Multimodal neuroimaging dissociates hemodynamic and electrophysiological correlates of error processing.

Recognizing errors and adjusting responses are fundamental to adaptive behavior. The error-related negativity (ERN) and error-related functional MRI (fMRI) activation of the dorsal anterior cingulate cortex (dACC) index these processes and are thought to reflect the same neural mechanism. In the present study, we evaluated this hypothesis. Although errors elicited robust dACC activation using fMRI, combined electroencephalography and magnetoencephalography data localized the ERN to the posterior cingulate cortex (PCC). ERN amplitude correlated with fMRI activation in both the PCC and dACC, and these two regions showed coordinated activity based on functional connectivity MRI. Finally, increased microstructural integrity of the posterior cingulum bundle, as measured by diffusion tensor imaging, predicted faster error correction. These findings suggest that the PCC generates the ERN and communicates with the dACC to subserve error processing. They challenge current models that view fMRI activation of the dACC as the hemodynamic reflection of the ERN.

Pre-cue fronto-occipital alpha phase and distributed cortical oscillations predict failures of cognitive control.

Cognitive control is required for correct performance on antisaccade tasks, including the ability to inhibit an externally driven ocular motor response (a saccade to a peripheral stimulus) in favor of an internally driven ocular motor goal (a saccade directed away from a peripheral stimulus). Healthy humans occasionally produce errors during antisaccade tasks, but the mechanisms associated with such failures of cognitive control are uncertain. Most research on cognitive control failures focuses on poststimulus processing, although a growing body of literature highlights a role of intrinsic brain activity in perceptual and cognitive performance. The current investigation used dense array electroencephalography and distributed source analyses to examine brain oscillations across a wide frequency bandwidth in the period before antisaccade cue onset. Results highlight four important aspects of ongoing and preparatory brain activations that differentiate error from correct antisaccade trials: (1) ongoing oscillatory beta (20-30 Hz) power in anterior cingulate before trial initiation (lower for error trials); (2) instantaneous phase of ongoing alpha/theta (7 Hz) in frontal and occipital cortices immediately before trial initiation (opposite between trial types); (3) gamma power (35-60 Hz) in posterior parietal cortex 100 ms before cue onset (greater for error trials); and (4) phase locking of alpha (5-12 Hz) in parietal and occipital cortices immediately before cue onset (lower for error trials). These findings extend recently reported effects of pre-trial alpha phase on perception to cognitive control processes and help identify the cortical generators of such phase effects.

Practice-related changes in neural activation patterns investigated via wavelet-based clustering analysis.

OBJECTIVES: To evaluate brain activation using functional magnetic resonance imaging (fMRI) and specifically, activation changes across time associated with practice-related cognitive control during eye movement tasks. EXPERIMENTAL DESIGN: Participants were engaged in antisaccade performance (generating a glance away from a cue) while fMR images were acquired during two separate test sessions: (1) at pre-test before any exposure to the task and (2) at post-test, after 1 week of daily practice on antisaccades, prosaccades (glancing toward a target), or fixation (maintaining gaze on a target). PRINCIPAL OBSERVATIONS: The three practice groups were compared across the two test sessions, and analyses were conducted via the application of a model-free clustering technique based on wavelet analysis. This series of procedures was developed to avoid analysis problems inherent in fMRI data and was composed of several steps: detrending, data aggregation, wavelet transform and thresholding, no trend test, principal component analysis (PCA), and K-means clustering. The main clustering algorithm was built in the wavelet domain to account for temporal correlation. We applied a no trend test based on wavelets to significantly reduce the high dimension of the data. We clustered the thresholded wavelet coefficients of the remaining voxels using PCA K-means clustering. CONCLUSION: Over the series of analyses, we found that the antisaccade practice group was the only group to show decreased activation from pre-test to post-test in saccadic circuitry, particularly evident in supplementary eye field, frontal eye fields, superior parietal lobe, and cuneus.

Saccadic preparation in the frontal eye field is modulated by distinct trial history effects as revealed by magnetoencephalography.

