Method and system for calibrating cerebral hemodynamics

Abstract

To enable more accurate calibration of the brain, a system for creating a hemodynamic brain atlas for calibrating cerebral hemodynamics is provided. The system includes a non-invasive transcranial neurostimulator, a non-invasive neuromonitoring device, and a computing device. The non-invasive transcranial neurostimulator is configured to induce neural activity to induce a hemodynamic response in a target region of interest (ROI) of the brain of a human subject. The non-invasive neuromonitoring device is configured to monitor the induced hemodynamic response in the target ROI. The computing device is configured to determine a set of parameters representing a hemodynamic response function of the induced hemodynamic response in the target ROI and associate the set of parameters of the hemodynamic response function with the target ROI to form a hemodynamic brain atlas.

Description

Technical Field

[0001] The present invention relates to the calibration of cerebral hemodynamics, and in particular, to a system for creating a hemodynamic brain atlas for the calibration of cerebral hemodynamics, an apparatus for the calibration of cerebral hemodynamics, a nerve monitoring system, a method for creating a hemodynamic brain atlas, a computer-implemented method for the calibration of cerebral hemodynamics, and a computer program element.

Background Art

[0002] Functional magnetic resonance imaging (fMRI) is limited by the use of a standard hemodynamic response function (HRF) across the brain. The use of one single canonical HRF (which is the same across the whole brain and individually) can be limiting. The limitations of the standard HRF can be partially alleviated by the estimation of HRF parameters (HRF calibration) in response to an event. However, this calibration can only be performed in brain regions that have a close coupling between the event and the induced neural activity, i.e., the visual cortex.

[0003] US 2017 / 340260 A1 describes a system for determining neurovascular reactivity to brain stimulation. US Patent Application Publication No. 2014 / 058247 describes an information acquisition method for acquiring brain activity information from a living body to which a visual stimulus is applied. "Blood volume and haemoglobin oxygenation response following electrical stimulation of human cortex" by Suh M et al. (NeuroImage, Elsevier, Amsterdam, NL, vol. 31, no. 1, 15 May 2006, pages 66 to 75) reports the first measurements of deoxygenated haemoglobin in humans with high spatial and temporal resolution.

Summary of the Invention

Problems to be Solved by the Invention

[0004] The accuracy of cerebral hemodynamic calibration may need to be improved. [Means for solving the problem]

[0005] The object of the present invention is solved by the subject matter of the independent claims, and further embodiments are incorporated into the dependent claims. It should be noted that the embodiments described below of the present invention also apply to systems for creating hemodynamic brain atlases for cerebral hemodynamic calibration, apparatus for cerebral hemodynamic calibration, neurosurgical monitoring systems, methods for creating hemodynamic brain atlases, computer-based methods for cerebral hemodynamic calibration, and computer program elements.

[0006] According to a first aspect of the present invention, a system is provided for creating a hemodynamic brain atlas for the calibration of cerebral hemodynamics. The system comprises a non-invasive transcranial nerve stimulator, a non-invasive neuromonitoring device, and a computing device. The non-invasive transcranial nerve stimulator is configured to induce neural activity to induce a hemodynamic response in a target region of interest (ROI) of the brain of a human subject. The non-invasive transcranial nerve stimulator includes transcranial functional ultrasound stimulation (tFUS). The non-invasive neuromonitoring device is configured to monitor the evoked hemodynamic response in the target ROI. The computing device is configured to determine a set of parameters representing the hemodynamic response function (HRF) of the evoked hemodynamic response in the target ROI and to associate the set of parameters of the HRF with the target ROI to form a hemodynamic brain atlas.

[0007] In other words, it has been proposed to use tFUS as transcranial nerve stimulation to induce neural activity and then estimate HRF across various other brain regions. The advantage is that the neural stimulation can target any specific brain region, but it can also target multiple different brain regions. This could allow for more accurate fMRI calibration, not only for individuals but also for specific brain regions.

[0008] TFUS is a non-invasive technique that uses low-intensity ultrasound to induce neural activity. TFUS can safely and effectively modulate neural activity (neuronal activity) in animals and humans. Neural stimulation using tFUS requires far less energy compared to high-focus ultrasound (HIFU) used in ablation. TFUS is not limited to the superficial layers of the cortex; it can also target deep brain structures, allowing for highly focused areas that were previously impossible to target non-invasively. Conventional techniques such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) can only induce neural activity in areas close to the skull, on the cortical surface, and have a large modulated area (e.g., several centimeters). In addition, the effectiveness of tFUS in cortical and deep brain structures can be improved by the emergence of tFUS systems that use multiple ultrasound transducers, which can concentrate extra energy on local deep brain structures. Therefore, with tFUS, it is possible to determine HRF throughout the entire brain and create a hemodynamic brain atlas. This allows for HRF calibration across the entire brain, not just in sensory areas (e.g., sensorimotor, visual, or auditory cortex).

[0009] It is also proposed to develop a hemodynamic brain atlas that includes multiple brain regions. Each brain region is associated with its respective hemodynamic response function (HRF), which is represented by a set of parameters. Thus, the hemodynamic brain atlas includes multiple locally calibrated HRFs. An exemplary hemodynamic brain atlas is shown in Figure 2C. This atlas can improve the accuracy of fMRI measurements and can be extended by other methods of neural stimulation and neural monitoring.

[0010] Target ROIs can be defined anatomically, functionally, or clinically. Anatomically, a target ROI can be defined as a motor cortex, visual cortex, amygdala, volume in atlas coordinates, or a specific part of a brain region in the cortex (e.g., cortical layer IV of the MT in the left hemisphere), a subcortical region (e.g., substantia nigra, thalamus, hippocampus), or a region in the cerebellum. A target ROI can be functionally defined using localizer tasks in fMRI (motor, speech, etc.), using functional connectivity, using a functional atlas, or using a PET (positron emission tomography) tracer. Clinically, a target ROI may be, for example, a lesion in an epileptic seizure or stroke.

[0011] The set of parameters representing HRF may include one or more of the following: peak amplitude, trough amplitude, time to peak, time to fall, upward slope, downward slope, FWHM (full width at half maximum, or area under the curve).

[0012] According to one embodiment of the present invention, a non-invasive transcranial nerve stimulator is configured to induce multiple hemodynamic responses in multiple target ROIs, with each hemodynamic response being induced in its respective target ROI. For each induced hemodynamic response, the computing device is configured to determine a set of parameters representing the corresponding HRF and to associate each set of parameters with the corresponding target ROI in order to form a hemodynamic brain atlas.

[0013] For example, non-invasive transcranial nerve stimulators can use multiple transducers to sequentially or simultaneously target multiple different brain regions.

[0014] According to one embodiment of the present invention, a non-invasive neurosurveillance device is configured to monitor further evoked hemodynamic responses in one or more brain regions having sufficiently strong excitatory coupling with a target ROI. A computing device is configured to determine a set of parameters representing the HRF of further evoked hemodynamic responses in one or more brain regions and to associate the set of parameters with one or more brain regions to form a hemodynamic brain atlas.

[0015] Therefore, HRF is estimated not only in the stimulated ROI, but also in other regions that may show a consistent BOLD response after stimulation.

