Cerebellum (2011) 10:495–503 DOI 10.1007/s12311-010-0230-5 Modulatory Effects of Theta Burst Stimulation on Cerebellar Nonsomatic Functions Asli Demirtas-Tatlidede & Catarina Freitas & Alvaro Pascual-Leone & Jeremy D. Schmahmann Published online: 7 December 2010 # Springer Science+Business Media, LLC 2010 Abstract Clinical and functional imaging studies suggest the Profile of Mood States test. All 36 sessions of cerebellar that the cerebellar vermis is involved in the regulation of a stimulation were tolerated well without serious adverse range of nonsomatic functions including cardiovascular events. Cardiovascular monitoring pointed to a mild but control, thirst, feeding behavior, and primal emotions. significant decrease in heart rate subsequent to vermal Cerebello-hypothalamic circuits have been postulated to stimulation; no changes were detected in systolic or be a potential neuroanatomical substrate underlying this diastolic blood pressure measurements. Subjective ratings modulation. We tested this putative relationship between detected a significant increase in Thirst and a trend toward the cerebellar vermis and nonsomatic functions by stimu- increased Appetite following vermal stimulation. These lating the cerebellum noninvasively via neuronavigated observations are consistent with existing neurophysiological transcranial magnetic stimulation. In this randomized, and neuroimaging data indicating a role for the cerebellum in counter-balanced, within-subject study, intermittent theta the regulation of visceral responses. In conjunction with the burst stimulation (TBS) was applied on three different days modulatory function of the cerebellum, our results suggest a to the vermis and the right and left cerebellar hemispheres role for the vermis in somatovisceral integration likely of 12 right-handed normal subjects with the aim of through cerebello-hypothalamic pathways. Further research modulating activity in the targeted cerebellar structure. is warranted to elucidate the potential mechanisms underlying TBS-associated changes were investigated via cardiovascu- the cerebellar modulation of nonsomatic functions. lar monitoring, a series of emotionally arousing picture stimuli, subjective analog scales for primal emotions, and Keywords Transcranial magnetic stimulation (TMS) . Theta burst stimulation (TBS) . Vermis . Cerebellum . Somatovisceral integration . Nonsomatic modulation A. Demirtas-Tatlidede : C. Freitas : A. Pascual-Leone : J. D. Schmahmann Harvard Medical School, Boston, MA, USA Introduction A. Demirtas-Tatlidede : C. Freitas : A. Pascual-Leone Berenson-Allen Center for Noninvasive Brain Stimulation, Beyond the long-established role of the cerebellum in Behavioral Neurology Unit, Department of Neurology, somatic motor coordination, the cerebellum also appears to Beth Israel Deaconess Medical Center, be engaged in the integration of cognitive, emotional, and Boston, MA, USA visceral responses and modulation of behaviors around a J. D. Schmahmann (*) homeostatic baseline in response to the internal and Ataxia Unit, Cognitive Behavioral Neurology Unit, Laboratory external environmental stimuli [1–9]. Further, evidence for Neuroanatomy and Cerebellar Neurobiology, from clinical investigations and functional imaging and Department of Neurology, Massachusetts General Hospital, resting state connectivity studies corroborate the notion that CPZS-340, 175 Cambridge Street, Boston, MA 02114, USA the cerebellum is topographically and functionally orga- e-mail: [email protected] nized for motor, cognitive, and affective behaviors that map 496 Cerebellum (2011) 10:495–503 onto the underlying neuroanatomical circuits that subserve activity in the targeted cortical region and can induce these domains [10–17]. Cerebellar histological architecture distant effects by means of transsynaptic spread along is essentially uniform throughout [1, 6, 18], and thus, the functional networks [77]. Theta burst stimulation (TBS) is a diverse array of functions with which the cerebellum is relatively new asynchronous train paradigm of rTMS with involved is likely the consequence of its bidirectional shorter application time and longer-lasting neuromodula- connections with the prefrontal, posterior parietal and tory effects than traditional rTMS protocols [78, 79]. The superior temporal cortices, limbic system, monoamine aftereffects of TBS likely involve long-term potentiation producing brainstem nuclei, and the hypothalamus [5, 8, (LTP) or long-term depression (LTD)-like synaptic changes 9, 19–28]. depending on the stimulation protocol [80]. Intermittent The hypothalamus is a key neuroendocrine structure TBS (iTBS) induces an increase in the cortical excitability involved in the control of vegetative and behavioral of the motor