Repetitive transcranial magnetic stimulation (rTMS) is an emerging technology for the treatment of neurological and psychiatric illnesses. Recent interest has shifted to the cerebellum, where initial promising therapeutic investigations have been made disease such as schizophrenia and ataxia. Despite these developments, the understanding of which parameters are best suited to stimulate the cerebellum remains a mystery. Our proposal seeks to understand the relevant dose parameters of repetitive cerebellar stimulation, helping to unite studies which have selecting a single dose parameter. A barrier to understanding the dose impact of cerebellar rTMS on the brain has been the measurement of the network-based impact. Traditional optimization approaches have relied upon specific measures within the motor network that are difficult to translate into other domains. Unfortunately, cerebellar stimulation of motor cortex likely has a simultaneous non-motor association cortex impact. Our work to date demonstrates the utility of observing network connectivity from the cerebellum as a useful and reliable output measure, and pilot data demonstrate these connectivity changes are matched with improvements upon sustained attention tasks. We thus propose to apply repetitive TMS to the cerebellum to impact networks associated with attention, and observe the neuropsychological impact upon attention, relating parameters of stimulation to brain activity and psychological behavior.
Aim 1 contrasts 3 different stimulation intensities, similar to previously published protocols.
Aim 2 contrasts 3 different stimulation durations, investigating the role of increased or decreased stimulation relative to a standard. Our hypothesis is that network connectivity can act as a useful measure of stimulation outcome. Simultanous acquisition of attentional metrics will investigate of the dose-response relationship between stimulation and networks and stimulation and cognition, allowing for optimization of cerebellar stimulation protocols for effective therapeutic intervention, based on both anticipated behavioral measures and idealized brain network function. This approach allows for an unbiased model-free investigation of the impact of cerebellar stimulation, and a careful titration of the appropriate stimulus intensity and duration to impact cognitive circuits via the cerebellum.

Public Health Relevance

Non-invasive stimulation of the cerebellum represents a new frontier in the treatment of diseases such as schizophrenia, ataxia and epilepsy, yet the parameters which lead to efficacious treatment are poorly understood. We aim to use neuroimaging and behavioral metrics to track the impact of systematic changes in the parameters of repetitive stimulation to the cerebellum. These studies will enable optimization of parameters of stimulation that will result in greater efficacy of stimulation for the treatment of disease.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZMH1-ERB-S (05))
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Friedman, Fred K
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Beth Israel Deaconess Medical Center
United States
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Brissenden, James A; Tobyne, Sean M; Osher, David E et al. (2018) Topographic Cortico-cerebellar Networks Revealed by Visual Attention and Working Memory. Curr Biol 28:3364-3372.e5
Esterman, Michael; Thai, Michelle; Okabe, Hidefusa et al. (2017) Network-targeted cerebellar transcranial magnetic stimulation improves attentional control. Neuroimage 156:190-198