Optimizing outcomes involves rapidly and continuously adjusting behavior based on context. While most behavioral studies focus on immediate task conditions, responses to events are also influenced by recent history. We used magnetoencephalography and a saccadic paradigm to investigate the neural bases of 2 trial history effects that are well characterized in the behavioral eye movement literature: task-switching and the prior-antisaccade effect. We found that switched trials were associated with increased errors and transient increases in activity in the frontal eye field (FEF) and anterior cingulate cortex early in the preparatory period. These activity changes are consistent with active reconfiguration of the task set, a time-limited process that is triggered by the instructional cue. Following an antisaccade versus prosaccade, there was increased activity in the FEF and prefrontal cortex that persisted into the preparatory period of the subsequent trial, and saccadic latencies were prolonged. We attribute these effects to persistent inhibition of the ocular motor response system from the prior antisaccade. These findings refine our understanding of how trial history interacts with current task demands to adjust responses. Such dynamic modulations of neural activity and behavior by recent experience are at the heart of adaptive flexible behavior.

Preparatory activations across a distributed cortical network determine production of express saccades in humans.

Reaction time variability across trials to identical stimuli may arise from both ongoing and transient neural processes occurring before trial onset. These processes were examined with dense-array EEG as humans completed saccades in a "gap" paradigm known to elicit bimodal variability in response times, including separate populations of "express" and regular reaction time saccades. Results indicated that express reaction time trials could be differentiated from regular reaction time trials by (1) pretrial phase synchrony of occipital cortex oscillations in the 8-9 Hz (low alpha) frequency range (lower phase synchrony preceding express trials), (2) subsequent mid- and late-gap period cortical activities across a distributed occipital-parietal network (stronger activations preceding express trials), and (3) posttarget parietal activations locked to response generation (weaker preceding express trials). A post hoc path analysis suggested that the observed cortical activations leading to express saccades are best understood as an interdependent chain of events that affect express saccade production. These results highlight the importance of a distributed posterior cortical network, particularly in right hemisphere, that prepares the saccade system for rapid responding.

Reduced functional connectivity in a right-hemisphere network for volitional ocular motor control in schizophrenia.

Patients with schizophrenia consistently show deficient performance on tasks requiring volitional saccades. We previously reported reduced fractional anisotropy in the white matter underlying right dorsal anterior cingulate cortex in schizophrenia, which, along with lower fractional anisotropy in the right frontal eye field and posterior parietal cortex, predicted longer latencies of volitional saccades. This suggests that reduced microstructural integrity of dorsal anterior cingulate cortex white matter disrupts connectivity in the right hemisphere-dominant network for spatial attention and volitional ocular motor control. To test this hypothesis, we examined functional connectivity of the cingulate eye field component of this network, which is located in dorsal anterior cingulate cortex, during a task comprising volitional prosaccades and antisaccades. In patients with schizophrenia, we expected to find reduced functional connectivity, specifically in the right hemisphere, which predicted prolonged saccadic latency. Twenty-seven medicated schizophrenia outpatients and 21 demographically matched healthy controls performed volitional saccades during functional magnetic resonance imaging. Based on task-related activation, seed regions in the right and left cingulate eye field were defined. In both groups, the right and left cingulate eye field showed positive correlations with the ocular motor network and negative correlations with the default network. Patients showed reduced positive functional connectivity of the cingulate eye field, specifically in the right hemisphere. Negative functional connectivity of the right cingulate eye field predicted faster saccades, but these relations differed by group, and were only present in controls. This pattern of relations suggests that the coordination of activity between ocular motor and default networks is important for efficient task performance and is disrupted in schizophrenia. Along with prior observations of reduced white matter microstructural integrity (fractional anisotropy) in schizophrenia, the present finding of reduced functional connectivity suggests that functional and structural abnormalities of the right cingulate eye field disrupt connectivity in the network for spatial attention and volitional ocular motor control. These abnormalities may contribute to deficits in overcoming prepotency in the service of directing eye gaze and attention to the parts of the environment that are the most behaviourally relevant.

Neurophysiology and neuroanatomy of reflexive and volitional saccades: evidence from studies of humans.

