Carotid sinus nerve stimulation to treat mental health disorders

Abstract

Disclosed are methods and apparatuses for treating mental health disorders through electrical stimulation of the carotid sinus nerve (CSN). The systems may include implantable or wearable stimulating electrode arrays configured to preferentially activate baro-afferent fibers of the CSN while minimizing stimulation of chemo-afferent fibers. The stimulation may be delivered in open-loop, closed-loop, or semi-closed-loop modes, with feedback provided by sensors monitoring physiological parameters such as heart rate, blood pressure, respiratory rate, and biochemical markers. The apparatus may include a controller that maps electrode contacts to specific nerve fiber types and dynamically adjusts stimulation parameters to optimize therapeutic outcomes. These systems and methods are designed to address autonomic imbalances associated with neuropsychiatric conditions including depression, anxiety, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD), particularly in patients refractory to conventional therapies.

Description

CAROTID SINUS NERVE STIMULATION TO TREAT MENTAL HEALTH DISORDERSCLAIM OF PRIORITY

[0001] This patent application claims priority to U.S. provisional patent application no. 63 / 678,317, filed on August 1, 2024, titled “CAROTID SINUS NERVE STIMULATION TO TREAT MENTAL HEALTH DISORDERS” and herein incorporated by reference in its entirety.BACKGROUND

[0002] Several mental health disorders are associated with autonomic nervous system imbalances that can include sympathetic overactivation and possibly a relative decrease in parasympathetic activity. These conditions include depression, anxiety, post-traumatic stress disorder and obsessive-compulsive disorders among others. Typically, these conditions are treated with medications and, in rare cases, more invasive modalities but, in a proportion of these patients, the currently available therapeutics do not achieve effective or durable control of symptoms. These patients are then deemed to be resistant or refractory to conventional therapy who are left with no good options. There is a pressing need for treatments, including methods and treatment apparatuses, that may treat mental health disorders, particularly (though not exclusively) in patients that are refractory for conventional therapies. The methods and apparatuses described herein may address this need.SUMMARY OF THE DISCLOSURE

[0003] Described herein are methods and apparatuses (e.g., devices, systems, etc.) for treating a mental health disorder such as, but not limited to, , anxiety, depression (including post- traumatic stress disorder, PTSD), obsessive compulsive disorders (OCD) and / or other mental health disorders. These methods and apparatuses may be configured as closed loop systems or semi-closed loop systems, any of these apparatuses and methods may include carotid sinus nerve stimulation to address autonomic nervous system imbalances that contribute to underlying pathophysiology. These methods and apparatuses may link the carotid sinus nerve (CSN) with internally implanted, wearable and / or external sensors providing feedback to the stimulation system to prevent over-treatment and enhance safety.

[0004] In particular, these methods and apparatuses may selectively apply stimulation within an effective range of energy (e.g., current, voltage, charge over time) to differentially stimulate afferent nerve fibers that carry sensory information from baroreceptors to the central nervous system (baro-afferent fibers) preferentially compared to chemo-afferent fibers. Chemo-afferentfibers typically carry signals related to blood gas and pH levels from chemoreceptors, while baro-afferent fibers carry signals related to blood pressure from baroreceptors.

[0005] In some examples these methods and apparatuses may apply electrical stimulation to the CSN after it has branched in a manner that differentially stimulates fibers traveling either to the carotid body or sinus. This enables preferential stimulation (and selection) of either the baro- afferent or chemo-afferent fibers to achieve effects that treat or ameliorate the manifestations of mental health disorders as described herein. Any of these apparatuses and methods may include one or more sensing leads within the body to provide feedback, such as (but not limited) to sensing on the external carotid artery (ECA) and / or internal carotid artery (ICA).

[0006] Any appropriate sensing lead may be used. For example, a sensing lead on the ECA may be configured as a flexible pressure sensor (see, e.g., the sensing leads described in US 2024 / 0023821, herein incorporated by reference in its entirety) and / or other biometric sensors that may be used to produce feedback data that allows use of a control algorithm to enable closed loop (autonomous) control of CSN stimulation for treatment of mental health disorders.

[0007] In any of the methods and apparatuses described herein, the treatment (open loop, closed loop or semi-closed loop treatment) may apply treatment by stimulation of the carotid sinus nerve (CSN). The carotid sinus nerve contains fibers that interface in the brainstem with the autonomic nervous system and some of those fibers suppress sympathetic activation and activate the parasympathetic system. As described herein, by stimulating particular fibers within the carotid sinus nerve (which include but are not limited to the baro-afferent fibers) the autonomic imbalances associated with depression, anxiety, PTSD, OCD and other mental health conditions can be improved, ameliorated or eliminated leading to more effective abatement of the symptoms of these disorders and offer the potential for a durable cure or control of the disease. The stimulation systems and methods described herein may include hardware, firmware and / or software (including stimulation settings and software controls) for treatment specific to mental health disorders. In addition, any of the apparatuses and methods described herein may include a feedback mechanism to prevent overtreatment or overstimulation of the carotid sinus nerve.

[0008] Any appropriate stimulating electrode may be used. In any of these methods and apparatuses the stimulation electrode(s) may include an array of electrodes; for example, the stimulating electrodes may include multi-contact micro-electrode array electrodes. Any appropriate array may be used.

[0009] For example, described herein are methods of treating a mental health disorder by applying electrical stimulation to a carotid sinus nerve (CSN), and in particular any of these methods may apply electrical stimulation preferentially to the baro-afferent fibers of the CSNand not chemo-afferent fibers. In some cases “preferential stimulation of baro-afferent fibers in the CSN as compared to chemo-afferent fibers in the CSN” may refer to X % or less chemo- afferent fibers, so that X % or less of the stimulated fibers are chemo-afferent fibers (e.g., 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, 3% or less, 2% or less, 1% or less, etc.). Generally speaking, in humans, baro-afferent fibers are generally considered to be more prevalent in the CSN than chemo-afferent fibers in adult humans. Thus, the methods and apparatuses described herein are configured to selectively apply electrical stimulation to baro-afferent fibers. In any of these methods and apparatuses, electrical stimulation applied to the CSN may be applied to baro-afferent fiber, while substantially excluding chemo-afferent fibers.

[0010] Stimulation applied to the CSN may be applied, for example, to the region of the CSN on the internal carotid artery (ICN) after it begins branching, e.g., placing the array of stimulating electrodes on the CSN after it has branched. The stimulating electrodes may be placed, e.g., over the branches formed by the CSN over the carotid sinus (e.g., including or just proximal to the terminal ramifications of the CSN that innervate the carotid sinus and the carotid body. Given the complex, and variable, distribution of baro-afferent and chemo-afferent fibers within the CSN, any of these methods and apparatuses may include feedback to determine which electrodes are primarily stimulate baro-afferent and which primarily stimulate chemo-afferent fibers and the controller may then drive stimulation of those primarily stimulating baro-afferent fibers using the stimulation parameters specific to treating a neuropsychiatric disorder (such as anxiety, depression, etc.).

