Activity In Medial Frontal Cortex Research Articles

Identifying a consistent pattern of neural function in attention deficit hyperactivity disorder: a meta-analysis

The neurobiological underpinnings of attention deficit hyperactivity disorder (ADHD) are inconclusive. Activation abnormalities across brain regions in ADHD compared with healthy controls highlighted in task-based functional magnetic resonance imaging (fMRI) studies are heterogeneous. To identify a consistent pattern of neural dysfunction in ADHD, a meta-analysis of fMRI studies using Go/no-go, Stop and N-back tasks was undertaken. Several databases were searched using the key words: 'ADHD and fMRI' and 'ADHD and fMRI task'. In all, 20 studies met inclusion criteria comprising 334 patients with ADHD and 372 healthy controls and were split into N-back, Stop task and Go/no-go case-control groups. Using Signed Differential Mapping each batch was meta-analysed individually and meta-regression analyses were used to examine the effects of exposure to methylphenidate (MPH), length of MPH wash-out period, ADHD subtype, age and intelligence quotient (IQ) differences upon neural dysfunction in ADHD. Across all tasks less activity in frontal lobe regions compared with controls was detected. Less exposure to treatment and lengthier wash-out times resulted in less left medial frontal cortex activation in N-back and Go/no-go studies. Higher percentage of combined-type ADHD resulted in less superior and inferior frontal gyrus activation. Different IQ scores between groups were linked to reduced right caudate activity in ADHD. Consistent frontal deficits imply homogeneous cognitive strategies involved in ADHD behavioural control. Our findings suggest a link between fMRI results and the potentially normalizing effect of treatment and signify a need for segregated examination and contrast of differences in sample characteristics in future studies.

Frontal Oscillatory Dynamics Predict Feedback Learning and Action Adjustment

Frontal oscillatory dynamics in the theta (4-8 Hz) and beta (20-30 Hz) frequency bands have been implicated in cognitive control processes. Here we investigated the changes in coordinated activity within and between frontal brain areas during feedback-based response learning. In a time estimation task, participants learned to press a button after specific, randomly selected time intervals (300-2000 msec) using the feedback after each button press (correct, too fast, too slow). Consistent with previous findings, theta-band activity over medial frontal scalp sites (presumably reflecting medial frontal cortex activity) was stronger after negative feedback, whereas beta-band activity was stronger after positive feedback. Theta-band power predicted learning only after negative feedback, and beta-band power predicted learning after positive and negative feedback. Furthermore, negative feedback increased theta-band intersite phase synchrony (a millisecond resolution measure of functional connectivity) among right lateral prefrontal, medial frontal, and sensorimotor sites. These results demonstrate the importance of frontal theta- and beta-band oscillations and intersite communication in the realization of reinforcement learning.

One Action System or Two? Evidence for Common Central Preparatory Mechanisms in Voluntary and Stimulus-Driven Actions

Human behavior is comprised of an interaction between intentionally driven actions and reactions to changes in the environment. Existing data are equivocal concerning the question of whether these two action systems are independent, involve different brain regions, or overlap. To address this question we investigated whether the degree to which the voluntary action system is activated at the time of stimulus onset predicts reaction times to external stimuli. We recorded event-related potentials while participants prepared and executed left- or right-hand voluntary actions, which were occasionally interrupted by a stimulus requiring either a left- or right-hand response. In trials where participants successfully performed the stimulus-driven response, increased voluntary motor preparation was associated with faster responses on congruent trials (where participants were preparing a voluntary action with the same hand that was then required by the target stimulus), and slower responses on incongruent trials. This suggests that early hand-specific activity in medial frontal cortex for voluntary action trials can be used by the stimulus-driven system to speed responding. This finding questions the clear distinction between voluntary and stimulus-driven action systems.

