Neural correlates of transfer of learning in motor coordination tasks: role of inhibitory and excitatory neurometabolites.

We aimed to investigate transfer of learning, whereby previously acquired skills impact new task learning. While it has been debated whether such transfer may yield positive, negative, or no effects on performance, very little is known about the underlying neural mechanisms, especially concerning the role of inhibitory (GABA) and excitatory (Glu) (measured as Glu + glutamine (Glx)) neurometabolites, as measured by magnetic resonance spectroscopy (MRS). Participants practiced a bimanual coordination task across four days. The Experimental group trained a task variant with the right hand moving faster than the left (Task A) for three days and then switched to the opposite variant (Task B) on Day4. The control group trained Task B across four days. MRS data were collected before, during, and after task performance on Day4 in the somatosensory (S1) and visual (MT/V5) cortex. Results showed that both groups improved performance consistently across three days. On Day4, the Experimental group experienced performance decline due to negative task transfer while the control group continuously improved. GABA and Glx concentrations obtained during task performance showed no significant group-level changes. However, individual Glx levels during task performance correlated with better (less negative) transfer performance. These findings provide a first window into the neurochemical mechanisms underlying task transfer.

Baseline GABA+ levels in areas associated with sensorimotor control predict initial and long-term motor learning progress.

Synaptic plasticity relies on the balance between excitation and inhibition in the brain. As the primary inhibitory and excitatory neurotransmitters, gamma-aminobutyric acid (GABA) and glutamate (Glu), play critical roles in synaptic plasticity and learning. However, the role of these neurometabolites in motor learning is still unclear. Furthermore, it remains to be investigated which neurometabolite levels from the regions composing the sensorimotor network predict future learning outcome. Here, we studied the role of baseline neurometabolite levels in four task-related brain areas during different stages of motor skill learning under two different feedback (FB) conditions. Fifty-one healthy participants were trained on a bimanual motor task over 5 days while receiving either concurrent augmented visual FB (CA-VFB group, N = 25) or terminal intrinsic visual FB (TA-VFB group, N = 26) of their performance. Additionally, MRS-measured baseline GABA+ (GABA + macromolecules) and Glx (Glu + glutamine) levels were measured in the primary motor cortex (M1), primary somatosensory cortex (S1), dorsolateral prefrontal cortex (DLPFC), and medial temporal cortex (MT/V5). Behaviorally, our results revealed that the CA-VFB group outperformed the TA-VFB group during task performance in the presence of augmented VFB, while the TA-VFB group outperformed the CA-VFB group in the absence of augmented FB. Moreover, baseline M1 GABA+ levels positively predicted and DLPFC GABA+ levels negatively predicted both initial and long-term motor learning progress in the TA-VFB group. In contrast, baseline S1 GABA+ levels positively predicted initial and long-term motor learning progress in the CA-VFB group. Glx levels did not predict learning progress. Together, these findings suggest that baseline GABA+ levels predict motor learning capability, yet depending on the FB training conditions afforded to the participants.

Neurological soft signs are associated with reduced medial-lateral postural control in adolescent athletes.

INTRODUCTION: Neurological soft signs (NSS) are minor deviations from the norm in motor performance that are commonly assessed using neurological examinations. NSS may be of clinical relevance for evaluating the developmental status of adolescents. Here we investigate whether quantitative force plate measures may add relevant information to observer-based neurological examinations. METHODS: Male adolescent athletes (n = 141) aged 13-16 years from three European sites underwent a neurological examination including 28 tests grouped into six functional clusters. The performance of tests and functional clusters was rated as optimal/non-optimal resulting in NSS+/NSS- groups and a continuous total NSS score. Participants performed a postural control task on a Balance Tracking System measured as path length, root mean square and sway area. ANCOVAs were applied to test for group differences in postural control between the NSS+ and NSS- group, and between optimal/non-optimal performance on a cluster- and test-level. Moreover, we tested for correlations between the total NSS score and postural control variables. RESULTS: There was no significant overall difference between the NSS+ and NSS- group in postural control. However, non-optimal performing participants in the diadochokinesis test swayed significantly more in the medial-lateral direction than optimal performing participants. Moreover, a lower total NSS score was associated with reduced postural control in the medial-lateral direction. CONCLUSION: Our findings demonstrate that NSS are related to postural control in adolescent athletes. Thus, force plate measures may add a quantitative, objective measurement of postural control to observer-based qualitative assessments, and thus, may complement clinical testing.

