**3. Clinical studies**

Notwithstanding the challenges that will be discussed later, non-invasive stimulation methods promise a useful avenue for clinical therapy of many neurological and psychiatric conditions. Such an approach is attractive because of the ease of use, suitability for high-risk populations (elderly, overweight, and those who elect against surgical interventions), low cost (especially in the case of tDCS), and good safety record, with only mild, transient side effects [55, 56]. The cerebellum is well placed to be a target for treatment of a number of clinical impairments [57].

#### **3.1. Parkinson's disease and essential tremor**

A number of TMS protocols have indicated that targeting the motor cortex with non-invasive stimulation can lead to short term improvements in Parkinsonian symptoms, most commonly motor aspects, but also depression [58]. Parkinson's has classically been associated with the degeneration of the dopaminergic pathways of the basal ganglia, leading to both motor and affective symptoms. Recent studies propose however that the disease mechanism(s) may be better understood as a dysfunction of a basal ganglia-cortical-cerebellar network [59], and evidence for a role of the cerebellum has been building [60]. Indeed there are Parkinsonian symptoms (particularly resting tremor) in populations with spinocerebellar ataxia type 3 [61], which support a cerebellar link in such symptoms.

Compared to a sham protocol, low frequency repetitive TMS over the cerebellum in early stage Parkinson's patients has been shown to improve gross upper limb motor function (around a 10% improvement), but a non-significant decrease in fine finger control [62]. Significant decreases in fine motor control have also been noted in healthy participants [63]. The beneficial effect on gross motor function is thought to be mediated by a reduction in the tonic inhibitory influence of the cerebellum on the motor cortex, however the opposing effects on fine motor control remain unexplained. Since it may be undesirable to modestly improve gross motor functions at the detriment of fine motor control, further studies are needed to resolve the mixed results of this TMS protocol before it can be considered a reliable clinical intervention for early stage Parkinson's.

Cerebellar targeted theta burst repetitive TMS over a 2-week period in Parkinson's patients who had developed levodopa-induced dyskinesia, resulted in improvements in dyskinesia symptoms up to 4-weeks after the stimulation period [64]. By contrast, a 15 minute, 1 Hz repetitive TMS stimulation over the supplementary motor cortex has been reported to have no long term effect [65]. A recent report revealed that cerebellar (as well as motor cortical) tDCS may also provide positive therapeutic outcomes in levodopa-induced dyskinesia [66]. The mechanisms of action remain poorly defined, but one possibility is the overall increase in CBI (see above). Overall, the cerebellum may therefore provide a promising target for manipulating network activity underlying motor symptoms of Parkinson's disease.

#### **3.2. Cerebellar ataxia**

the left lateral cerebellum resulted in participants overestimating the duration of short (up to 600 ms) tone durations, but had no effect on tone durations longer than 1600 ms [52]. Together these experiments provide evidence that the cerebellum plays an important role in maintaining the perception of rhythmic time intervals when such intervals are short (sub-second), but not necessarily at longer intervals. In support of this view, Purkinje cell simple spike discharge have been shown to be consistent with a predictive timing role, in relation to operation of an internal model of a target's motion, with operating ranges of at least 200–300 ms [53].

In summary, these studies demonstrate how non-invasive stimulation of the cerebellum has been utilised to investigate functional connectivity between the cerebellum and other brain structures associated with cognition, complementing anatomical and neuroimaging based studies [10, 54]. Such an approach also has the potential to be used to influence higher cogni-

Notwithstanding the challenges that will be discussed later, non-invasive stimulation methods promise a useful avenue for clinical therapy of many neurological and psychiatric conditions. Such an approach is attractive because of the ease of use, suitability for high-risk populations (elderly, overweight, and those who elect against surgical interventions), low cost (especially in the case of tDCS), and good safety record, with only mild, transient side effects [55, 56]. The cerebellum is well placed to be a target for treatment of a number of clini-

A number of TMS protocols have indicated that targeting the motor cortex with non-invasive stimulation can lead to short term improvements in Parkinsonian symptoms, most commonly motor aspects, but also depression [58]. Parkinson's has classically been associated with the degeneration of the dopaminergic pathways of the basal ganglia, leading to both motor and affective symptoms. Recent studies propose however that the disease mechanism(s) may be better understood as a dysfunction of a basal ganglia-cortical-cerebellar network [59], and evidence for a role of the cerebellum has been building [60]. Indeed there are Parkinsonian symptoms (particularly resting tremor) in populations with spinocerebellar ataxia type 3 [61],

Compared to a sham protocol, low frequency repetitive TMS over the cerebellum in early stage Parkinson's patients has been shown to improve gross upper limb motor function (around a 10% improvement), but a non-significant decrease in fine finger control [62]. Significant decreases in fine motor control have also been noted in healthy participants [63]. The beneficial effect on gross motor function is thought to be mediated by a reduction in the tonic inhibitory influence of the cerebellum on the motor cortex, however the opposing effects on fine motor control remain unexplained. Since it may be undesirable to modestly improve gross motor functions at the detriment of fine motor control, further studies are needed to

tive processing in both health and disease.

28 Transcranial Magnetic Stimulation in Neuropsychiatry

**3.1. Parkinson's disease and essential tremor**

which support a cerebellar link in such symptoms.

**3. Clinical studies**

cal impairments [57].