[0016] For example, tFUS can also induce neurons and ensure a BOLD response in distal brain regions with strong excitability.

[0017] According to one embodiment of the present invention, the system further comprises a sensory stimulator configured to apply at least one sensory stimulus to a human subject in order to induce neural activity in order to induce a hemodynamic response in a target ROI. A computing device is configured to perform a comparison between the hemodynamic response induced by the non-invasive transcranial nerve stimulator and the hemodynamic response induced by the sensory stimulator to correct for potential neuron-induced confounding on the HRF.

[0018] In other words, this system can also correct for potential neuron-induced confounding of HRF by, for example, comparing tFUS-induced HRF with sensory / motor-induced HRF. For a single, distinct brain region, the deconvolution of neuron-induced HRF can be compared to the deconvolution of sensory-induced HRF.

[0019] Sensory stimuli may include one or more of the following: visual stimuli, auditory stimuli, tactile stimuli, thermal stimuli, etc.

[0020] According to one embodiment of the present invention, a non-invasive transcranial nerve stimulation device is configured to induce a series of hemodynamic responses in a target ROI. A non-invasive nerve monitoring device is configured to monitor a sequence of induced hemodynamic responses in the target ROI. A computing device is configured to perform a comparison between sequences of induced hemodynamic responses to correct for potential nerve stimulation-induced crosstalk on the HRF.

[0021] In one example, the non-invasive nerve monitoring device may be an MRI. The MRI can better separate the effects of changes in cerebral blood flow and BOLD using specific fMRI sequences, such as VASO-dependent BOLD fMRI or FMR sequences that allow for a better estimate of the effects of temperature changes and BOLD.

[0022] According to one embodiment of the present invention, the target ROI is selected from a set of calibration brain regions. The HRF in other brain regions of the brain can be derived from the HRF in the set of calibration brain regions.

[0023] The optimal set of calibration regions can be defined by exploring the regularity across brain regions. Although the HRF varies by brain region, there are regularities (e.g., inter-hemispheric). Once a sufficient number of patients are mapped to a hemodynamic brain atlas, these regularities can be utilized to define the optimal set of calibration regions.

[0024] Using a small set of individual calibration regions, e.g., one per lobe, the method can infer whole-brain hemodynamics.

[0025] According to one embodiment of the present invention, the non-invasive transcranial nerve stimulation device further comprises one or more of transcranial electrical stimulation (tDCS / tACS) and transcranial magnetic stimulation (TMS). ​​​ According to one embodiment of the present invention, the non-invasive nerve monitoring device includes one or more of a device for nerve monitoring of cerebral hemodynamics and a device for measuring electrical signals generated by neurons for measuring brain activity.

[0027] The hemodynamic nerve imaging device may include, for example, MRI, low-intensity focused ultrasound imaging (LIFU), and near-infrared spectroscopy (NIRS).

[0028] Other methods of non-invasive nerve monitoring, such as electroencephalography (EEG), magnetoencephalography (MEG), optically pumped magnetometer (OPM), or motion-induced response, can be used to estimate the amount of nerve activity induced by nerve stimulation.

[0029] According to a second aspect of the present invention, a device for calibration of cerebral hemodynamics is provided. The device includes an input unit, a processing unit, and an output unit. The input unit is configured to receive (i) a hemodynamic response in a region of interest (ROI) of the brain of a human subject acquired by a non-invasive nerve monitoring device, and (ii) a hemodynamic brain atlas. The hemodynamic brain atlas includes a plurality of brain regions, and each brain region is associated with a respective hemodynamic response function HRF represented by a set of parameters. The processing unit calibrates the acquired hemodynamic response using the hemodynamic brain atlas. The output unit is configured to output the calibrated hemodynamic response.

[0030] In other words, a system for deploying a hemodynamic brain atlas, for example on an MRI system, is proposed using a newly and accurately calibrated HRF.

[0031] This hemodynamic brain atlas may include an average from a group of healthy adults, from a specific patient group, and / or from a single patient in which many brain regions are calibrated. This external atlas may also include HRF parameters derived from different individuals for different brain regions.

[0032] According to one embodiment of the present invention, a hemodynamic brain atlas can be derived from one or more of the following: previous HRF measurements of a human subject; previous HRF measurements of a group of healthy adults arbitrarily stratified by age, sex, or other factors; previous HRF measurements of a specific patient group; and previous HRF measurements of a single patient whose brain region may be calibrated.

[0033] According to one embodiment of the present invention, the target ROI is different from multiple brain regions in the hemodynamic brain atlas.

[0034] The HRF being calibrated may be applied to brain regions other than those that showed a response during calibration. For example, a hemodynamic brain atlas with a set of ROIs to be calibrated from the left hemisphere can be used to estimate brain activity in the contralateral hemisphere.

[0035] A third aspect of the present invention provides a neurosurveillance system. The neurosurveillance system comprises a non-invasive neurosurveillance device for acquiring hemodynamic responses in a region of interest (ROI) of the brain of a human subject, a device according to a second aspect, and any relevant examples for calibrating the acquired hemodynamic responses.

[0036] According to a fourth aspect of the present invention, a method for creating a hemodynamic brain atlas for the calibration of cerebral hemodynamics, A non-invasive transcranial nerve stimulator is used to induce neural activity in a target region of interest of the brain of a human subject, wherein the non-invasive nerve stimulator has transcranial functional ultrasound stimulation. The steps include monitoring the evoked hemodynamic response in the target region of interest using the non-invasive neuromonitoring device, The steps include: determining a set of parameters representing the hemodynamic response function of the induced hemodynamic response in the target region of interest using a computing device; The computing device performs the steps of associating the set of parameters of the hemodynamic response function with the target region of interest to form the hemodynamic brain atlas. A method is provided that has the following characteristics.

[0037] According to a fifth aspect of the present invention, a computer implementation method for calibrating cerebral hemodynamics, The input unit receives (i) hemodynamic responses in a region of interest of the brain of a human subject acquired by a non-invasive neuromonitoring device, and (ii) a hemodynamic brain atlas, wherein the hemodynamic brain atlas has one or more brain regions, and each brain region is associated with a hemodynamic response function represented by a set of parameters. The processing unit performs the steps of calibrating the acquired hemodynamic response using the hemodynamic brain atlas, The output unit outputs the calibrated hemodynamic response. A method is provided that has the following characteristics.

[0038] According to another aspect of the present invention, a computer program element is provided for controlling a system according to the first aspect and any related example, or a device according to the second aspect and any related example, which is configured to perform a method according to the third or fourth aspect when executed by a processor.

[0039] It is understood that all combinations of the aforementioned concepts and additional concepts discussed in more detail below (provided that such concepts are not mutually contradictory) are intended to be part of the subject matter of the invention disclosed herein. In particular, the claims at the end of this disclosure are intended to be part of the subject matter of the invention disclosed herein.

[0040] These and other aspects of the present invention are evident from the embodiments described below and will be explained with reference thereto.

