The human subthalamic nucleus transiently inhibits active attentional processes.

The subthalamic nucleus (STN) of the basal ganglia is key to the inhibitory control of movement. Consequently, it is a primary target for the neurosurgical treatment of movement disorders like Parkinson's disease, where modulating the STN via deep brain stimulation (DBS) can release excess inhibition of thalamocortical motor circuits. However, the STN is also anatomically connected to other thalamocortical circuits, including those underlying cognitive processes like attention. Notably, STN-DBS can also affect these processes. This suggests that the STN may also contribute to the inhibition of non-motor activity and that STN-DBS may cause changes to this inhibition. Here we tested this hypothesis in humans. We used a novel, wireless outpatient method to record intracranial local field potentials (LFP) from STN DBS implants during a visual attention task (Experiment 1, n = 12). These outpatient measurements allowed the simultaneous recording of high-density EEG, which we used to derive the steady state visual evoked potential (SSVEP), a well established neural index of visual attentional engagement. By relating STN activity to this neural marker of attention (instead of overt behaviour), we avoided possible confounds resulting from STN's motor role. We aimed to test whether the STN contributes to the momentary inhibition of the SSVEP caused by unexpected, distracting sounds. Furthermore, we causally tested this association in a second experiment, where we modulated STN via DBS across two sessions of the task, spaced at least 1 week apart (n = 21, no sample overlap with Experiment 1). The LFP recordings in Experiment 1 showed that reductions of the SSVEP after distracting sounds were preceded by sound-related γ-frequency (>60 Hz) activity in the STN. Trial-to-trial modelling further showed that this STN activity statistically mediated the sounds' suppressive effect on the SSVEP. In Experiment 2, modulating STN activity via DBS significantly reduced these sound-related SSVEP reductions. This provides causal evidence for the role of the STN in the surprise-related inhibition of attention. These findings suggest that the human STN contributes to the inhibition of attention, a non-motor process. This supports a domain-general view of the inhibitory role of the STN. Furthermore, these findings also suggest a potential mechanism underlying some of the known cognitive side effects of STN-DBS treatment, especially on attentional processes. Finally, our newly established outpatient LFP recording technique facilitates the testing of the role of subcortical nuclei in complex cognitive tasks, alongside recordings from the rest of the brain, and in much shorter time than peri-surgical recordings.

A causal role for the human subthalamic nucleus in non-selective cortico-motor inhibition.

Common cortico-basal ganglia models of motor control suggest a key role for the subthalamic nucleus (STN) in motor inhibition.1-3 In particular, when already-initiated actions have to be suddenly stopped, the STN is purportedly recruited via a hyperdirect pathway to net inhibit the cortico-motor system in a broad, non-selective fashion.4 Indeed, the suppression of cortico-spinal excitability (CSE) during rapid action stopping extends beyond the stopped muscle and affects even task-irrelevant motor representations.5,6 Although such non-selective CSE suppression has long been attributed to the broad inhibitory influence of STN on the motor system, causal evidence for this association is hitherto lacking. Here, 20 Parkinson's disease patients treated with STN deep-brain stimulation (DBS) and 20 matched healthy controls performed a verbal stop-signal task while CSE was measured from a task-unrelated hand muscle. DBS allowed a causal manipulation of STN, while CSE was measured using transcranial magnetic stimulation (TMS) over primary motor cortex and concurrent electromyography. In patients OFF-DBS and controls, the CSE of the hand was non-selectively suppressed when the verbal response was successfully stopped. Crucially, this effect disappeared when STN was disrupted via DBS in the patient group. Using this unique combination of DBS and TMS during human behavior, the current study provides first causal evidence that STN is likely involved in non-selectively suppressing the physiological excitability of the cortico-motor system during action stopping. This confirms a core prediction of long-held cortico-basal ganglia circuit models of movement. The absence of cortico-motor inhibition during STN-DBS may also provide potential insights into the common side effects of STN-DBS, such as increased impulsivity.7-11.