Biophysical Modeling of Frontocentral ERP Generation Links Circuit-Level Mechanisms of Action-Stopping to a Behavioral Race Model.

Human frontocentral event-related potentials (FC-ERPs) are ubiquitous neural correlates of cognition and control, but their generating multiscale mechanisms remain mostly unknown. We used the Human Neocortical Neurosolver's biophysical model of a canonical neocortical circuit under exogenous thalamic and cortical drive to simulate the cell and circuit mechanisms underpinning the P2, N2, and P3 features of the FC-ERP observed after Stop-Signals in the Stop-Signal task (SST; N = 234 humans, 137 female). We demonstrate that a sequence of simulated external thalamocortical and corticocortical drives can produce the FC-ERP, similar to what has been shown for primary sensory cortices. We used this model of the FC-ERP to examine likely circuit-mechanisms underlying FC-ERP features that distinguish between successful and failed action-stopping. We also tested their adherence to the predictions of the horse-race model of the SST, with specific hypotheses motivated by theoretical links between the P3 and Stop process. These simulations revealed that a difference in P3 onset between successful and failed Stops is most likely due to a later arrival of thalamocortical drive in failed Stops, rather than, for example, a difference in the effective strength of the input. In contrast, the same model predicted that early thalamocortical drives underpinning the P2 and N2 differed in both strength and timing across stopping accuracy conditions. Overall, this model generates novel testable predictions of the thalamocortical dynamics underlying FC-ERP generation during action-stopping. Moreover, it provides a detailed cellular and circuit-level interpretation that supports links between these macroscale signatures and predictions of the behavioral race model.

The human subthalamic nucleus transiently inhibits active attentional processes.

The subthalamic nucleus (STN) of the basal ganglia is key to the inhibitory control of movement. Consequently, it is a primary target for the neurosurgical treatment of movement disorders like Parkinson's Disease, where modulating the STN via deep-brain stimulation (DBS) can release excess inhibition of thalamo-cortical motor circuits. However, the STN is also anatomically connected to other thalamo-cortical circuits, including those underlying cognitive processes like attention. Notably, STN-DBS can also affect these processes. This suggests that the STN may also contribute to the inhibition of non-motor activity, and that STN-DBS may cause changes to this inhibition. We here tested this hypothesis in humans. We used a novel, wireless outpatient method to record intracranial local field potentials (LFP) from STN DBS implants during a visual attention task (Experiment 1, N=12). These outpatient measurements allowed the simultaneous recording of high-density EEG, which we used to derive the steady-state visual evoked potential (SSVEP), a well-established neural index of visual attentional engagement. By relating STN activity to this neural marker of attention (instead of overt behavior), we avoided possible confounds resulting from STN's motor role. We aimed to test whether the STN contributes to the momentary inhibition of the SSVEP caused by unexpected, distracting sounds. Furthermore, we causally tested this association in a second experiment, where we modulated STN via DBS across two sessions of the task, spaced at least one week apart (N=21, no sample overlap with Experiment 1). The LFP recordings in Experiment 1 showed that reductions of the SSVEP after distracting sounds were preceded by sound-related γ-frequency (>60Hz) activity in the STN. Trial-to-trial modeling further showed that this STN activity statistically mediated the sounds' suppressive effect on the SSVEP. In Experiment 2, modulating STN activity via DBS significantly reduced these sound-related SSVEP reductions. This provides causal evidence for the role of the STN in the surprise-related inhibition of attention. These findings suggest that the human STN contributes to the inhibition of attention, a non-motor process. This supports a domain-general view of the inhibitory role of the STN. Furthermore, these findings also suggest a potential mechanism underlying some of the known cognitive side-effects of STN-DBS treatment, especially on attentional processes. Finally, our newly-established outpatient LFP recording technique facilitates the testing of the role of subcortical nuclei in complex cognitive tasks, alongside recordings from the rest of the brain, and in much shorter time than perisurgical recordings.

Low blood concentration of alcohol enhances activity related to stopping failure in the right inferior frontal cortex.

