The functional neuroanatomical correlates of response variability: evidence from a response inhibition task

Intra-individual performance variability may be an important index of the efficiency with which executive control processes are implemented, Lesion studies suggest that damage to the frontal lobes is accompanied by an increase in such variability. Here we sought for the first time to investigate how the functional neuroanatomy of executive control is modulated by performance variability in healthy subjects by using an event-related functional magnetic resonance imaging (ER-fMRI) design and a Go/No-go response inhibition paradigm. Behavioural results revealed that individual differences in Go response time variability were a strong predictor of inhibitory success and that differences in mean Go response time could not account for this effect. Task-related brain activation was positively correlated with intra-individual variability within a distributed inhibitory network consisting of bilateral middle frontal areas and right inferior parietal and thalamic regions. Both the behavioural and fMRI data are consistent with the interpretation that those subjects with relatively higher intra-individual variability activate inhibitory regions to a greater extent, perhaps reflecting a greater requirement for top-down executive control in this group, a finding that may be relevant to disorders of executive/attentional control.     

Fast responders have blinders on: ERP correlates of response inhibition in competition

Recent studies have demonstrated that individuals acting in a social context form shared representations, resulting in incorporating another person's action plan into their own. The present study investigated the extent to which shared representations are formed in a competitive task. Specifically, it was tested whether in competition the process of response inhibition is affected by explicit knowledge of another's task. Event-related potential (ERP) correlates of response inhibition were measured while pairs of participants competed with each other on a speeded go/no-go task. Participants were instructed to always try to respond faster than their direct competitor. No-go stimuli requiring an inhibitory response of the other person as well (compatible action) or no-go stimuli to which the other person should respond (incompatible action) were directly compared. Behavioral performance measures and response inhibition, as reflected in the no-go P3, were decreased on incompatible actions compared to compatible ones. Interestingly, both the behavioral and the ERP effects were caused by the slow responding and thus unsuccessful competitors. These findings indicate that shared representations are formed in competitive tasks, but differently for successful and unsuccessful competitors. Only the slow responders are impeded by incompatible actions. The present study therefore demonstrates that the formation of shared representations is not a fully automatic process. People can differ in the extent to which they incorporate the other's action plan into their own and this may be closely related to successful performance in competitive action.     

Functional developmental changes underlying response inhibition and error-detection processes

This study examined the developmental trajectories associated with response inhibition and error processing as exemplar executive processes. We present fMRI data showing developmental changes to the functional networks underlying response inhibition and error-monitoring, comparing activation between adults and young adolescents performing the sustained attention to response task (SART). During successful inhibitions, we observed greater activation for the young adolescents than for the adults, in a widely distributed network including frontal, parietal and medial regions. When inhibition failed, however, adults showed increased activation compared to young adolescents in a number of regions, including bilateral parahippocampal gyrus, left and right lingual gyri, the right insula, and cerebellar regions. These differences largely remained even when the two groups were matched for performance, suggesting that performance differences are unlikely to be the driving factor behind these developmental differences. Instead, the neurodevelopmental trajectory of these important executive functions may reveal the basis for the immature executive functioning of the young adolescent.     

事件相关电位评估反应抑制功能的研究进展

反应抑制是指要求抑制与当前任务无关但具有支配性的想法或行为的能力,是执行功能的核心组成部分.反应抑制一般被分为3类:抑制无关刺激的激活,制止已经被激活但与当前任务无关的行为准备状态,抑制优势反应[1].事件相关电位(Event Related Potentials,ERP)是观察脑活动过程的窗口,能够反映一定的心理活动(即事件)引起的脑电位变化,与信号感知、注意、辨别分析、工作记忆等认知过程相关[2],其中Go/Nogo范式用于反应抑制的检测,涉及对冲突的监控、行为选择、认知控制等反应抑制过程.本文主要就Go/Nogo范式在神经疾病及精神疾病中对抑制控制功能的评估做一综述.     

