Targeted transcranial magnetic stimulation for cognitive rehabilitation after

Targeted transcranial magnetic stimulation for cognitive rehabilitation after traumatic brain injury George T. Gitchel Ph. D. June 23, 2017

Introduction TRAUMATIC BRAIN INJURY � � ~25, 000 adults with new TBI/year ~50, 000 with long term complications � Signature injury of middle east wars SEQUELAE � Communication difficulty � Sensory deficits � Neurobehavioral Emotional problems Personality changes Psychiatric illness Cognitive deficits ▪ Most common initial and persistent symptom of TBI 2

Study motivation �No well-supported intervention available to remediate/rebuild cognitive deficits after TBI �Compensatory strategies are typically used �Pharmaceutical therapies offer only limited potential for improvement �Repetitive transcranial magnetic stimulation (r. TMS) has shown some promise in improving cognition in persons with neurologic and psychiatric disorders �Case reports of cognitive outcomes after r. TMS in TBI are encouraging �More controlled studies are necessary (Osier, 2015; Warden, 2006) (Nadeau, 2014; Demirtas-Tatlidede, 2013; Guse 2010) (Dhaliwal, 2015)

TBI and neural communication � Severe TBI -> shifts in EEG frequency -> reduced consciousness (Schiff, 2014) � Other cognitive deficits (Alzheimer’s disease, schizophrenia), also exhibit similar changes in EEG frequency (Babilioni, 2006; Paus, 1999, Gattaz, 1992) �Shifts of EEG frequency come from changes in the communication between large groups of cortical neurons �Our team previously examined EEG changes after mild TBI in Veterans Found similar pattern of prefrontal EEG slowing (Franke, 2016)

EEG delta activity associated with m. TBI, scalp view VENTRAL LEFT RIGHT DORSAL Right prefrontal and temporal increases in EEG delta activity were associated with a history of m. TBI with posttraumatic amnesia (median 11 months since worst injury) compared to no m. TBI Franke et al. , 2016

r. TMS alters neural communication High frequency TMS (>1 Hz) depolarizes (activates) neurons under the stimulating coil (Haraldsson, 2004) � Prefrontal r. TMS stimulation at 10 Hz shown to decrease prefrontal and temporal delta activity: � “We found a significant decrease of delta and theta power on left prefrontal electrodes, mainly localized in the left DLPFC” (Wozniak-Kwasniewska, 2014) “EEG frequency bands were changed fronto-temporally (right) and were mainly decreases in delta and beta and increases in alpha 1 -activity” (Jandl, 2005) “After treatment, the resting electroencephalography revealed a significant decrease in the delta-band activity, which originated in the right prefrontal cortex and correlated with improvements in facial affect recognition. ” (Kamp, 2016)

Hypothesis �TBI and cognitive deficits are correlated with increased delta activity �r. TMS has been shown to reduce delta activity in many conditions �We hypothesize that r. TMS stimulation will reduce delta activity, thereby inducing sustained increases in cortical excitability, thus improving attention and learning 7

Specific Aims �Determine efficacy of r. TMS on : 1. Objective measures of attention, learning and 2. 3. 4. 5. cognitive control Neurophysiological measures of resting state CNS function Self-reported symptoms Cognitive and functional potential Practical utility and feasibility of using r. TMS in a TBI population 8

Outcome measures � � � � Ruff 2 and 7 Selective attention test DKEFS Verbal Fluency Test California Verbal Learning test 2 10 minute resting EEG Event related potentials Cortical excitability (i. e. motor threshold) Neurobehavioral symptom inventory (NSI) Mild brain injury atypical symptom scale (MBIAS) Pittsburg Sleep quality index (PSQI) Clinician administered PTSD scale 5 (CAPS-5) Patient health questionnaire (PHQ-9) PROMIS short form pain scale Mc. Gill Pain questionnaire short form Traumatic brain injury quality of life (TBI-QOL) General self efficacy scale (GSE) 9

Study Design 10

Navigated Repetitive Transcranial Magnetic Stimulation 11

Motor mapping with TMS 12

Nexstim Advantages �MRI navigated, EMG calibrated �Focal stimulation �High frequency stimulation possible �Navigation ensures consistency 13

Stimulation parameters �Based on our findings and the previously reviewed literature, high frequency (10 Hz) stimulation of the right frontal cortex (site of EEG changes) was chosen �Stimulation duration and inter-train intervals were chosen to remain at the low end of recommended safety parameters due to TBI population �Similar parameters have been used in a PTSD population with no adverse psychological effect (Cohen, 2004)

Progress to date �All VA related “hurdles” overcome �Research coordinator and EEG tech interviewed and hired. �New IRB protocol submitted 1 st round of contingencies re-submitted �Anticipate enrollment by Aug 1. 15

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