This review provides a summary of the contributions made by human functional neuroimaging studies to the understanding of neural correlates of saccadic control. The generation of simple visually guided saccades (redirections of gaze to a visual stimulus or pro-saccades) and more complex volitional saccades require similar basic neural circuitry with additional neural regions supporting requisite higher level processes. The saccadic system has been studied extensively in non-human (e.g., single-unit recordings) and human (e.g., lesions and neuroimaging) primates. Considerable knowledge of this system's functional neuroanatomy makes it useful for investigating models of cognitive control. The network involved in pro-saccade generation (by definition largely exogenously-driven) includes subcortical (striatum, thalamus, superior colliculus, and cerebellar vermis) and cortical (primary visual, extrastriate, and parietal cortices, and frontal and supplementary eye fields) structures. Activation in these regions is also observed during endogenously-driven voluntary saccades (e.g., anti-saccades, ocular motor delayed response or memory saccades, predictive tracking tasks and anticipatory saccades, and saccade sequencing), all of which require complex cognitive processes like inhibition and working memory. These additional requirements are supported by changes in neural activity in basic saccade circuitry and by recruitment of additional neural regions (such as prefrontal and anterior cingulate cortices). Activity in visual cortex is modulated as a function of task demands and may predict the type of saccade to be generated, perhaps via top-down control mechanisms. Neuroimaging studies suggest two foci of activation within FEF - medial and lateral - which may correspond to volitional and reflexive demands, respectively. Future research on saccade control could usefully (i) delineate important anatomical subdivisions that underlie functional differences, (ii) evaluate functional connectivity of anatomical regions supporting saccade generation using methods such as ICA and structural equation modeling, (iii) investigate how context affects behavior and brain activity, and (iv) use multi-modal neuroimaging to maximize spatial and temporal resolution.

Basal ganglia-thalamocortical circuitry disruptions in schizophrenia during delayed response tasks.

BACKGROUND: Schizophrenia is characterized by executive functioning deficits, presumably mediated by prefrontal cortex dysfunction. For example, schizophrenia participants show performance deficits on ocular motor delayed response (ODR) tasks, which require both inhibition and spatial working memory for correct performance. METHODS: The present functional magnetic resonance imaging (fMRI) study compared neural activity of 14 schizophrenia and 14 normal participants while they performed ODR tasks. RESULTS: Schizophrenia participants generated: 1) more trials with anticipatory saccades (saccades made during the delay period), 2) memory saccades with longer latencies, and 3) memory saccades of decreased accuracy. Increased blood oxygenation level-dependent (BOLD) signal changes were observed in both groups in ocular motor circuitry (e.g., supplementary eye fields [SEF], lateral frontal eye fields [FEF], inferior parietal lobule [IPL], cuneus, and precuneus). The normal, but not the schizophrenia, group demonstrated BOLD signal changes in dorsolateral prefrontal regions (right Brodmann area [BA] 9 and bilateral BA 10), medial FEF, insula, thalamus, and basal ganglia. Correlations between percentage of anticipatory saccade trials and BOLD signal changes were more similar between groups for subcortical regions and less similar for cortical regions. CONCLUSIONS: These results suggest that executive functioning deficits in schizophrenia may be associated with dysfunction of the basal ganglia-thalamocortical circuitry, evidenced by decreased prefrontal cortex, basal ganglia, and thalamus activity in the schizophrenia group during ODR task performance.

Electroencephalography/magnetoencephalography study of cortical activities preceding prosaccades and antisaccades.

The temporal and spatial characteristics of brain activity preceding prosaccades and antisaccades were investigated using source reconstructions of 64-channel electroencephalography and 148-channel magnetoencephalography data. Stimulus-locked data showed early cuneus activity was stronger during antisaccades, and later occipital gyrus activity was stronger preceding prosaccades, which suggests a top-down influence on early visual processing. Response-locked data showed that supplementary eye field, prefrontal cortex, and medial frontal eye field activity was greater for antisaccades than for prosaccades prior to saccade generation. Lateral frontal eye field activity appeared to be inhibited prior to antisaccade response generation. The spatial and temporal resolution of combined electroencephalography/magnetoencephalography data allows the evaluation of specific cortical activities preceding saccades and for demonstration of how activities differ as a function of response contingencies.

Neural correlates of behavioral variation in healthy adults' antisaccade performance.

Cognitive control is required for correct antisaccade performance. High antisaccade error rates characterize certain psychiatric disorders, but can be highly variable, even among healthy groups. Antisaccade data were acquired from a large sample of healthy undergraduates, and error rate was quantified. Participants who reliably made few errors (good, n = 13) or many errors (poor, n = 13) were recruited back to perform antisaccades during fMRI acquisition. A data-derived model was used to compare signal between good and poor performers during blocks of antisaccade trials. Behaviorally derived regressors were used to compare signal between good and poor performers during correct and error trials. Results show differential activation in middle frontal gyrus and inferior parietal lobule between good and poor performers, suggesting that failure to recruit these top-down control regions corresponds to poor antisaccade performance in healthy young adults.

