IBIA Multimodal Talk Download the PPT Slideshow

Multi-Modal Therapy for Multi-Modal Therapy for Disorders of ConsciousnessDisorders of Consciousness

Philip DeFina, Ph.D. Philip DeFina, Ph.D. International Brain Research FoundationInternational Brain Research Foundation

Jonathan Fellus, M.D.Jonathan Fellus, M.D.Kessler Institute for RehabilitationKessler Institute for Rehabilitation

Eighth World Congress on Brain Eighth World Congress on Brain InjuryInjury

Washington, D.C.Washington, D.C.March 10-14, 2010March 10-14, 2010

Presentation OutlinePresentation Outline

1.1. Need for Improved Therapies for DOCNeed for Improved Therapies for DOC2.2. Theory of Brain Reorganization and Theory of Brain Reorganization and

PlasticityPlasticity3.3. Multi-modal Care Protocol (MCP)Multi-modal Care Protocol (MCP)4.4. Future Directions: DoD Research GrantFuture Directions: DoD Research Grant

1. Need for Improved Therapies1. Need for Improved Therapies

Traumatic brain injury:Traumatic brain injury: 33% of adults in PVS for one month 33% of adults in PVS for one month

recovered within three months, and 52% recovered within three months, and 52% recovered within one year. (Multi-Society recovered within one year. (Multi-Society Task Force, Task Force, NEJMNEJM))

Non-traumatic brain injury:Non-traumatic brain injury: 11% of adults in PVS for one month 11% of adults in PVS for one month

recovered within three, and 13% recovered recovered within three, and 13% recovered within one year. within one year.

Need for Improved TherapiesNeed for Improved Therapies

The literature suggests that Severe Disorders The literature suggests that Severe Disorders of Consciousness (SDOC) patients in the of Consciousness (SDOC) patients in the United States, with severe TBI and VS for United States, with severe TBI and VS for greater than 12 months, or with severe greater than 12 months, or with severe nonTBI and VS for greater than 3 months, will nonTBI and VS for greater than 3 months, will likely never recover.likely never recover.

Need for Improved TherapiesNeed for Improved Therapies

These patients are typically medically categorized as These patients are typically medically categorized as untreatable. untreatable. often placed in long-term care facilities or home care often placed in long-term care facilities or home care

that provides only palliative support and deteriorate or that provides only palliative support and deteriorate or die due to lack of proactive medical treatment and/or die due to lack of proactive medical treatment and/or opportunistic infectious processes. opportunistic infectious processes.

Places an immense burden on family, community, and the Places an immense burden on family, community, and the health care system, as it is estimated that 70% of those health care system, as it is estimated that 70% of those who are in a minimally conscious state due to trauma who are in a minimally conscious state due to trauma remain at a moderate to extremely severe level of remain at a moderate to extremely severe level of disability one year post injury (Mohonk Report, 2006). disability one year post injury (Mohonk Report, 2006).

Need for Improved TherapiesNeed for Improved Therapies

In the US, the insurance industry does not recognize treatment for DOC, as evident in the lack of Diagnosis-Related Groups (DRGs) and Current Procedural Terminology (CPT) codes (AMA, 2009).

Life expectance of 8-10 years (MSTF)

Need for Improved TherapiesNeed for Improved Therapies

Specific pharmacological interventions, Specific pharmacological interventions, particularly single medication particularly single medication interventions, have been studied, in an interventions, have been studied, in an attempt to improve recovery from MCS attempt to improve recovery from MCS and VS. and VS.

2. Theory of Post-Injury 2. Theory of Post-Injury Reorganization and PlasticityReorganization and Plasticity

Injured brain reacts in specific Injured brain reacts in specific and significant ways.and significant ways.

Metabolic cascadesMetabolic cascades ExcitotoxicityExcitotoxicity

Cell death and Apoptosis.Cell death and Apoptosis.

