Increased acetylcholine release in the rat medial prefrontal cortex during performance of a visual attentional task

Recent studies have suggested a functional link between cortical cholinergic output and attentional task demands, whereby acetylcholine (ACh) release is regulated according to the outcome of ongoing behaviour. To explore this hypothesis we measured ACh efflux in the rat medial prefrontal cortex (mPFC) during between-session manipulations of the cognitive demands of an attentional task. Rats were trained to detect visual stimuli in a five-choice serial reaction time task (5-CSRTT) which involves sustained and divided attention. Following habituation to tethering and implantation with a microdialysis probe in the mPFC, rats were tested in the 5-CSRTT for three consecutive days, with different lengths of stimulus duration. During performance of the 5-CSRTT we measured robust, reproducible, task-related increases in ACh release in the mPFC across all sessions. Variations of the stimulus duration from the standard 0.5 s resulted in the predicted behavioural effects (reductions and increases in choice accuracy with 0.25 s and 5 s, respectively), but there was no evidence of either greater changes in ACh release in the more demanding condition or smaller changes in the less demanding condition. By contrast, in the session with 5-s stimulus duration there was a positive correlation between prefrontal cortical ACh efflux and the total number of trials completed. In summary, the present study shows that ACh efflux in the rat mPFC is increased during performance of a 5-CSRTT, but has found no evidence to support a specific relationship between cholinergic cortical output and attentional performance.     

Functional and effective connectivity in an fMRI study of an auditory-related task

This study investigates the sets of brain areas that are functionally connected during an auditory goal-directed task. We used a paradigm including a resting state condition and an active condition, which consisted in active listening to the footsteps of walking humans. The regional brain activity was measured using fMRI and the adjusted values of activity in brain regions involved in the task were analysed using both principal component analysis and structural equation modelling. A first set of connected areas includes regions located in Heschl's gyrus, planum temporale, posterior superior temporal sulcus (in the so-called 'social cognition' area), and parietal lobe. This network could be responsible for the perceptual integration of the auditory signal. A second set encompassing frontal regions is related to attentional control. Dorsolateral- and medial-prefrontal cortex have mutual negative influences which are similar to those described during a visual goal-directed task [T. Chaminade & P. Fonlupt (2003) Eur. J. Neurosci., 18, 675-679.]. Moreover, the dorsolateral prefrontal cortex (DLPFC) exerts a positive influence on the auditory areas during the task, as well as a strong negative influence on the visual areas. These results show that: (i) the negative influence between the medial and lateral parts of the frontal cortex during a goal-directed task is not dependent on the input modality (visual or auditory), and (ii) the DLPFC activates the pathway of the relevant sensory modality and inhibits the nonrelevant sensory modality pathway.     

Functional activity and effective connectivity of the posterior medial prefrontal cortex during processing of incongruent mental states

The neurocognitive components of Theory of Mind reasoning remain poorly understood. In particular the role of the posterior medial prefrontal cortex in the processing of other's mental states such as beliefs that are incongruent with one's own knowledge of reality is not clear‐cut. It is unknown whether this region is involved in computing discrepant mental states or in subsequently resolving a response conflict between the discrepant others' and one's own beliefs. To test this, we adapted a false belief paradigm for the separate inspection of functional brain activity related to (1) the computation of diverging beliefs and (2) the subsequent consideration and selection of another's or one's own belief. Based on statistical parametric findings from functional neuroimaging, we employed dynamic causal modelling combined with Bayesian model selection to further characterize the interplay of resulting brain regions. In the initial computation of diverging beliefs, the posterior medial prefrontal cortex (pMPFC) and the bilateral temporoparietal cortex were crucially involved. The findings suggest that the bilateral temporal cortex engages in the construction and adjustment of diverging mental states by encoding relevant environmental information. The pMPFC inhibits this stimulus‐bound processing which helps to compute discrepant mental states and process another's false belief decoupled from one's own perception of reality. In the subsequent question phase the right temporoparietal cortex showed increased activity related to switching to and reconsidering another's beliefs in order to select the correct response. Hum Brain Mapp 35:2950–2965, 2014. © 2013 Wiley Periodicals, Inc.     

Differential functional connectivity of prefrontal and medial temporal cortices during episodic memory retrieval

Some theories of brain function emphasize the interactions between brain areas as the major determinant of cognitive and behavioral operations. We explored such interactions in a PET study of episodic memory retrieval having three retrieval conditions, with differing levels of retrieval success. Functional connectivity of voxels located within Brodmann areas 10 and 45/47 in the right prefrontal cortex (RPFC) and the left hippocampus (LGH) with the rest of the brain was estimated using partial least squares. Area 10 and LGH showed an opposite pattern of functional connectivity, with a large expanse of bilateral limbic cortices that was equivalent in all tasks. However, during high retrieval, area 45/47 was included in this pattern. The results suggest that activity in portions of the RPFC reflects either memory retrieval mode or retrieval success, depending on other brain regions to which it is functionally linked. Hum. Brain Mapping 5:323–327, 1997. © 1997 Wiley-Liss, Inc.     

Architectonic subdivision of the human orbital and medial prefrontal cortex

The structure of the human orbital and medial prefrontal cortex (OMPFC) was investigated using five histological and immunohistochemical stains and was correlated with a previous analysis in macaque monkeys [Carmichael and Price (1994) J. Comp. Neurol. 346:366-402]. A cortical area was recognized if it was distinct with at least two stains and was found in similar locations in different brains. All of the areas recognized in the macaque OMPFC have counterparts in humans. Areas 11, 13, and 14 were subdivided into areas 11m, 11l, 13a, 13b, 13m, 13l, 14r, and 14c. Within area 10, the region corresponding to area 10m in monkeys was divided into 10m and 10r, and area 10o (orbital) was renamed area 10p (polar). Areas 47/12r, 47/12m, 47/12l, and 47/12s occupy the lateral orbital cortex, corresponding to monkey areas 12r, 12m, 12l, and 12o. The agranular insula (areas Iam, Iapm, Iai, and Ial) extends onto the caudal orbital surface and into the horizontal ramus of the lateral sulcus. The growth of the frontal pole in humans has pushed area 25 and area 32pl, which corresponds to the prelimbic area 32 in Brodmann's monkey brain map, caudal and ventral to the genu of the corpus callosum. Anterior cingulate areas 24a and 24b also extend ventral to the genu of the corpus callosum. Area 32ac, corresponding to the dorsal anterior cingulate area 32 in Brodmann's human brain map, is anterior and dorsal to the genu. The parallel organization of the OMPFC in monkeys and humans allows experimental data from monkeys to be applied to studies of the human cortex.     

Age-related valence-based reversal in recruitment of medial prefrontal cortex on a visual search task

Previous behavioral research has revealed a positivity effect that occurs with aging, with older adults focusing more on positive information and less on negative emotional stimuli as compared to young adults. Questions have been raised as to whether this effect exists in the rapid detection of information or whether it operates only at later stages of processing. In the present study, we used eye-tracking and neuroimaging methodologies to examine whether the two age groups accomplished the detection of emotional information on a visual search task using the same mechanisms. Eye-tracking results revealed no significant age differences in detection or viewing time of emotional targets as a function of valence. Despite their general similarity in task performance, neuroimaging results revealed an age-related valence-based reversal in medial prefrontal cortex (MPFC) activity, with detection of negative compared to positive targets activating the MPFC more for younger adults, and detection of positive compared to negative targets activating the MPFC more for older adults. These results suggest that age-related valence reversals in neural activity can exist even on tasks that require only relatively automatic processing of emotional information.     

Age-related valence-based reversal in recruitment of medial prefrontal cortex on a visual search task

Previous behavioral research has revealed a positivity effect that occurs with aging, with older adults focusing more on positive information and less on negative emotional stimuli as compared to young adults. Questions have been raised as to whether this effect exists in the rapid detection of information or whether it operates only at later stages of processing. In the present study, we used eye-tracking and neuroimaging methodologies to examine whether the two age groups accomplished the detection of emotional information on a visual search task using the same mechanisms. Eye-tracking results revealed no significant age differences in detection or viewing time of emotional targets as a function of valence. Despite their general similarity in task performance, neuroimaging results revealed an age-related valence-based reversal in medial prefrontal cortex (MPFC) activity, with detection of negative compared to positive targets activating the MPFC more for younger adults, and detection of positive compared to negative targets activating the MPFC more for older adults. These results suggest that age-related valence reversals in neural activity can exist even on tasks that require only relatively automatic processing of emotional information.     

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.     

Response channel activation and the lateral prefrontal cortex

The role of lateral prefrontal cortex in transducing perception into action was studied in 10 patients with chronic, unilateral lesions. They identified colors in the center of a visual display, while a flanking, distractor color was presented simultaneously in either the ipsilesional or contralesional field. The flanker could be either the same color as the target, or incompatible with the correct response. The effects of compatible and incompatible flankers on reaction time (RT) served as a measure of response channel activation by the flanker. Flankers in the contralesional field influenced RT less than did those in the ipsilesional field. These results suggest that the lateral prefrontal cortex is involved in maintaining stimulus-response channels.     

Endogenous cortisol is associated with functional connectivity between the amygdala and medial prefrontal cortex

Whether glucocorticoids mediate medial prefrontal cortex (mPFC) regulation of the amygdala in humans remains unclear. In the current study we investigated whether cortisol levels under relatively stress-free circumstances are related to amygdala resting-state functional connectivity with the mPFC. Resting-state fMRI data were acquired from 20 healthy male participants. Salivary cortisol was sampled at multiple times throughout the experiment. The cortisol area under the curve increase (AUCi) was calculated as a measure of cortisol dynamics. Next, seed based correlations were employed on the resting-state fMRI data to reveal regions of amygdala functional connectivity related to variations in cortisol AUCi. The resulting statistical maps were corrected for multiple comparisons using cluster based thresholding (Z>2.3, p<.05). Two regions in the mPFC showed decreasing negative functional connectivity with the amygdala when a lesser decrease in cortisol AUCi was observed: the perigenual anterior cingulate cortex and medial frontal pole (BA10). Although we initially showed a relation with cortisol AUCi, it seemed that the baseline cortisol levels were actually driving this effect: higher baseline cortisol levels related to stronger negative functional connectivity with the mPFC. Endogenous cortisol levels may modulate amygdala functional connectivity with specific regions in the mPFC, even under relatively stress-free circumstances. Our results corroborate previous findings from both animal and human studies, suggesting cortisol-mediated regulation of the amygdala by the mPFC. We propose that through this feedback mechanism the stress response might be adjusted, pointing to the putative role of cortisol in modulating stress- and, more generally, emotional responses.     

Functional deficit in the medial prefrontal cortex during a language comprehension task in patients with schizophrenia

OBJECTIVE: We and others have observed that patients with schizophrenia commonly presented a reduced left recruitment in language semantic brain regions. However, most studies include patients with leftward and rightward lateralizations for language. We investigated whether a cohort comprised purely of patients with typical lateralization (leftward) presented a reduced left recruitment in semantic regions during a language comprehension task. The goal was to reduce the inter-subject variability and thus improve the resolution for studying functional abnormalities in the language network. METHODS: Twenty-three patients with schizophrenia (DSM-IV) were matched with healthy subjects in age, sex, level of education and handedness. All patients exhibited leftward lateralization for language. Functional MRI was performed as subjects listened to a story comprising characters and social interactions. Functional MRI signal variations were analyzed individually and compared among groups. RESULTS: Although no differences were observed in the recruitment of the semantic language network, patients with schizophrenia presented significantly lower signal variations compared to controls in the medial part of the left superior frontal gyrus (MF1) (x=-6, y=58, z=20; Z(score)=5.6; p<0.001 uncorrected). This region corresponded to the Theory of Mind (ToM) network. Only 5 of the 23 patients (21.7%) and 21 of the 23 (91.3%) control subjects demonstrated a positive signal variation in this area. CONCLUSIONS: A left functional deficit was observed in a core region of the ToM network in patients with schizophrenia and typical lateralizations for language. This functional defect could represent a neural basis for impaired social interaction and communication in patients with schizophrenia.     

