We have investigated the safety of repeated applications of iTBS over the cerebellar vermis in patients with schizophrenia, and have observed no cognitive decline, psychiatric worsening, or serious systemic adverse events. No seizures occurred; indeed, previous reports indicate reduced seizure activity following electrical stimulation of the cerebellar cortex (Cooper et al., 1976
; Heath, 1977
; Brighina et al., 2006
). Side effects of mild occipital headache were similar to those reported following single cerebellar TBS sessions (Koch et al., 2008
). Fluctuations in BP were noted and were generally mild except in one patient with hypertension. The posterior vermis (lobules VI–VII) and fastigial nucleus constitute a cardiovascular module in cerebellum (Bradley et al., 1991
), and we consider it likely that the BP changes were related to the cerebellar stimulation.
Serial psychiatric assessments and neuropsychological testing revealed no safety concerns. On the contrary, evidence of efficacy was detected for negative symptoms, mood, and cognition, in agreement with earlier reports following invasive electrical stimulation (Cooper et al., 1976
; Heath, 1977
). Increased cerebellar activity in PET studies has been considered a compensatory mechanism for dysfunctional cerebrocerebellar circuitry in patients with hypofrontal/negative symptoms (Andreasen et al., 1997
; Kim et al., 2000
; Potkin et al., 2002
) and, given the changes in frontal gamma spectrum following excitatory stimulation of the vermis (Schutter et al., 2003
), it is theoretically plausible that potentiation of cerebellar inhibitory output via excitatory iTBS may modulate impairments in frontal gamma activity (Farzan et al., 2010
; Cho et al., 2006
). While the mechanism of improvement remains to be shown, our findings provide empirical support for the dysmetria of thought theory (Schmahmann 1991
), that cerebellum acts to correct errors in the realms of thought and emotion maintaining behavior around a homeostatic baseline, and loss of the universal cerebellar transform in schizophrenia.
In this study, stimulation intensity was set at 100% AMT, with a slight modification from the original protocol described by Huang et al. (2005)
, because the estimated vermis-coil distance is approximately 2.5cm (Schmahmann et al., 1999
). However, the applicability of motor threshold intensities to cerebellum is still under debate (Del Olmo et al., 2007
), and future studies employing cerebellar TBS should specifically address this issue. We chose a twice-daily regimen of iTBS to minimize length of inpatient stay and maximize patient compliance, but other combinations of TBS protocols may also prove effective. It is now well established that TBS can be safely performed using a range of stimulation parameters. Twice daily iTBS each comprising 1800 stimuli, performed at 100% AMT over the dorsolateral prefrontal cortex (DLPFC) in patients with depression was reported to be safe without significant adverse effects (Chistyakov et al., 2010
), and twice daily iTBS over the DLPFC at 80% MT resulted in improvement of negative symptoms in a patient with schizophrenia (Bor et al., 2009
). EEG recordings of standard TBS protocols over the DLPFC proved safe with no epileptiform activity in normal subjects (Grossheinrich et al., 2009
). Standard TBS protocols targeting the motor cortex in patients with multiple sclerosis and amyotrophic lateral sclerosis did not produce serious adverse events (Mori et al., 2010
; Di Lazzaro et a., 2009
), and weekly use of TBS for up to 12 consecutive months has provided evidence in favor of its long-term safety (Di Lazzaro et al., 2009
). Finally, ten consecutive sessions of TBS to lateral cerebellar hemispheres in levodopa-induced dyskinesias reported no adverse events (Koch et al., 2009
It is not possible to know whether cerebellar vermal iTBS could be more effective in schizophrenia than invasive electrical stimulation; early data on electrical stimulation are limited. Invasive stimulation offers the advantage of being able to stimulate any desired location while TBS is mostly limited to more superficial structures. The major advantage of TBS, however, lies in its noninvasive, morbidity-free application and its safe use within a range of stimulation parameters. Future modifications of TBS may result in clinically significant changes in efficacy, but the safety of such protocols could differ (Rossi et al., 2009
The strengths of this study include the novel hypothesis-driven approach of stimulating the cerebellum and particularly the vermis in this disorder, the precise targeting of the vermis and minimized interindividual anatomical variability achieved via the use of neuronavigation, and continuous monitoring of the patients in the CRC unit to ensure their safety. There are notable limitations in this exploratory study. The principal limitation is the open-label nature and the absence of a control intervention; this was not included because of our primary focus on safety. Whereas our results demonstrate the safety and tolerability of repeated sessions of rTMS over the vermis in schizophrenia and provide early proof of principle to proceed further, future placebo controlled trials will need to define clinical efficacy. Electroencephalography and functional neuroimaging may help characterize changes in neural circuitry induced by cerebellar stimulation, and shed light on the neurobiology of this disorder. A second limitation is the number of patients studied which can lead to type II errors. Despite the small n, psychiatric and cognitive results actually showed improvement in some functions. Lastly, smoking habits, caffeine restriction and medications may have influenced our results. The refractoriness of our patients precluded withdrawal or changing their existing medications in favor of one antipsychotic, although it would be desirable to study medication-free patients because psychotropics may affect the response to TBS.
In sum, this study demonstrates that repeated sessions of iTBS to the cerebellar vermis in patients with refractory schizophrenia are safe and well-tolerated. Improvement in negative symptoms, mood and cognition represents an encouraging initial step towards treatment of refractory schizophrenia through noninvasive neuromodulation of the cerebellum. These findings are potentially important because available treatments for negative symptoms of schizophrenia remain only partially effective (Alphs et al., 2006
). Further studies of clinical efficacy and mechanisms of cerebellar TBS are warranted. By demonstrating the safety of cerebellar vermal iTBS in schizophrenia, it may be possible to perform future studies in the outpatient setting, although caution is warranted in patients with hypertension.