[0041] In the drawings, as in the literature, similar reference numerals generally refer to the same parts across different drawings. Furthermore, the drawings are not necessarily to scale, and the emphasis is on illustrating the principles of the present invention. [Brief explanation of the drawing]

[0042] [Figure 1] An example of a system for creating a hemodynamic brain atlas for the calibration of cerebral hemodynamics is outlined below. [Figure 2A] This document outlines an example of using the tFUSMRI system to create a hemodynamic brain atlas. [Figure 2B] This document outlines an example of using the tFUSMRI system to create a hemodynamic brain atlas. [Figure 2C] This document outlines an example of using the tFUSMRI system to create a hemodynamic brain atlas. [Figure 3] Further examples of systems for creating hemodynamic brain atlases for cerebral hemodynamic calibration are outlined. [Figure 4] A schematic diagram of a device for calibrating cerebral hemodynamics is shown. [Figure 5] An example of a neural monitoring system is shown in schematic form. [Figure 6] This shows a flowchart of the method for creating a hemodynamic brain atlas for the calibration of cerebral hemodynamics. [Figure 7] A flowchart of methods for calibrating cerebral hemodynamics is shown. [Modes for carrying out the invention]

[0043] Functional magnetic resonance imaging (fMRI) is a non-invasive tool used to measure neural activity in response to stimuli, tasks, or resting conditions. Unfortunately, fMRI does not directly measure neuronal activity, i.e., the action potential of single-cell neurons, but rather relies on the coupling between neuronal metabolism and blood flow. Functional MRI sequences typically use blood oxygen level-dependent (BOLD) contrast to estimate brain activity. Therefore, fMRI relies on the response of blood vessels in the brain and is thus limited and transiently filtered by the hemodynamics of the brain's vascular system.

[0044] Event-related fMRI studies identify the brain's standard hemodynamic response function (HRF). An event, such as the presentation of a short visual stimulus, elicits nearly instantaneous neuronal activity in the visual cortex. In contrast to this neuronal activity, the HRF is delayed. In the visual cortex, the stimulus elicits a delayed increase in the BOLD signal due to vasodilation and a massive influx of oxygenated blood. This significant increase in signal is the primary source of fMRI. The HRF typically peaks about 6 seconds after the visual stimulus. After about 15–20 seconds, the HRF slowly returns to baseline. The HRF can be used to estimate brain activity in task-based fMRI by convolution with stimulus or task events. Furthermore, the HRF can be used to deconvolve fMRI time series to estimate neuronal events and task-induced changes in brain connectivity. In short, the HRF is a critical component of fMRI for linking changes in the BOLD signal to events, and vice versa.

[0045] The use of a single canonical HRF is considered a limitation because it is identical across the brain and from individual to individual. Furthermore, HRF function has also been shown to be age-dependent.

[0046] The aforementioned limitations, such as the use of a single canonical HRF across the entire brain and individual regions, can be partially mitigated by estimating HRF parameters in response to specific events, i.e., HRF calibration. However, this calibration can only be performed in brain regions where there is a close coupling between these events and evoked neural activity. For example, the visual cortex shows a reliable response to visual stimuli. Using fMRI and presentation of visual stimuli, HRF can be deconvoluted in the visual cortex, and individualized HRF parameters can be derived. In a similar manner, HRF can be estimated for auditory and sensory motor regions. However, most brain regions do not reliably modulate neural activity in response to stimuli. As a result, HRF cannot be calibrated for the majority of the brain.

[0047] To address at least one of the limitations described above, Figure 1 shows an example of a system 100 for creating a hemodynamic brain atlas for calibration of cerebral hemodynamics. The system 100 comprises a non-invasive transcranial nerve stimulator 10, a non-invasive neuromonitoring device 12, and a computing device 14. The target ROI may be, for example, the amygdala, a volume in atlas coordinates, or a specific part of a brain region (e.g., cortical layer IV of the MT in the left hemisphere).

[0048] The non-invasive transcranial nerve stimulator 10 is configured to induce neural activity and thereby elicit a hemodynamic response in a target region of interest (ROI) in the brain of a human subject.

[0049] In the example shown in Figure 1, the non-invasive transcranial nerve stimulator 10 is a transcranial focused ultrasound (tFUS) device. TFUS is a non-invasive technique that uses low-intensity ultrasound to induce neural activity. TFUS can safely and effectively regulate neural activity in animals and humans. Neural stimulation using tFUS requires far less energy compared to high-focus ultrasound (HIFU) used for ablation. TFUS is not limited to the superficial layers of the cortex but can also target deep brain structures and can be highly focused. In addition, the effectiveness of tFUS in the cortex and deep brain structures has been improved by the emergence of tFUS systems that use multiple ultrasound transducers that can concentrate extra energy on local deep brain structures.

[0050] As shown in Figure 1, the tFUS device is configured to transcranially deliver pulsed low-intensity FUS to an ROI, thereby allowing similar frequency ranges to modulate human brain activity and achieve appropriate transcranial transmission through the skull. In the example shown in Figure 1, the tFUS device is positioned inside the MR head coil 16 within an MRI system 20, and the diagram of the sonication pathway is shown by a dashed line. The tFUS can be applied to the ROI via a coupling hydrogel 18, such as a polyvinyl alcohol (PVA) hydrogel. The coupling hydrogel 18 may be around the contour of the skin to achieve tight acoustic coupling while maintaining the orientation of the sonication entry as perpendicular as possible to the scalp. In the example in Figure 1, the tFUS device comprises a single FUS transducer 19 configured to induce a hemodynamic response in a single target ROI. In other examples (not shown), the tFUS may be configured to induce multiple hemodynamic responses in multiple target ROIs. Each hemodynamic response is induced in its respective target ROI. This can be achieved by sequentially delivering pulsed low-intensity FUS to multiple ROIs using a single FUS transducer 19, or by simultaneously delivering multiple pulsed low-intensity FUS to multiple ROIs using multiple transducers (not shown). In other words, neural stimulation can target any specific brain region, or (if desired) multiple different brain regions.

[0051] Other non-invasive brain stimulation methods (not shown), such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), may be used in conjunction with tFUS to induce neural activity. However, the size of the modulation area may be large (e.g., several centimeters), while the ability to reach specific areas in the deep cortical / subcortical regions may be limited compared to tFUS.

[0052] The non-invasive neuromonitoring device 12 is configured to monitor evoked hemodynamic responses in a target ROI.

[0053] In some cases, functional neuroimaging modalities such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) can be used to characterize the spatial and temporal features of neural responses to FUS-mediated brain stimulation.

[0054] In the example shown in Figure 1, the non-invasive neuromonitoring device 12 comprises an MRI system 20 that provides high-resolution anatomical MRI usable for stereotactic guidance of tFUS. The MRI system 20 may also be used as the non-invasive neuromonitoring device 12. For example, fMRI may be used to measure neural activity in response to stimuli. Functional MRI sequences typically use blood oxygen level-dependent (BOLD) contrast to estimate brain activity. Thus, fMRI relies on the response of blood vessels in the brain and is therefore limited and transiently filtered by the hemodynamics of the cerebral vascular system.