Diffuse Axonal Injury Result of mechanically induced stretching, shearing or tearing

of nerve fibers

primary pathologic feature of brain injury in all severity levels of concussion (Kushner, 2001).

increase in neuronal permeability, especially to Ca2+ (reduced mitochondrial metabolism, reduced ATP production)

not detectable by MRI, CT. EEG can detect DAI (Thatcher, 1998; Collins, 2007; Pardini ,2007)

DAI causes damage to cortical structures

excitatory inputs to the brainstem reticular cells suppressed due to lack of input (Gaetz, 2004)

Decreased arousal or LOC

Plasticity Following Injury

Long-Term Potentiation (LTP) is reduced (Hebb, 1949)

Long-Term Depression (LTD) increased; i.e. a reduction in efficacy of neuronal synapses (Stent, 1973)

Membrane excitability reduced

Anatomical changes – axon terminals damaged & synapses reduced

NeuromodulationNeuromodulation

By identifying the unique injury By identifying the unique injury characteristics within the brain’s characteristics within the brain’s electrochemical environment, we can electrochemical environment, we can identify and measure identify and measure neuromarkersneuromarkers. . SSpecific interventions and treatments are pecific interventions and treatments are then applied in an effort to facilitate and then applied in an effort to facilitate and guide neural plasticity. guide neural plasticity.

Defina, P. et al, (2009). The new neuroscience frontier: Promoting neuroplasticity Defina, P. et al, (2009). The new neuroscience frontier: Promoting neuroplasticity and brain repair in traumatic brain injury,and brain repair in traumatic brain injury,

The Clinical NeuropsychologistThe Clinical Neuropsychologist, 23 (8), 1391-1399 ., 23 (8), 1391-1399 .

Complex Intervention vs. Single Complex Intervention vs. Single Variable Research Paradigm Variable Research Paradigm

Traditional Research: single, controlled variablesTraditional Research: single, controlled variables Reality of Medical Treatments is Complex.Reality of Medical Treatments is Complex. Multiple Medications and Interventions.Multiple Medications and Interventions. Single design: Unrealistic, ungeneralizable.Single design: Unrealistic, ungeneralizable. Paradigm Shift: Paradigm Shift: Shepperd and others (2009).Shepperd and others (2009). Must move to conduct and review Complex Must move to conduct and review Complex

Interventions.Interventions. Use Key Components: Trial data, Qualitative Use Key Components: Trial data, Qualitative

data, Theory.data, Theory.

StandardStandard Model for Assessment/Treatment of Model for Assessment/Treatment of AcuteAcute Stage TBI Stage TBI

Coma Rating ScalesComa Rating Scales CT ScanCT Scan Neurologic exam (e.g. cranial nerves, pupil reactivity)Neurologic exam (e.g. cranial nerves, pupil reactivity) Seizure prophylaxisSeizure prophylaxis Blood pressure controlBlood pressure control Blood gases - MonitorBlood gases - Monitor Electrolyte balance – MonitorElectrolyte balance – Monitor Nutritional statusNutritional status Regulate fluid intakeRegulate fluid intake

“Improved survival rates … THEN … sit and wait”

Do not greatly improve or speed recovery

Not predictive of outcome

IBRFIBRF Model for Assessment/Treatment of Model for Assessment/Treatment of AcuteAcute Stage TBI Stage TBI

Directional Normalization of brain: ElectrochemistryO2 perfusion Glucose metabolism

Improve/Optimize: CNS tissue survival arousal cognition motor skills

StandardStandard Model for Assessment/Treatment of Model for Assessment/Treatment of ChronicChronic Stage TBI Stage TBI

Assorted NP test measuresAssorted NP test measures Rating scalesRating scales Symptom monitoringSymptom monitoring StandardStandard MRI, CT, EEG (limited correlation with MRI, CT, EEG (limited correlation with

functional recovery)functional recovery) ““sit and wait”sit and wait”

Poor predictor of outcomesPoor predictor of outcomes No subtypingNo subtyping Does not translate to (guide) treatment protocolDoes not translate to (guide) treatment protocol Administered beyond critical time windowAdministered beyond critical time window

IBRFIBRF Model for Assessment/Treatment of Model for Assessment/Treatment of ChronicChronic Stage TBI Stage TBI

Identification of NeuromarkersIdentification of Neuromarkers Subtyping of injurySubtyping of injury Predicting recovery timelinePredicting recovery timeline Direct relationship between assessment and Direct relationship between assessment and

treatment protocolstreatment protocols Neuromarkers/assessments DRIVE interventionsNeuromarkers/assessments DRIVE interventions

Intensive multi-modal therapeutic interventions Intensive multi-modal therapeutic interventions through full potential functional recoverythrough full potential functional recovery

IBRF Integrated Multi-modal IBRF Integrated Multi-modal ApproachApproach

IBRF Program Goals:IBRF Program Goals:

1)1) Identify Identify functional neuromarkersfunctional neuromarkers to establish TBI to establish TBI subtypes. subtypes.

