Role for Subthalamic Nucleus Neurons in Switching from Automatic to Controlled Eye Movement

Abstract

The subthalamic nucleus (STN) of the basal ganglia is an important element of motor control. This is demonstrated by involuntary movements induced by STN lesions and the successful treatment of Parkinson's disease by STN stimulation. However, it is still unclear how individual STN neurons participate in motor control. Here, we report that the STN has a function in switching from automatic to volitionally controlled eye movement. In the STN of trained macaque monkeys, we found neurons that showed a phasic change in activity specifically before volitionally controlled saccades which were switched from automatic saccades. A majority of switch-related neurons were considered to inhibit no-longer-valid automatic processes, and the inhibition started early enough to enable the animal to switch. We suggest that the STN mediates the control signal originated from the medial frontal cortex and implements the behavioral switching function using its connections with other basal ganglia nuclei and the superior colliculus.

Response inhibition rapidly increases single-neuron responses in the subthalamic nucleus of patients with Parkinson's disease

“…To further characterize the functional role of STN cells during the task and following previous studies in human (Bastin et al, 2014) and in animals (Isoda and Hikosaka, 2008;Schmidt et al, 2013), we performed a second set of analyses after classifying each individual cell as a motor cell (GO cell) or a stopping cell (STOP cell, see methods). Fig.…”

“…Finally, instead of quantifying STN neuronal activity using the entire pool of task-responsive neurons, we ran a more specific analysis that classified individual task-responsive neurons according to the pattern of activity that was observed during the task, using a previously validated approach (Bastin et al, 2014;Isoda and Hikosaka, 2008;Schmidt et al, 2013): units were classified into two functional clusters: STOP units and motor (GO) units. STOP units were defined according to the following criteria: STOP unit's firing rate had to increase significantly (i.e., the firing rate had to exceed the statistical threshold estimated from the resampling method) and selectively during Successful STOP trials (i.e., at least one 75 msec bin in the peristimulus histogram aligned on the STOP cue within a time window of 775 msec following the occurrence of the STOP cue).…”

“…This raises an interesting question: how can two neuronal subpopulations in the same structure mimic the two independent GO and STOP processes of the horse race model? In a previous study, a potential mechanism has been suggested to explain this phenomenon through differential downstream connections of both populations (Isoda & Hikosaka, 2008). Accordingly, while STOP neurons could present a direct excitatory connectivity with the substantia nigra pars reticulata (SNr) and internal Globus Pallidus (GPi) to inhibit the thalamus, GO neurons could be indirectly connected with the SNr through the external Globus Pallidus (GPe), so that GO cells would have an opposite excitatory effect on the thalamus (Isoda & Hikosaka, 2008).…”

“…This finding also confirms previous extracellular recordings of STN activity during cognitive tasks that tapped on similar executive control processes. In monkeys, a population of STN neurons was shown to increase its firing rate as early as 175 msec after a NOGO cue during an action reprograming task (Isoda & Hikosaka, 2008). However, the design of the GO/NOGO task does not allow a clear estimation of the precise duration of inhibitory processes and therefore lacks a measure such as SSRT to interpret this latency.…”

“…Finally, effects of bilateral high frequency stimulation of the STN in patients with Parkinson's disease (PD) remain to be firmly established, as both improvement (Mirabella et al, 2012;Swann et al, 2011;van den Wildenberg et al, 2006) or worsening of inhibitory performance (Obeso, Wilkinson, Rodríguez-Oroz, Obeso, & Jahanshahi, 2013;Ray et al, 2009) have been reported. The STN is thus modeled as an important region within the response inhibition brain-network, but the functional mechanisms involved at the cellular level during response inhibition remain unclear despite recent advances in monkeys and rats (Isoda & Hikosaka, 2008;Schmidt, Leventhal, Mallet, Chen, & Berke, 2013). Thus, even if a consensus seems to emerge from many models that hypothesize that a neuronal population within the STN should increase its firing rate during successful stopping at a latency that should precede the SSRT (Boucher, Palmeri, Logan, & Schall, 2007;Frank, 2006;Logan & Cowan, 1984;Ratcliff & Frank, 2012;Schall, Stuphorn, & Brown, 2002;Wiecki & Frank, 2013), the electrophysiological evidence supporting this idea remains weak.…”