Configuration of cerebellar closed loop neurostimulation using biomarkers

Abstract

The invention relates to methods and systems of treating or preventing a neural disorder in a subject by (1) receiving one or more bioelectrical signals from the subject; (2) identifying one or more biomarkers from the bioelectrical signals; (3) mapping the biomarkers to one or more cerebellar stimulation parameters; and (4) modulating cerebellar stimulation based on the cerebellar stimulation parameters. The methods and systems may also include steps or instructions for: (5) receiving one or more bioelectrical signals from the subject after modulating the cerebellar stimulation; (6) identifying changes in the biomarkers from the bioelectrical signals relative to the biomarkers prior to modulating the cerebellar stimulation; (7) adjusting the cerebellar stimulation parameters based on the identified changes; and (8) re-modulating cerebellar stimulation based on the adjusted cerebellar stimulation parameters.

Description

PCT Application Attorney Docket No. AF44111.P045WOBLG Ref. No. 25-002TITLECONFIGURATION OF CEREBELLAR CLOSED LOOP NEUROSTIMULATION USING BIOMARKERSSTATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0001] This invention was made with government support under R01NS119301, awarded by the National Institutes of Health. The government has certain rights in the invention.CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 734,597, filed on December 16, 2024. The entirety of the aforementioned application is incorporated herein by reference.BACKGROUND

[0003] A need exists for improved and versatile deep brain stimulation methods and systems that may be optimized for different neural disorders, such as dystonia. Numerous embodiments of the present disclosure aim to address the aforementioned need.SUMMARY

[0004] Embodiments of the present disclosure pertain to a method of treating or preventing a neural disorder in a subject by (1) receiving one or more bioelectrical signals from the subject; (2) identifying one or more biomarkers from the bioelectrical signals; (3) mapping the biomarkers to one or more cerebellar stimulation parameters; and (4) modulating cerebellar stimulation based on the cerebellar stimulation parameters. In some embodiments, the methods of the present disclosure also include steps of: (5) receiving one or more bioelectrical signals from the subject after modulating the cerebellar stimulation; (6) identifying changes in the biomarkers from the bioelectrical signals relative to the biomarkers prior to modulating the cerebellar stimulation; (7) adjusting the cerebellar stimulation parameters based on the identified changes; and (8) re-modulating cerebellar stimulation based on the adjusted cerebellar stimulation parameters.PCT Application Attorney Docket No. AF44111.P045WOBLG 25-002

[0005] Additional embodiments of the present disclosure pertain to a system operable for treating or preventing a neural disorder in a subject. In some embodiments, the system includes: (1) a processing unit operable for receiving one or more bioelectrical signals from the subject; (2) a programmer with programming instructions for: (a) identifying one or more biomarkers from the bioelectrical signals, (b) mapping the biomarkers to one or more cerebellar stimulation parameters, and (c) modulating cerebellar stimulation based on the cerebellar stimulation parameters; and (3) a deep brain stimulation system operable for delivering the cerebellar stimulation to the subject.

[0006] In some embodiments, the processor is also operable for receiving one or more bioelectrical signals from a subject after modulating the cerebellar stimulation. In some embodiments, the programmer further includes programming instructions for: (d) identifying changes in the biomarkers from the bioelectrical signals relative to the biomarkers prior to modulating the cerebellar stimulation, (e) adjusting the cerebellar stimulation parameters based on the identified changes, and (f) remodulating cerebellar stimulation based on the adjusted cerebellar stimulation parameters.DESCRIPTION OF THE DRAWINGS

[0007] FIG. 1 provides an illustration of a method of treating or preventing a neural disorder in a subject.

[0008] FIG. 2 provides a schematic demonstrating an example of closed-loop deep brain stimulation systems (DBS) used in Example 1.

[0009] FIG. 3 provides an example of a DBS programmer implemented with different confinements of symptom-specific sensor parameters.

[0010] FIG. 4 provides a flow chart illustrating courses of events and interactions between a processing unit, programmer, and a DBS unit that allow a refinement of cerebellar therapy for a specific symptom.PCT Application Attorney Docket No. AF44111.P045WOBLG 25-002

[0011] FIG. 5 provides an example of how electromyography (EMG) signals being monitored are used to define and detect either over- or co-contraction episodes. Once these symptoms are detected, cerebellar DBS is triggered in their presence, terminated in their absence, and can be adjusted in its stimulation parameter. The example shows stimulation intensity being adjusted by different powers of muscle contraction. However, this Example is not limited to adjusting intensity of the stimulation but may include adjusting other aspects of stimulation parameters such as frequency, pulse width and / or patterned stimulation.

[0012] FIG. 6 demonstrates online monitoring of spike variability of a cerebellar nuclei neuron to trigger and terminate cerebellar DBS. Repeated applications of cerebellar DBS restore typical spike variability in cerebellar nuclei neurons.

[0013] FIG. 7 demonstrates that the utilization of closed-loop DBS has long-lasting benefits.

[0014] FIGS. 8A-8C demonstrate that closed-loop cerebellar DBS entrains neural spiking and produces lasting effects.

[0015] FIGS. 9A-9B provide experimental results related to DBS-induced local field potential (LFP) entrainment to monitor changes in neural circuits.

