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In humans, the ability to withhold manual motor responses seems to rely on a right-lateralized frontal–basal ganglia–thalamic network, including the pre-supplementary motor area and the inferior frontal gyrus (IFG). These areas should drive subthalamic nuclei to implement movement inhibition via the hyperdirect pathway. The output of this network is expected to influence those cortical areas underlying limb movement preparation and initiation, i.e., premotor (PMA) and primary motor (M1) cortices. Electroencephalographic (EEG) studies have shown an enhancement of the N200/P300 complex in the event-related potentials (ERPs) when a planned reaching movement is successfully stopped after the presentation of an infrequent stop-signal. PMA and M1 have been suggested as possible neural sources of this ERP complex but, due to the limited spatial resolution of scalp EEG, it is not yet clear which cortical areas contribute to its generation. To elucidate the role of motor cortices, we recorded epicortical ERPs from the lateral surface of the fronto-temporal lobes of five pharmacoresistant epileptic patients performing a reaching version of the countermanding task while undergoing presurgical monitoring. We consistently found a stereotyped ERP complex on a single-trial level when a movement was successfully cancelled. These ERPs were selectively expressed in M1, PMA, and Brodmann's area (BA) 9 and their onsets preceded the end of the stop process, suggesting a causal involvement in this executive function. Such ERPs also occurred in unsuccessful-stop (US) trials, that is, when subjects moved despite the occurrence of a stop-signal, mostly when they had long reaction times (RTs). These findings support the hypothesis that motor cortices are the final target of the inhibitory command elaborated by the frontal–basal ganglia–thalamic network.

The endocannabinoid system plays a regulatory role in a number of physiological processes and has been found altered in different pathological conditions, including movement disorders. The interactions between cannabinoids and dopamine in the basal ganglia are remarkably complex and involve both the modulation of other neurotransmitters (γ-aminobutyric acid, glutamate, opioids, peptides) and the activation of different receptors subtypes (cannabinoid receptor type 1 and 2). In the last years, experimental studies contributed to enrich this scenario reporting interactions between cannabinoids and other receptor systems (transient receptor potential vanilloid type 1 cation channel, adenosine receptors, 5-hydroxytryptamine receptors). The improved knowledge, adding new interpretation on the biochemical interaction between cannabinoids and other signaling pathways, may contribute to develop new pharmacological strategies. A number of preclinical studies in different experimental Parkinson's disease (PD) models demonstrated that modulating the cannabinoid system may be useful to treat some motor symptoms. Despite new cannabinoid-based medicines have been proposed for motor and nonmotor symptoms of PD, so far, results from clinical studies are controversial and inconclusive. Further clinical studies involving larger samples of patients, appropriate molecular targets, and specific clinical outcome measures are needed to clarify the effectiveness of cannabinoid-based therapies.

Despite the relevance of inhibitory control in shaping our behavior its neural substrates are still hotly debated. In this regard, it has been suggested that inhibitory control relies upon a right-lateralized network which involves the right subthalamic nucleus (STN). To assess the role of STN, we took advantage of a relatively rare model, i.e., advanced Parkinson's patients who received unilateral deep-brain stimulation (DBS) of the STN either of the left (n = 10) or of the right (n = 10) hemisphere. We gave them a stop-signal reaching task, and we compared patients' performance in two experimental conditions, DBS-ON and DBS-OFF. In addition, we also tested 22 age-matched healthy participants. As expected, we found that inhibitory control is impaired in Parkinson's patients with respect to healthy participants. However, neither reactive nor proactive inhibition is improved when either the right or the left DBS is active. We interpreted these findings in light of the fact that previous studies, exploiting exactly the same task, have shown that only bilateral STN DBS restores a near-normal inhibitory control. Thus, although null results have to be interpreted with caution, our current findings confirm that the right STN does not play a key role in suppressing pending actions. However, on the ground of previous studies, it is very likely that this subcortical structure is part of the brain network subserving inhibition but to implement this executive function both subthalamic nuclei must be simultaneously active. Our findings are of significance to other researchers studying the effects of STN DBS on key executive functions, such as impulsivity and inhibition and they are also of clinical relevance for determining the therapeutic benefits of STN DBS as they suggest that, at least as far as inhibitory control is concerned, it is better to implant DBS bilaterally than unilaterally.

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