ABSTRACT
The goal of this project is to test the hypothesis that a cerebellar-striatal circuit regulates satiety in humans.
Obesity currently affects 42% of U.S. adults, with projections that by 2030, 50% of U.S. adults will have obesity.
These trends forecast a parallel increase in risk of obesity-related morbidity and mortality. Behavior, emergent
from brain function, likely governs several primary sources of obesity, yet therapeutic intervention based on
known brain circuits has not yielded dramatic success, suggesting a need to identify and rigorously evaluate
neural circuits associated with appetite and food intake. We used a reverse-translational approach to identify the
cerebellum as a regulator of appetite and feeding behavior. Animal studies determined that this effect is due to
cerebellar regulation of food related reward activity in ventral striatum (VS). Our prior studies of this circuit in
humans have been observational. Rigorous examination of the causal role of this circuit in modulating reward-
related food intake in humans requires well-designed acute, mechanistic, state-of-the-art neuromodulation
studies. Our group has evidence that cerebellar transcranial magnetic stimulation (TMS) can selectively
modulate network function in cerebellar networks in healthy adults, and when applied therapeutically, can reduce
symptom severity in patient populations. Thus, given the nascent nature of human data collected to date, we will
integrate TMS and neuroimaging techniques to validate the role of the cerebellar-VS circuit in satiation in
humans. We hypothesize that TMS modulation of the cerebellar-VS circuit will elicit neural and behavioral
responses that are consistent with state-dependent cerebellar-induced satiation. These include increases in
cerebellar activation, reductions in VS activation, and reduced food reward behaviors and intake. This proposal
will innovatively combine cerebellar TMS with neuroimaging and behavioral measures of food-related reward
under varying appetitive states. We will study the acute impact of cerebellar TMS on the satiation response to
palatable food in neural systems and behavioral endpoints using a double-blinded, randomized, sham-controlled,
mechanistic parallel trial involving cerebellar TMS neuromodulation in 150 healthy adults with BMIs spanning
the healthy weight to obese range. The approach, completed under fasted and fed states to identify state-specific
functioning of the cerebellar-VS circuit, will include functional MRI to ascertain neural reactivity to high-palatable
food in the cerebellum and VS, as measures of target engagement. Food reward behavior will be measured
using objective assessments and subjective ratings, in addition to ad libitum intake of palatable food. This
proposal has public health impact because it will provide a mechanistic understanding of how this novel
cerebellar-ventral striatal circuit functions to induce a reward-related satiation response in humans, which in turn
will allow development of obesity therapeutics that target these validated and novel neurobiological pathways.