Connecting the dots: harnessing dual-site transcranial magnetic stimulation to quantify the causal influence of medial frontal areas on the motor cortex.

Dual-site transcranial magnetic stimulation has been widely employed to investigate the influence of cortical structures on the primary motor cortex. Here, we leveraged this technique to probe the causal influence of two key areas of the medial frontal cortex, namely the supplementary motor area and the medial orbitofrontal cortex, on primary motor cortex. We show that supplementary motor area stimulation facilitates primary motor cortex activity across short (6 and 8 ms) and long (12 ms) inter-stimulation intervals, putatively recruiting cortico-cortical and cortico-subcortico-cortical circuits, respectively. Crucially, magnetic resonance imaging revealed that this facilitatory effect depended on a key morphometric feature of supplementary motor area: individuals with larger supplementary motor area volumes exhibited more facilitation from supplementary motor area to primary motor cortex for both short and long inter-stimulation intervals. Notably, we also provide evidence that the facilitatory effect of supplementary motor area stimulation at short intervals is unlikely to arise from spinal interactions of volleys descending simultaneously from supplementary motor area and primary motor cortex. On the other hand, medial orbitofrontal cortex stimulation moderately suppressed primary motor cortex activity at both short and long intervals, irrespective of medial orbitofrontal cortex volume. These results suggest that dual-site transcranial magnetic stimulation is a fruitful approach to investigate the differential influence of supplementary motor area and medial orbitofrontal cortex on primary motor cortex activity, paving the way for the multimodal assessment of these fronto-motor circuits in health and disease.

Pain, No Gain: Acute Pain Interrupts Motor Imagery Processes and Affects Mental Training-Induced Plasticity.

Pain influences both motor behavior and neuroplastic adaptations induced by physical training. Motor imagery (MI) is a promising method to recover motor functions, for instance in clinical populations with limited endurance or concomitant pain. However, the influence of pain on the MI processes is not well established. This study investigated whether acute experimental pain could modulate corticospinal excitability assessed at rest and during MI (Exp. 1) and limit the use-dependent plasticity induced by MI practice (Exp. 2). Participants imagined thumb movements without pain or with painful electrical stimulations applied either on digit V or over the knee. We used transcranial magnetic stimulation to measure corticospinal excitability at rest and during MI (Exp. 1) and to evoke involuntary thumb movements before and after MI practice (Exp. 2). Regardless of its location, pain prevented the increase of corticospinal excitability that is classically observed during MI. In addition, pain blocked use-dependent plasticity following MI practice, as testified by a lack of significant posttraining deviations. These findings suggest that pain interferes with MI processes, preventing the corticospinal excitability facilitation needed to induce use-dependent plasticity. Pain should be carefully considered for rehabilitation programs using MI to restore motor function.

The recruitment of indirect waves within primary motor cortex during motor imagery: A directional transcranial magnetic stimulation study.

Motor imagery (MI) refers to the mental simulation of an action without overt movement. While numerous transcranial magnetic stimulation (TMS) studies provided evidence for a modulation of corticospinal excitability and intracortical inhibition during MI, the neural signature within the primary motor cortex is not clearly established. In the current study, we used directional TMS to probe the modulation of the excitability of early and late indirect waves (I-waves) generating pathways during MI. Corticospinal responses evoked by TMS with posterior-anterior (PA) and anterior-posterior (AP) current flow within the primary motor cortex evoke preferentially early and late I-waves, respectively. Seventeen participants were instructed to stay at rest or to imagine maximal isometric contractions of the right flexor carpi radialis. We demonstrated that the increase of corticospinal excitability during MI is greater with PA than AP orientation. By using paired-pulse stimulations, we confirmed that short-interval intracortical inhibition (SICI) increased during MI in comparison to rest with PA orientation, whereas we found that it decreased with AP orientation. Overall, these results indicate that the pathways recruited by PA and AP orientations that generate early and late I-waves are differentially modulated by MI.

