fMRI evidence that the neural basis of response inhibition is task-dependent

Event-related fMRI was used to investigate the hypothesis that neural activity involved in response inhibition depends upon the nature of the response being inhibited. Two different Go/No-go tasks were compared-one with a high working memory load and one with low. The 'simple' Go/No-go task with low working memory load required subjects to push a button in response to green spaceships but not red spaceships. A 'counting' Go/No-go task (high working memory load) required subjects to respond to green spaceships as well as to those red spaceships preceded by an even number of green spaceships. In both tasks, stimuli were presented every 1.5 s with a 5:1 ratio of green-to-red spaceships. fMRI group data for each task were analyzed using random effects models to determine signal change patterns associated with Go events and No-go events (corrected P< or =0.05). For both tasks, Go responses were associated with signal change in the left primary sensorimotor cortex, supplementary motor area (SMA) proper, and anterior cerebellum (right>left). For the simple task, No-go events were associated with activation in the pre-SMA; the working memory-loaded 'counting' task elicited additional No-go activation in the right dorsolateral prefrontal cortex. The findings suggest that neural contributions to response inhibition may be task dependent; the pre-SMA appears necessary for inhibition of unwanted movements, while the dorsolateral prefrontal cortex is recruited for tasks involving increased working memory load.     

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.     

Functional brain correlates of response time variability in children

During tasks requiring response inhibition, intra-individual response time variability, a measure of motor response preparation, has been found to correlate with errors of commission, such that individuals with higher variability show increased commission errors. This study used fMRI to examine the neural correlates of response variability in 30 typically developing children, ages 8-12, using a simplified Go/No-go task with minimal cognitive demands. Lower variability was associated with Go activation in the anterior cerebellum (culmen) and with No-go activation in the rostral supplementary motor area (pre-SMA), the postcentral gyrus, the anterior cerebellum (culmen) and the inferior parietal lobule. For both Go and No-go events, higher variability was associated with activation in prefrontal cortex and the caudate. The findings have implications for neuropsychiatric disorders such as ADHD and suggest that during response inhibition, children with more consistent performance are able to rely on premotor circuits involving the pre-SMA, important for response selection; those with less consistent performance instead recruit prefrontal circuits involved in more complex aspects of behavioral control.     

Executive functions with different motor outputs in somatosensory Go/Nogo tasks: an event-related functional MRI study

The aim of this event-related functional magnetic resonance imaging (fMRI) study was to investigate and compare executive functions with different motor outputs in somatosensory Go/Nogo tasks: (1) Button press and (2) Count. Go and Nogo stimuli were presented with an even probability. We observed a common network for Movement and Count Go trials in several regions of the brain including the dorsolateral (DLPFC) and ventrolateral prefrontal cortices (VLPFC), supplementary motor area (SMA), posterior parietal cortex (PPC), inferior parietal lobule (IPL), Insula, and superior temporal gyrus (STG). Direct comparison revealed that primary sensorimotor area (SMI), premotor area (PM), and anterior cingulate cortex (ACC) were more activated during Movement than Count Go trials. In contrast, the VLPFC was more activated during Count than Movement Go trials. Our results suggest that there were two neural networks for the supramodal executive function, common and uncommon, depending on the required response mode.     

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.     

Impaired mesial frontal and putamen activation in Parkinson's disease: a positron emission tomography study.

Selection of movement in normal subjects has been shown to involve the premotor, supplementary motor, anterior cingulate, posterior parietal, and dorsolateral prefrontal areas. In Parkinson's disease (PD), the primary pathological change is degeneration of the nigrostriatal dopaminergic projections, and this is associated with difficulty in initiating actions. We wished to investigate the effect of the nigral abnormality in PD on cortical activation during movement. Using C15O2 and positron emission tomography (PET), we studied regional cerebral blood flow in 6 patients with PD and 6 control subjects while they performed motor tasks. Subjects were scanned while at rest, while repeatedly moving a joystick forward, and while freely choosing which of four possible directions to move the joystick. Significant increases in regional cerebral blood flow were determined with covariance analysis. In normal subjects, compared to the rest condition, the free-choice task activated the left primary sensorimotor cortex, left premotor cortex, left putamen, right dorsolateral prefrontal cortex and supplementary motor area, anterior cingulate area, and parietal association areas bilaterally. In the patients with PD, for the free-choice task, compared with the rest condition, there was significant activation in the left sensorimotor and premotor cortices but there was impaired activation of the contralateral putamen, the anterior cingulate, supplementary motor area, and dorsolateral prefrontal cortex. Impaired activation of the medial frontal areas may account for the difficulties PD patients have in initiating movements.     