Studies utilising TMS over motor cortex have shown abnormal motor cortex excitability in cerebellar ataxic patients, attributed both to direct cerebellar influence [67], and compensatory motor cortical mechanisms [68]. The heterogeneous origins of individual ataxias (with degeneration possible in both cortical, and peduncle locations) likely means that this is not strictly the case for all patients [69]. Indeed, cerebellar ataxia may not be explained solely by disruption to motor cortical excitability, but disruption of the cerebellum's role in co-ordinating multiple muscle groups to produce smooth, accurate movements [70].

Despite the limited literature on the use of therapeutic non-invasive cerebellar stimulation in patients [71], cerebellar TMS has shown the potential for therapeutic use, successfully alleviating ataxic symptoms [72, 73] through facilitation of motor cortex excitability [74]. Conversely, a study testing the effects of anodal cerebellar tDCS on grip force in both ataxic patients and healthy controls did not reveal any effects in either group [75]. Regardless of the unresolved, and probably heterogeneous causes of motor disability in ataxic patients, cerebellar TMS stimulation may be well placed to rescue cerebellar function in cases of partial cerebellar degeneration, but is unlikely to benefit those with substantial dysfunction of cerebellar structures.

#### **3.3. Cerebral stroke**

Cerebral stroke can affect motor, cognitive, and/or emotional abilities depending on the size and location of the insult. Non-invasive stimulation procedures over the motor cortex have been investigated, however the effectiveness of targeting the motor cortex has been questioned [76]. As detailed above, cerebellar stimulation can modulate a wide range of behaviours in healthy subjects, and so has the potential to influence symptoms suffered by stroke patients. Certainly, a few small scale studies have shown success in improving post-stroke symptoms, such as greater recovery of language and spelling abilities with multiple sessions of cerebellar tDCS combined with spelling therapy compared to therapy alone [77].

A prevalent outcome of stroke is the development of depression [78]. Repetitive TMS of frontal sites has been shown to have some beneficial effect, although questions still remain over the longer term success [79]. Direct stimulation of the cerebellar fastigial nucleus alleviates some depression-like symptoms in rat, including weight loss, reduced sucrose preference, and reduced locomotor activities [80]. However, translating these results to non-invasive human stimulation will be challenging; particularly as non-invasive techniques have so far been limited to modulating cerebellar cortex.

local circuitry of the target area can be considered homogenous. However, it is now recognised that this is almost certainly an oversimplification. Even in the localised space of a single cerebral cortical gyrus or cerebellar folium, neurones can be hyperpolarised or depolarised by the same field because of differences in the orientation of the cellular compartments (see **Figure 1**), and differences in the geometry of current flow [86–88]. Consequently, small interindividual variations in brain morphology, or inaccurate electrode/coil placements could lead to significant differences in the polarisation of the target tissue. Given the much greater level of cortical folding in cerebellar folia compared to cerebral areas, this is likely of greater influence on cerebellar circuitry than cerebral circuitry. Certainly, data collected from cerebral

Non-invasive Stimulation of the Cerebellum in Health and Disease

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Such issues can be investigated directly in animal models which allow investigation of neurophysiological mechanisms at the cellular level. Different compartments of individual neurones (dendritic vs. somatic) have been shown to exhibit opposing polarities in an electric field in *ex vivo* preparations of rodent cerebral tissue [89–91], and turtle cerebellar tissue [92]. How such effects translate to the whole living brain remains an open question, and further

**Figure 1.** Representation of non-uniform Purkinje cell polarisation in a uniform electric field. Schematic showing cerebellar folia with Purkinje cells polarised in a uniform electric field. Inset shows cerebellum in sagittal plane, with location of expanded region shown in dotted box. Direction of the electric field *E* shown by arrow. This field orientation will generate hyperpolarisation (−) in dorsal cell compartments and depolarisation (+) in ventral cell compartments. Note how the orientation of Purkinje cells in different locations affects the relative polarisation of the soma and dendrites.

tissue may not accurately reflect patterns of polarisation in cerebellar tissue.

*in vivo* studies are needed in animals [93–96].

Another common consequence of cerebellar stroke is the inability to swallow effectively (post-stroke dysphagia) [81]. Although the precise mechanisms leading to dysphagia are unresolved, non-invasive brain stimulation techniques have been explored as potential tools for the management of dysphagia [81]. The cerebellum has been implicated in effective swallowing [6], and repetitive TMS of the cerebellum has been shown to improve swallowing mechanisms (reviewed in [82]), as measured by an increase in pharyngeal motor evoked potential following stimulation.

Taken together these findings therefore suggest that non-invasive stimulation of the cerebellum may be a useful method for the treatment of a range of post stroke symptoms.

#### **3.4. Major depression and schizophrenia**

The majority of interest in using non-invasive brain stimulation methods to treat psychiatric disorders has focussed on cerebral targets [83]. However, in a rodent model of schizophrenic deficits in interval timing tasks, optogenetic stimulation of cerebellar projections at 2 Hz resulted in a return of control level performance in an interval timing task, which correlated with a return of medial-frontal delta (1–4 Hz) oscillations, not observed in unstimulated animals [30]. In addition, a study in schizophrenic patients has shown the potential utility of non-invasive cerebellar stimulation to alleviate some of the symptoms of the disorder; such as reduced depression (measured on the Calgary Depression Scale), and fewer omissions in working memory tasks [84]. Given the growing understanding of the brain-wide networks involved in these types of disorder, the cerebellum is clearly a potential target for further investigation [57].
