George T. Gitchel Ph.D. June 23, 2017

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

2. Introduction Traumatic brain injury Sequelae Communication difficulty Sensory deficits Neurobehavioral Emotional problems Personality changes Psychiatric illness Cognitive deficits Most common initial and persistent symptom of TBI • ~25,000 adults with new TBI/year • ~50,000 with long term complications • Signature injury of middle east wars

3. 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 (Osier, 2015; Warden, 2006) • Repetitive transcranial magnetic stimulation (rTMS) has shown some promise in improving cognition in persons with neurologic and psychiatric disorders (Nadeau, 2014; Demirtas-Tatlidede, 2013; Guse 2010) • Case reports of cognitive outcomes after rTMS in TBI are encouraging (Dhaliwal, 2015) • More controlled studies are necessary

4. 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)

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

6. rTMS alters neural communication • High frequency TMS (>1Hz) depolarizes (activates) neurons under the stimulating coil (Haraldsson, 2004) • Prefrontal rTMS stimulation at 10Hz 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 alpha1-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)

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

8. Specific Aims • Determine efficacy of rTMS on : • Objective measures of attention, learning and cognitive control • Neurophysiological measures of resting state CNS function • Self-reported symptoms • Cognitive and functional potential • Practical utility and feasibility of using rTMS in a TBI population

9. 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 • McGill Pain questionnaire short form • Traumatic brain injury quality of life (TBI-QOL) • General self efficacy scale (GSE)

10. Study Design

11. Navigated Repetitive Transcranial Magnetic Stimulation

12. Motor mapping with TMS

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

14. Stimulation parameters • Based on our findings and the previously reviewed literature, high frequency (10Hz) 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)