Posterior Medial Frontal Cortex Activity Predicts Post-Error Adaptations in Task-Related Visual and Motor Areas

As Seneca the Younger put it, "To err is human, but to persist is diabolical." To prevent repetition of errors, human performance monitoring often triggers adaptations such as general slowing and/or attentional focusing. The posterior medial frontal cortex (pMFC) is assumed to monitor performance problems and to interact with other brain areas that implement the necessary adaptations. Whereas previous research showed interactions between pMFC and lateral-prefrontal regions, here we demonstrate that upon the occurrence of errors the pMFC selectively interacts with perceptual and motor regions and thereby drives attentional focusing toward task-relevant information and induces motor adaptation observed as post-error slowing. Functional magnetic resonance imaging data from an interference task reveal that error-related pMFC activity predicts the following: (1) subsequent activity enhancement in perceptual areas encoding task-relevant stimulus features; (2) activity suppression in perceptual areas encoding distracting stimulus features; and (3) post-error slowing-related activity decrease in the motor system. Additionally, diffusion-weighted imaging revealed a correlation of individual post-error slowing and white matter integrity beneath pMFC regions that are connected to the motor inhibition system, encompassing right inferior frontal gyrus and subthalamic nucleus. Thus, disturbances in task performance are remedied by functional interactions of the pMFC with multiple task-related brain regions beyond prefrontal cortex that result in a broad repertoire of adaptive processes at perceptual as well as motor levels.

Error-related medial frontal theta activity predicts cingulate-related structural connectivity

Studies on electrophysiological signatures of error processing have focused on the medial frontal cortex, although widespread neuroanatomical networks support error/action monitoring. Here, electrophysiological responses to errors were combined with structural white matter diffusion tensor imaging (DTI) to investigate the long-range anatomical networks that support error processing. The approach taken here was to link individual differences in error-related EEG responses to individual differences in white matter connectional anatomy. Twenty subjects performed a speeded instructed choice task (a variant of the Simon task) designed to elicit response errors, and also underwent DTI scanning in a separate session. In the EEG data, significantly enhanced theta (4–8Hz) oscillations were observed over medial frontal electrodes (centered on FCz) during response errors. Mid-frontal scalp sites (likely reflecting medial frontal cortex activity) also functioned as a strong “hub” for information flow, measured through theta-band phase synchronization degree. Next, a dipole source of the error-related theta-band activity was localized for each subject, accounting for approximately 80% of the topographical variance. Correlating individual differences in medial frontal theta dynamics with white matter tracts linking these dipole sources to the rest of the brain revealed that subjects with stronger error-related theta also had stronger white matter connectivity with the ventral striatum and inferior frontal gyrus. Further, subjects in whom medial frontal regions acted as a stronger synchronization “hub” had stronger connectivity between the dipole source location and the corpus callosum and dorsomedial prefrontal white matter pathways. These findings provide novel evidence for the role of widespread fronto-striatal networks in monitoring actions and signaling behavioral errors.

Conditional differences in mean reaction time explain effects of response congruency, but not accuracy, on posterior medial frontal cortex activity

According to the conflict-monitoring model of cognitive control, the posterior medial frontal cortex (pMFC) plays an important role in detecting conflict between competing motor responses. Consistent with this view, pMFC activity is greater in high-conflict trials (e.g., incongruent trials and errors) than in low-conflict trials (e.g., congruent trials and correct responses) of distractor interference tasks. However, in both low- and high-conflict trials, pMFC activity increases linearly with reaction time (RT). Thus, heightened pMFC activity in high-conflict trials may simply reflect the fact that mean RT is longer in high-conflict than in low-conflict trials. To investigate this hypothesis, we reanalyzed data from a previously published fMRI study in which participants performed an event-related version of the multi-source interference task. Critically, after controlling for conditional differences in mean RT, effects of response congruency on pMFC activity were eliminated; in contrast, effects of response accuracy on pMFC activity remained robust. These findings indicate that effects of response congruency on pMFC activity may index any of several processes whose recruitment increases with time on task (e.g., sustained attention). However, effects of response accuracy reflect processes unique to error trials. We conclude that effects of response accuracy on pMFC activity provide stronger support for the conflict-monitoring model than effects of response congruency.