[0016] FIGS. 10A-10E demonstrate that neural biomarkers anticipate dystonic muscle contractions seconds before onset.DETAILED DESCRIPTION

[0017] It is to be understood that both the foregoing general description and the following detailed description are illustrative and explanatory, and are not restrictive of the subject matter, as claimed. In this application, the use of the singular includes the plural, the word “a” or “an” means “at least one”, and the use of “or” means “and / or”, unless specifically stated otherwise. Furthermore, the use of the term “including”, as well as other forms, such as “includes” and “included”, is not limiting. Also, terms such as “element” or “component” encompass both elements or components comprising one unit and elements or components that include more than one unit unless specifically stated otherwise.PCT Application Attorney Docket No. AF44111.P045WOBLG 25-002

[0018] The section headings used herein are for organizational purposes and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, and treatises, are hereby expressly incorporated herein by reference in their entirety for any purpose. In the event that one or more of the incorporated literature and similar materials defines a term in a manner that contradicts the definition of that term in this application, this application controls.

[0019] Conventional deep brain stimulation therapies have been utilized to treat or prevent various neural disorders. However, conventional deep brain stimulation therapies may not be optimized for specific diseases. For instance, conventional deep brain stimulation therapies that typically target the basal ganglia or thalamic regions are not optimized for the spectrum of dystonia manifestations or any existing co-morbidities. Moreover, conventional deep brain stimulation therapies do not consider aberrant cerebellar outflow to the network.

[0020] Furthermore, dysfunctions of cerebellar nuclei neurons, the main output of the cerebellum, are a common consequence among several etiologically distinct mouse models of movement disorders. Importantly, Purkinje cells (the predominant modulators of cerebellar nuclei firing patterns) and cerebellar nuclei neurons also exhibit abnormal burst firing in human patients with athetosis.

[0021] As such, a need exists for improved and versatile deep brain stimulation methods and systems that may be optimized for different neural disorders, such as dystonia. Numerous embodiments of the present disclosure aim to address the aforementioned need.

[0022] In some embodiments, the present disclosure pertains to a method of treating or preventing a neural disorder in a subject. In some embodiments illustrated in FIG. 1, the methods of the present disclosure include: receiving one or more bioelectrical signals from the subject (step 10); identifying one or more biomarkers from the bioelectrical signals (step 12); mapping the biomarkers to one or more cerebellar stimulation parameters (step 14); and modulating cerebellar stimulation based on the cerebellar stimulation parameters (step 16). In some embodiments, the methods of the present disclosure also include: receiving one or more bioelectrical signals from the subject after modulating the cerebellar stimulation (step 18); identifying changes in the biomarkers from the bioelectrical signals relative to the biomarkers prior to modulating the cerebellar stimulation (step 20); adjusting the cerebellar stimulation parameters based on the identified changes (step 22); and re-modulating cerebellar stimulation based on the adjusted cerebellar stimulation parameters (step 24).PCT Application Attorney Docket No. AF44111.P045WOBLG 25-002

[0023] Additional embodiments of the present disclosure pertain to a system operable for treating or preventing a neural disorder in a subject. In some embodiments, the system includes: (1) a processing unit operable for receiving one or more bioelectrical signals from the subject; (2) a programmer with programming instructions for: (a) identifying one or more biomarkers from the bioelectrical signals, (b) mapping the biomarkers to one or more cerebellar stimulation parameters, and (c) modulating cerebellar stimulation based on the cerebellar stimulation parameters; and (3) a deep brain stimulation system operable for delivering the cerebellar stimulation to the subject.

[0024] In some embodiments, the processor is also operable for receiving one or more bioelectrical signals from a subject after modulating the cerebellar stimulation. In some embodiments, the programmer further includes programming instructions for: (d) identifying changes in the biomarkers from the bioelectrical signals relative to the biomarkers prior to modulating the cerebellar stimulation, (e) adjusting the cerebellar stimulation parameters based on the identified changes, and (f) remodulating cerebellar stimulation based on the adjusted cerebellar stimulation parameters.

[0025] As set forth in more detail herein, the methods and systems of the present disclosure can have numerous embodiments.

[0026] Receiving bioelectrical signals from subjects

[0027] The methods and systems of the present disclosure may receive various bioelectrical signals from subjects. For instance, in some embodiments, the bioelectrical signals include, without limitation, electromyography (EMG) signals, cerebellar nuclei (CN) extracellular activity signals (single or multi-unit). Purkinje cell extracellular activity signals (single or multi-unit), local field potential (LFP) signals, electroencephalogram (EEG) signals, electrocorticogram (ECoG) signals, or combinations thereof. In some embodiments, the bioelectrical signals include cerebellar nuclei (CN) extracellular activity signals. In some embodiments, the bioelectrical signals include electromyography (EMG) signals.PCT Application Attorney Docket No. AF44111.P045WOBLG 25-002

[0028] Bioelectrical signals may be received from various regions of subjects. For instance, in some embodiments, bioelectrical signals may be received from the cerebellar nuclei, Purkinje cells, the cerebellum, brain cortical regions, extracerebellar brain regions, the cerebellar cortex, single cells, population of cells, single or multiple extracerebellar brain regions, one or more muscles, or combinations thereof. In some embodiments, bioelectrical signals may be received from the cerebellar nuclei of a subject. In some embodiments, bioelectrical signals may be received from the cerebellar cortex of a subject. In some embodiments, bioelectrical signals may be received from single cells of subjects. In some embodiments, bioelectrical signals may be received from a population of cells from subjects. In some embodiments, bioelectrical signals may be received from single or multiple extracerebellar brain regions. In some embodiments, bioelectrical signals may be received from one or more muscles of subjects.

