Dosing rTMS for Depression Post-SCI

Depression is a leading cause of disability worldwide and is one of the most prevalent neuropsychiatric manifestations following spinal cord injury (SCI). Based on an estimated 42,000 Veterans having an SCI1 and an estimated prevalence of depression among Veterans post-SCI of 19-28%, nearly 12,000 Veterans with SCI have comorbid depression at any time. The burden of depression post-SCI is significant, as it can impact quality of life and is associated with increased healthcare utilization and higher mortality. As noted by the updated Clinical Practice Guidelines from the Paralyzed Veterans of America, treating depression is essential, but further research is needed specifically within the SCI population to help formulate stronger evidence-based guidelines.

Repetitive transcranial magnetic stimulation (rTMS), a type of non-invasive brain stimulation, is an FDA-approved treatment option for major depressive disorder (MDD) that is utilized throughout the Veterans Affairs (VA) health system. However, to date, no published studies have examined its effectiveness post-SCI. A critical challenge for widespread administration of rTMS for depression post-SCI is dosing, as the resting motor threshold (rMT), a motor response to transcranial magnetic stimulation (TMS), of the right abductor pollicis brevis (APB) is used to dose rTMS. Approximately 60% of the SCI population has incomplete or complete tetraplegia, indicating some degree of upper extremity (UE) impairment, making rMT not reliably attainable. Thus, it is plausible to conclude that over half the SCI population could be excluded from receiving rTMS treatment for depression or may receive an improper dose, impacting its safety and effectiveness. This represents a major gap in the field of SCI rehabilitation in that a large portion of individuals with SCI have concurrent MDD. As such, evidence-based treatment options are necessary to address the needs of this large clinical cohort, thereby improving the lives of these Veterans, their caregivers, and their families.

This study will examine the potential of rTMS, dosed by reverse-calculation electric-field modeling, to improve depressive symptoms in individuals with MDD post-SCI via a randomized, 2-arm, sham-controlled pilot clinical trial. Over four years, twenty-four individual post-SCI with MDD will be enrolled and randomized to receive 6 weeks (5 sessions/week) of either active or sham rTMS treatment. Using an unbalanced design, a quarter of the sample (n=6) randomized to the sham group and the remainder (n=18) randomized to receive active rTMS. Dosing parameters will follow the FDA-approved protocol of 3,000 pulses/session at 10Hz, and intensity will be determined by reverse-calculation electric-field modeling. The primary outcome measure for this study will be the Hamilton Rating Scale for Depression-17. Participants will also complete a 12- and 24-week post-intervention follow-up assessments. It is hypothesized that rTMS treatment dosed using reverse-calculation electric-field modeling will result in a moderate between-group effect size favoring the anti-depressant benefits of rTMS treatment (vs. sham).

In addition to its established anti-depressive effects, rTMS has also been shown to improve patient-reported outcomes such as quality of life and depression-related disability. An extremely exciting possibility is that effective treatment of MDD results in a virtuous cycle whereby reducing depression concomitantly facilitates improvements in other psychosocial domains. The second aim seeks to explore this possibility by determining the extent to which improvements in depressive symptoms are associated with changes in quality of life and participation in Veterans post-SCI with MDD. This trial is an essential step toward optimizing SCI rehabilitation, while simultaneously providing a unique opportunity to study the effects of depression on psychosocial responses to rehabilitation.

The data generated could inform the development of additional interventions focused on neuromodulation to improve function and quality of life for individuals following SCI and other clinical cohorts with upper extremity motor impairment, (e.g., traumatic brain injury, multiple sclerosis, amputees) who otherwise may not be able to benefit from the anti-depressant effects of rTMS treatment.

• Change from baseline in Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) at timepoints noted below [Срок оценки: Baseline; Following Week 2 of 6-week intervention Following Week 4 of 6-week intervention; Immediately post-intervention; 12-weeks post-intervention; 24-weeks post-intervention]
• Change from baseline in Sheehan Disability Scale (SDS) Score at timepoints noted below [Срок оценки: Baseline; Following Week 2 of 6-week intervention Following Week 4 of 6-week intervention; Immediately post-intervention; 12-weeks post-intervention; 24-weeks post-intervention]
• Change from baseline in Leisure Time Physical Activity Questionnaire for People with Spinal Cord Injury (LTPAQ-SCI) Score at timepoints noted below [Срок оценки: Baseline; Following Week 2 of 6-week intervention Following Week 4 of 6-week intervention; Immediately post-intervention; 12-weeks post-intervention; 24-weeks post-intervention]
• Change from baseline in Craig Handicap Assessment and Reporting Tool - Short Form (CHART-SF) Score at timepoints noted below [Срок оценки: Baseline; Following Week 2 of 6-week intervention Following Week 4 of 6-week intervention; Immediately post-intervention; 12-weeks post-intervention; 24-weeks post-intervention]
• Change from baseline in Reintegration to Normal Living Index (RNL) Score at timepoints noted below [Срок оценки: Baseline; Following Week 2 of 6-week intervention Following Week 4 of 6-week intervention; Immediately post-intervention; 12-weeks post-intervention; 24-weeks post-intervention]
• Change from baseline Hamilton Depression Rating Scale-17 (HAM-D17) Score at timepoints noted below [Срок оценки: Baseline; Following Week 2 of 6-week intervention Following Week 4 of 6-week intervention; 12-weeks post-intervention; 24-weeks post-intervention]