Neurological soft signs in adolescents are associated with brain structure.

Neurological soft signs (NSS) are minor deviations in motor performance. During childhood and adolescence, NSS are examined for functional motor phenotyping to describe development, to screen for comorbidities, and to identify developmental vulnerabilities. Here, we investigate underlying brain structure alterations in association with NSS in physically trained adolescents. Male adolescent athletes (n = 136, 13-16 years) underwent a standardized neurological examination including 28 tests grouped into 6 functional clusters. Non-optimal performance in at least 1 cluster was rated as NSS (NSS+ group). Participants underwent T1- and diffusion-weighted magnetic resonance imaging. Cortical volume, thickness, and local gyrification were calculated using Freesurfer. Measures of white matter microstructure (Free-water (FW), FW-corrected fractional anisotropy (FAt), axial and radial diffusivity (ADt, RDt)) were calculated using tract-based spatial statistics. General linear models with age and handedness as covariates were applied to assess differences between NSS+ and NSS- group. We found higher gyrification in a large cluster spanning the left superior frontal and parietal areas, and widespread lower FAt and higher RDt compared with the NSS- group. This study shows that NSS in adolescents are associated with brain structure alterations. Underlying mechanisms may include alterations in synaptic pruning and axon myelination, which are hallmark processes of brain maturation.

Inhibition, Shifting and Updating: Inter and intra-domain commonalities and differences from an executive functions activation likelihood estimation meta-analysis.

Executive functions are higher-order mental processes that support goal-directed behavior. Among these processes, Inhibition, Updating, and Shifting have been considered core executive domains. In this meta-analysis, we comprehensively investigate the neural networks of these executive domains and we synthesize for the first time the neural convergences and divergences among the most frequently used executive paradigms within those domains. A systematic search yielded 1055 published neuroimaging studies (including 26,191 participants in total). Our study revealed that a fronto-parietal network was shared by the three main domains. Furthermore, we executed conjunction analyses among the paradigms of the same domain to extract the core distinctive components of the main executive domains. This approach showed that Inhibition and Shifting are characterized by a strongly lateralized neural activation in the right and left hemisphere, respectively. In addition, both networks overlapped with the Updating network but not with each other. Remarkably, our study detected heterogeneity among the paradigms from the same domain. More specifically, analysis of Inhibition tasks revealed differing activations for Response Inhibition compared to Interference Control paradigms, suggesting that Inhibition encompasses relatively heterogeneous sub-functions. Shifting analyses revealed a bilateral overlap of the Wisconsin Card Sorting Task with the Updating network, but this pattern was absent for Rule Switching and Dual Task paradigms. Moreover, our Updating meta-analyses revealed the neural signatures associated with the specific modules of the Working Memory model from Baddeley and Hitch. To our knowledge, this is the most comprehensive meta-analysis of executive functions to date. Its paradigm-driven analyses provide a unique contribution to a better understanding of the neural convergences and divergences among executive processes that are relevant for clinical applications, such as cognitive enhancement and neurorehabilitation interventions.

Bridging cognition and action: executive functioning mediates the relationship between white matter fiber density and complex motor abilities in older adults.

Aging may be associated with motor decline that is attributed to deteriorating white matter microstructure of the corpus callosum (CC), among other brain-related factors. Similar to motor functioning, executive functioning (EF) typically declines during aging, with age-associated changes in EF likewise being linked to altered white matter connectivity in the CC. Given that both motor and executive functions rely on white matter connectivity via the CC, and that bimanual control is thought to rely on EF, the question arises whether EF can at least party account for the proposed link between CC-connectivity and motor control in older adults. To address this, diffusion magnetic resonance imaging data were obtained from 84 older adults. A fiber-specific approach was used to obtain fiber density (FD), fiber cross-section (FC), and a combination of both metrics in eight transcallosal white matter tracts. Motor control was assessed using a bimanual coordination task. EF was determined by a domain-general latent EF-factor extracted from multiple EF tasks, based on a comprehensive test battery. FD of transcallosal prefrontal fibers was associated with cognitive and motor performance. EF partly accounted for the relationship between FD of prefrontal transcallosal pathways and motor control. Our results underscore the multidimensional interrelations between callosal white matter connectivity (especially in prefrontal brain regions), EF across multiple domains, and motor control in the older population. They also highlight the importance of considering EF when investigating brain-motor behavior associations in older adults.

