**Non-invasive Stimulation of the Cerebellum in Health and Disease and Disease**

**Non-invasive Stimulation of the Cerebellum in Health** 

DOI: 10.5772/intechopen.73218

Henry T. Darch, Nadia L. Cerminara, Iain D. Gilchrist and Richard Apps Richard Apps Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Henry T. Darch, Nadia L. Cerminara, Iain D. Gilchrist and

http://dx.doi.org/10.5772/intechopen.73218

#### **Abstract**

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The cerebellum is linked to motor, cognitive and affective functions. Anatomically, the cerebellum is part of an interconnected network including a wide range of other brain structures. This chapter reviews ways in which non-invasive stimulation has been used to activate or inhibit these circuits and how this has contributed to our understanding of cerebellar function in both motor and non-motor domains. The utility of non-invasive stimulation of the cerebellum in the treatment of neurological and psychiatric diseases (Parkinson's disease, cerebellar ataxia, stroke, depression and schizophrenia) is discussed. The chapter concludes with consideration of the challenges that must be overcome if noninvasive cerebellar stimulation is to be adopted in a wider clinical setting.

**Keywords:** cerebellum, tDCS, tACS, TMS, motor learning, emotion and cognition

#### **1. Introduction**

The mammalian cerebellum is a highly folded structure at the back of the brain, which contains the majority of all neurones within the central nervous system (approximately 80% in humans and other species [1]). It has long been known to play a key role in movement control, regulating a range of motor functions (both reflexive and voluntary) [2, 3].

There is now also growing evidence that cerebellar contributions to behaviour are not restricted to motor control but also extend to the cognitive domain (for a review, see [4]). There is a high degree of interconnectivity between the cerebellum and almost all other brain regions, with connections from cerebrum to the cerebellum primarily through the pontocerebellar tract, and reciprocal connections to the cerebral hemispheres primarily from the lateral

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

cerebellum via the dentato-thalamo-cortical tract [5]. Other cerebellar output pathways originate from its paravermal and vermal compartments and these are known to play significant roles in motor and non-motor functions [6, 7].

**2. Basic research**

(reviewed in [6, 27]).

**2.1. Direct cerebellar stimulation**

stimulation to alter behaviour.

Neurophysiological investigations of the cerebellum have long utilised manipulation of neuronal activity to explore its function. Of interest to this review is the use of direct cerebellar

Non-invasive Stimulation of the Cerebellum in Health and Disease

http://dx.doi.org/10.5772/intechopen.73218

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Direct electrical stimulation of fastigial nucleus afferents and cerebellar nuclei have been shown to activate groups of muscles leading to multi-joint movements [24–26], suggesting that the cerebellum is able to directly shape complex movements. Stimulation of the cerebellar nuclei has also been shown to affect autonomic physiology such as cardiovascular and respiratory control and gut motility, but also integrated responses related to emotional behaviour

Clinically, chronic stimulation of cerebellar cortex in epileptic patients was observed to improve not only motor symptoms, but cognitive and affective symptoms (increased alertness, attention, and suppression of rage reactions) [28]. However, whether the latter effects were due to the direct cerebellar stimulation or were a secondary effect of relief from the

Recent findings in mice have also shown that electrical stimulation of the cerebellar cortex and dentate nucleus are able to moderate dopamine release in the prefrontal cortex, consistent with a cerebellar role in cognition [29]. In addition, optogenetic stimulation of cerebellothalamic projections in a mouse model of frontal schizophrenia has been shown to rescue timing performance deficits in an interval timing task [30]. In relation to epilepsy, optogenetic stimulation of a subtype of Purkinje cells in a mouse model of temporal lobe epilepsy led to the suppression of either seizure duration, or seizure occurrence, depending on specific cerebellar target [31]. Overall, a growing body of evidence therefore points toward the cerebellum playing an important role in a myriad of physiological and pathophysiological processes,

with direct stimulation of the cerebellum capable of manipulating these processes.

In contrast to animal studies, direct stimulation of neural tissue in humans is restricted by the availability of patients with implanted electrodes, especially in the cerebellum. The advent of non-invasive methods has therefore provided a valuable alternative approach to manipulate

Typically, transcranial electrical stimulation (direct or alternating current) of the cerebellum is

back of the skull approximately 2–3 cm left or right of inion for activating the cerebellar hemisphere of interest. Note that the cerebellum exhibits mainly ipsilateral control for motor related tasks. The opposing polarity electrode (often referred to as the 'return' electrode) is usually placed over a deltoid/buccinator muscle or at a frontal-supraorbital location. Such an arrangement is thought to help draw current flow primarily through the cerebellar cortex and away from other structures so that any observed effects are due mainly to manipulations of cerebellar

saline soaked sponge, placed over the

epileptic seizures and debilitating motor symptoms remains unclear.

cerebellar activity in humans, in both healthy and disease states.

**2.2. Non-invasive stimulation of the cerebellum**

achieved with an active electrode, usually a 20–35 cm<sup>2</sup>

Given the interconnectivity between the cerebellum and other structures such as hippocampus [8, 9], and prefrontal cortex [10–12], a role in higher order information processing is perhaps unsurprising. Indeed, there is now a substantial literature based on functional imaging and reports of cerebellar patients linking the cerebellum with cognitive functions such as verbal working memory, attention and emotion [13–18].

However, a comprehensive understanding of the way the cerebellum makes its contribution to behaviour (motor and non-motor) remains unresolved. Two major classes of theory dominate current thinking. On the one hand are those that suggest that the cerebellum acts to learn associations between stimuli (learning hypotheses), and on the other, those that suggest the cerebellum acts as a timing device (timing hypotheses).

Learning hypotheses stem from Marr's original theoretical proposal [19] and typically centre on the plasticity of synaptic inputs to the principal neurones of the cerebellar cortex—the Purkinje cells (for a review of cerebellar anatomy, see [3]). The numerous synaptic inputs to each Purkinje cell, via the mossy fibre-granule cell pathway, are thought to transmit sensorimotor information during movement. When a behavioural error occurs (thought to be a mismatch in the sensory consequences of the predicted movement) this is signalled to the Purkinje cells, via their powerful synaptic input from climbing fibres (originating from the inferior olive). This teaching signal induces plasticity mechanisms in the mossy fibre-granule cell synaptic connections to the same Purkinje cells, modifying synaptic weights and thereby adjusting the pattern of sensorimotor integration performed by Purkinje cells [20].

By contrast, timing hypotheses generally propose that the olivocerebellar circuit (made up of a feedback loop between inferior olive neurones, cerebellar cortical Purkinje cells and the output of the cerebellum, the cerebellar nuclei) is able to generate rhythmic and synchronised activity, to drive timing and spatial organisation of motor sequences [21], and other functions [22].

While studies of the cerebellum have generally considered its function in the context of either learning or timing hypotheses, they have been discussed together with the view that the two hypotheses are not mutually exclusive [23].

In order to further our understanding of cerebellar function, non-invasive methods of neurostimulation have been used to manipulate cerebellar function in humans. This chapter will focus on studies of non-invasive techniques to alter cerebellar activity in both health and disease—however it is by no means an exhaustive account of current literature. We will begin by outlining basic research involving direct (invasive) stimulation of the cerebellum, and highlight how manipulation of cerebellar activity can lead to changes in a wide variety of behaviours. Research using the two major forms of non-invasive stimulation (transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS)) will then be discussed, including possible mechanisms of action. We will then discuss the use of these techniques as potential therapeutic methods to treat neurological and psychiatric conditions, including both motor and affective disorders. The chapter will conclude with a consideration of the challenges facing the use of non-invasive stimulation of the cerebellum.
