Efficacy of Repetitive Transcranial Magnetic Stimulation for Improvement of Memory in Older Adults With TBI

Recent advances in both AD and TBI test non-pharmaceutical interventions that target chronic
symptom improvement (e.g., non- invasive brain stimulation, exercise and cognitive training).
In order to provide targeted therapies to patients who suffer from chronic sequela of TBI it
is necessary to understand mechanisms of repair within the context of an aging brain.
Repetitive TMS (rTMS) delivers therapeutic, noninvasive brain stimulation, is FDA-approved
for treatment for major depression and currently used for treatment of pain, PTSD, anxiety,
improvement of executive function in mild and moderate TBI, severe TBI, memory enhancement
and dementia.

This treatment can induce neuronal long-term potentiation resulting in synaptic repair
leading to improvements in memory function through hippocampal- cortical circuits and brain
connectivity measured by resting state-fMRI (rs fMRI) particularly in default mode and
central executive network (DMN & CEN). The study primarily proposes to assess the efficacy of
rTMS to improve memory performance and to test rs-fMRI (i.e. DMN) as a potential biomarker to
capture response to treatment in older patients suffering with chronic symptoms related to
previous brain injuries (depression, PTSD etc). In addition, the study will assess other
established biomarkers longitudinally (e.g.,hypometabolism via PET FDG, cortical oscillation
via electroencephalography (EEG), Brain Derived Nerve Growth Factor (BDNF)and hippocampal
volume from structural MRI) to capture patient response to treatment that may signal early
dementia.

HYPOTHESES:

Primary:

Subjects with TBI who receive active rTMS treatment (rTMS_A) will: a) show significantly
greater improvement from baseline in memory performance post rTMS intervention compared to
subjects who received sham rTMS treatment (rTMS_S), and b) show stronger functional
connectivity within and between DMN and CEN post rTMS intervention compared to patients who
received sham (rTMS_S).

Secondary:

1. Quality of Life (QOL): scores on QOL scale will improve with rTMS treatment in patients
who receive rTMS treatment.

2. Sustained Improvement: At 6-month follow-up, patients with TBI in rTMS_A group would be
more likely to have sustained greater brain connectivity compared to patients in the
rTMS_S group predicting better memory performance.

3. Moderators of Response: The following variables may moderate memory function improvement
in patients with TBI post intervention and at 6-month follow-up: Age, health condition
variables (severity of symptoms at baseline, time to injury, baseline cognitive
performance, TBI type,comorbidities (PTSD, sleep, depression), substance abuse,
medication use, fatigue); physiological and biological variables (baseline hippocampal
volume and/or microstructure, baseline connectivity in DMN & CEN, EEG resting and
task-related cortical oscillations, and Brain Derived Neurotrophic Factor (BDNF)
genotype.

4. Mediators of Response: To assess the mechanism of rTMS in synaptic repair/regeneration,
pre and post changes will be assessed in depression and PTSD measures, Plasma BDNF, FDG
PET hypometabolism in precuneus/posterior cingulate area, EEG resting and task-related
cortical oscillations, and connectivity of DLPFC (stimulation site & part of CEN) with
other DMN.

SPECIFIC OBJECTIVES:

Primary Objective: a) To assess the efficacy of rTMS to predict improvement in memory
performance pre and post rTMS intervention in older patients with TBI, and b) To assess
rs-fMRI as a biomarker to detect these changes in memory performance.

Secondary Objective: To assess the mechanism of rTMS in synaptic repair/regeneration by
assessment of structure & functional brain activity (PET/MRI, fMRI, & EEG), genetic,
cognitive and behavioral function factors (including QOL, depression and PTSD).

Inclusion Criteria:

- Age 50-75 years, with a high school education

- History of mild or moderate TBI as defined by the DoD/VA Clinical Practice Guidelines
for Definition of TBI

- Ability to obtain a Motor Threshold (MT) will be determined during the screening
process

- Must be in the chronic stable phase of recovery (>6 months post injury) with residual
cognitive difficulties that are affecting daily functioning (including self-reported
memory or cognition problems)

- If on a psychotropic medication regimen, that regimen will be stable for at least 4
weeks prior to entry to the study and patient will be willing to remain on a stable
regimen during the acute treatment phase

- Has an adequately stable condition and environment to enable attendance at scheduled
clinic visits

- For female participants of child bearing potential, agrees to use one of the following
acceptable methods of birth control: abstinence, oral contraceptive, Norplant,
Depo-Provera, a condom with spermicide, a cervical cap with spermicide, a diaphragm
with spermicide, an intrauterine device, surgical sterilization (having your tubes
tied)

- Able to read, verbalize understanding, and voluntarily sign the Informed Consent Form
prior to participating in any study-specific procedures or assessments

- Individuals who meet the study criteria but have impaired decision making capacity may
participate provided they are able to voluntarily sign an Assent Form and have an LAR
who can sign a Consent Form and accompany the participant to all study visits

Exclusion Criteria:

- Diagnosed with Dementia

- Pregnant or lactating female.

- Unable to be safely withdrawn, at least two-weeks prior to beginning treatment, from
medications that substantially increase the risk of seizures

- Have a cardiac pacemaker or a cochlear implant

- Have an implanted device (deep brain stimulation) or metal in the brain (see standard
MRI exclusion criteria including metal screening section in telephone screen, Appendix
A)

- Have a mass lesion, cerebral infarct or other active CNS disease, including a seizure
disorder

- Known current psychosis as determined by DSM-IV coding in chart (Axis I, psychotic
disorder, schizophrenia) or a history of a non-mood psychotic disorder

- Diagnosis of Bipolar Affective Disorder I (as determined by chart review and intake
interview), since this in conjunction with TBI increases seizure risk

- Current amnesic disorders, dementia, MOCA ≤ 16, or delirium.

- Current substance abuse (not including caffeine or nicotine) as determined by positive
toxicology screen, or by history via AUDIT, within 3 months prior to screening

- Prior history of seizures

- Severe TBI or open head injury

- TBI within last 6 months

- Participation in another concurrent clinical trial

- Patients with prior exposure to rTMS (NOTE: TMS is allowed) or ECT

- Active current suicidal intent or plan. Patients at risk for suicide will be required
to establish a written safety plan involving their primary psychiatrist. All patients
at risk for suicide will be excluded from the study (as per FDA recommendation).