This study investigated the effects of low doses of alcohol, which are acceptable for driving a car, on inhibitory control and neural processing using the stop-signal task (SST) in 17 healthy right-handed social drinkers. The study employed simultaneous functional magnetic resonance imaging and electromyography (EMG) recordings to assess behavioral and neural responses under conditions of low-dose alcohol (breath-alcohol concentration of 0.15 mg/L) and placebo. The results demonstrated that even a small amount of alcohol consumption prolonged Go reaction times in the SST and modified stopping behavior, as evidenced by a decrease in the frequency and magnitude of partial response EMG that did not result in button pressing during successful inhibitory control. Furthermore, alcohol intake enhanced neural activity during failed inhibitory responses in the right inferior frontal cortex, suggesting its potential role in behavioral adaptation following stop-signal failure. These findings suggest that even low levels of alcohol consumption within legal driving limits can greatly impact both the cognitive performance and brain activity involved in inhibiting responses. This research provides important evidence on the neurobehavioral effects of low-dose alcohol consumption, with implications for understanding the biological basis of impaired motor control and decision-making and potentially informing legal guidelines on alcohol consumption.

Cognitive and neural mechanisms of voluntary versus forced language switching in Chinese-English bilinguals: an fMRI study.

The ecological validity of bilingual code-switching has garnered increasing attention in recent years. Contrary to traditional studies that have focused on forced language switching, emerging theories posit that voluntary switching may not incur such a cost. To test these claims and understand differences between forced and voluntary switching, the present study conducted a systematic comparison through both behavioral and neural perspectives. Utilizing fMRI alongside picture-naming tasks, our findings diverge from prior work. Voluntary language switching not only demonstrated switching costs at the behavioral level but also significantly activated brain regions associated with inhibitory control. Direct comparisons of voluntary and forced language switching revealed no significant behavioral differences in switching costs, and both shared several common brain regions that were activated. On the other hand, a nuanced difference between the two types of language switching was revealed by whole-brain analysis: voluntary switching engaged fewer language control regions than forced switching. These findings offer a comprehensive view of the neural and behavioral dynamics involved in bilingual language switching, challenging prior claims that voluntary switching imposes no behavioral or neural costs, and thus providing behavioral and neuroimaging evidence for the involvement of inhibitory control in voluntary language switching.

Effect of short-term intensive design-based STEM learning on executive function: an fNIRS study of the left-behind children.

Design-based STEM learning is believed to be an effective cross-disciplinary strategy for promoting children's cognitive development. Yet, its impact on executive functions, particularly for disadvantaged children, still need to be explored. This study investigated the effects of short-term intensive design-based STEM learning on executive function among left-behind children. Sixty-one Grade 4 students from a school dedicated to the left-behind children in China were sampled and randomly assigned to an experimental group (10.70 ± 0.47 years old, n = 30) or a control group (10.77 ± 0.43 years old, n = 31). The experimental group underwent a two-week design-based STEM training program, while the control group participated in a 2-week STEM-related reading program. Both groups were assessed with the brain activation from 4 brain regions of interest using functional near-infrared spectroscopy (fNIRS) and behavioral measures during a Stroop task before and after the training. Analysis disclosed: (i) a significant within-group time effect in the experimental group, with posttest brain activation in Brodmann Area 10 and 46 being notably lower during neutral and word conditions; (ii) a significant between-group difference at posttest, with the experimental group showing considerably lower brain activation in Brodmann Area 10 and Brodmann Area 46 than the control group; and (iii) a significant task effect in brain activity among the three conditions of the Stroop task. These findings indicated that this STEM learning effectively enhanced executive function in left-behind children. The discrepancy between the non-significant differences in behavioral performance and the significant ones in brain activation implies a compensatory mechanism in brain activation. This study enriches current theories about the impact of Science, Technology, Engineering, and Mathematics (STEM) learning on children's executive function development, providing biological evidence and valuable insights for educational curriculum design and assessment.

The effect of learning to drum on behavior and brain function in autistic adolescents.

This current study aimed to investigate the impact of drum training on behavior and brain function in autistic adolescents with no prior drumming experience. Thirty-six autistic adolescents were recruited and randomly assigned to one of two groups. The drum group received individual drum tuition (two lessons per week over an 8-wk period), while the control group did not. All participants attended a testing session before and after the 8-wk period. Each session included a drumming assessment, an MRI scan, and a parent completing questionnaires relating to the participants' behavioral difficulties. Results showed that improvements in drumming performance were associated with a significant reduction in hyperactivity and inattention difficulties in drummers compared to controls. The fMRI results demonstrated increased functional connectivity in brain areas responsible for inhibitory control, action outcomes monitoring, and self-regulation. In particular, seed-to-voxel analyses revealed an increased functional connectivity in the right inferior frontal gyrus and the right dorsolateral prefrontal cortex. A multivariate pattern analysis demonstrated significant changes in the medial frontal cortex, the left and right paracingulate cortex, the subcallosal cortex, the left frontal pole, the caudate, and the left nucleus accumbens. In conclusion, this study investigates the impact of a drum-based intervention on neural and behavioral outcomes in autistic adolescents. We hope that these findings will inform further research and trials into the potential use of drum-based interventions in benefitting clinical populations with inhibition-related disorders and emotional and behavioral difficulties.