Network dynamics underlying speed-accuracy trade-offs in response to errors.

The ability to dynamically and rapidly adjust task performance based on its outcome is fundamental to adaptive, flexible behavior. Over trials of a task, responses speed up until an error is committed and after the error responses slow down. These dynamic adjustments serve to optimize performance and are well-described by the speed-accuracy trade-off (SATO) function. We hypothesized that SATOs based on outcomes reflect reciprocal changes in the allocation of attention between the internal milieu and the task-at-hand, as indexed by reciprocal changes in activity between the default and dorsal attention brain networks. We tested this hypothesis using functional MRI to examine the pattern of network activation over a series of trials surrounding and including an error. We further hypothesized that these reciprocal changes in network activity are coordinated by the posterior cingulate cortex (PCC) and would rely on the structural integrity of its white matter connections. Using diffusion tensor imaging, we examined whether fractional anisotropy of the posterior cingulum bundle correlated with the magnitude of reciprocal changes in network activation around errors. As expected, reaction time (RT) in trials surrounding errors was consistent with predictions from the SATO function. Activation in the default network was: (i) inversely correlated with RT, (ii) greater on trials before than after an error and (iii) maximal at the error. In contrast, activation in the right intraparietal sulcus of the dorsal attention network was (i) positively correlated with RT and showed the opposite pattern: (ii) less activation before than after an error and (iii) the least activation on the error. Greater integrity of the posterior cingulum bundle was associated with greater reciprocity in network activation around errors. These findings suggest that dynamic changes in attention to the internal versus external milieu in response to errors underlie SATOs in RT and are mediated by the PCC.

Anomalous use of context during task preparation in schizophrenia: a magnetoencephalography study.

BACKGROUND: Impaired ability to use contextual information to optimally prepare for tasks contributes to performance deficits in schizophrenia. We used magnetoencephalography and an antisaccade task to investigate the neural basis of this deficit. METHODS: In schizophrenia patients and healthy control participants, we examined the difference in preparatory activation to cues indicating an impending antisaccade or prosaccade. We analyzed activation for correct trials only and focused on the network for volitional ocular motor control-frontal eye field (FEF), dorsal anterior cingulate cortex (dACC), and the ventrolateral and dorsolateral prefrontal cortex (VLPFC, DLPFC). RESULTS: Compared with control subjects, patients made more antisaccade errors and showed reduced differential preparatory activation in the dACC and increased differential preparatory activation in the VLPFC. In patients only, antisaccade error rates correlated with preparatory activation in the FEF, DLPFC, and VLPFC. CONCLUSIONS: In schizophrenia, reduced differential preparatory activation of the dACC may reflect reduced signaling of the need for control. Greater preparatory activation in the VLPFC and the correlations of error rate with FEF, DLPFC, and VLPFC activation may reflect that patients who are more error prone require stronger activation in these regions for correct performance. These findings provide the first evidence of abnormal task preparation, distinct from response generation, during volitional saccades in schizophrenia. We conclude that schizophrenia patients are impaired in using task cues to modulate cognitive control and that this contributes to deficits inhibiting prepotent but contextually inappropriate responses and to behavior that is stimulus bound and error prone rather than flexibly guided by context.

Evidence from cluster analysis for differentiation of antisaccade performance groups based on speed/accuracy trade-offs.

Anti and pro-saccade performance in single or mixed contexts was explored in a large sample of young adults (n=281). ANOVAs were first conducted to evaluate trial type, context and gender effects. A cluster analysis was then used to determine whether subgroups could be identified based on saccadic performance variables. Increased antisaccade errors were observed among females and during mixed-saccade runs. Cluster analysis identified two groups: 1) increased errors clustered with faster latencies and 2) decreased errors clustered with slower latencies. These data offer justification for examining subgroups based on saccadic performance and may help elucidate mechanisms underlying response variability within and between different populations.

Abnormally persistent fMRI activation during antisaccades in schizophrenia: a neural correlate of perseveration?

