Consensus Paper: Experimental Neurostimulation of the Cerebellum

Abstract

The cerebellum is best known for its role in controlling motor behaviors. However, recent work supports the view that it also influences non-motor behaviors. The contribution of the cerebellum towards different brain functions is underscored by its involvement in a diverse and increasing number of neurological and neuropsychiatric conditions including ataxia, dystonia, essential tremor, Parkinson's disease (PD), epilepsy, stroke, multiple sclerosis, autism spectrum disorders, dyslexia, attention deficit hyperactivity disorder (ADHD), and schizophrenia. Although there are no cures for these conditions, cerebellar stimulation is quickly gaining attention for symptomatic alleviation, as cerebellar circuitry has arisen as a promising target for invasive and non-invasive neuromodulation. This consensus paper brings together experts from the fields of neurophysiology, neurology, and neurosurgery to discuss recent efforts in using the cerebellum as a therapeutic intervention. We report on the most advanced techniques for manipulating cerebellar circuits in humans and animal models and define key hurdles and questions for moving forward.

Keywords: Cerebellum; DBS; Neuromodulation; Neurostimulation; Non-invasive therapy; Optogenetics.

Fig. 1

Schematic of the canonical cerebellar cortical circuit. a Cartoon drawing of the mouse brain (left) and a sagittal section illustrating the three layers of the cerebellar cortex (right). Schematic of the neurons in the cerebellar cortex (bottom, enlarged) illustrating the repeating basic circuitry that is comprised of Purkinje cells (gray), granule cells (green, with parallel fiber axons that bifurcate in the ml), climbing fiber afferents (blue), mossy fiber afferents (orange), stellate cell interneurons (red) and basket cell interneurons (black), Golgi cell interneurons (magenta), and unipolar brush cell interneurons (yellow). The excitatory synapses are labeled with a “+” and the inhibitory synapses with a “−” sign. The main output of the Purkinje cells is to the cerebellar nuclei, climbing fibers derive from inferior olive neurons, and mossy fibers come from a number of regions including the pontine nuclei, spinal cord, vestibular nuclei, and reticular formation. For simplicity, we have not shown the Lugaro cells or the candelabrum cells. Abbreviations: Cb = cerebellum, ml = molecular layer, pcl = Purkinje cell layer, gl = granular layer, cn = cerebellar nuclei, IO = inferior olive, SC = spinal cord, VN = vestibular nuclei, RF = reticular formation

Fig. 2

Deep brain stimulation of the mouse cerebellum. a Cartoon schematic of a mouse implanted with deep brain stimulation electrodes into the cerebellum. Even though this approach uses wires to connect the stimulator to the electrode port, there is enough flexibility for analysis in behaving animals. b Schematic of a tissue section cut through the mouse cerebellum illustrating the bilateral targeting of the bipolar stimulating electrodes to the interposed (middle) nucleus (red)

Fig. 3

Deep brain stimulation of the human cerebellum. Cartoon drawing illustrating the general approach of deep brain stimulation targeting the dentate (lateral) nucleus in human

Fig. 4

Electrical stimulation to the dentate nucleus advances sensory prediction. a Neurons in the dentate nucleus exhibited firing modulation when the monkey attempted to detect a single omission of periodic visual stimuli. b Electrical stimulation applied to the recording site shortened the reaction time for the stimulus omission. Adapted with permission from [350]