Inhibitory control in WM gate-opening: Insights from alpha desynchronization and norepinephrine activity under atDCS stimulation.

Our everyday activities require the maintenance and continuous updating of information in working memory (WM). To control this dynamic, WM gating mechanisms have been suggested to be in place, but the neurophysiological mechanisms behind these processes are far from being understood. This is especially the case when it comes to the role of oscillatory neural activity. In the current study we combined EEG recordings, and anodal transcranial direct current stimulation (atDCS) and pupil diameter recordings to triangulate neurophysiology, functional neuroanatomy and neurobiology. The results revealed that atDCS, compared to sham stimulation, affected the WM gate opening mechanism, but not the WM gate closing mechanism. The altered behavioral performance was associated with specific changes in alpha band activities (reflected by alpha desynchronization), indicating a role for inhibitory control during WM gate opening. Functionally, the left superior and inferior parietal cortices, were associated with these processes. The findings are the first to show a causal relevance of alpha desynchronization processes in WM gating processes. Notably, pupil diameter recordings as an indirect index of the norepinephrine (NE) system activity revealed that individuals with stronger inhibitory control (as indexed through alpha desynchronization) showed less pupil dilation, suggesting they needed less NE activity to support WM gate opening. However, when atDCS was applied, this connection disappeared. The study suggests a close link between inhibitory controlled WM gating in parietal cortices, alpha band dynamics and the NE system.

Out-of-phase transcranial alternating current stimulation modulates the neurodynamics of inhibitory control.

Transcranial alternating current stimulation (tACS) is an efficient neuromodulation technique that enhances cognitive function in a non-invasive manner. Using functional magnetic resonance imaging, we investigated whether tACS with different phase lags (0° and 180°) between the dorsal anterior cingulate and left dorsolateral prefrontal cortices modulated inhibitory control performance during the Stroop task. We found out-of-phase tACS mediated improvements in task performance, which was neurodynamically reflected as putamen, dorsolateral prefrontal, and primary motor cortical activation as well as prefrontal-based top-down functional connectivity. Our observations uncover the neurophysiological bases of tACS-phase-dependent neuromodulation and provide a feasible non-invasive approach to effectively modulate inhibitory control.

The relationship between frontal alpha asymmetry and behavioral and brain activity indices of reactive inhibitory control.

Reactive inhibitory control plays an important role in phenotype of different diseases/different phases of a disease. One candidate electrophysiological marker of inhibitory control is frontal alpha asymmetry (FAA). FAA reflects the relative difference in contralateral frontal brain activity. However, the relationship between FAA and potential behavioral/brain activity indices of reactive inhibitory control is not yet clear. We assessed the relationship between resting-state FAA and indicators of reactive inhibitory control. Additionally, we investigated the effect of modulation of FAA via transcranial direct current stimulation (tDCS). We implemented a randomized sham-controlled design with 65 healthy humans (Mage = 23.93, SDage = 6.08; 46 female). Before and after 2-mA anodal tDCS of the right frontal site (with the cathode at the contralateral site) for 20 min, we collected EEG data and reactive inhibitory performance in neutral and food-reward conditions, using the stop signal task (SST). There was no support for the effect of tDCS on FAA or any indices of reactive inhibitory control. Our correlation analysis revealed an association between inhibitory brain activity in the food-reward condition and (pre-tDCS) asymmetry. Higher right relative to left frontal brain activity was correlated with reduced early-onset inhibitory activity and, in contrast, linked with higher late-onset inhibitory control in the food-reward condition. Similarly, event-related potential analyses showed reduced early-onset and enhanced late-onset inhibitory brain activity over time, particularly in the food-reward condition. These results suggest that there can be a dissociation regarding the lateralization of frontal brain activity and early- and late-onset inhibitory brain activity.NEW & NOTEWORTHY This research reveals dissociation between baseline frontal alpha asymmetry and the timing of reactive inhibitory brain activities in food-reward contexts. Whereas inhibitory control performance decreases over time in a stop signal task, electrophysiological indices show reduced early- and heightened late-onset inhibitory brain activity, especially in the reward condition. Additionally, greater right frontal activity correlates with reduced early-onset and increased late-onset inhibitory brain activity.

