High frequency repetitive transcranial magnetic stimulation (rTMS) to left dorsolateral prefrontal cortex (dlPFC) is FDA-approved for the treatment of major depression. The left dlPFC site typically targeted with rTMS is seated in an area of cortex integral to intact higher order cognition (i.e., executive function). The PI has demonstrated that this left dlPFC region is commonly hypoactivated during cognitive tasks across neuropsychiatric disorders. Accordingly, cognitive improvements have been reported as ancillary benefits to rTMS treatment and that rTMS improves cognition in mild to moderate cognitive impairment. We propose that because rTMS to dlPFC is targeting cognitive neurocircuitry integral to adaptive cognitive functioning, promoting neuroplasticity in this network with rTMS could be more precisely optimized to improve quality of life across psychosocial domains and across neuropsychiatric presentations. We postulate that through up-regulating cognitive control circuitry with rTMS that an individual would have 1) enhanced capacity for successfully contending with the shifting contingencies of daily life and 2) improved ability to regulate intrusive affect and impulses. As a function of these processes an individual is expected to experience reduced psychosocial impairment. Thus, we propose that rather than targeting specific symptom reductions in specific disorders, rTMS could be dosed for efficacy in enhancing psychosocial functioning. Such an approach has the potential to enhance rehabilitation for far more veterans suffering a range of neuropsychiatric conditions. A therapeutic course of rTMS typically consists of approximately 30-40 minutes of high-frequency (i.e., 10 Hz) treatment on each weekday, for 4 to 6 weeks. This schedule can be burdensome and reduce adherence. Recently, Co-investigator Mark George, M.D. and colleagues demonstrated that delivering multiple high-dose sessions to veterans on each of three consecutive days was safe, feasible, and suggestive of rapid antidepressant effects. These patients received in three days, the equivalent dose (i.e., total number of pulses) of a conventional 4- to 6-week course. We propose that establishing an efficacious accelerated protocol delivered within 1 week would greatly increase the likelihood of implementation in the VA healthcare system. Furthermore, an accelerated course of rTMS that enhances psychosocial functioning across disorders, would be a ready adjunct for other modalities of rehabilitation already utilized in the VA healthcare system including pharmacotherapy and cognitive-behavioral therapy as well as occupational and physical therapy. In light of the goal to utilize accelerated rTMS to reduce psychosocial functional impairment, it is essential to establish the associated dose-response curve as a first step in laying the foundation for this line of work. Prior rTMS investigations have relied upon rational decision trees in determining TMS dose, typically founded upon the rTMS outcomes for depression in non-veteran samples. For example, accelerated protocols have typically endeavored to fit the conventional rTMS dose for depression (i.e., 54,000 total pulses) into a truncated time period. We propose that the SPiRE mechanism is ideal for empirically determining the dose-response curve specific to accelerated rTMS to left dlPFC for improving psychosocial functional impairment. In the current study we propose to randomize a transdiagnostic sample of veterans [ (n=40) ] with moderate to severe psychosocial impairment. Participants would be randomized to 10 different doses of accelerated rTMS. For appropriate randomization across different doses in this pilot study, participants would be restricted to meeting criteria for an anxiety and/or depressive disorder. Cutting-edge neuronavigation-based targeting with structural MRI would be performed to ensure individualized placement at left dlPFC. In summary, we propose to innovate veteran care with this SPiRE proposal by 1) implementing a 1-week accelerated rTMS protocol, 2) establishing the dose-response curve, and 3) optimizing the treatment to enhance transdiagnostic psychosocial functioning.

Public Health Relevance

Mental illness rarely occurs as a single, easily categorized condition. Instead, multiple disorders often co-occur. This complicates the treatment plan for many Veterans, especially those suffering the most severe dysfunction. This also means that clinical research aimed at one specific disorder may not be optimized to treat the real- world presentation of neuropsychiatric illness. We propose in this study to develop a novel, non-invasive brain stimulation treatment that would promote rehabilitation for Veterans suffering a wide range of emotional difficulties. More specifically, we propose to up-regulate the brain circuitry that supports flexible problem solving and contending with daily demands. Rather than focusing on reducing the symptoms of a specific disorder to reduce the intrusion into daily life, we propose to augment those brain circuits that promote adaptive cognition and thus quality of life.

National Institute of Health (NIH)
Veterans Affairs (VA)
Veterans Administration (I21)
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Rehabilitation Research and Development SPiRE Program (RRDS)
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Ralph H Johnson VA Medical Center
United States
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