Do nociceptive stimulation intensity and temporal predictability influence pain-induced corticospinal excitability modulation?

Temporal predictability and intensity of an impending nociceptive input both shape pain experience and modulate laser-evoked potentials (LEPs) amplitude. However, it remains unclear whether and how these two factors could influence pain-induced corticospinal excitability modulation. The current study investigated the influence of nociceptive stimulation intensity and temporal predictability on motor-evoked potentials (MEPs) modulation, in parallel to their effect on pain perception and LEPs amplitude. Twenty participants completed electroencephalographic and transcranial magnetic stimulation experiments during which two laser nociceptive stimulation intensities (high and low) were either unpredictably delivered (random delay) or preceded by a fixed-timing cue (fixed delay). The amplitude of the conditioned MEPs was significantly reduced only for the high nociceptive stimulation and was not affected by the temporal predictability of pain (despite the fact that temporal predictability modulated the amplitude of P2 LEP component amplitude). However, a posteriori analyses based on patterns of pain-induced MEPs modulation revealed that participants in which nociceptive stimulation resulted in an increase in corticospinal excitability were more affected by the predictability of pain (i.e. increasing corticospinal excitability even more when pain occurrence was predictable), regardless of the nociceptive stimulation intensity; whereas participants in which nociceptive stimulation resulted in a decrease in corticospinal excitability were sensitive to the intensity of the stimulation but not its predictability. These results suggest a potential influence of cognitive factors such as temporal predictability on the response of the motor system in the presence of pain for some participants, contributing to explain, at least in part, the high variability highlighted in a number of previous studies.

Effect of movement-related pain on behaviour and corticospinal excitability changes associated with arm movement preparation.

KEY POINTS: Experimental pain or its anticipation influence motor preparation processes as well as upcoming movement execution, but the underlying physiological mechanisms remain unknown. Our results showed that movement-related pain modulates corticospinal excitability during motor preparation. In accordance with the pain adaptation theory, corticospinal excitability was higher when the muscle has an antagonist (vs. an agonist) role for the upcoming movement associated with pain. Anticipation of movement-related pain also affects motor initiation and execution, with slower movement initiation (longer reaction times) and faster movement execution compared to movements that do not evoke pain. These results confirm the implementation of protective strategies during motor preparation known to be relevant for acute pain, but which may potentially have detrimental long-term consequences and lead to the development of chronic pain. ABSTRACT: When a movement repeatedly generates pain, we anticipate movement-related pain and establish self-protective strategies during motor preparation, but the underlying mechanisms remains poorly understood. The current study investigated the effect of movement-related pain anticipation on the modulation of behaviour and corticospinal excitability during the preparation of arm movements. Participants completed an instructed-delay reaction-time (RT) task consisting of elbow flexions and extensions instructed by visual cues. Nociceptive laser stimulations (unconditioned stimuli) were applied to the lateral epicondyle during movement execution in a specific direction (CS+) but not in the other (CS-), depending on experimental group. During motor preparation, transcranial magnetic stimulation was used to measure corticospinal excitability in the biceps brachii (BB). RT and peak end-point velocity were also measured. Neurophysiological results revealed an opposite modulation of corticospinal excitability in BB depending on whether it plays an agonist (i.e. flexion) or antagonist (i.e. extension) role for the CS+ movements (P < 0.001). Moreover, behavioural results showed that for the CS+ movements RT did not change relative to baseline, whereas the CS- movements were initiated more quickly (P = 0.023) and the CS+ flexion movements were faster relative to the CS- flexion movements (P < 0.001). This is consistent with the pain adaptation theory which proposes that in order to protect the body from further pain, agonist muscle activity is reduced and antagonist muscle activity is increased. If these strategies are initially relevant and lead to short-term pain alleviation, they may potentially have detrimental long-term consequences and lead to the development of chronic pain.

Stimulating the Healthy Brain to Investigate Neural Correlates of Motor Preparation: A Systematic Review.

