Blinded Randomized Controlled Trial of rTMS to the Dorsolateral Prefrontal Cortex in Progressive Supranuclear Palsy: Effects on Gait, Cognition, and Brain Perfusion

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique shown to be useful in treating a number of neuropsychiatric conditions including depression, neuropathic pain and Parkinson’s disease (PD). While in depression, rTMS is being increasingly used, its use in Parkinsonian syndromes has been impeded by lack of high-quality evidence. A few studies have explored rTMS in PD and atypical Parkinsonian syndromes such as Progressive supranuclear palsy (PSP). However, most studies are limited by small samples, inadequate dosage of intervention and lack of patho-physiological study correlates.

The use of rTMS in depression has gained widespread attention and acceptance. The runaway success of rTMS in major depressive disorder (MDD) is rooted in a firm biological basis with the dorsolateral prefrontal cortex (DLPFC) at its heart. In MDD, the left DLPFC is hypoactive and right DLPFC is hyperactive. Therefore, logic dictates that improvement in activity of left DLPFC or inhibition of right DLPFC activity would be able to reverse depression. rTMS is capable of neuro stimulation at high frequency and inhibition at low frequency. Taken together, rTMS is a convenient non-invasive tool that has tremendous potential to modulate neural circuits in depression and this has been applied by multiple researchers.

DLPFC, especially the left DLPFC, is a large specialized area of the prefrontal cortex with a significant role in maintaining working memory. Working memory is the ability to hold information online for a few seconds to minutes. This is essential to keep track of ongoing activity, the components of activity that have been executed and the pending components that have to be executed in order to complete a task. Working memory research has been predominantly focused on specific sensory modalities such as visuospatial (visual) working memory or phonological (verbal) working memory. Recent research has shown evidence to suggest existence of motor working memory along similar lines. Deficits in working memory have been shown to be associated with increased falls in elderly. This is an important realization as interventions improving cognition may improve falls and gait.

In general, older adults demonstrate relative hyperactivity of brain during a given task when compared to younger individuals. This is thought to be a compensatory phenomenon as older brains recruit additional brain regions to compensate for age related degeneration. The left DLPFC plays an important role in gait. In elderly, there is a relative hyperactivity of left DLPFC during walking. By corollary, dysfunction of DLPFC can therefore lead to abnormalities in walking and gait, and by extension can lead to increased risk of falls.

In PSP, there is evidence to suggest dysfunction of left DLPFC. A recent study evaluated the effects of transcranial direct current stimulation (tDCS) over left DLPFC in PSP and found it to be ineffective in improving cognitive and motor functions. However, the study was severely limited with only 16 subjects receiving real tDCS for only 5 days per week for 2 weeks. While there have been rTMS studies on gait in PSP, none of them evaluated DLPFC stimulation. Both these studies were limited by small sample size and limited rTMS dosage. Therefore, a sufficiently powered study with appropriate sample size and appropriate rTMS dosage on DLPFC in PSP is lacking. This study aims to assess the efficacy of DLPFC rTMS in improving gait and cognition, and to evaluate associated changes in cerebral perfusion using arterial spin labeling (ASL) MRI in PSP patients.