of the hollow tube 604.

[0286] In this manner, it is possible to ensure that the distal portion of the electrode lead comprising the multiple electrodes 102 is inserted to an appropriate depth into the subject's brain. This may also serve to ensure that the proximal electrode 104 on the electrode lead 100 is properly aligned with the window 606. The second limiter 622 may be secured to the electrode lead 100 using any suitable means, such as, for example, a suture, adhesive, or clamping mechanism.

[0287] After inserting the electrode lead 100 into the hollow tube 604, the proximal portion of the hollow tube 604 and the electrode lead 100 protruding from the cap 608 may be bent at an angle of approximately 90 degrees. The first limiter 618 is then secured to the subject's skull via a fastener 624 (e.g., a mini-plate) that may be screwed into the subject's skull using a bone screw (not shown). Such a configuration is shown in Figures 6a, 6b, and 6c.

[0288] The hollow tube 604 can be made from a thermoplastic material to facilitate bending the hollow tube 604 at an angle of approximately 90 degrees, for example, the thermoplastic material can be heated to bend the hollow tube 604, and then the hollow tube can harden upon cooling.

[0289] The first limiter 618 includes a groove formed in its outer surface for receiving the fastener 624. The engagement between the groove and the fastener 624 can ensure that the first limiter 618 is firmly held in place by the fastener 624. When the first limiter 618 is secured to the hollow tube 604, the fastener 624 can prevent the hollow tube 604 from moving relative to the skull.

[0290] FIG. 6b shows a cross-sectional view of the device 600 along the plane AA shown in FIG. 6c. The device 600 is attached to the subject's skull 630. The cap 608 is fixed to a hole formed in the subject's skull 630, and the hollow tube 604 is inserted into the subject's brain 632 through the passage 612 in the cap 608. The hollow tube 604 is fixed to the subject's skull 630 through a fastener 624 that engages with a groove in the first limiter 618, and the fastener 624 is screwed to the subject's skull 630. FIG. 6c shows a top view of the device 600 attached to the subject's skull 630.

[0291] Figures 7a and 7b show a device 701 according to an embodiment of the invention, which includes a guide tube 700 (also an embodiment of the invention). Guide tube 700 is similar to guide tube 602 described above, but does not include a window for exposing the proximal electrode. Thus, features of guide tube 700 that correspond to those described in relation to guide tube 604 are shown in Figures 7a and 7b with the same reference numbers as in Figures 6a, 6b and 6c, and will not be described again. Device 701 further includes an electrode lead 702.

[0292] 7a illustrates a cross-sectional view of a portion of the hollow tube 604 of the guide tube 700. In the example shown, an electrode lead 702 is received in a longitudinal channel of the hollow tube 604. The electrode lead 702 has a similar configuration to the electrode lead 100 described above. In particular, the electrode lead 702 includes a distal portion having a plurality of electrodes 704 thereon and a proximal electrode 706 spaced apart from the plurality of electrodes 704.

[0293] The hollow tube 604 of the guide tube 700 includes a cylindrical conductor 708 embedded within the plastic material forming the hollow tube 604. The inner surface of the cylindrical conductor 708 forms a section of a longitudinal channel within the hollow tube 604. In this manner, when the electrode lead 702 is received in the longitudinal channel of the hollow tube 604, the proximal electrode 706 can contact the cylindrical conductor 708, as shown in FIG.

[0294] A window 710 is formed in the plastic material of the hollow tube 604, exposing a portion of the cylindrical conductor 708. The exposed portion of the cylindrical conductor 708 thus constitutes an outer electrode exposed at the exterior surface of the hollow tube 604. In this manner, a neuromodulation signal applied to the proximal electrode 706 of the electrode lead 702 can be transmitted to the cylindrical conductor 708, which can apply the neuromodulation signal to the target tissue through the window 710. The window 710 can be dimensioned to allow for directional neurostimulation of the DACC and / or CC. Because the proximal electrode 706 of the electrode lead 702 is not used to directly apply neuromodulation signals to the DACC, it may be possible to reduce the length of the proximal electrode 706.

[0295] Similar to the guide tube 602, the hollow tube 604 of the guide tube 700 is insertable through a passage in the cap 608 so that the length of the hollow tube 604 inserted into the subject's brain can be adjusted. A first limiter 618 on the proximal portion of the hollow tube 604 can be positioned and fixed to ensure that the window 710 is positioned at a desired depth within the subject's brain. The hollow tube 604 of the guide tube 700 includes a staging line 712 that indicates the orientation of the window 710, i.e., the direction in which the window 606 faces. The staging line 712 also includes a distance marker to indicate the distance between the cap 608 and the window 710 when the hollow tube 604 is inserted through the passage in the cap 608.

[0296] In the example shown in Figure 7b, the hollow tube 604 and electrode lead 702 are in a straight configuration, i.e., prior to bending the hollow tube 604 and electrode lead 702 and attaching the first limiter to the subject's skull (discussed above in connection with Figures 6a, 6b and 6c). As seen in Figure 7b, the electrode lead 702 includes a second limiter 714 secured to its proximal end to ensure that a desired length of the electrode lead protrudes from the opening at the distal end 616 of the hollow tube 604.

[0297] In practice, the relative positions of the hollow tube distal end 616, the window 710, and the cap 608 can be determined by selecting appropriate values ​​of the dimensions X and Y shown in FIG. 7b. The dimension X, which corresponds to the distance between the distal end 616 of the hollow tube 604 and the window 710, can be adjusted by cutting the distal end 616 of the hollow tube 604. The dimension Y, which corresponds to the distance between the cap 608 and the window 710, can be adjusted by sliding the cap 608 relative to the hollow tube 604. The proximal portion of the hollow tube 604 protruding from the cap 608 can be cut to an appropriate length (shown as Z in FIG. 7b) to accommodate the first limiter 618. Similar principles can be applied to adjust the various dimensions of the guide tube 602 described above.

[0298] FIG. 8 is a schematic diagram showing a device 800 according to an embodiment of the present invention. In the example shown, the device is used on a subject 801. The device includes an electrode lead 802 that is implanted into the subject's brain via a guide tube 804. The electrode lead 802 can correspond, for example, to the electrode lead 100 described above, while the guide tube 804 can correspond to the guide tubes 200 or 300 described above. Any of the electrode leads and guide tubes described above can be used as part of the device 800. The guide tube 804 is inserted into the subject's brain via a burr hole in the subject's skull, and the cap of the guide tube 804 is fixed to the subject's skull. The electrode lead 802 is implanted into the subject's brain along a linear trajectory that runs adjacent to the DACC, through the DMN, adjacent to the LH and PC, and into the VL-PAG. In this way, neuromodulation signals can be applied to the DACC and / or CC via proximal electrodes, while the DMN, LH, PC and VL-PAG can be stimulated via multiple electrodes on the electrode lead 802.

[0299] The electrode leads 802 are connected to a controller 806 in the form of an IPG. The controller 806 is implanted in a pocket formed in the subject's skull. The controller 806 is configured to generate neuromodulation signals that are applied by the electrodes on the electrode leads 802.

[0300] The device 800 includes a number of sensors communicatively coupled to a controller and configured to detect various physiological parameters of the subject 801. The device 800 includes an intracranial pressure (ICP) sensor 808 configured to detect the ICP of the subject 801. In the illustrated example, the ICP sensor 808 is implanted under the subject's skull through a second burr hole in the subject's skull. The ICP sensor 808 is communicatively coupled to the controller 806 via wires such that the ICP sensor 808 can transmit a signal related to the subject's ICP to the controller 806. Additionally or alternatively, the ICP sensor can be incorporated into the guide tube 804 and / or the electrode lead 802. Incorporating the ICP sensor into the guide tube 804 and / or the electrode lead 802 can avoid the need to drill a second burr hole in the subject's skull.