Objective: Noninvasive brain stimulation techniques can be used to selectively increase or decrease the excitability of a cortical region, providing a unique opportunity to assess the causal contribution of that region to the process being assessed. The objective of this paper is to systematically examine studies investigating changes in reaction time induced by noninvasive brain stimulation in healthy participants during movement preparation. Methods: A systematic review of the literature was performed in the PubMed, MEDLINE, EMBASE, PsycINFO, and Web of science databases. A combination of keywords related to motor preparation, associated behavioral outcomes, and noninvasive brain stimulation methods was used. Results: Twenty-seven studies were included, and systematic data extraction and quality assessment were performed. Reaction time results were transformed in standardised mean difference and graphically pooled in forest plots depending on the targeted cortical area and the type of stimulation. Conclusions: Despite methodological heterogeneity among studies, results support a functional implication of five cortical regions (dorsolateral prefrontal cortex, posterior parietal cortex, supplementary motor area, dorsal premotor cortex, and primary motor cortex), integrated into a frontoparietal network, in various components of motor preparation ranging from attentional to motor aspects.

Effect of Cutaneous Heat Pain on Corticospinal Excitability of the Tibialis Anterior at Rest and during Submaximal Contraction.

Previous studies have shown that pain can interfere with motor control. The neural mechanisms underlying these effects remain largely unknown. At the upper limb, mounting evidence suggests that pain-induced reduction in corticospinal excitability is involved. No equivalent data is currently available at the lower limb. The present study therefore examined the effect of thermal pain on the corticospinal drive to tibialis anterior (TA) at rest and during an isometric submaximal dorsiflexion. Transcranial magnetic stimulation was used to induce motor-evoked potentials (MEPs) in the TA at rest and during contraction in the presence or absence of cutaneous heat pain induced by a thermode positioned above the TA (51°C during 1 s). With similar pain ratings between conditions (3.9/10 at rest and 3.6/10 during contraction), results indicate significant decreases in MEP amplitude during both rest (-9%) and active conditions (-13%) (main effect of pain, p = 0.02). These results therefore suggest that cutaneous heat pain can reduce corticospinal excitability in the TA muscle and that such reduction in corticospinal excitability could contribute to the interference of pain on motor control/motor learning.

Unraveling the brain mechanisms of source monitoring with non-invasive brain stimulation: A systematic review.

Background/Objective: Source monitoring refers to the ability to determine the source of memories and encompasses three subprocesses: internal source monitoring, reality monitoring, and external source monitoring. Neuroimaging studies provide valuable insights about neural correlates of source monitoring, but the causal relationship between brain and behavior is lacking. This study aimed to identify brain circuits involved in source monitoring by synthesizing the effects of brain stimulation on source monitoring as a function of the targeted brain regions or circuits. Method: We conducted a systematic review of interventional studies that have examined the effects of brain stimulation on source monitoring across six databases. The principal outcome was the difference of source monitoring performance between active and control stimulation conditions. Results: 23 studies (920 healthy participants and 54 patients with schizophrenia) were included. Our findings revealed the involvement of i) the lateral prefrontal and temporoparietal cortices in internal source monitoring, ii) the medial prefrontal and temporoparietal cortices in reality monitoring, and iii) the precuneus and the left angular gyrus in external source monitoring. Conclusions: These findings deepen our understanding of the brain mechanisms of source monitoring and highlight specific stimulation targets to alleviate source monitoring deficits.

Combining a Breath-Synchronized Olfactometer with Brain Simulation to Study the Impact of Odors on Corticospinal Excitability and Effective Connectivity.