Error-related brain activation during a Go/NoGo response inhibition task

Inhibitory control and performance monitoring are critical executive functions of the human brain. Lesion and imaging studies have shown that the inferior frontal cortex plays an important role in inhibition of inappropriate response. In contrast, specific brain areas involved in error processing and their relation to those implicated in inhibitory control processes are unknown. In this study, we used a random effects model to investigate error-related brain activity associated with failure to inhibit response during a Go/NoGo task. Error-related brain activation was observed in the rostral aspect of the right anterior cingulate (BA 24/32) and adjoining medial prefrontal cortex, the left and right insular cortex and adjoining frontal operculum (BA 47) and left precuneus/posterior cingulate (BA 7/31/29). Brain activation related to response inhibition and competition was observed bilaterally in the dorsolateral prefrontal cortex (BA 9/46), pars triangularis region of the inferior frontal cortex (BA 45/47), premotor cortex (BA 6), inferior parietal lobule (BA 39), lingual gyrus and the caudate, as well as in the right dorsal anterior cingulate cortex (BA 24). These findings provide evidence for a distributed error processing system in the human brain that overlaps partially, but not completely, with brain regions involved in response inhibition and competition. In particular, the rostal anterior cingulate and posterior cingulate/precuneus as well as the left and right anterior insular cortex were activated only during error processing, but not during response competition, inhibition, selection, or execution. Our results also suggest that the brain regions involved in the error processing system overlap with brain areas implicated in the formulation and execution of articulatory plans.     

Attention-related unit activity in the frontal association cortex during a go/no-go visual discrimination task

Unit activity related to a go/no-go visual discrimination task was studied in four rhesus monkeys. We recorded 272 task-related cells from frontal cortex in a region extending from the midprincipal sulcus to the central sulcus, and medially to the cingulate sulcus. Units located in anterior regions (dorsolateral prefrontal and anterior cingulate cortex) were typically related to both go and no-go trials (designated type II units) and showed similar ("symmetrical") activity in both kinds of trials; some of them also showed prestimulus ("anticipatory") activity. Such units were present but less common in posterior regions (postarcuate and precentral and posterior cingulate cortex). Units in these posterior regions were active predominantly in go trials (designated type I units). Also found posteriorly were "asymmetrical" type II cells whose activity was greater in go trials and occurred later in the trial, around the behavioral response. The anterior symmetrical and anticipatory type II units in the frontal association cortex were similar to such units described earlier in the brain stem reticular formation and may have similar functions in supporting focused and preparatory attention. On the other hand, asymmetrical type II units in the posterior frontal regions may have a role in the initiation of visually guided motor behavior.     

An fMRI study of reduced left prefrontal activation in schizophrenia during normal inhibitory function

Functional magnetic resonance imaging (fMRI) was used to investigate the hypothesis that schizophrenia is associated with a dysfunction of prefrontal brain regions during motor response inhibition. Generic brain activation of six male medicated patients with schizophrenia was compared to that of seven healthy comparison subjects matched for sex, age, and education level while performing 'stop' and 'go-no-go' tasks. No group differences were observed in task performance. Patients, however, showed reduced BOLD signal response in left anterior cingulate during both inhibition tasks and reduced left rostral dorsolateral prefrontal and increased thalamus and putamen BOLD signal response during stop task performance. Despite good task performance, patients with schizophrenia thus showed abnormal neural network patterns of reduced left prefrontal activation and increased subcortical activation when challenged with motor response inhibition.     

