Primed vs. Unprimed rTMS in Chronic Stroke

Recovery following stroke is difficult not only because of the neuronal death from the ischemic insult but also because of maladaptive brain reorganization occurring from exaggerated inhibition imparted by the over-compensating contralesional primary motor area (M1) onto the ipsilesional M1 via transcallosal pathways. Advancement in stroke rehabilitation depends on innovative treatments like repetitive transcranial magnetic stimulation (rTMS) that possess the ability to disrupt this excessive inhibition. Through previous NIH/NICHD funding, my sponsor's research team confirmed the safety and efficacy of rTMS in both adult (1R01 HD053153-01A2) and children (1RC1 HD063838-01) with stroke using 6-Hz primed low-frequency rTMS applied to the contralesional M1 to produce disinhibition of the ipsilesional M1. With feasibility of primed rTMS now demonstrated, the proposed research plan will directly compare primed rTMS to unprimed rTMS. The investigators will investigate whether pretreatment of inhibitory low-frequency rTMS with excitatory high-frequency priming is more effective than sham-primed low-frequency rTMS in correcting the exaggerated interhemispheric inhibition acting on ipsilesional M1. While this may sound contradictory, the Bienenstock-Cooper-Munro theory of bidirectional plasticity supports this concept. The long-term goal is to discover the most effective rTMS protocol with which to safely up-regulate ipsilesional M1, rendering a more potent neuronal network for voluntary recruitment. By studying the efficacy of priming as measured by the amount of cortical excitability in both ipsilesional and contralesional hemispheres, a more advantageous delivery of rTMS may be realized and eventually incorporated into research trials and clinical practice. The study poses significant innovation as it explores the role of metaplasticity in rehabilitation using rTMS. The investigators will employ a double-blind crossover study using twelve adult participants with stroke. Because of heterogeneity in stroke type and location between subjects, a crossover design will reduce variability as each subject serves as their own control. Specific Aim #1: Compare the effect of 6-Hz primed vs. unprimed low-frequency rTMS on cortical excitability in chronic stroke.Cortical excitability will be explored with TMS using ipsilesional paired-pulse testing, cortical silent period testing, and interhemispheric inhibition (IHI) paired-pulse testing. Working hypotheses are: 1. Primed rTMS will result in greater increases in the 3-ms and 15-ms ipsilesional paired-pulse to single-pulse (ipsilesional PP/SP) ratios than unprimed rTMS, indicating of decreased intracortical inhibition (GABAA-mediated) and greater intracortical facilitation, respectively. 2. Primed rTMS will result in greater decreases than unprimed rTMS in duration of cortical silent period, indicating decreased inhibition (GABAB-mediated). 3. Primed rTMS will result in a greater increase in the IHI PP/SP ratio in the non-stroke to stroke hemisphere direction and a corresponding decrease in the IHI PP/SP ratio in the stroke to non-stroke hemisphere direction than unprimed rTMS. This is consistent with less inhibition imparted onto the stroke hemisphere from the non-stroke hemisphere and greater inhibition imparted on the non-stroke hemisphere from the stroke hemisphere. Specific Aim #2: Compare the effect of 6-Hz primed vs. unprimed low-frequency rTMS on functional outcome in chronic stroke. Functional outcome will be assessed by paretic hand performance on the Box and Block test. Working hypothesis is: 1\. Primed rTMS will result in greater improvements on the Box and Block test.