[0011] In any of these methods and apparatuses, electrical stimulation applied to the CSN may be applied to baro-afferent fiber, while substantially excluding chemo-afferent fibers.

[0012] The stimulation parameters may be selected to preferentially stimulated baro-afferent fibers and provoke the desired therapeutic effect (e.g., a feeling of well-being, reduction in anxiety, reduction in depression, etc.). For example, the electrical stimulation may be applied at a frequency of between about 10-125Hz, a pulse width of between about 25-500 microseconds, and an amplitude of between about 0.25-15.0 mA. The electrical stimulation can be continuous or intermittently applied. In some cases the energy may be applied at a duty cycle of about 1- 90% (e.g., between 1-50%, 1-40%, 1-35%, 1-30%, 40-90%, 50-90%, 55-90%, 60-90%, 65-90%, 70-90%, 20-70%, 25-75%, 30-60%, etc.).

[0013] Any of these methods and apparatuses may include feedback to modify the applied stimulation. For example, feedback may include one or more sensors (or array of sensors) on a nerve, such as (but not limited to) the external carotid artery (ECA), and / or the internal carotid artery, such as the same region of the internal carotid artery (ICA) as the stimulation array(electrodes) or another region of the ICA. For example, applying electrical stimulation may comprise applying stimulation based on feedback from one or more biomarkers associated with a mental health disorder. Feedback may include detection of electrical activity, pulse, heart rate, respiratory rate, blood oxygenation, blood pressure, etc.

[0014] Any appropriate stimulation electrodes may be used, including one or more arrays of stimulation electrodes. The array of stimulation electrodes may be arranged in any appropriate pattern, such as a grid, line / row, ring, plurality of rings, etc. The electrodes in the array of electrodes may be configured to have a relatively large surface area (contact area) compared to the overall dimensions (e.g., span, such as edge-to-edge distance) of each electrode. In some cases the electrodes may include an enlarged surface area with relatively small span by including a texture and / or three-dimensional structure. Such larger surface-area electrodes may therefore provide enhanced contact with the nerve fibers. The span of each electrode may be, for example, between about 4 mm2and 0.2 mm2. For example, the span of the stimulation electrodes forming part of the apparatus may be approximately 1 mm2, while the surface (contact) area may be greater than 1 mm2, because the surface peaks and valleys on the electrode that may make contact with the underlying tissue.

[0015] As mentioned, any of these apparatuses and methods may be configured to treat a mental health disorder such as a mental health disorder selected from the group of: depression, anxiety, post-traumatic stress disorder and / or obsessive-compulsive disorders.

[0016] For example, described herein are methods of treating a mental health disorder, the method comprising: applying electrical stimulation to a carotid sinus nerve (CSN) of a patient; wherein the electrical stimulation is configured to preferentially stimulate baro-afferent fibers as compared to chemo-afferent fibers. The mental health disorder is one or more of: depression, anxiety, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD). Applying electrical stimulation may comprise applying electrical stimulation at a frequency between 10-125 Hz, a pulse width between 25-500 microseconds, and an amplitude between 0.25-15 mA. Applying electrical stimulation may comprise applying electrical stimulation to a subset of an array of electrodes on the CSN that map to baro-afferent fibers as compared to chemo-afferent fibers.

[0017] Any of these methods may include mapping the electrode array to identify electrodes that stimulate baro-afferent fibers; storing the mapping in a controller; and applying stimulation only through electrodes identified as stimulating baro-afferent fibers.

[0018] Any of these methods may include repeating the application of electrical stimulation to the CSN on a pre-programmed schedule and / or repeating the application of electrical stimulation to the CSN as part of a closed-loop protocol based on detection of a marker for themental health disorder. The stimulation may be titrated based on feedback from one or more implanted or wearable sensors. The stimulation may be applied intermittently at a duty cycle between about 1% and 90%.

[0019] Also described herein are apparatus for treating a mental health disorder (e.g., for performing any of these methods). For example, the apparatus may include: a stimulating electrode array configured to be implanted to stimulate fibers of a carotid sinus nerve (CSN); a pulse generator operatively coupled to the electrode array and configured to apply electrical stimulation to the CSN; a controller coupled to or integrated with the pulse generator, wherein the controller comprises control logic configured to selectively activate electrodes that stimulate baro-afferent fibers of the CSN while minimizing stimulation of chemo-afferent fibers by applying electrical stimulation to a subset of electrodes of the stimulation electrode array that are in communication with primarily baro-afferent fibers as determined by a mapping maintained by the controller. The electrode array may comprise a multi-contact micro-electrode array. The controller may be configured to operate in an open-loop, closed-loop, or semi-closed-loop mode. The apparatus may include one or more sensors providing input to the controller for closed-loop or semi-closed-loop operation, wherein the one or more sensors are selected from the group of: pressure sensors, heart rate monitors, respiratory rate sensors, blood oxygenation sensors, and biochemical sensors for detecting catecholamines. The controller may include a machine learning model trained to detect neuropsychiatric events based on sensor input. The stimulating electrode array may include a multi-contact micro-electrode array configured to be surgically implanted adjacent to the carotid sinus nerve. The mapping maintained by the controller may be generated by applying stimulation to individual electrodes and detecting a baroreflex response. The controller may be configured to update the mapping dynamically based on feedback from one or more sensors.

[0020] Any of these apparatuses may include one or more sensors configured to detect physiological parameters selected from the group consisting of heart rate, blood pressure, respiratory rate, and heart rate variability.

[0021] The electrical stimulation may be applied at a frequency between 10 Hz and 125 Hz, a pulse width between 25 microseconds and 500 microseconds, and an amplitude between 0.25 mA and 15 mA.

[0022] The controller may be configured to selectively inhibit chemo-afferent fibers using high-frequency blocking stimulation.

[0023] Also described herein are closed-loop neuromodulation system, the system comprising: a stimulating electrode array configured to be positioned on or near the carotid sinus nerve (CSN); one or more sensors configured to detect physiological parameters associated withautonomic nervous system activity; a controller configured to: receive input from the one or more sensors; and apply electrical stimulation to the CSN in response to detection of a neuropsychiatric event and / or based on a stimulation schedule.