Lateral and medial hypofrontality in first-episode schizophrenia: functional activity in a medication-naive state and effects of short-term atypical antipsychotic treatment

OBJECTIVE: The dorsolateral prefrontal cortex and the anterior cingulate cortex are critical components of the brain circuitry underlying executive control. The objective of this study was to investigate control-related dorsolateral prefrontal cortex functioning and conflict-related anterior cingulate cortex functioning in a group of never medicated first-episode schizophrenia patients to determine whether both regions show dysfunction at illness onset. A second objective was to assess short-term effects of atypical antipsychotic medication on dorsolateral prefrontal cortex and anterior cingulate cortex functioning. METHOD: First-episode schizophrenia patients (N=23) and healthy comparison subjects (N=24) underwent event-related fMRI and performed a cognitive task designed to functionally dissociate the two regions. Four weeks after initiation of pharmacotherapy for patients, a subset of 11 patients and 16 comparison subjects underwent a repeat assessment. RESULTS: At baseline, patients exhibited hypoactivation in the dorsolateral prefrontal cortex and anterior cingulate cortex. After 4 weeks of antipsychotic treatment, the patients demonstrated improved functioning in the anterior cingulate cortex but not in the dorsolateral prefrontal cortex. CONCLUSIONS: These findings confirm the presence of dorsolateral prefrontal cortex dysfunction early in the course of schizophrenia and suggest that anterior cingulate cortex functioning may be altered at illness onset as well. Results also suggest that anterior cingulate cortex functioning may be especially sensitive to remedial antipsychotic treatment effects. These findings are consistent with an emerging literature documenting short-term benefits of atypical antipsychotic medication for the neural circuitry underlying cognitive deficits in schizophrenia.     

Dissociation of inhibition from error processing using a parametric inhibitory task during functional magnetic resonance imaging

Inhibition, the process that overrides and reverses the execution of a thought, action, or emotion, is important in daily life. Sixteen healthy volunteers performed a parametrically modulated motor inhibition task during functional magnetic resonance imaging. Two results were observed: (1) increased error-related anterior cingulate cortex activation and, (2) increased inferior frontal gyrus and medial prefrontal cortex activation during inhibition, irrespective of errors. Thus, the parametric nature of the task elucidated a functional dissociation of brain structures involved in motor inhibition from those involved in error processing. Additionally, this task allowed the identification of unique areas of increased activation within specific subregions of the anterior cingulate cortex related to errors made during trials with a high (dorsal anterior cingulate cortex) and low (ventral anterior cingulate cortex) inhibitory load.     

fMRI of intrasubject variability in ADHD: anomalous premotor activity with prefrontal compensation

ObjectiveChildren with attention-deficit/hyperactivity disorder (ADHD) consistently display increased intrasubject variability (ISV) in response time across varying tasks, signifying inefficiency of response preparation compared to typically developing (TD) children. Children with ADHD also demonstrate impaired response inhibition; inhibitory deficits correlate with ISV, suggesting that similar brain circuits may underlie both processes. To better understand the neural mechanisms underlying increased ISV and inhibitory deficits in children with ADHD, functional magnetic resonance imaging was used to examine the neural correlates of ISV during Go/No-go task performance.MethodEvent-related functional magnetic resonance imaging was used to study 25 children with ADHD and 25 TD children ages 8 to 13 years performing a simplified Go/No-go task. Brain-behavior correlations were examined between functional magnetic resonance imaging activation and ISV within and between groups.ResultsFor TD children, increased rostral supplementary motor area (pre-supplementary motor area) activation during No-go events was associated with less ISV, whereas the reverse was true for children with ADHD for whom increased pre-supplementary motor area activation was associated with more ISV. In contrast, children with ADHD with less ISV showed greater prefrontal activation, whereas TD children with more prefrontal activation demonstrated more ISV.ConclusionsThese findings add to evidence that dysfunction of premotor systems may contribute to increased variability and impaired response inhibition in children with ADHD and that compensatory strategies eliciting increased cognitive control may improve function. However, recruitment of prefrontal resources as a compensatory mechanism for motor task performance may preclude the use of those prefrontal resources for higher order, more novel executive functions with which children with ADHD often struggle.     