Increased Dependence of Action Selection on Recent Motor History in Parkinson's Disease

It is well known that the basal ganglia are involved in switching between movement sequences. Here we test the hypothesis that this contribution is an instance of a more general role of the basal ganglia in selecting actions that deviate from the context defined by the recent motor history, even when there is no sequential structure to learn or implement. We investigated the effect of striatal dopamine depletion [in Parkinson's disease (PD)] on the ability to switch between independent action plans. PD patients with markedly lateralized signs performed a hand laterality judgment task that involved action selection of their most and least affected hand. Trials where patients selected the same (repeat) or the alternative (switch) hand as in a previous trial were compared, and this was done separately for the most and least affected hand. Behaviorally, PD patients showed switch-costs that were specific to the most affected hand and that increased with disease severity. Functional magnetic resonance imaging (fMRI) showed that this behavioral effect was related to the state of the frontostriatal system: as disease severity increased, contributions of the basal ganglia to the selection process and their effective connectivity with the medial frontal cortex (MFC) decreased, whereas involvement of the MFC increased. We conclude that the basal ganglia are important for rapidly switching toward novel motor plans even when there is no sequential structure to learn or implement. The enhanced MFC activity may result either from reduced focusing abilities of the basal ganglia or from compensatory processes.

Topographic analysis of individual activation patterns in medial frontal cortex in schizophrenia

Individual variability in the location of neural activations poses a unique problem for neuroimaging studies employing group averaging techniques to investigate the neural bases of cognitive and emotional functions. This may be especially challenging for studies examining patient groups, which often have limited sample sizes and increased intersubject variability. In particular, medial frontal cortex (MFC) dysfunction is thought to underlie performance monitoring dysfunction among patients with schizophrenia, yet previous studies using group averaging to compare schizophrenic patients to controls have yielded conflicting results. To examine individual activations in MFC associated with two aspects of performance monitoring, interference and error processing, functional magnetic resonance imaging data were acquired while 17 patients with schizophrenia and 21 healthy controls (HCs) performed an event-related version of the multisource interference task. Comparisons of averaged data revealed few differences between the groups. By contrast, topographic analysis of individual activations for errors showed that control subjects exhibited activations spanning across both posterior and anterior regions of MFC while patients primarily activated posterior MFC, possibly reflecting an impaired emotional response to errors in schizophrenia. This discrepancy between topographic and group-averaged results may be due to the significant dispersion among individual activations, particularly in HCs, highlighting the importance of considering intersubject variability when interpreting the medial frontal response to error commission.

Human Medial Frontal Cortex Activity Predicts Learning from Errors

Learning from errors is a critical feature of human cognition. It underlies our ability to adapt to changing environmental demands and to tune behavior for optimal performance. The posterior medial frontal cortex (pMFC) has been implicated in the evaluation of errors to control behavior, although it has not previously been shown that activity in this region predicts learning from errors. Using functional magnetic resonance imaging, we examined activity in the pMFC during an associative learning task in which participants had to recall the spatial locations of 2-digit targets and were provided with immediate feedback regarding accuracy. Activity within the pMFC was significantly greater for errors that were subsequently corrected than for errors that were repeated. Moreover, pMFC activity during recall errors predicted future responses (correct vs. incorrect), despite a sizeable interval (on average 70 s) between an error and the next presentation of the same recall probe. Activity within the hippocampus also predicted future performance and correlated with error-feedback-related pMFC activity. A relationship between performance expectations and pMFC activity, in the absence of differing reinforcement value for errors, is consistent with the idea that error-related pMFC activity reflects the extent to which an outcome is "worse than expected."

Drink alcohol and dim the lights: The impact of cognitive deficits on medial frontal cortex function

Scalp electroencephalogram (EEG) recordings indicate that regions in the medial frontal cortex (MFC) are active following errors. Alcohol consumption reduces this error-related activity, perhaps suggesting that alcohol disrupts the operation of an error-monitoring system in the MFC. However, it could also be that alcohol consumption affects the MFC only indirectly, by impairing stimulus processing and thus making errors harder to detect. This interpretation leads to the prediction that stimulus degradation should likewise reduce error-related activity in the MFC. To test this hypothesis, behavioral and EEG data were collected as participants performed a speeded response task with either bright or very dim stimuli. The results using dim stimuli replicated the observed effects of alcohol consumption-with slowed responses accompanied by reduced error-related MFC activity. The sensitivity of the MFC to disrupted processing elsewhere in the brain suggests complications in interpreting evidence of disturbed MFC function.