Frontostriatal dysfunction during response inhibition in Williams syndrome.

BACKGROUND: Williams syndrome (WS) has provided researchers with an exciting opportunity to understand the complex interplay among genes, neurobiological and cognitive functions. However, despite a well-characterized cognitive and behavioral phenotype, little attention has been paid to the marked deficits in social and behavioral inhibition. Here we explore the neural systems that mediate response inhibition in WS. METHODS: We used functional MRI (fMRI) to obtain blood oxygenation level dependence (BOLD) signal maps during the performance of a Go/NoGo response inhibition task from 11 clinically and genetically diagnosed WS patients and 11 age- and gender-matched typically developing (TD) control subjects. Correlations between behavioral, neuropsychological measures, and BOLD signal were also conducted. RESULTS: Although TD control subjects showed significantly faster response times, no group differences in behavioral accuracy were observed. Compared with control subjects, WS participants demonstrated significantly reduced activity in the striatum, dorsolateral prefrontal, and dorsal anterior cingulate cortices. These findings support the hypothesis that persons with WS fail to activate critical cortical and subcortical structures involved in behavioral inhibition. CONCLUSIONS: Our results provide important evidence for reduced engagement of the frontostriatal circuits in WS and provide putative biological markers for the deficits in response inhibition and the unusual social phenotype.     

The neural basis of response inhibition and attention allocation as mediated by gestational age

Children and adolescents born before 33 weeks of gestation, that is very preterm, may experience problems with the inhibitory control of behaviour and the allocation of attention. Previous functional magnetic resonance imaging (fMRI) studies have found preterm-born adolescents to display altered brain activation in tasks measuring inhibitory control. However, adolescence is a period during which dynamic changes are occurring in the brain, and it is not yet known whether these functional alterations will persist into adulthood, or instead reflect developmental delay. This study used an event-related fMRI Go/No-Go motor response inhibition paradigm, which included an oddball task measuring attention allocation to infrequent stimuli, to compare blood-oxygen-level-dependent (BOLD) signal between 26 preterm-born adults and 21 controls. Group differences in brain activation were observed in inhibition and attention networks during both conditions. During motor response inhibition, preterm-born participants compared to controls showed increased BOLD signal in medial and right lateral posterior brain regions, including middle temporal/occipital gyrus, posterior cingulate gyrus and precuneus. During oddball trials, preterm-born young adults displayed attenuated brain activation in a fronto-parietal-cerebellar network which is involved in mediating attention allocation. This pattern of reduced brain activation in task-relevant regions of attention allocation, and increased activation in posterior brain regions during inhibitory control, suggests adult alteration of inhibition and attention processing following very preterm birth, which may reflect a developmental delay.     

Interactions between cognition and motivation during response inhibition

A growing number of studies have investigated how motivation interacts with particular cognitive functions, including attention, working memory, and other executive functions. In these studies, the emphasis has been on understanding how motivation impacts brain regions that contribute to improving behavioral performance. Less is understood about how positive incentives may actually impair behavioral performance. Here, we were interested in investigating a situation in which reward would be potentially deleterious to behavioral performance. Specifically, we hypothesized that rewarding participants for correct going would impair stopping performance. Critically, we hypothesized that the effects on inhibition would be specific, namely, not simply attributable to a speeding-up of reaction time during go trials. To investigate the interaction between inhibition and motivation, participants performed a stop-signal task during two conditions, namely, during a neutral, control condition and during a rewarded condition during which they were rewarded for correct go performance. Behaviorally, participants exhibited longer stop-signal reaction times during the reward relative to the control condition, indicating that it was harder to inhibit their responses during the former condition. Neuroimaging findings revealed that a host of brain regions were involved in stop-signal inhibition, as indexed via the contrast of successful and unsuccessful stop trials. Critically, a subset of these regions, which included the right inferior frontal gyrus, the left precentral gyrus, and bilateral putamen, exhibited significant inhibition by condition interactions, demonstrating that cognitive and motivational signals interact in the brain during inhibitory control.     