Prefrontal and cingulate unit activity during timing behavior in the monkey

Single unit activity was recorded from the dorsolateral prefrontal cortex and the anterior cingulate cortex while monkeys were performing a modified differential reinforcement of long latencies (DRLL) task. A total of 252 prefrontal units and 218 anterior cingulate units showed an obvious change in discharge rate (increase or decrease) in association with one or more of the events of a DRLL task. Related units were classified into 3 main groups: S--R event units, reward-error units, and timing units. S--R event units consisted of three subtypes: stimulus-related, response-related, and stimulus--response-related units. Reward-error units contained reward-related units and error-recognition units. Error-recognition units showed a vigorous increase in firing only after incorrect responses. These units were also responsive to omission of reinforcement on correct trials. Three types of timing units were distinguishable. The first one showed an anticipatory change prior to stimulus onset, and the second one exhibited a gradual anticipatory change preceding the time of responding. The third one manifested a sustained change during delay and an abrupt cessation of change in firing at the time of response initiation.     

No altered dorsal anterior cingulate activation in bipolar II disorder patients during a Go/No-go task: an fMRI study

Objectives:  It has been reported that one of the core features in patients with bipolar disorder II (BD II) is increased impulsivity. The aim of this study was to investigate whether patients with BD II showed decreased activation in the dorsal anterior cingulate cortex (dACC) as compared to healthy controls when performing a task sensitive to impulsivity.
Methods:  Twenty-seven BD II patients and 28 healthy controls performed a Go/No-go task during a functional magnetic resonance imaging (fMRI) session. Eleven of the patients were unmedicated, and possible group differences between medicated and unmedicated patients were also assessed.
Results:  The groups did not differ in behavioral performance on the Go/No-go task.
Both BD II subjects and healthy controls demonstrated dACC activity during the task, and analyses revealed no statistically significant group differences. Medicated and unmedicated patients also did not differ in the degree of fMRI activation.
Conclusions:  These findings do not support the hypothesis of abnormal dACC activity during a Go/No-go task in BD II patients.     

Negative correlation between right prefrontal activity during response inhibition and impulsiveness: A fMRI study

Behavioral disinhibition in Go/No-Go task is thought to be associated with impulsiveness in humans. Recent imaging studies showed that neural circuits involving diverse areas of the frontal cortex and other association cortex sites such as the parietal cortex are implicated in the inhibition of response during No-Go trials. The aim of the present study was to investigate the association between regional cerebral activation during No-Go trials and impulsiveness. Seventeen right-handed healthy volunteers participated in the study. We used functional magnetic resonance imaging to measure the brain activation during a Go/No-Go task. The Barratt Impulsiveness Scale, 11(th) version (BIS-11) was used to measure impulsiveness. Activated regions included the right middle frontal gyrus and the inferior parietal lobe, which is consistent with previous neuroimaging studies. A negative correlation was observed between the motor impulsiveness of BIS-11 and No-Go-related activation in the right dorsolateral prefrontal cortex (RDLPFC). Our results suggest that the RDLPFC is the area most sensitive to differences in individual motor impulsiveness and its activity may be an indicator of the individual capacity for response inhibition.     

Developmental changes in within- and between-network connectivity between late childhood and adulthood

A number of behavioral changes occur between late childhood and adulthood, including maturation of social cognition, reward receptivity, impulsiveness, risk-taking and cognitive control. Although some of these abilities show linear improvements with age, some abilities may temporarily worsen, reflecting both the restructuring and/or strengthening of connections within some brain systems. The current study uses resting state functional connectivity to examine developmental differences between late childhood and adulthood in task positive (TP) regions, which play a role in cognitive control functions, and task negative (TN) regions, which play a role in social cognition, self-referential, and internally-directed thought. Within the TP network, developmental differences in connectivity were found with the left dorsolateral prefrontal cortex. Within the TN network, developmental differences in connectivity were found with a broad area of the medial prefrontal cortex and the right parahippocampal gyrus. Connections between the two networks also showed significant developmental differences. Stronger anticorrelations were found in the TN maps of the adult group for the right anterior insula/inferior frontal gyrus, bilateral anterior inferior parietal lobule, bilateral superior parietal lobule and an anterior portion of the right posterior cingulate cortex. There was a significant brain–behavior relationship between the strength of anticorrelation in these regions and inhibitory control performance on two Go/No-go tasks suggesting that the development of anticorrelations between late childhood and adulthood supports mature inhibitory control. Overall, maturation of these networks occurred in specific regions which are associated with cognitive control of goal-directed behavior, including those involved in working memory, social cognition, and inhibitory control.     