It is widely accepted that olfactory stimulation elicits motor behaviors, such as approaching pleasant odorants and avoiding unpleasant ones, in animals and humans. Recently, studies using electroencephalography and transcranial magnetic stimulation (TMS) have demonstrated a strong link between processing in the olfactory system and activity in the motor cortex in humans. To better understand the interactions between the olfactory and the motor systems and to overcome some of the previous methodological limitations, we developed a new method combining an olfactometer that synchronizes the random order presentation of odorants with different hedonic values and the TMS (single- and dual-coil) triggering with nasal breathing phases. This method allows probing the modulations of corticospinal excitability and effective ipsilateral connectivity between the dorsolateral prefrontal cortex and the primary motor cortex that could occur during pleasant and unpleasant odor perception. The application of this method will allow for objectively discriminating the pleasantness value of an odorant in a given participant, indicating the biological impact of the odorant on brain effective connectivity and excitability. In addition, this could pave the way for clinical investigations in patients with neurological or neuropsychiatric disorders who may exhibit odor hedonic alterations and maladaptive approach-avoidance behaviors.

Eye-tracking evidence of a relationship between attentional bias for emotional faces and depression severity in patients with treatment-resistant depression.

In a retrospective study, 54 patients with treatment-resistant major depressive disorder (TRD) completed a free-viewing task in which they had to freely explore pairs of faces (an emotional face (happy or sad) opposite to a neutral face). Attentional bias to emotional faces was calculated for early and sustained attention. We observed a significant negative correlation between depression severity as measured by the 10-item Montgomery-Åsberg Depression Rating Scale (MADRS) and sustained attention to happy faces. In addition, we observed a positive correlation between depression severity and sustained attention to sad faces. No significant correlation between depression severity and early attention was found for either happy or sad faces. Although conclusions from the current study are limited by the lack of comparison with a control group, the eye-tracking free-viewing task appears to be a relevant, accessible and easy-to-use tool for measuring depression severity through emotional attentional biases in TRD.

Case report: accelerated cathodal HD-tDCS over the right dorsolateral prefrontal cortex in hoarding disorder.

Hoarding disorder is an under-recognized condition characterized by the excessive acquisition of possessions and difficulty in disposing of them, which can have dramatic consequences. As hoarding disorder is difficult to treat and associated with high levels of disability in all areas of functioning, there appears to be a critical need to develop novel, tailored therapeutic strategies. Non-invasive brain stimulation techniques hold promise as potential therapeutic interventions for various psychiatric conditions and as a tool to modulate impulsivity when applied over the dorsolateral prefrontal cortex (DLPFC). Therefore, we hypothesized that delivering accelerated cathodal high-definition direct transcranial stimulation (HD-tDCS) over the right DLPFC could be a suitable approach to alleviate symptoms in patients with hoarding disorder. In a case report, we observed beneficial clinical effects on acquisition and depressive symptoms after 15 sessions of three daily 20-min sessions. Accelerated cathodal HD-tDCS over the right DLPFC appears to be a safe and appropriate intervention for patients with hoarding disorder. However, randomized, sham-controlled trials are needed to further validate these encouraging findings.

Corticospinal Excitability Quantification During a Visually-Guided Precision Walking Task in Humans: Potential for Neurorehabilitation.

The corticospinal tract has been shown to be involved in normal walking in humans. However, its contribution during more challenging locomotor tasks is still unclear. As the corticospinal tract can be a potential target to promote gait recovery after neurological injury, it is of primary importance to quantify its use during human walking. The aims of the current study were to: (1) quantify the effects of precision walking on corticospinal excitability as compared to normal walking; (2) assess if corticospinal modulation is related to task difficulty or participants' performance. Sixteen healthy participants walked on a treadmill during 2 tasks: regular walking (simple task) and stepping onto virtual targets (precision task). Virtual targets appeared randomly at 3 different step lengths: preferred, and ±20%. To assess corticospinal excitability, 25 motor evoked potentials (MEPs) were recorded from the tibialis anterior muscle in each task during walking. Performance for each participant (global success score; % of target hit) and task difficulty related to step length adjustments (success score for each step length) were also calculated. MEP size was larger during the precision task in all participants (mean increase of 93% ± 72%; P < .05) compared to the simple task. There was a correlation between MEP facilitation and individual performance (r = -.64; P < .05), but no difference in MEP size associated with task difficulty (P > .05). In conclusion, corticospinal excitability exhibits a large increase during the precision task. This effect needs to be confirmed in neurological populations to potentially provide a simple and non-invasive approach to increase corticospinal drive during gait rehabilitation.

