**4. Challenges and the future of non-invasive cerebellar stimulation**

Since the revival of interest in non-invasive stimulation techniques about 2–3 decades ago, there have been clear advances made in both their use as research tools—advancing our knowledge about neurophysiological processes—and as therapeutic interventions. However, the literature is still awash with many uncertainties about the efficacy of the techniques, and there is typically a high degree of variability in the results. For example, a recent attempt to replicate an experiment dissociating the roles of the cerebellum and M1 in motor adaptation [41] was unsuccessful in a like-for-like experiment [85]. The study went further and pooled data across several experiments (varying some parameters of the design). The pooled data re-captured the effects of the original experiment, however the effect size was reduced. The authors concluded that some publications may be overestimating the effects of tDCS, possibly because of underpowered experiments.

Although changing, many studies assume that the electrical fields induced in the underlying brain tissue are uniform—or at least quasi-uniform—and so the stimulation delivered to the 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 tissue may not accurately reflect patterns of polarisation in cerebellar tissue.

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

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

Taken together these findings therefore suggest that non-invasive stimulation of the cerebel-

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

lum may be a useful method for the treatment of a range of post stroke symptoms.

disorder, the cerebellum is clearly a potential target for further investigation [57].

**4. Challenges and the future of non-invasive cerebellar stimulation**

Since the revival of interest in non-invasive stimulation techniques about 2–3 decades ago, there have been clear advances made in both their use as research tools—advancing our knowledge about neurophysiological processes—and as therapeutic interventions. However, the literature is still awash with many uncertainties about the efficacy of the techniques, and there is typically a high degree of variability in the results. For example, a recent attempt to replicate an experiment dissociating the roles of the cerebellum and M1 in motor adaptation [41] was unsuccessful in a like-for-like experiment [85]. The study went further and pooled data across several experiments (varying some parameters of the design). The pooled data re-captured the effects of the original experiment, however the effect size was reduced. The authors concluded that some publications may be overestimating the effects of tDCS, possibly because of underpowered experiments.

Although changing, many studies assume that the electrical fields induced in the underlying brain tissue are uniform—or at least quasi-uniform—and so the stimulation delivered to the

been limited to modulating cerebellar cortex.

30 Transcranial Magnetic Stimulation in Neuropsychiatry

potential following stimulation.

**3.4. Major depression and schizophrenia**

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

**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.

An additional consideration not commonly controlled for in non-invasive stimulation (particularly electrical stimulation) studies are factors such as individual skull thickness [87], gender [97], time of day [98], and brain network state [99]. With electrical stimulation, variability can also result from the specific arrangement (montage) of electrodes used—influencing the intensity, and focality of stimulation [56, 87, 100]—while for magnetic stimulation, coil geometry has been shown to alter the effectiveness of TMS [32], and positioning of the coils will clearly affect the focus of stimulation.

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Stimulation intensity is also an important variable. In the case of electrical stimulation, a current of between 1 and 2 mA is typically used. The consensus is that these levels of current are well below any thresholds that will lead to neuronal damage [101, 102]. Large scale systematic studies testing the effects of increasing stimulation intensities (remaining within safety limits) would establish if there is a relationship between stimulus intensity and effect size/consistency. Advances in the use of modelling induced electric fields and the availability of individualised computational models to predict these fields would help electrode/coil placement for optimal targeting in individual subjects [86]. Furthermore, a large proportion of TMS research utilises MRI based registration methods to aid targeting. Perhaps more widespread adoption of MRI registration techniques in tDCS research to aid electrode placement might further benefit standardised targeting of tDCS. Careful choice of stimulation montages, and clear reporting of stimulus parameters would also be helpful.

In conclusion, a growing body of evidence suggests that the cerebellum is an important node in brain networks, associated with a wide range of motor and cognitive functions; and noninvasive stimulation of the cerebellum can manipulate these circuits. However, a greater understanding of the neurophysiological effects of such stimulation are needed in animal models. This could lead to more consistent approaches across human studies. As a result, the cerebellum may prove to be a useful and reliable target in altering brain activity in both health and disease.