Cognition and action: a latent variable approach to study contributions of executive functions to motor control in older adults.

Aging is associated with profound alterations in motor control that may be exacerbated by age-related executive functioning decline. Executive functions span multiple facets including inhibition (suppressing unwanted response tendencies), shifting (switching between cognitive operations), and updating (managing working memory content). However, comprehensive studies regarding the contributions of single facets of executive functioning to movement control in older adults are still lacking. A battery of nine neuropsychological tasks was administered to n = 92 older adults in order to derive latent factors for inhibition, shifting, and updating by structural equation modeling. A bimanual task was used to assess complex motor control. A sample of n = 26 young adults served as a control group to verify age-related performance differences. In older adults, structural equation models revealed that performance on the most challenging condition of the complex motor task was best predicted by the updating factor and by general executive functioning performance. These data suggest a central role for working memory updating in complex motor performance and contribute to our understanding of how individual differences in executive functioning relate to movement control in older adults.

Evaluating the validity of self-report as a method for quantifying heading exposure in male youth soccer.

Assessing heading exposure in football is important when exploring the association between heading and brain alterations. To this end, questionnaires have been developed for use in adult populations. However, the validity of self-report in adolescents remains to be elucidated. Male youth soccer players (n = 34) completed a questionnaire on heading exposure after a two-week period, which included matches and training sessions. Self-reported numbers were compared to observation (considered reference). In total, we observed 157 training sessions and 64 matches. Self-reported heading exposure correlated with observed heading exposure (Spearman's rho 0.68; p < 0.001). Players systematically overestimated their heading exposure by a factor of 3 with the random error of 46%. Area under the curve was 0.87 (95% CI 0.67-1) utilizing self-report for identifying players from high- and low-exposure groups. Thus, in this study, self-reported data could be used to group youth players into high and low heading exposure groups, but not to quantify individual heading exposure.

Dopaminergic modulation of novelty repetition in Parkinson's disease: A study of P3 event-related brain potentials.

OBJECTIVE: Parkinson's Disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic neurons. Cognitive impairments have been reported using the event-related potential (ERP) technique. Patients show reduced novelty P3 (nP3) amplitudes in oddball experiments, a response to infrequent, surprising stimuli, linked to the orienting response of the brain. The nP3 is thought to depend on dopaminergic neuronal pathways though the effect of dopaminergic medication in PD has not yet been investigated. METHODS: Twenty-two patients with PD were examined "on" and "off" their regular dopaminergic medication in a novelty 3-stimulus-oddball task. Thirty-four healthy controls were also examined over two sessions, but received no medication. P3 amplitudes were compared throughout experimental conditions. RESULTS: All participants showed sizeable novelty difference ERP effects, i.e. ndP3 amplitudes, during both testing sessions. An interaction of diagnosis, medication and testing order was also found, indicating that dopaminergic medication modulated ndP3 in patients with PD across the two testing sessions: We observed enhanced ndP3 amplitudes from PD patients who were off medication on the second testing session. CONCLUSION: Patients with PD 'off' medication showed ERP evidence for repetition-related enhancement of novelty responses. Dopamine depletion in neuronal pathways that are affected by mid-stage PD possibly accounts for this modulation of novelty processing. SIGNIFICANCE: The data in this study potentially suggest that repetition effects on novelty processing in patients with PD are enhanced by dopaminergic depletion.

A Computational Study of Executive Dysfunction in Amyotrophic Lateral Sclerosis.