OBJECTIVE: Impaired antisaccade performance is a consistent cognitive finding in schizophrenia. Antisaccades require both response inhibition and volitional motor programming, functions that are essential to flexible responding. We investigated whether abnormal timing of hemodynamic responses (HDRs) to antisaccades might contribute to perseveration of ocular motor responses in schizophrenia. We focused on the frontal eye field (FEF), which has been implicated in the persistent effects of antisaccades on subsequent responses in healthy individuals. METHOD: Eighteen chronic, medicated schizophrenia outpatients and 15 healthy controls performed antisaccades and prosaccades during functional MRI. Finite impulse response models provided unbiased estimates of event-related HDRs. We compared groups on the peak amplitude, time-to-peak, and full-width half-max of the HDRs. RESULTS: In patients, HDRs in bilateral FEF were delayed and prolonged but ultimately of similar amplitude to that of controls. These abnormalities were present for antisaccades, but not prosaccades, and were not seen in a control region. More prolonged HDRs predicted slower responses in trials that followed an antisaccade. This suggests that persistent FEF activity following an antisaccade contributes to inter-trial effects on latency. CONCLUSIONS: Delayed and prolonged HDRs for antisaccades in schizophrenia suggest that the functions necessary for successful antisaccade performance take longer to implement and are more persistent. If abnormally persistent neural responses on cognitively demanding tasks are a more general feature of schizophrenia, they may contribute to response perseveration, a classic behavioral abnormality. These findings also underscore the importance of evaluating the temporal dynamics of neural activity to understand cognitive dysfunction in schizophrenia.

MTHFR 677C>T effects on anterior cingulate structure and function during response monitoring in schizophrenia: a preliminary study.

Patients with schizophrenia exhibit deficient response monitoring as indexed by blunted activation of the dorsal anterior cingulate cortex (dACC) and functionally related regions during error commission. This pattern may reflect heritable alterations of dACC function. We examined whether the hypofunctional 677C>T variant in MTHFR, a candidate schizophrenia risk gene, contributed to our previous findings of blunted error-related dACC activation and reduced microstructural integrity of dACC white matter. Eighteen medicated outpatients with schizophrenia underwent diffusion tensor imaging and performed an antisaccade paradigm during functional magnetic resonance imaging (fMRI). T allele carriers exhibited significantly less error-related activation than C/C patients in bilateral dACC and substantia nigra, regions that are thought to mediate dopamine-dependent error-based reinforcement learning. T carrier patients also showed significantly lower fractional anisotropy in bilateral dACC. These findings suggest that the MTHFR 677T allele blunts response monitoring in schizophrenia, presumably via effects on dopamine signaling and dACC white matter microstructural integrity.

A hypomethylating variant of MTHFR, 677C>T, blunts the neural response to errors in patients with schizophrenia and healthy individuals.

BACKGROUND: Responding to errors is a critical first step in learning from mistakes, a process that is abnormal in schizophrenia. To gain insight into the neural and molecular mechanisms of error processing, we used functional MRI to examine effects of a genetic variant in methylenetetrahydrofolate reductase (MTHFR 677C>T, rs1801133) that increases risk for schizophrenia and that has been specifically associated with increased perseverative errors among patients. MTHFR is a key regulator of the intracellular one-carbon milieu, including DNA methylation, and each copy of the 677T allele reduces MTHFR activity by 35%. METHODOLOGY/PRINCIPAL FINDINGS: Using an antisaccade paradigm, we found that the 677T allele induces a dose-dependent blunting of dorsal anterior cingulate cortex (dACC) activation in response to errors, a pattern that was identical in healthy individuals and patients with schizophrenia. Further, the normal relationship between dACC activation and error rate was disrupted among carriers of the 677T allele. CONCLUSIONS/SIGNIFICANCE: These findings implicate an epigenetic mechanism in the neural response to errors, and provide insight into normal cognitive variation through a schizophrenia risk gene.

Common neural circuitry supporting volitional saccades and its disruption in schizophrenia patients and relatives.