[0301] The device 800 further includes an internal sensor 810 for detecting blood flow and / or blood pressure. In the illustrated example, the internal sensor 810 is implanted above the carotid bifurcation. The internal sensor 810 is communicatively coupled to the controller 806 via wires such that the internal sensor 810 can transmit signals related to the subject's blood flow and / or blood pressure to the controller 806. The device may also include a wearable sensor, for example in the form of a wrist-mountable sensor 812. The wrist-mountable sensor 812 can be configured to detect, for example, blood pressure, heart rate, or blood flow. The wrist-mountable sensor 812 can be communicatively coupled to the controller via a wireless connection between the controller 806 and the sensor 812 such that the sensor 812 can transmit signals related to the measured physiological parameter(s) to the controller 806. Different embodiments may include different types of sensors configured to detect different physiological parameters of the subject and communicate signals related to the detected physiological parameters to the controller 806.

[0302] The controller 806 is configured to adjust the one or more neuromodulation signals applied via the electrode leads 802 based on physiological parameters detected by the sensors (e.g., the ICP sensor 808 and / or the wrist-mountable sensor 812). In this manner, control of the neuromodulation signals can be based on feedback provided by the subject's physiological parameters. The controller 806 can be configured to adjust the one or more neuromodulation signals applied via the electrode leads 802 to reach a set point associated with one of the physiological parameters.

[0303] The controller 806 can further be configured to detect the circadian rhythm of the subject 801. This can be done by monitoring physiological parameters of the subject, such as blood pressure and / or heart rate, that vary from day to day depending on the subject's circadian rhythm. Similarly, the controller 806 can be configured to detect a disruption of the subject's circadian rhythm, for example, by comparing the diurnal variation of the measured physiological parameter with a model diurnal variation corresponding to an undisturbed circadian rhythm. The controller 806 can then adjust one or more neuromodulation signals based on the circadian rhythm and / or to re-establish a normal circadian rhythm in the subject 801.

[0304] 8 shows the location of the carotid baroreceptors and carotid body. The ascending aorta 820 supplies the carotid artery 822. The bifurcation of the internal carotid artery 824 and the external carotid artery 826 forms a saddle where the carotid body 828 is located. The aortic arch baroreceptors 816 supply the vagus nerve which supplies to the medulla. The carotid baroreceptors are located in the carotid sinus 814 above the internal carotid artery 824. Both the carotid body and the carotid baroreceptors supply the sinus of Hering nerve which joins with the glossopharyngeal nerve before reaching the medulla.

[0305] In some embodiments, device 800 may further include one or more stimulation electrodes for applying one or more stimulation signals to the carotid body and / or carotid baroreceptors of subject 801. For example, internal sensor 810 may include a stimulation electrode configured to apply a stimulation signal to baroreceptors in the carotid sinus 814 and / or carotid body 828. Alternatively, a separate stimulation electrode may be provided to apply a stimulation signal to baroreceptors in the carotid sinus 814. A separate stimulation electrode may also be provided to apply a stimulation signal to baroreceptors 816 of the aortic arch.

[0306] The one or more stimulation electrodes may form part of an implantable lead that is implanted in the subject. The implantable lead may be similar to that described in U.S. Patent Application Publication No. 2015 / 0112359. For example, the implantable lead may include a semicircular hook that allows the implantable lead to be placed over the bifurcation of the internal carotid artery 824 and the external carotid artery 826. The semicircular hook may include a stimulation electrode configured to be held in close proximity to the carotid baroreceptors in the carotid body and / or carotid sinus. The implantable lead may be implanted in the subject 801 using a guide tube or needle.

[0307] The stimulation signal applied by the one or more stimulation electrodes may be generated by the controller 806, in which case a wired connection may be provided between the controller 806 and the stimulation electrodes. Alternatively, a separate controller (not shown) may be provided for generating the stimulation signal applied by the one or more stimulation electrodes.

[0308] The stimulation signal applied by the one or more stimulation electrodes can be in the form of a pulsed RF electrical signal. The pulse duration of the stimulation signal can be 2-10 ms, or preferably 5-8 ms, with each pulse consisting of many cycles of a 200-600 kHz, or preferably 250-500 kHz RF waveform. The pulses can be repeated at 2-8 Hz, preferably 5 Hz, with an interval of about 120-500 ms between each pulse. Typically, the amplitude of the pulsed RF signal can be 25-100V, or 10V-140V is utilized. Such a pulsed RF signal can avoid the buildup of heat generated in the one or more stimulation electrodes to avoid tissue ablation that can cause long-term damage to the nerve or carotid body. Such a stimulation signal can be applied intermittently to the carotid body.

[0309] Alternatively, the stimulation signal applied to the carotid baroreceptors can have a pulse amplitude of typically 5-10 mA, a pulse width of typically 45-210 ms, and a pulse frequency of typically 40-80 Hz. Such stimulation signals have been demonstrated to evoke a blood pressure response. Such stimulation signals can be applied continuously to the carotid baroreceptors, for example with appropriate cycling or bursts.

[0310] 9 is a schematic diagram illustrating a device 900 according to an embodiment of the present invention. In the illustrated example, the device 900 is attached to a subject's skull 901. The device 900 includes a controller 902 in the form of an IPG that is implanted in a pocket formed in the subject's skull 901. The controller 902 is electrically connected to an electrode lead 904 that is implanted in the subject's brain through a hole in the subject's skull 901. The electrode lead may, for example, be similar in configuration to the electrode lead 100 described above. The electrode lead 904 is fixed to the subject's skull via a fixator (e.g., a mini-plate) 906.

[0311] The controller 902 is powered by an external power source including a transmit coil 908 configured to be placed on the subject's scalp. The transmit coil 908 is configured to transmit power to the controller 902 via inductive coupling between the transmit coil 908 and the controller (e.g., a receive coil within the controller). In this manner, power can be wirelessly transmitted from the external power source to the controller 902. This can avoid the need to include an internal power source in the controller 906 and can facilitate coupling of the controller 902 to an external power source. The external power source can be configured to provide power continuously, for example, or in bursts at programmed times. The device 900 can further include a cap (not shown) configured to hold the transmit coil 908 in place on the controller 906.

[0312] 10a and 10b show the placement of electrode leads in a subject's brain along a preferred trajectory to enable treatment according to one embodiment of the present invention.

[0313] In the example shown in Fig. 10a, the electrode lead 100 is implanted in the subject's brain via the guide tube 200 described above. However, other electrode leads and guide tubes described herein may be implanted along the trajectory shown in Fig. 10a. Fig. 10b shows a side view of the subject's head and indicates section line 51 (AA). Fig. 10a shows a cross-sectional view of the subject's head along section line 51.

[0314] The cap 204 of the guide tube 200 is fixed to a hole in the skull 49 of the subject. The hollow tube 202 of the guide tube 200 is implanted into the brain of the subject along a linear trajectory that passes laterally through the DACC 53 and corpus callosum 50, and further through the DMN 57 adjacent to the LH 58 and PC 59 to the VL-PAG 60. The hollow tube 202 crosses the lateral ventricle 56, and the distal opening 208 of the hollow tube 202 is positioned a few millimeters below the lateral ventricle 56. The electrode lead 100 is implanted into the brain of the subject through the guide tube 200 along a linear trajectory.

[0315] A distal portion of the electrode lead, including multiple electrodes 102, protrudes from the distal opening 208 of the guide tube, passing through the DMN 57 adjacent to the LH 58 and PC 59, and into the VL-PAG 60.