[0024] All of the methods and apparatuses described herein, in any combination, are herein contemplated and can be used to achieve the benefits as described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0025] A better understanding of the features and advantages of the methods and apparatuses described herein will be obtained by reference to the following detailed description that sets forth illustrative embodiments, and the accompanying drawings of which:

[0026] FIG. 1 shows a first schematic representation of an apparatus described herein, shown implanted into a patient. In FIG. 1, the stimulating electrode(s) is / are on and / or around the CSN adjacent to the internal carotid artery.

[0027] FIG. 2 shows a schematic representation of an apparatus described herein; in this example, the apparatus includes a sensing input, e.g., shown as a sensing lead wrapped around the external carotid artery; this sensing lead in this example is configured to take hemodynamic measurements in real time and the apparatus may use them as feedback for modulating carotid sinus nerve stimulation to treat a neuropsychiatric disorder, such as depression, anxiety, etc.

[0028] FIG. 3 graphically illustrates examples of direct carotid sinus nerve stimulation (in a porcine model) as recorded by both an implanted hemodynamic sensor (bottom) and direct arterial pressure measurements (top) for reference.

[0029] FIG. 4 shows examples of metrics that can be measured from an implanted sensor (e.g., implanted hemodynamic sensor in a porcine model) and used as feedback to control operation of the apparatuses described herein. The top figure shows unfiltered pulse wave representing the cardiac cycle. The second panel is extracted heart rate, the third shows blood pressure and the lowest panel shows respiratory rate.

[0030] FIG. 5 shows an example of a method of performing an apparatus as described herein.DETAILED DESCRIPTION

[0031] The methods and apparatuses described herein may be used to treat neuropsychiatric disorders. These methods may include the use of an electrode, or more preferably an array of electrodes for applying electrical stimulation to the carotid sinus nerve (CSN). In some examples the methods and apparatuses described herein may be configured to preferentially stimulate baro- aff erent fibers. Patient’s may be treated with stimulation parameters and treatment regimes in apredetermined and / or customized or customizable manner to allows for anatomical and physiological customization of stimulus energy. In general, these methods and apparatus may include an electrode array that is driven by a pulse generator. The electrode array may be separate from the pulse generator or integrated with it. The electrode array is configured to be placed in electrical communication with the carotid sinus nerve and a controller, including one or more processors, may drive the application of the electrical energy at the appropriate stimulation parameters and treatment regimen. Furthermore, the controller may determine and / or maintain a subset of the electrodes, which may be customized to the patient initially and / or in an ongoing manner, to apply energy to activate primarily baro-afferent fibers of the CSN. For example, the controller may be configured for automatic, manual, or semi-automatic mapping of the electrodes in the electrode array to determine which electrodes will result in primarily baro- afferent stimulation. The resulting mapping may be dynamic (e.g., may be updated manually, automatically or semi-automatically) and may be used for the application of treatment to the patient, so that only those electrodes that result in primarily or exclusively baro-afferent stimulation may be used.

[0032] In general, these apparatuses may be surgically implanted. A surgical approach may be used both to implant the electrode (e.g., electrode array) and to at least initially program (e.g., determine electrode mapping) the apparatus specific to a patient. In general, the methods described herein, including the specific electrode configuration, may enable discreet target fiber stimulation with specific effects as applies to mental health.

[0033] Implantable pulse generator (IPG) which supplies power and houses the software with a control algorithm to maintain treatment within defined physician-controlled parameters. It can be controlled remotely.

[0034] For example, FIGS. 1 and 2 illustrate different examples of apparatuses implanted for use as described herein. In FIG. 1, the apparatus 100 includes a pulse generator 101, connected via a lead 103 to a stimulating electrode array 105. In this example the electrode array is separated from the pulse generator (implantable pulse generator, IPG) by the lead 103. Examples of stimulation leads are provided herein; in general, these leads may be arrays of electrodes that may be separately addressable so that only a subset of the electrodes forming the array may be activated to treat the patient. The treatment may be applied through all of the electrodes that are mapped to stimulate primarily baro-afferent fibers.

[0035] In FIG. 2, the apparatus also includes a sensor (e.g., sensing lead 211) configured to sense one or more properties of the patient, and preferably one or more properties related to sympathetic and / or parasympathetic activity. In some cases the sensor is one or more sensing lead. In FIG. 2 the sensing lead 211 is shown positioned on the external carotid artery (ECA); thesensing lead may be, for example, a flexible pressure sensor (see, e.g., US20240023821, herein incorporated by reference in its entirety). In some cases a different or additional biometric sensor can be used to produce feedback data that allows use of a control algorithm to enable closed loop (e.g., autonomous) control of CSN stimulation for treatment of mental health disorders as described herein.

[0036] In any of these methods and apparatuses, contact mapping may be used to identify which contacts are interfacing with baro-afferent (or other) fibers. In some cases this may be done intra-operatively (e.g., manually, automatically, or semis-automatically), by applying stimulation to one or more (e.g., a subset of) electrodes of the electrode array 105 and identifying when a baro-afferent response, such as the baro-afferent reflex, is triggered. For example, the system may track blood pressure (BP) and / or heart rate (HR) responses that fall synchronously with each other when the baro-afferent reflex is elicited by application of energy to one or more of the electrodes in the electrode array 105. In this manner the system may derive a patientspecific ‘map’ of the which electrodes correspond primarily to the baro-afferent fibers and may store this map for use during future and / or ongoing treatments as described herein. This map may be held and / or maintained by the controller, which may then use it to determine which electrodes to use for treatment. These electrode may be multiplexed within the controller for driving electrical stimulation.

[0037] Similarly or simultaneously, the controller may be used to determine stimulation parameters (e.g., amplitude, pulse length, pulse width, total charge over time, etc.) to be delivered. For example, stimulation parameters may be determined based on response in awake titration sessions. These stimulation parameters may be calibrated to the user, can be continuous or intermittent and / or may fall in the following ranges, or sub-ranges thereof. For example, the frequency of applied energy may be between about: 10-125Hz range (e.g., 20-50 Hz, 20-75 Hz, 20-100Hz, 30-125 Hz, 40-125 Hz, 50-125 Hz, 60-125Hz, 75-125 Hz, 50-100 Hz, etc.). The amplitude may be between about: 0.25-15mA (e.g., 0.25-10 mA, 025-8 mA, 0.25-7 mA, 0.25-6 mA, 0.25-5 mA, 0.25-4 mA, 1-12.5 mA, 2-12.5 mA, 3-12.5 mA, 5-12.5 mA, 4-12.5 mA, 1-10 mA, 2-9 mA, 9-15mA etc.). The pulse width may be between about 25-500 microseconds (e.g., 25-450 ps, 25-400 ps, 25-300 ps, 25-250 ps, 50-200 ps, 25-150 ps, 25-100 ps, 50-500 ps, 50- 450 ps, 50-400 ps, 100-500 ps, 200-500 ps, 250-500 ps, 300-500 ps, 350-500 ps, 400-500 ps, 100-400 ps, 150-350 ps, etc.).

