WO2014152110A1 - Multi-modal pharmaco-diagnostic assessment of brian helath - Google Patents
Multi-modal pharmaco-diagnostic assessment of brian helath Download PDFInfo
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- WO2014152110A1 WO2014152110A1 PCT/US2014/026962 US2014026962W WO2014152110A1 WO 2014152110 A1 WO2014152110 A1 WO 2014152110A1 US 2014026962 W US2014026962 W US 2014026962W WO 2014152110 A1 WO2014152110 A1 WO 2014152110A1
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Definitions
- the invention relates to the diagnosis and analysis of brain health information through the use of activated tasks and stimuli in combination with single doses of approved drugs, biologies, and biochemical CNS active agents in a system to dynamically assess brain health, function and cerebral activity.
- neuropsychiatric or cognition testing involve significant operator expertise, inpatient or office- based testing, significant time and significant expense.
- One potential technique that may be adapted to serve a broader role as a facile biomarker of the central nervous system function is a multi-modal assessment of the brain from a number of different forms of data, including electroencephalography (EEG), which measures the brain's electrical activity.
- EEG electroencephalography
- formal clinical lab-based EEG approaches typically require significant operator training, cumbersome and expensive equipment, and a dedicated area for testing and are used primarily to evaluate patients for seizures, cognitive slowing and brain death.
- the systems and methods of the invention utilize a single diagnostic dose of a chemical agent such as a regulatory agency approved drug, biologic, vitamin, ingredient, or other chemical or biologic agent that can bind with molecular specificity or provide a well characterized molecular effect on a mammalian host (including humans).
- a chemical agent such as a regulatory agency approved drug, biologic, vitamin, ingredient, or other chemical or biologic agent that can bind with molecular specificity or provide a well characterized molecular effect on a mammalian host (including humans).
- the method typically involves at least one pre-dose multi-modal diagnostic scan of the subject followed by a waiting period, on the order of minutes to a couple of hours, after the point in time when the chemical agent is taken. Thereafter, a second post-dose multi-modal diagnostic scan will take place.
- a comparison, in the form of a difference or ratio, between data streams or extracted features from the data streams before versus after the diagnostic dose of the chemical agent will indicate with molecular specificity the tone in the brain of that subject to the molecular agent.
- the multi-modal diagnostic scan could be replaced by more traditional neuro- diagnostic techniques such as EEG, MRI, PET, CT, SPECT, MEG, fMRI, MRS and other neuro- diagnostic modalities in order to provide molecular specificity to those traditional neuro- diagnostics modalities.
- the systems and methods of the invention enable one to use one or more than one molecular agent to assess the brain's response across multiple neurotransmitter systems.
- selective serotonin reuptake inhibitors as a class of pharmaco-diagnostic agents could be used to probe the serotonergic tone of a human subject's brain as part of a multi-modal diagnostic response (or traditional neuro-diagnostics response) to a single dose of one of these agents, especially in the case of someone suspected of a concussion and/or traumatic brain injury.
- the systems and methods may also be used with approved therapeutic agents for Alzheimer's disease, including the class of acetylcholinesterase inhibitors.
- an NMDA-receptor antagonist like Memantine could alternatively be used to probe the tone in an alternate neurotransmitter system for important complementary or standalone diagnostic information.
- the systems and methods of the invention may also be used with epilepsy and seizure management agents to aid in the diagnosis of seizures or epilepsy, identify those at risk for seizures or epilepsy, and evaluate a patient for potential efficacy of an epilepsy and seizure management agent.
- NDMA and GABA therapeutic drugs in single diagnostic dose form also may be used to probe the tone of the developing human brain, in particular for evidence of autism spectrum disorders in infants and toddlers.
- regulatory agency approved SSRI therapeutic class agents may be used to aid in probing the serotonin tone, in particular for neuropsychiatric conditions like depression.
- Approved Gamma-Aminobutyric acid (GABA) "GABAinergic” agents may also be used to aid in probing the GABAinergic tone, in particular for neuropsychiatric conditions like anxiety, schizophrenia, bi-polar disorder as well as pain and the cerebral cortex.
- Antipsychotic agents may also be used to probe the brain tone, in particular for neuropsychiatric conditions like anxiety, schizophrenia, schizoaffective disorders, OCD, Tourette's disease, tic disorders, bi-polar disorder and other mental health issues dealing with delusions, hallucinations, or disordered or disorganized thoughts.
- Approved stimulant agents such as methylphenidate or dextro-amphetamine, may also be used to aid in probing the tone of the brain.
- Non-stimulants also could offer interesting diagnostic information from agents such as atomoxetine that could be used to probe the tone of a human subject's brain to test the multimodal diagnostic response to a single dose of one of these agents.
- the systems and methods of the invention may also be used with approved norepinephrine agents to aid in probing the Norepinephrinergic tone, in particular for neuropsychiatric conditions like depression, anxiety, schizophrenia, bi-polar disorder, ADHD and narcolepsy.
- Another embodiment of the present invention includes the use of a multi-modal brain assessment system (or a more traditional modality) at (i) a physician's offices, (ii) field- derived locations or (iii) at home in order to proctor these brain health scans on a regular, longitudinal basis, either with or without use of a pharmaco-diagnostic agent, in order to monitor a Sickle Cell disease patient's brain for evidence of reduced or abnormal activity.
- a multi-modal brain assessment system or a more traditional modality
- the present invention also includes the use of multi-modal neuro diagnostic scanning, either with or without a pharmaco-diagnostic CNS active agents, to provide prognostic biomarkers of, for example, a post anoxic encephalopathy subject who is in the emergency department or intensive care unit of a hospital, physician office or clinic.
- Prognostic markers could enable clinicians to predict patient outcomes and enable appropriate clinical decisions in light of the prognostic information.
- cardiologists, intensivists and neurologists may find the present invention useful in any patient who presents after an anoxic cerebral event such as, but not limited to, cardiac arrest, cardiac arrhythmia, near-drowning, respiratory failure or suicide attempt.
- multi-modal neuro- diagnostic scanning is used to provide objective clinical evidence of impaired brain health or a lack thereof in relation to workers compensation insurance cases or Medicare insurance benefits related to brain injury and disorders. Because certain brain injuries are "invisible” as defined by the patient manifesting only subjective complaints without objective, corroborating diagnostic evidence, it is very difficult today to tell who is legitimately hurt and in need of appropriate medical care and who is malingering and should get off insurance and return to work. Objective multi-modal diagnostic biomarker evidence from the present invention could enable clinicians and thus insurance companies to understand with objective clinical evidence who has suffered a brain-related injury and/or is still suffering from this injury.
- Such multi- modal neuro-diagnostic scanning may be used to provide objective clinical evidence of fatigue and lethargy.
- Memantine or another NMDA receptor antagonist also may be used to treat patients diagnosed with a concussion or mild Traumatic Brain Injury.
- multi-modal neuro-diagnostic scanning is used with dopaminergic agents to create a time series of the effectiveness of such agents to a subject to, for example, determine if that subject should enroll in a clinical trial of that agent.
- Such techniques may also be used to screen different medications for effectiveness for a given subject and to provide data for use in predictive analytics exercises for other subjects considering use of the same medications. This latter technique may be used to cut short therapy selections for new patients.
- FIG. 1 is a schematic diagram illustrating in the upper timeline the pre and post diagnostic dose temporal scan sequence to practice the present invention.
- the lower timeline illustrates how the pre-post diagnostic dose scan sequence can be used on an every other day basis from home without the need to visit a hospital, clinic or doctor's office.
- FIG. 2 is a schematic diagram illustrating how the present invention could be used to manage return to work, return to learn, or return to driving decisions, in a similar fashion to return to play decisions for athletes or return to duty decisions for soldiers. This could be generally called return-to-activity decisions.