What About Inhibition in the Wisconsin Card Sorting Test?

The commercially available Wisconsin Card Sorting Test (WCST) is one of the most commonly used tests for assessing executive functions within clinical settings. Importantly, however, it remains relatively unclear exactly what processes are assessed by the test. Conceptually, increased perseverative errors in sorting cards are usually related to deficient inhibition processes. Empirically, evidence supporting this conclusion is limited. In a sample of 38 healthy adults we addressed the question to what extent inhibition mechanisms assessed by the go/no-go and the stop-signal paradigm are related to WCST performances. Inhibition-related scores were found to predict non-perseverative errors better than perseverative errors. Consequently we conclude that the non-perseverative errors score reflects processes that are partly dependent on inhibition functions.     

Neural correlates of STN DBS-induced cognitive variability in Parkinson disease

BACKGROUND: Although deep brain stimulation of the subthalamic nucleus (STN DBS) in Parkinson disease (PD) improves motor function, it has variable effects on working memory (WM) and response inhibition (RI) performance. The purpose of this study was to determine the neural correlates of STN DBS-induced variability in cognitive performance. METHODS: We measured bilateral STN DBS-induced blood flow changes (PET and [(15)O]-water on one day) in the supplementary motor area (SMA), dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), and right inferior frontal cortex (rIFC) as well as in exploratory ROIs defined by published meta-analyses. STN DBS-induced WM and RI changes (Spatial Delayed Response and Go-No-Go on the next day) were measured in 24 PD participants. On both days, participants withheld PD medications overnight and conditions (OFF vs. ON) were administered in a counterbalanced, double-blind manner. RESULTS: As predicted, STN DBS-induced DLPFC blood flow change correlated with change in WM, but not RI performance. Furthermore, ACC blood flow change correlated with change in RI but not WM performance. For both relationships, increased blood flow related to decreased cognitive performance in response to STN DBS. Of the exploratory regions, only blood flow changes in DLPFC and ACC were correlated with performance. CONCLUSIONS: These results demonstrate that variability in the effects of STN DBS on cognitive performance relates to STN DBS-induced cortical blood flow changes in DLPFC and ACC. This relationship highlights the need to further understand the factors that mediate the variability in neural and cognitive response to STN DBS.     

Functional imaging of the hemodynamic sensory gating response in schizophrenia

The cortical (auditory and prefrontal) and/or subcortical (thalamic and hippocampal) generators of abnormal electrophysiological responses during sensory gating remain actively debated in the schizophrenia literature. Functional magnetic resonance imaging has the spatial resolution for disambiguating deep or simultaneous sources but has been relatively under‐utilized to investigate generators of the gating response. Thirty patients with chronic schizophrenia (SP) and 30 matched controls participated in the current experiment. Hemodynamic response functions (HRFs) for single (S1) and pairs (S1 + S2) of identical (“gating‐out” redundant information) or nonidentical (“gating‐in” novel information) tones were generated through deconvolution. Increased or prolonged activation for patients in conjunction with deactivation for controls was observed within auditory cortex, prefrontal cortex, and thalamus in response to single tones during the late hemodynamic response, and these group differences were not associated with clinical or cognitive symptomatology. Although patient hyperactivation to paired‐tones conditions was present in several regions of interest, the effects were not statistically significant for either the gating‐out or gating‐in conditions. Finally, abnormalities in the postundershoot of the auditory HRF were also observed for both single and paired‐tones conditions in patients. In conclusion, the amalgamation of the entire electrophysiological response to both S1 and S2 stimuli may limit hemodynamic sensitivity to paired tones during sensory gating, which may be more readily overcome by paradigms that use multiple stimuli rather than pairs. Patient hyperactivation following single tones is suggestive of deficits in basic inhibition, neurovascular abnormalities, or a combination of both factors. Hum Brain Mapp 34:2302–2312, 2013. © 2012 Wiley Periodicals, Inc.     