[0038] If not continuous, frequency of stimulation and duty cycle (ratio of ‘stim on’ to ‘stim off’ which could cover a broad range from 1% to >90%) may be titrated over time and will be based both on validated mental health rating instruments as well as biometric feedback.

[0039] As mentioned, in general, these methods and apparatuses may include an implanted sensor for measuring an indicator of sympathetic and / or parasympathetic response. The sensor may input data into the controller (e.g., in FIGS. 1 and 2, the pulse generator 101). For example, the sensor may be a sensor that detect blood pressure and heart rate that inputs directly to the IPG. Any of these apparatuses may include one or more other implanted, external, and / or associated sensors (e.g., biometric sensors) that can measure biomarkers associated both with a mental health disorder and / or increased sympathetic activity. This sensor input may provide biomarkers that may be used as feedback both during normal operation and / or during programming of the apparatus. For example, when incorporated as a feedback mechanism (e.g., by transmitting a signal to the pulse generator / controller) the level (or intensity) of these markers (“biomarker levels”) may inform the stimulation paradigm as well as the degree and frequency of stimulation.

[0040] In some cases the biomarkers may include one or more of: cortisol levels, catecholamines (e.g., epinephrine / adrenaline, norepinephrine / noradrenaline, dopamine, etc.) and catecholamine derivatives, chromogranin and other markers of sympathetic activity which may be measured via internal or blood sampling sensors. In some cases the biomarker may include one or more salivary marker (e.g., salivary alpha- amylase and / or chromogranin) which may be measured with a saliva sampling sensor. In some cases the marker / biomarker may be a galvanic skin response which may be part of a wearable device that transmits a signal to the controller (e.g., within the implantable pulse generator).

[0041] Any of the apparatuses described herein may include an external programmer and / or controller (which may be separate or combined) for remote control to remotely program the IPG and / or titrate therapy. The remote (e.g., external) programmer and / or controller may be dedicated device or may be software / firmware / adapted hardware used with a smartphone, computer or hand-held or wearable device. Some or all of these features may be primarily or exclusively programmable by the physician team while some features may be accessible to the patient for control / modification.Functionality

[0042] The methods and apparatuses described herein may be used to treat mental health conditions such as depression, anxiety, PTSD, and / or OCDs or ameliorate the symptoms of these disorders. These methods and apparatuses may be indicated for these conditions when they are resistant to conventional front-line therapies, such as drugs.

[0043] The software based algorithm may be configured to utilize the input data from one or more sensors (e.g., from the BP / HR, biochemical, and / or skin sensors) to inform the stimulation paradigm and / or in some cases the degree and frequency of stimulation.

[0044] Any of these methods and apparatuses may be configured to have safety features that prevent over treatment and / or facilitate titration of therapy. For example, these systems may be configured to function within physician-controlled parameters.

[0045] In general, these apparatuses may be implanted into the body. FIGS. 1 and 2 illustrate systems that have been implanted into a body. The electrode (electrode array 105) and controller (e.g., IPG 101), may be implanted via a surgical approach such as that shown in FIG. 1 in which the electrode (array 105) is couped to the ICA over the CSN in the region of the carotid sinus.

[0046] Specifically, in FIGS. 1 and 2, the apparatus is inserted so that the array is positioned over the carotid sinus nerve (CSN) just distal to the carotid bifurcation, over the carotid sinus, and / or carotid body on internal carotid artery. The stimulating electrode in this example is a multi-contact micro-electrode array (such as the C-FINE device, see, e.g., US20080046055, herein incorporated by reference in its entirety) that when, placed on the CSN after it has branched, can be used to differentially stimulate fibers traveling either to the carotid body or sinus. This enables stimulation of either the baro-afferent or chemo-afferent fibers to achieve effects that treat or ameliorate the manifestations of mental health disorders. In FIG. 2, the sensing lead is positioned on the ECA such as a flexible pressure sensor (see, e.g., US20240023821, incorporated by reference herein) or other biometric sensors can be used to produce feedback data that allows use of a control algorithm to enable closed loop (autonomous) control of CSN stimulation for treatment of mental health disorders.

[0047] Alternatively, any of these methods and / or apparatuses may include the use of the neuromodulatory therapies as described herein to include electrically contacting the carotid sinus (stimulation of the mechanoreceptors that sit in the wall of the vessel) and indirectly coupling to the CSN. This may be performed in addition to direct CSN stimulation or as an alternative to CSN stimulation. Thus in some cases electrical stimulation of the carotid sinus may be used to drive stimulation for therapy.Stimulating Electrode

[0048] The stimulating electrode may be a micro -electrode array that can have one or more different configurations. In some examples the array of electrodes may be similar to configurations that include but are not limited to a flat array such as the Composite Flat Interface Nerve Electrode (CWRU / Tyler), a self-sizing circular electrode (see, e.g., US Patent 10,004,904) a spiral electrode array (see, e.g., EP4364789A1 and / or “Spiral Nerve Cuff Electrode” by Naples et al., IEEE, and / or US11975197B2). In some examples the electrode may be placed around the distal branches of the carotid sinus nerve after the nerve has arborized (branched) which may allow the electrode to differentiate between different branches of the nerve. This may be donethrough a surgical approach. Alternatively or additionally, the electrode may be placed around the carotid sinus itself to interface directly with mechanoreceptors in the sinus wall. With respect to the carotid sinus nerve specifically, the location may be chosen to target either baro-afferent or chemo-afferent fibers. The baro-afferent and chemo-afferent fibers may separate and diverge from one another as the carotid sinus nerve descends toward the carotid bifurcation, permitting a surgical approach together with the electrode design to enhance stimulation of one or the other. Stimulation of the baroreflex typically causes sympathetic suppression and parasympathetic activation. In some cases these methods and apparatuses may enhance the baroreflex. In some cases, these methods and apparatuses may reduce or suppress the chemoreflex when applying the electrical stimulation, which may result in a different effect such as sympathetic activation and increased respiratory rate and tidal volume which, in the case of mental health disorders such as depression anxiety PTSD OCD, may not be beneficial (or not as beneficial). In some cases, chemo-afferent activation can be a useful therapeutic modality as well, for example, as a respiratory stimulant.