- FIG. 3 is a schematic diagram illustrating how the present invention could be used to manage risk and identify potential fraud in a work stream of claims within an insurance company for worker's compensation and other injury related claims.
- FIGS. 1-3 The invention will be described in detail below with reference to FIGS. 1-3. Those skilled in the art will appreciate that the description given herein with respect to FIGS. 1-3 is for exemplary purposes only and is not intended in any way to limit the scope of the invention. All questions regarding the scope of the invention may be resolved by referring to the appended claims.
- electrode to the scalp we mean to include, without limitation, those electrodes requiring gel, dry electrode sensors, contactless sensors and any other means of measuring the electrical potential or apparent electrical induced potential by electromagnetic means.
- monitoring the brain and central nervous system we mean to include, without limitation, surveillance of normal brain health and aging, the early detection and monitoring of brain dysfunction, detection and monitoring of brain injury and recovery, identification of disease onset, progression and response to therapy, for the discovery and optimization of treatment and drug therapies, including without limitation, monitoring investigational compounds and registered pharmaceutical agents, as well as the monitoring of illegal substances and their presence or influence on an individual while driving, playing sports, or engaged in other regulated behaviors.
- a "medical therapy” as used herein is intended to encompass any form of therapy with a potential biological, physiologic or biochemical effect, including, without limitation, any pharmaceutical agent or treatment, compounds, biologies, medical device therapy, exercise, biofeedback or combinations thereof.
- EEG data we mean to include without limitation the raw time series, any spectral properties determined after Fourier transformation, any nonlinear properties after nonlinear analysis, any wavelet properties, any summary biometric variables and any combinations thereof.
- a "sensory and cognitive challenge” as used herein is intended to encompass any form of sensory stimuli (to the five senses), cognitive challenges (to the mind), and other physiological challenges (such as a respiratory CO 2 challenge, virtual reality balance challenge, hammer to knee reflex challenge, etc.).
- a “sensory and cognitive challenge state” as used herein is intended to encompass any state of the brain and central nervous system during the exposure to the sensory and cognitive challenge.
- An "electronic system” as used herein is intended to encompass, without limitation, hardware, software, firmware, analog circuits, DC-coupled or AC-coupled circuits, digital circuits, FPGA, ASICS, visual displays, audio transducers, temperature transducers, olfactory and odor generators, or any combination of the above.
- spectral bands we mean without limitation the generally accepted definitions in the standard literature conventions such that the bands of the Power Spectral Densities (PSD) are often separated into the Delta band (f ⁇ 4 Hz), the Theta band (4 ⁇ f ⁇ 7 Hz), the Alpha band (8 ⁇ f ⁇ 12 Hz), the Beta band (12 ⁇ f ⁇ 30 Hz), and the Gamma band (30 ⁇ f ⁇ 100 Hz).
- PSD Power Spectral Densities
- measuring we mean the process of putting known inputs into the system and adjusting internal gain, offset or other adjustable parameters in order to bring the system to a quantitative state of reproducibility.
- conducting quality control we mean conducting assessments of the system with known input signals and verifying that the output of the system is as expected. Moreover, verifying the output to known input reference signals constitutes a form of quality control which assures that the system was in good working order either before or just after a block of data was collected on a human subject.
- biomarker we mean an objective measure of a biological or physiological function or process.
- biomarker features or metrics we mean a variable, biomarker, metric or feature which characterizes some aspect of the raw underlying time series data. These terms are equivalent for a biomarker as an objective measure and can be used interchangeably.
- non-invasively we mean lacking the need to penetrate the skin or tissue of a human subject.
- electros module or "EM” or “reusable electronic module” or “REM” or “multi-functional biosensor” or “MFB”
- EM electronics module
- REM reusable electronic module
- MFB multi-functional biosensor
- diagnostic we mean any one of the multiple intended uses of a diagnostic, including to classify subjects in categorical groups, to aid in the diagnosis when used with other additional information, to screen at a high level where no a priori reason exists, to be used as a prognostic marker, to be used as a disease or injury progression marker, to be used as a treatment response marker or even as a treatment monitoring endpoint.
- a biomarker can confer, which include but are not limited to: (1) as an aid in the diagnosis of a disease, disorder or condition, preferably early in a diagnostic algorithm; (2) as a prognostic marker to determine the likelihood or probability of a future event or brain condition later in time; (3) as a drug response marker to determine who might respond well to a candidate intervention or therapy before they start the therapy; (4) as a response to therapy marker for someone after they start an therapeutic intervention; (5) as a brain injury or disease progression marker to be quantitatively serially assessed over time to assess if things improve, deteriorate, stay the same or return back to normal; (6) as a non-invasive screening tool in healthy normal subjects to discover initial evidence of issues and problems; (7) as an at-home daily, weekly or other periodicity measurement to track longitudinal marker change within a subject; (8) as a drug compliance marker looking for a given benefit or signature that the therapy has been taken or conducted; (9) as a safety marker to show either the absence or
- multi-modal neuro-diagnostic scanning we typically mean a diagnostic procedure that includes more than one modality of brain health assessment, often including two, three, or four modalities of biosignal data. In some instances, there can be five, six or seven different modalities of diagnostic information being collected. It should also be explicit that this term also includes the use of individual modalities of neuro-diagnostic scanning, such as EEG, MRI, PET, CT or SPECT in isolation.
- a single dose we typically mean only one dose, but it would be contemplated that dividing a single dose into N equivalently reduced Dose/N doses would be equivalent to the original dose and thus be equivalent to a “single” dose.
- the systems and methods of the invention comprise utilization of a single diagnostic dose of a chemical agent such as a regulatory agency approved drug, biologic, vitamin, ingredient, or other chemical or biologic agent which can bind with molecular specificity or provide a well characterized molecular effect on a mammalian host (including humans).
- a chemical agent such as a regulatory agency approved drug, biologic, vitamin, ingredient, or other chemical or biologic agent which can bind with molecular specificity or provide a well characterized molecular effect on a mammalian host (including humans).
- the systems and methods of the invention compare a first scan taken pre-dose to a second scan taken some period of time post-dose of the regulatory agency approved or acceptable chemical or biological moiety which confers molecular specificity. This dual scan process would then enable not only sensory, cognitive and physical assessment of the brain to various challenges, but it would also allow for a pre-dose versus a post-dose comparison of the molecularly specific biological challenge from the chemical agent or stimulus.
- an embodiment of the invention also includes the use of this pre versus post scan sequence in conventional neuro imaging scanners, such as MRI, fMRI, CT, PET, SPECT, and MEG scanners.
- conventional neuro imaging scanners such as MRI, fMRI, CT, PET, SPECT, and MEG scanners.
- the conventional scanners do not have as many modes of information, it is clearly contemplated that this molecularly conferred diagnostic approach would be valuable in traditional neuro imaging modalities as well.
- Typical delay times T p between the scans would range between 15 to 60 minutes, but could be shorter or longer, after ingestion of the molecularly specific agent, but this time could be much longer if desirable based on the time constant characteristics of the therapies pharmacokinetics (PK) or pharmacodynamics (PD), depending on which properties are of interest.
- PK pharmacokinetics
- PD pharmacodynamics
- the pre-dose versus post-dose response will be compared across the multi-modal biosignal data streams and extracted features to identify univariate or multivariate signatures that can help classify, identify, prognosticate or otherwise help a doctor, nurse, ATC, EMT, or parent assess a patient, subject or themselves.
- the baseline scan would include a first pre-dose scan battery including physical, sensory, and cognitive challenge tasks. Then, a single dose of a regulatory agency approved or acceptable chemical, drug, biologic or therapy would be taken for diagnostic purposes. After an appropriate pause time T p , which would depend on the physical PK properties as well as the
- pharmacodynamic (PD) properties of the chemical agent an identical second post-dose scan would be conducted.