Subcortical contributions to multitasking and response inhibition

The involvement of the prefrontal cortex in executive control has been well established. It is, however, as yet unclear whether the basal ganglia and the cerebellum as components of frontostriatal/frontocerebellar networks also contribute to the executive domains multitasking and response inhibition. To investigate this issue, groups of patients with selective vascular lesions of the basal ganglia (n=13) or the cerebellum (n=14) were compared with matched healthy control groups. Several paradigms assessing the ability to process concurrent visual and auditory input and to simultaneously perform verbal and manual responses as well as the inhibition of habitual or newly acquired response tendencies were administered. Basal ganglia patients showed marked response slowing during coordination of sensory input from different modalities and high error rates during the inhibition of overlearned responses. There was no clear evidence of a cerebellar involvement in multitasking or response suppression. Taken together, the findings provided evidence for a striatal involvement in both multitasking and response inhibition, emphasizing the functional implication of subcortical components in frontostriatal circuits.     

Prefrontal unit activity during delayed conditional Go/No-go discrimination in the monkey. II. Relation to Go and No-go responses

Three monkeys were trained to perform a Go/No-go discrimination task where the animals were required to perform a muscular movement (Go) or to withhold it (No-go) depending on the previously presented signal. Single unit activity was recorded from the prefrontal cortex during the performance of the task. Among 512 task-related prefrontal units, 253 units showed differential activity in relation to the type of the trial (Go or No-go) either at the time of the response or both during the preparatory period for the response and at the time of the response. These units were classified into 3 types depending on whether the changes in unit activity were observed selectively on Go trials (Go units, n = 47), or selectively on No-go trials (No-go units, n = 28) or on both Go and No-go trials (Go/No-go units, n = 178). A small number of units from the premotor cortex (n = 31) were examined inadvertently and the 3 types of units were present in this area as well. The existence of the 3 types of prefrontal units (Go, No-go and Go/No-go) indicates that the prefrontal cortex is involved in the behavioral inhibitory mechanism besides participating in the behavioral excitatory mechanism.     

GRM8 genotype is associated with externalizing disorders and greater inter-trial variability in brain activation during a response inhibition task

ObjectiveThe present investigation tested the association of a novel measure of brain activation recorded during a simple motor inhibition task with a GRM8 genetic locus implicated in risk for substance dependence.Methods122 European-American adults were genotyped at rs1361995 and evaluated against DSM-IV criteria for Alcohol Dependence, Cocaine Dependence, Conduct Disorder, and Antisocial Personality Disorder. Also, their brain activity was recorded in response to rare, so-called “No-Go” stimuli presented during a continuous performance test. Brain activity was quantified with two indices: (1) the amplitude of the No-Go P300 electroencephalographic response averaged across trials; and (2) the inter-trial variability of the response.ResultsThe absence of the minor allele at the candidate locus was associated with all of the evaluated diagnoses. In comparison to minor allele carriers, major allele homozygotes also demonstrated increased inter-trial variability in No-Go P300 response amplitude but no difference in average amplitude.ConclusionsGRM8 genotype is associated with Alcohol and Cocaine Dependence as well as personality risk factors for dependence. The association may be mediated through an inherited instability in brain function that affects cognitive control.SignificanceThe present study focuses on a metric and brain mechanism not typically considered or theorized in studies of patients with substance use disorders.     