[0029] In some embodiments, the methods of the present disclosure also include a step of detecting bioelectrical signals. In some embodiments, the bioelectrical signals are detected by sensors. In some embodiments, the systems of the present disclosure also include one or more sensors in electrical communication with a processing unit. In some embodiments, the sensors are operable to detect one or more bioelectrical signals from a subject.

[0030] In some embodiments, the sensors include, without limitation, single unit extracellular sensors, multi-unit extracellular sensors, local field potential (LFP) sensors, electroencephalogram (EEG) sensors, electrocorticogram (ECoG) sensors, electromyogram (EMG) sensors, or combinations thereof. In some embodiments, the sensors include electrodes. In some embodiments, the bioelectrical signals are detected by sensors in real-time.

[0031] Various methods may be utilized to receive bioelectrical signals from subjects. For instance, in some embodiments, the bioelectrical signals are received by a processing unit.PCT Application Attorney Docket No. AF44111.P045WOBLG 25-002

[0032] In some embodiments, the methods of the present disclosure also include a step of amplifying and filtering bioelectrical signals. In some embodiments, the bioelectrical signals are amplified and filtered at 0.3-13 kHz (NPI). In some embodiments, bioelectrical signals may be digitized and analyzed using a software, such as Spike2 software. In some embodiments, threshold-based spike detection and template-matched spike sorting are applied in real-time. In some embodiments, a custom Spike2 script may be used to continuously monitor the state of incoming bioelectrical signals, along with a Spike2 configuration paradigm that initiates pre-programmed deep brain stimulation (DBS) protocols (STG4002, multichannel system).

[0033] Identifying biomarkers from bioelectrical signals

[0034] The methods and systems of the present disclosure may identify various biomarkers from bioelectrical signals. For instance, in some embodiments, the identified biomarkers include, without limitation, cerebellar nuclei (CN) or Purkinje cell (PC) firing rate thresholds, pattern thresholds, global coefficient of variance (CV) thresholds, local coefficient of variance (CV2) thresholds, spike pattern thresholds, pause thresholds, rhythmicity thresholds, degree of modulation thresholds, synchrony thresholds, local field potential (LFP) thresholds, electroencephalogram (EEG) power thresholds, electrocorticogram (ECoG) power thresholds, frequency band power thresholds, ratio power thresholds, electromyography (EMG) power value thresholds, EMG power timing thresholds, EMG power duration thresholds, spectral power value thresholds, spectral power timing thresholds, spectral power duration thresholds, ratio band power thresholds, coherence of signals thresholds, complexity of signals thresholds, or combinations thereof.PCT Application Attorney Docket No. AF44111.P045WOBLG 25-002

[0035] In some embodiments, the identified biomarkers include cerebellar nuclei (CN) firing rate thresholds, global coefficient of variance (CV) thresholds, local coefficient of variance (CV2) thresholds, spike pattern thresholds, pause thresholds, rhythmicity thresholds, degree of modulation thresholds, synchrony thresholds, or combinations thereof. In some embodiments, the identified biomarkers include Purkinje cell firing (simple spikes or complex spikes) rate thresholds, global coefficient of variance (CV) thresholds, local coefficient of variance (CV2) thresholds, spike pattern thresholds, pause thresholds, rhythmicity thresholds, degree of modulation thresholds, synchrony thresholds, or combinations thereof. In some embodiments, the identified biomarkers include local field potential (LFP), electroencephalogram (EEG) power thresholds, electrocorticogram (ECoG) power thresholds, frequency band power thresholds, ratio power thresholds, or combinations thereof. In some embodiments, the identified biomarkers include electromyography (EMG) power value thresholds, EMG power timing thresholds, EMG power duration thresholds, spectral power value thresholds, spectral power timing thresholds, spectral power duration thresholds, or combinations thereof. In some embodiments, the identified biomarkers include global coefficient of variance (CV) thresholds, local coefficient of variance (CV2) thresholds, or combinations thereof. In some embodiments one such biomarker or combinations thereof may be identified.

[0036] Biomarkers may be identified from bioelectrical signals in various manners. For instance, in some embodiments, the biomarkers are identified from the bioelectrical signals by a programmer.

[0037] Mapping biomarkers to cerebellar stimulation parameters

[0038] Identified biomarkers may be mapped to various cerebellar stimulation parameters. For instance, in some embodiments, the cerebellar stimulation parameters include, without limitation, stimulation intensity, pulse phase, pulse width, pulse shape, stimulation pattern, stimulation frequency, stimulation timing, stimulation duration, or combinations thereof.

[0039] Biomarkers may be mapped to cerebellar stimulation parameters in various manners. For instance, in some embodiments, the biomarkers are mapped to cerebellar stimulation parameters by a programmer. In some embodiments, the mapping of biomarkers to cerebellar stimulation parameters include correlating the biomarkers to cerebellar stimulation parameters.