- a pre-dose versus post-dose comparison would provide a measure of response of that individual to the drug or molecular agent of choice.
- This molecularly specific response from the baseline pre-dose scan to Tp minutes post-dose scan can serve as a diagnostic biomarker of the neurotransmitter tone or molecular response of the human subject's brain.
- acetylcholinesterase inhibitor e.g.
- Donepezil is utilized, it would probe the cholinergic tone of the human subject's brain.
- FIG. 1 A schematic illustration of such a diagnostic scan session scheme is presented in the upper half of FIG. 1.
- a subject With time in minutes along the x-axis of the upper timeline 2, a subject would undergo a pre-dose baseline multi-modal assessment scan of their brain 4 which could include any number of various sensory, cognitive, emotional, physical or other tasks, typically constructed to physiologically focus on the disease or diagnostic criteria known from previous studies including those identified in the published literature.
- a baseline pre- dose multi-modal assessment scan 4 indicated to begin and end in time by the pair of vertical bars, a single diagnostic dose 6 of a molecularly specific agent would be administered according to the manufacturer's instructions.
- One would wait a time T p , typically defined by the PK T max or a PD effect time.
- a second or subsequent but identical post-dose scan 10 would be conducted. A comparison would be done between the two scans looking typically at either the difference of a marker M equal to M 2 -M 1 or the ratio M 1 /M 2 of a given univariate marker or multi-variate composite signature.
- Standard biomarker intended uses include but are not limited to: (1) as an aid in the diagnosis of a disease, disorder or condition, preferably early in a diagnostic algorithm; (2) as a prognostic marker to determine the likelihood or probability of a future event or brain condition later in time; (3) as a drug response marker to determine who might respond well to a candidate intervention or therapy before they start the therapy; (4) as a response to therapy marker for someone after they start an therapeutic intervention; (5) as a brain injury or disease progression marker to be quantitatively serially assessed longitudinally over time to assess if things improve, deteriorate, stay the same or return back to normal; (6) as a non-invasive screening tool in healthy normal subjects to discover initial evidence of issues and problems; (7) as an at-home daily, weekly or other periodicity measurement to track longitudinal marker change within a subject; (8) as a drug compliance marker looking for a given benefit or signature that the therapy has been taken or conducted; (9) as a safety marker to show either the absence or presence of important changes in the safety profile of a human brain (
- continuously monitoring is equal to a 100% measurement duty cycle.
- the desire is to use immediate release drugs that exhibit short half-life, preferably those which have good PK properties such that their adsorption T max is reasonable and practical from a dual scan perspective. This would facilitate looking at the difference or ratio pre-dose versus post-dose in a given subject in a time frame that is practical to implement in clinical care or home care setting.
- immediate release drugs that exhibit short half-life, preferably those which have good PK properties such that their adsorption T max is reasonable and practical from a dual scan perspective.
- One particular embodiment of the present invention includes the use of carbodopa/levodopa, Pramipexole, Ropinirole, Bromocriptine or other similar dopaminergic acting regulatory agency approved drugs, biologies or active ingredients as a pharmacologic dose to probe the dopaminergic tone of the brain of a human patient or subject, in particular, for someone suspected of a dopaminergic brain disorder such as Parkinson's disease.
- T 30, 60, or 90 minutes post-dose versus pre-dose in the same subject to assess for pre-motor deficit evidence to aid in the diagnosis of a Parkinson's patient (ICD-9 code 332.0 or cross-walk equivalents).
- the pre-dose versus post-dose (i) difference and/or (ii) ratio "effect size" alone or in combination with other markers would form a multi-variate composite signature in an unknown individual would be compared to a first normative set of data from individuals classified in state A as well as potentially a second, third and/or fourth population of subjects with state B, state C and state D.
- the health care practitioner most typically a neurologist but also a family physician or other licensed professional, would calculate the response of the human subject and compare the signature of the unknown subject to the comparator groups of state A, B, C, and D. Once a best match classification or regression to a number is found, this information can be provided in the form of a data and analysis report to licensed healthcare practitioners to aid in the diagnosis of the subject according to the various intended uses already discussed.
- normative comparator groups can be not only random in nature but the present invention also contemplates matching as demographically as possible the normative group to the unknown individual using simple co-variates such as gender, age, weight, height, smoking status, BMI, pulse rate, blood pressure or any other commonly available demographic or laboratory co-variate marker or variable.
- the process can alternatively incorporate very sophisticated selection algorithms that match analytically a given subject to the closest 300 subjects that look like them in a database of thousands to millions of individuals and then compare the unknown subject to their personalized closest 300 subjects to see if they are within the normal range for those individuals.
- the same approach can be used to pre-select the closest normative groups in each of states A, B, C, and D so that the comparison of unknown subject is to signatures created from the closest and most meaningfully controlled sub-sets of subjects in the super set of patients/subjects available. This provides then the opportunity to control for as many unknown variables as possible in the selection of the normative 300 subject population, as a non-limiting example.
- Another important embodiment of the present invention includes the use of the selective serotonin reuptake inhibitors (SSRI) as a class of pharmaco-diagnostic agents, including citalopram, escitalopram, Fluvoxamine, paroxetine, fluoxetine, and sertraline, that could be used to probe the serotinergic tone of a human subject's brain as part of a multi-modal diagnostic response to a single dose of one of these agents, especially in the case of someone suspected of a concussion and/or traumatic brain injury.
- the present invention contemplates use of the tricyclic antidepressants including specifically Amitriptyline,
- Imipramine Tofranil
- Nortriptyline Pamelor
- Clomipramine Anafranil
- Desipramine Norpramin
- glutaminergic medications like methylphenidate or amphetamine, in addition to NMDA receptor antagonist Ketamine, lamotrigine (glumate modulator), Memantine, and riluzole.
- a dopamine agonist in the stimulant class, like Adderall would be diagnostically informative to assess the brain's response to a single diagnostic dose.
- Adderall would be diagnostically informative to assess the brain's response to a single diagnostic dose.
- CNS active regulatory agency approved drugs, biologies or active ingredients that could be tested as a pharmacologic dose to probe the tone of the brain of a human subject.
- pre-dose versus post-dose (i) difference and/or (ii) ratio could serve to provide biomarker evidence to help clinical practice and improve outcomes. Improved health outcomes and reduced costs could be documented in the following fashion: (1) the number of days N out of activity (school, sport, work, duty) could be counted for each case i with the expectation that those who were diagnosed and managed with the diagnostic device of the present invention would return to work, return to play, return to school (return to learn), and/or return to duty sooner than those who were not diagnosed or managed with the present device, as measured by the number of days out of activity; (2) one would document that the "return-to-activity" is safer when managed with the present invention than those cases which were managed without the diagnostic device as quantified by fewer cases or reduced frequency of negative health outcomes defined by deaths, paralysis, Post-Concussion Syndrome cases, Second Impact Syndrome cases, Depression cases, PTSD cases, or other adverse clinical outcome. Lastly, this invention could be used to identify fraud and "malingering" and
- Another important embodiment of the present invention includes the use of the approved therapeutic agents for Alzheimer's disease in a pharmaco-diagnostic capacity.
- the class of acetylcholinesterase inhibitors including donepezil, tacrine, rivastigmine, and galantamine could be used to probe the cholinergic tone of a human subject's brain to test the multi-modal diagnostic response to a single dose of one of these agents.
- an NMDA-receptor antagonist like Memantine could alternatively be used to probe the tone in an alternate neurotransmitter system for important complementary or standalone diagnostic information.