cortex, similar to high frequency rTMS, functions, with a sizeable influence on vital homeostatic whereas continuous TBS (cTBS) leads to the opposite functions including thirst, feeding behavior, energy metabo- effects [78]. In a similar vein, cerebellar iTBS has been lism, thermal regulation, and circadian rhythms in addition to shown to result in increased contralateral motor-evoked its role in the endocrine system [29]. Further, as an integral potential (MEP) amplitudes while cTBS led to decreased component of the limbic system, it participates in the MEP amplitudes [81]. TBS of the cerebellar hemispheres expression of emotion and formation of behavioral seems capable of inducing distant changes as revealed by responses, mainly by triggering primal emotions related to the modulation in the intracortical circuits of the preservation and/or survival of the species, such as fear, interconnected contralateral motor cortex [81]. Further, the anger, aggression, or sexual excitement. possibility of TBS-induced long-lasting plastic modification The cerebellum shares bidirectional connections with in the cerebello-thalamo-cortical circuits has been the hypothalamus [30–35]. Cerebello-hypothalamic axons highlighted by two recent studies which reported originate from all cerebellar nuclei (fastigial, interposed, clinically appreciable benefits in patients following ten and dentate nuclei), course in the superior cerebellar consequent sessions of cerebellar TBS [82, 83]. The peduncle, decussate, and follow the cerebello-thalamic precise mechanisms of the TBS effects on the cerebellum bundle before entering the hypothalamus [36]. Most are yet to be elucidated. cerebello-hypothalamic fibers terminate contralateral to their In the light of several reports providing evidence origin while sparse numbers recross and terminate ipsilaterally for LTP/LTD-like changes in the cerebellum [84, 85]and in the lateral, dorsomedial, ventromedial, and paraventricular the possibility that TBS induces lasting changes in nuclei of the hypothalamus [37, 38]. Indirect multisynaptic cerebellar activity, we aimed to modulate activity in the projections have also been demonstrated between the cerebel- right, left, or midline regions of the posterior cerebellum lum and the hypothalamus through brain stem reticular nuclei using intermittent TBS. We hypothesized that stimulation [39]. Electrophysiological studies describe evoked potentials of the vermal region would result in more robust changes in the hypothalamus following stimulation of the cerebellum, in nonsomatic functions compared with stimulation of the notably in vermal regions [19, 40, 41]. cerebellar hemispheres. In an attempt to search for It has been proposed that the cerebello-hypothalamic cerebellar involvement in nonsomatic functions comprising circuits might provide the essential neuroanatomical pathways autonomic responses, survival functions, and emotional for cerebellar modulation of visceral activities [42]. Indeed, processes, we measured changes in the cardiovascular there is accumulating evidence regarding cerebellar involve- system, regulation of food and water intake, defense ment in feeding [43–51], thirst [52, 53], cardiovascular against attack, sexual arousal, and emotional behavior. regulation [54–59], sexual function [60–65], fear condition- ing [66–72], and nociception [73–76]. These reports suggest a functional relationship between the cerebellum and the Methods hypothalamus in the control of autonomic states relevant to emotional expression. Participants Given the reciprocal connections between the cerebellum and the hypothalamus, we were interested to determine Twelve healthy subjects (six males, all right-handed, mean whether modulating cerebellar activity might lead to age 28.8±9.94 years) were recruited to participate in these changes in nonsomatic functions. In this study, we aimed studies. None had a history of neurological or psychiatric to examine the cerebellar topographic organization of disease and all had normal or corrected to normal vision. nonsomatic functions using repetitive transcranial magnetic Subject selection followed the guidelines for TMS research stimulation (rTMS), which enables the noninvasive modu- [86, 87]. All participants provided written informed consent lation of brain activity. TMS can temporarily modulate the before being enrolled in the study in accordance with the Cerebellum (2011) 10:495–503 497 Beth Israel Deaconess Medical Center Institutional Review Board and were paid for their participation. Participants were not informed of the hypotheses of the study. Experimental Design Transcranial Magnetic Stimulation All subjects underwent a T1-weighted whole brain anatomic magnetic resonance imaging (MRI) scan (0.5 mm resolution)