Non-invasive Cerebellar Stimulation: Moving Towards Clinical Applications for Cerebellar and Extra-Cerebellar Disorders
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The field of non-invasive stimulation of the cerebellum is quickly expanding. The anatomical structure of the cerebellum with a high density of neurons in the superficial layer, its electrical properties, and its participation in numerous closed-loop circuits involved in motor, cognitive, and affective operations both in children and in adults make of the cerebellum a target with very high potential for neuromodulation of both cerebellar and extra-cerebellar disorders, in neurology, psychiatry, and neurosurgery. A common research effort is required to extract the optimal parameters of stimulation and to identify how non-invasive stimulation of the cerebellum modifies cerebellar plasticity and functional connectivity in remote cortical and subcortical areas. A patient stratification should be considered.
The exact cellular/network consequences of cerebellar stimulation are not yet unraveled. Several studies have focused on the neurophysiological effects upon neural networks (especially motor and cognitive) and on cerebellar plasticity. The most recent studies show that cerebellar stimulation using continuous theta-burst stimulation (cTBS) is NMDA receptor-dependent and most likely involves long-term potentiation (LTP) and long-term depression (LTD) . This translates to an altered functional connectivity with remote cortical areas , which is also observed after transcranial alternating current stimulation (tACS)  and after transcranial direct current stimulation (tDCS) . Although tACS and tDCS modulate cerebellar plasticity and functional connectivity, these electric techniques most likely operate in a different way than the transcranial magnetic stimulation (TMS) techniques such as cTBS . Obviously, more will be learned from animal models .
In the last year alone, 42 articles employing non-invasive cerebellar neurostimulation have been published (search on PubMed: “transcranial” AND “cerebell*” AND “stimulation”; 42 of 73 remained after abstract screening). Most of these articles relate to the investigations of the physiological mechanisms of cerebellar stimulation in a healthy population. These studies focus primarily on different motor functions such as visuomotor adaptation , motor learning , or balance control , but some also focus on cognitive functions such as probabilistic classification learning , verb generation , or attentional control . Recently, Oldrati and Schutter  published a quantitative review of 32 sham-controlled studies employing cerebellar tDCS to modulate both motor- and non-motor-related cerebellar functions. They showed that cerebellar tDCS was indeed effective in changing performance, but they could not find the expected polarity-dependent effects as demonstrated in the works of Nitsche and Paulus . Unfortunately, the variability in the various protocols (sites of stimulation, montages, intensities, durations, and patterns of stimulation) and the distinct domains of research make it difficult to predict the exact impact of cerebellar stimulation on specific motor and non-motor functions .
Besides the studies investigating healthy subjects, the use of cerebellar stimulation as a therapeutic aid in patients is gaining great attention not only in cerebellar patients, but also beyond. In particular, it has been shown that several neuropsychiatric disorders, such as bipolar disorder  or schizophrenia , are associated with dysfunction of cerebello-cerebral networks, which can be normalized by cerebellar stimulation through modulation of the cerebellar brain inhibition (CBI) or surround-motor inhibition (SMI) [23, 24]. The clinical implications extend, therefore, towards neuropsychiatric disorders, filling a gap between conventional neurology and conventional psychiatry.
Cerebellar tDCS might be beneficial for patients with cerebellar neurodegenerative diseases such as ataxia (e.g., spinocerebellar ataxias (SCAs)) [27, 28, 29] and tremor (e.g., essential tremor (ET)) [30, 31, 32], but only a few studies have assessed the role of cerebellar stimulation during rehabilitation after cerebellar stroke [e.g., 31, 32, 33, 34]. Despite the substantial differences in the stimulation protocol (four studies; Calzolari et al. : excitatory anodal tDCS over the lesioned hemisphere; Torriero et al. : inhibitory 1 Hz rTMS over the unlesioned hemisphere; Kim et al. : inhibitory 1 Hz rTMS over the lesioned hemisphere; and Bonnì et al. : excitatory iTBS over the lesioned hemisphere), all studies found have marked improvements after cerebellar stimulation. These findings deserve further attention with focus on the different stimulation protocols.
The cerebellum might also be an interesting target in patients with cerebral cortical damage. Indeed, the cerebellum might provide a structurally intact gateway to the affected neural networks of the cerebrum . Wessel and Hummel (in press)  argue that cerebellar stimulation could be an answer to handle the heterogeneous features of stroke. By targeting the cerebellum, the same protocol can be used in different patient populations, leading to a better patient stratification. A recent study by Sebastian et al.  showed that cerebellar stimulation indeed improves cognitive functions after stroke. The authors applied tDCS over the right cerebellar hemisphere in order to enhance the effects of behavioral aphasia therapy (spelling to dictation) in a patient who suffered anarthria and aphasia after a large bilateral stroke. A greater improvement after therapy combined with cerebellar tDCS (compared to therapy combined with sham) with better generalization was observed. In addition, an increase in cerebello-cerebral connectivity was demonstrated. Marangolo et al.  replicated these results in a study group of 12 patients with chronic aphasia after left-hemispheric stroke for verb generation. However, they did not find an effect on verb naming and argued that cerebellar stimulation might only be meaningful if the language task also involved nonlinguistic processes . Obviously, these findings now require a replication in a large population of patients, but this could indicate that there are opportunities for multi-focal stimulation to target specific networks . By strengthening the entire affected network, and not just the damaged area, a better and/or faster recovery of the lost functions is becoming a realistic goal. Moreover, this type of stimulation might also allow for targeting different functions (motor and non-motor) at the same time. Furthermore, the simultaneous stimulation of the sensorimotor cerebellum and the prefrontal cortex is now technically feasible.
The large spectrum of potential clinical applications of non-invasive cerebellar stimulation
Clinical population/deficit presented
Extensive bilateral cerebral cortical damage (trauma)
Control of (multi-focal) seizures
Cerebellar ataxia (cognitive, motor, and affective)
Cerebral cortical stroke
Impaired fine motor skills
Impaired cognitive functions
Spinocerebellar ataxias (SCAs)
Progressive supranuclear palsy (PSP)
Ataxic cerebral palsy
Developmental deficits in preterm children
Drafting of the manuscript and approval of the final version: KvD and MM.
Kim van Dun is a doctoral researcher involved in project G035714N granted by the Fund for Scientific Research Flanders (FWO). MM is supported by the FNRS and the Fonds Erasme.
Compliance with Ethical Standards
Conflict of Interest
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