Exploring cortico-cortical interactions during action preparation by means of dual-coil transcranial magnetic stimulation: A systematic review.

Action preparation is characterized by a set of complex and distributed processes that occur in multiple brain areas. Interestingly, dual-coil transcranial magnetic stimulation (TMS) is a relevant technique to probe effective connectivity between cortical areas, with a high temporal resolution. In the current systematic review, we aimed at providing a detailed picture of the cortico-cortical interactions underlying action preparation focusing on dual-coil TMS studies. We considered four theoretical processes (impulse control, action selection, movement initiation and action reprogramming) and one task modulator (movement complexity). The main findings highlight 1) the interplay between primary motor cortex (M1) and premotor, prefrontal and parietal cortices during action preparation, 2) the varying (facilitatory or inhibitory) cortico-cortical influence depending on the theoretical processes and the TMS timing, and 3) the key role of the supplementary motor area-M1 interactions that shape the preparation of simple and complex movements. These findings are of particular interest for clinical perspectives, with a need to better characterize functional connectivity deficiency in clinical population with altered action preparation.

Response-locked component of error monitoring in psychopathy: A systematic review and meta-analysis of error-related negativity/positivity.

Evidence suggests that psychopathic individuals display difficulties to adapt their behavior in accordance with the demands of the environment and show altered performance monitoring. Studies investigating the error-related negativity (ERN) and the error-positivity (Pe) as electrophysiological markers of error monitoring reported contradictory results for this population. To explain these discrepancies, we hypothesized that psychopathy dimensions influence electrophysiological outcomes. We predicted that individuals with impulsive-antisocial features would display abnormal ERN compared to individuals with interpersonal-affective features. A systematic review and meta-analysis of studies investigating ERN and Pe components were conducted. A factorial analysis was undertaken to investigate the role of psychopathy dimensions on ERN and Pe. Compared to controls, psychopathic individuals (n = 940) showed a reduced ERN and Pe amplitude. The factorial analysis indicates a dissociation regarding the construct of psychopathy. The models reported that psychopathic individuals related specifically to the interpersonal-affective dimension displayed normal ERN component and efficient error-monitoring, while psychopathic individuals with a marked impulsive-antisocial dimension display a decreased ERN component and altered performance monitoring.

Influence of Voluntary Contraction Level, Test Stimulus Intensity and Normalization Procedures on the Evaluation of Short-Interval Intracortical Inhibition.

Short-interval intracortical inhibition (SICI) represents an inhibitory phenomenon acting at the cortical level. However, SICI estimation is based on the amplitude of a motor-evoked potential (MEP), which depends on the discharge of spinal motoneurones and the generation of compound muscle action potential (M-wave). In this study, we underpin the importance of taking into account the proportion of spinal motoneurones that are activated or not when investigating the SICI of the right flexor carpi radialis (normalization with maximal M-wave (Mmax) and MEPtest, respectively), in 15 healthy subjects. We probed SICI changes according to various MEPtest amplitudes that were modulated actively (four levels of muscle contraction: rest, 10%, 20% and 30% of maximal voluntary contraction (MVC)) and passively (two intensities of test transcranial magnetic stimulation (TMS): 120 and 130% of motor thresholds). When normalized to MEPtest, SICI remained unchanged by stimulation intensity and only decreased at 30% of MVC when compared with rest. However, when normalized to Mmax, we provided the first evidence of a strong individual relationship between SICI and MEPtest, which was ultimately independent from experimental conditions (muscle states and TMS intensities). Under similar experimental conditions, it is thus possible to predict SICI individually from a specific level of corticospinal excitability in healthy subjects.

Unravelling the Modulation of Intracortical Inhibition During Motor Imagery: An Adaptive Threshold-Hunting Study.