- Alzheimer's disease, Mild Cognitive Impairment, or other forms of dementia or cognitive disorders ICD-9 codes 331.0, 331.83, 290.0 and those between 290.0-295 and 330.0-340, or cross-walk equivalent codes
- pre-dose versus post-dose i) difference and/or (ii) ratio could serve to provide biomarker evidence to help clinical practice and improve outcomes.
- Another important embodiment of the present invention includes the use of epilepsy and seizure management agents to (i) aid in the diagnosis of seizures or epilepsy, (ii) identify those at risk for seizures or epilepsy and (iii) evaluate the patient for potential efficacy of an epilepsy and seizure management agent.
- agents such as Gabapentin, carbamazepine, fosphenytoin, divalproex sodium, acetazolamide, phenytoin, carbamazepine, felbamate, perampanel, levetiracetam, pregabalin, ezogabine, vigabatrin, carbamazepine, oxcarbazepine, ethosuximide, tiagabine, mephobarbital, ethotoin, phenytoin, topiramate, and trimethadione to identify non-limiting examples, can be used in single doses to probe the tone of the human subject's brain under assessment for clinical response evidence that they may be more susceptible to seizures and epilepsy or that one epilepsy and seizure management agent may prove more efficacious.
- CNS active regulatory agency approved drugs, biologies or active ingredients that can be used as a pharmacologic dose to probe the tone of the brain of a human subject.
- pre-dose versus post-dose (i) difference and/or (ii) ratio could serve to provide biomarker evidence to help clinical practice and improve outcomes.
- improved health outcomes and reduced costs could be documented in the following fashion: (1) earlier return to work through earlier return to driving; (2) decrease trial and error of antiepileptic medication prescription, as measured by reduced time (in days) to stable therapy or reduced number of medications trialed before achieving stable therapy; (3) reduce potential unnecessary use of antiepileptic medications; (4) decrease potential health hazard to patient and others on the road if the patient has an undiagnosed seizure while driving; and (5) limit the use of prolonged hospitalizations to identify seizure disorders.
- Another important embodiment of the present invention includes the use of the NDMA and GABA therapeutic drugs to probe the tone of the developing human brain, in particular for evidence of Autism Spectrum Disorders (ASD) in infants and toddlers.
- agents which modulate metabotropic glutamate 5 receptor (mGluR 5) might serve well to help aid in the diagnosis and management of Autism Spectrum Disorder and other development neurological disorders.
- ICD-9 code 315 or cross-walk equivalents developmental disorders
- pre-dose versus post-dose (i) difference and/or (ii) ratio could serve to provide biomarker evidence to help clinical practice and improve outcomes.
- improved health outcomes and reduced costs have been well documented in the following fashion: (1) when diagnosis is made early in life between 6 months and 24 months of age, cognitive behavioral therapy and other interventions has been shown to dramatically affect clinical outcome for the patient (Fein, D, et al, Optimal Outcome in individuals with a history of Autism. J Child and Adolescent Psychiatry 54:2 (2013); Dawson, G, et al, Randomized controlled trial of an intervention for toddlers with autism; the Early Start Denver Model.
- Another important embodiment of the present invention includes the use of the approved SSRI therapeutic class of agents in a pharmaco-diagnostic capacity to aid in probing the serotonin tone, in particular, for neuropsychiatric conditions like depression.
- the class of SSRI's including citalopram, escitalopram, Fluvoxamine, paroxetine, fluoxetine, and sertraline could be used to probe the serotinergic tone of a human subject's brain to test the multi-modal diagnostic response to a single dose of one of these agents.
- an MDA- receptor antagonist like Memantine could alternatively be used to probe the tone in an alternate neurotransmitter system for important complementary or standalone diagnostic information in the case of depression.
- pre-dose versus post-dose (i) difference and/or (ii) ratio could serve to provide biomarker evidence to help clinical practice and improve outcomes.
- improved health outcomes and reduced costs could be documented in the following fashion: (1) safety could be established by preventing patients from continuing to drive beyond their appropriate time; (2) overall reduced cost to the healthcare system could be established by decreasing the resources necessary to watch after someone in an independent living environment with the subsequent and inevitable hospitalization and healthcare costs without benefit of the present invention compared to those who would utilize the present invention.
- GABA Gamma-Aminobutyric acid
- CNS Central Nervous System
- GABAinergic agents including GAD, GABA, Valerian, Gepirone, Buspirone, Sedatives, Zopiclone, Triazolam, Fengabine, Midazolam, Alprazolam, Adinazolam, Temazepam, Barbiturates, Methaqualone, Benzodiazepines, Neuroactive steroids, Clorazepam, lorazepam, and Diazepam (Valium), could be used to probe the GABAinergic tone of a human subject's brain to test the multi-modal diagnostic response to a single dose of one of these agents.
- Another important embodiment of the present invention includes the use of approved antipsychotic agents in a pharmaco-diagnostic capacity to aid in probing the tone, in particular for neuropsychiatric conditions like anxiety, schizophrenia, schizoaffective disorders, OCD, Tourette's disease, tic disorders, bi-polar disorder and other mental health issues dealing with delusions, hallucinations, or disordered or disorganized thoughts.
- neuropsychiatric conditions like anxiety, schizophrenia, schizoaffective disorders, OCD, Tourette's disease, tic disorders, bi-polar disorder and other mental health issues dealing with delusions, hallucinations, or disordered or disorganized thoughts.
- the class of antipsychotics agents including haloperidol, droperidol, chlorpromazine, fluphenazine, perphenazine, thioridazine, trifluoperazine, mesoridazine, triflupromazine, levomepromazine, promethazine, pimozide, cyamemazine, chlorprothixine, clopenthixol, flupenthixol, thiothixinem zuclopenthixol, clozipine, olanzapine, rispirdone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, iloperidone, zotepine, sertindole, azipiprazole and lurasidone could be used to probe the tone of a human subject's brain to test the multi-modal diagnostic response to a single dose of one of these agents.
- Another important embodiment of the present invention includes the use of regulatory agency approved stimulant agents in a pharmaco-diagnostic capacity to aid in probing the tone of the brain.
- the stimulant class includes Adderall (amphetamine and dextroamphetamine), Dexedrine (amphetamine salts), and methylphenidate.
- Adderall amphetamine and dextroamphetamine
- Dexedrine amphetamine salts
- methylphenidate methylphenidate.
- non-stimulants could offer interesting diagnostic information from agents such as atomoxetine that could be used to probe the tone of a human subject's brain to test the multimodal diagnostic response to a single dose of one of these agents.
- Another important embodiment of the present invention includes the use of approved norepinephrine agents in a pharmaco-diagnostic capacity to aid in probing the Norepinephrinergic tone, in particular for neuropsychiatric conditions like depression, anxiety, schizophrenia, bi-polar disorder, ADHD and narcolepsy.
- the class of norepinephrine agents in a pharmaco-diagnostic capacity to aid in probing the Norepinephrinergic tone, in particular for neuropsychiatric conditions like depression, anxiety, schizophrenia, bi-polar disorder, ADHD and narcolepsy.
- norepinephrinergic agents including tricyclic antidepressants such as Amitriptyline,
- SNRI serotonin norepinephrine receptor inhibitors
- Another important embodiment of the present invention includes its use at physician offices, field-derived locations or at home in order to proctor these brain health scans on a regular, longitudinal basis, either with or without use of a pharmaco-diagnostic agent, in order to monitor a Sickle Cell disease patient's brain for evidence of reduced or abnormal activity. For instance, weekly or twice a week monitoring of multi-modal brain health could provide objective evidence of changes taking place in a Sickle Cell patient such as cerebral ischemia, alteration in cerebral blood flow or neurocognitive decline.
- the present invention also includes multi-modal biosignal evidence gathered in any one of an inpatient, outpatient or home/field setting.