Functional and Biochemical Alterations of the Medial Frontal Cortex in Obsessive-Compulsive Disorder

The medial frontal cortex (MFC), including the dorsal anterior cingulate and the supplementary motor area, is critical for adaptive and inhibitory control of behavior. Abnormally high MFC activity has been a consistent finding in functional neuroimaging studies of obsessive-compulsive disorder (OCD). However, the precise regions and the neural alterations associated with this abnormality remain unclear. To examine the functional and biochemical properties of the MFC in patients with OCD. Cross-sectional study combining volume-localized proton magnetic resonance spectroscopy and functional magnetic resonance imaging with a task encompassing inhibitory control processes (the Multi-Source Interference Task) designed to activate the MFC. Healthy control participants and OCD patients recruited from the general community. Nineteen OCD patients (10 males and 9 females) and 19 age-, sex-, education-, and intelligence-matched control participants recruited from the general community. Psychometric measures of symptom severity, Multi-Source Interference Task behavioral performance, blood oxygen level-dependent activation, and proton magnetic resonance spectroscopy brain metabolite concentrations. Multi-Source Interference Task behavioral performance did not differ between OCD patients and control subjects. Reaction time interference and response errors were correlated with blood oxygen level-dependent activation in the dorsal anterior cingulate region in both groups. Compared with controls, OCD patients had greater relative activation of the supplementary motor area and deactivation of the rostral anterior cingulate during high- vs low-conflict (incongruent > congruent) trials. Patients with OCD also showed reduced levels of neuronal N-acetylaspartate in the dorsal anterior cingulate region, which was negatively correlated with their blood oxygen level-dependent activation of the region. Hyperactivation of the MFC during high- vs low-conflict conditions in patients with OCD may be a compensatory response to a neuronal abnormality in the region. This relationship may partly explain the nature of inhibitory control deficits that are frequently seen in this group and may serve as a focus of future treatment studies.

When Things Are Better or Worse than Expected: The Medial Frontal Cortex and the Allocation of Processing Resources

Access to limited-capacity neural systems of cognitive control must be restricted to the most relevant information. How the brain identifies and selects items for preferential processing is not fully understood. Anatomical models often place the selection mechanism in the medial frontal cortex (MFC), and one computational model proposes that the mesotelencephalic dopamine (DA) system, via its reward prediction properties, provides a "gate" through which information gains access to limited-capacity systems. There is a medial frontal event-related potential (ERP) index of attention selection, the anterior positivity (P2a), associated with DA reward system input to the MFC for the identification of task-relevant perceptual representations. The P2a has a similar spatio-temporal distribution as the medial frontal negativity (MFN), elicited to error responses or choices resulting in monetary loss. The MFN has also been linked to DA projections to the MFC but for action monitoring rather than attention selection. This study proposes that the P2a and the MFN reflect the same MFC evaluation function and use a passive reward prediction design containing neither instructed attention nor response to demonstrate that the ERP over medial frontal leads at the P2a/MFN latency is consistent with activity of midbrain DA neurons, positive to unpredicted rewards and negative when a predicted reward is withheld. This result suggests that MFC activity is regulated by DA reward system input and may function to identify items or actions that exceed or fail to meet motivational prediction.

Medial Frontal Cortex Activity and Loss-Related Responses to Errors

Making an error elicits activity from brain regions that monitor performance, especially the medial frontal cortex (MFC). However, uncertainty exists about whether the posterior or anterior/rostral MFC processes errors and to what degree affective responses to errors are mediated in the MFC, specifically the rostral anterior cingulate cortex (rACC). To test the hypothesis that rACC mediates a type of affective response, we conceptualized affect in response to an error as a reaction to loss and amplified this response with a monetary penalty. While subjects performed a cognitive interference task during functional magnetic resonance imaging, hemodynamic activity in the rACC was significantly greater when subjects lost money as a result of an error compared with errors that did not lead to monetary loss. A significant interaction between the incentive conditions and error events demonstrated that the effect was not merely attributable to working harder to win (or not lose) money, although an effect of motivation was noted in the mid-MFC. Activation foci also occurred in similar regions of the posterior MFC for error and interference processing, which were not modulated by the incentive conditions. However, at the level of the individual subject, substantial functional variability occurred along the MFC during error processing, including foci in the rostral/anterior extent of the MFC not appearing in the group analysis. The findings support the hypothesis that the rostral extent of the MFC (rACC) processes loss-related responses to errors, and individual differences may account for some of the reported variation of error-related foci in the MFC.

Neurophysiological correlates of error correction in sensorimotor-synchronization

In a sensorimotor synchronization task requiring subjects to tap in synchrony with an auditory stimulus, occasional perturbations (i.e., interval changes) in an otherwise isochronous sequence of auditory metronome stimuli are known to be compensated remarkably swift and with surprising precision, even when they are too small to be consciously perceived. To investigate the neural substrate and the informational basis of error correction in sensorimotor synchronization, we recorded movement-related, auditory-evoked, and error-related EEG potentials. Experiment 1 confirmed rapid adjustment to stimulus phase shifts, with faster correction of large (50 ms) compared to small (15 ms) shifts. In addition to being corrected faster, there was overcorrection of the 50 ms shifts, attributed to engagement of period correction mechanisms. For +50 ms shifts, a neural correlate of period correction was identified in the form of medial frontal cortex activation, preceded by an error-related brain potential (ERN). Auditory-evoked potential (AEP) amplitudes were sensitive to stimulus phase shifts of both large and small magnitude. Further experiments with a smaller magnitude 10 ms phase shift (Experiment 2) and passive auditory stimulation (Experiment 3) provided evidence that the modulation of AEP amplitudes is not due to metronome interval changes, but may represent auditory-somatosensory activation. Together, behavioral and neurophysiological data support the hypothesis that phase correction is a largely automatic process, not dependent on conscious perception of changes in timing. By contrast, perceivable phase shifts may invoke timekeeper adjustments accompanied by medial frontal cortex activity.

Perception and judgement of physical causality involve different brain structures

One basic type of ‘mechanical’ causality is that which occurs between physical objects. Subjects were presented with mechanically causal events (ball collides with and causes movement of another ball) or two non-causal events (a ball either passes underneath another ball, or rolls across the screen and changes colour). We investigated which brain regions exhibit increased activity during the judgement of causality (‘judged causality’) as compared with judgement of movement direction (‘perceived causality’). We show an increase of medial frontal cortex activity when subjects were explicitly instructed to search for causality. Moreover, this increase was specifically associated with the search for causality and not with the perception of causality because the signal increase occurs whatever the nature of the stimulus (causal or non causal). Our study provides evidence for brain regions involved in a conscious level of inference about the presence of causality.

Fear Conditioning-Induced Alterations of Phospholipase C-β1a Protein Level and Enzyme Activity in Rat Hippocampal Formation and Medial Frontal Cortex

We investigated the effects of one-trial fear conditioning on phospholipase C-β1a catalytic activity and protein level in hippocampal formation and medial frontal cortex of untreated control rats and rats prenatally exposed to ethanol. One hour following fear conditioning of untreated control rats, phospholipase C-β1a protein level was increased in the hippocampal cytosolic fraction and decreased in the hippocampal membrane and cortical cytosolic and cortical membrane fractions. Twenty-four hours after fear conditioning, phospholipase C-β1a protein level was reduced in the hippocampal cytosolic fraction and elevated in the cortical nuclear fraction; in addition, 24 h after conditioning, phospholipase C-β1a activity in the cortical cytosolic fraction was increased. Rats that were exposed prenatally to ethanol displayed attenuated contextual fear conditioning, whereas conditioning to the acoustic-conditioned stimulus was not different from controls. In behavioral control (unconditioned) rats, fetal ethanol exposure was associated with reduced phospholipase C-β1a enzyme activity in the hippocampal nuclear, cortical cytosolic, and cortical membrane fractions and increased phospholipase C-β1a protein level in the hippocampal membrane and cortical cytosolic fractions. In certain cases, prenatal ethanol exposure modified the relationship between fear conditioning and changes in phospholipase C-β1a protein level and/or activity. The majority of these effects occurred 1 h, rather than 24 h, after fear conditioning. Multivariate analysis of variance revealed interactions between fear conditioning, subcellular fraction, and prenatal ethanol exposure for measures of phospholipase C-β1a protein level in hippocampal formation and phospholipase C-β1a enzyme activity in medial frontal cortex. In the majority of cases, fear conditioning-induced changes in hippocampal phospholipase C-β1a protein level were augmented in rats prenatally exposed to ethanol. In contrast, fear conditioning-induced changes in cortical phospholipase C-β1a activity were, often, in opposite directions in prenatal ethanol-exposed compared to diet control rats. We speculate that alterations in subcellular phospholipase C-β1a catalytic activity and protein level contribute to contextual fear conditioning and that learning deficits observed in rats exposed prenatally to ethanol result, in part, from dysfunctions in phospholipase C-β1a signal transduction.

Prefrontal-cingulate interactions in action monitoring.

We found that medial frontal cortex activity associated with action monitoring (detecting errors and behavioral conflict) depended on activity in the lateral prefrontal cortex. We recorded the error-related negativity (ERN), an event-related brain potential proposed to reflect anterior cingulate action monitoring, from individuals with lateral prefrontal damage or age-matched or young control participants. In controls, error trials generated greater ERN activity than correct trials. In individuals with lateral prefrontal damage, however, correct-trial ERN activity was equal to error-trial ERN activity. Lateral prefrontal damage also affected corrective behavior. Thus the lateral prefrontal cortex seemed to interact with the anterior cingulate cortex in monitoring behavior and in guiding compensatory systems.

Activation of Medial Frontal Cortex due to Deep Brain Stimulation of Subthalamic Nucleus in Parkinson's Disease-Positron Emission Tomography Study

Activation of Medial Frontal Cortex due to Deep Brain Stimulation of Subthalamic Nucleus in Parkinson's Disease-Positron Emission Tomography Study

Neuronal activity in medial frontal cortex during learning of sequential procedures.

To study the role of medial frontal cortex in learning and memory of sequential procedures, we examined neuronal activity of the presupplementary motor area (pre-SMA) and supplementary motor area (SMA) while monkeys (n = 2) performed a sequential button press task, "2 x 5 task." In this paradigm, 2 of 16 (4 x 4 matrix) light-emitting diode buttons (called "set") were illuminated simultaneously and the monkey had to press them in a predetermined order. A total of five sets (called "hyperset") was presented in a fixed order for completion of a trial. We examined the neuronal activity of each cell using two kinds of hypersets: new hypersets that the monkey experienced for the first time for which he had to find the correct orders of button presses by trial-and-error and learned hypersets that the monkey had learned with extensive practice (n = 16 and 10 for each monkey). To investigate whether cells in medial frontal cortex are involved in the acquisition of new sequences or execution of well-learned procedures, we examined three to five new hypersets and three to five learned hypersets for each cell. Among 345 task-related cells, we found 78 cells that were more active during performance of new hypersets than learned hypersets (new-preferring cells) and 18 cells that were more active for learned hypersets (learned-preferring cells). Among new-preferring cells, 33 cells showed a learning-dependent decrease of cell activity: their activity was highest at the beginning of learning and decreased as the animal acquired the correct response for each set with increasing reliability. In contrast, 11 learned-preferring cells showed a learning-dependent increase of neuronal activity. We found a difference in the anatomic distribution of new-preferring cells. The proportion of new-preferring cells was greater in the rostral part of the medial frontal cortex, corresponding to the pre-SMA, than the posterior part, the SMA. There was some trend that learned-preferring cells were more abundant in the SMA. These results suggest that the pre-SMA, rather than SMA, is more involved in the acquisition of new sequential procedures.