[0040] Modulating cerebellar stimulationPCT Application Attorney Docket No. AF44111.P045WOBLG 25-002

[0041] Various methods may be utilized to modulate cerebellar stimulation based on cerebellar stimulation parameters. For instance, in some embodiments, the modulating of cerebellar stimulation includes terminating cerebellar stimulation. In some embodiments, the modulating of cerebellar stimulation includes administering cerebellar stimulation. In some embodiments, the modulating of cerebellar stimulation includes adjusting cerebellar stimulation (e.g., adjusting the intensity, frequency, pulse width, and / or pattern of cerebellar stimulation). In some embodiments, the adjustment of cerebellar stimulation includes increasing cerebellar stimulation, decreasing cerebellar stimulation, or combinations thereof. In some embodiments, the modulating of cerebellar stimulation includes administering or adjusting cerebellar stimulation.

[0042] The methods and systems of the present disclosure may be utilized to administer various types of cerebellar stimulation. For instance, in some embodiments, the cerebellar stimulation is administered by an electrode. In some embodiments, cerebellar stimulation includes deep brain stimulation (DBS) by a DBS system. In some embodiments, the DBS system includes an electrode operable for delivering cerebellar stimulation to a subject. In some embodiments, cerebellar stimulation is administered by a programmer coupled to a DBS system.

[0043] In some embodiments where the bioelectrical signals include electromyography (EMG) signals, the EMG signals may be mapped to an EMG power value threshold above or below a value representing muscle contraction (e.g., inappropriately timed muscle contraction, co-contraction, overcontraction and / or abnormal muscle contraction). In such embodiments, the modulation of cerebellar stimulation may include administering cerebellar stimulation if the EMG power value represents muscle contraction and terminating cerebellar stimulation if the EMG power value does not represent muscle contraction.PCT Application Attorney Docket No. AF44111.P045WOBLG 25-002

[0044] In some embodiments, the EMG signals may be mapped to the timing of muscle contractions of two or more muscles. In such embodiments, the modulation of cerebellar stimulation may include administering cerebellar stimulation if the EMG power values represent the co-contraction of two or more muscles and terminating cerebellar stimulation if the EMG power values do not represent cocontraction. In some embodiments, the modulation of cerebellar stimulation may include administering cerebellar stimulation if the EMG power value represents a muscle contraction exceeding a set duration threshold. In such embodiments, the modulation of cerebellar stimulation may include administering cerebellar stimulation if the EMG power value exceeds a set duration threshold and terminating cerebellar stimulation if the EMG power value does not exceed the set duration threshold.

[0045] In some embodiments where the bioelectrical signals include cerebellar nuclei (CN) extracellular activity signals or Purkinje cell (PC) cellular activity signals, the activity signals may be mapped to a spike threshold. In such embodiments, the modulation of cerebellar stimulation includes administering cerebellar stimulation if the spike threshold value maps with muscle contraction (e.g., crosses rate thresholds, pattern thresholds, pause thresholds, rhythmicity thresholds, global coefficient of variance (CV) thresholds, local coefficient of variance (CV2) thresholds, degree of modulation thresholds, and / or synchrony thresholds) and terminating cerebellar stimulation if the spike threshold value does not map with muscle contraction. Additionally, in some of such embodiments, the modulation of cerebellar stimulation includes administering or modifying cerebellar stimulation if the spikes exhibit features including a pattern, rate, pause, coefficient of variance (or other measures of irregularity), rhythmicity, degree of modulation, complexity (entropy) or synchrony that is outside of the bounds of a set minimum or maximum threshold and terminating or modifying cerebellar stimulation if within the bounds.

[0046] In some embodiments, the bioelectrical signals include local field potential (LFP) signals. In some of such embodiments, cerebellar stimulation may be administered or modified if LFP frequency band power values, the power ratio values of one or more frequency bands, phase amplitude coupling of signals, coherence between signals, durations of either frequency band power values, power ratio values, entropy values, 1 / f slope values, or Lempel-Ziv complexity values are outside of the bounds of a set minimum or maximum threshold. In some embodiments, cerebellar stimulation may be terminated or modulated if values or ratio of values are within the bounds.PCT Application Attorney Docket No. AF44111.P045WOBLG 25-002

[0047] In some embodiments, the bioelectrical signals include electroencephalogram (EEG) signals or electrocorticogram (ECoG) signals. In some of such embodiments, cerebellar stimulation may be administered or modulated if EEG or ECoG frequency band power values, the power ratio values, durations of either frequency band power values, phase amplitude coupling of signals, coherence between signals, entropy values, or 1 / f slope values or Lempel-Ziv complexity values of one or more locations or the ratio of values of one or more locations are outside of the bounds of a set minimum or maximum threshold. In some embodiments, cerebellar stimulation may be terminated or modulated if values or ratio of values are within the bounds.

[0048] The modulation of cerebellar stimulation may have various effects on subjects. For instance, in some embodiments, the modulation of cerebellar stimulation may be utilized to restore aberrant neuronal dynamics responsible for dystonic symptoms. In some embodiments, the modulation of cerebellar stimulation may be utilized to restore healthy neuronal dynamics responsible for typical behavior, block aberrant neuronal dynamics responsible for atypical behavior (including motor, cognitive, affective, neuropsychiatric, and / or sleep symptoms), or create new therapeutic neural dynamics.

[0049] Modes of operation

[0050] The methods and systems of the present disclosure may occur through various modes of operation. For instance, in some embodiments, the methods of the present disclosure occur through the use of a closed-loop deep brain stimulation system. In some embodiments, the methods of the present disclosure occur through the use of a cerebellar closed-loop deep brain stimulation system. In some embodiments, the systems of the present disclosure are in the form of a closed-loop system. In some embodiments, the systems of the present disclosure are in the form of a cerebellar closed-loop system.