[0316] A window 210 in the hollow tube 210 is positioned adjacent to the DACC 53 and the corpus callosum 50. A portion of the proximal electrode 104 on the electrode lead 100 is exposed through the window 210 in the hollow tube. In this manner, neuromodulation signals can be applied to the DACC 53 and the CC 50 via the proximal electrode 104. Additionally, a plurality of electrodes 102 on the distal portion of the electrode lead 100 can be used to apply neuromodulation signals to one or more of the DMN 57, the LH 58, the PC 59, and the VL-PAG 60. A controller 48 in the form of an IPG is implanted in a pocket formed in the subject's skull 49. The controller 48 is configured to generate neuromodulation signals that are applied by the plurality of electrodes 102 and the proximal electrode 104.

[0317] 11 is a photograph of a subject's brain showing a preferred trajectory 21 for implanting an electrode lead according to the method of the present invention. The trajectory 21 is a straight trajectory that extends laterally of the DACC 22 and CC 24, crosses the DMN 23, extends adjacent to the LH 25, bypasses the third ventricle 28, extends adjacent to the PC 26, and terminates in the VL-PAG 27. Thus, when an electrode lead is implanted in the subject's brain along the trajectory 21, one or more of the DACC, CC, DMN, LH, PC, and VL-PAG can be stimulated.

[0318] Figures 12a and 12b show images of a guide tube 31 implanted in a subject's brain along the trajectory 21 shown in Figure 11, prior to insertion of the electrode leads. Figure 12a corresponds to an anterior-posterior projection of the trajectory 21, while Figure 12b corresponds to a side view of the trajectory 21. A guide rod 32 made from a radiopaque material is used to implant the guide tube along the correct trajectory, for example using a stereotactic frame or a stereotactic robot.

[0319] FIG. 13 is an image of a subject's brain showing the electrode lead 11 implanted in the subject's brain. The image shows the distance between the implanted electrode lead 11 and the LH 12. As shown in FIG. 13, in this case the distance is greater than 5 mm, between 5 and 7 mm. The inventors found that when the electrode lead was implanted along a trajectory passing more than 5 mm anterior to the LH and PC, as shown in FIG. 13, the subject did not respond to combined stimulation of the DMN and VL-PAG. This was because the electrode lead was too far away from the LH and PC to effectively apply neuromodulatory signals to the LH and PC.

[0320] In one study subject, the electrode leads were as shown in Figure 13, and the subject did not respond to combined stimulation of the DMN and / or VL-PAG. We found that by modifying the trajectory to be closer to the LH and PC (i.e., less than 5 mm away from the LH and PC), we were able to obtain a positive response by combined stimulation of the DMN and VL-PAG along with the LH and PC.

[0321] This has led to the inventors' realization that it is possible to enhance a subject's response to neural stimulation of the DMN and / or VL-PAG by applying neuromodulatory signals to the LH and PC. To ensure that neuromodulatory signals can be effectively applied to the LH and PC, it may be preferable for the electrode lead trajectories to pass less than 5 mm from the LH and PC.

[0322] According to the present invention, a higher frequency neuromodulation signal can be applied to the DMN, while a lower frequency neuromodulation signal can be applied to the LH and PC. When a neuromodulation signal is also applied to the VL-PAG, a neuromodulation signal having a lower frequency can also be applied to the VL-PAG.

[0323] Higher frequency neuromodulatory signals applied to the DMN can be, for example, pulse trains with forward pulse widths of 25-350 microseconds, more preferably 60-90 microseconds, at repetition frequencies greater than 70 Hz, more preferably in the range of 100-200 Hz, or 130 or 150 Hz. Forward (negative) pulses are delivered at amplitudes of typically 1 or 2-3 or 5 mA by a current-controlled output, or at amplitudes of 1-3 V by a voltage-controlled output, with a balanced counter charge typically delivered at the same or lower intensity. Higher frequency neuromodulatory signals can serve to inhibit neurons in structures such as the dorsomedial nucleus, anterior nucleus, and median median nucleus / parafascicular complex.

[0324] The lower neuromodulatory signals applied to one or more of the LH, PC, and VL-PAG consist of a pulse train of 50-450 microsecond forward pulse widths at a repetition frequency of 5 or 10-40 or 50 Hz, 1 or 2-3 or 5 mA amplitude by the current-controlled output, or typically 90-180 microsecond pulses of 1-5 V amplitude by the voltage-controlled output. Balanced reverse charging may be required. Preferably, the repetition frequency is 5-10 Hz or 20 Hz, but in some cases the response may be maximized at 40 Hz. Such low frequency neuromodulatory signals can act to excite neural activity in the target being stimulated. Lower frequency neuromodulatory signals can serve to excite neurons in structures such as the pineal gland.

[0325] Table 1 below summarizes a series of tests performed on subjects showing the effects of various neurostimulation techniques according to embodiments of the present invention. Neuromodulation signals were applied to each subject to treat their hypertension.

[0326] The left column of Table 1 indicates the subjects on whom the tests were performed. The column labeled "Stimulation Target" indicates the various targets in the subject's brain to which the neuromodulation signal was applied during each test. When "Bilateral," "Left," and "Right" are mentioned, this provides an indication of whether the neuromodulation signal was applied to targets in both hemispheres of the brain, or the left or right hemisphere. The column labeled "Stimulation On / Off" indicates whether the measurement was taken during application of the neuromodulation signal ("On") or when the neuromodulation signal was turned off ("Off"). The final three columns indicate the values ​​measured during the test. The column labeled "CBF" indicates an indication of cerebral blood flow. The column labeled "CBV" indicates an indication of cerebral blood volume. The column labeled "MTT" indicates the mean transit time of blood through the brain, i.e., the time blood spends in the brain between the time it enters the brain and the time it leaves the brain.

[0327] CBV is measured in milliliters of blood per 100 grams of brain and is defined as the amount of blood flowing through a given brain volume. MTT is measured in seconds and is defined as the average time it takes blood to pass through a given brain volume. CBF is measured in milliliters of blood per 100 grams of brain tissue per minute and is defined as the amount of blood flowing through a given brain volume in a specific time.

[0328] As can be seen from Table 1, the general effect of applying neuromodulatory signals to targets in the brain is to increase cerebral blood flow and volume. In many cases, the mean transit time for blood through the brain is also decreased.

[0329] [Table 1]

[0330] Below is a brief description of some of the conditions that can be treated using the methods of the present invention.

[0331] High blood pressure Hypertension is one of the most important challenges for public health systems. The prevalence of resistant hypertension suggests that existing pharmacological interventions are failing for many patients. This, combined with the fact that some medications are poorly tolerated by patients, associated with non-adherence, suggests that there is a need for improved medical care. The globally accepted diagnosis of treatment-resistant hypertension is an office blood pressure measurement of more than 140 / 90 mmHg during pharmacological intervention with three or more antihypertensive drugs (including diuretics).

[0332] Arterial blood pressure normally exhibits a physiological diurnal variation, with higher levels during the day and lower levels at night. Several studies have reported that hypertensive patients whose pressure remains elevated at night (non-dippers) exhibit more target organ damage than patients whose pressure shows a normal pattern (dippers). Typically, blood pressure during sleep decreases (drops) by more than 10% from the daytime baseline blood pressure. Moreover, in the general population, non-dipping has been shown to be a risk factor for cardiovascular mortality, independent of the overall 24-hour blood pressure, and is associated with cardiac hypertrophy and remodeling.

[0333] Non-dipping has been shown to be present in approximately 40% of untreated hypertension and more than 50% of treated hypertension. Non-dipping may be an early change in a person's blood pressure pattern, and the loss of nocturnal blood pressure decline may occur prior to the onset of clinical hypertension.