Rethinking the external globus pallidus and information flow in cortico-basal ganglia-thalamic circuits.

For decades, the external globus pallidus (GPe) has been viewed as a passive way-station in the indirect pathway of the cortico-basal ganglia-thalamic (CBGT) circuit, sandwiched between striatal inputs and basal ganglia outputs. According to this model, one-way descending striatal signals in the indirect pathway amplify the suppression of downstream thalamic nuclei by inhibiting GPe activity. Here, we revisit this assumption, in light of new and emerging work on the cellular complexity, connectivity and functional role of the GPe in behaviour. We show how, according to this new circuit-level logic, the GPe is ideally positioned for relaying ascending and descending control signals within the basal ganglia. Focusing on the problem of inhibitory control, we illustrate how this bidirectional flow of information allows for the integration of reactive and proactive control mechanisms during action selection. Taken together, this new evidence points to the GPe as being a central hub in the CBGT circuit, participating in bidirectional information flow and linking multifaceted control signals to regulate behaviour.

White matter fibre density in the brain's inhibitory control network is associated with falling in low activity older adults.

Recent research has indicated that the relationship between age-related cognitive decline and falling may be mediated by the individual's capacity to quickly cancel or inhibit a motor response. This longitudinal investigation demonstrates that higher white matter fibre density in the motor inhibition network paired with low physical activity was associated with falling in elderly participants. We measured the density of white matter fibre tracts connecting key nodes in the inhibitory control network in a large sample (n = 414) of older adults. We modelled their self-reported frequency of falling over a 4-year period with white matter fibre density in pathways corresponding to the direct and hyperdirect cortical-subcortical loops implicated in the inhibitory control network. Only connectivity between right inferior frontal gyrus and right subthalamic nucleus was associated with falling as measured cross-sectionally. The connectivity was not, however, predictive of future falling when measured 2 and 4 years later. Higher white matter fibre density was associated with falling, but only in combination with low levels of physical activity. No such relationship existed for selected control brain regions that are not implicated in the inhibitory control network. Albeit statistically robust, the direction of this effect was counterintuitive (more dense connectivity associated with falling) and warrants further longitudinal investigation into whether white matter fibre density changes over time in a manner correlated with falling, and mediated by physical activity.

Domain-general cognitive control processes in bilingual switching: Evidence from midfrontal theta oscillations.

Language control in bilingual speakers is thought to be implicated in effectively switching between languages, inhibiting the non-intended language, and continuously monitoring what to say and what has been said. It has been a matter of controversy concerning whether language control operates in a comparable manner to cognitive control processes in non-linguistic domains (domain-general) or if it is exclusive to language processing (domain-specific). As midfrontal theta oscillations have been considered as an index of cognitive control, examining whether a midfrontal theta effect is evident in tasks requiring bilingual control could bring new insights to the ongoing debate. To this end, we reanalysed the EEG data from two previous bilingual production studies where Dutch-English bilinguals named pictures based on colour cues. Specifically, we focused on three fundamental control processes in bilingual production: switching between languages, inhibition of the nontarget language, and monitoring of speech errors. Theta power increase was observed in switch trials compared to repeat trials, with a midfrontal scalp distribution. However, no theta power difference was observed in switch trials following a shorter sequence of same-language trials compared to a longer sequence, suggesting a missing modulation of inhibitory control. Similarly, increased midfrontal theta power was observed when participants failed to switch to the intended language compared to correct responses. Altogether, these findings tentatively support the involvement of domain-general cognitive control mechanisms in bilingual switching.

An event-related potential study of prepotent motor activity and response inhibition deficits in schizophrenia.