[0051] Neural disorders

[0052] The methods and systems of the present disclosure may be utilized to treat or prevent various neural disorders. For instance, in some embodiments, the neural disorder includes, without limitation, movement disorders, tremors, ataxia, dyskinesia, dystonia, neuropsychiatric disorders, cognitive impairment, affective impairment, sleep impairment, or combinations thereof. In some embodiments, the neural disorder includes dystonia.

[0053] SubjectsPCT Application Attorney Docket No. AF44111.P045WOBLG 25-002

[0054] The methods and systems of the present disclosure may be utilized to treat or prevent neural disorders in various subjects. For instance, in some embodiments, the subject is a human being. In some embodiments, the subject is a non-human mammal. In some embodiments, the non-human mammal includes, without limitation, a non-human primate, a horse, a rabbit, a mouse, a rat, a pig, a sheep, a cow, a dog, or a cat. In some embodiments, the non-human mammal is a domestic animal, such as a dog or a cat.

[0055] In some embodiments, the subject is suffering from a neural disorder. In some embodiments, the subject is vulnerable to a neural disorder.

[0056] Additional embodiments

[0057] Reference will now be made to more specific embodiments of the present disclosure and experimental results that provide support for such embodiments. However, Applicant notes that the disclosure below is for illustrative purposes only and is not intended to limit the scope of the claimed subject matter in any way.

[0058] Example 1. Configuration of cerebellar stimulation modulated by symptom types and severity

[0059] This Example relates to configuring cerebellar stimulation to control different movement disorder symptoms that vary in types, duration, and / or severity. In this Example. Applicant leverages sensitivity and signature signals from the cerebellar nuclei to provide a cerebellar fingerprint-guided therapeutic approach for movement disorders. The approach allows accurate dialing and dosing of cerebellar stimulation to restore aberrant neuronal dynamics responsible for different dystonic symptoms.

[0060] Applicant’s approach includes a closed-loop deep brain stimulation methodology where cerebellar nuclei activity and EMG signals captured from the subject serve as biomarkers for different dystonic symptoms varying in types, severity and / or duration, and which can be used to trigger adjustable cerebellar stimulation. The adjustments can be based on the effectiveness of the cerebellar stimulation, which can be captured by changes in one or more of these predetermined biomarkers.

[0061] This Example pertains broadly to neurological disorders and specifically focuses on configuring symptom-targeted cerebellar stimulation to address movement disorders and various other neurological conditions. This Example is also directed towards fine-tuning and automizing optimal cerebellar stimulation parameters to control different symptoms of dystonia.PCT Application Attorney Docket No. AF44111.P045WOBLG 25-002

[0062] The technology may contribute to the treatment of dystonia by itself (i.e., cerebellar electrical stimulation) or in conjunction with other treatments (e.g., medication, transcranial magnetic stimulation, other neuromodulation techniques applied to the brain, etc.). In particular, cerebellar activity is monitored to determine the presence or absence of predetermined pathological, dystonia symptom- driving features of the cerebellar activity. Unlike current methods of neural stimulation used today, this method combines real-time detection of biomarkers to both initiate and modulate stimulation parameters to result in both short-term and long-term alleviation of neurological dysfunction. This method also takes the unusual approach of targeting stimulation to the cerebellum. The combination of biomarker detection, stimulation modulation, and stimulation targeting has the unexpected ability to result in long term alleviation of symptoms.

[0063] Cerebellar pathological activity may be detected using recordings in the form of single unit extracellular recordings, multi-unit extracellular recordings, local field potential (LFP), electroencephalogram (EEG) or electrocorticogram (ECoG).

[0064] Example 1.1. System components

[0065] The system components include biomarker identification, programming, and additional elements.

[0066] Example 1.1.1. Biomarker identification

[0067] Biomarker identification can be based on electromyogram recordings or neural recordings, including single cell recordings, local field recordings, electroencephalogram recordings, electrocorticogram recordings, and non-invasive recordings. The biomarkers can be directed towards dystonia specific muscle activity patterns, cerebellar or extracerebellar neural recordings with a potential for extension to other disorders. Signals may be amplified and filtered at 0.3-13 kHz (NPI). Signals may also be digitized and analyzed using Spike2 software. Threshold-based spike detection and template-matched spike sorting may be applied in real time. A custom Spike2 script may be used to continuously monitor the state of incoming signals, along with a Spike2 configuration paradigm that initiates pre-programmed DBS protocols (STG4002, multichannel system).

[0068] Example 1.1.2. Programming

[0069] The programming can be based on stimulation parameters based on biomarkers. The programming can include trigger appropriate cerebellar therapy, and closed loop adjustments based on changes in biomarkers.PCT Application Attorney Docket No. AF44111.P045WOBLG 25-002

[0070] Example 1.1.3. Additional elements

[0071] Additional elements can include fast response time, achievement of long-term after-effects that last without cerebellar stimulation, potential for application to other neurological indications, and potential for integration with different methods of neural measurements and stimulation.

