Controlling Your Impulses: Electrical Stimulation of the Human Supplementary Motor Complex Prevents Impulsive Errors

To err is human. However, an inappropriate urge does not always result in error. Impulsive errors thus entail both a motor system capture by an urge to act and a failed inhibition of that impulse. Here we show that neuromodulatory electrical stimulation of the supplementary motor complex in healthy humans leaves action urges unchanged but prevents them from turning into overt errors. Subjects performed a choice reaction-time task known to trigger impulsive responses, leading to fast errors that can be revealed by analyzing accuracy as a function of poststimulus time. Yet, such fast errors are only the tip of the iceberg: electromyography (EMG) revealed fast subthreshold muscle activation in the incorrect response hand in an even larger proportion of overtly correct trials, revealing covert response impulses not discernible in overt behavior. Analyzing both overt and covert response tendencies enables to gauge the ability to prevent these incorrect impulses from turning into overt action errors. Hyperpolarizing the supplementary motor complex using transcranial direct current stimulation (tDCS) preserves action impulses but prevents their behavioral expression. This new combination of detailed behavioral, EMG, and tDCS techniques clarifies the neurophysiology of impulse control, and may point to avenues for improving impulse control deficits in various neurologic and psychiatric disorders

Mechanisms and dynamics of cortical motor inhibition in the stop-signal paradigm: a TMS study

Abstract ■ The ability to stop ongoing motor responses in a splitsecond is a vital element of human cognitive control and flexibility that relies in large part on prefrontal cortex. We used the stop-signal paradigm to elucidate the engagement of primary motor cortex (M1) in inhibiting an ongoing voluntary motor response. The stop-signal paradigm taps the ability to flexibly countermand ongoing voluntary behavior upon presentation of a stop signal. We applied single-pulse TMS to M1 at several intervals following the stop signal to track the time course of excitability of the motor system related to generating and stopping a manual response. Electromyography recorded from the flexor pollicis brevis allowed quantification of the excitability of the corticospinal tract and the involvement of intracortical GABA B ergic circuits within M1, indexed respectively by the amplitude of the motor-evoked potential and the duration of the late part of the cortical silent period (SP). The results extend our knowledge of the neural basis of inhibitory control in three ways. First, the results revealed a dynamic interplay between response activation and stopping processes at M1 level during stop-signal inhibition of an ongoing response. Second, increased excitability of inhibitory interneurons that drives SP prolongation was evident as early as 134 msec following the instruction to stop. Third, this pattern was followed by a stoprelated reduction of corticospinal excitability implemented around 180 after the stop signal. These findings point to the recruitment of GABA B ergic intracortical inhibitory circuits within M1 in stop-signal inhibition and support the notion of stopping as an active act of control.

Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn’s disease: results of a phase I

Mesenchymal stromal cells (MSCs) are pluripotent cells that have immunosuppressive effects both in vitro and in experimental colitis. Promising results of MSC therapy have been obtained in patients with severe graft versus host disease of the gut. Our objective was to determine the safety and feasibility of autologous bone marrow derived MSC therapy in patients with refractory Crohn's disease. 10 adult patients with refractory Crohn's disease (eight females and two males) underwent bone marrow aspiration under local anaesthesia. Bone marrow MSCs were isolated and expanded ex vivo. MSCs were tested for phenotype and functionality in vitro. 9 patients received two doses of 1-2×10(6) cells/kg body weight, intravenously, 7 days apart. During follow-up, possible side effects and changes in patients' Crohn's disease activity index (CDAI) scores were monitored. Colonoscopies were performed at weeks 0 and 6, and mucosal inflammation was assessed by using the Crohn's disease endoscopic index of severity. MSCs isolated from patients with Crohn's disease showed similar morphology, phenotype and growth potential compared to MSCs from healthy donors. Importantly, immunomodulatory capacity was intact, as Crohn's disease MSCs significantly reduced peripheral blood mononuclear cell proliferation in vitro. MSC infusion was without side effects, besides a mild allergic reaction probably due to the cryopreservant DMSO in one patient. Baseline median CDAI was 326 (224-378). Three patients showed clinical response (CDAI decrease ≥70 from baseline) 6 weeks post-treatment; conversely three patients required surgery due to disease worsening. Administration of autologous bone marrow derived MSCs appears safe and feasible in the treatment of refractory Crohn's disease. No serious adverse events were detected during bone marrow harvesting and administratio

Dopamine and inhibitory action control: evidence from spontaneous eye blink rates

The inhibitory control of actions has been claimed to rely on dopaminergic pathways. Given that this hypothesis is mainly based on patient and drug studies, some authors have questioned its validity and suggested that beneficial effects of dopaminergic stimulants on response inhibition may be limited to cases of suboptimal inhibitory functioning. We present evidence that, in carefully selected healthy adults, spontaneous eyeblink rate, a marker of central dopaminergic functioning, reliably predicts the efficiency in inhibiting unwanted action tendencies in a stop-signal task. These findings support the assumption of a modulatory role for dopamine in inhibitory action control

On the Role of the Striatum in Response Inhibition

BACKGROUND: Stopping a manual response requires suppression of the primary motor cortex (M1) and has been linked to activation of the striatum. Here, we test three hypotheses regarding the role of the striatum in stopping: striatum activation during successful stopping may reflect suppression of M1, anticipation of a stop-signal occurring, or a slower response build-up. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-four healthy volunteers underwent functional magnetic resonance imaging (fMRI) while performing a stop-signal paradigm, in which anticipation of stopping was manipulated using a visual cue indicating stop-signal probability, with their right hand. We observed activation of the striatum and deactivation of left M1 during successful versus unsuccessful stopping. In addition, striatum activation was proportional to the degree of left M1 deactivation during successful stopping, implicating the striatum in response suppression. Furthermore, striatum activation increased as a function of stop-signal probability and was to linked to activation in the supplementary motor complex (SMC) and right inferior frontal cortex (rIFC) during successful stopping, suggesting a role in anticipation of stopping. Finally, trial-to-trial variations in response time did not affect striatum activation. CONCLUSIONS/SIGNIFICANCE: The results identify the striatum as a critical node in the neural network associated with stopping motor responses. As striatum activation was related to both suppression of M1 and anticipation of a stop-signal occurring, these findings suggest that the striatum is involved in proactive inhibitory control over M1, most likely in interaction with SMC and rIFC

Distributional reaction time properties in the Eriksen task: marked differences or hidden similarities with the Simon task?

In conflict tasks, the irrelevant stimulus attribute needs to be suppressed for the correct response to be produced. In the Simon task, earlier researchers have proposed that this suppression is the reason that, after an initial increase, the interference effect decreases for longer RTs, as reflected by late, negative-going delta plots. This view has been challenged by observations of positive-going delta plots, even for long RTs, in other conflict tasks, despite a similar necessity for suppression. For late negative-going delta plots to be interpreted as reflecting suppression, a necessary, although maybe not sufficient, condition is that similar patterns should be observed for other conflict tasks. We reasoned that a similar suppression could be present, but hidden, in the Eriksen flanker task. By recording and analyzing electromyograms of the muscles involved in response execution, we could compute delta plots separately for trials that elicited a subthreshold incorrect response activation (partial error). Late negative-going delta plots were observable on partial-error trials, although they were weaker than for the Simon task, reducing the impact of this inversion on the overall distribution. We further showed that this pattern is modulated by time pressure. Those results indicate that mechanisms leading to negative-going delta plots, similar to those observed in the Simon task, are also at play in the Eriksen task. The link between negative-going delta plots and executive online control is discussed