[0334] The antihypertensive effect of VL-PAG DBS has been observed in patients undergoing treatment for neuropathic pain who have also been diagnosed with hypertension (Green 2005) (Patel 2011). In some patients, blood pressure could be acutely increased or decreased during surgery by stimulating the dorsal or ventral PAG, respectively. Chronic DBS of the VL-PAG caused a reduction in arterial pressure and analgesia associated with changes in heart rate variability indicating inhibition of sympathetic vasomotor turn and increased parasympathetic cardiac activity (Pereira 2010), which led the inventors to describe "Method and Apparatus for Regulating Blood Pressure" WO 2007007058. Muscle sympathetic nerve activity was reduced during acute ventrolateral PAG DBS in some patients (Sverris Dottir 2014).

[0335] We observed a remarkable response in blood pressure reduction after DBS of the VL-PAG, with acute complete normalization of chronic hypertension from shock that usually did not last beyond a few days to a week. Using a robot to localize the electrodes by visual image-based confirmation of the position of pre-inserted guide tubes and guide rods (Renishaw PLC) (Patel 2007), we targeted the VL-PAG reliably and with high precision. In 2011 (Neurology, 2011), we reported the first case study in which stimulation of the VL-PAG reduced neuropathic pain and incidentally led to a sustained (>3 years) normalization of arterial pressure that was not secondary to pain relief, as the patient's pain score returned to ventrolateral PAG stimulation levels after 4 months. More recently, in 2017 (Hypertension, 2017), we reported the first case study in which habitual deep brain stimulation was able to reduce blood pressure and sympathetic nerve activity in a drug- and device-resistant severely hypertensive patient.

[0336] The Oxford group further found that the inhibitory and bradycardic effects of acute VL-PAG DBS were associated with increased baroreflex sensitivity, although the prevailing thinking in these cases was that the beneficial blood pressure effects were a secondary response to the relief of chronic pain.

[0337] In the inventors' experience, consistent with studies in spontaneously hypertensive rats in which the VL-PAG has been stereotactically targeted, stimulation of the VL-PAG alone is insufficient for a sustained hypertensive response. Of five treated cases with hypertensive disease, with or without pain, two showed no response. Close examination of the location and trajectory of the implanted leads confirmed that the trajectory of the non-responders did not traverse along the lateral habenula and posterior commissure, but was 5-7 mm anterior (see Figure 13). In both chronic non-responders, the distal electrode was in the VL-PAG. Both showed an acute response, probably related to impingement and swelling extending to the lateral habenula and posterior commissure, which disappeared upon relaxation.

[0338] vascular dementia Damage to blood vessels in the brain can occur as a result of many conditions, such as high blood pressure, heart disease, high cholesterol, and diabetes. Vascular dementia can be caused by events occurring in the cerebral blood vessels, firstly stroke, and secondly small vessel disease. Vascular dementia resulting from stroke is classified as either single infarct or multi-infarct, depending on whether it was caused by a single occurrence of stroke or multiple occurrences. Small vessel disease results from damage to blood vessels located within the subcortical, deep, and periventricular white matter, as well as the small spaces of the central gray matter, including the thalamus and basal ganglia. Small vessel disease can be present in the absence of cognitive impairment and when there are various levels of cognitive impairment, ranging from mild cognitive impairment to dementia.

[0339] There are multiple experimental data showing the progression of vascular dementia caused by small vessel disease that tends to be continuous rather than gradual. In a study of patients with vascular dementia, a decline of 4.5 MMSE points per year was seen. Vascular dementia is associated with increased mortality, especially in the presence of white matter lesions and lacunar cerebral infarction. The presence of white matter lesions in patients with lacunar cerebral infarction is also a predictor of functional impairment. Further studies of patients with small vessel disease associated with dementia and mild cognitive impairment yielded a 70% survival rate after 2.6 years and a 50% survival rate after 4.3 years. Patients show a decline of 3.9 points on the abbreviated MMSE scale. (Bennet HP and Corbett AJ 2002 subcortical vascular disease and functional decline - a six year proeditor study.Journal of American Geriatrics Society 50 1969 to 1977;Frisoni GB et al 2002 mild cognitive impairment with subcortical vascular features-clinical characteristics and outcomes.249,1423-1432;Ballard C et al 2001 the progression of cognitive impairment and dementia with lewy bodies,vascular dementia and Alzheimer's disease.International Journal of Geriatric Psychiatry 16,499 to 503.) Deep brain stimulation leads were implanted in two patients presenting with post-stroke pain secondary to hypertensive disease at North Bristol NHS Trust. Patient 1 had a history of up to six TIAs, which ultimately led to a more severe right internal capsule, ventrolateral thalamic, and insular stroke. A Medtronic 3387 lead (4x1.5mm contacts separated by 1.5mm intervals) was implanted in the VL-PAG. On further examination, we found that the proximal contacts were adjacent to the posterior commissure and lateral habenula, and extended into the dorsomedial thalamic nucleus. With stimulation, patient 1 only obtained a pain response lasting 3 months, but blood pressure remained controlled at 2 years (Patel et al, Neurology 2011).

[0340] Patient 2 suffered up to 10 stroke episodes leading to hospitalization. Patient 2 was implanted with Boston Scientific 8-contact leads (8x1.5mm contacts separated by 0.5mm intervals) in the ventrolateral PAG across the dorsomedial thalamic nucleus, lateral habenula, and posterior commissure. Low frequency stimulation over the VL-PAG, LH, and PC, and high frequency stimulation over the DMN, controlled both patient's pain and blood pressure.

[0341] Currently, 12 and 5 years after surgery, Patient 1 and Patient 2 have suffered no further stroke events. Due to failure of pain management, Patient 1 underwent implantation of bilateral dorsal anterior cingulate cortex leads in 2011. For surgical planning, Patient 1 had existing leads removed and underwent MR imaging, which compared with the 2006 imaging to rule out progression of small vessel disease, white matter lesions and lacunar cerebral infarction. Patient 2 also showed stability of neuropsychometric tests at 5 years without deterioration after implantation and stimulation, with significant deterioration by temporary stimulation cessation.

[0342] Epilepsy Epileptic seizures, resulting from excessive and uncontrolled desynchronization of cortical neuro-brain electrical activity, occur in approximately 1% of the world's population and can be controlled with pharmacological therapy only in approximately 70% of cases. In the remaining 30% surgical treatment is required and neuromodulation techniques are becoming a new treatment option, especially since, unlike techniques that cause damage, they allow the modification of brain activity in a controlled manner while the effects are reversible.

[0343] Bilateral anterior thalamic nucleus radiofrequency deep brain stimulation has been shown to progressively reduce seizure frequency and severity, especially in patients with generalized tonic-clonic seizures who do not have a surgically amenable target. This has been shown as part of the SANTE and MORE studies conducted by Medtronic Inc. In patients with medically refractory partial seizures and secondarily generalized seizures, bilateral stimulation of the anterior nuclei has been demonstrated to reduce seizures by more than 70% over a 7-year period (SANTE trial).

[0344] In two cases where deep brain stimulation systems were implanted for hypertension, both patients had a long medical history of associated seizures. The deep brain stimulation system was implanted in the VL-PAG over the right medial thalamus. By combining low-frequency stimulation over the ventrolateral periaqueductal gray, periventricular gray, posterior commissure and habenula with high-frequency stimulation of the parafascicular and dorsomedial thalamic nuclei (along the upper extent of the leads), both patients showed complete relief of seizure activity. Cerebral blood flow studies in the second patient with stimulation switched on and off, as shown by CT perfusion, confirmed a 39.5% increase in cerebral blood flow, a 16.7% increase in cerebral blood volume, and a 12.5% ​​decrease in mean transit time.