[0072] This Example demonstrates that both neural and muscle activity associated with dystonia improve when using cerebellar nuclei spike activity and EMG as biomarkers to trigger and modify cerebellar DBS, with long-lasting benefit. Single cerebellar nuclei cell spike activity was recorded and analyzed in real-time from awake head-fixed mice (FIG. 2) to determine the values of the global and local coefficient of variation measures (CV and CV2), and firing rate (number of spikes per 0.1 s). EMG signals were recorded and analyzed in real-time to determine the value of the EMG root mean square (RMS) power amplitude. These values were compared to two thresholds to initiate either low dose (30 pA) or high dose (60 pA) DBS. Respective thresholds for low dose include: CV greater than 0.65, CV2 greater than 0.5, firing rate less than 20 Hz if baseline firing rate is less than or equal to 30 Hz and 80 Hz if baseline firing rate is greater than 30 Hz, and EMG amplitude greater than 5 mV from baseline. Respective thresholds for high dose include: CV greater than 0.8. CV2 greater than 0.7. firing rate less than 10 Hz if baseline firing rate is less than or equal to 30 Hz and 30 Hz if baseline firing rate is greater than 30 Hz, and EMG amplitude greater than power value detected at the onset of locomotion (FIG. 3).

[0073] EMG power values were also monitored across an antagonistic muscle pair (e.g., gastrocnemius (GC) and tibialis anterior (TA)) or from the nuchal muscles for co- and overcontractions, to initiate DBS at low dose when over-contraction was detected and to initiate DBS at high dose when the strength of over-contraction increased and crossed the high power value threshold (FIG. 5). Co-contraction was detected when two EMG power signals both crossed their respective low power thresholds. DBS stimulation was initiated at the respective dose whenever any biomarker crossed the threshold for that dose, with preference for applying the high dose if any high dose threshold had been crossed. DBS was terminated when no thresholds were actively being crossed (FIG. 4).PCT Application Attorney Docket No. AF44111.P045WOBLG 25-002

[0074] Cerebellar nuclei spike variability measures (CV and CV2) and spike firing rate are monitored to initiate and terminate cerebellar DBS based on their low and high threshold values. Long-lasting improvement in dystonia-related biomarkers was achieved using these biomarkers and thresholds to initiate, modulate, and terminate cerebellar DBS (FIG. 6).

[0075] FIG. 7 demonstrates that the closed-loop DBS method described in this Example performs better than random (non-biomarker-informed) DBS bouts, improves behavior within days of beginning stimulation, and has long term effects lasting months after neuromodulation has been stopped. Dystonia rating scale is performed in the morning before each day’s DBS session. While mice start at a similar level of impairment on day 1, those receiving closed-loop DBS improve starting on day 2 and can maintain improvement of phenotype after stimulation has been ceased (> 2 months).

[0076] FIGS. 8A-8C demonstrate that the closed-loop DBS method described in this Example entrains spike activity contralateral to DBS stimulation during the application of stimulation with lasting effects post stimulation, representing a detectable effect of closed-loop DBS on circuit activity. Autocorrelation of spike activity is performed before (FIG. 8A), during (FIG. 8B), and after (FIG. 8C), closed-loop DBS application. An increase in the correlation coefficient is observed between about + 0.2 - 0.25 s lag time during DBS and remains elevated post-DBS but is not present pre-DBS (arrows).

[0077] FIGS. 9A-9B show that closed-loop DBS induces dynamic entrainment of contralateral local field potentials (LFPs), indicative of DBS-induced circuit modulation. During delivery of 130 Hz DBS (shown in black vertical event tick marks), LFP exhibits increased power across different frequency bands (130 Hz entrainment on day 1 shown in FIG. 9A and multiple bands appearing in day 2 in the same mouse in FIG. 9B). These entrainments change over the course of stimulation and may persist following DBS offset, indicating a plasticity-related modulation of network dynamics. Tracking the appearance, magnitude, and / or time course of these entrainments enables real-time monitoring of plasticity during neuromodulation across trials and days.PCT Application Attorney Docket No. AF44111.P045WOBLG 25-002

[0078] FIGS. 10A-10E represent that biomarkers can provide different lag times of predictiveness of abnormal phenotypes. The left column represents data from a control mouse, and the right column represents data from a dystonic mouse. Applicant utilized continuous monitoring of electrical activity from nuchal muscles as a readout of dystonic phenotype. Applicant calculated root mean squared (RMS) of ongoing electromyography (EMG) recordings of the left (ipsilateral to DBS, contralateral to neural recording (FIG. 10A)) and right (contralateral to DBS. ipsilateral to neural recording (FIG. 10B)) nuchal muscles. High RMS detects over-contraction of the muscles and indicates dystonic behavior.

[0079] Applicant then performed a normalized cross-correlation analysis of the firing rate (FIG. 10C) and CV (FIG. 10D) to the EMG RMS to represent the predictiveness of these biomarkers to muscle activity. There is no predictiveness (correlation coefficient > 0.25 before 0 s lag time) of either firing rate or CV in control animals (FIG. 10E, left). However, there is an increase in predictiveness in both firing rate and CV in dystonia. The dystonic EMG vs firing rate correlation coefficient crosses 0.25 at -4.8 s and peaks at 0.0 s while the dystonic EMG vs CV correlation coefficient crosses 0.25 at -1.0 s and peaks at -0.8 s (FIG. 10E, right) when 15 seconds of data are block bootstrapped 2000 times. RMS and firing rate are binned over 0.1 seconds and normalized to z-score. CV is binned over 100 spikes and normalized to z-score. Shaded region in E represents 95% confidence interval.