Meta-analysis of Go/No-go tasks demonstrating that fMRI activation associated with response inhibition is task-dependent

FMRI studies of response inhibition consistently reveal frontal lobe activation. Localization within the frontal cortex, however, varies across studies and appears dependent on the nature of the task. Activation likelihood estimate (ALE) meta-analysis is a powerful quantitative method of establishing concurrence of activation across functional neuroimaging studies. For this study, ALE was used to investigate concurrent neural correlates of successfully inhibited No-go stimuli across studies of healthy adults performing a Go/No-go task, a paradigm frequently used to measure response inhibition. Due to the potential overlap of neural circuits for response selection and response inhibition, the analysis included only event-related studies contrasting No-go activation with baseline, which allowed for inclusion of all regions that may be critical to visually guided motor response inhibition, including those involved in response selection. These Go/No-go studies were then divided into two groups: "simple" Go/No-go tasks in which the No-go stimulus was always the same, and "complex" Go/No-go tasks, in which the No-go stimulus changed depending on context, requiring frequent updating of stimulus-response associations in working memory. The simple and complex tasks demonstrated distinct patterns of concurrence, with right dorsolateral prefrontal and inferior parietal circuits recruited under conditions of increased working memory demand. Common to both simple and complex Go/No-go tasks was concurrence in the pre-SMA and the left fusiform gyrus. As the pre-SMA has also been shown to be involved in response selection, the results support the notion that the pre-SMA is critical for selection of appropriate behavior, whether selecting to execute an appropriate response or selecting to inhibit an inappropriate response.     

Increased intra-individual reaction time variability in attention-deficit/hyperactivity disorder across response inhibition tasks with different cognitive demands

One of the most consistent findings in children with ADHD is increased moment-to-moment variability in reaction time (RT). The source of increased RT variability can be examined using ex-Gaussian analyses that divide variability into normal and exponential components and Fast Fourier transform (FFT) that allow for detailed examination of the frequency of responses in the exponential distribution. Prior studies of ADHD using these methods have produced variable results, potentially related to differences in task demand. The present study sought to examine the profile of RT variability in ADHD using two Go/No-go tasks with differing levels of cognitive demand. A total of 140 children (57 with ADHD and 83 typically developing controls), ages 8–13 years, completed both a “simple” Go/No-go task and a more “complex” Go/No-go task with increased working memory load. Repeated measures ANOVA of ex-Gaussian functions revealed for both tasks children with ADHD demonstrated increased variability in both the normal/Gaussian (significantly elevated sigma) and the exponential (significantly elevated tau) components. In contrast, FFT analysis of the exponential component revealed a significant task × diagnosis interaction, such that infrequent slow responses in ADHD differed depending on task demand (i.e., for the simple task, increased power in the 0.027–0.074 Hz frequency band; for the complex task, decreased power in the 0.074–0.202 Hz band). The ex-Gaussian findings revealing increased variability in both the normal (sigma) and exponential (tau) components for the ADHD group, suggest that both impaired response preparation and infrequent “lapses in attention” contribute to increased variability in ADHD. FFT analyses reveal that the periodicity of intermittent lapses of attention in ADHD varies with task demand. The findings provide further support for intra-individual variability as a candidate intermediate endophenotype of ADHD.     

Functional deactivations: multiple ipsilateral brain areas engaged in the processing of somatosensory information

Somatosensory signals modulate activity throughout a widespread network in both of the brain hemispheres: the contralateral as well as the ipsilateral side of the brain relative to the stimulated limb. To analyze the ipsilateral somatosensory brain areas that are engaged during limb stimulation, we performed functional magnetic resonance imaging (fMRI) in 12 healthy subjects during electrical median nerve stimulation using both a block- and an event-related fMRI design. Data were analyzed through the use of model-dependent (SPM) and model-independent (ICA) approaches. Beyond the well-known positive blood oxygenation level-dependent (BOLD) responses, negative deflections of the BOLD response were found consistently in several ipsilateral brain areas, including the primary somatosensory cortex, the supplementary motor area, the insula, the dorsal part of the posterior cingulate cortex, and the contralateral cerebellum. Compared to their positive counterparts, the negative hemodynamic responses showed a different time course, with an onset time delay of 2.4 s and a peak delay of 0.7 s. This characteristic delay was observed in all investigated areas and verified by a second (purely tactile) event-related paradigm, suggesting a systematic difference for brain areas involved in the processing of somatosensory information. These findings may indicate that the physiological basis of these deactivations differs from that of the positive BOLD responses. Therefore, an altered model for the negative BOLD response may be beneficial to further model-dependent fMRI analyses.     