Executive dysfunction is a well-documented, yet nonspecific corollary of various neurological diseases and psychiatric disorders. Here, we applied computational modeling of latent cognition for executive control in amyotrophic lateral sclerosis (ALS) patients. We utilized a parallel reinforcement learning model of trial-by-trial Wisconsin Card Sorting Test (WCST) behavior. Eighteen ALS patients and 21 matched healthy control participants were assessed on a computerized variant of the WCST (cWCST). ALS patients showed latent cognitive symptoms, which can be characterized as bradyphrenia and haphazard responding. A comparison with results from a recent computational Parkinson's disease (PD) study (Steinke et al., 2020, J Clin Med) suggests that bradyphrenia represents a disease-nonspecific latent cognitive symptom of ALS and PD patients alike. Haphazard responding seems to be a disease-specific latent cognitive symptom of ALS, whereas impaired stimulus-response learning seems to be a disease-specific latent cognitive symptom of PD. These data were obtained from the careful modeling of trial-by-trial behavior on the cWCST, and they suggest that computational cognitive neuropsychology provides nosologically specific indicators of latent facets of executive dysfunction in ALS (and PD) patients, which remain undiscoverable for traditional behavioral cognitive neuropsychology. We discuss implications for neuropsychological assessment, and we discuss opportunities for confirmatory computational brain imaging studies.

Computational Modeling for Neuropsychological Assessment of Bradyphrenia in Parkinson's Disease.

The neural mechanisms of cognitive dysfunctions in neurological diseases remain poorly understood. Here, we conjecture that this unsatisfying state-of-the-art is in part due to the non-specificity of the typical behavioral indicators for cognitive dysfunctions. Our study addresses the topic by advancing the assessment of cognitive dysfunctions through computational modeling. We investigate bradyphrenia in Parkinson's disease (PD) as an exemplary case of cognitive dysfunctions in neurological diseases. Our computational model conceptualizes trial-by-trial behavioral data as resulting from parallel cognitive and sensorimotor reinforcement learning. We assessed PD patients 'on' and 'off' their dopaminergic medication and matched healthy control (HC) participants on a computerized version of the Wisconsin Card Sorting Test. PD patients showed increased retention of learned cognitive information and decreased retention of learned sensorimotor information from previous trials in comparison to HC participants. Systemic dopamine replacement therapy did not remedy these cognitive dysfunctions in PD patients but incurred non-desirable side effects such as decreasing cognitive learning from positive feedback. Our results reveal novel insights into facets of bradyphrenia that are indiscernible by observable behavioral indicators of cognitive dysfunctions. We discuss how computational modeling may contribute to the advancement of future research on brain-behavior relationships and neuropsychological assessment.

Flanker Task Performance in Isolated Dystonia (Blepharospasm): A Focus on Sequential Effects.

Isolated dystonia manifests with involuntary muscle hyperactivity, but the extent of cognitive impairment remains controversial. We examined the executive functions in blepharospasm while accounting for motor symptom-related distractions as a factor often limiting the interpretability of neuropsychological studies in dystonia. Our control group comprised of patients with hemifacial spasm, which is a condition producing similar motor symptoms without any central nervous system pathology. Nineteen patients with blepharospasm and 22 patients with hemifacial spasm completed a flanker task. Stimulus congruency on the current trial, on the preceding trial, and a response sequence served as independent variables. We analyzed the response time and accuracy. Gross overall group differences were not discernible. While congruency, congruency sequence, and response sequence exerted the expected effects, no group differences emerged with regard to these variables. A difference between patients with blepharospasm and those with hemifacial spasm consisted in longer reaction times when responses had to be repeated following stimulus incongruency on the preceding trial. We conclude that patients with blepharospasm seem to have difficulties in repeating their responses when incongruency on preceding trials interferes with habit formation or other forms of fast routes to action. Our specific finding may provide an opportunity to study altered basal ganglia plasticity in focal dystonia.

Neural correlates of performance monitoring in adult patients with Gilles de la Tourette syndrome: A study of event-related potentials.

OBJECTIVES: Gilles de la Tourette syndrome (GTS) is a neuropsychiatric condition characterized by motor and vocal tics. There is undoubtedly basal ganglia involvement, which are also important for cognitive processes including performance monitoring and interference resolution. We investigated these functions in adult patients with GTS compared to healthy controls (HCs). METHODS: We compared a group of N = 23 adult patients with GTS to N = 27 HC on a flanker task during an EEG recording. Reaction times and error rates were recorded, as well as N2 and Ne/ERN amplitudes. The N2 is an index of interference resolution. The Ne/ERN is a negative fronto-central component, occurring when participants make mistakes. RESULTS: Patients' reaction times were enhanced on incongruent trials compared to HC. Electrophysiological data revealed more frontal components, as well as significantly increased Ne/ERN amplitudes in patients with GTS compared to HC (p = 0.026). CONCLUSIONS: Altered electrophysiological correlates of error processing in adult patients with GTS compared to HC cannot be attributed to differential error probabilities. Potentially, patients recruit compensatory resources from frontal networks to maintain behavioural performance. SIGNIFICANCE: This study gives further insight into cognitive deficits of patients with GTS, and the underlying neural processes of these functions.