[0049] The sensing component of device / platform may include a surgically implanted and / or wearable device that detects a sympathetic and / or parasympathetic signal. For example, the apparatus and method may detect a blood pressure pulse wave which allows sensing of heart rate, blood pressure, respiratory function, vessel size and compliance, and other cardiovascular and autonomic features. See, e.g., FIGS. 3 and 4, described below. In some examples these apparatuses may include an implanted biometric sensor(s) that can measure chemicals such as catecholamines and catecholamine derivatives. For example, a hemodynamic sensor may be a flexible pressure sensor such as that shown in US20240023821, US Patent application US20240298904A1, each of these is herein incorporated by reference.

[0050] In general, the methods and apparatuses described herein may include software and / or firmware for guiding the treatment of the mental health disorders and / or underlying pathophysiology. These methods and apparatuses may include software / artificial intelligence (e.g., Al), including one or more trained machine learning agent that may be used to determine when to apply the therapy from the implant and / or how to program the implant, as described herein. For example an apparatus configured to treat one a neuropsychiatric disorder may identify a feature or features indicative of one or more of PTSD, an anxiety disorder, obsessive compulsive disorder and events associated with depression; these features may be associated with both acute and chronic changes in cardiovascular and hemodynamic function as well as other biochemical (e.g., hormonal, etc.) with various types of manifestations. The hemodynamic manifestations of these diseases contain features that enable a sensitive hemodynamic or biometric sensor capable of feature extraction to recognize and distinguish when a person isexperiencing emotional stressors. This allows for a closed loop system that can treat various mental health disorders autonomously but within physician defined parameters. This may be performed at least in part using a deep machine learning model (e.g., artificial intelligence) that can be trained for different applications.

[0051] For example, PTSD is linked with to a higher resting heart rate and blood pressure with increases that can be exaggerated in particular during acute stress or trauma reminders. Similarly anxiety OCD and certain presentations of depression can be associated with chronic and acute stress that trigger the well-known sympathetic fight or flight response that is readily identifiable through sensing. The mechanism by which this occurs is through an autonomic nervous system mediated response. The sympathetic nervous system, through its release of adrenaline and noradrenaline, causes very specific changes in heart rate, heart rate variability and with vessel constriction, which may be detected and used as described herein as input for feedback to the controller, which may use this information to trigger application of therapy and / or for mapping of electrodes. Other biochemical markers of stress can be detected by using one or more implanted sensors.

[0052] For example, reactive hemodynamic manifestations of mental health disease may occur both at rest and more so during stress. These emotional and psychological reactions may manifest as physiological changes to blood pressure breathing levels (both rate and tidal volume) and heart rate in patients with depression PTSD and chronic or acute anxiety and other mental health disorders. Of particular note is heart rate variability, a detectable feature which can be a sensitive marker of stressors. Normally heart rate variability is fairly high and reflects a healthy parasympathetic activation. However in patients with various mental disorders including PTSD depression and anxiety, there can be reduced heart rate variability.

[0053] In one particular example, a sensor may detect acute episodes of stress or anxiety OCD, PTSD (or other mental health) flare ups because conditions can cause a surge in various hormones that cause near-immediate increase in heart rate and blood pressure via activation of the sympathetic nervous system. During acute moments of stress people typically manifest a higher blood pressure and heart rate compared to those not in stress and these can be measured in real time via an implanted sensor as described herein. It has also been shown that following the conclusion of a stressor, heart rate and blood pressure usually return to the patient’s normal baseline levels. However with repeated episodes, Heart rate blood pressure can remain elevated necessitating longer term treatment of the underlying autonomic imbalance. This too can be measured by an implantable sensors, and / or a wearable sensor in communication with the controller.

[0054] In addition to the stress-related changes and surges in both blood pressure, heart rate and respiratory may be detectable with a hemodynamic sensor, there are trends and aspects of the response to stressors that may be used as feedback to control operation of the apparatus. For example, reduced heart rate variability (HRV) is frequently seen in acute stress (in multiple mental health disorders) and has been directly associated or linked to short term stressful events. HRV is generally considered to be more sensitive than heart rate alone in detecting acute mentally or emotionally stressful events providing more detailed insight into the autonomic mechanisms and responses to stressors. The apparatuses described herein may be configured to identify short term HRV indices which can be computed from short time segments and can effectively differentiate a stressful event in healthy subjects. HRV measures can also be used to provide feedback to a therapeutic system in longer term time frames as well. Some HRV metrics like the Autonomic Complexity Index may be used to reliably provide a real time stress / arousal detection, enabling near real time stress monitoring.

[0055] In general, cardiovascular and respiratory metrics (especially when taken together) may respond uniquely to mental health stressors as opposed to other drivers of increased heart rate, blood pressure & breathing such as exercise. The unique effect of stressors on cardiovascular and respiratory function mediated predominantly via autonomic regulation are noted below using exercise as an example.

[0056] Heart rate may be increased in both emotional stress and physical exercise. However in stress heart rate primarily rises due to sympathetic nervous activation and catecholamine release. These changes are often sudden and highly variable and irregular reflecting some degree of autonomic imbalance. However, in exercise there is a predictable and linear increase in heart rate that’s proportional to the level of exertion and oxygen demand. Ramp down (transitioning between exercise and rest) is also associated with predictable and linear decreases in heart rate. Blood pressure similarly rises in mental health mediated stress but typically the increased blood pressure is through sympathetically driven vasoconstriction. Systolic and diastolic pressures rise together sometimes abruptly and erratically with acute psychological mental or emotional stress. However in aerobic exercise, generally systolic pressure elevates commensurate with the level of exertion, Whereas diastolic pressure does not elevate as much and sometimes even decreases due to vasodilation in the skeletal muscles. Ventilation often increases in response to mental or emotional stressors, but it is often irregular and shallow due to autonomic arousal. This produces an erratic shallow respiratory pattern that sometimes even exacerbates stress leading to a vicious cycle. In exercise, ventilation like hemodynamics increases linearly with both respiratory rate and tidal volume (depth of breath) increasing proportionally in a predictable manner with a linear decrease after completion of exertion.

[0057] FIG. 3 and 4 illustrate examples of sensor (feedback) data that may be used as part of any of these methods and apparatuses. For example, FIG. 3 shows an example of recordings from an implanted hemodynamic sensor (bottom graph) showing direct carotid sinus nerve stimulation in a pig and by direct arterial pressure measurements (top graph), for reference. Stimulation of baro-afferent fibers (shown by the lines above the X-axis) results in a near- immediate and synchronous drop in blood pressure and heart rate, demonstrating differential stimulation of the baroreflex. Note that the pulse wave in the blown-up FPS recording (right) bears the dicrotic notch suggestive of high hemodynamic sensitivity

[0058] FIG. 4 shows examples of metrics that can be extracted from a surgically implanted sensor (e.g., a hemodynamic sensor). In this example a hemodynamic sensor, such as that shown in US 2024 / 0023821, was implanted into a pig at ~2months. In FIG. 4, the top graph shows unfiltered pulse wave representing the cardiac cycle. Note that superimposed on the higher frequency pulse waves is a lower frequency sinusoidal wave pattern that represents respirations. The second panel is extracted heart rate, the third blood pressure and the lowest panel displays respiratory rate. This data can be used to feed a control algorithm that informs the mental health treatment stimulation paradigm in real time.