[0055] In some examples (not shown), the non-invasive neuromonitoring device 12 can perform hemodynamic imaging using low-intensity focused ultrasound (LIFU) imaging or near-infrared spectroscopy. Both methods can also be combined with MRI for both neuromonitoring and / or stereotactic navigation. In the case of LIFU, a Doppler aspect of ultrasound imaging can be used to obtain real-time (absolute) blood flow measurements. LIFU images can also be used to measure blood flow in real time with high sensitivity, high spatiotemporal resolution (typically 100 μm and 10 ms), and a large field of view (ranging from square cm to tens of square cm). LIFU is sometimes called functional ultrasound imaging. Thereafter, LIFU can be used instead of, or in conjunction with, fMRI measurements to deconvolve HRF and improve calibration for novel fMRI or LIFU measurements. Furthermore, it is possible to use LIFU to measure blood flow in a vessel of interest before (Fmin) and at its peak (Fmax) of tFUS stimulation. LIFU images provide absolute values ​​of flow velocity, but this can be improved by using anatomical images of vessel size to calculate the total change in blood volume. For example, in the case of a visual stimulus, it can be expected that the size of the vessel changes from the initial region of the vessel (Amin) and reaches its maximum size (e.g., region of vessel Amax) after 6 seconds. Therefore, if a second, more specialized scan (i.e., with higher resolution, etc.) is performed after 6 seconds, the (absolute) change in blood flow will be: V max =V min × (F max ×A max ) / (F min ×A min ) It is expressed as follows.

[0056] This is another method for calibrating the BOLD response using LIFU and fMRI measurements. In addition, any changes resulting from thermal events caused by stimulation (i.e., changes in blood viscosity) can also be identified, for example, by using near-infrared spectroscopy.

[0057] In some further examples (not shown), a non-invasive electrical monitoring device 12 can measure brain currents to estimate the amount of electrical activity induced by a non-invasive transcranial electrical stimulator 10. Exemplary non-invasive neural monitoring methods include, but are not limited to, electroencephalography (EEG), magnetoencephalography (MEG), optical magnetometry (OPM), and motor evoked responses. Additional estimates of neural activity may be used to estimate the expected HRF. These independent estimates of neural activity may further improve calibration procedures and help inform tFUS parameters, such as tFUS intensity, frequency, or duration.

[0058] The computing device 14 is configured to determine a set of parameters representing the hemodynamic response function (HRF) of the induced hemodynamic response at the target ROI. The computing device 14 is further configured to associate the set of HRF parameters with the target ROI in order to form a hemodynamic brain atlas. The set of parameters representing the HRF may include one or more of the following: peak amplitude, trough amplitude, time to peak, time to fall, rise slope, fall slope, FWHM, etc.

[0059] If hemodynamic brain atlases are obtained before and after drug therapy, the effects of this drug therapy on several regions or networks can be registered, for example, to investigate the efficacy of the drug therapy. This can be used to evaluate the effects of drug therapy, such as psychoactive drugs, on brain activity. This can enable personalized drug administration to its full potential, as each person has different sensitivities to brain drug administration. Side effects of brain drug administration are high and can be predicted in advance.

[0060] An example of operation using the tFUSMRI system is shown in Figures 2A to 2C. The patient is placed inside the MRI system 20. First, a high-resolution anatomical MRI is created for tFUS stereotactic guidance, as shown in Figure 2(a), and various measurements are registered. Then, one or more tFUS devices are used to induce HRF in one or more target ROIs (e.g., amygdala, volume in atlas coordinates, or a specific part of a brain region). During and immediately after transcranial nerve stimulation, the evoked hemodynamic response is measured using fMRI. This can be compared to baseline measurements without stimulation or spurious signals. The scanner is optimized to monitor the ROI with high temporal and spatial resolution to sample the shape of the hemodynamic response and filter out potential confounding factors. From each measurement, the HRF can be deconvoluted and the function parameters can be estimated. This procedure may be repeated several times to reduce noise and estimate the variance in the HRF. An exemplary HRF deconvolution is shown in Figure 2B. HRF deconvolution yields individualized HRF parameters for the stimulated brain ROI (e.g., peak amplitude, trough amplitude, time to peak, time to fall, rise slope, fall slope, and / or FWHM). Using anatomical MRI information, the HRF parameters are mapped onto a hemodynamic brain atlas. An exemplary hemodynamic brain atlas is shown in Figure 2C, which is mapped onto stereotactic space and stored in a digital file.

[0061] In the examples in Figures 2A to 2C, there is a single brain region determined by the ROI and the spatial resolution of tFUS (and fMRI). The same calibration procedure can be repeated to calibrate HRF for a series of other brain regions, resulting in a hemodynamic brain atlas.

[0062] Locally calibrated HRF based on hemodynamic brain atlases can be used during the acquisition of new fMRI measurements. Estimating new fMRI activity functions similarly to current statistical parametric mapping studies, but instead of standard HRF, it convolves locally calibrated HRF to estimate fMRI activity. Therefore, a more accurate estimate of the patient's brain activity is obtained, which supports the formation of accurate conclusions or diagnostics.

[0063] Optionally, the target ROI may be selected from a set of calibrated brain regions. HRF in other brain regions may be derivable from HRF in the set of calibrated brain regions. HRF varies by brain region but exhibits regularity (e.g., interhemispheric). For example, once a sufficient number of patients are mapped to a hemodynamic brain atlas, these regularities can be utilized to define an optimal set of calibration regions. For instance, after stimulation, HRF in the entorhinal cortex may peak half as late as HRF in the hippocampus, on average. Also, in some patients, HRF may have a 20% larger amplitude than in others. The set of calibrated brain regions can take these regularities between brain regions and individuals into account. By calibrating HRF in a single (or optimal set of) brain region, HRF parameters are inferred for uncalibrated brain regions. In this way, the hemodynamic brain atlas is extended using transfer functions. This means infers whole-brain hemodynamics by using a small set of individual calibration regions, e.g., one for each lobe.

[0064] Optionally, the non-invasive neuromonitoring device 12 may be configured to monitor further evoked hemodynamic responses in one or more brain regions having sufficiently strong excitatory connectivity to the target ROI. The computing device 14 may be configured to determine a set of parameters representing the HRF of the further evoked hemodynamic responses in one or more brain regions and to associate the set of parameters with one or more brain regions to form a hemodynamic brain atlas. In other words, the HRF is estimated not only in the stimulated ROI but also in other regions that may exhibit a consistent BOLD response after stimulation. This is because neural activity is known to propagate to brain regions with high density of excitatory connectivity. Thus, in some cases, neural stimulation may also evoke neurons in distal brain regions with strong excitatory connectivity, ensuring a BOLD response. Using comparison with baseline measurements performed without stimulation, the system can calibrate multiple brain regions using only neural stimulation of a single ROI or a small number of ROIs.

[0065] Optionally, the non-invasive transcranial nerve stimulator 10 may be configured to induce a sequence of hemodynamic responses in a target ROI. The non-invasive neuromonitoring device 12 is configured to monitor the sequence of evoked hemodynamic responses in the target ROI. The computing device 14 is configured to perform comparisons between sequences of evoked hemodynamic responses to correct for potential neurostimulation-induced confounding on the HRF. For example, the non-invasive transcranial nerve stimulator may be an MRI. The MRI may use an fMRI sequence to better isolate the effects of changes in cerebral blood flow and bold, such as vascular space occupancy-dependent fMRI, or an FMR sequence to better estimate the effects of temperature changes and bold.