[0080] Example 1.2, Summary

[0081] In sum, Applicant has leveraged signature signals from the cerebellar nuclei to provide a cerebellar-guided therapeutic approach for movement disorders. Applicant’s approach allows accurate dialing and dosing of cerebellar stimulation on the fly to restore aberrant neuronal dynamics responsible for different dystonic symptoms.

[0082] Applicant’s approach includes a closed-loop deep brain stimulation methodology where cerebellar nuclei activity signals captured from the subject serves as a biomarker for different dystonic symptoms varying in types, severity and / or duration to trigger cerebellar stimulation that can be adjusted on the fly. The adjustments will be based on the effectiveness of the cerebellar stimulation, which are captured by changes in one or more of these predetermined biomarkers.PCT Application Attorney Docket No. AF44111.P045WOBLG 25-002

[0083] In some embodiments, the technology in this Example can be adjusted to alleviate different neurological symptoms such as dystonia, tremor, ataxia, and dyskinesia. One or more biomarkers that reflect the current state(s) of different neurological symptoms are identified to trigger, adjust, and / or terminate the corresponding cerebellar stimulation protocol to treat the symptom(s) on the fly. These biomarkers may be used to demonstrate: 1) the acute effectiveness of cerebellar stimulation, 2) reduction in triggering cerebellar stimulations over time within and / or across therapy sessions, and 3) achievement of long-term after-effects that last without cerebellar stimulation.

[0084] In some embodiments, the technology in this Example may contribute to the treatment of dystonia by itself (cerebellar electrical stimulation) or in conjunction with other treatments (medication, transcranial magnetic stimulation, and / or other neuromodulation techniques applied to the brain). In particular, cerebellar activity may be monitored to determine the presence or absence of predetermined pathological, dystonia symptom-driving features of the cerebellar activity.

[0085] Without further elaboration, it is believed that one skilled in the art can, using the description herein, utilize the present disclosure to its fullest extent. The embodiments described herein are to be construed as illustrative and not as constraining the remainder of the disclosure in any way whatsoever. While the embodiments have been shown and described, many variations and modifications thereof can be made by one skilled in the art without departing from the spirit and teachings of the invention. Accordingly, the scope of protection is not limited by the description set out above, but is only limited by the claims, including all equivalents of the subject matter of the claims. The disclosures of all patents, patent applications and publications cited herein are hereby incorporated herein by reference, to the extent that they provide procedural or other details consistent with and supplementary to those set forth herein.

Claims

PCT Application Attorney Docket No. AF44111.P045WOBLG 25-002CLAIMS1. A method of treating or preventing a neural disorder in a subject, said method comprising: receiving one or more bioelectrical signals from the subject; identifying one or more biomarkers from the bioelectrical signals; mapping the one or more biomarkers to one or more cerebellar stimulation parameters; and modulating cerebellar stimulation based on the one or more cerebellar stimulation parameters.

2. The method of claim 1, further comprising: receiving one or more bioelectrical signals from the subject after modulating the cerebellar stimulation; identifying changes in the one or more biomarkers from the bioelectrical signals relative to the biomarkers prior to modulating the cerebellar stimulation; adjusting the one or more cerebellar stimulation parameters based on the identified changes; and re-modulating cerebellar stimulation based on the one or more adjusted cerebellar stimulation parameters.

3. The method of claim 1, wherein the one or more bioelectrical signals are received by a processing unit.PCT Application Attorney Docket No. AF44111.P045WOBLG 25-0024. The method of claim 1, further comprising a step of detecting the one or more bioelectrical signals.

5. The method of claim 4, wherein the one or more bioelectrical signals are detected by sensors.

6. The method of claim 5, wherein the sensors are selected from the group consisting of single unit extracellular sensors, multi-unit extracellular sensors, local field potential (LFP) sensors, electroencephalogram (EEG) sensors, electrocorticogram (ECoG) sensors, electromyography (EMG) sensors, or combinations thereof.

7. The method of claim 5, wherein the sensors comprise electrodes.

8. The method of claim 5, wherein the one or more bioelectrical signals are detected by sensors in real-time.

9. The method of claim 1, wherein the one or more bioelectrical signals are received from the cerebellar nuclei, Purkinje cells, the cerebellum, brain cortical regions, extracerebellar brain regions, the cerebellar cortex, single cells, population of cells, single or multiple extracerebellar brain regions, one or more muscles, or combinations thereof.

10. The method of claim 1, wherein the one or more bioelectrical signals are received from the cerebellum, extracerebellar brain regions, or muscles.

11. The method of claim 1, further comprising a step of amplifying and filtering the one or more bioelectrical signals.

12. The method of claim 1, wherein the one or more bioelectrical signals are selected from the group consisting of electromyography (EMG) signals, cerebellar nuclei (CN) extracellular activity signals, Purkinje cell (PC) extracellular activity signals, local field potential (LFP) signals, electrocorticogram (ECoG) signals, electroencephalogram (EEG) signals, or combinations thereof.PCT Application Attorney Docket No. AF44111.P045WOBLG 25-00213. The method of claim 1, wherein the one or more bioelectrical signals comprise cerebellar nuclei (CN) extracellular activity signals or Purkinje cell (PC) extracellular activity signals.