[0059] Thus, various cardiovascular and respiratory trends including but not limited to one or more of: HRV, heart rate, blood pressure, vessel size, respiratory rate and changes acutely and chronically whether in the upward or downward direction can be used by the methods and apparatuses described herein to reliably detect mental health related conditions and differentiate from other more physiologically based causes of hemodynamic changes. Particularly in combination, when evaluating trends of each of these metrics in association with each other a trained machine learning agent (e.g., a deep machine leaning / AI) may be used for treatment of mental health disorders such as anxiety, PTSD, OCD and depression. In any of these cases detection of these stressors based on one more of these indicators may be compared to a threshold value to trigger the application of therapy. In some cases the trained machine learning agent may determine when to trigger the application of therapy. The system may include a governor to limit application of the therapeutic energy.

[0060] Method of use

[0061] FIG. 5 schematically illustrates one example of a method of treatment of a neuropsychiatric disorder as described herein. Optionally, in any these methods an implant including an electrode (e.g., an electrode assembly, which may include an array of electrodes) is applied to deliver electrical stimulation to regions of the CSN either directly (by attaching against the nerve or region of the nerve), or indirectly (e.g., by applying stimulation to the carotid sinus, rather than (or in addition to) the CSN. A pulse generator, including a controller,may be implanted and may include or be coupled to the electrode array 501. In some cases the method may also include implanting and coupling one or more additional sensors (such as a hemodynamic sensor) to the controller to receive input from the one or more sensors. Any of these methods may also optionally then generate a mapping of the electrodes to determine which electrodes of the array result in stimulation of baro-aff erent and / or chemo-afferent fibers 503. This mapping may be performed, for example, by applying energy to selective sub-electrodes or groups of electrodes of the electrode array and detecting a sympathetic and / or parasympathetic response in the patient. In some cases the response may be detected using the one or more sensors (e.g., hemodynamic sensor). The controller may then use and apply this mapping. Optionally any of these methods may then determine one or more stimulation parameters (frequency, amplitude, pulse width, etc.) for applying energy to result in a robust response, e.g., sympathetic and / or parasympathetic response 503.

[0062] The controller may then be operated 507 either with or without feedback (e.g., open loop or closed loop, or semi-closed loop). For example, in an open-loop method, the apparatus may be programmed to automatically apply electrical energy to the carotid sinus nerve (CSN) on a therapeutic schedule (e.g., x times per day, hour, week, etc., where x may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.), and / or the patient may apply it on demand. The therapeutic schedule may be set by a clinician and / or may be modified by the patient.

[0063] In a closed-loop method, the apparatus may be configured to apply energy when one or more threshold events occurs as determined by control logic in the controller that receives input from the one or more sensors, as described above 505. For example, the method may include detecting a change in a marker, including a marker of sympathetic activity (e.g., based on HR, HRV, etc.) indicating a neuropsychiatric episode (e.g., depression, anxiety, etc.), and may trigger a therapeutic dose, e.g., applying electrical energy to all or a subset of the CSN, such as primarily or exclusively those electrodes in contact with baro-afferent fibers.

[0064] This process may be repeated in an ongoing manner. In some cases the method may include adjusting or modifying the map 509, as described above.

[0065] Although the methods described herein primary focus on the use of treating neuropsychiatric disorders by stimulating primarily baro-afferent fibers, in some cases these methods may also or alternatively include chemo-afferent fiber activation. Chemo-afferent activation may activate sympathetics as well as respiratory effort which would not conventionally be considered desirable in most mental health disorders. However, in some cases it may be useful with certain stimulation paradigms to provide a respiratory stimulant, e.g., as a means to stimulate a more regular and deeper respiratory effort and / or to eliminate shallow erratic breathing sometimes seen with anxiety.

[0066] Alternatively and additionally, in any of these methods and apparatuses, chemo- afferent simulation may be applied (e.g., by stimulating chemo-afferent-facing electrodes) to block nerve transmission, e.g., by applying high-frequency energy (e.g., kilohertz frequency blocking stimulation, KHFAC) which is a neuromodulatory technique capable of reversibly inhibiting nerve conduction in a rapid timeframe. In this way, these methods and apparatuses may reduce sympathetic activation. In some cases this may be provided by preferential stimulation of the baro-afferent fibers (e.g., at lower, stimulating frequencies), and / or by electrical inhibition of the chemo-afferent fibers (e.g., by higher, > 1 kHz, frequency stimulation, such as >3 kHz, >5 kHz, >10 kHz, etc.). This may be done in conjunction with CSN stimulation strategies that activate parasympathetic activity. Thus, any of these methods and apparatuses may be configured to provide primarily chemo-efferent stimulation

[0067] All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Furthermore, it should be appreciated that all combinations of the foregoing concepts and additional concepts discussed in greater detail below (provided such concepts are not mutually inconsistent) are contemplated as being part of the inventive subject matter disclosed herein and may be used to achieve the benefits described herein.

[0068] Any of the methods (including user interfaces) described herein may be implemented as software, hardware or firmware, and may be described as a non-transitory computer-readable storage medium storing a set of instructions capable of being executed by a processor (e.g., computer, tablet, smartphone, etc.), that when executed by the processor causes the processor to control perform any of the steps, including but not limited to: displaying, communicating with the user, analyzing, modifying parameters (including timing, frequency, intensity, etc.), determining, alerting, or the like. For example, any of the methods described herein may be performed, at least in part, by an apparatus including one or more processors having a memory storing a non-transitory computer-readable storage medium storing a set of instructions for the processes(s) of the method.

[0069] While various embodiments have been described and / or illustrated herein in the context of fully functional computing systems, one or more of these example embodiments may be distributed as a program product in a variety of forms, regardless of the particular type of computer-readable media used to actually carry out the distribution. The embodiments disclosed herein may also be implemented using software modules that perform certain tasks. These software modules may include script, batch, or other executable files that may be stored on a computer-readable storage medium or in a computing system. In some embodiments, thesesoftware modules may configure a computing system to perform one or more of the example embodiments disclosed herein.