[0345] Although cerebral vasoconstriction and reduced cerebral blood flow are hypothesized to be precursor events to seizures or seizure activity, studies have confirmed a general increase in cerebral blood flow after an attack in anticipation of recovery of cerebral blood flow. Postictal hypotension is commonly identified in epilepsy patients and may contribute to cardiovascular collapse leading to sudden onset of death in epilepsy (SUDEP). This is interestingly more prevalent at night, consistent with the loss of circadian rhythm commonly seen in chronic hypertensive disorders.

[0346] DBS leads with electrode coverage extending from the anterior thalamic nuclei to the ventrolateral periaqueductal gray are implanted via a transventricular trajectory with appropriate collision avoidance of the vasculature. Contacts extend from the anterior thalamic nuclei through the dorsomedial thalamic nucleus, the parathalamic nucleus adjacent to the lateral habenula, the periventricular gray adjacent to the posterior commissure, and into the ventrolateral periaqueductal gray.

[0347] The anterior thalamic nuclei are well established for the treatment of generalized seizures, but bilateral median nucleus-parafascicular nucleus stimulation also shows efficacy. Stimulation of the periaqueductal gray has been shown to eliminate cortical rhythm desynchronization in animal models, making it a potential adjuvant for stabilizing brain rhythms and controlling seizures.

[0348] Brain glioma disease Iodine-123 labeled hydroxy-iodo-propyl-diamine (HIPDm) is a diffusible indicator with 85-90% extraction rate, stable retention in the brain for more than 2 hours, and diffusibility by SPECT (single photon emission computed tomography) scanning, and HIPDm diffusion has been shown to occur in proportion to regional cerebral blood flow. Consistently, in the distribution of middle cerebral artery ligation, there is a marked reduction in HIPDm accumulation and calculated cerebral blood flow due to cerebral infarction. Interestingly, patients with glioma disease have been shown to have reduced HIPDm accumulation due to reduced cerebral blood flow in the area of ​​the neoplasm, associated with vasogenic edema in the surrounding area and also within the overlying gray matter.

[0349] Enhancement of cerebral blood flow is likely to benefit the body's own immune system and the enhanced delivery of immunoglobulins and white blood cells to combat this diffuse disease, which is enhanced by chemotherapy and immunotherapy. Therefore, the neurostimulation technology described herein can be used to enhance cerebral blood flow to treat brain glioma disease.

[0350] Psychosis, depression and schizophrenia Habenular dysfunction has been implicated in psychoses including depression, schizophrenia and drug-induced psychosis (Sandyk, 1991-Scheibel, 1997). In rat models of depression, local glucose metabolism is more consistently elevated in the lateral habenular nucleus than in any other brain region (Caldecott-Hazard et al, 1988). Transient depressive relapse in volunteer patients by acute depletion of plasma tryptophan, a precursor of serotonin (5-HT), is associated with a correlated increase in habenular and dorsal raphe activity as rates of depressed mood increase (Morris et al, 1999).

[0351] Habenular calcifications occur much more frequently in patients with chronic schizophrenia than in age-matched controls (Sandyk, 1992; Caputo et al, 1998). Influenza virus, which increases the risk of schizophrenia if experienced prenatally, selectively damages the habenula when introduced into the brain via the olfactory bulb (Mori et al, 1999). Refractory schizophrenia remains a major unsolved clinical problem, with 10–30% of patients not responding to standard treatment options. Similarly, at Southmead Hospital, a 70-year-old man who had been diagnosed with late-onset psychosis 2 years earlier has now been diagnosed with central lymphoma affecting the habenula.

[0352] We found that high amplitude low frequency stimulation of the habenula in one patient resulted in the intensification of both auditory and visual hallucinations. The latter related to a 58-year-old woman who presented with postoperative trigeminal anesthesia, and underwent implantation of right-sided deep brain stimulation leads in the ventrolateral periaqueductal gray and parafascicular nucleus in 2010 (at age 49). Stimulation of the ventrolateral periaqueductal gray combined with high frequency stimulation of the medial thalamus (dorsomedial nucleus), combined with auditory and sometimes visual hallucinations, resulted in some progression of the long-standing disruption between thinking and speaking from 2012 to 2017. Cessation of stimulation for 4 days resulted in complete relief of confusion and hallucinations, while pain worsened severely. Reprogramming of stimulation with the left medial thalamus (reduced amplitude) combined with high frequency stimulation of the proximal ventrolateral PAG lead spanning the lateral habenula resulted in complete relief of the visual hallucinations and a 50% reduction in confusion and auditory hallucinations, while her facial pain remained as controlled as before. Thus, high-frequency stimulation of the DMN combined with low-frequency stimulation of the VL-PAG produced cognitive impairment and hallucinations, possibly as a result of inhibition of the lateral habenula. High-frequency stimulation of the DMN combined with low-frequency stimulation of the LH improved cognitive impairment and psychosis. Further amplitude reduction within the DMN cumulatively improved cognitive and psychiatric impairment, while reducing pain control. High-frequency stimulation of the DMN combined with low-frequency stimulation extending from the LH to the VL-PAG may optimize the control of pain, mood, cognition and psychosis.

[0353] renal failure Consistent with the dorsal PAG inducing a fight-or-flight response and the VL-PAG inducing a stiffness response, stimulation of the dorsal PAG invariably induces a significant decrease in glomerular filtration rate (GFR), with lasting effects that may lead to acute renal failure, whereas stimulation of the VL-PAG helps to improve GFR and alleviate acute renal failure.

[0354] We found that low-frequency stimulation over the lateral habenula to the VL-PAG, when combined with high-frequency stimulation of the DMN and / or DACC, can result in a gradual normalization of GFR and prevent deterioration. This may be the result of reversing autonomic imbalance. This may therefore be useful in the use of stimulation for the treatment of renal failure, particularly in pre-dialysis patients who could utilize this combined stimulation paradigm to minimize progression and potentially promote recovery and prevent the need for dialysis.

[0355] Autoregulation of cerebral blood flow Cerebral blood flow autoregulation is the brain's ability to maintain a relatively constant blood flow despite changes in perfusion pressure. Although autoregulation is present in many vascular beds, it is particularly well developed in the brain, probably due to the need for a constant blood supply and water homeostasis. In normotensive adults, cerebral blood flow is maintained at approximately 50 ml per 100 grams of brain tissue per minute if the cerebral perfusion pressure is in the range of 60-160 mmHg. Above and below this limit, autoregulation is lost and cerebral blood flow becomes linearly dependent on mean arterial pressure. When cerebral perfusion pressure falls below the lower limit of autoregulation, cerebral ischemia occurs. The decrease in cerebral blood flow is compensated by increased extraction of oxygen from the blood.

[0356] Cerebral autoregulation aims to stabilize blood flow to the brain during perfusion pressure fluctuations, thus protecting the brain from the risk of systemic blood pressure drops and rises. This important mechanism is severely impaired in transgenic mouse models of Alzheimer's disease that produce abundant amyloid beta peptide beta 1-42. Experiments have revealed that total cerebral blood flow is 20% lower in Alzheimer's disease patients compared to age-matched non-demented controls (Roher AE et al Cerebral Blood Flow in Alzheimer's Disease, Vascular Health and Risk Management 2012 Volume 8 pages 599 to 611). The presence of small vessel disease, lacunar cerebral infarctions and strokes may precipitate the development of dementia or worsen the clinical course of Alzheimer's disease, clearly indicating that cerebral blood flow deficiencies are involved in the global pathogenesis of cognitive decline. In elderly individuals, chronic hypoperfusion caused by reduced cardiac output correlates with white matter hyperintensities and abnormal brain aging. In Alzheimer's disease, patients experience reduced systolic and pulse pressure. Reduced blood flow in the brain should ideally be compensated for by increased cardiac output, which would increase systolic blood pressure to maintain adequate cerebral perfusion, but in chronic progressive disease, low blood pressure is altered.