- pre-dose versus post-dose (i) difference and/or (ii) ratio could serve to provide biomarker evidence to help clinical practice and improve outcomes.
- improved health outcomes and reduced costs could be documented in the following fashion: (1) safety could be established by preventing patients from major adverse events like death, cerebral ischemia, neurocognitive decline, early disability and the inability to work.
- the present invention could serve to (2) improve patient satisfaction by reducing travel time and expense to visit an ER or physician's office when not managed properly.
- Another important embodiment of the present invention includes the use of multi-modal neuro diagnostic scanning, either with or without pharmaco-diagnostic CNS active agents, to provide prognostic biomarkers of a postanoxic encephalopathy subject who is in the emergency department or intensive care unit of a hospital, physician office or clinic.
- Prognostic markers could enable clinicians to predict patient outcomes and enable appropriate clinical decisions in light of the prognostic information.
- cardiologists, intensivists and neurologists may find the present invention useful in any patient who presents after an anoxic cerebral event such as, but not limited to, cardiac arrest, cardiac arrhythmia, near-drowning, respiratory failure or suicide attempt.
- pre-dose versus post-dose (i) difference and/or (ii) ratio could serve to provide biomarker evidence to help clinical practice and improve outcomes.
- improved health outcomes and reduced costs could be documented in the following fashion: (1) identify patients who would benefit from more aggressive treatments; (2) identify patients that treatment would prove futile in regaining any meaningful neurological function; and (3) identify which pharmacological therapies would be most advantageous to the patient.
- the present invention could serve to (4) aid in the diagnosis, treatment and prognostication in patients who suffered an anoxic cerebral insult.
- Another important embodiment of the present invention includes the use of multi-modal neuro-diagnostic scanning, either with or without pharmaco-diagnostic CNS active agents, to provide objective clinical evidence of impaired brain health or a lack thereof in relation to workers compensation insurance cases or Medicare/government insurance benefits related to brain injury and disorders, as well as other CNS related injuries like low back pain, amputation pain and neuropathic pain. Because many brain injuries are "invisible” as defined by the patient manifesting only subjective complaints without objective, corroborating diagnostic clinical evidence, it is very difficult today to tell who is legitimately hurt and in need of appropriate medical care and who is malingering and should get off insurance and return to work. Objective multi-modal diagnostic biomarker evidence from the present invention could enable clinicians and thus insurance companies to understand with objective clinical evidence who has suffered a brain-related or CNS associated injury and/or is still suffering from this injury.
- the screening scans can be used to legitimately determine the presence or absence of abnormal brain health in order to substantiate or reject enrollment claims for both short term and long term benefits. It should be emphasized that the "truth" is what the present invention seeks, such that those with brain injury should get appropriate care and benefits and those without brain injury should be prevented from receiving care and benefits fraudulently.
- the aim would be to obtain a scan immediately after injury with as little scan interval (the time between the putative event and the scan) as possible. If a baseline scan was taken and stored prior to the putative event, direct comparison could provide an aid in the diagnosis of the concussive, brain-related or CNS-related injury, including low back pain and chronic pain. Alternatively, if one had several baselines scans profiling each of the dominant neurotransmitter systems (glutamate, GABA, dopamine, serotonin, acetylcholine,
- this phenotype or profile could be repeated post putative traumatic event and the neurotransmitter level information determined could objectively inform diagnosis, prognostication and case management.
- similar assessments can be done serially over time to aid in the management of the worker during the return to work progression (or in the case of the military, in return to duty decisions) or a determination of Maximum Medical Improvement (MMI, described below) as illustrated in FIG. 2.
- FIG. 2 is a schematic diagram illustrating how the present invention could be used to manage return to work decisions, in a similar fashion to return to play decisions for athletes, return to learn decisions for students, or return to duty decisions for soldiers. This could be generally called "return-to-activity" decisions.
- a baseline diagnostic measurement Dx is taken at a point in time 20 prior to a putative accident or injury 22.
- a first diagnostic Dx assessment scan post-putative event is taken at a point in time 24 after the putative accident or injury 22.
- One or more subsequent Dx assessment scans may be taken at times 26 before a final Dx assessment scan it taken at time 28.
- the scan results may be compared with previous scans to identify a change in the subject's brain, central nervous system and/or pain level as a result of the incident or injury that is outside a normal range of variation.
- the scan data may be used to estimate a probability that changes in the subject's brain, central nervous system and/or pain level as a result of said incident or injury are outside the normal range of variation.
- the actual or estimated values may be used to determine whether the subject is ready to either return to work at 32 and/or whether the subject has reached MMI at 34. Similar assessments may be done for each of the examples set forth herein.
- the multi-modal bio-sensor based assessment of the present invention can include any multiple combinations of a single, dual or few lead EEG device, ECG and heart rate variability measurements (since the brain and the heart are well linked between the two), respiration sensor: single or dual-band, actigraphy, audio, blood pressure, diary events, electroencephalogram, electromyogram, galvanic skin response
- the preferred data collection paradigm includes collection of a baseline clinical assessment data of the subject before an injury occurs. This could be stored but not analyzed to reduce cost and only analyzed in the event of a putative accident or injury. Then, post putative event/injury, another set of data can be collected in the same set or subsets of tests such that a direct within subject comparison is possible enabling a more informed and meaningful difference. Standard statistical analysis will be able to place a probability on the retest individual's difference from their baseline in order to help quantify the probability of a significant difference, which would offset any general inaccuracies in the bio-sensor measurements.
- an adaptive normative data set (so called "adaptive norm") could be created and the subject in question compared to the adaptive norm established by the demographically matched peer group. For instance, if a 33-male, 6'2", 185 pound construction worker with A-positive blood, married, non-smoker hurts their back on the job without a baseline assessment before the putative injury, one can gather electronically from the database of bio-sensor data records as many other 33 year old male, 6'2", 185 pound, A-positive blood, married, non-smokers and assemble a norm from these individuals.
- One particular embodiment of the present invention is about determining a risk factor, risk factors, adjusted probably or classification scheme about the objective truthfulness that employees and other insurance beneficiaries are self-reporting.
- this clinical information would be very helpful when it concerns subjective or invisible injuries, in particular soft tissue injuries, low back pain and brain related injuries (migraine, post-concussive headaches, post-concussive neurocognitive problems, and dizziness as non-limiting examples).
- One particular embodiment of the present invention is used to manage the injury recovery of an individual subject and to enable better return-to-work decisions.
- a multi-modal bio-sensor based approach is used to generate clinical information about the status of an injury and use multiple measures throughout the recovery period to monitor objectively the progress a subject is making without having to only rely on the self-report by the individual themselves, which is often biased.
- One particular embodiment of the present invention is about determining maximum medical improvement (MMI) and providing objective evidence to standardize maximum medical improvement (MMI) guidelines. Also, this embodiment could provide objective and quantifiable data to help a physician determine when medical therapy and/or treatment has reached a plateau in its efficacy. Because many invisible injuries, in particular soft tissue injuries, low back pain and brain related injuries (migraine, post-concussive headaches, post-concussive neurocognitive problems, and dizziness) are subjective in nature without quantifiable evidence to validate the patient's complaints, the determination of MMI by a physician is also subjective in nature and without any standardized format. Thus, physician's
- MMI determination has traditionally been physician-dependent, variable per practitioner and without a uniform, standardized consensus.
- the physician would be able to quantify and accurately follow the progression of these subjective complaints.
- accurate guidelines could be created, based upon objective diagnostic information, which could standardize the criteria for the determination for MMI.
- the current, subjective physician determination of MMI would be replaced by guidelines based upon validated diagnostic criteria based on diagnostic information.
- the current embodiment would be utilized to create these guidelines that would help maximize physician's time with patients, reduce unnecessary testing, procedures and medication administration and minimize the variability in the physician's determination of MMI.