Comparative analysis of event-related potentials during Go/NoGo and CPT: decomposition of electrophysiological markers of response inhibition and sustained attention

Neuropsychological tests target specific cognitive functions; however, numerous cognitive subcomponents are involved in each test. The aim of this study was to decompose the components of two frontal executive function tests, Go/NoGo (GNG) and cued continuous performance task (CPT), by analyzing event-related potentials (ERPs) of 24 subjects both in time and time-frequency domains. In the time domain, P1, N1, P2, N2 and P3 peak amplitudes and latencies and mean amplitudes of 100 ms time windows of the post-P3 time period were measured. For GNG, the N1 amplitude and for both GNG and CPT N2 amplitudes were significantly higher in the NoGo condition compared with the Go condition. P3 had a central maximum in the NoGo conditions of both paradigms in contrast to a parietal maximum in the Go conditions. All peaks except P1 and mean amplitudes of the post-P3 period were more positive in CPT compared to those of GNG. N1, N2 and P3 latencies were longer for the NoGo condition than the Go condition in the CPT. In time-frequency analyses, the NoGo condition evoked higher theta coefficients than the Go condition, whereas the CPT and GNG paradigms differed mainly in the delta band. These results suggest that theta component reflects response inhibition in both GNG and CPT, whereas delta component reflects the more demanding sustained attention requirement of the CPT. The latency prolongation observed with the NoGo condition of the CPT paradigm was thought to be due to perseverance/inhibition conflict enhanced by the primer stimuli in CPT.     

Bilateral decrease in ventrolateral prefrontal cortex activation during motor response inhibition in mania

Mania has been frequently associated with impaired inhibitory control. The present study aimed to identify brain functional abnormalities specifically related to motor response inhibition in mania by using event-related fMRI in combination with a Go/NoGo task designed to control for extraneous cognitive processes involved in task performance. Sixteen manic patients and 16 healthy subjects, group-matched for age and sex, were imaged while performing a warned equiprobable Go/NoGo task during event-related fMRI. Between-group differences in brain activation associated with motor response inhibition were assessed using analyses of covariance. Although no significant between-group differences in task performance accuracy were observed, patients showed significantly longer response times on Go trials. After controlling for covariates, the only brain region that differentiated the two groups during motor response inhibition was the ventrolateral prefrontal cortex (VLPFC), where activation was significantly decreased in both the right and left hemispheres in manic patients. Our data suggest that response inhibition in mania is associated with a lack of engagement of the bilateral VLPFC, which is known to play a primary role in the suppression of irrelevant responses. This result might give clues to understanding the pathophysiology of dishinhibition and impulsivity that characterize mania.     

Gender Differences in Cognitive Control: an Extended Investigation of the Stop Signal Task

Men and women show important differences in clinical conditions in which deficits in cognitive control are implicated. We used functional magnetic resonance imaging to examine gender differences in the neural processes of cognitive control during a stop-signal task. We observed greater activation in men, compared to women, in a wide array of cortical and sub-cortical areas, during stop success (SS) as compared to stop error (SE). Conversely, women showed greater regional brain activation during SE > SS, compared to men. Furthermore, compared to women, men engaged the right inferior parietal lobule to a greater extent during post-SE go compared to post-go go trials. Women engaged greater posterior cingulate cortical activation than men during post-SS slowing in go trial reaction time (RT) but did not differ during post-SE slowing in go trial RT. These findings extended our previous results of gender differences in regional brain activation during response inhibition. The results may have clinical implications by, for instance, helping initiate studies to understand why women are more vulnerable to depression while men are more vulnerable to impulse control disorders.