2)2) Comprehensively evaluate the Comprehensively evaluate the unique patternsunique patterns associated with individual TBI subtypes.associated with individual TBI subtypes.

3)3) Refine integrated Refine integrated multi-modalmulti-modal assessments that assessments that directly guide directly guide multi-modalmulti-modal treatment. treatment.

4)4) Predict treatment outcomes based on TBI Predict treatment outcomes based on TBI subtypessubtypes..

IBRF Brain Injury ModelIBRF Brain Injury Model Assessing Non-Invasive Multimodal Functional Assessing Non-Invasive Multimodal Functional

Neuromarkers creates a dynamic and integrated Neuromarkers creates a dynamic and integrated ““Brain MapBrain Map” ”

Neuromarkers are used to recognize multianalyte Neuromarkers are used to recognize multianalyte profiles of:profiles of: altered neurophysiological function (electrical, altered neurophysiological function (electrical,

chemical, metabolic).chemical, metabolic). neuronal & structural integrityneuronal & structural integrity chemical homeostasischemical homeostasis

The The Brain MapBrain Map directly guides treatment directly guides treatment interventions which are correlated to the interventions which are correlated to the assessment measures.assessment measures.

IBRF IBRF Assessment – Treatment – Feedback LoopAssessment – Treatment – Feedback Loop

Clinical Outcome

TreatmentIntervention

Neuro-Biomarkers(Neurologic, Physiologic,

Psychologic, Biologic)

Multi-Modal Neurofunctional

Assessment

Integrated Functional Mapping: Integrated Functional Mapping: The IBRF ApproachThe IBRF Approach

Measure Marker Strengths Associated Treatment

EEG, qEEG electrophysiology High temporal resolution (ms)

Source localization of electrical generators in cortex

EEG brain-computer interface (BCI) training

Guides tDCS and TMS

EP, ERP electrophysiological High temporal resolution (ms)

Measure processing speed

Measure intactness of sensory pathways

EEG BCI training

Guides tDCS and TMS

MEG Brain electromagnetism High temporal resolution

Subcortical structures

Guides tDCS and TMS

B.I.S. Monitor Level of consciousness Real-time measure of patient level of consciousness

Determine patient receptiveness to treatment

MRI w/ DTI Structural anomalies

Brain volume

Brain connectivity

Guides medical and surgical interventions

Neurosurgery

Pharmacotherapy

MRI Spectroscopy Brain chemistry / metabolites Provides chemical neuromarkers

Pharmacotherapy, nutraceuticals

PET-CT Metabolic functions Multiple metabolic neuromarkers

Pharmacotherapy, nutraceuticals

Near Infra-red Spectroscopy O2 concentrations/uptake Non-invasive O2 exchange method

Pharmacotherapy, nutraceuticals

Median nerve stim

Combined neurologic assessment modalities: limitations of one modality are compensated for by others

IBRF-DOC Theoretical Paradigm IBRF-DOC Theoretical Paradigm – – A Model Based on Neurochemical Autoregulation A Model Based on Neurochemical Autoregulation

Down RegulationDown Regulation

Agonist NT’sAgonist NT’s

ConsciousnessConsciousness

MCSMCS

PVSPVS Agonist NT’sAgonist NT’s

Up Regulation Up Regulation COMA COMA

down regulation manifests as reduced down regulation manifests as reduced

perceptual awareness & unresponsivenessperceptual awareness & unresponsiveness

This model developed by Dr. Philip A. De Fina ©This model developed by Dr. Philip A. De Fina ©

Brain’s Inherent Protective Mechanism to Sustain Life

Endorphins

GABA

Increase Inhibitory NT’s Antagonist NT’s Block Receptors

Multi-modal Care Protocol Multi-modal Care Protocol (MCP)(MCP)

Screening: Screening: Inclusion/Exclusion CriteriaInclusion/Exclusion Criteria

Diagnostics: Diagnostics: functional neuroimaging (e.g., qEEG)functional neuroimaging (e.g., qEEG) neurophysiological signal processingneurophysiological signal processing measures of chemical metabolites measures of chemical metabolites

Treatment: Treatment: Off-label PharmacologicalOff-label Pharmacological Median Nerve StimulationMedian Nerve Stimulation Nutraceutical ComponentsNutraceutical Components

MCP Retrospective StudyMCP Retrospective Study Retrospective Case Series of data Retrospective Case Series of data

collected at KIR from 2005-2009 (IRB collected at KIR from 2005-2009 (IRB approved retrospective).approved retrospective).

