Large-scale functional neural network correlates of response inhibition: an fMRI meta-analysis

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Effects of transcranial magnetic stimulation on reactive response inhibition

Reactive response inhibition cancels impending actions to enable adaptive behavior in ever-changing environments and has wide neuropsychiatric implications. A canonical paradigm to measure the covert inhibition latency is the stop-signal task (SST). To probe the cortico-subcortical network underlying motor inhibition, transcranial magnetic stimulation (TMS) has been applied over central nodes to modulate SST performance, especially to the right inferior frontal cortex and the presupplementary motor area. Since the vast parameter spaces of SST and TMS enabled diverse implementations, the insights delivered by emerging TMS-SST studies remain inconclusive. Therefore, a systematic review was conducted to account for variability and synthesize converging evidence. Results indicate certain protocol specificity through the consistent perturbations induced by online TMS, whereas offline protocols show paradoxical effects on different target regions besides numerous null effects. Ancillary neuroimaging findings have verified and dissociated the underpinning network dynamics. Sources of heterogeneity in designs and risk of bias are highlighted. Finally, we outline best-practice recommendations to bridge methodological gaps and subserve the validity as well as replicability of future work.</p

An EEG Source-Space Analysis of the Neural Correlates Underlying Self-Regulation

Self-regulation is the cognitive process of controlling our thoughts and behaviors to be aligned with our goals. This process is used in many different contexts and has been associated with contributions from several brain regions. This research aimed to investigate differences in four prefrontal areas of the brain while participants applied four different self-regulation strategies. We recorded EEG while participants (N = 132) performed three tasks which engaged each of the four self-regulation strategies: the AX-CPT task engaged proactive and reactive control, the Go/Nogo task engaged inhibitory control, and the hybrid Flanker Global/Local task engaged the resolution of response conflict. This study used the N2 event-related potential (ERP) to capture the neural activity related to each self-regulation strategy and then source-space analyses (eLORETA) were conducted to estimate the activity in four regions of interest (ROIs): dorsolateral (DL) PFC, ventrolateral (VL) PFC, ventromedial (VM) PFC, and dorsal ACC. The dorsal ACC was most activated for proactive control, indicative of performance monitoring. The right VLPFC was indicative of conflict adaptation in reactive control and response conflict, and indicative of motor inhibition in inhibitory control. DLPFC was most active for goal maintenance during proactive and reactive control. The left VLPFC was most active during reactive control, indicating its importance in memory of goal information. These results are in line with much of the previous literature. VMPFC did not show any differences across the strategies likely due to the lack of emotional context. This study builds on the extant literature by directly comparing neural processes across four different self-regulation strategies within one large sample, highlighting the fact that various self-regulation strategies recruit unique patterns of activation and thus future research should not collapse across these strategies

Action control in uncertain environments

A long-standing dichotomy in neuroscience pits automatic or reflexive drivers of behaviour against deliberate or reflective processes. In this thesis I explore how this concept applies to two stages of action control: decision-making and response inhibition. The first part of this thesis examines the decision-making process itself during which actions need to be selected that maximise rewards. Decisions arise through influences from model-free stimulus-response associations as well as model-based, goal-directed thought. Using a task that quantifies their respective contributions, I describe three studies that manipulate the balance of control between these two systems. I find that a pharmacological manipulation with levodopa increases model-based control without affecting model-free function; disruption of dorsolateral prefrontal cortex via magnetic stimulation disrupts model-based control; and direct current stimulation to the same prefrontal region has no effect on decision-making. I then examine how the intricate anatomy of frontostriatal circuits subserves reinforcement learning using functional, structural and diffusion magnetic resonance imaging (MRI). A second stage of action control discussed in this thesis is post-decision monitoring and adjustment of action. Specifically, I develop a response inhibition task that dissociates reactive, bottom-up inhibitory control from proactive, top-down forms of inhibition. Using functional MRI I show that, unlike the strong neural segregation in decision-making systems, neural mechanisms of reactive and proactive response inhibition overlap to a great extent in their frontostriatal circuitry. This leads to the hypothesis that neural decline, for 4 example in the context of ageing, might affect reactive and proactive control similarly. I test this in a large population study administered through a smartphone app. This shows that, against my prediction, reactive control reliably declines with age but proactive control shows no such decline. Furthermore, in line with data on gender differences in age-related neural degradation, reactive control in men declines faster with age than that of women