- Stimulation of the body can include any of the following non-limiting means of stimulating the nervous system: visual or sight, sound, drugs, thermal grill illusion (see (1) Thunberg T (1896) F5rnimmelserna vid till samma stalle thanksiserad, cryingidigt pagaende k51d- och varmeretning. Uppsala Lakf5ren F5rh 2: 489 ⁇ 195, (2) Boettger MK et al, 2012.
- One non-limiting embodiment would be articulation of the back under load or strain (such as picking up a 20 lb weight off the floor) or the pressing of the head of a subject complaining of neck pain directly onto a vertical force plate and simultaneously recording (i) the force plate measurements (to quantify the stimulation) along with recording the various multi-modal response bio-sensors including but not limited to (ii) the EEG brainwaves, (iii) eye movements during the articulation including the transition from so- called pain-free to painful states, and (iv) a 3 axis accelerometer with or without a 3 axis gyrometer recording the motion of a subject, also from the pain-free to painful states, to determine if in fact there is objective clinical evidence of pain from measurements of the CNS.
- TBI / concussion or head trauma e.g. from a fall off a ladder at work, or by getting hit in the head by a moving machine
- metrics that could be assessed.
- the subject could be put through a battery of tasks which physiologically focus on the cognitive elements, balance/vestibular elements, as well as the self-report elements. This may also include wearing an EEG headband and looking for evidence of a TBI in the transition to sleep where it has been reported that modulation in delta, theta, alpha and beta powers are irregular after TBI.
- a so-called "tidal wave test” which is a form of a modified Romberg test, could be employed where the subject is asked to close their eyes and shake their head vigorously back and forth left to right in the form of a head "no" response three to five times rapidly.
- a truly concussed subject will get dizzy by such a test and feel as if hit by a "tidal wave,” have difficulty with balance and vestibular activity.
- a normal person is not adversely affected. This could be further revealed by the EEG brainwave data, eye tracking measurements made immediately after the vigorous head movements, as well as by accelerometer based bio-sensor measurements taken during the actual vigorous head shaking and immediately preceding and following the head shaking.
- neurocognitive tests could be administered via computer without operator present and an EEG headset could record brainwave activity.
- Leading neurocognitive tests for concussion include but are not limited to Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT, U. Pittsburgh Medical Center), Computerized Cognitive Assessment Tool (CCAT, Axon Sports, CogState), Concussion Resolution Index (CRI, Headminder Inc., NY, NY), Automated Neuropsychological Assessment Metrics system (ANAM, National Rehabilitation Hospital Assistive Technology and Neuroscience Center, Washington, DC), Concussion Vital Signs (CNS Vital Signs, marketed by Pearson).
- an eye tracking device could independently monitor the left and/or right eye positions in time, or alternatively calculate a mean position of the eyes together.
- accelerometer in the EEG headset could measure accelerations during the course of time of interest, for instance at 100 samples/sec in all three directions (e.g. a 3-axis accelerometer).
- Various balance tests such as the static BESS test, or a dynamic "walk and 180 degree turn” test could assess the motion, brainwaves and eye movement of a subject.
- Pre-defined signatures already reported in the literature could be further developed into normative standards.
- Non-limiting examples include (a) lowered relative beta brainwave power in TBI/concussion (see (i) Slobounov, Cao, Sebastinelli, Clin Neurophysiol (2009) and (ii) McCrea M, Prichep L, Powell MR, Chabot R, Barr WB, (2010).
- a photic and/or auditory stimulation could be administered independently to a patient, while the patient is simultaneously being monitored by multi-modal bio-sensor system which includes an EEG headset, recording brainwave activity.
- multi-modal bio-sensor system which includes an EEG headset, recording brainwave activity.
- Auditory stimulants such as white or pink noise, binaural beats, isochronic tones and monaural beats could be used to attempt to induce the migraine and objectively measure the physiologic response.
- auditory and/or visual/photic stimulation could also be employed to bring onset of migraine and measure of physiologic change to then be tested for consistency, or not, with the self-report claims of the subject under test.
- the thermal grill in which metal fingers are interwoven and placed at either similar or dissimilar
- temperatures to create an artificial pain sensation can be used to look for heightened sensation to pain in those suffering compared to those who are not.
- a test like this is important to use because most folks are unfamiliar with the test and therefore it is more difficult to guess what the truly injured profile of behavior and response should be to mimic in an attempt to defraud the insurance company and employer.
- the best tests rely on the objective bio-sensor measurements which are much more difficult to intentionally adjust. Very few of us have the ability to control our brainwaves, nor to control our automated eye movements and voice. These inexpensively available bio-sensor streams should then form the basis of normal versus injured response.
- an accelerometer in the EEG headset could measure accelerations during motion, for instance at a rate of 20, 40, 60, 80, 100 or 120 samples/sec in all three directions (e.g. with a 3-axis accelerometer with or without a 3-axis gyrometer).
- balance tests such as the static Balanced Error Scoring System (BESS) test, "tidal wave test", or a dynamic "walk and 180 degree turn” test could assess the motion, brainwaves and eye movement of a subject.
- BESS static Balanced Error Scoring System
- Tidal wave test or a dynamic "walk and 180 degree turn” test could assess the motion, brainwaves and eye movement of a subject.
- BESS static Balanced Error Scoring System
- tilt and 180 degree turn a dynamic "walk and 180 degree turn” test
- COG/COM center-of-gravity or center-of-mass
- COG/COM center-of-mass
- fraudulent individuals will do their best to emulate someone with a vertigo or vestibular dysfunction, but quantitative analysis of the motion sampled should reveal subtle differences such as a stochastic nature to the variation (e.g.
- One of the most straightforward embodiments of the present invention would be the use of established as well as novel neurocognitive tests in the evaluation of a claim of neurocognitive impairment. Cognition is often broken down into six domains, including Verbal learning and memory, Nonverbal learning and memory, Executive function abilities, Language,
- Established tests and batteries include those from Cantab, CogState, CNS NeuroVitals, the ANAM from the US military, etc.
- Individual tasks and instruments of interest could include but are not limited to the Mini-Mental State Exam (MMSE), the Montreal Cognitive Assessment, (MOCA), the CAMCOG, the Free and Cued Selective Reminding Task (FCSRT), Wechsler recall and delayed recall task, the California Verbal Learning Test - first or second edition (CVLT, CVLT-II), the Paced Auditory Serial Addition Test (PASAT) to name but a few.
- MMSE Mini-Mental State Exam
- MOCA Montreal Cognitive Assessment
- FCSRT Free and Cued Selective Reminding Task
- CVLT California Verbal Learning Test - first or second edition
- CVLT-II the Paced Auditory Serial Addition Test
- PASAT Paced Auditory Serial Addition Test
- binaural beats, monaural beats, isochronic tones and other auditory stimulations can be applied to the tinnitus person's ears with high quality ear buds. If there is a registration between the auditory stimulus and characteristic brainwave changes associated with the pain (e.g. destruction of the alpha peak) in an eyes closed state, then this would provide objective evidence to support a claim of tinnitus.
- This sort of data mining model additional care and prevention can be taken with those individuals that begin to fit a pattern based on previous claim history.
- Another important embodiment of the present invention includes the use of multi-modal neuro-diagnostic scanning, either with or without pharmaco-diagnostic CNS active agents, to provide objective clinical evidence of fatigue and lethargy.
- agents such as, but not limited to, modafinil, armodaiinil and amantadine can be used in single doses to probe the tone of the human subject's brain under assessment for clinical response evidence that they may be more susceptible to fatigue and lethargy.
- the previously mentioned agents used as single doses can be utilized to assess the brain response in a patient who suffers from fatigue and lethargy.