Response inhibition deficits in schizophrenia (SZ) are accompanied by reduced neural activities using event-related potential (ERP) measurements. However, it remains unclear whether the reduction in inhibition-related ERPs in SZ is contingent upon prepotent motor tendencies. This study aimed to examine the relationship between ERP markers of prepotent motor activity (lateralised readiness potential, LRP) and response inhibition (P3) by collecting behavioural and EEG data from healthy control (HC) subjects and SZ patients during a modified Go/No-Go task. A trial-averaged analysis revealed that SZ patients made more commission errors in No-Go trials compared with HC subjects, although there was no significant difference in the inhibition-related P3 effect (i.e. larger P3 amplitudes in No-Go compared with Go trials) between the two groups. Subsequently, No-Go trials were sorted and median-split into bins of stronger and weaker motor tendencies. Both HC and SZ participants made more commission errors when faced with stronger motor tendencies. The LRP-sorted P3 data indicated that HC subjects exhibited larger P3 effects in response to stronger motor tendencies, whereas this trial-by-trial association between P3 and motor tendencies was absent in SZ patients. Furthermore, SZ patients displayed diminished P3 effects in No-Go trials with stronger motor tendencies but not in trials with weaker motor tendencies, relative to HC subjects. Taken together, these findings suggest that SZ patients are unable to dynamically adjust inhibition-related neural activities in response to changing inhibitory control demands and emphasise the importance of considering prepotent motor activity when investigating the neural mechanisms underlying response inhibition deficits in SZ.

Left OFC Activation in Functional Near-Infrared Spectroscopy during an Inhibitory Control Task in an Early Years Sample: Integrating Stress Responses with Cognitive Function and Brain Activation.

INTRODUCTION: Previous functional near-infrared spectroscopy (fNIRS) studies using Go/No-Go (GNG) tasks have focused on brain activation in relation to cognitive processes, particularly inhibitory control (IC). The results of these studies commonly describe right hemispheric engagement of the dorsolateral, ventromedial, or inferior frontal regions of the prefrontal cortex. Considering that typical healthy cognitive development is negatively correlated with higher cortisol levels (which may alter brain development), the overarching aim of the current study was to investigate how elevated stress (due to unforeseeable events such as the pandemic) impacts early cognitive development. METHOD: In this study, we examined fNIRS data collected from a sample of children (aged 2-4 years) during a GNG task relative to the response to stressors measured via hair cortisol concentrations. We acquired data in an ecological setting (Early Childhood Education and Care) during the coronavirus pandemic. RESULTS: We found that children with higher stress levels and a less efficient IC recruited more neural terrain and our group-level analysis indicated activation in the left orbitofrontal area during IC performance. CONCLUSIONS: A contextual stressor may disrupt accuracy in the executive function of IC early in development. More research efforts are needed to understand better how an orbitofrontal network subserves goal-directed behavior.

Wild raccoons demonstrate flexibility and individuality in innovative problem-solving.

Cognitive skills, such as innovative problem-solving, are hypothesized to aid animals in urban environments. However, the significance of innovation in wild populations, and its expression across individuals and socio-ecological conditions, is poorly understood. To identify how and when innovation arises in urban-dwelling species, we used advanced technologies and new testing and analytical methods to evaluate innovative problem-solving abilities of wild raccoons (Procyon lotor). We deployed multi-compartment puzzle boxes with either one or multiple solution types and identified raccoons using radio frequency identification. Raccoons solved these novel extractive foraging tasks, and their success was influenced by age and exploratory diversity. Successful raccoons always discovered multiple different solution types, highlighting flexible problem-solving. Using a unique, comparative sequence analysis approach, we found that variation in raccoon solving techniques was greater between individuals than within individuals, and this self-similarity intensified during times of competition. Finally, the inclusion of an easier solution in the multi-solution trials enabled previously unsuccessful raccoons to bootstrap their learning and successfully open multiple difficult solutions. Our study suggests that innovative problem-solving is probably influenced by many factors and has provided novel field and analytical methods, as well as new insights on the socio-ecological dynamics of urban populations.

Cognitive Correlates of Risky Decision-Making in Individuals with and without ADHD: A Meta-analysis.

This meta-analytic study aims to investigate the cognitive correlates of risky decision-making in individuals with attention-deficit/hyperactivity disorder (ADHD) and typically developing (TD) individuals. A systematic analysis of existing literature was conducted, encompassing 38 studies (496 ADHD and 1493 TD). Findings revealed a consistent propensity for riskier decision-making in individuals with ADHD, supported by significant correlations with attention, cognitive flexibility, inhibitory control, time perception, and working memory. The study underscores the relevance of these cognitive functions in shaping decision-making tendencies, with nuanced patterns observed within the ADHD and TD subgroups. Individuals with ADHD often demonstrate altered patterns of correlation, reflecting the specific cognitive challenges characteristic of the disorder.

The Ability to Voluntarily Regulate Theta Band Activity Affects How Pharmacological Manipulation of the Catecholaminergic System Impacts Cognitive Control.

