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Central Thalamic Deep Brain Stimulation for Treatment of Chronic Post-Traumatic Minimally Conscious State: Challenges and Opportunities

Joseph T. Giacino, Ph.D.Director of Rehabilitation Neuropsychology, Spaulding Rehabilitation HospitalAssociate Professor, Harvard Medical School

Disclosure

Dr. Giacino has no significant financial relationship with any commercial or proprietary entity that produces healthcare-related products and/or services relevant to the content of this presentation.

Minimally Conscious State

The minimally conscious state is a condition of severely altered consciousness in which minimal but definite behavioral evidence of self or environmental awareness is demonstrated.

(Giacino, et al., Neurol, 2002)

Clinical Rationale for DBS in MCS

• Permanent minimally conscious state represents a devastating functional, social and economic outcome.

• Despite preservation of volitional behavior, response consistency frequently insufficient to support rehabilitation interventions and assistive devices designed to facilitate reliable communication and environmental control

• No existing treatment proven to alter the course of recovery from MCS.

Clinical Rationale for DBS in MCS

• fMRI findings demonstrate widely preserved cortical networks responsible for mediating language and visuoperceptual functions in MCS pts unable to follow commands or communicate reliably.

• Recent primate and rodent studies show dramatic modulation of behavioral performance in intact animals exposed to DBS

Neurophysiologic Rationale for DBS in MCS

• Thalamic intralaminar nuclei (ILN) influence parallel cortico-striato-pallidal-thalamocortical loop circuits of anterior forebrain.

• ILN provide wide, but selective, projections to downstream cortical fields.

• ILN comprised of neuronal populations that selectively activate and modulate cortical signals related to vigilance, sustained attention, motor intention, working memory.

Projections from ILN

Scannell et al. 1999

Multidimensional scaling of thalamocortical

connectivitiesAdapted from:Posner and Raichle 1994, Munkle et al. 2000.

Striatum

DMN Connectivity in DoC

(Vanhaudenhuyse, et al. Brain 2010)

Thalamic cell loss and outcomes ofmulti-focal severe brain injury

•Moderately disabled: neuronal loss in Anterior intralaminar nuclei •Severely disabled/MCS: inclusion of medial aspect of posterior intralaminar nuclei •Vegetative state: progressive loss of neurons across central thalamus extending into the more lateral posterior intralaminar nuclei

Maxwell, et al. Thalamic Nuclei after Human Blunt Head Injury J. Neuropathol Exp Neurol 2006. 65:478-488

Purpose of Current Research

To determine if deep brain stimulation applied to the thalamic ILN of patients in the chronic form of the minimally conscious state can facilitate further functional improvement.

Primary Aims

• To determine the acute, sub-acute and chronic effects of CT-DBS in promoting behavioral responsiveness and functional outcome in patients diagnosed with chronic MCS.

• To identify clinical and neurophysiologic predictors of response to CT-DBS

• To determine the relationship between behavioral, electrophysiologic and functional neuroimaging changes associated with CT-DBS.

Inclusion Criteria

• TBI• Medically stable• Meet diagnostic criteria for MCS• Inconsistent command-following,

verbalization or communication• > 12 months post-injury• Recovery plateaued• Age 18-55• Legal surrogate available for consent

Exclusion Criteria

• No large infarcts (> 50 cc’s) involving Broca’s or Wernicke’s areas

• No paramedian mesodiencephalic infarct• No co-morbid condition w/ life expectancy <

5 years• No contraindication for general anesthesia,

craniotomy or travel by air or train• No quadriparesis

Primary Outcome Measure:Coma Recovery Scale- Revised

Frequency of best score on selected subscales of the Coma Recovery Scale- Revised

(Giacino, et al, 1991, 2004)

• Arousal• Expressive speech• Purposeful limb movement• Dysphagia

Secondary Outcome Measures

Study Phases

Pre-operative Baseline Evaluation

• ~ 1 month duration • Standard rehabilitation provided• CRS-R assessments and other

secondary assessments• Primary outcome variable(s)

selected Inpatient Stay/ DBS Implant

• ~7-10 days• DBS implantation surgery• Post operative physiological

studies/fMRI• Externalized stimulation

programmingPost-operative Baseline Assessment

• 1 month duration• DBS OFF• Standard rehabilitation continues• Serial CRS-R and other secondary

neuropsychological assessments continue

DBS Stimulation Titration & Recovery

• 2 week stimulation titration• Optimize stimulation parameters• 2 week wash-out• Continue standard rehabilitation

program• Serial CRS-R and other secondary

neuropsychological assessments continue Double-blind, Cross-over

Intervention• 6 month duration• Randomized to monthly ON/OFF

sequences• Continue standard rehabilitation

program• Serial CRS-R and secondary

neuropsychological assessments continue

Open-Label Follow-up• Through 24 months post-

implantation• DBS stimulation and

rehabilitation as indicated• Continued safety monitoring

Patient 1

• 33 y/o RH male• Injury: Blunt head trauma following assault resulting in b/l SDH

