Subthalamic nucleus activity dissociates proactive and reactive inhibition in patients with Parkinson's disease

Abstract

a b s t r a c t a r t i c l e i n f oModels of action selection postulate the critical involvement of the subthalamic nucleus (STN), especially in reactive inhibition processes when inappropriate responses to a sudden stimulus must be overridden. The STN could also play a key role during proactive inhibition, when subjects prepare to potentially suppress their actions. Here, we hypothesized that STN responses to reactive and proactive inhibitory control might be driven by different underlying mechanisms with specific temporal profiles. Direct neural recordings in twelve Parkinson's disease patients during a modified stop signal task (SST) revealed a decrease of beta band activity (βA, 13-35 Hz) in the STN during reactive inhibition of smaller amplitude and shorter duration than during motor execution. Crucially, the onset latency of this relative increase of βA took place before the stop signal reaction time. It could thus be thought of as a "stop" signal inhibiting thalamo-cortical activity that would have supported motor execution. Finally, results also revealed a higher level of βA in the STN during proactive inhibition, which correlated with patient's inhibitory performances. We propose that βA in the STN would here participate in the implementation of a "hold your horse" signal to delay motor responses, thus prioritizing accuracy as compared to speed. In brief, our results provide strong electrophysiological support for the hypothesized role of the STN during executive control underlying proactive and reactive response suppression.

Cognitive control involves theta power within trials and beta power across trials in the prefrontal-subthalamic network

“…These decreases prematurely return to resting levels during NoGo trials that require complete response inhibition. Though it is unclear if the return to baseline observed during the NoGo trials is due to an increase in an anti-kinetic signal or an attenuation of a pro-kinetic signal, the relative power differences between movement trials and NoGo trials as well as the timing of the STN beta power changes are consistent with previous studies investigating STN beta activity when motor and non-motor actions are stopped (Kühn et al, 2004; Ray et al, 2012; Alegre et al, 2013; Bastin et al, 2014; Benis et al, 2014; Wessel et al, 2016; Zavala et al, 2017b). Of note, the reductions in STN beta band power during each movement trial were accompanied by a significant reduction in beta band spiking entrainment.…”

“…The STN receives afferent connections from cortical regions involved in cognitive control (Alexander et al, 1986; Aron et al, 2007; Kelley et al, 2018), and projects efferent connections to other basal ganglia structures involved in movement inhibition (Albin et al, 1989; DeLong, 1990). Beta oscillations (10–30 Hz) within the STN regulate both motor and non-motor actions and increase when individuals must cancel or slow down a pre-planned action (Kühn et al, 2004; Brittain et al, 2012; Leventhal et al, 2012; Ray et al, 2012; Alegre et al, 2013; Bastin et al, 2014; Benis et al, 2014; Wessel et al, 2016; Herz et al, 2017; Zavala et al, 2017b). Theta oscillations (2–8 Hz) and spiking activity in the STN also increase when individuals are making decisions in the presence of conflict (Zaghloul et al, 2012; Zavala et al, 2013), and importantly, conflict-related increases in theta oscillations are coherent with theta activity in the mPFC (Zavala et al, 2014, 2016).…”

Association of Protein Phosphatase PPM1G With Alcohol Use Disorder and Brain Activity During Behavioral Control in a Genome-Wide Methylation Analysis

“…This points toward an increased effort to carry out successful behavioral inhibition in those individuals with increased methylation of PPM1G . The subthalamic nucleus is a basal ganglia structure whose functions include transmission of inhibitory cortical signals to basal ganglia, including the striatum (46, 50, 51). Several studies have suggested that the right subthalamic nucleus and right inferior frontal gyrus are correlated with response inhibition, suggesting that they form a frontal-subcortical pathway of control inhibition (40, 45, 46).…”

“…Several studies have suggested that the right subthalamic nucleus and right inferior frontal gyrus are correlated with response inhibition, suggesting that they form a frontal-subcortical pathway of control inhibition (40, 45, 46). The right-lateralized subthalamic nucleus and inferior frontal gyrus have been used as regions of interest for response inhibition tasks (i.e., the stop signal task and go/no-go task) in studies reporting compromised impulse control in alcohol-dependent individuals (37, 38) and reduced ability to cancel prepotent responses (47), as well as in lesion studies (48), deep brain stimulation studies (49), and fMRI studies (50) of response inhibition in individuals with Parkinson's disease. Studies of in vivo deep brain stimulation of the sub-thalamic nucleus in Parkinson's patients (51) and in animal models (52) have shown a decrease in craving and regulation of substance preference, indicating the involvement of this brain region in neural processes that underlie addictive behavior.…”

“…PPM1G is expressed in different brain areas, including in the subthalamic nucleus, where its gene product is thought to be involved in the dephosphorylation of metabotropic glutamate receptors (mGluR2/3) (57, 58), thus potentially regulating the transmission of cortical signals to the striatum (46, 50, 51). …”