BACKGROUND: The catecholaminergic system influences response inhibition, but the magnitude of the impact of catecholaminergic manipulation is heterogeneous. Theoretical considerations suggest that the voluntary modulability of theta band activity can explain this variance. The study aimed to investigate to what extent interindividual differences in catecholaminergic effects on response inhibition depend on voluntary theta band activity modulation. METHODS: A total of 67 healthy adults were tested in a randomized, double-blind, cross-over study design. At each appointment, they received a single dose of methylphenidate or placebo and performed a Go/Nogo task with stimuli of varying complexity. Before the first appointment, the individual's ability to modulate theta band activity was measured. Recorded EEG data were analyzed using temporal decomposition and multivariate pattern analysis. RESULTS: Methylphenidate effects and voluntary modulability of theta band activity showed an interactive effect on the false alarm rates of the different Nogo conditions. The multivariate pattern analysis revealed that methylphenidate effects interacted with voluntary modulability of theta band activity at a stimulus processing level, whereas during response selection methylphenidate effects interacted with the complexity of the Nogo condition. CONCLUSIONS: The findings reveal that the individual's theta band modulability affects the responsiveness of an individual's catecholaminergic system to pharmacological modulation. Thus, the impact of pharmacological manipulation of the catecholaminergic system on cognitive control most likely depends on the existing ability to self-modulate relevant brain oscillatory patterns underlying the cognitive processes being targeted by pharmacological modulations.

Distinct Inhibitory-Control Processes Underlie Children's Judgments of Fairness.

We examined how 5- to 8-year-olds (N = 51; Mage = 83 months; 27 female, 24 male; 69% White, 12% Black/African American, 8% Asian/Asian American, 6% Hispanic, 6% not reported) and adults (N = 18; Mage = 20.13 years; 11 female, 7 male) accepted or rejected different distributions of resources between themselves and others. We used a reach-tracking method to track finger movement in 3D space over time. This allowed us to dissociate two inhibitory processes. One involved pausing motor responses to detect conflict between observed information and how participants thought resources should be divided; the other involved resolving the conflict between the response and the alternative. Reasoning about disadvantageous inequities involved more of the first system, and this was stable across development. Reasoning about advantageous inequities involved more of the second system and showed more of a developmental progression. Generally, reach tracking offers an on-line measure of inhibitory control for the study of cognition.

Multivariate Assessment of Inhibitory Control in Youth: Links With Psychopathology and Brain Function.

Inhibitory control is central to many theories of cognitive and brain development, and impairments in inhibitory control are posited to underlie developmental psychopathology. In this study, we tested the possibility of shared versus unique associations between inhibitory control and three common symptom dimensions in youth psychopathology: attention-deficit/hyperactivity disorder (ADHD), anxiety, and irritability. We quantified inhibitory control using four different experimental tasks to estimate a latent variable in 246 youth (8-18 years old) with varying symptom types and levels. Participants were recruited from the Washington, D.C., metro region. Results of structural equation modeling integrating a bifactor model of psychopathology revealed that inhibitory control predicted a shared or general psychopathology dimension, but not ADHD-specific, anxiety-specific, or irritability-specific dimensions. Inhibitory control also showed a significant, selective association with global efficiency in a frontoparietal control network delineated during resting-state functional magnetic resonance imaging. These results support performance-based inhibitory control linked to resting-state brain function as an important predictor of comorbidity in youth psychopathology.

Abnormalities of the Descending Inhibitory Nociceptive Pathway in Functional Motor Disorders.

BACKGROUND: Pain is a common disabling non-motor symptom affecting patients with functional motor disorders (FMD). OBJECTIVE: We aimed to explore ascending and descending nociceptive pathways with laser evoked potentials (LEPs) in FMD. METHODS: We studied a "bottom-up and top-down" noxious paradigm applying a conditioned pain modulation (CPM) protocol and recorded N2/P2 amplitude in 21 FMD and 20 controls following stimulation of both right arm and leg at baseline (BS) (bottom-up), during heterotopic noxious conditioning stimulation (HNCS) with ice test (top-down) and post-HNCS. RESULTS: We found a normal ascending pathway, but reduced CPM response (lower reduction of the N2/P2 amplitude) in FMD patients, by stimulating both upper and lower limbs. The N2/P2 amplitude ratio*100 (between the HNCS and BS) was significantly higher in patients with FMD than HC. CONCLUSIONS: Our results suggest that pain in FMD possibly reflects a descending pain inhibitory control impairment, therefore, providing a novel venue to explore the pathophysiology of pain in FMD. © 2024 International Parkinson and Movement Disorder Society.