[0357] There may be several causal relationships between cerebrovascular disease and Alzheimer's disease in elderly people. The association of thromboembolic disease and multi-infarct or vascular dementia with Alzheimer's disease is well recognized. The destruction of smooth muscle cells of leptomeningeal and intracerebral arteries in cerebral amyloid angiopathy may not only predispose to intracerebral hemorrhage but also affect cerebral blood flow and autoregulation. Cerebral amyloid angiopathy impedes the evacuation of interstitial fluid and peptides such as soluble amyloid-β from the brain, therefore strategies to promote the drainage of amyloid-β along perivascular routes may be highly beneficial for future therapeutic interventions in patients with Alzheimer's disease. In particular, measures to increase cerebral blood flow in combination with drugs and molecules administered to increase fibrinolysis and amyloid-β solubility are likely to be highly beneficial in the treatment of Alzheimer's disease.

[0358] In cognitively normal older adults, white matter hyperintensities (WMHs) are commonly considered a marker of cerebral small vessel disease (SVD). SVD results from exposure to systemic vascular damaging processes associated with highly prevalent vascular risk factors such as hypertension, high cholesterol, and diabetes. However, cerebral amyloid accumulation is also prevalent in this population and is associated with the development of WMHs. Greater amyloid burden and a history of hypertension have been shown to be independently associated with greater WMH volume.

[0359] Autoregulation may or may not be impaired in patients with significant disease of the cerebral arteries, and furthermore, autoregulatory capacity may be partially or completely lost by Alzheimer's disease, vascular dementia, cerebral multiple small vessel disease or infarction, progressive multiple sclerosis, traumatic brain disease, and vasospastic disease following subarachnoid hemorrhage.

[0360] In minimally conscious subjects, arterial spin labeling has identified globally decreased serum blood flow and selectively decreased serum blood flow in medial prefrontal and midfrontal cortical regions, as well as within gray matter (Liu et al Neurology 2011 Volume 77 No 16 Pages 1518-1523).

[0361] The neurostimulation techniques described herein can be used to enhance and regulate cerebral blood flow to treat conditions associated with impaired autoregulation or reduced cerebral blood flow. In particular, by using one or more physiological parameters of the subject (e.g., cerebral blood flow, intracranial pressure, blood pressure, etc.) as feedback to control the neurostimulation, it may be possible to precisely regulate and control the cerebral blood flow of the subject.

[0362] Conditions in which reduced cerebral blood flow and impaired autoregulation have been reported include resistant hypertension, ischemic stroke, hemorrhagic stroke, traumatic brain injury, vasospasm, subarachnoid hemorrhage, reduced state of consciousness, vascular dementia, Alzheimer's disease, multiple sclerosis, depression, schizophrenia, and migraine with aura.

[0363] Autonomic dysfunction Conditions associated with autonomic dysfunction include alcoholism, amyloidosis, cerebral infarction, diabetes mellitus, Huntington's disease, multiple sclerosis, multiple system atrophy, Parkinson's disease, Alzheimer's disease, toxic neuropathies, and brain tumors.

[0364] In conditions associated with autonomic dysfunction, there is autonomic dysfunction or imbalance, resulting in increased sympathetic activity and decreased parasympathetic activity. With compound neurostimulation of targets in the brain in the proper formulation, deep brain stimulation can reverse this imbalance and restore normal autonomic function, which is essential to enhancing cerebral blood flow, re-establishing circadian rhythms, and treating the condition.

[0365] Circadian rhythm and sleep: Many features of human behavior and its underlying molecular and biochemical processes are driven by circadian rhythms. Disruptions of circadian rhythms are increasingly associated with many clinical conditions, including metabolic syndrome and obesity, premature aging, diabetes, immune deficiency, cardiac arrhythmias, cardiovascular disease, hypertension and cancer. Disruptions of sleep and circadian rhythms are common features of Alzheimer's disease, dementia and other neurodegenerative diseases, as well as schizophrenia, depression and other psychiatric disorders.

[0366] Emerging data suggest that restoration of circadian rhythms, sleep, and chronobiology may prove crucial in treating pathologies. There is ample evidence that sleep function is important for memory consolidation and is increasingly required for effective removal of waste products from the brain via the brain's glymphatic and lymphatic systems, which has important implications for the treatment of Alzheimer's disease, dementia, and other neurodegenerative diseases.

[0367] Brain coherence and synchronization: The "communication through coherence" hypothesis is now widely accepted, and as a consequence, the presence or absence of rhythmic synchrony, respectively, can result in effective or inefficient anatomical communication. It is known that communication between selective brain structures and their oscillatory activity can be violated in neurological disorders (e.g. epilepsy), neurodegenerative disorders (e.g. Alzheimer's disease), and psychiatric disorders (e.g. schizophrenia). Accumulating evidence shows that coupling between the phase of slow oscillations (especially in the theta frequency range 4-12 Hz) and the amplitude of fast oscillations (gamma 30-100 Hz range) is involved in information processing, and disturbances of this theta and gamma rhythmic coherence are found in diseases.

[0368] term The present invention is described in the following sections.

[0369] 1. A method of treatment performed on a subject's brain, the method comprising the step of applying one or more neuromodulatory signals to the lateral habenula and the posterior commissure.

[0370] 2. The method of claim 1, further comprising applying one or more neuromodulation signals to one or more additional targets in the subject's brain.

[0371] 3. The method of paragraph 2, wherein the one or more additional targets include the medial dorsal thalamic nucleus. 4. The method of claim 3, wherein a first neuromodulation signal having a first frequency is applied to the dorsomedial nucleus and one or more second neuromodulation signals are applied to the lateral habenular nucleus and the posterior commissure, each of the one or more second neuromodulation signals having a frequency lower than the first frequency.

[0372] 5. The method of claim 4, wherein the first frequency is greater than 70 Hz and each of the one or more second neuromodulation signals has a frequency between 4 and 50 Hz.

[0373] 6. The method of any one of paragraphs 2 to 5, wherein the one or more additional targets include the ventrolateral periaqueductal gray matter (VL-PAG).

[0374] 7. The method of claim 6, dependent on claim 4 or 5, wherein one or more second neuromodulatory signals are applied to the lateral habenula, the posterior commissure, and the VL-PAG.

[0375] 8. Identifying trajectories in the subject's brain, identifying a trajectory that connects the VL-PAG with the dorsomedial nucleus over the lateral habenula and posterior commissure; Implanting an electrode lead into the subject's brain along the identified trajectory, the electrode lead including a plurality of electrodes for applying one or more neuromodulation signals; Item 11. The method of any one of the preceding items, further comprising:

[0376] 9. The method of claim 8, wherein the trajectory is such that the distance between the electrode lead and the lateral habenula is less than 5 mm and / or the distance between the electrode lead and the posterior commissure is less than 5 mm.

[0377] 10. The method of any one of the preceding clauses, further comprising applying a neuromodulation signal to the dorsal anterior cingulate cortex and / or the corpus callosum.

[0378] 11. The method of claim 10, dependent on claim 8 or 9, wherein the trajectory further passes adjacent to the dorsal anterior cingulate cortex and the electrode lead includes an electrode configured to apply a neuromodulation signal to the dorsal anterior cingulate cortex, and / or the trajectory further passes adjacent to the corpus callosum and the electrode lead includes an electrode configured to apply a neuromodulation signal to the corpus callosum.

[0379] 12. The method of claim 10, which is dependent on claim 8 or 9, further comprising the step of implanting a second electrode lead into the subject's brain, the second electrode lead comprising an electrode configured to apply a neuromodulation signal to the dorsal anterior cingulate cortex and / or the corpus callosum.