14. The method of claim 1, wherein the one or more biomarkers are identified from the bioelectrical signals by a programmer.

15. The method of claim 1, wherein the one or more biomarkers are selected from the group consisting of cerebellar nuclei (CN) or Purkinje cell (PC) firing rate thresholds, pattern thresholds, global coefficient of variance (CV) thresholds, local coefficient of variance (CV2) thresholds, spike pattern thresholds, pause thresholds, rhythmicity thresholds, degree of modulation thresholds, synchrony thresholds, local field potential (LFP) thresholds, electroencephalogram (EEG) power thresholds, electrocorticogram (ECoG) power thresholds, frequency band power thresholds, ratio power thresholds, electromyography (EMG) power value thresholds, EMG power timing thresholds, EMG power duration thresholds, spectral power value thresholds, spectral power timing thresholds, spectral power duration thresholds, frequency band power thresholds, ratio band power thresholds, coherence of signals thresholds, complexity of signals thresholds, or combinations thereof.

16. The method of claim 1, wherein the one or more biomarkers are mapped to one or more cerebellar stimulation parameters by a programmer.

17. The method of claim 1, wherein the cerebellar stimulation parameters are selected from the group consisting of stimulation intensity, pulse phase, pulse width, pulse shape, stimulation pattern, stimulation frequency, stimulation timing, stimulation duration, or combinations thereof.

18. The method of claim 1, wherein the modulating of cerebellar stimulation comprises terminating cerebellar stimulation.

19. The method of claim 1, wherein the modulating of cerebellar stimulation comprises administering or adjusting cerebellar stimulation.PCT Application Attorney Docket No. AF44111.P045WOBLG 25-00220. The method of claim 19, wherein the cerebellar stimulation comprises deep brain stimulation.

21. The method of claim 20, wherein the cerebellar stimulation is administered by a programmer coupled to a deep brain stimulation system.

22. The method of claim 19, wherein the cerebellar stimulation is administered by an electrode.

23. The method of claim 1, wherein the one or more bioelectrical signals comprise electromyography (EMG) signals, wherein the EMG signals are mapped to an EMG power value threshold above or below a value representing muscle contraction, and wherein the modulating comprises administering cerebellar stimulation if the EMG power value represents muscle contraction, and terminating cerebellar stimulation if the EMG power value does not represent muscle contraction.

24. The method of claim 1, wherein the one or more bioelectrical signals comprise cerebellar nuclei (CN) activity signals and / or Purkinje cell (PC) activity signals, wherein the activity signals are mapped to a spike threshold, and wherein the modulating comprises administering cerebellar stimulation if the spike threshold value maps with muscle contraction, and terminating cerebellar stimulation if the spike threshold value does not map with muscle contraction.

25. The method of claim 1 , wherein the method restores healthy neuronal dynamics responsible for typical behavior, blocks aberrant neuronal dynamics responsible for atypical behavior, or creates new therapeutic neural dynamics.

26. The method of claim 1, wherein the method restores aberrant neuronal dynamics responsible for dystonic symptoms.

27. The method of claim 1, wherein the method occurs through the use of a closed-loop deep brain stimulation system.PCT Application Attorney Docket No. AF44111.P045WOBLG 25-00228. The method of claim 1. wherein the neural disorder is selected from the group consisting of movement disorders, tremors, ataxia, dyskinesia, dystonia, neuropsychiatric disorders, cognitive impairment, affective impairment, sleep impairment, or combinations thereof.

29. The method of claim 1, wherein the neural disorder comprises dystonia.

30. The method of claim 1, wherein the subject is a human being or non-human mammal.

31. A system operable for treating or preventing a neural disorder in a subject, said system comprising: a processing unit operable for receiving one or more bioelectrical signals from the subject; a programmer comprising programming instructions for: identifying one or more biomarkers from the bioelectrical signals, mapping the one or more biomarkers to one or more cerebellar stimulation parameters, and modulating cerebellar stimulation based on the one or more cerebellar stimulation parameters; and a deep brain stimulation system operable for delivering the cerebellar stimulation to the subject.

32. The system of claim 31, wherein the processor is operable for receiving one or more bioelectrical signals from the subject after modulating the cerebellar stimulation, and wherein the programmer further comprises programming instructions for: identifying changes in the one or more biomarkers from the bioelectrical signals relative to the biomarkers prior to modulating the cerebellar stimulation,PCT Application Attorney Docket No. AF44111.P045WOBLG 25-002 adjusting the one or more cerebellar stimulation parameters based on the identified changes, and re-modulating cerebellar stimulation based on the one or more adjusted cerebellar stimulation parameters.

33. The system of claim 31, further comprising one or more sensors in electrical communication with the processing unit, wherein the sensors are operable to detect one or more bioelectrical signals from the subject.

34. The system of claim 33, wherein the sensors are selected from the group consisting of single unit extracellular sensors, multi-unit extracellular sensors, local field potential (LFP) sensors, electroencephalogram (EEG) sensors, electrocorticogram (ECoG) sensors, electromyogram (EMG) sensors, or combinations thereof.

35. The system of claim 33, wherein the sensors comprise electrodes.

36. The system of claim 31, wherein the deep brain stimulation system comprises an electrode operable for delivering the cerebellar stimulation to the subject.

37. The system of claim 31 , wherein the system is in the form of a closed-loop system.

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