Choosing between different possible responses requires substantial monitoring and inhibition to prevent incorrect reactions.25,26
The ability of PD patients to slow down when faced with high-conflict decisions is impaired under STN-DBS.7
Based on a recent proposal that withholding automatic response to external stimuli is the default state of sensorimotor reactivity in healthy subjects (ie, not restricted to high-conflict decisions but generalized to simple sensorimotor actions),14,15
we hypothesized that the executive control consisting of switching from controlled proactive tonic inhibition to automatic sensorimotor processing (ie, in releasing the brake) may also play a certain role in the pathogenesis of akinetic symptoms. Because the STN is placed in a neuroanatomical position that may allow it to be an important operating relay in the modulation of the inhibitory network that prevents erroneous responses,27
we assumed that STN-DBS effects in PD patients may exert a strong influence on the ability to control this basic inhibitory mechanism.
As expected, STN-DBS produced a significant improvement in the motor symptoms of PD patients. Consistent with the clinical evaluation, behavioral data indicate that STN stimulation yields faster generation of motor responses irrespective of the task. The present findings also demonstrated that STN stimulation induced significant increase of commission errors during the Go/NoGo task, that is, a greater difficulty inhibiting responses to NoGo signals. It is worth noting that commission error rate in a Go/NoGo task is usually considered as the primary measure of impulsivity.5,28,29
Accordingly, the pattern of behavioral results observed in the present study suggests that STN-DBS improved motor functions at the expense of response inhibition in simple sensorimotor tasks. The cerebral patterns of brain activity were found to be consistent with the behavioral outcome. In fact, STN-DBS influenced different cortical areas associated with the predictions of both reactive and proactive models of response inhibition.
The broad effect of STN stimulation was associated with a reduced activation in the left PMC and pre-SMA, as well as the dorsal ACC and IFC. As proposed in the “hold you horses” model, these interconnected structures are known to be activated during inhibitory tasks, detection and integration of response conflict, and error-related processing.10,30–32
They are particularly engaged when preventing the execution of any response in face of high-conflict decisions.7,12
The recent observation that STN-DBS reduces coupling between cingulate and basal ganglia output6
supports our finding of reduced activation of the dorsal ACC. This cortical area is well known to be activated by a wide range of higher cognitive functions, including tasks in which a prepotent or over-learned response tendency has to be overcome (such as the Stroop and the GNG task) and tasks that typically elicit response conflict. Thus, the impaired activation observed in the dorsal ACC may be accountable for the reduced ability of PD patients to inhibit responses during the GNG task. Finally, the deactivation of the right IFC, known to be involved in the active inhibitory process of ongoing responses,10,33
supports the hypothesis that STN-DBS may influence motor impulsivity by also compromising directly reactive inhibitory commands.
STN stimulation was also associated with a reduced activation in key structures supporting the proactive inhibitory control of movement-triggering mechanisms, such as the precuneus, PCC, and left inferior parietal cortex. In particular, the negative correlation observed between the amount of activation in the area of the precuneus and the number of commission errors strongly emphasizes our hypothesis. The precuneus is crucial in the process of preparing an individual to engage the inhibitory circuitry34
along with the left inferior parietal cortex, a structure involved in the initiation of a motor program35–36
that may act as a possible relay in movement initiation and modulations of the tonic inhibitory state.15
Because no effect was observed in the mPFC, the acknowledged source of the proactive inhibitory command,15,34
we could speculate that STN-DBS may compromise only its integration within posterior sensorimotor networks. This hypothesis is consistent with the observed deactivation of the precuneus/PCC node, which plays a pivotal role within the default network, acting as a convergence node where cognitive information arising from different subsystems interact.37
Thus a deactivation of this node would have a significant detrimental effect on the process monitoring of different cognitive subsystems (eg, executive).
An interesting observation was represented by the increased rCBF in the subgenual limbic ACC,38–40
a region reported to be abnormally activated in diseases associated with impulsive behavior.41,42
Thus, we could speculate that the increased activity observed in the subgenual ACC may reflect an elevated motivational drive43
related to impulsivity in PD patients with STN-DBS. Overall, the cerebral patterns of activation and deactivation observed in the ACC suggest that although STN-DBS may enhance the ventral emotional circuit, it alters the dorsal cognitive circuit involved in the performance of various executive functions.
These findings favor the hypothesis that modulation of STN hyperactivity with DBS, although it improves parkinsonian features in PD patients, induces a global impairment of response inhibition pattern that tends to increase impulsivity. Consistent with these observations, STN lesioning studies in experimental animals with dopaminergic degeneration have shown that, although they improve motor performance, they also produce selective nonmotor deficits such as increased premature response during both simple and complex RT tasks.44–47
Our results and conclusions find their rationale in the strategic position that the STN holds within the corticobasal ganglia circuitry,9,11,48
providing it with a pivotal role as a brake in the motor network.27
Importantly, the present study suggests that this deficit in response inhibition likely applies to both tonic (proactive) and phasic (reactive) inhibitory processes. Based on these observations, we propose that the impairment of the response inhibition network may play an important role in both akinesia (which may be viewed as global difficulty in releasing proactive inhibition OFF stimulation, ie, to “release the horses”) and impulsivity (which may conversely be considered as global difficulty in locking movement-triggering processes ON stimulation, ie, to “hold the horses”). In other words, akinesia and impulsivity could represent opposite sides of the same coin. We believe that this new theoretical approach may provide novel insights and better understanding of movement disorders. Further work is needed to extend this observation and to explore the hypothesis that this role of the STN may be generalized to other cognitive and behavioral aspects, as suggested by the other forms of inhibitory deficits observed with STN-DBS.3,4,6,48