Motor imagery (MI) is the mental simulation of an action without any apparent muscular contraction. By means of transcranial magnetic stimulation (TMS), few studies revealed a decrease of short-interval intracortical inhibition (SICI) within the primary motor cortex. However, this decrease is ambiguous, as one would expect greater inhibition during MI to prevent overt motor output. The current study investigated the extent of SICI modulation during MI through a methodological and a conceptual reconsideration of (i) the importance of parameters to assess SICI (Exp.1) and (ii) the inhibitory process within the primary motor cortex as an inherent feature of MI (Exp.2). Participants performed two tasks: (1) rest and (2) imagery of isometric abduction of the right index finger. Using TMS, motor evoked potentials were elicited in the right first dorsal interosseous (FDI) muscle. An adaptive threshold-hunting paradigm was used, where the stimulus intensity required to maintain a fixed motor evoked potential amplitude was quantified. To test SICI, we conditioned the test stimulus with a conditioning stimulus (CS) of different intensities. Results revealed an Intensity by Task interaction showing that SICI decreased during MI as compared to rest only for the higher CS intensity (Exp.1). At the lowest CS intensities, a Task main effect revealed that SICI increased during MI (Exp.2). SICI modulation during MI depends critically on the CS intensity. By optimising CS intensity, we have shown that SICI circuits may increase during MI, revealing a potential mechanism to prevent the production of a movement while the motor system is activated.

Modulation of Corticospinal Excitability of Trunk Muscles in Preparation of Rapid Arm Movement.

Many studies have described the dynamic modulation of corticospinal excitability of the prime movers during motor preparation. However although anticipatory postural adjustments (APA) are an inherent part of most voluntary movements, investigation of trunk muscle corticospinal excitability during motor preparation has been neglected in the literature. In the present study, the corticospinal excitability of the superficial multifidus (sMF) and rectus abdominis (RA) muscle has been assessed during the preparation of rapid arm flexions and extensions in fifteen participants. A Warning signal informed participants to prepare to move prior to a Go signal. Transcranial magnetic stimulation was applied during baseline and at 6 time intervals before (Delay period) or after (Motor execution period) the Go signal. Results revealed a significant inhibition of the amplitude of sMF motor-evoked potentials in both flexion and extension movements within the Delay period compared to baseline, while no significant modulation was observed for RA. During the Motor Execution period for arm extension, sMF displayed even more inhibition, along with a large and significant facilitation of RA. During the Motor execution period for arm flexion, sMF presented a trend toward larger motor-evoked potential amplitude compared to Delay period. These results suggest the existence of two concurrent mechanisms underlying motor preparation for APA: (i) before the Go signal, a nonspecific inhibitory mechanism for sMF, likely to preclude motor program release; (ii) after the Go signal, a task-specific modulation of corticospinal excitability consistent with the EMG pattern during the early phase of movement.

Effect of Experimental Hand Pain on Training-Induced Changes in Motor Performance and Corticospinal Excitability.

Pain influences plasticity within the sensorimotor system and the aim of this study was to assess the effect of pain on changes in motor performance and corticospinal excitability during training for a novel motor task. A total of 30 subjects were allocated to one of two groups (Pain, NoPain) and performed ten training blocks of a visually-guided isometric pinch task. Each block consisted of 15 force sequences, and subjects modulated the force applied to a transducer in order to reach one of five target forces. Pain was induced by applying capsaicin cream to the thumb. Motor performance was assessed by a skill index that measured shifts in the speed-accuracy trade-off function. Neurophysiological measures were taken from the first dorsal interosseous using transcranial magnetic stimulation. Overall, the Pain group performed better throughout the training (p = 0.03), but both groups showed similar improvements across training blocks (p < 0.001), and there was no significant interaction. Corticospinal excitability in the NoPain group increased halfway through the training, but this was not observed in the Pain group (Time × Group interaction; p = 0.01). These results suggest that, even when pain does not negatively impact on the acquisition of a novel motor task, it can affect training-related changes in corticospinal excitability.