Anterior cingulate activation relates to local cortical thickness

Few studies have examined the relationship between local anatomic thickness of the cortex and the activation signals arising from it. Using structural and functional MRI, we examined whether a relationship exists between cortical thickness and brain activation. Twenty-eight participants were asked to perform the Go/NoGo response inhibition task known to activate the anterior cingulate and the prefrontal cortex. Structural data of the same regions were simultaneously collected. We hypothesized that cortical thickness in these brain regions would positively correlate with brain activation. Data from the structural MRI were aligned with those of functional MRI activation. There was a positive linear correlation between cortical thickness and activation during response inhibition in the right anterior cingulate cortex (Brodmann's Area 24). No significant thickness-activation correlations were found in the prefrontal cortex. Correlations between cortical thickness and activation may occur only in certain brain regions.     

Putative Tests of Frontal Lobe Function: A PET-Study of Brain Activation During Stroop's Test and Verbal Fluency

Stroop's test and the Verbal Fluency test are commonly argued to be measures of the integrity of the prefrontal cortex. This assumption has only to some degree been confirmed by lesion studies. In the present study, Positron Emission Tomography (PET) with H 2 15 O was used to further validate Stroop's test and the Verbal Fluency as measures of frontal lobe function; both tests were implemented as activation paradigms during scanning of normal middleaged individuals. Stroop interference was found to activate the left anterior cingulate cortex, the supplementary motor cortex, thalamus, and the cerebellum. Although the prominent anterior cingulate activation is in the frontal lobe, it is not prefrontal. Verbal Fluency activated the left inferior frontal cortex and the left dorsolateral prefrontal cortex, the supplementary motor cortex, the anterior cingulate cortex and the cerebellum. These results bring this latter test closer to being a specific test of prefrontal function.     

Comparison of differential neuronal responsiveness for different regions of the prefrontal cortex in a conditional visual discrimination task

To investigate neuronal processing during monkeys' performance of a visual conditional discrimination task, recordings were made from four areas of prefrontal cortex (ventromedial, orbitofrontal, dorsolateral and anterior cingulate) where lesions have been shown to produce impairment of such tasks. Of 1911 recorded neurons, 573 (31%) responded to elements of the task. This proportion was less than the 50% previously reported as responsive in temporal cortex under the same conditions, suggesting sparser encoding in prefrontal than temporal cortex. Of the responsive prefrontal neurons, 165 (29%) responded differently on the different types of trial, so signalling various types of information relevant to task performance and cognition. In line with recent lesion findings, in the dorsolateral region the incidence of such differentially responsive neurons was only an eighth that in the other regions. The relatively high incidence of neuronal responses that encoded a potential instruction cue rather than specific individual stimulus arrangements was consistent with the animals solving the task by using such information, though other neuronal responses could have enabled the task to have been solved by rote learning. Compared to temporal neurons, prefrontal responses more frequently coded information relating to the planned behavioural response rather than perceptual aspects of the task. Population differential response latencies were long (> approximately 225 ms) in prefrontal cortex. A comparison of such differential latencies between temporal and prefrontal cortex indicated that potential information flow was likely to be primarily from temporal to prefrontal cortex rather than vice versa.     

Putative tests of frontal lobe function: a PET-study of brain activation during Stroop's Test and verbal fluency

Stroop's test and the Verbal Fluency test are commonly argued to be measures of the integrity of the prefrontal cortex. This assumption has only to some degree been confirmed by lesion studies. In the present study, Positron Emission Tomography (PET) with H(2)(15)O was used to further validate Stroop's test and the Verbal Fluency as measures of frontal lobe function; both tests were implemented as activation paradigms during scanning of normal middleaged individuals. Stroop interference was found to activate the left anterior cingulate cortex, the supplementary motor cortex, thalamus, and the cerebellum. Although the prominent anterior cingulate activation is in the frontal lobe, it is not prefrontal. Verbal Fluency activated the left inferior frontal cortex and the left dorsolateral prefrontal cortex, the supplementary motor cortex, the anterior cingulate cortex and the cerebellum. These results bring this latter test closer to being a specific test of prefrontal function.