[0380] 13. The method of any one of the preceding clauses, further comprising detecting a physiological parameter of the subject and adjusting at least one of the one or more neuromodulation signals based on the detected physiological parameter.

[0381] 14. The method of any one of the preceding clauses, further comprising adjusting at least one of the one or more neuromodulatory signals based on the subject's circadian rhythm.

[0382] 15. The method of any one of the preceding claims, further comprising the step of applying a stimulation signal to the subject's carotid body and / or carotid baroreceptors.

[0383] 16. The method of any one of the preceding clauses, wherein the method is for treating one or more of hypertension, traumatic brain injury, cerebral vasospasm, cerebral infarction, brain tumor, brain glioma, Parkinson's disease, Alzheimer's disease, vascular dementia, amyotrophic lateral sclerosis, Huntington's disease, multiple system atrophy, multiple sclerosis, addiction, depression, schizophrenia, obesity, renal failure, epilepsy and attention deficit hyperactivity disorder.

[0384] 17. An apparatus for administering therapy to a subject's brain, comprising: an electrode lead configured for insertion into the subject's brain, a distal portion of the electrode lead having a plurality of electrodes configured to apply one or more neuromodulation signals to the lateral habenula and posterior commissure of the subject's brain; a controller configured to generate one or more neuromodulation signals applied by the plurality of electrodes; An apparatus comprising:

[0385] 18. The device of clause 17, wherein the multiple electrodes are further configured to apply one or more neuromodulation signals to one or more additional targets in the subject's brain.

[0386] 19. The device of paragraph 18, wherein the one or more additional targets include the dorsomedial thalamic nucleus. 20. The device of paragraph 18 or 19, wherein the one or more additional targets include VL-PAG.

[0387] 21. The device of any one of paragraphs 17 to 20, wherein a plurality of electrodes are equally spaced longitudinally along the length of the distal portion of the electrode lead.

[0388] 22. The device described in item 21, wherein the multiple electrodes span a length of 20 to 25 mm. 23. The device of any one of paragraphs 17 to 22, further comprising a proximal electrode configured to apply a neuromodulatory signal to the dorsal anterior cingulate cortex and / or corpus callosum.

[0389] 24. The device described in paragraph 23, wherein the proximal electrode comprises a proximal electrode disposed on an electrode lead.

[0390] 25. The device described in item 24, wherein the length of the proximal electrode disposed on the electrode lead is longer than the length of each of the multiple electrodes.

[0391] 26. The device described in item 25, wherein the length of the proximal electrode placed on the electrode lead is 10 to 30 mm.

[0392] 27. The device of any one of claims 17 to 26, further comprising a guide tube for insertion into the subject's brain, the guide tube comprising a hollow tube defining a longitudinal channel capable of receiving an electrode lead.

[0393] 28. The device described in clause 27, which is dependent on any one of clauses 24 to 26, wherein the guide tube includes a window formed in a side wall of the hollow tube, the window being configured to expose a proximal electrode disposed on the electrode lead to the outside of the hollow tube when the electrode lead is received within the longitudinal channel of the hollow tube.

[0394] 29. The device described in paragraph 28, wherein the length of the window is shorter than the length of the proximal electrode disposed in the electrode lead.

[0395] 30. The device of claim 28 or 29, wherein the guide tube includes a marker to indicate the direction in which the window is facing.

[0396] 31. The device of any one of paragraphs 28 to 30, wherein the window comprises two or more openings in a side wall of the hollow tube.

[0397] 32. The device described in clause 27, which is dependent on any one of clauses 24 to 26, wherein the proximal electrode includes an outer electrode on an outer surface of the hollow tube, the outer electrode being configured for electrical connection to the proximal electrode disposed on the electrode lead when the electrode lead is received in the longitudinal channel of the hollow tube.

[0398] 33. A device according to claim 27, which is dependent on claim 23, wherein the proximal electrode includes an outer electrode on an outer surface of the hollow tube, the outer electrode being electrically connected to the controller via a connecting lead extending through the hollow tube.

[0399] 34. The device described in any one of claims 27 to 33, wherein the guide tube further comprises a cap that can be fixed to a hole in the subject's skull, the cap including a passage through which the hollow tube can be inserted for inserting the hollow tube into the subject's brain.

[0400] 35. The device of claim 34, further comprising a first limiter secured to a proximal portion of the hollow tube, the first limiter configured to abut the cap when a predetermined length of the hollow tube is inserted through the passage.

[0401] 36. The device described in any one of paragraphs 27 to 35, further comprising a second limiter, the second limiter being fixed to a proximal portion of the electrode lead and configured to abut the proximal end of the guide tube when a predetermined length of the electrode lead protrudes from the distal opening of the hollow tube.

[0402] 37. An apparatus described in any one of clauses 17 to 36, further comprising a sensor configured to detect a physiological parameter of the subject and generate an output signal related to the detected physiological parameter, and the controller is configured to adjust at least one of the one or more neuromodulation signals based on the output signal from the sensor.

[0403] 38. The device of any one of clauses 17 to 37, further comprising an external power source, the external power source including a transmitter for wirelessly transmitting power to the controller.

[0404] 39. The device of clause 38, further comprising a wearable cap configured to hold the transmitter in proximity to the controller.

[0405] 40. The device of any one of clauses 17 to 39, further comprising one or more stimulation electrodes for applying one or more stimulation signals to the subject's carotid body and / or carotid baroreceptors.

[0406] 41. The apparatus of claim 40, wherein the controller is further configured to generate a stimulation signal.

[0407] 42. A guide tube for insertion into a subject's brain, the guide tube comprising a hollow tube defining a longitudinal channel capable of receiving an electrode lead; The guide tube includes a window formed in a side wall of the hollow tube, the window being configured to expose a proximal electrode on the electrode lead to an outside of the hollow tube when the electrode lead is received in the longitudinal channel of the hollow tube.

[0408] 43. The guide tube according to claim 42, wherein the guide tube includes a marker to indicate the direction in which the window is facing.

[0409] 44. The guide tube according to paragraph 42 or 43, wherein the window comprises two or more openings in a side wall of the hollow tube.

[0410] 45. A guide tube for insertion into a subject's brain, the guide tube including a hollow tube defining a longitudinal channel capable of receiving an electrode lead; The guide tube includes an outer electrode on an exterior surface of the hollow tube.

[0411] 46. ​​The guide tube of claim 45, further comprising a connecting lead extending through the hollow tube for connecting the outer electrode to a controller.

[0412] 47. The guide tube of claim 45, wherein the outer electrode is configured for electrical connection to a proximal electrode on the electrode lead when the electrode lead is received within the longitudinal channel of the hollow tube.

[0413] 48. A guide tube described in any one of items 42 to 47, further comprising a cap that can be fixed to a hole in the subject's skull, the cap including a passage through which the hollow tube can be inserted to insert the hollow tube into the subject's brain.

[0414] 49. The guide tube of paragraph 48, further comprising a first limiter secured to a proximal portion of the hollow tube, the first limiter configured to abut the cap when a predetermined length of the hollow tube is inserted through the passage.

