The role of the subthalamic nucleus in response inhibition: Evidence from deep brain stimulation for Parkinson's disease
Introduction
The ability to inhibit a pre-planned or ongoing motor response is essential for optimal performance of almost every motor act. It is frequently studied using a stop-signal paradigm (see Logan, Cowan, & Davis, 1984) in which a “stop” response is pitted in a race against a “go” response, described as the race model. Typically, choice reaction times to an imperative go-stimulus are measured, and are followed on a proportion of trials by a stop-stimulus instructing participants to withhold their response. The delay between the go- and stop-signal is adapted to each subjects’ ability to inhibit their responses, so that 50% of the stop-signals lead to successful inhibition. The stop-signal reaction time (SSRT) is then estimated by calculating the difference between the median go- and the average stop-signal.
Response inhibition is found to be dependent on activity in the right inferior frontal cortex (IFC) (Aron and Poldrack, 2006, Aron et al., 2004, Forstmann et al., 2008, Xue et al., 2008). The left IFC is not thought to be involved, as event related potentials (ERPs) (Schmajuk, Liotti, Busse, & Woldorff, 2006) and BOLD responses (Aron & Poldrack, 2006) in this area were not evoked during stopping, and repetitive transcranial magnetic stimulation (rTMS) did not affect stopping performance (Chambers et al., 2007). However, see (Swick, Ashley, & Turken, 2008).
Recently, it has been suggested that the subthalamic nucleus (STN) of the basal ganglia is also involved in response inhibition (Aron et al., 2007, Aron and Poldrack, 2006, Eagle et al., 2008, Ray Li et al., 2008, van den Wildenberg et al., 2006). It has been proposed that, during stopping, the right IFC sends a signal via the “hyperdirect” pathway (Nambu, Tokuno, & Takada, 2002) to the right STN, which enables the inhibition of activity in thalamocortical loops related to the action to be inhibited (Aron & Poldrack, 2006). The STN is also an important node in associative/limbic basal ganglia-thalamocortical loops, which may have implications for the cognitive aspects of stop-signal tasks.
Deep brain stimulation (DBS) of the STN in Parkinson's disease (PD) patients was found to improve SSRTs (van den Wildenberg et al., 2006). However, SSRTs also improved during stimulation of the ventral intermediate nucleus of the thalamus (VIM), suggesting that decreases in reaction times depended on more general improvements in Parkinson's function. To address this issue we measured SSRTs in PD patients during stimulation of either the right or left STN alone, and while neither STN was being stimulated. Unilateral stimulation was used in order to limit the treatment effect of DBS, which is greater for each hemibody during bilateral than unilateral stimulation (Bastian et al., 2003, Tabbal et al., 2008). Next, to more fully control for DBS induced improvements on the task, we selected only those patients who performed the SSRT task within normal limits based on the 95% confidence intervals of a control sample (see Chen et al., 2006). We were also interested in determining if DBS of the right STN affects SSRTs more than DBS of the left STN, since the right IFC and the right STN are thought to be dominant for response inhibition.
Section snippets
Participants
Participants were 16 right-handed Parkinson's patients (Table 1 summarises patient's details), recruited during routine follow-up clinic appointments after DBS surgery. Patients had been receiving bilateral DBS of the STN for an average of 0.5 years at the time of testing. All had significant benefit to Parkinson's disease motor symptoms on both sides during stimulation. The stop-signal task was always performed while the patients were on their usual Parkinsonian medication, specified in Table 1
Stop-signal task
Patients and controls were seated in front of a computer screen on which the task was displayed. The task started with a fixation cross, followed by a green arrow (the “go” stimulus) pointing either left or right. Participants are instructed to respond by pressing the appropriate left or right button on a button box as fast as possible. On 34% of the trials the green arrow turns red (the “stop” stimulus), indicating that the participant should withhold their response. The “stop” stimulus
Results
All patients completed the stop-signal task while on and off DBS, Table 2 summarises the observed SSRTs and GORTs. Other parameters of interest are accuracy and reaction times of uninhibited stop-trials. SSRTs and GORTs were compared for all hemibodies on and off STN DBS. For the statistical analysis we will treat each hemibody as an independent sample (see discussion below). Paired samples t-tests revealed that DBS induced a significant improvement to GORTs (t = 2.6, P < 0.05, df = 20), but not
Discussion
Across all patients, unilateral DBS of the STN improved GORTs but not SSRTs with the contralateral hand. However, in patients already performing within normal limits of a control sample, DBS continued to improve GORTs, but significantly impaired SSRTs. We also compared the effects of stimulating the left and right STN separately. We found that DBS of the right STN had no effect on SSRTs, but DBS of the left STN significantly impaired them.
Before we attempt to interpret these findings, some
Conclusion
In conclusion, we show that response inhibition is adversely effected by STN DBS when more general DBS induced improvements are controlled for. This suggests that, whether the impairment is induced by a functional lesion of the STN or by abnormal stimulation of thalamocortical loops necessary for cognitive processes, STN DBS can disrupt processes normally dependent on the integrity of STN. We also found that stimulation of the left STN is particularly deleterious to response inhibition, as
Acknowledgments
This work was funded by The Norman Collison Foundation, The Charles Wolfson Charitable Trust, Oxford Biomedical Research Centre & educational grant from Medtronic.
References (39)
- et al.
Functional architecture of basal ganglia circuits: Neural substrates of parallel processing
Trends in Neurosciences
(1990) - et al.
Inhibition and the right inferior frontal cortex
Trends in Cognitive Sciences
(2004) - et al.
Therapeutic electrical stimulation of the central nervous system
Comptes Rendus Biologies
(2005) - et al.
Involvement of human basal ganglia in offline feedback control of voluntary movement
Current Biology
(2006) - et al.
Neural correlates of STN DBS-induced cognitive variability in Parkinson disease
Neuropsychologia
(2008) - et al.
Deep brain stimulation of the subthalamic nucleus: A two-edged sword
Current Biology
(2006) - et al.
Subthalamic oscillatory activities at beta or higher frequency do not change after high-frequency DBS in Parkinson's disease
Brain Research Bulletin
(2006) - et al.
Pathological synchronisation in the subthalamic nucleus of patients with Parkinson's disease relates to both bradykinesia and rigidity
Experimental Neurology
(2009) - et al.
Electric field and stimulating influence generated by deep brain stimulation of the subthalamic nucleus
Clinical Neurophysiology
(2004) - et al.
Functional significance of the cortico-subthalamo-pallidal ‘hyperdirect’ pathway
Neuroscience Research
(2002)