- pre-dose versus post-dose (i) difference and/or (ii) ratio could serve to provide biomarker evidence to help clinical practice and improve outcomes.
- improved health outcomes and reduced costs could be documented in the following fashion: (1) minimize the negative effects of shift work on patient's health and job by identifying patients who would perform poorly under these circumstances or who has become impaired due to their shift work schedule; (2) prevent motor vehicle accidents by identifying when certain drivers should stay off the road such as truck drivers who had little sleep; (3) reduce air-related accidents by identifying which pilots are too impaired to fly a plane; and (4) reduce time off work by identifying which potential medications may cause or is causing patients excessive fatigue/tiredness and the inability to maintain properly their work schedule.
- Another aspect of the present invention is the use of Memantine, an NMDA receptor antagonist to treat patients diagnosed with a concussion or mild Traumatic Brain Injury.
- the idea is that when a patient suffers a concussive event a cascade of biochemical events occur in the brain. The byproduct of this cascade is neurotoxic chemicals which promote, worsen and potentiate the deleterious effect the concussive injury has upon the brain.
- NMDA receptor antagonists such as, but not limited to, memantine block the NMDA channel in the central nervous system, it is hypothesized that it may counteract at least some of the deleterious effects that these neurotoxic chemical can have on the brain.
- Another aspect of the present invention is the use of vitamins to treat patients diagnosed with Parkinson's disease.
- the idea is that the antioxidant effects of vitamins could have a beneficial impact on the motor control and gait of a Parkinson's patient.
- a physician could scan the brain of a patient using a multimodal system and follow-up analytics of the type described above.
- a subject would be scanned pre-dose to gather a baseline assessment. Then they would be administered a single diagnostic dose of Sinemet and asked to wait in the waiting room for 30, 60, or 90 minutes or until the
- T max of the drug as known from the drug label and Pharmacokinetic studies. Then they would be scanned a second time in identical fashion. They could also be scanned a third, fourth and/or fifth time at earlier and later time points than T max in order to derive a time series view of the effect of Sinemet.
- Characteristic features of the before scan data in comparison to the after dose scan data, either as a difference between the two scans or the ratio between the two scans, could be used to provide objective biomarker information of an abnormal dopaminergic tone. This could aid in the enrollment process for clinical trials in Parkinson's disease as well as in clinical practice and management of the disease.
- a physician could scan the brain of a patient using a conventional neuro-diagnostic system (e.g., EEG, fMRI, PET, SPECT, etc.) and follow the pre-dose vs. post-dose active pharmacologic agent protocol described above.
- a subject would be scanned pre-dose to gather a baseline assessment, for instance using a DAT
- PET ligand in a PET scanner or using a conventional 10-20 montage EEG. Then they would be administered a single diagnostic dose of Sinemet (or other active dopaminergic agent) and asked to wait in the waiting room for 30, 60, or 90 minutes or until the T max of the drug, as known from the drug label and Pharmacokinetic studies. Then they would be PET scanned a second time in identical fashion with the DAT ligand or recorded in EC and EO states with the 10-20 montage EEG. They could also be scanned a third, fourth and/or fifth time at earlier and later time points than T max in order to derive a time series view of the effect of Sinemet.
- Example 2 Use of ice cube or other cold object to aid in the identification of pain and return-to-work (RtW) decisions
- a physician could scan the brain of a patient using a multimodal system and follow-up analytics of the type described above.
- a subject would be scanned pre-injury to gather a baseline assessment whenever possible.
- a claim of soft tissue related pain was made, one could use the methods of the present invention.
- MindSet Pro from NeuroSky
- FIG. 3 is a schematic diagram illustrating how the present invention could be used to manage risk and identify potential fraud in a work stream of claims within an insurance company for worker's compensation and other injury related claims by, for example, identifying the alpha peak in the scan data.
- This same paradigm could be used for the evaluation of back pain, asking a subject to sit comfortably with eyes closed, then lift a box with eyes closed, and then sit quietly with eyes closed. If the alpha peak is present in all conditions, then this would not be supportive of a pain claim.
- this process could be monitored periodically, for instance every day, week or other frequency which the insurance company and/or physician should set. This would enable serial or longitudinal monitoring of the signal over time to determine when it has returned to baseline or alternatively, when it has flattened out and is now consistent over time.
- Example 3 Use of a thermal grill to aid in the identification of pain and return to work decisions
- a physician could scan the brain of a patient using a multimodal system and follow-up analytics of the type described above.
- a subject would be scanned pre-injury to gather a baseline assessment whenever possible.
- a claim of soft tissue related pain was made, one could use the methods of the present invention.
- the subject could place their hand on a thermal grill, made of two independent pieces of metal with interlaced fingers held at various temperatures. It is known that pain circuits are sensitized when activated. Thus if a subject shows a heightened sensitivity to a thermal grill with mixed high and low temperatures, this would support a claim of pain related injury. As in the previous example, the prominence or lack thereof of the alpha peak is an excellent starting point. Other biomarkers can be identified that correspond to the painful state. This same paradigm could be used for the evaluation of back pain, asking a subject to sit comfortably with eyes closed on a thermal grill, then lift a box with eyes closed, and then sit quietly with eyes closed with their hand on a thermal grill.
- the alpha peak is present in all conditions, then this would not be supportive of a pain claim. If it shifted while undergoing the EC lift condition or it became more sensitive to lower temperature difference between the two temperatures, this would support some shift. If it diminished, it would be consistent with the pain condition.
- this process could be monitored periodically, for instance every day, week or other frequency which the insurance company and/or physician should set. This would enable serial or longitudinal monitoring of the signal over time to determine when it has returned to baseline or alternatively, when it has flattened out and is now consistent over time.
- a physician could scan the brain of a patient using a multimodal system and follow-up analytics of the type described above.
- a subject would be scanned pre-injury to gather a baseline assessment whenever possible. Then, if a claim of soft tissue related pain was made, one could use the methods of the present invention.
- vertigo the eye movement of the subject is abnormal relative to healthy controls.
- the subject could record their eye movement while standing still in place. Then, they could be asked to move slowly and record their eye movement. Then as a final return position, they could be asked to record eye movement at rest again.
- the saccadic movements of the eye should appear abnormal relative to their pre-injury or adaptive norm group.
- this process could be monitored periodically, for instance every day, week or other frequency which the insurance company and/or physician should set. This would enable serial or longitudinal monitoring of the signal over time to determine when it has returned to baseline or alternatively, when it has flattened out and is now consistent but not back to baseline over time.