[0415] 50. A method of treatment administered to a subject, comprising: applying one or more neuromodulation signals to one or more targets in the subject's brain; applying a stimulation signal to the carotid body and / or carotid baroreceptors of the subject; A method comprising:

[0416] 51. An apparatus for applying one or more neuromodulation signals to one or more targets in a subject's brain; a stimulation electrode for applying a stimulation signal to the carotid body and / or carotid baroreceptors of the subject; A system comprising:

Claims

1. 1. An apparatus for administering therapy to a brain of a subject, comprising: an electrode lead configured for insertion into the brain of the subject, a distal portion of the electrode lead having a plurality of electrodes configured to apply one or more neuromodulation signals to the lateral habenula and posterior commissure of the brain of the subject; a controller configured to generate the one or more neuromodulation signals applied by the plurality of electrodes; a proximal electrode disposed on the electrode lead; Equipped with the apparatus further comprising a guide tube for insertion into the subject's brain, the guide tube including a hollow tube defining a longitudinal channel capable of receiving the electrode lead; The guide tube includes a window formed in a side wall of the hollow tube, the window configured to expose the proximal electrode disposed on the electrode lead to the outside of the hollow tube when the electrode lead is received within the longitudinal channel of the hollow tube.

2. The device of claim 1 , wherein the length of the window is less than the length of the proximal electrode disposed on the electrode lead.

3. The apparatus of claim 1 or 2, wherein the guide tube includes a marker to indicate the direction in which the window faces.

4. The apparatus of any one of claims 1 to 3, wherein the window comprises two or more openings in the side wall of the hollow tube.

5. An apparatus for administering therapy to a subject's brain, comprising: an electrode lead configured for insertion into the subject's brain, a distal portion of the electrode lead having a plurality of electrodes configured to apply one or more neuromodulatory signals to the lateral habenula and posterior commissure of the subject's brain; a controller configured to generate the one or more neuromodulation signals applied by the plurality of electrodes; a proximal electrode disposed on the electrode lead; Equipped with the apparatus further comprising a guide tube for insertion into the subject's brain, the guide tube including a hollow tube defining a longitudinal channel capable of receiving the electrode lead; the proximal electrode includes an outer electrode on an exterior surface of the hollow tube, the outer electrode configured for electrical connection to the proximal electrode disposed on the electrode lead when the electrode lead is received in the longitudinal channel of the hollow tube.

6. An apparatus for administering therapy to a subject's brain, comprising: an electrode lead configured for insertion into the subject's brain, a distal portion of the electrode lead having a plurality of electrodes configured to apply one or more neuromodulatory signals to the lateral habenula and posterior commissure of the subject's brain; and a controller configured to generate the one or more neuromodulation signals applied by the plurality of electrodes; a proximal electrode disposed on the electrode lead; Equipped with the apparatus further comprising a guide tube for insertion into the subject's brain, the guide tube including a hollow tube defining a longitudinal channel capable of receiving the electrode lead; The device, wherein the proximal electrode includes an outer electrode on an exterior surface of the hollow tube, the outer electrode being electrically connected to the controller via a connecting lead extending through the hollow tube.

7. An apparatus as described in any one of claims 1 to 6, wherein the proximal electrode is configured to apply a neuromodulatory signal to the dorsal anterior cingulate cortex and / or corpus callosum.

8. The device according to any one of claims 1 to 7, wherein the length of the proximal electrode disposed on the electrode lead is greater than the length of each of the plurality of electrodes.

9. The device of claim 8, wherein the length of the proximal electrode disposed on the electrode lead is between 10 and 30 mm.

10. An apparatus for administering therapy to a subject's brain, comprising: an electrode lead configured for insertion into the subject's brain, a distal portion of the electrode lead having a plurality of electrodes configured to apply one or more neuromodulatory signals to the lateral habenula and posterior commissure of the subject's brain; a controller configured to generate the one or more neuromodulation signals applied by the plurality of electrodes; Equipped with the apparatus further comprising a guide tube for insertion into the subject's brain, the guide tube including a hollow tube defining a longitudinal channel capable of receiving the electrode lead; the guide tube further comprises a cap securable to a hole in the skull of the subject, the cap including a passageway through which the hollow tube can be inserted for inserting the hollow tube into the brain of the subject; The device further comprises a first limiter secured to a proximal portion of the hollow tube, the first limiter configured to abut the cap when a predetermined length of the hollow tube is inserted through the passage.

11. 11. The device of claim 10, further comprising a second limiter secured to a proximal portion of the electrode lead and configured to abut a proximal end of the guide tube when a predetermined length of the electrode lead protrudes from a distal opening of the hollow tube.

12. The device described in claim 10 or 11, further comprising a proximal electrode configured to apply a neuromodulatory signal to the dorsal anterior cingulate cortex and / or corpus callosum.

13. The device described in claim 12, wherein the proximal electrode includes a proximal electrode disposed on the electrode lead.

14. The device described in claim 13, wherein the length of the proximal electrode disposed on the electrode lead wire is longer than the length of each of the multiple electrodes.

15. The device of claim 14, wherein the length of the proximal electrode disposed on the electrode lead is between 10 and 30 mm.

16. The apparatus of any one of claims 1 to 15, wherein the plurality of electrodes is further configured to apply one or more neuromodulation signals to one or more additional targets in the subject's brain.

17. 17. The apparatus of claim 16, wherein the one or more additional targets include the medial dorsal thalamic nucleus.

18. The device of claim 16 or 17, wherein the one or more additional targets comprises a VL-PAG.

19. The device of any preceding claim, wherein the plurality of electrodes are equally spaced longitudinally along the length of the distal portion of the electrode lead.

20. 20. The device of claim 19, wherein the plurality of electrodes spans a length of 20-25 mm.

21. 21. The apparatus of any one of claims 1 to 20, further comprising a sensor configured to detect a physiological parameter of the subject and generate an output signal related to the detected physiological parameter, wherein the controller is configured to adjust at least one of the one or more neuromodulation signals based on the output signal from the sensor.

22. 22. The apparatus of any preceding claim, further comprising an external power source, the external power source including a transmitter for wirelessly transmitting power to the controller.

23. 23. The apparatus of claim 22, further comprising a wearable cap configured to hold the transmitter in proximity to the controller.

24. 24. Apparatus according to any one of claims 1 to 23, further comprising one or more stimulation electrodes for applying one or more stimulation signals to the carotid body and / or carotid baroreceptors of the subject.

25. The apparatus of claim 24 , wherein the controller is further configured to generate the stimulation signal.

26. A guide tube for insertion into a subject's brain, the guide tube comprising a hollow tube defining a longitudinal channel capable of receiving an electrode lead; The guide tube includes a window formed in a side wall of the hollow tube, the window being configured to expose a proximal electrode on the electrode lead to the outside of the hollow tube when the electrode lead is received in the longitudinal channel of the hollow tube.

27. 27. The guide tube of claim 26, wherein the guide tube includes a marker to indicate the direction in which the window faces.

28. 28. The guide tube of claim 26 or 27, wherein the window comprises two or more openings in the side wall of the hollow tube.

29. A guide tube for insertion into a subject's brain, the guide tube including a hollow tube defining a longitudinal channel capable of receiving an electrode lead; The guide tube includes an outer electrode on an exterior surface of the hollow tube.

30. 30. The guide tube of claim 29, further comprising a connecting lead extending through the hollow tube for connecting the outer electrode to a controller.

31. The guide tube of claim 30 , wherein the outer electrode is configured for electrical connection to a proximal electrode on the electrode lead when the electrode lead is received within the longitudinal channel of the hollow tube.

32. A guide tube as described in any one of claims 26 to 31, further comprising a cap that can be fixed to a hole in the subject's skull, the cap including a passage through which the hollow tube can be inserted for inserting the hollow tube into the subject's brain.

33. 33. The guide tube of claim 32, further comprising a first limiter secured to a proximal portion of the hollow tube, the first limiter configured to abut the cap when a predetermined length of the hollow tube is inserted through the passage.

34. Apparatus according to any one of claims 1 to 25 for applying one or more neuromodulation signals to one or more targets in the brain of a subject; a stimulation electrode for applying a stimulation signal to the carotid body and / or carotid baroreceptors of the subject; A system comprising:

Images