(R>L)– Initial GCS=3– VS to MCS in mth 2-3

• Course: 2 yrs inpatient rehab + 4 yrs nursing home– Total care required, Unable to communicate with family/staff

• Clinical status on re-admission (6.5 yrs post-injury): – Inconsistent command-following– Nonverbal except for rare single-word verbalization – Unable to communicate reliably (yes/no)– Unable to use common objects– Diagnosis: MCS– MRI: R frontal encephalomalacia + small R paramedian

thalamic infarct (2ndary to central herniation)

100

85

75

65

55

45

35

Co-registrationFDG-PET/MRI

T2*-Weighted MRI w/ Co-registered fMRI

FORWARD BACKWARD OVERLAP

20

Electrode placement

ILN DBS PatientPatient 1: Electrode placement

Results

0

100

200

300

400

500

600

700

800

900

-309

-296

-283

-270

-257

-244

-231

-218

-205

-192

-179

-166

-153

-140

-127

-114

-101 -88

-75

-62

-49

-36

-23

-10

Cumulative Hours of Rehab/DBS Exposure

Days

Rehab

23

123

456

Surgery

Intelligible Words

-303 -253 -203 -153 -103 -53 -3

DBS ON

Vocalization OnlySustained AttentionEyes Open w/o StimEyes Open w/ Stim

Functional Object Use

Object Manipulation

Automatic Movement

CRS-R Scores

DBS ONDBS OFF

Results O/V

Arousal

Motor

Behavioral Performance: Pre-DBS v. DBS On v. DBS Off

Conclusions

• Results support DBS modulation of specific cognitive and behavioral functions (arousal, functional limb movement, swallowing).– Target behaviors occur more frequently with DBS on.

• Some evidence of DBS carryover effects (speech)• Mechanism of effect:

– CL co-activates with anterior cingulate and SMA– Mesial frontal circuit (incl. cingulate/SMA) mediates

response preparedness, motor intention and drive functions.

Implications

• DBS may be able to be linked to cognitive rehabilitation and/or pharmacologic interventions– Augment existing treatment strategies by

supporting neuronal mechanisms.– Improve attentional and intentional functions• Working memory, selective attention, initiation,

planning, execution, self-monitoring, spatial awareness.

– Restore functional capacity/independence.

Non-functional communication

MCS EMCS pI-ADL I-ADL

Functional communication

Partial Independence

Independent

Cognitiveslowing

I-Work I-SchoolI-Social

Severe disability

Therapeutic aims for cognitively-based DBS

following TBI Moderate disability

Mild disability

Impaired NoParticipation Impairment

Study Aims

1.To establish the feasibility of targeting and activating central thalamic fiber projections (central lateral and parafascicular nuclei) carrying brainstem arousal afferents en route to downstream cortical fields.

2.To determine the effects of CT-DBS on executive functions in persons with persistent disability lasting ≥ 24 months after moderate-severe TBI.

3.To determine whether exposure to CT-DBS is associated with improvements in vocational productivity, social participation, self-reported psychological health and quality of life.

4.To establish the safety profile of CT-DBS when administered to survivors of moderate-severe TBI in the chronic phase of recovery.

Research Team/Supporting Agencies (DBS TBI I: MCS)

Weill - Cornell JFK Medical Center Cleveland Clinic

Nicholas Schiff, MD (PI) Joseph T. Giacino, PhD (PI) Ali Rezai, MD (PI)Joseph Fins, MD Kathleen Kalmar, PhD Andre Machado, MD, PhDJonathan Victor, MD, PhD Caroline McCagg, MD Ken Baker, PhD

Erik Kobylarz, MD, PhD Jeanne O’Connor, PA-C Cindy Kubu, PhDMary Conte, PhD Brian Fritz, PhD Sierra Farris, PA-CJennifer Hersh, MA Mindy Gerber, MA, CCC-SLP Chris Butson, PhDFred Plum, MD Kathleen Donahue, OTR Cameron McIntyre, PhD

Beth Isenberg, CTRSTraci Biondi, OTR

Supported in part by:

National Institute of Health- National Center for Medical Rehabilitation Research: R21HD40987:“Multidisciplinary assessment of severe brain injury.”Charles A. Dana FoundationFood and Drug Administration: IDE # G030240 (for Kinetra Neurostimulator)Cleveland Clinic Foundation Brain Neuromodulation CenterOhio Department of Development BRTT and Third Frontier programJane and Lee Seidman Neuromodulation Research FundCleveland Clinic Innovations, IntElect Medical, Inc.

• Weill-Cornell Medical College– Nicholas Schiff, MD (PI)– Joseph Fins, MD– Jonathan Baker, PhD– Sudhin Shah, MD

• Spaulding Rehabilitation Hospital– Joseph Giacino, PhD (PI)– Sabrina Taylor, PhD

Research Team (DBS TBI II Severe TBI)

• Stanford University– Jaimie Henderson, PhD (PI)– Stephanie Kolakowsky-

Hayner, PhD

• Cleveland Clinic– Andre Machado, MD, PhD

• University of Utah– Chris Butson, PhD– Guido Gerig, PhD