[0070] As described herein, the computing devices and systems described and / or illustrated herein broadly represent any type or form of computing device or system capable of executing computer-readable instructions, such as those contained within the modules described herein. In their most basic configuration, these computing device(s) may each comprise at least one memory device and at least one physical processor.

[0071] The term “memory” or “memory device,” as used herein, generally represents any type or form of volatile or non-volatile storage device or medium capable of storing data and / or computer-readable instructions. In one example, a memory device may store, load, and / or maintain one or more of the modules described herein. Examples of memory devices comprise, without limitation, Random Access Memory (RAM), Read Only Memory (ROM), flash memory, Hard Disk Drives (HDDs), Solid-State Drives (SSDs), optical disk drives, caches, variations or combinations of one or more of the same, or any other suitable storage memory.

[0072] In addition, the term “processor” or “physical processor,” as used herein, generally refers to any type or form of hardware-implemented processing unit capable of interpreting and / or executing computer-readable instructions. In one example, a physical processor may access and / or modify one or more modules stored in the above-described memory device.Examples of physical processors comprise, without limitation, microprocessors, microcontrollers, Central Processing Units (CPUs), Field-Programmable Gate Arrays (FPGAs) that implement softcore processors, Application-Specific Integrated Circuits (ASICs), portions of one or more of the same, variations or combinations of one or more of the same, or any other suitable physical processor.

[0073] Although illustrated as separate elements, the method steps described and / or illustrated herein may represent portions of a single application. In addition, in some embodiments one or more of these steps may represent or correspond to one or more software applications or programs that, when executed by a computing device, may cause the computing device to perform one or more tasks, such as the method step.

[0074] In addition, one or more of the devices described herein may transform data, physical devices, and / or representations of physical devices from one form to another. Additionally or alternatively, one or more of the modules recited herein may transform a processor, volatile memory, non-volatile memory, and / or any other portion of a physical computing device from one form of computing device to another form of computing device by executing on the computing device, storing data on the computing device, and / or otherwise interacting with the computing device.

[0075] The term “computer-readable medium,” as used herein, generally refers to any form of device, carrier, or medium capable of storing or carrying computer-readable instructions. Examples of computer-readable media comprise, without limitation, transmission-type media, such as carrier waves, and non-transitory-type media, such as magnetic-storage media (e.g., hard disk drives, tape drives, and floppy disks), optical-storage media (e.g., Compact Disks (CDs), Digital Video Disks (DVDs), and BLU-RAY disks), electronic- storage media (e.g., solid-state drives and flash media), and other distribution systems.

[0076] A person of ordinary skill in the art will recognize that any process or method disclosed herein can be modified in many ways. The process parameters and sequence of the steps described and / or illustrated herein are given by way of example only and can be varied as desired. For example, while the steps illustrated and / or described herein may be shown or discussed in a particular order, these steps do not necessarily need to be performed in the order illustrated or discussed.

[0077] The various exemplary methods described and / or illustrated herein may also omit one or more of the steps described or illustrated herein or comprise additional steps in addition to those disclosed. Further, a step of any method as disclosed herein can be combined with any one or more steps of any other method as disclosed herein.

[0078] The processor as described herein can be configured to perform one or more steps of any method disclosed herein. Alternatively or in combination, the processor can be configured to combine one or more steps of one or more methods as disclosed herein.

[0079] When a feature or element is herein referred to as being "on" another feature or element, it can be directly on the other feature or element or intervening features and / or elements may also be present. In contrast, when a feature or element is referred to as being "directly on" another feature or element, there are no intervening features or elements present. It will also be understood that, when a feature or element is referred to as being "connected", "attached" or "coupled" to another feature or element, it can be directly connected, attached or coupled to the other feature or element or intervening features or elements may be present. In contrast, when a feature or element is referred to as being "directly connected", "directly attached" or "directly coupled" to another feature or element, there are no intervening features or elements present. Although described or shown with respect to one embodiment, the features and elements so described or shown can apply to other embodiments. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed "adjacent" another feature may have portions that overlap or underlie the adjacent feature.

[0080] Terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. For example, as used herein, the singularforms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and / or "comprising," when used in this specification, specify the presence of stated features, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups thereof. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items and may be abbreviated as " / ".

[0081] Spatially relative terms, such as "under", "below", "lower", "over", "upper" and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is inverted, elements described as "under”, or "beneath" other elements or features would then be oriented "over" the other elements or features. Thus, the exemplary term "under" can encompass both an orientation of over and under. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Similarly, the terms "upwardly", "downwardly", "vertical", "horizontal" and the like are used herein for the purpose of explanation only unless specifically indicated otherwise.

[0082] Although the terms “first” and “second” may be used herein to describe various features / elements (including steps), these features / elements should not be limited by these terms, unless the context indicates otherwise. These terms may be used to distinguish one feature / element from another feature / element. Thus, a first feature / element discussed below could be termed a second feature / element, and similarly, a second feature / element discussed below could be termed a first feature / element without departing from the teachings of the present invention.

[0083] In general, any of the apparatuses and methods described herein should be understood to be inclusive, but all or a sub-set of the components and / or steps may alternatively be exclusive and may be expressed as “consisting of’ or alternatively “consisting essentially of’ the various components, steps, sub-components or sub-steps.

[0084] ‘An embodiment,” “in an embodiment”, “in another embodiment,” “embodiments,” “certain embodiments,” or “in some embodiments” each has the meaning herein of “in one or more embodiments”. Similarly, “a configuration,” “in a configuration,” in one configuration,” “in another configuration,” “configurations,” “certain configurations,” or “in some configurations” each has the meaning herein of “in one or more configurations.”

[0085] The terms “e.g.,” “such as,” “for example,” “and so forth,” and “etc.” mean that what follows the “e.g.,” “such as,” or “for example” or what precedes the “etc.” or “and so forth,” is a list of examples and there may be other items that could also serve as examples but are not listed.

[0086]

[0087] As used herein in the specification and claims, including as used in the examples and unless otherwise expressly specified, all numbers may be read as if prefaced by the word "about" or “approximately,” even if the term does not expressly appear. The phrase “about” or “approximately” may be used when describing magnitude and / or position to indicate that the value and / or position described is within a reasonable expected range of values and / or positions. For example, a numeric value may have a value that is + / - 0.1% of the stated value (or range of values), + / - 1% of the stated value (or range of values), + / - 2% of the stated value (or range of values), + / - 5% of the stated value (or range of values), + / - 10% of the stated value (or range of values), etc. Any numerical values given herein should also be understood to include about or approximately that value, unless the context indicates otherwise. For example, if the value "10" is disclosed, then "about 10" is also disclosed. Any numerical range recited herein is intended to include all sub-ranges subsumed therein. It is also understood that when a value is disclosed that "less than or equal to" the value, "greater than or equal to the value" and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value "X" is disclosed the "less than or equal to X" as well as "greater than or equal to X" (e.g., where X is a numerical value) is also disclosed. It is also understood that the throughout the application, data is provided in a number of different formats, and that this data, represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point “15” are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0088] Although various illustrative embodiments are described above, any of a number of changes may be made to various embodiments without departing from the scope of the invention as described by the claims. Optional features of various device and system embodiments may be included in some embodiments and not in others. Therefore, the foregoing description is provided primarily for exemplary purposes and should not be interpreted to limit the scope of the invention as it is set forth in the claims.

