Clinical trial NCT02152540: rTMS to Improve Cognitive Function in TBI
Official title: Repetitive Transcranial Magnetic Stimulation to Improve Cognitive Function in TBI
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Traumatic Brain Injury
Keywords: TBI
Transcranial Magnetic Stimulation, Repetitive
magnetic resonance imaging functional
Quality of life
Executive Function
Veterans
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2014-06-02
Enrollment: 33
Sex: ALL
Minimum age (years): 20
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This project will study 40 Veterans identified with symptoms understood to characterize mild to moderate Traumatic Brain Injury (TBI) including Post Traumatic Stress Disorder (PTSD). Following screening and informed consent, Veterans will be randomly assigned to treatment with repetitive Transcranial Magnetic Stimulation (rTMS) or sham rTMS (placebo). Additional examinations will compare brain imaging (structural and functional MRI scans at rest) across participants at baseline, after acute rTMS treatment, and at 6 month followup. The VA population differs significantly from populations that have been included in prior trials of rTMS for many conditions such as depression, chronic pain, and PTSD. Many returning Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF) personnel and Veterans with concussion histories report cognitive problems, such as impaired attention, verbal fluency, poor planning, reduced working memory, and mental flexibility. The investigators hope to show the efficacy and durability of rTMS in treating these symptoms safely in Veterans with co-morbidities.

Detailed description: The goal of the present study is to evaluate the efficacy and durability of benefits of repetitive Transcranial Magnetic Stimulation (rTMS) as a promising non-invasive therapeutic treatment for executive function deficits reported in Veterans with mild to moderate Traumatic Brain Injury (TBI) patients. Although much progress has been made towards understanding the various deficits following TBI, progress has yet to be made towards identifying and assessing therapeutic treatment options that are responsive to TBI symptoms. Many returning OEF/OIF Veterans with concussion histories report cognitive symptoms that may last for months or years, and affect every day function. Symptoms faced by Veterans with mild to moderate TBI include executive function deficits such as impaired attention (including shifting sets), verbal fluency, poor planning, reduced working memory, and mental flexibility. The primary objective is to assess the efficacy of rTMS in Veterans with mild to moderate TBI in improving executive functioning.

A recent VA study reported improvements in PTSD and related symptoms in Veterans with PTSD who received rTMS (Watts et al., 2012). Repetitive TMS is a method of delivering therapeutic, non-invasive brain stimulation that is currently being used at the VA Palo Alto and Stanford University in a number of clinical trials.

For this pilot study the investigators propose to enroll 40 Veterans diagnosed with mild to moderate TBI (age range 20-65). Inclusion Criteria: mild and moderate TBI will be defined as: post-traumatic amnesia (PTA \< 1 day for mild; 1 day\> x \< 7days for moderate). Because of the extensively documented co-occurrence of TBI with PTSD, (Veterans with TBI with and without PTSD will be enrolled). PTSD will be assessed using standard clinical measures. Exclusionary criteria: patients will be screened for TMS and MRI safety. The duration of the study will be two years, with a 1.5 year enrollment period, and a final half-year of follow-up completion. Following a preliminary telephone screen, Veterans will be scheduled for onsite informed consent, screening, and baseline assessments. Using an electronic randomization form, participants will be enrolled into two groups: active rTMS or sham rTMS. As this is a double blind placebo controlled study, only the subject ID number is provided to the nurse administrating the rTMS treatment. After randomization, the rTMS nurse will test the motor threshold (MT) for rTMS. Each participant will be in the trial for a total of approximately (28) weeks: 1-2 weeks screening, (2) weeks acute treatment phase (including MRI pre and post rTMS) and 24 weeks (6 month) follow-up phase (with MRI, neuropsychological testing and self-report measures). Left Dorsolateral Prefrontal Cortex (DLPFC) will be the stimulation site as it is shown to be affective in treatment of depression and approved by FDA. All participants will receive a minimum of 20 treatments before being evaluated for change in executive function (primary outcome measure).

The primary hypothesis is that Veterans receiving active rTMS will show improvement more than sham treated Veterans in (performance between baseline and last assessment of \>1 SD on either the Trail Making Test part B, Delis-Kaplan Executive Function System \[D-KEFS\] Verbal Fluency and/or D-KEFS Color-Word Interference Test). Additional analysis will include: Sustained Improvement on executive function composite score; secondary consequences of TBI scores on Quality of Life (QOL) scale, moderators of response such as age, severity of symptoms at baseline, type of comorbidity (e.g., PTSD); and, functional brain activity changes with rTMS treatment. This pilot study will be one of the first to demonstrate rTMS as a treatment for executive function deficit in Veterans with mild to moderate TBI. Additionally, it would also report on the efficacy of using functional MRI (fMRI) as a biomarker to capture this improvement in executive function.

Eligibility criteria: Inclusion Criteria:

* Veteran of any combat era
* Both Genders
* 20-65years
* (History of (Post Traumatic Amnesia \< 1 day for mild TBI; 1 day\> x \< 7days for moderate TBI))
* Ability to obtain a Motor Threshold (MT) will be determined during the screening process.
* 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, agrees to use one of the following acceptable methods of birth control: abstinence, oral contraceptive; Norplant
* Able to read, verbalize understanding, and voluntarily sign the Informed Consent Form prior to participating in any study-specific procedures or assessments.

Exclusion Criteria:

* Pregnant or lactating female.
* Unable to be safely withdraw, at least two-weeks prior to treatment commencement, from medications that substantially increase the risk of having 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 central nervous system (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 (as determined by chart review and intake interview)
* Current amnesic disorders, dementia, mini mental state examination (MMSE) 24 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 two months or in acute stage
* Participation in another concurrent clinical trial
* Patients with prior exposure to rTMS/ECT
* Active current suicidal intent or plan. Patient at risk for suicide will be required to establish a written safety plan involving their primary psychiatrist and the treatment team before entering the clinical trial

Primary outcomes:
measure: Trail Making Test Part B
timeFrame: Baseline (up to two weeks after screening visit); Post-Treatment (2 weeks from end of Baseline up to one month from entering the study but always the day of last treatment)
Secondary outcomes:
measure: Sustained Improvement on Executive Function
timeFrame: 6-month post treatment follow up
measure: Change in Quality of Life (QOL) Scale
timeFrame: baseline and immediately post treatment (~two weeks)
measure: Moderators of Response: PTSD Score
timeFrame: Baseline only
measure: Treatment Induced Change in Functional Connectivity
timeFrame: post treatment (2 weeks) and 6-months
measure: Change in a Mediator of Response: Brain Derived Neurotrophic Factor (BDNF)
timeFrame: baseline and post treatment (2 weeks)
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care System, Palo Alto, CA
state: California
Study officials:
affiliation: VA Palo Alto Health Care System, Palo Alto, CA
name: Maheen M Adamson, PhD
role: PRINCIPAL_INVESTIGATOR
References: