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.     

Prefrontal unit activity during delayed alternation in the monkey. I. Relation to direction of response

Single unit activity was recorded from the area midprincipalis of the dorsolateral prefrontal cortex during delayed alternation (DA) in one monkey. Out of 502 units studied in both hemispheres, 198 showed a relation to aspects of the DA task. Half of these related units showed a differential firing pattern depending on the trial (left or right). In 26 units the discharge frequency during delay was different between right and left trials. In no case, however, was such selectivity during delay found in a cue-guided control task.An anticipatory change toward the end of the delay period was observed in many units.Possible functional roles of related units were discussed.     

Attenuated left prefrontal activation during a verbal fluency task in patients with depression

Functional neuroimaging studies on patients with depression have found abnormal activity in the left prefrontal and anterior cingulate cortex compared with healthy controls. Other studies have shown that these regions become active in healthy subjects during verbal fluency tasks, while patients with depression show impaired performance on such tasks. We used functional magnetic resonance imaging to investigate changes in cerebral blood oxygenation associated with a verbal fluency task in depressed patients and healthy volunteers. In contrast to 10 age- and sex-matched healthy control subjects who activated the left prefrontal cortex and the anterior cingulate cortex during word generation, 10 depressed subjects showed attenuated activation in the left prefrontal cortex and did not show significant activation in the anterior cingulate cortex. These findings suggest that impaired performance during verbal fluency task in depressed patients is associated with abnormal neural responses within these regions.     

Anticipatory activity in rat medial prefrontal cortex during a working memory task

Objective Working memory is a key cognitive function in which the prefrontal cortex plays a crucial role. This study aimed to show the firing patterns of a neuronal population in the prefrontal cortex of the rat in a working memory task and to explore how a neuronal ensemble encodes a working memory event.Methods Sprague-Dawley rats were trained in a Y-maze until they reached an 80%correct rate in a working memory task.Then a 16-channel microelectrode array was implanted in the prefrontal cortex.After recovery,neuronal population activity was recorded during the task, using the Cerebus data-acquisition system.Spatio-temporal trains of action potentials were obtained from the original neuronal population signals.Results During the Y-maze working memory task,some neurons showed significantly increased firing rates and evident neuronal ensemble activity.Moreover,the anticipatory activity was associated with the delayed alternate choice of the upcoming movement.In correct trials,the averaged pre-event firing rate(10.86±1.82 spikes/ bin) was higher than the post-event rate(8.17±1.15 spikes/bin)(P <0.05).However,in incorrect trials,the rates did not differ.Conclusion The results indicate that the anticipatory activity of a neuronal ensemble in the prefrontal cortex may play a role in encoding working memory events.     

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.     

The effect of cingulate cortex lesions on task switching and working memory

Anatomic interconnections between the prefrontal and anterior cingulate cortices suggest that these areas may have similar functions. Here we report the effect of anterior cingulate removal on task switching, error monitoring, and working memory. Neuroimaging studies have implicated the cingulate cortex in all these processes. Six macaques were taught task switching (TS) and delayed alternation (DA) paradigms. TS required switching between two conditional response tasks with mutually incompatible response selection rules. DA required alternation between two identically covered food-well positions. In the first set of experiments, anterior cingulate lesions did not consistently impair TS or DA performance. One animal performed worst on both TS and DA and in this animal the cingulate sulcus lesion was most complete. In the second set of experiments, we confirmed that larger anterior cingulate lesions, which included the sulcus, consistently impaired TS but only led to a mild and equivocal impairment of DA. The TS error pattern, however, did not suggest an impairment of TS per se. The consequence of a cingulate lesion is, therefore, distinct to that of a prefrontal lesion. TS error distribution analyses provided some support for a cingulate role in monitoring responses for errors and subsequent correction but the pattern of reaction time change in TS was also indicative of a failure to sustain attention to the task and the responses being made.     

A response‐locking protocol to boost sensitivity for fMRI‐based neurochronometry

The timeline of brain‐wide neural activity relative to a behavioral event is crucial when decoding the neural implementation of a cognitive process. Yet, fMRI assesses neural processes indirectly via delayed and regionally variable hemodynamics. This method‐inherent temporal distortion impacts the interpretation of behavior‐linked neural timing. Here we describe a novel behavioral protocol that aims at disentangling the BOLD dynamics of the pre‐ and post‐response periods in response time tasks. We tested this response‐locking protocol in a perceptual decision‐making (random dot) task. Increasing perceptual difficulty produced expected activity increases over a broad network involving the lateral/medial prefrontal cortex and the anterior insula. However, response‐locking revealed a previously unreported functional dissociation within this network. preSMA and anterior premotor cortex (prePMV) showed post‐response activity modulations while anterior insula and anterior cingulate cortex did not. Furthermore, post‐response BOLD activity at preSMA showed a modulation in timing but not amplitude while this pattern was reversed at prePMV. These timeline dissociations with response‐locking thus revealed three functionally distinct sub‐networks in what was seemingly one shared distributed network modulated by perceptual difficulty. These findings suggest that our novel response‐locked protocol could boost the timing‐related sensitivity of fMRI.     

Neural correlates of the classic color and emotional stroop in women with abuse-related posttraumatic stress disorder.

BACKGROUND: The anterior cingulate and medial prefrontal cortex play an important role in the inhibition of responses, as measured by the Stroop task, as well as in emotional regulation. Dysfunction of the anterior cingulate/medial prefrontal cortex has been implicated in posttraumatic stress disorder (PTSD). The purpose of this study was to use the Stroop task as a probe of anterior cingulate function in PTSD. METHODS: Women with early childhood sexual abuse-related PTSD (n = 12) and women with abuse but without PTSD (n = 9) underwent positron emission tomographic measurement of cerebral blood flow during exposure to control, color Stroop, and emotional Stroop conditions. RESULTS: Women with abuse with PTSD (but not abused non-PTSD women) had a relative decrease in anterior cingulate blood flow during exposure to the emotional (but not color) classic Stroop task. During the color Stroop there were also relatively greater increases in blood flow in non-PTSD compared with PTSD women in right visual association cortex, cuneus, and right inferior parietal lobule. CONCLUSIONS: These findings add further evidence for dysfunction of a network of brain regions, including anterior cingulate and visual and parietal cortex, in abuse-related PTSD.     

The contribution of ventrolateral and dorsolateral prefrontal cortex to response reversal

Studies investigating response reversal consistently implicate regions of medial and lateral prefrontal cortex when reinforcement contingencies change. However, it is unclear from these studies how these regions give rise to the individual components of response reversal, such as reinforcement value encoding, response inhibition, and response change. Here we report a novel instrumental learning task designed to determine whether regions implicated in processing reversal errors are uniquely involved in this process, or whether they play a more general role in representing response competition, reinforcement value, or punishment value in the absence of demands for response change. In line with previous findings, reversal errors activated orbitofrontal cortex, dorsomedial prefrontal cortex, ventrolateral prefrontal cortex, caudate, and dorsolateral prefrontal cortex. These regions also showed increased activity to errors in the absence of contingency changes. In addition, ventrolateral PFC, caudate, and dorsolateral PFC each exhibited increased activity following correct reversals. Activity in these regions was not significantly modulated by changes in reinforcement value that were not sufficient to make an alternative response advantageous. These data do not support punishment-processing or prepotent response inhibition accounts of ventrolateral prefrontal cortex function. Instead, they support recent conceptualizations of ventrolateral prefrontal cortex function that implicate this region in resolving response competition by manipulating the representation of either motor response options, or object features. These data also suggest that dorsolateral prefrontal cortex plays a role in reversal learning, probably through top down attentional control of object or reinforcement features when task demands increase.     

A functional magnetic resonance imaging study of bipolar disorder: state- and trait-related dysfunction in ventral prefrontal cortices

BACKGROUND: Abnormalities in prefrontal and anterior cingulate cortices are implicated in disturbances of attention, cognition, and impulse regulation in bipolar disorder. Acute episodes have been associated with dysfunction in these brain regions, and more enduring trait-related dysfunction has been implicated by volumetric and cellular abnormalities in these regions. The relative contributions of prefrontal regions to state and trait disturbances in bipolar disorder, however, have not been defined. We sought to characterize state- and trait-related functional impairment in frontal systems in bipolar disorder. METHODS: Thirty-six individuals with bipolar disorder I (11 with elevated, 10 with depressed, and 15 with euthymic mood states) and 20 healthy control subjects matched for handedness and sex participated in an event-related functional magnetic resonance imaging study of the color-word Stroop to determine mean percentage of regional task-related signal change. RESULTS: Signal increased during the Stroop task similarly across diagnostic groups in a distribution that included dorsal anterior cingulate and prefrontal cortices, consistent with previously reported activations in this task. Signal changes associated with specific mood states in bipolar disorder were detected in ventral prefrontal cortex, with a blunted increase in signal on the right side in the elevated mood group (P =.005) and an exaggerated increase in signal on the left side in the depressed group (P =.02) compared with the euthymic group. Patients (vs healthy controls) demonstrated blunted activation in a spatially distinct, rostral region of left ventral prefrontal cortex that was independent of mood state (P<.005). CONCLUSIONS: Bipolar disorder is associated with a trait abnormality in left ventral prefrontal cortex. Additional ventral prefrontal abnormalities may be associated with specific acute mood states. The hemispheric laterality of the abnormality and the directions of signal change may relate to the valence of the mood episode.     

Anxiety reduction through detachment: subjective, physiological, and neural effects

The ability to volitionally regulate emotions helps to adapt behavior to changing environmental demands and can alleviate subjective distress. We show that a cognitive strategy of detachment attenuates subjective and physiological measures of anticipatory anxiety for pain and reduces reactivity to receipt of pain itself. Using functional magnetic resonance imaging, we locate the potential site and source of this modulation of anticipatory anxiety in the medial prefrontal/anterior cingulate and anterolateral prefrontal cortex, respectively.     

Regional brain activity in women grieving a romantic relationship breakup

OBJECTIVE: Separation from loved ones commonly leads to grief reactions. In some individuals, grief can evolve into a major depressive episode. The brain regions involved in grief have not been specifically studied. The authors studied brain activity in women actively grieving a recent romantic relationship breakup. It was hypothesized that while remembering their ex-partner, subjects would have altered brain activity in regions identified in sadness imaging studies: the cerebellum, anterior temporal cortex, insula, anterior cingulate, and prefrontal cortex. METHOD: Nine right-handed women whose romantic relationship ended within the preceding 4 months were studied. Subjects were scanned using blood-oxygen-level-dependent functional magnetic resonance imaging while they alternated between recalling a sad, ruminative thought about their loved one (grief state) and a neutral thought about a different person they knew an equally long time. RESULTS: Acute grief (grief minus neutral state) was associated with increased group activity in posterior brain regions, including the cerebellum, posterior brainstem, and posterior temporoparietal and occipital brain regions. Decreased activity was more prominent anteriorly and on the left and included the anterior brainstem, thalamus, striatum, temporal cortex, insula, and dorsal and ventral anterior cingulate/prefrontal cortex. When a more lenient statistical threshold for regions of interest was used, additional increases were found in the lateral temporal cortex, supragenual anterior cingulate/medial prefrontal cortex, and right inferomedial dorsolateral prefrontal cortex, all of which were adjacent to spatially more prominent decreases. In nearly all brain regions showing brain activity decreases with acute grief, activity decreases were greater in women reporting higher grief levels over the past 2 weeks. CONCLUSIONS: During acute grief, subjects showed brain activity changes in the cerebellum, anterior temporal cortex, insula, anterior cingulate, and prefrontal cortex, consistent with the hypothesis. Subjects with greater baseline grief showed greater decreases in all these regions except for the cerebellum. Further imaging studies are needed to understand the relationship between normal sadness, grief, and depression.     

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.     

Parietal dysfunction is associated with increased outcome-related decision-making in schizophrenia patients.

BACKGROUND: Decision-making is a complex process and depends on a network of fronto-parietal and cingulate areas. Decision-making dysfunctions in schizophrenia patients are characterized by an alternation between stereotypic and unpredictable responses. This study tested the hypothesis that schizophrenia patients show less decision-making-related activation in the prefrontal and parietal cortex.METHODS: Fifteen schizophrenia patients were matched with fifteen normal comparison subjects. During functional magnetic resonance imaging (fMRI) scanning, subjects were tested on the two-choice prediction task (predicting the location of a randomly presented stimulus) and the two-choice response task (responding according to the location of the stimulus).RESULTS: Schizophrenia patients relative to comparison subjects generated more outcome-dependent responses. Schizophrenia patients and normal comparison subjects showed decision-making-related activation in right prefrontal cortex, insula, anterior cingulate, and bilateral precuneus. Schizophrenia patients showed less activation in inferior, medial prefrontal, and right superior temporal cortex and more activation in the postcentral and inferior parietal cortex. Decision-making-related activation in both right prefrontal and bilateral parietal cortex was higher in medicated compared to unmedicated schizophrenia patients.CONCLUSIONS: These results support the hypothesis that the interaction between prefrontal and parietal cortex during decision-making by schizophrenia patients is dysregulated, which results in an increased outcome-dependent response selection.     

Event-related fMRI study of response inhibition

Event-related functional magnetic resonance imaging (erfMRI) was employed to measure the hemodynamic response during a Go/No-go task in 16 healthy subjects. The task was designed so that Go and No-go events were equally probable, allowing an unbiased comparison of cerebral activity during these two types of trials. In accordance with prediction, anterior cingulate was active during both the Go and No-go trials, dorsolateral and ventrolateral prefrontal cortex was more active during the No-go trials, while primary motor cortex, supplementary motor area, pre-motor cortex and cerebellum were more active during Go trials. These findings are consistent with the hypothesis that the anterior cingulate cortex is principally engaged in making and monitoring of decisions, while dorsolateral and ventral lateral prefrontal sites play a specific role in response inhibition.     

Brain activation patterns during a selective attention test-a functional MRI study in healthy volunteers and patients with schizophrenia

Functional magnetic resonance imaging was used to compare cortical activation patterns in healthy volunteers with those in patients with schizophrenia during a modified verbal Stroop task. Healthy subjects (n=13) and patients with schizophrenia (n=13) on stable antipsychotic treatment, matched on demographic variables, were included. Patients were preselected on the basis of good performance on a selective attention test. Patients with schizophrenia showed a significantly increased pattern of activation in the left and right inferior frontal cortex and the anterior cingulate cortex. A significant negative correlation between activation of the left prefrontal cortex and accuracy in the modified Stroop test was observed for healthy controls but not schizophrenia patients. Although both groups recruited the prefrontal cortex during the modified Stroop task, for the schizophrenia patients this activation was bilateral, whereas for the controls this activation was primarily in the left hemisphere, suggesting that patients with schizophrenia recruited more prefrontal regions to perform the task with the same accuracy as healthy controls. Our findings of increased activity across multiple areas of the brain, including dorsolateral frontal cortex and anterior cingulate, in patients with schizophrenia who perform relatively well on a task of selective attention give further evidence that task performance may be a confounding factor in the interpretation of neuroimaging results.     

The role of the prefrontal cortex in object-place learning: a test of the attribute specificity model

In order to test an attribute specificity model of prefrontal cortex function, rats with lesions in the prelimbic-infralimbic (PL-IL) or anterior cingulate and precentral (AC-PC) subregions of the medial prefrontal cortex and controls were trained on an object-place paired associate task. Rats with AC-PC lesions acquired the task as readily as controls. In contrast, the PL-IL lesioned rats did not learn the task. Whenever higher order processing is required to solve a task, the data support an attribute-specificity model of prefrontal cortex function in that the PL-IL cortices support both object and place attribute information in a variety of tasks including object-place paired associate learning.     

Common firing patterns of hippocampal cells in a differential reinforcement of low rates of response schedule.

Lesion studies show that the hippocampus is critically involved in timing behavior, but so far there has been little analysis of how it might encode time. We recorded the activity of 266 CA1 neurons, 51 CA3 neurons, and 219 entorhinal neurons from rats performing on a differential reinforcement of low rates (DRL) 15 sec schedule in which reinforcement was contingent on responses that occurred at least 15 sec after the preceding response. The unit data were analyzed using two different methods. First, each unit was subjected to an ANOVA that examined the effects of the following: (1) the outcome of the previous response (reward or nonreward); (2) the outcome of the response on which the firing of the cell was synchronized; and (3) time. This showed that, for CA1, CA3, and entorhinal cortex, changes in unit activity were related to all aspects of the task, with the firing of >90% of units recorded in each region being related to at least one of the three factors. Second, intercorrelations between the firing profiles of individual units revealed several functional categories of hippocampal neurons but no clear categories of entorhinal neurons. Of the hippocampal categories, the most common profile was an initial increase in unit activity at the beginning of the DRL interval, followed by a gradual decrease throughout the interval. We suggest that this profile reflects temporal decay in circuits that may code details of the previous trial and that could be used to "time" the DRL interval.     

State and trait influences on mood regulation in bipolar disorder: blood flow differences with an acute mood challenge.

BACKGROUND: Even in remission, patients with bipolar disorder (BD) remain sensitive to external stressors that can trigger new episodes. Imitating such stressors by the controlled transient exposure to an emotional stimulus may help to identify brain regions modulating this sensitivity. METHODS: Transient sadness was induced in 9 euthymic and in 11 depressed subjects with BD. Regional blood flow (rCBF) changes were measured using (15)O-water positron emission tomography. RESULTS: Common changes in both groups were increased rCBF in anterior insula and cerebellum and decreased rCBF in dorsal-ventral-medial frontal cortex, posterior cingulate, inferior parietal, and temporal cortices. Decreases in dorsal ventral medial frontal cortices occurred in both groups, but subjects in remission showed a greater magnitude of change. Unique to remitted subjects with BD were rCBF increases in dorsal anterior cingulate and in premotor cortex. Lateral prefrontal rCBF decreases were unique to depressed subjects with BD. At baseline, remitted subjects showed a unique increase in dorsal anterior cingulate and orbitofrontal cortex. CONCLUSIONS: Common rCBF changes in remitted and depressed subjects identifies potential sites of disease vulnerability. Unique cingulate and orbitofrontal changes both at baseline and with induced sadness seen in the absence of prefrontal rCBF decreases may identify regional interactions important to the euthymic state in this population.     

Error detection in patients with lesions to the medial prefrontal cortex: an ERP study

When people detect their own errors in a discrimination task, a negative-going waveform can be observed in scalp-recorded EEG that has been coined the error-related negativity (Ne/ERN). Generation of the Ne/ERN has been associated with structures in the prefrontal cortex, especially the anterior cingulate region, but also the supplementary motor cortex and subcortical structures. There is some controversy as to whether the Ne/ERN is a necessary concomitant to error detection. We examined the Ne/ERN in five patients with damage to the medial prefrontal cortex, including the anterior cingulate region. Our findings support the implication of the rostral anterior cingulate in Ne/ERN production, but they also show that subjects can be aware of errors and yet not produce an Ne/ERN. Thus, error detection leads to the Ne/ERN process and damage to the anterior cingulate region may interrupt this relay, suggesting that error detection may be supported by circuits outside the anterior cingulate region.