Motivational context for response inhibition influences proactive involvement of attention

Motoric inhibition is ingrained in human cognition and implicated in pervasive neurological diseases and disorders. The present electroencephalographic (EEG) study investigated proactive motivational adjustments in attention during response inhibition. We compared go-trial data from a stop-signal task, in which infrequently presented stop-signals required response cancellation without extrinsic incentives ("standard-stop"), to data where a monetary reward was posted on some stop-signals ("rewarded-stop"). A novel EEG analysis was used to directly model the covariation between response time and the attention-related N1 component. A positive relationship between response time and N1 amplitudes was found in the standard-stop context, but not in the rewarded-stop context. Simultaneously, average go-trial N1 amplitudes were larger in the rewarded-stop context. This suggests that down-regulation of go-signal-directed attention is dynamically adjusted in the standard-stop trials, but is overridden by a more generalized increase in attention in reward-motivated trials. Further, a diffusion process model indicated that behavior between contexts was the result of partially opposing evidence accumulation processes. Together these analyses suggest that response inhibition relies on dynamic and flexible proactive adjustments of low-level processes and that contextual changes can alter their interplay. This could prove to have ramifications for clinical disorders involving deficient response inhibition and impulsivity

Tourette Syndrome: Electrophysiological Insights and Prospects for Deep Brain Stimulation

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by the presence of motor and vocal tics. The underlying pathophysiology of TS remains incompletely understood. Cognitive alterations in TS and their neural correlates can provide valuable insights into the clinical features and underlying pathophysiology. Deep Brain Stimulation (DBS) emerges a promising treatment avenue for patients with treatment-refractory TS. However, optimal DBS target selection remains controversial due to unclear differences in target-specific clinical effects and mechanisms of action. The primary objective of this dissertation was to conduct an extensive electrophysiological investigation into cognitive processes potentially contributing to tic occurrence. Using the task switching paradigm, various cognitive processes were examined, unraveling the complex cognitive foundations of TS and their neurophysiological correlates. While cognitive control and perceptual binding processes appear unchanged, individuals with TS exhibit significant alterations in the neural processes underlying perception-action binding. This highlights the pivotal role of the interplay between perceptual processes, such as the premonitory urge, and motor actions, such as tics, in understanding tic occurrence. The secondary objective focused on evaluating the efficacy of DBS in TS and systematically comparing target-specific clinical effects through a systematic review and meta-analysis. The findings reveal that DBS is generally an effective therapeutic option for TS, with pallidal DBS yielding the highest rates of improvement when compared to thalamic DBS. However, these results do not favor one target over another. Instead, they emphasize that no single DBS target can address the heterogeneous phenotypes and comorbidities in TS. Thus, personalized DBS target selection tailored to each patient's specific symptoms and characteristics becomes essential. Achieving this personalized precision approach requires a deeper understanding of biomarkers related to the underlying neurophysiological mechanisms driving tics in TS. This dissertation extensively discusses potential biomarkers for neuromodulation, encompassing neural mechanisms related to urges, perception-action binding, tic initiation, and tic control. In conclusion, this dissertation represents a crucial step towards an advanced comprehension of TS pathophysiology and the applications of DBS, thereby illuminating the path towards personalized stimulation-based treatment strategies, underlining the need for further research

Conduct Problems, Callous-Unemotional Traits and Emotion Processing: Adversity and Diversity, a Functional Neuroimaging Study