N=41; VS-TBI, VS-nonTBI, MCS-TBI, N=41; VS-TBI, VS-nonTBI, MCS-TBI, MCS-nonTBI.MCS-nonTBI.

Twelve week interventionTwelve week intervention Traditional OT, Speech, PTTraditional OT, Speech, PT Off-label PharmaceuticalsOff-label Pharmaceuticals Median Nerve StimulationMedian Nerve Stimulation NutraceuticalsNutraceuticals

Participant CharacteristicsParticipant Characteristics

Pre and Post MeasuresPre and Post Measures

Disability Rating ScaleDisability Rating Scale Functional Independence MeasureFunctional Independence Measure Glasgow Coma ScaleGlasgow Coma Scale Coma Recovery Scale-RevisedComa Recovery Scale-Revised Clinical DX (VS, MCS, Emerged); based Clinical DX (VS, MCS, Emerged); based

on Mohonk criteriaon Mohonk criteria EEG/QEEG - (data in analysis stage)EEG/QEEG - (data in analysis stage)

DRS, GCS, CRS-R, and Total FIM Scores Between Admission and Discharge for Entire Sample.

Prognosis for Recovery in DOC Patients Receiving ACP vs. Standard Care in Published Literature.*

*Clinical change for VS patients was compared to the MSTF11 study; clinical change for MCS patients was estimated based on published DRS scores ranging from none to moderate disability (see page 43 and Table 4 of Giacino & Kalmar, 1997).

Retrospective ResultsRetrospective Results

Patients showed statistically significant Patients showed statistically significant improvement across all measures.improvement across all measures.

100% clinical improvement in MCS.100% clinical improvement in MCS. 78-86% clinical improvement in VS.78-86% clinical improvement in VS. Significant differences between MCP and Significant differences between MCP and

published literature, based on multiple outcome published literature, based on multiple outcome measures.measures.

Sample EEG Data from Retrospective Analysis

Polypharmacy and RiskPolypharmacy and Risk

Use of multiple medications is routine in Use of multiple medications is routine in medical treatment: Psychiatric, Stroke, medical treatment: Psychiatric, Stroke, etc.etc.

Retrospective Study: No adverse effects.Retrospective Study: No adverse effects. This patient population has been offered This patient population has been offered

little hope, given limited life expectancy.little hope, given limited life expectancy.

Limitations Limitations of Retrospective Studyof Retrospective Study

Not a controlled, randomized, double-blinded Not a controlled, randomized, double-blinded clinical trial.clinical trial.

No separate standard of care control group.No separate standard of care control group. Small sample size.Small sample size. Treatments used in combination, therefore Treatments used in combination, therefore

efficacy of single or different combinations efficacy of single or different combinations not observed. Nevertheless…it is the not observed. Nevertheless…it is the combination that seems to have the most combination that seems to have the most impact.impact.

5. Future Directions

Department of DefenseDepartment of Defense

Research Grant ProjectResearch Grant Project

Implementation of Advanced Care Implementation of Advanced Care Protocol (ACP) Research ProjectProtocol (ACP) Research Project

for Patients with Disorders of for Patients with Disorders of ConsciousnessConsciousness

DoD Research GrantDoD Research GrantGeneral HypothesesGeneral Hypotheses

1.1. By optimizing the electrochemical status of the brain with the By optimizing the electrochemical status of the brain with the IBRF ACP/MCP, patients with DOC will exhibit more positive IBRF ACP/MCP, patients with DOC will exhibit more positive health outcomes than patients who receive a placebo ACP/MCP.health outcomes than patients who receive a placebo ACP/MCP.

2.2. Recovery from DOC is marked by unique and specific patterns of Recovery from DOC is marked by unique and specific patterns of electrical and chemical neuromarkers.electrical and chemical neuromarkers.

There will be two groups of participants:There will be two groups of participants:

Group 1: Participants receive 12 weeks of the ACP ProtocolGroup 1: Participants receive 12 weeks of the ACP Protocol

Group 2: Participants in a Placebo control group receiving current Group 2: Participants in a Placebo control group receiving current medical standard care and placebo ACP Protocol interventions. medical standard care and placebo ACP Protocol interventions.