[0089] The examples and illustrations included herein show, by way of illustration and not of limitation, specific embodiments in which the subject matter may be practiced. As mentioned,other embodiments may be utilized and derived there from, such that structural and logical substitutions and changes may be made without departing from the scope of this disclosure. Such embodiments of the inventive subject matter may be referred to herein individually or collectively by the term “invention” merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept, if more than one is, in fact, disclosed. Thus, although specific embodiments have been illustrated and described herein, any arrangement calculated to achieve the same purpose may be substituted for the specific embodiments shown. This disclosure is intended to cover any and all adaptations or variations of various embodiments. Combinations of the above embodiments, and other embodiments not specifically described herein, will be apparent to those of skill in the art upon reviewing the above description.

Claims

CLAIMSWhat is claimed is:

1. A method of treating a mental health disorder, the method comprising: applying electrical stimulation to a carotid sinus nerve (CSN) of a patient; wherein the electrical stimulation is configured to preferentially stimulate baro- afferent fibers as compared to chemo-afferent fibers.

2. The method of claim 1, wherein the mental health disorder is one or more of: depression, anxiety, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD).

3. The method of claim 1, wherein applying electrical stimulation comprises applying electrical stimulation at a frequency between 10-125 Hz, a pulse width between 25-500 microseconds, and an amplitude between 0.25-15 mA.

4. The method of claim 1, wherein applying electrical stimulation comprises applying electrical stimulation to a subset of an array of electrodes on the CSN that map to baro- afferent fibers as compared to chemo-afferent fibers.

5. The method of claim 1, further comprising: mapping the electrode array to identify electrodes that stimulate baro-afferent fibers; storing the mapping in a controller; applying stimulation only through electrodes identified as stimulating baro-afferent fibers.

6. The method of claim 1, further comprising repeating the application of electrical stimulation to the CSN on a pre-programmed schedule.

7. The method of claim 1, further comprising repeating the application of electrical stimulation to the CSN as part of a closed-loop protocol based on detection of a marker for the mental health disorder.

8. The method of claim 1, wherein the stimulation is titrated based on feedback from one or more implanted or wearable sensors.

9. The method of claim 1, wherein the stimulation is applied intermittently at a duty cycle between about 1% and 90%.

10. An apparatus for treating a mental health disorder, the apparatus comprising: a stimulating electrode array configured to be implanted to stimulate fibers of a carotid sinus nerve (CSN); a pulse generator operatively coupled to the electrode array and configured to apply electrical stimulation to the CSN;a controller coupled to or integrated with the pulse generator, wherein the controller comprises control logic configured to selectively activate electrodes that stimulate baro-afferent fibers of the CSN while minimizing stimulation of chemo-afferent fibers by applying electrical stimulation to a subset of electrodes of the simulation electrode array that are in communication with primarily baro-afferent fibers as determined by a mapping maintained by the controller.

11. The apparatus of claim 10, wherein the electrode array comprises a multi-contact microelectrode array.

12. The apparatus of claim 10, wherein the controller is configured to operate in an openloop, closed-loop, or semi-closed-loop mode.

13. The apparatus of claim 10, further comprising one or more sensors providing input to the controller for closed-loop or semi-closed-loop operation, wherein the one or more sensors are selected from the group of: pressure sensors, heart rate monitors, respiratory rate sensors, blood oxygenation sensors, and biochemical sensors for detecting catecholamines.

14. The apparatus of claim 10, wherein the controller includes a machine learning model trained to detect neuropsychiatric events based on sensor input.

15. The apparatus of claim 10, wherein the stimulating electrode array comprises a multicontact micro-electrode array configured to be surgically implanted adjacent to the carotid sinus nerve.

16. The apparatus of claim 10, wherein the mapping maintained by the controller is generated by applying stimulation to individual electrodes and detecting a baroreflex response.

17. The apparatus of claim 10, wherein the controller is configured to update the mapping dynamically based on feedback from one or more sensors.

18. The apparatus of claim 10, further comprising one or more sensors configured to detect physiological parameters selected from the group consisting of heart rate, blood pressure, respiratory rate, and heart rate variability.

19. The apparatus of claim 10, wherein the electrical stimulation is applied at a frequency between 10 Hz and 125 Hz, a pulse width between 25 microseconds and 500 microseconds, and an amplitude between 0.25 mA and 15 mA.

20. The apparatus of claim 10, wherein the controller is configured to selectively inhibit chemo-afferent fibers using high-frequency blocking stimulation.

21. A closed-loop neuromodulation system, the system comprising: a stimulating electrode array configured to be positioned on or near the carotid sinus nerve (CSN);one or more sensors configured to detect physiological parameters associated with autonomic nervous system activity; a controller configured to: receive input from the one or more sensors; and apply electrical stimulation to the CSN in response to detection of a neuropsychiatric event and / or based on a stimulation schedule.

22. The system of claim 21, wherein the one or more sensors are selected from the group consisting of heart rate sensors, blood pressure sensors, respiratory rate sensors, and biochemical sensors configured to detect catecholamines and / or cortisol.

23. The system of claim 21, wherein the controller is configured to apply stimulation only to electrodes mapped to baro-afferent fibers of the CSN.

24. The system of claim 21, wherein the controller comprises a machine learning model trained to identify neuropsychiatric events based on sensor input.

25. The system of claim 21, wherein the stimulating electrode array comprises a multicontact micro-electrode array configured to be surgically implanted adjacent to the CSN.

26. The system of claim 21, wherein the controller is configured to update stimulation parameters dynamically based on feedback from the one or more sensors.

27. The system of claim 21, wherein the electrical stimulation is applied at a frequency between 10 Hz and 125 Hz, a pulse width between 25 microseconds and 500 microseconds, and an amplitude between 0.25 mA and 15 mA.

28. The system of claim 21, wherein the controller is configured to inhibit stimulation of chemo-afferent fibers using high-frequency blocking stimulation.

29. The system of claim 21, wherein the controller is configured to trigger stimulation in response to detection of reduced heart rate variability indicative of a neuropsychiatric episode.

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