This thesis focused on youths who present with conduct problems (CP), callous-unemotional traits and functional neuroimaging. PART 1: A narrative review of current neuroimaging literature regarding youths with CP. Firstly, this review outlined general CP related considerations regarding neuroimaging literature and common CP risk factors before summarising structural neuroimaging literature. Functional neuroimaging research was then summarised using neurocognitive domains of functioning: acute threat response, social cognition, cognitive control and reinforcement learning. Findings were discussed with reference to how risk factors and neurocognitive functioning interact to produce behavioural syndromes associated with CP. Future CP related neuroimaging research should focus on domains of functioning and the influence of risk factors on heterogeneity. PART 2: A functional MRI study that used facial expressions (angry/sad/happy) to investigate neural differences in emotion processing amongst boys with CP split between high and low callous-unemotional (CU) traits, compared to matched controls. Findings highlighted perturbations in limbic, frontal, temporal and medial regions for both high and low CU trait boys compared to controls. CP boys demonstrated specific atypical activation in the amygdala, insula and prefrontal cortex when processing negative facial expressions and were associated with more severe pathological parenting practices than controls. Potential explanations and clinical implications were explored. PART 3: A critical appraisal of my learning regarding neuroimaging and youths with CP including my perspective from clinical practice. This appraisal focused on the theoretical, diagnostic, research, clinical and narrative implications of transitioning understandings of neural function from a behavioural, damaged and functionally specialised paradigm toward a dimensional, adapted and interrelated paradigm

Joint impact on attention, alertness and inhibition of lesions at a frontal white matter crossroad.

In everyday life, information from different cognitive domains - such as visuospatial attention, alertness, and inhibition - needs to be integrated between different brain regions. Early models suggested that completely segregated brain networks control these three cognitive domains. However, more recent accounts, mainly based on neuroimaging data in healthy participants, indicate that different tasks lead to specific patterns of activation within the same, higher-order and "multiple-demand" network. If so, then a lesion to critical substrates of this common network should determine a concomitant impairment in all three cognitive domains. The aim of the present study was to critically investigate this hypothesis, i.e., to identify focal stroke lesions within the network that can concomitantly impact visuospatial attention, alertness and inhibition. We studied an unselected sample of 60 first-ever right-hemispheric, subacute stroke patients using a data-driven, bottom-up approach. Patients performed 12 standardized neuropsychological and oculomotor tests, four per cognitive domain. Principal component analyses revealed a strong relationship between all three cognitive domains: 10 of 12 tests loaded on a first, Common Component. Analysis of the neuroanatomical lesion correlates using different approaches (i.e., Voxel-Based and Tractwise Lesion-Symptom Mapping, Disconnectome maps) provided convergent evidence on the association between severe impairment of this Common Component and lesions at the intersection of Superior Longitudinal Fasciculus II and III, Frontal Aslant Tract and, to a lesser extent, the Putamen and Inferior Fronto-Occipital Fasciculus. Moreover, patients with a lesion involving this region were significantly more impaired in daily living cognition, which provides an ecological validation of our results. A probabilistic functional atlas of the multiple-demand network was performed to confirm the potential relationship between patients' lesion substrates and observed cognitive impairments as a function of the MD-network connectivity disruption. These findings show, for the first time, that a lesion to a specific white matter crossroad can determine a concurrent breakdown in all three considered cognitive domains. Our results support the multiple-demand network model, proposing that different cognitive operations depend on specific collaborators and their interaction, within the same underlying neural network. Our findings also extend this hypothesis by showing (1) the contribution of SLF and FAT to the multiple-demand network, and (2) a critical neuroanatomical intersection, crossed by a vast amount of long-range white matter tracts, many of which interconnect cortical areas of the multiple-demand network. The vulnerability of this crossroad to stroke has specific cognitive and clinical consequences; this has the potential to influence future rehabilitative approaches