Functional Measurement Instruments

Functional Independence Measure (FIM) Glasgow Coma Scale (GCS) Rancho Level of Cognitive Functioning

Scale (LCFS) Coma Rating Scale-Revised (CRS-R) Disability Rating Scale (DRS) Orientation Log (O-Log).

Neuromarker Measurement Instruments

Electroencephalography (EEG) Quantitative EEG (qEEG) Evoked Potentials (EPs) Event Related Potentials (ERP) Magnetic Resonance Imaging (MRI) Diffusion Tensor Imaging (DTI) Susceptibility Weighted Imaging (SWI) Magnetic Resonance Spectroscopy (MRS) Autonomic Nervous System monitoring (ANS) Near Infrared Spectroscopy (NIRS) Bispectral Index (BIS).

ACP Interventions Neuropsychiatric Pharmacology: Off-label use of pharmaceuticals will be employed

to stabilize neurotransmitter functions.

Nutraceuticals: Nutritive Pharmacology will be used to further brain functions while maintaining effective brain metabolism. A combination of pharmaceutical grade nutrients, vitamins, and antioxidants are used with very specific dosing requirements.

Median Nerve Stimulation (MNS): MNS assists in perfusing oxygen to the brain and increasing blood-brain-barrier permeability. It enhances the effects of medications in regulating neurotransmitter stability cortically and sub-cortically (see Cooper & Cooper)

Occupational, Physical, and Speech Therapies: Administration as is customary in rehabilitation facilities.

Cognitive Enhancement: Cognitive enhancement is a tailored program of

individualized interventions that will be applied at the post emergent level. It is the application of a variety of training tasks and methods to help improve brain functions. Such methods may include training in perception, attention, concentration, visual-motor-sensory skills, command following, and use of objects.

Contact InformationContact InformationPhilip A. DeFina, PhD Philip A. DeFina, PhD

Chief Executive and Scientific OfficerChief Executive and Scientific Officer

International Brain Research Foundation, Inc. International Brain Research Foundation, Inc.

100 Menlo Park, Suite 412100 Menlo Park, Suite 412

Edison, NJ 08837Edison, NJ 08837

732-494-7600732-494-7600

732-494-7611 FX732-494-7611 FX

pdefina@ibrfinc.org

www.ibrfinc.orgwww.ibrfinc.org

IBRF ACP TeamIBRF ACP Team(alphabetically)(alphabetically)

Philip A. DeFina, PhD, CEO, CSO, IBRFPhilip A. DeFina, PhD, CEO, CSO, IBRF John DeLuca, PhD, VP Research., KFRC; Advisory Board, IBRFJohn DeLuca, PhD, VP Research., KFRC; Advisory Board, IBRF Monika Eller, OTR, Clinical Manager of Inpatient OT, KIRMonika Eller, OTR, Clinical Manager of Inpatient OT, KIR Jonathan Fellus, MD, Director BI Services, KIR; Advisory Board, IBRFJonathan Fellus, MD, Director BI Services, KIR; Advisory Board, IBRF Pasquale G. Frisina, PhD, Res. & Outcomes Director., KIR; Assisstant Pasquale G. Frisina, PhD, Res. & Outcomes Director., KIR; Assisstant

Professor, Mt. Sinai School of Medicine.Professor, Mt. Sinai School of Medicine. Rosemarie Scolaro Moser, PhD, Dir. Res. Prog., IBRF; Dir. RSM Psych.Ctr.Rosemarie Scolaro Moser, PhD, Dir. Res. Prog., IBRF; Dir. RSM Psych.Ctr. Charles J. Prestigiacomo, MD, Assoc. Prof, Neurol. Surgery, UMDNJ; Charles J. Prestigiacomo, MD, Assoc. Prof, Neurol. Surgery, UMDNJ;

Board Member, IBRFBoard Member, IBRF Philip Schatz, PhD, Prof., Saint Joseph’s University; IBRF ConsultantPhilip Schatz, PhD, Prof., Saint Joseph’s University; IBRF Consultant James W.G. Thompson, PhD, Director of Research-TBI/SDOC, IBRFJames W.G. Thompson, PhD, Director of Research-TBI/SDOC, IBRF