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Principal Investigator: Chen Lin
Organization: BIRMINGHAM VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
Veterans with post-traumatic stress disorder (PTSD) have an increased risk of developing
ischemic stroke. Veterans enduring PTSD face difficulties in managing their PTSD severity after
suffering from a stroke. Currently, clinical trials in PTSD exclude patients with stroke and patients
with significant premorbid psychological conditions like PTSD are usually excluded from stroke
clinical trials. Methylphenidate (MPH) is a central nervous system stimulant that blocks dopamine
and norepinephrine transporters, selectively increasing prefrontal cortex (PFC) activity. MPH can
improve PTSD symptoms: avoidance behaviors, social withdrawal, hyperarousal, and working
memory. The suspected mechanism is MPH activates PFC, enhancing fear extinction [60] and
improving PTSD symptoms. MPH can also improve post-stroke outcomes: mood, activities of
daily living, and motor functioning. In clinical trials for PTSD or stroke, MPH has been shown to
be well-tolerated with minimal adverse events. The high prevalence of PTSD in Veterans with
stroke provides strong justification for development of interventions that effectively and
simultaneously target both conditions. The overarching goal of our proposal is to understand
how MPH improves PTSD severity in Veterans with comorbid stroke.
This proposal is a single-site, phase 2, randomized double-blind placebo-controlled trial of
MPH in the treatment of Veterans with a diagnosis of PTSD who are within 1-12 months of
cerebral stroke. The purpose of the clinical trial is to evaluate the therapeutic effects on PTSD
symptoms and post-stroke recovery of placebo-controlled MPH in Veterans diagnosed with
PTSD and cerebral stroke. The outcome of the proposed work is expected to develop an
intervention for patients with PTSD and stroke, thus improving their outcome by reducing
symptom severity. Following successful screening and baseline randomization, eligible patients
will be treated with a regimen of MPH vs placebo and treated for 12 weeks. They are assessed
every 4 weeks (4, 8, 12) followed by a 2-week taper period and concluding with a [final follow-
up at 30 days.] 50 participants will be randomized in a 1:1 ratio to placebo or MPH.
Aim 1: Determine the feasibility of the efficacy study design in comparing rTMS and exercise
versus sham rTMS and exercise to reduce pain in patients with chronic post-stroke pain.
Hypothesis 1: Our feasibility pilot proposal will focus on collecting limited efficacy data for
effect-size estimation to conduct a larger clinical trial using validated pain and functional
measures in patients with chronic post-stroke pain using rTMS and exercise.
Aim 2: Evaluate the safety of rTMS combined with aerobic exercise in patients with a history of
ischemic stroke and chronic post-stroke pain.
Hypothesis 2: The combined intervention of aerobic exercise plus rTMS will have both a low
number of adverse events and a similar rate as aerobic exercise plus sham rTMS.
Aim 3: To assess the correlation between the neuronal connectivity of the prefrontal cortex with
PTSD outcomes and stroke outcomes following MPH vs Placebo in Veterans.
Hypothesis 3: Compared to placebo, Veterans receiving MPH will show enhanced
strengthening of the structural and functional connectivity of the prefrontal cortex with other
regional structures. This strengthened connectivity will correlate to changes in PTSD and
Stroke outcomes.
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