[0066] Figure 3 shows a further example of system 100 for creating a hemodynamic brain atlas for calibration of cerebral hemodynamics. In this example, system 100 further comprises a sensory stimulator 22 configured to apply at least one sensory stimulus to a human subject in order to induce neural activity in order to elicit a hemodynamic response in a target ROI.

[0067] In the example shown in Figure 3, the sensory stimulation device 22 is a visual stimulation device. The visual stimulation device may be a computer monitor or a screen such as a television for displaying any combination of still images and videos on a predetermined area of ​​the screen for a predetermined period of time. The visual stimulation is brought to the scanner using a mirror configuration, and the patient can be provided with an MRI-compatible head-mounted display or the like, allowing the patient to view the (inverted) display in the mirror.

[0068] In another example (not shown), the sensory stimulator 22 may be an auditory stimulator such as a speaker that is connected to an audio source and outputs a predetermined sound at a predetermined timing according to a control signal.

[0069] In further examples (not shown), the sensory stimulator 22 may be a tactile stimulator such as a vibrator that is in contact with (or very close to) the subject and vibrates at a predetermined timing with a predetermined vibration intensity and frequency in response to a control signal.

[0070] The computing device 14 may be configured to perform a comparison between hemodynamic responses induced by a non-invasive transcranial nerve stimulator and hemodynamic responses induced by a sensory stimulator to correct potential neuron-induced confounding on the HRF.

[0071] In other words, for a single, distinct brain region, the deconvolution of neuronal stimulation-induced HRF can be compared to the deconvolution of sensory-induced HRF. This direct comparison allows the system to control neuronal stimulation-induced confounding of HRF. Slight heating of the tissue (within a safety margin) can result in a larger HRF response. Calibration procedures involve comparing sensory-induced HRF in the same brain region, thereby creating an additional criterion. For example, the visual cortex may be calibrated twice, using visual stimulation via a projector and tFUS, as shown in Figure 3. Comparisons between both types of stimulation allow for estimation and correction of tFUS-induced effects on HRF.

[0072] Figure 4 schematically shows the device 200 for calibrating cerebral hemodynamics. The device 200 comprises an input unit 210, a processing unit 220, and an output unit 230.

[0073] The input unit 210 is configured to receive (i) hemodynamic responses in a region of interest (ROI) of the brain of a human subject acquired by a non-invasive neurosurgical device, and (ii) a hemodynamic brain atlas.

[0074] In some cases, hemodynamic responses can be obtained using functional neuroimaging modalities such as fMRI and PET. In some cases, hemodynamic responses can be obtained using hemodynamic imaging with low-intensity focused ultrasound imaging or near-infrared spectroscopy.

[0075] A hemodynamic brain atlas includes multiple brain regions. Each brain region is associated with its respective hemodynamic response function (HRF), which is represented by a set of parameters such as peak amplitude, trough amplitude, time to peak, time to fall, ascending slope, descending slope, and FWHM. An exemplary hemodynamic brain atlas is shown in Figure 2B.

[0076] In some cases, hemodynamic brain atlases may include parameters based on previous information from measurements taken earlier in the same patient. For example, it is possible to combine several HRF measurements taken in the same brain region of the same person over a period of several weeks or years. This can be considered a diagnostic tool in itself, as it can show how the shape and timing of HRF in a particular brain region changes or worsens over time.

[0077] In some cases, a hemodynamic brain atlas may include parameters based on earlier information from measurements taken earlier in other patients. Such hemodynamic brain atlases are sometimes called “external atlases.” For example, a hemodynamic brain atlas may be derived from previous HRF measurements of a group of healthy adults arbitrarily stratified by age, sex, or other factors, previous HRF measurements of a specific patient group, and previous HRF measurements of a single patient from whom brain regions are calibrated. This external atlas may also include HRF parameters derived from different individuals for various brain regions. For example, the visual cortex may be estimated in one patient, but the amygdala, for instance, may be in another patient. Before application, the system or operator may use various patient characteristics (e.g., age, sex, diagnosis) to select the most appropriate hemodynamic brain atlas.

[0078] The input unit 210 may be implemented, for example, as an Ethernet® interface, a USB® interface, a wireless interface such as WiFi® or Bluetooth®, or any equivalent data transfer interface that enables data transfer between input peripherals and the processing unit 220.

[0079] The processing unit 220 is configured to calibrate the acquired hemodynamic responses using a hemodynamic response atlas. The calibrated HRF based on the hemodynamic brain atlas is used during the acquisition of new fMRI measurements. For example, the estimation of fMRI activity functions similarly to current statistical parametric mapping studies, but instead of a standard HRF, locally calibrated HRF is convolved to estimate fMRI activity. Thus, a more accurate estimate of the patient's brain activity is obtained, which supports the formation of accurate conclusions or diagnoses.

[0080] In some cases, the target ROI(s) may differ from multiple brain regions in the hemodynamic brain atlas. In other words, the calibrated HRF in the hemodynamic brain atlas may be applied to brain regions other than those that showed a response during calibration. For example, a hemodynamic brain atlas with a set of calibrated ROIs from the left hemisphere can be used to estimate brain activity in the contralateral hemisphere. During a new fMRI acquisition, a larger set of regions including brain regions in the contralateral hemisphere may be used, regardless of whether these additional regions showed a bold response induced after stimulation of the ROIs.

[0081] The processing unit 220 refers to, or may include, application-specific integrated circuits (ASICs), electronic circuits, processors (shared, dedicated, or grouped) and / or memory (shared, dedicated, or grouped) that run one or more software or firmware programs, combinational logic circuits, and / or other suitable components that provide the functions described. Furthermore, such a processing unit 14 may be connected to volatile or non-volatile storage devices, display interfaces, communication interfaces, etc., as is known to those skilled in the art.

[0082] The output unit 230 is configured to output the hemodynamic response to be calibrated.

[0083] Figure 5 schematically shows an example of the neurosurveillance system 300. As described with respect to Figure 4, the neurosurveillance system 300 comprises a non-invasive neurosurveillance device 310 and a device 200.

[0084] The non-invasive neuromonitoring device 310 is configured to acquire hemodynamic responses in a region of interest (ROI) of the brain of a human subject.

[0085] In the example shown in Figure 5, the non-invasive neuromonitoring device 310 is an MRI machine. In other examples (not shown), the non-invasive neuromonitoring device 310 can perform functional neuroimaging using PET.

[0086] The device 200 is configured, for example, to calibrate the acquired hemodynamic response by convolving locally calibrated HRFs within a hemodynamic brain atlas in order to estimate fMRI activity.

[0087] Figure 6 shows a flowchart of Method 400 for creating a hemodynamic brain atlas for the calibration of cerebral hemodynamics.

[0088] In step 410, a non-invasive transcranial nerve stimulator induces neural activity to trigger a hemodynamic response in a target region of interest (ROI) in the brain of a human subject.