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

16. References Woźniak-Kwaśniewska A, Szekely D, Aussedat P, Bougerol T, David O. Changes of oscillatory brain activity induced by repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex in healthy subjects. Neuroimage. 2014;88:91–99. Nielson DM, McKnight CA, Patel RN, Kalnin AJ, Mysiw WJ. Preliminary guidelines for safe and effective use of repetitive transcranial magnetic stimulation in moderate to severe traumatic brain injury. Arch Phys Med Rehabil. 2015;96(4):S138–S144. Rossi S, Hallett M, Rossini PM, Pascual-Leone A, Group S of TC, others. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. ClinNeurophysiol. 2009;120(12):2008–2039. Pascual-Leone A, Houser CM, Reese K, et al. Safety of rapid-rate transcranial magnetic stimulation in normal volunteers. ElectroencephalogrClinNeurophysiol Potentials Sect. 1993;89(2):120–130. CFR. Code of Federal Regulations Title 21 CFR882.5805 Part 882-Neurological Devices; Subpart F Therapeutic Devices; Sec.882.5805 Repetitive Transcranial Magnetic Stimulation. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=882.5805. Accessed March 24, 2016. Faul F, Erdfelder E, Lang AG, Buchner A. G* Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39(2):175–191. Walker WC, Cifu DX, Hudak AM, Goldberg G, Kunz RD, Sima AP. Structured Interview for Mild Traumatic Brain Injury after Military Blast: Inter-Rater Agreement and Development of Diagnostic Algorithm. J Neurotrauma. 2015;32(7):464–473. The management of Concussion/mTBI Working Grou, Department of Veterans Affairs. VA/DoD Clinical Practice Guideline for the Management of Concussion/Mild Traumatic Brain Injury (MTBI).; 2009. http://www.healthquality.va.gov/guidelines/Rehab/mtbi/concussion_mtbi_full_1_0.pdf. Ruff RM, Niemann H, Allen CC, Farrow CE, Wylie T. The Ruff 2 And 7 Selective Attention Test-A Neuropsychological Application. Percept Mot Skills. 1992;75(3f):1311–1319. Delis DC, Kaplan E, Kramer JH. Delis-Kaplan Executive Function System (D-KEFS). San Antonio, TX: The Psychological Corporation; 2001. Delis DC. California Verbal Learning Test. Psychological Corporation; 2000. Luck SJ. Event-related potentials. In: Cooper H, Camic PM, Long DL, Panter AT, Rindskopf D, Sher KJ, eds. APA Handbook of Research Methods in Psychology, Vol 1: Foundations, Planning, Measures, and Psychometrics. Washington: American Psychological Association; 2012:523-546. http://content.apa.org/books/13619-028. Accessed February 5, 2016. Cicerone KD, Kalmar K. Persistent postconcussion syndrome: The structure of subjective complaints after mild traumatic brain injury. J Head Trauma Rehabil. 1995;10(3):1-17. doi:10.1097/00001199-199510030-00002. Cooper DB, Nelson L, Armistead-Jehle P, Bowles AO. Utility of the Mild Brain Injury Atypical Symptoms Scale as a Screening Measure for Symptom Over-Reporting in Operation Enduring Freedom/Operation Iraqi Freedom Service Members with Post-Concussive Complaints. Arch ClinNeuropsychol. 2011. Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989;28(2):193–213. Huber R, Esser SK, Ferrarelli F, Massimini M, Peterson MJ, Tononi G. TMS-induced cortical potentiation during wakefulness locally increases slow wave activity during sleep. PLoS One. 2007;2(3):e276. Blake DD, Weathers FW, Nagy LM, et al. The development of a clinician-administered PTSD scale. J Trauma Stress. 1995;8(1):75–90. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9):606-613. Cella D, Riley W, Stone A, et al. The Patient-Reported Outcomes Measurement Information System (PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005–2008. J ClinEpidemiol. 2010;63(11):1179–1194. Melzack R. The short-form McGill Pain Questionnaire. Pain. 1987;30(2):191-197. Tulsky DS, Kisala PA, Victorson D, et al. TBI-QOL: Development and Calibration of Item Banks to Measure Patient Reported Outcomes Following Traumatic Brain Injury. J Head Trauma Rehabil. 2016;31(1):40-51. doi:10.1097/HTR.0000000000000131. Schwarzer R, Jerusalem M. R.(1995). Generalized self-efficacy scale. J Weinman Wright M Johns Meas Health Psychol Users Portf Casual Control Beliefs.:35–37. Anderson B, Mishory A, Nahas Z, et al. Tolerability and safety of high daily doses of repetitive transcranial magnetic stimulation in healthy young men. J ECT. 2006;22(1):49–53. Angeleri F, Majkowski J, Cacchio G, et al. Posttraumatic Epilepsy Risk Factors: One-Year Prospective Study After Head Injury. Epilepsia. 1999;40(9):1222–1230. Reti IM, Schwarz N, Bower A, Tibbs M, Rao V. Transcranial magnetic stimulation: A potential new treatment for depression associated with traumatic brain injury. Brain Inj. 2015;29(7-8):789-797. doi:10.3109/02699052.2015.1009168. • Diamond PT. Brain injury in the Commonwealth of Virginia: an analysis of Central Registry data, 1988-1993. Brain Inj. 1996;10(6):413-420. doi:10.1080/026990596124278. • Virginia Brain Injury Council. Neurobehavioral Treatment for Virginians with Brain Injury: A Virginia Brain Injury Council Position Paper. Virginia Department of Rehabilitative Services; 2010. http://www.vadars.org/cbs/biscis.htm. Accessed February 5, 2016. • Ettenhofer ML, Melrose RJ, Delawalla Z, Castellon SA, Okonek A. Correlates of Functional Status Among OEF/OIF Veterans With a History of Traumatic Brain Injury. Mil Med. 2012;177(11):1272-1278. doi:10.7205/MILMED-D-12-00095. • Whyte J, Hart T, Vaccaro M, et al. Effects of methylphenidate on attention deficits after traumatic brain injury: a multidimensional, randomized, controlled trial. Am J Phys Med Rehabil. 2004;83(6):401. • Warden DL, Gordon B, McAllister TW, et al. Guidelines for the Pharmacologic Treatment of Neurobehavioral Sequelae of Traumatic Brain Injury. J Neurotrauma. 2006;23(10):1468-1501. doi:10.1089/neu.2006.23.1468. • Osier ND, Dixon CE. Catecholaminergic based therapies for functional recovery after TBI. Brain Res. 2015. http://www.sciencedirect.com/science/article/pii/S0006899315009658. Accessed February 5, 2016. • Schwedt TJ, Vargas B. Neurostimulation for treatment of migraine and cluster headache. Pain Med. 2015;16(9):1827–1834. • Demirtas-Tatlidede A, Vahabzadeh-Hagh AM, Pascual-Leone A. Can noninvasive brain stimulation enhance cognition in neuropsychiatric disorders? Neuropharmacology. 2013;64:566-578. doi:10.1016/j.neuropharm.2012.06.020. • Nadeau SE, Bowers D, Jones TL, Wu SS, Triggs WJ, Heilman KM. Cognitive Effects of Treatment of Depression with Repetitive Transcranial Magnetic Stimulation: CognBehav Neurol. 2014;27(2):77-87. doi:10.1097/WNN.0000000000000031. • Wang JX, Rogers LM, Gross EZ, et al. Targeted enhancement of cortical-hippocampal brain networks and associative memory. Science. 2014;345(6200):1054–1057. • Dhaliwal SK, Meek BP, Modirrousta MM. Non-Invasive Brain Stimulation for the Treatment of Symptoms Following Traumatic Brain Injury. Front Psychiatry. 2015;6. doi:10.3389/fpsyt.2015.00119. • Franke LM, Walker WC, Hoke KW, Wares JR. Distinction in EEG slow oscillations between chronic mild traumatic brain injury and PTSD. Int J Psychophysiol. 2016;106:21–29. • Schiff ND, Nauvel T, Victor JD. Large-scale brain dynamics in disorders of consciousness. CurrOpinNeurobiol. 2014;25:7–14. • Paus T, Zatorre RJ, Hofle N, et al. Time-related changes in neural systems underlying attention and arousal during the performance of an auditory vigilance task. CognNeurosci J Of. 1997;9(3):392–408. • Pascual-Leone A, Valls-Solé J, Wassermann EM, Hallett M. Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain. 1994;117(4):847–858. • Pascual-Leone A, Amedi A, Fregni F, Merabet LB. The plastic human brain cortex. Annu Rev Neurosci. 2005;28:377–401.