BACKGROUND: People with schizophrenia and their biological relatives have deficits in executive control processes such as inhibition and working memory as evidenced by performance abnormalities on antisaccade (AS) and ocular motor delayed response (ODR) tasks. METHODS: The present functional magnetic resonance imaging (fMRI) study was conducted to investigate brain activity associated with these putative indices of schizophrenia risk by: 1) directly comparing neural functioning in 15 schizophrenia patients, 13 of their first-degree biological relatives (primarily siblings), and 14 healthy participants; and 2) assessing executive function associated with volitional saccades by using a combination of AS and ODR tasks. RESULTS: Behavioral data showed that patients and relatives both made more volitional saccade errors. Imaging data demonstrated that within the context of preserved activity in some neural regions in patients and relatives, there were two distinct patterns of disruptions in other regions. First, there were deficits observed only in the schizophrenia group (decreased activity in lateral frontal eye field and supplementary eye field), suggesting a change associated with disease manifestation. Second, there were deficits observed in both patients and relatives (decreased activity in middle occipital gyrus, insula, cuneus, anterior cingulate, and Brodmann area 10 in prefrontal cortex), indicating a potential association with disease risk. CONCLUSIONS: Results indicate that decreased brain activation in regions involved in managing and evaluating early sensory and attention processing might be associated with poor volitional saccade control and risk for developing schizophrenia.

An effect of context on saccade-related behavior and brain activity.

The present study evaluated the effect of context on behavior and brain activity during saccade tasks. FMRI and eye movement data were collected while 36 participants completed three runs in a block design: (1) fixation alternating with pro-saccades, (2) fixation alternating with anti-saccades, and (3) pro- alternating with anti-saccades. Two task-related data-driven regressors, identified using independent component analysis, were used in GLM analyses. Brain activity associated with anti- and pro-saccades were compared under both single (runs 1 and 2) and mixed saccade (run 3) conditions. Brain areas consistently associated with anti-saccades in previous studies, including striatum, thalamus, cuneus, precuneus, lateral and medial frontal eye fields (FEF), supplementary eye fields (SEF), and prefrontal cortex (PFC) showed significantly greater percent signal change during the fixation/anti- compared with the fixation/pro-saccade run. During the pro/anti run, however, only precuneus, SEF and FEF showed greater activation during the anti-saccade trials. This is a clear demonstration that the saccade-related neural circuitry is affected by context. Behavioral results suggest that performance on saccade tasks is also affected by context. Participants made more direction errors on pro-trials that followed anti-trials than on pro-trials that followed fixation. Results from this study indicate that precuneus, SEF and FEF, which showed anti-saccade-related activity during both comparisons, may be more important for supporting this complex behavioral response. Other brain regions, such as PFC, however, which showed anti-saccade-related activity during only the single task comparison, may be more involved in response selection and/or context updating.

A magnetoencephalography investigation of neural correlates for social exclusion and self-control.

Past research indicates that social exclusion leads to self-control failure. The present research examined the neural substrates of this effect. Participants were randomly assigned to either a social exclusion (n=15) or control (n=15) condition. Self-control was assessed by having participants solve 180 moderately difficult math problems while measuring how quickly they identified a supplied answer as correct or incorrect. Magnetoencephalography (MEG) was used to assess neural activity during this task. Socially excluded participants showed lesser activity in occipital and parietal cortex from 100-350 ms after the presentation of the math problems. When presented with the answers, socially excluded participants showed lesser activity in several regions, including occipital, parietal, and right prefrontal cortex from 100-300 ms post-stimulus. Furthermore, activation in the parietal and right prefrontal cortex mediated exclusion-control performance differences on math problems. The findings suggest that social exclusion interferes with the executive control of attention, and this effect is manifest in specific aspects of cognitive performance and brain function.

Behavioral plasticity of antisaccade performance following daily practice.

The ability to change behavior to adapt to the environment, known as behavioral plasticity, is an important part of daily life. In the present study subjects' performances on antisaccade tasks were manipulated by training them on one of three different eye movement tasks (antisaccade, prosaccade, and fixation). Thirty subjects were tested at three time points over a 2-week period and practiced their assigned task every day between test sessions. Subjects who trained on antisaccades significantly decreased their error rates, while maintaining their reaction time, suggesting that accuracy did not improve at the expense of speed. Subjects who practiced the prosaccade task made more errors on the antisaccade task on subsequent test sessions, while those who practiced the fixation task showed no change across test sessions. These results suggest that deliberate practice of eye movement tasks can alter antisaccade performance, and that the direction of the effect is dependent upon the type of practice in which the subject engages.