Abstract
Description
Claims
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EP14770223.7A EP2967354A4 (en) | 2013-03-15 | 2014-03-14 | Multi-modal pharmaco-diagnostic assessment of brian helath |
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CA2906595A CA2906595A1 (en) | 2013-03-15 | 2014-03-14 | Multi-modal pharmaco-diagnostic assessment of brain health |
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AU2014240105A AU2014240105B2 (en) | 2013-03-15 | 2014-03-14 | Multi-modal pharmaco-diagnostic assessment of brain health |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016204282A1 (en) * | 2015-06-18 | 2016-12-22 | 大学共同利用機関法人自然科学研究機構 | Evaluation of inhibitory circuit and use thereof |
WO2017194828A1 (en) * | 2016-05-11 | 2017-11-16 | Cerenion Oy | Apparatus and method for electroencephalographic measurement |
US10779747B2 (en) | 2013-03-15 | 2020-09-22 | Cerora, Inc. | System and signatures for the multi-modal physiological stimulation and assessment of brain health |
US11517235B2 (en) | 2017-05-22 | 2022-12-06 | Genetesis, Inc. | Machine differentiation of abnormalities in bioelectromagnetic fields |
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020052311A1 (en) * | 1999-09-03 | 2002-05-02 | Beka Solomon | Methods and compostions for the treatment and/or diagnosis of neurological diseases and disorders |
US6741888B2 (en) * | 2000-12-18 | 2004-05-25 | Brain Functions Laboratory, Inc. | Method and apparatus for estimating degree of neuronal impairment in brain cortex |
US6947790B2 (en) * | 2000-06-26 | 2005-09-20 | Sam Technology, Inc. | Neurocognitive function EEG measurement method and system |
US20060129324A1 (en) * | 2004-12-15 | 2006-06-15 | Biogenesys, Inc. | Use of quantitative EEG (QEEG) alone and/or other imaging technology and/or in combination with genomics and/or proteomics and/or biochemical analysis and/or other diagnostic modalities, and CART and/or AI and/or statistical and/or other mathematical analysis methods for improved medical and other diagnosis, psychiatric and other disease treatment, and also for veracity verification and/or lie detection applications. |
US20130035579A1 (en) * | 2011-08-02 | 2013-02-07 | Tan Le | Methods for modeling neurological development and diagnosing a neurological impairment of a patient |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6622036B1 (en) * | 2000-02-09 | 2003-09-16 | Cns Response | Method for classifying and treating physiologic brain imbalances using quantitative EEG |
US20010056115A1 (en) * | 1998-06-18 | 2001-12-27 | Tulloch Ian Frederic | Novel therapeutic method |
ATE433163T1 (en) * | 2001-07-11 | 2009-06-15 | Cns Response Inc | METHOD FOR PREDICTING TREATMENT RESULTS |
JP2009521403A (en) * | 2005-11-14 | 2009-06-04 | ザ・トラスティーズ・オブ・コランビア・ユニバーシティー・イン・ザ・シティー・オブ・ニューヨーク | Imaging method of correlation of neurogenesis by MRI |
KR20080081005A (en) * | 2005-11-30 | 2008-09-05 | 니혼 메디피직스 가부시키가이샤 | Head degenerative disease detection method, detecting program, and detector |
US8521270B2 (en) * | 2006-06-05 | 2013-08-27 | The Regents Of The University Of California | Quantitative EEG method to identify individuals at risk for adverse antidepressant effects |
US20100312105A1 (en) * | 2007-10-31 | 2010-12-09 | Alseres Pharmaceuticals, Inc. | Methods for diagnosing and monitoring treatment of lewy body dementia by assessing dopamine transporter level |
US8352021B2 (en) * | 2008-04-15 | 2013-01-08 | Christopher Scheib | Method and system for jointly monitoring physiological conditions |
EP2682053A1 (en) * | 2009-06-15 | 2014-01-08 | Brain Computer Interface LLC | A brain-computer interface test battery for the physiological assessment of nervous system health |
WO2012106593A2 (en) * | 2011-02-03 | 2012-08-09 | University Of Utah Research Foundation | Devices, systems, and methods for assessing peripheral nerve damage |
US20140107429A1 (en) * | 2011-04-01 | 2014-04-17 | Charles A. Simkovich | Computer-executed method, system, and computer readable medium for testing neuromechanical function |
-
2014
- 2014-03-14 KR KR1020157029756A patent/KR20160138339A/en not_active Application Discontinuation
- 2014-03-14 US US14/773,872 patent/US20160022206A1/en not_active Abandoned
- 2014-03-14 WO PCT/US2014/026962 patent/WO2014152110A1/en active Application Filing
- 2014-03-14 AU AU2014240105A patent/AU2014240105B2/en not_active Ceased
- 2014-03-14 CN CN201480028481.5A patent/CN105658134B/en not_active Expired - Fee Related
- 2014-03-14 JP JP2016502292A patent/JP2016521998A/en active Pending
- 2014-03-14 CA CA2906595A patent/CA2906595A1/en not_active Abandoned
- 2014-03-14 EP EP14770223.7A patent/EP2967354A4/en not_active Withdrawn
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020052311A1 (en) * | 1999-09-03 | 2002-05-02 | Beka Solomon | Methods and compostions for the treatment and/or diagnosis of neurological diseases and disorders |
US6947790B2 (en) * | 2000-06-26 | 2005-09-20 | Sam Technology, Inc. | Neurocognitive function EEG measurement method and system |
US6741888B2 (en) * | 2000-12-18 | 2004-05-25 | Brain Functions Laboratory, Inc. | Method and apparatus for estimating degree of neuronal impairment in brain cortex |
US20060129324A1 (en) * | 2004-12-15 | 2006-06-15 | Biogenesys, Inc. | Use of quantitative EEG (QEEG) alone and/or other imaging technology and/or in combination with genomics and/or proteomics and/or biochemical analysis and/or other diagnostic modalities, and CART and/or AI and/or statistical and/or other mathematical analysis methods for improved medical and other diagnosis, psychiatric and other disease treatment, and also for veracity verification and/or lie detection applications. |
US20130035579A1 (en) * | 2011-08-02 | 2013-02-07 | Tan Le | Methods for modeling neurological development and diagnosing a neurological impairment of a patient |
Non-Patent Citations (2)
Title |
---|
BERENDSE, HW ET AL.: "Diagnosing premotor Parkinson's disease using a two-step approach combining olfactory testing and DAT SPECT imaging.", PARKINSONISM AND RELATED DISORDERS, vol. 15, December 2009 (2009-12-01), pages S28 - S30, XP055283369, Retrieved from the Internet <URL:http://www.ncbi.nlm.nih.gov/pubmed/20083001> * |
See also references of EP2967354A4 * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10779747B2 (en) | 2013-03-15 | 2020-09-22 | Cerora, Inc. | System and signatures for the multi-modal physiological stimulation and assessment of brain health |
WO2016204282A1 (en) * | 2015-06-18 | 2016-12-22 | 大学共同利用機関法人自然科学研究機構 | Evaluation of inhibitory circuit and use thereof |
JPWO2016204282A1 (en) * | 2015-06-18 | 2017-06-29 | 大学共同利用機関法人自然科学研究機構 | Evaluation and use of inhibitory circuits. |
KR20180018574A (en) * | 2015-06-18 | 2018-02-21 | 다이가쿠쿄도리요기깐호우징 시젠카가꾸켄뀨기꼬 | Evaluation and Use of Inhibitor Circuits |
KR101935275B1 (en) | 2015-06-18 | 2019-04-05 | 토카이 옵티칼 주식회사 | Evaluation and Use of Inhibitor Circuits |
AU2016279532B2 (en) * | 2015-06-18 | 2020-01-23 | Inter-University Research Institute Corporation National Institutes Of Natural Sciences | Evaluation of inhibitory circuit and use thereof |
US10820823B2 (en) | 2015-06-18 | 2020-11-03 | Inter-University Research Institute Corporation National Institutes Of Natural Sciences | Evaluation of inhibitory circuit and use thereof |
WO2017194828A1 (en) * | 2016-05-11 | 2017-11-16 | Cerenion Oy | Apparatus and method for electroencephalographic measurement |
US10342450B2 (en) | 2016-05-11 | 2019-07-09 | Cerenion Oy | Apparatus and method for electroencephalographic measurement |
US11517235B2 (en) | 2017-05-22 | 2022-12-06 | Genetesis, Inc. | Machine differentiation of abnormalities in bioelectromagnetic fields |
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CA2906595A1 (en) | 2014-09-25 |
AU2014240105A1 (en) | 2015-11-05 |
EP2967354A4 (en) | 2017-05-31 |
CN105658134A (en) | 2016-06-08 |
US20160022206A1 (en) | 2016-01-28 |
AU2014240105B2 (en) | 2019-10-31 |
CN105658134B (en) | 2019-11-19 |
KR20160138339A (en) | 2016-12-05 |
EP2967354A1 (en) | 2016-01-20 |
JP2016521998A (en) | 2016-07-28 |
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