[0089] Non-invasive transcranial nerve stimulation devices may include one or more of tFUS, tDCS / tACS, and TMS.

[0090] Target ROIs can be defined anatomically, functionally, or clinically. An ROI can be anatomically defined as a motor cortex, visual cortex, amygdala, volume in atlas coordinates, or a specific part of a brain region in the cortex (e.g., cortical layer IV of the MT in the left hemisphere), a subcortical region (e.g., substantia nigra, thalamus, hippocampus), or a region in the cerebellum. An ROI can be functionally defined using localizer tasks in fMRI (motor, speech, etc.), functional connectivity, a functional atlas, or a PET tracer. Clinically, an ROI may be, for example, a lesion in an epileptic seizure or stroke.

[0091] If necessary, non-invasive transcranial nerve stimulators can target multiple different brain regions sequentially with a single transducer or simultaneously with multiple transducers.

[0092] In step 420, a non-invasive neuromonitoring device monitors the evoked hemodynamic response in the target ROI.

[0093] Non-invasive neurosurgical devices may include one or more of fMRI, PET, functional ultrasound, LIFU, NIRS, EEG, MEG, and OPM.

[0094] In step 430, the computing device determines a set of parameters representing the HRF of the induced hemodynamic response at the target ROI. The set of parameters may include one or more of the following: peak amplitude, trough amplitude, time to peak, time to fall, rise slope, fall slope, FWHM, etc.

[0095] In step 440, the computing device associates a set of HRF parameters with a target ROI to form a hemodynamic brain atlas. Thus, the hemodynamic brain atlas includes multiple locally calibrated HRFs.

[0096] Figure 7 shows a flowchart of 500 methods for calibrating cerebral hemodynamics.

[0097] In step 510, the input unit receives (ii) hemodynamic responses in a region of interest (ROI) of the brain of a human subject acquired by a non-invasive neuromonitoring device, and (ii) a hemodynamic brain atlas. The hemodynamic brain atlas includes multiple brain regions, each associated with its respective hemodynamic response function (HRF), which is represented by a set of parameters.

[0098] In some cases, hemodynamic brain atlases may include parameters based on previous information from measurements taken earlier in the same patient.

[0099] In some cases, a hemodynamic brain atlas, also called an external atlas, may include parameters based on prior information from measurements in other patients. This external hemodynamic brain atlas may consist of averages from a group of healthy adults, a specific group of patients, or a single patient whose brain regions have been calibrated.

[0100] In step 520, the processing unit calibrates the acquired hemodynamic responses using a hemodynamic brain atlas.

[0101] In step 530, the output unit outputs the hemodynamic response to be calibrated.

[0102] All definitions defined and used herein should be understood to govern the dictionary definitions, definitions in documents referenced by citation, and / or the ordinary meanings of the terms being defined.

[0103] The indefinite articles "a" and "an" should be understood to mean "at least one" in the specification and claims, as used herein, unless the opposite is explicitly indicated.

[0104] The phrase "and / or," as used herein in the specification and claims, should be understood to mean "either or both" of the elements thus linked, i.e., elements that exist simultaneously in some cases and not simultaneously in other cases. The numerous elements listed in "and / or" should similarly be interpreted as "one or more" of the elements thus linked. Other elements may exist, if desired, other than those specifically identified by the "and / or" clause, whether related to or not to those specifically identified elements.

[0105] In the specification and claims, “or” as used herein should be understood to have the same meaning as “and / or” as previously defined. For example, when separating items in a list, “or” or “and / or” should be interpreted as inclusive, that is, including at least one, and more than one, of the number or list of elements and, if desired, any further unlisted items. Only terms that are explicitly indicated, such as “one of” or “exactly one of” or, when used in the claims, “consisting of” refer to including exactly one element of the number or list of elements. In general, the term “or” should be interpreted as simply indicating exclusive substitutes (i.e., “one or the other, but not both”) when preceded by terms of exclusivity such as “either,” “one of,” “one of” or “exactly one of” as used herein.

[0106] As used herein in the specification and claims, the phrase “at least one” should be understood to mean, in a reference to a list of one or more elements, at least one selected from any one or more elements in the list of elements, but not necessarily including at least one of each and every element specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. This definition allows for the optional presence of elements other than those specifically identified in the list of elements referred to by the phrase “at least one,” whether or not they are related to the specifically identified elements.

[0107] In the claims and specification, all transitional phrases such as “include,” “include,” “carry,” “have,” “contain,” “related,” “maintain,” and “composed of” should be understood as open-ended, meaning they include but are not limiting. Only the transitional phrases “consisting of” and “consisting essentially of” are closed or semi-closed transitional phrases, respectively.

[0108] In another exemplary embodiment of the present invention, a computer program or computer program element is provided, characterized in that it is adapted to perform a method step of a method according to one of the embodiments described above on a suitable system.

[0109] Accordingly, the computer program elements may be stored in a computer unit, which may be part of an embodiment of the present invention. This computing unit may be adapted to perform or trigger the execution of the steps of the method described above. Furthermore, it may be adapted to operate the components of the apparatus described above. The computing unit may be adapted to operate automatically and / or to execute user sequences. The computer program may be loaded into the working memory of a data processor. Accordingly, the data processor may be equipped to perform the method of the present invention.

[0110] This exemplary embodiment of the present invention encompasses both computer programs that use the present invention from the outset and computer programs that, by means of updating, transform an existing program into a program that uses the present invention.

[0111] Furthermore, computer program elements can provide all the steps necessary to satisfy the procedure of the exemplary embodiment of the procedure described above.

[0112] According to a further exemplary embodiment of the present invention, a computer-readable medium such as a CD-ROM is presented, having computer program elements stored thereon, which are described in the previous section.

[0113] Computer programs may be stored and / or distributed on suitable media such as optical storage media or solid-state media supplied together with or as part of other hardware, but may also be distributed in other forms, such as via the Internet or other wired or wireless communication systems.

[0114] However, computer programs may also be presented over a network such as the World Wide Web and downloaded from such a network into the working memory of a data processor. According to a further exemplary embodiment of the present invention, a medium is provided for making a computer program element available for download, and this computer program element is configured to perform a method according to one of the aforementioned embodiments of the present invention.

[0115] While several embodiments of the present invention have been described and illustrated herein, those skilled in the art will readily conceive of various other means and / or structures for performing the functions described herein and / or obtaining one or more of the results described herein, and each of such variations and / or modifications will be considered to fall within the scope of the embodiments of the present invention described herein. More generally, those skilled in the art will readily recognize that all parameters, dimensions, materials and configurations described herein are intended to be illustrative, and that actual parameters, dimensions, materials and / or configurations will depend on the specific application or application in which the teachings of the invention are used. Those skilled in the art will be able to recognize or confirm many equivalents to the specific inventive embodiments described herein using methods no more than routine experimentation. Accordingly, it should be understood that the embodiments described herein are presented only by example, and that within the appended claims and their equivalents, the inventive embodiments may be implemented in a manner different from those specifically described and claimed. The inventive embodiments of this disclosure are directed toward each individual feature, system, product, material, kit and / or method described herein. In addition, any combination of two or more such features, systems, products, materials, kits, and / or methods falls within the inventive scope of this disclosure, provided that such features, systems, products, materials, kits, and / or methods are not contradictory to each other. The embodiments of the present invention are described below. (Note 1) A system for creating a hemodynamic brain atlas for the calibration of cerebral hemodynamics, A non-invasive transcranial nerve stimulator configured to induce neural activity in a target region of interest of the brain of a human subject to induce a hemodynamic response, the non-invasive transcranial nerve stimulator having transcranial functional ultrasound stimulation, A non-invasive neuromonitoring device configured to monitor evoked hemodynamic responses in the aforementioned target region of interest, A computing device configured to determine a set of parameters representing the hemodynamic response function of the induced hemodynamic response in the target region of interest, and to associate the set of parameters of the hemodynamic response function with the target region of interest to form the hemodynamic brain atlas. A system that has (Note 2) The non-invasive transcranial nerve stimulator is configured to induce multiple hemodynamic responses in multiple target regions of interest, and each hemodynamic response is induced in each target region of interest. The computing device is configured to determine each set of parameters representing the corresponding hemodynamic response function for each induced hemodynamic response, and to associate each set of parameters with the corresponding target region of interest in order to form the hemodynamic brain atlas. The system described in Appendix 1. (Note 3) The non-invasive neuromonitoring device is configured to monitor further evoked hemodynamic responses in one or more brain regions having sufficiently strong excitatory connectivity to the target region of interest. The computing device is configured to determine a set of parameters representing the hemodynamic response function of further induced hemodynamic responses in one or more brain regions, and to associate the set of parameters with the one or more brain regions to form the hemodynamic brain atlas. The system described in Appendix 1 or 2. (Note 4) A sensory stimulation device configured to apply at least one sensory stimulus to a human subject in order to induce neural activity in order to elicit a hemodynamic response in the aforementioned target region of interest. It has, The computing device is configured to perform a comparison between the hemodynamic response induced by the non-invasive transcranial nerve stimulator and the hemodynamic response induced by the sensory stimulator, and to correct for potential neuron-induced confounding on the hemodynamic response function. The system described in any one of the appendices 1 to 3. (Note 5) The non-invasive transcranial nerve stimulator is configured to induce a sequence of hemodynamic responses in the target region of interest. The non-invasive neuromonitoring device is configured to monitor the sequence of evoked hemodynamic responses in the target region of interest. The computing device is configured to perform comparisons between sequences of evoked hemodynamic responses in order to correct for potential neuron-induced confounding on the hemodynamic response function. The system described in any one of the appendices 1 to 3. (Note 6) The aforementioned target region of interest is selected from a set of calibration brain regions. The hemodynamic response function in other brain regions of the aforementioned brain can be derived from the hemodynamic response function in the set of calibrated brain regions. The system described in any one of the appendices 1 through 5. (Note 7) The aforementioned non-invasive transcranial nerve stimulator is Transcranial electrical stimulation, and Transcranial magnetic stimulation A system according to any one of the appendices 1 to 6, further comprising one or more of the above. (Note 8) The non-invasive nerve monitoring device, A device for neurological monitoring of cerebral hemodynamics, A device for measuring electrical signals generated by neurons in order to measure brain activity, A system according to any one of the appendices 1 to 7, further comprising one or more of the above. (Note 9) A device for calibrating cerebral hemodynamics, (i) hemodynamic responses in a region of interest of the brain of a human subject acquired by a non-invasive neurosurgical device, and (ii) an input unit configured to receive a hemodynamic brain atlas, wherein the hemodynamic brain atlas comprises multiple brain regions, each brain region being associated with a hemodynamic response function represented by a set of parameters, the input unit and A processing unit configured to calibrate the acquired hemodynamic response using the hemodynamic brain atlas, An output unit configured to output the calibrated hemodynamic response, A device having. (Note 10) The aforementioned hemodynamic brain atlas is Previous hemodynamic response function measurements of the aforementioned human subject, Previous hemodynamic response function measurements of a group of healthy adults, Previous hemodynamic response function measurements for a specific patient group, and Previous hemodynamic response function measurements of a single patient, potentially calibrated in brain regions. The apparatus described in Appendix 9, which can be derived from one or more of the above. (Note 11) The apparatus as described in Appendix 9 or 10, wherein the region of interest is different from the multiple brain regions of the hemodynamic brain atlas. (Note 12) It is a neural monitoring system, A non-invasive neurosurveillance device for acquiring hemodynamic responses in regions of interest of the brain of human subjects, A device described in any one of the appendices 9 to 11 for calibrating the acquired hemodynamic response, A device having. (Note 13) A method for creating a hemodynamic brain atlas for the calibration of cerebral hemodynamics, A non-invasive transcranial nerve stimulator is used to induce neural activity in a target region of interest of the brain of a human subject, wherein the non-invasive nerve stimulator has transcranial functional ultrasound stimulation. The steps include monitoring the evoked hemodynamic response in the target region of interest using the non-invasive neuromonitoring device, The steps include: determining a set of parameters representing the hemodynamic response function of the induced hemodynamic response in the target region of interest using a computing device; The computing device performs the steps of associating the set of parameters of the hemodynamic response function with the target region of interest to form the hemodynamic brain atlas. A method having (Note 14) A computer implementation method for calibrating cerebral hemodynamics, The input unit receives (i) hemodynamic responses in a region of interest of the brain of a human subject acquired by a non-invasive neuromonitoring device, and (ii) a hemodynamic brain atlas, wherein the hemodynamic brain atlas has one or more brain regions, and each brain region is associated with a hemodynamic response function represented by a set of parameters. The processing unit performs the steps of calibrating the acquired hemodynamic response using the hemodynamic brain atlas, The output unit outputs the calibrated hemodynamic response. A method having (Note 15) A computer program element for controlling a system described in any one of Appendices 1 to 8 or a device described in any one of Appendices 9 to 11, which, when executed by a processor, is configured to perform the method described in Appendice 13 or 14.

Claims

1. A system for creating a hemodynamic brain atlas for the calibration of cerebral hemodynamics, A non-invasive transcranial nerve stimulator configured to induce neural activity in a target region of interest of the brain of a human subject to induce a hemodynamic response, the non-invasive transcranial nerve stimulator having transcranial functional ultrasound stimulation, A non-invasive neuromonitoring device configured to monitor evoked hemodynamic responses in the aforementioned target region of interest, A computing device configured to determine a set of parameters representing the hemodynamic response function of the induced hemodynamic response in the target region of interest, and to associate the set of parameters of the hemodynamic response function with the target region of interest to form the hemodynamic brain atlas. It has, The non-invasive transcranial nerve stimulator is configured to induce multiple hemodynamic responses in multiple target regions of interest, and each hemodynamic response is induced in each target region of interest. The computing device is configured to determine, for each induced hemodynamic response, a set of parameters representing the hemodynamic response function of the induced hemodynamic response, and to associate each of the sets of parameters with the target region of interest in which the induced hemodynamic response was induced, thereby forming a hemodynamic brain atlas usable for calibration of brain hemodynamics. The system further includes a sensory stimulation device configured to apply at least one sensory stimulus to a human subject in order to induce neural activity in order to elicit a hemodynamic response in the target region of interest. The computing device is configured to perform a comparison between the hemodynamic response induced by the non-invasive transcranial nerve stimulator and the hemodynamic response induced by the sensory stimulator, and to correct for potential neuron-induced confounding on the hemodynamic response function. system.

