The cerebellum plays a fundamental role in motor control in humans, contributing to coordination, precision of movements, and accurate timing of muscle activities. It receives sensory inputs from the spinal cord and integrates these inputs to fine-tune motor activity via multiple loops with the cerebral cortex and brainstem. The two main afferent paths to the cerebellum are the mossy fibers and the climbing fibers, which both project to the cerebellar cortex and nuclei. The activation of Purkinje cells results in inhibition of cerebellar nuclei, consequently reducing excitatory input on the motor cortex via the dentato-thalamo-cortical pathway. The facilitatory/disfacilitatory effect of cerebellar nuclei upon remote targets is an essential mode of action of the cerebellar circuitry.

The first in vivo neurophysiological evidence that the cerebellum has an inhibitory influence on the motor cortex via the cerebellar cortex dates back to 1991, when Ugawa et al. used electric stimulation to suppress motor cortex output, confirming earlier findings of Ito [1]. In 1995, Ugawa et al. obtained the same suppressive effect on the motor cortex with magnetic stimulation over the contralateral cerebellar hemisphere [2], a paradigm now known as cerebellum-brain inhibition (CBI). Several years later, the seminal study by Galea et al. showed that CBI could be modulated via transcranial direct current stimulation (tDCS) using a weak (2 mA) electrical current applied over the cerebellum with a polarity-specific aspect. Cathodal tDCS decreased CBI, while anodal tDCS increased CBI [3]. Several studies followed, showing that CBI could be modulated by anodal cerebellar tDCS in both healthy subjects and patients with neurodegenerative disorders, including cerebellar ataxia [4, 5]. However, until now, evidence of remote effects of cerebellar tDCS activity was mostly limited to the effects on CBI using neurophysiological tools.

In this issue of The Cerebellum, Shoaib et al. ingeniously adopted an emerging neuroimaging modality called functional near-infrared spectroscopy (fNIRS) to study the effects of cerebellar tDCS on motor cortex activity [6]. Using fNIRS, brain activity is measured by using near-infrared light to estimate cortical hemodynamic activity which occurs in response to neural activity. Differences in the absorption spectra of deoxy-hemoglobin and oxy-hemoglobin allow the measurement of relative changes in hemoglobin concentration through the use of light attenuation at multiple wavelengths. The advantage compared to other functional neuroimaging modalities is that fNIRS can be used simultaneously with tDCS to measure brain activity even during the stimulation period without significant electro-optic interference.

Here, the authors used a well-designed sham-controlled, cross-over study to evaluate the effects of anodal tDCS over the right cerebellar hemisphere on hemodynamic responses on the contralateral and ipsilateral primary motor cortices (M1). They observed that during anodal stimulation there was a significant decrease in oxyhemoglobin concentrations on the contralateral M1 and a significant increase in oxyhemoglobin concentrations on the ipsilateral M1, while sham stimulation did not modify hemodynamic responses, providing novel insights into the hemisphere-based hemodynamic effects of non-invasive cerebellar stimulation. Interestingly, changes in oxyhemoglobin concentrations in both M1 occurred approximately 10 min after anodal cerebellar tDCS, tending to increase through the stimulation period and even after the stimulation ended, possibly inferring that the effect on neuronal hemodynamics may require a sufficiently prolonged stimulation.

Another fascinating observation is that anodal cerebellar tDCS did not only decrease oxyhemoglobin concentrations on the contralateral M1 but increased oxyhemoglobin concentrations on the ipsilateral M1. This phenomenon, as the authors suggest, could be secondary to mechanisms of interhemispheric inhibition between right and left M1, as observed, for example, in stroke patients [7].

Several considerations have to be made: first, this study highlights once more the considerable variability observed in other studies employing tDCS [8]. In this study, Shoaib et al. observed that 44% of patients exhibited both contralateral inhibitory and ipsilateral excitatory responses simultaneously, while 72% showed contralateral inhibitory and 69% showed ipsilateral excitatory responses. The observed effect is thus variable and may depend on differences in individual anatomy such as skull size, anatomical organization of cerebellar lobules, or respective size of the cerebellar cortex. Second, these findings should be confirmed using other non-invasive neurophysiological modalities, for instance, by using transcranial magnetic stimulation combined with electroencephalography (TMS-EEG), as it has been recently demonstrated by other groups using repetitive cerebellar TMS [9]. Third, the cerebellum contributes to numerous functions other than motor control, such as learning, cognition, emotions, and behavior or affect, through multiple loops connecting the cerebellum to prefrontal, temporal, and parietal cortical areas [10]. It would be thus interesting to evaluate a larger area of interest on both cerebral hemispheres in a systematic way, not precluding different effects other than the observed M1 inhibition-excitation phenomenon. Fourth, if anodal cerebellar tDCS modulates neuronal hemodynamics on the contralateral and ipsilateral M1, what should we expect after cathodal cerebellar tDCS? This last question is not trivial, as the complex anatomy and physiology of the cerebellum and its response to a still not completely characterized effect of tDCS might conceal some unexpected results.

Overall, this study provides novel evidence strengthening the notion that anodal cerebellar tDCS modulates M1 excitability via the dentato-thalamo-cortical tract, with effects on both the contralateral and ipsilateral M1, answering many questions but still proposing new ones for future studies to unravel.