Stimulus- and response-based interference contributes to the costs of switching between cognitive tasks.

Little is known about how stimulus- and response-based interference might interact to contribute to the costs of switching between cognitive tasks. We analyzed switch costs in a novel cued task-switching/card-matching paradigm in a large study (N = 95). We reasoned that interference from previously active task sets may be contingent upon the retrieval of these task sets via stimulus processing, or alternatively, via response processing. We examined the efficacy of these two factors through eligibility manipulations. That is, stimulus/response features that were capable of retrieving task sets from the previous trial remained eligible (or not) on the current trial. We report three main findings: first, no switch costs were found when neither stimulus features, nor response features, were adequate for the retrieval of the previously executed task sets. Second, we found substantial switch costs when, on switch trials, stimulus features kept the previously executed task eligible, and we found roughly equivalent switch costs when the previously executed response remained eligible. Third, evidence for stimulus-induced switch costs was exclusively observed when previously executed responses remained ineligible. These data indicate that stimulus-based interference, and of importance, response-based interference, contribute comparably to switch costs. Possible interpretations of non-additive switch costs are discussed.

Effects of rule uncertainty on cognitive flexibility in a card-sorting paradigm.

Cognitive flexibility has been studied in two separate research traditions. Neuropsychologists typically rely on rather complex assessment tools such as the Wisconsin Card Sorting Test (WCST). In contrast, task-switching paradigms are used in experimental psychology to obtain more specific measures of cognitive flexibility. We aim to contribute to the integration of these research traditions by examining the role of the key factor that differs between the WCST and experimental task-switching paradigms: rule uncertainty. In two experimental studies, we manipulated the degree of rule uncertainty after rule switches in a computerized version of the WCST. Across a variety of task parameters, reducing rule uncertainty consistently impaired the speed and accuracy of responses when the rule designated to be more likely turned out to be incorrect. Other performance measures such as the number of perseverative errors were not significantly affected by rule uncertainty. We conclude that a fine-grained analysis of WCST performance can dissociate behavioural indicators that are affected vs. unaffected by rule uncertainty. By this means, it is possible to integrate WCST results and findings obtained from task-switching paradigms that do not involve rule uncertainty.

Executive dysfunction in Parkinson's disease: A meta-analysis on the Wisconsin Card Sorting Test literature.

Executive dysfunctions are a frequently described non-motor symptom in patients with Parkinsonös disease (PD). However, the nature, extent, variability, and determinants of executive dysfunctions in PD are still poorly understood. To improve the characterization of executive dysfunctions in PD, we conducted a meta-analysis of the studies administering the Wisconsin Card Sorting Test (WCST) to patients with PD and healthy controls. We included k = 161 studies, which allowed us to precisely estimate the size of PD-related WCST deficits and to run powerful tests for potential moderators of these deficits. We found robust WCST deficits in PD, which were medium-to-large in size. These deficits were most pronounced in patients tested after withdrawal from dopaminergic medication and in samples characterized by severe motor impairment and long disease duration. Substantial WCST impairment was also detected in non-demented, non-depressed, and never-medicated patients with PD as well as after conservatively correcting for publication bias. Based on these findings, impaired WCST performance can be considered as a major hallmark of executive dysfunction in PD.

Cognitive flexibility in neurological disorders: Cognitive components and event-related potentials.

Performance deficits on the Wisconsin Card Sorting Test (WCST) in patients with prefrontal cortex (PFC) lesions are traditionally interpreted as evidence for a role of the PFC in cognitive flexibility. However, WCST deficits do not occur exclusively after PFC lesions, but also in various neurological and psychiatric disorders. We propose a multi-component approach that can accommodate this pattern of omnipresent WCST deficits: the WCST is not a pure test of cognitive flexibility, but relies on the effective functioning of multiple dissociable cognitive components. Our review of recent efforts to decompose WCST performance deficits supports this view by revealing that WCST deficits in different neurological disorders can be attributed to alterations in different components. Frontoparietal changes underlying impaired set shifting seem to give rise to WCST deficits in patients with amyotrophic lateral sclerosis, whereas the WCST deficits associated with primary dystonia and Parkinson's disease are rather related to frontostriatal changes underlying deficient rule inference. Clinical implications of these findings and of a multi-component view of WCST performance are discussed.

Cognitive flexibility and its electrophysiological correlates in Gilles de la Tourette syndrome.

Motor symptoms in Gilles de la Tourette syndrome (GTS) have been related to changes in frontostriatal brain networks. These changes may also give rise to alterations in cognitive flexibility. However, conclusive evidence for altered cognitive flexibility in patients with GTS is still lacking. Here, we meta-analyzed data from 20 neuropsychological studies that investigated cognitive flexibility in GTS using the Wisconsin Card Sorting Test (WCST). Results revealed medium-sized GTS-related performance deficits, which were significantly modulated by age: Whilst being substantial in children and adolescents with GTS, WCST deficits seem to dissolve in adult patients with GTS. This age-related normalization of WCST performance might result from the compensatory recruitment of cognitive control in adult patients with GTS. We addressed this possibility by examining neural correlates of proactive and reactive cognitive control in an event-related potential (ERP) study. We analyzed cue- and target-locked ERPs from 23 adult patients with GTS and 26 matched controls who completed a computerized version of the WCST. Compared to controls, patients with GTS showed a marked increase in parietal cue-locked P3 activity, indicating enhanced proactive cognitive control. We conclude that the additional recruitment of proactive cognitive control might ensure flexible cognitive functioning in adult patients with GTS.

Attenuated error-related potentials in amyotrophic lateral sclerosis with executive dysfunctions.

OBJECTIVE: Executive dysfunctions affect up to 50% of the patients with amyotrophic lateral sclerosis (ALS). Executive dysfunctions have been identified as negative prognostic factor and can affect quality of life in patients and their caregivers. Assessment of executive dysfunction may be impeded by the patients' motor impairments. Event-related potentials (ERP) have been proposed as a tool to overcome these assessment difficulties. The error(-related) negativity (Ne/ERN) is an ERP which can be recorded with minimal motor requirements for the patient. METHODS: We compared response-synchronized ERP amplitudes of 18 ALS patients and 19 healthy controls (HC) obtained on error trials on a flanker task. We also evaluated the relation between Ne/ERN amplitudes and executive functions as assessed by standardized neuropsychological measures. RESULTS: While response-synchronized ERP amplitudes were generally unaffected by ALS, we found an ALS-associated relation between Ne/ERN amplitudes and executive functions. ALS patients with poorer executive functioning showed attenuated Ne/ERN amplitudes. CONCLUSIONS: Our data suggest that Ne/ERN amplitudes reflect ALS-associated impairment of executive functions, potentially due to disturbances in neural networks that involve the anterior cingulate cortex. SIGNIFICANCE: Assessment of Ne/ERN amplitudes might provide a cost-efficient and non-invasive marker for executive dysfunction in ALS.

Dopaminergic modulation of performance monitoring in Parkinson's disease: An event-related potential study.

Monitoring one's actions is essential for goal-directed performance. In the event-related potential (ERP), errors are followed by fronto-centrally distributed negativities. These error(-related) negativity (Ne/ERN) amplitudes are often found to be attenuated in patients with Parkinson's disease (PD) compared to healthy controls (HC). Although Ne/ERN has been proposed to be related to dopaminergic neuronal activity, previous research did not find evidence for effects of dopaminergic medication on Ne/ERN amplitudes in PD. We examined 13 PD patients "on" and "off" dopaminergic medication. Their response-locked ERP amplitudes (obtained on correct [Nc/CRN] and error [Ne/ERN] trials of a flanker task) were compared to those of 13 HC who were tested twice as well, without receiving dopaminergic medication. While PD patients committed more errors than HC, error rates were not significantly modulated by dopaminergic medication. PD patients showed reduced Ne/ERN amplitudes relative to HC; however, this attenuation of response-locked ERP amplitudes was not specific to errors in this study. PD-related attenuation of response-locked ERP amplitudes was most pronounced when PD patients were on medication. These results suggest overdosing of dopaminergic pathways that are relatively spared in PD, but that are related to the generation of the Ne/ERN, notably pathways targeted on the medial prefrontal cortex.