2. A system for creating a hemodynamic brain atlas for calibration of cerebral hemodynamics, A non-invasive transcranial nerve stimulator configured to induce neural activity in a target region of interest of the brain of a human subject to induce a hemodynamic response, the non-invasive transcranial nerve stimulator having transcranial functional ultrasound stimulation, A non-invasive neuromonitoring device configured to monitor evoked hemodynamic responses in the aforementioned target region of interest, A computing device configured to determine a set of parameters representing the hemodynamic response function of the induced hemodynamic response in the target region of interest, and to associate the set of parameters of the hemodynamic response function with the target region of interest to form the hemodynamic brain atlas. It has, The non-invasive transcranial nerve stimulator is configured to induce multiple hemodynamic responses in multiple target regions of interest, and each hemodynamic response is induced in each target region of interest. The computing device is configured to determine, for each induced hemodynamic response, a set of parameters representing the hemodynamic response function of the induced hemodynamic response, and to associate each of the sets of parameters with the target region of interest in which the induced hemodynamic response was induced, thereby forming a hemodynamic brain atlas usable for calibration of brain hemodynamics. The non-invasive transcranial nerve stimulator is configured to induce a sequence of hemodynamic responses in the target region of interest. The non-invasive neuromonitoring device is configured to monitor the sequence of evoked hemodynamic responses in the target region of interest. The computing device is configured to perform comparisons between sequences of evoked hemodynamic responses in order to correct for potential neuron-induced confounding on the hemodynamic response function. system.

3. The non-invasive neuromonitoring device is configured to monitor further evoked hemodynamic responses in one or more brain regions having sufficiently strong excitatory connectivity to the target region of interest. The computing device is configured to determine a set of parameters representing the hemodynamic response function of further induced hemodynamic responses in one or more brain regions, and to associate the set of parameters with the one or more brain regions to form the hemodynamic brain atlas. The system according to claim 1 or 2.

4. The aforementioned target region of interest is selected from a set of calibration brain regions. The hemodynamic response function in other brain regions of the aforementioned brain can be derived from the hemodynamic response function in the set of calibrated brain regions. The system according to any one of claims 1 to 3.

5. The aforementioned non-invasive transcranial nerve stimulator is Transcranial electrical stimulation, and Transcranial magnetic stimulation The system according to any one of claims 1 to 4, further comprising one or more of the above.

6. The non-invasive nerve monitoring device, A device for neurological monitoring of cerebral hemodynamics, A device for measuring electrical signals generated by neurons in order to measure brain activity, The system according to any one of claims 1 to 5, further comprising one or more of the above.

7. A device for calibrating cerebral hemodynamics, (i) hemodynamic responses in a target region of interest of the brain of a human subject acquired by a non-invasive neurosurgical device, and (ii) an input unit configured to receive a hemodynamic brain atlas created by a system for creating a hemodynamic brain atlas for calibration of brain hemodynamics, wherein the hemodynamic brain atlas includes a plurality of brain regions, each brain region being associated with a hemodynamic response function represented by a set of parameters, A processing unit configured to calibrate the acquired hemodynamic response using the hemodynamic brain atlas, An output unit configured to output the calibrated hemodynamic response and It has, The aforementioned system, A non-invasive transcranial nerve stimulator configured to induce neural activity in a target region of interest of the brain of a human subject to induce a hemodynamic response, the non-invasive transcranial nerve stimulator having transcranial functional ultrasound stimulation, A non-invasive neuromonitoring device configured to monitor evoked hemodynamic responses in the aforementioned target region of interest, A computing device configured to determine a set of parameters representing the hemodynamic response function of the induced hemodynamic response in the target region of interest, and to associate the set of parameters of the hemodynamic response function with the target region of interest to form the hemodynamic brain atlas. It has, The non-invasive transcranial nerve stimulator is configured to induce multiple hemodynamic responses in multiple target regions of interest, and each hemodynamic response is induced in each target region of interest. The computing device is configured to determine a set of parameters representing the hemodynamic response function of each induced hemodynamic response, and to associate each of the sets of parameters with the target region of interest in which the induced hemodynamic response was triggered, thereby forming the hemodynamic brain atlas. Device.

8. The aforementioned hemodynamic brain atlas is Previous hemodynamic response function measurements of the aforementioned human subject, Previous hemodynamic response function measurements of a group of healthy adults, Previous hemodynamic response function measurements for a specific patient group, and Previous hemodynamic response function measurements of a single patient, potentially calibrated in brain regions. The apparatus according to claim 7, which can be derived from one or more of the following.

9. The apparatus according to claim 7 or 8, wherein the region of interest is different from the plurality of brain regions of the hemodynamic brain atlas.

10. It is a neural monitoring system, A non-invasive neurosurveillance device for acquiring hemodynamic responses in target regions of interest of the brain of human subjects, An apparatus according to any one of claims 7 to 9 for calibrating the acquired hemodynamic response, A system that has

11. A computer implementation method for calibrating cerebral hemodynamics, The input unit receives (i) hemodynamic responses in a target region of interest of the brain of a human subject acquired by a non-invasive neuromonitoring device, and (ii) a hemodynamic brain atlas prepared by a method for preparing a hemodynamic brain atlas for calibration of brain hemodynamics, wherein the hemodynamic brain atlas has one or more brain regions, each brain region being associated with each hemodynamic response function, which is represented by a set of parameters. The processing unit performs the steps of calibrating the acquired hemodynamic response using the hemodynamic brain atlas, The output unit outputs the calibrated hemodynamic response. It has, The aforementioned method further, A non-invasive transcranial nerve stimulator is used to induce neural activity in a target region of interest of the brain of a human subject, wherein the non-invasive transcranial nerve stimulator has transcranial functional ultrasound stimulation. The steps include monitoring the evoked hemodynamic response in the target region of interest using the non-invasive neuromonitoring device, The steps include: determining a set of parameters representing the hemodynamic response function of the induced hemodynamic response in the target region of interest using a computing device; The computing device performs the steps of associating the set of parameters of the hemodynamic response function with the target region of interest to form the hemodynamic brain atlas. It has, The non-invasive transcranial nerve stimulator is configured to induce multiple hemodynamic responses in multiple target regions of interest, and each hemodynamic response is induced in each target region of interest. The computing device is configured to determine, for each induced hemodynamic response, a set of parameters representing the hemodynamic response function of the induced hemodynamic response, and to associate each of the sets of parameters with the target region of interest in which the induced hemodynamic response was induced, thereby forming the hemodynamic brain atlas.

12. A computer program for controlling the system according to any one of claims 1 to 6 or the apparatus according to any one of claims 7 to 9, the computer program configured to perform the method according to claim 11 when executed by a processor.

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