Clonidine modulates the activity of the subthalamic-supplementary motor loop: evidence from a pharmacological study combining deep brain stimulation and electroencephalography recordings in Parkinsonian patients.

Clonidine is an anti-hypertensive medication which acts as an alpha-adrenergic receptor agonist. As the noradrenergic system is likely to support cognitive functions including attention and executive control, other clinical uses of clonidine have recently gained popularity for the treatment of neuropsychiatric disorders like attention-deficit hyperactivity disorder or Tourette syndrome, but the mechanism of action is still unclear. Here, we test the hypothesis that the noradrenergic system regulates the activity of subthalamo-motor cortical loops, and that this influence can be modulated by clonidine. We used pharmacological manipulation of clonidine in a placebo-controlled study in combination with subthalamic nucleus-deep brain stimulation (STN-DBS) in 16 Parkinson's disease patients performing a reaction time task requiring to refrain from reacting (proactive inhibition). We recorded electroencephalographical activity of the whole cortex, and applied spectral analyses directly at the source level after advanced blind source separation. We found only one cortical source localized to the supplementary motor area (SMA) that supported an interaction of pharmacological and subthalamic stimulation. Under placebo, STN-DBS reduced proactive alpha power in the SMA, a marker of local inhibitory activity. This effect was associated with the speeding-up of movement initiation. Clonidine substantially increased proactive alpha power from the SMA source, and canceled out the benefits of STN-DBS on movement initiation. These results provide the first direct neural evidence in humans that the tonic inhibitory activity of the subthalamocortical loops underlying the control of movement initiation is coupled to the noradrenergic system, and that this activity can be targeted by pharmacological agents acting on alpha-adrenergic receptors.

Tracking markers of response inhibition in electroencephalographic data: why should we and how can we go beyond the N2 component?

Response inhibition is a pivotal component of executive control, which is especially difficult to assess. Indeed, it is a substantial challenge to gauge brain-behavior relationships because this function is precisely intended to suppress overt measurable behaviors. A further complication is that no single neuroimaging method has been found that can disentangle the accurate time-course of concurrent excitatory and inhibitory mechanisms. Here, we argue that this objective can be achieved with electroencephalography (EEG) on some conditions. Based on a systematic review, we emphasize that the standard event-related potential N2 (N200) is not an appropriate marker of prepotent response inhibition. We provide guidelines for assessing the cortical brain dynamics of response inhibition with EEG. This includes the combined use of inseparable data processing steps (source separation, source localization, and single-trial and time-frequency analyses) as well as the amendment of the classical experimental designs to enable the recording of different kinds of electrophysiological activity predicted by different models of response inhibition. We conclude with an illustration based on recent findings of how fruitful this approach can be.

Interaction of noradrenergic pharmacological manipulation and subthalamic stimulation on movement initiation control in Parkinson's disease.

BACKGROUND: Slowness in movement initiation (akinesia) is a cardinal feature of Parkinson's disease (PD), which is still poorly understood. Notably, akinesia is restored by subthalamic nucleus deep brain stimulation (STN-DBS) but not fully reversed by current dopaminergic treatments. It was recently suggested that this disorder is of executive nature (related to inhibitory control of response) and of non-dopaminergic origin (possibly noradrenergic). OBJECTIVE: To test the double hypothesis that: 1) the ability to control movement initiation is modified by noradrenergic neurotransmission modulation, and 2) this effect is mediated by the regulation of STN activity. METHODS: Sixteen STN-DBS PD patients were enrolled in a placebo-controlled study investigating the effects of noradrenergic attenuation by clonidine (∝2-adrenergic receptor agonist). Movement initiation latency was assessed by means of a cue-target reaction time task. Patients, who remained on their chronic dopaminergic medication, were tested on four sessions: two with placebo (ON- or OFF-DBS), and two with a 150 µg oral dose of clonidine (ON- or OFF-DBS). RESULTS: In the OFF stimulation condition, patients were locked into a mode of control maintaining inappropriate response inhibition. This dysfunctional executive setting was overcome by STN-DBS. Clonidine, however, was found to impair specifically the ability to release inhibitory control in the ON-DBS state. CONCLUSIONS: Overall our results suggest an important implication of the noradrenergic system in the pathophysiology of akinesia in PD. Reducing the noradrenergic "tonus" may even block the positive action of STN-DBS on akinesia, suggesting, at least by part, a noradrenergic-dependent STN-DBS efficiency.

The dorsal medial frontal cortex mediates automatic motor inhibition in uncertain contexts: evidence from combined fMRI and EEG studies.

Response inhibition is commonly thought to rely on voluntary, reactive, selective, and relatively slow prefrontal mechanisms. In contrast, we suggest here that response inhibition is achieved automatically, nonselectively, within very short delays in uncertain environments. We modified a classical go/nogo protocol to probe context-dependent inhibitory mechanisms. Because no single neuroimaging method can definitely disentangle neural excitation and inhibition, we combined fMRI and EEG recordings in healthy humans. Any stimulus (go or nogo) presented in an uncertain context requiring action restraint was found to evoke activity changes in the supplementary motor complex (SMC) with respect to a control condition in which no response inhibition was required. These changes included: (1) An increase in event-related BOLD activity, (2) an attenuation of the early (170 ms) event related potential generated by a single, consistent source isolated by advanced blind source separation, and (3) an increase in the evoked-EEG Alpha power of this source. Considered together, these results suggest that the BOLD signal evoked by any stimulus in the SMC when the situation is unpredictable can be driven by automatic, nonselective, context-dependent inhibitory activities. This finding reveals the paradoxical mechanisms by which voluntary control of action may be achieved. The ability to provide controlled responses in unpredictable environments would require setting-up the automatic self-inhibitory circuitry within the SMC. Conversely, enabling automatic behavior when the environment becomes predictable would require top-down control to deactivate anticipatorily and temporarily the inhibitory set.

Attention to baseline: does orienting visuospatial attention really facilitate target detection?

Standard protocols testing the orientation of visuospatial attention usually present spatial cues before targets and compare valid-cue trials with invalid-cue trials. The valid/invalid contrast results in a relative behavioral or physiological difference that is generally interpreted as a benefit of attention orientation. However, growing evidence suggests that inhibitory control of response is closely involved in this kind of protocol that requires the subjects to withhold automatic responses to cues, probably biasing behavioral and physiological baselines. Here, we used two experiments to disentangle the inhibitory control of automatic responses from orienting of visuospatial attention in a saccadic reaction time task in humans, a variant of the classical cue-target detection task and a sustained visuospatial attentional task. Surprisingly, when referring to a simple target detection task in which there is no need to refrain from reacting to avoid inappropriate responses, we found no consistent evidence of facilitation of target detection at the attended location. Instead, we observed a cost at the unattended location. Departing from the classical view, our results suggest that reaction time measures of visuospatial attention probably relie on the attenuation of elementary processes involved in visual target detection and saccade initiation away from the attended location rather than on facilitation at the attended location. This highlights the need to use proper control conditions in experimental designs to disambiguate relative from absolute cueing benefits on target detection reaction times, both in psychophysical and neurophysiological studies.