Activation of the prefrontal cortex in a nonspatial working memory task with functional MRI

Functional magnetic resonance imaging (fMRI) was used to examine the pattern of activity of the prefrontal cortex during performance of subjects in a nonspatial working memory task. Subjects observed sequences of letters and responded whenever a letter repeated with exactly one nonidentical letter intervening. In a comparison task, subjects monitored similar sequences of letters for any occurrence of a single, prespecified target letter. Functional scanning was performed using a newly developed spiral scan image acquisition technique that provides high-resolution, multislice scanning at approximately five times the rate usually possible on conventional equipment (an average of one image per second). Using these methods, activation of the middle and inferior frontal gyri was reliably observed within individual subjects during performance of the working memory task relative to the comparison task. Effect sizes (2–4%) closely approximated those that have been observed within primary sensory and motor cortices using similar fMRI techniques. Furthermore, activation increased and decreased with a time course that was highly consistent with the task manipulations. These findings corroborate the results of positron emission tomography studies, which suggest that the prefrontal cortex is engaged by tasks that rely on working memory. Furthermore, they demonstrate the applicability of newly developed fMRI techniques using conventional scanners to study the associative cortex in individual subjects. © 1994 Wiley-Liss, Inc.     

Covariations in ERP and PET measures of spatial selective attention in human extrastriate visual cortex

In a previous study using positron emission tomography (PET), we demonstrated that focused attention to a location in the visual field produced increased regional cerebral blood flow in the fusiform gyrus contralateral to the attended hemifield (Heinze et al. [1994]: Nature 372:543). We related these effects to modulations in the amplitude of the P1 component (80–130 msec latency) of the visual event-related brain potentials (ERPs) recorded from the same subjects, under the identical stimulus and task conditions. Here, we replicate and extend these findings by showing that attention effects in the fusiform gyrus and the P1 component were similarly modulated by the perceptual load of the task. When subjects performed a perceptually demanding symbol-matching task within the focus of spatial attention, the fusiform activity and P1 component of the ERP were of greater magnitude than when the subjects performed a less perceptually demanding task that required only luminance detection at the attended location. In the latter condition, both the PET and ERP attention effects were reduced. In addition, in the present data significant activations were also obtained in the middle occipital gyrus contralateral to the attended hemifield, thereby demonstrating that multiple regions of extrastriate visual cortex are modulated by spatial attention. The findings of covariations between the P1 attention effect and activity in the posterior fusiform gyrus reinforce our hypothesis that common neural sources exist for these complementary, but very different measures of human brain activity. Hum. Brain Mapping 5:273–279, 1997. © 1997 Wiley-Liss, Inc.     

Large-scale functional coactivation patterns reflect the structural connectivity of the medial prefrontal cortex

The medial prefrontal cortex (MPFC) is among the most consistently implicated brain regions in social and affective neuroscience. Yet, this region is also highly functionally heterogeneous across many domains and has diverse patterns of connectivity. The extent to which the communication of functional networks in this area is facilitated by its underlying structural connectivity fingerprint is critical for understanding how psychological phenomena are represented within this region. In the current study, we combined diffusion magnetic resonance imaging and probabilistic tractography with large-scale meta-analysis to investigate the degree to which the functional coactivation patterns of the MPFC are reflected in its underlying structural connectivity. Using unsupervised machine learning techniques, we compared parcellations between the two modalities and found congruence between parcellations at multiple spatial scales. Additionally, using connectivity and coactivation similarity analyses, we found high correspondence in voxel-to-voxel similarity between each modality across most, but not all, subregions of the MPFC. These results provide evidence that meta-analytic functional coactivation patterns are meaningfully constrained by underlying neuroanatomical connectivity and provide convergent evidence of distinct subregions within the MPFC involved in affective processing and social cognition.     

Changes in molecular composition of rat medial prefrontal cortex synapses during adolescent development

Postnatal brain development continues throughout adolescence into young adulthood. In particular, synapse strengthening and elimination are prominent processes during adolescence. However, molecular data of this relatively late stage of synaptic development are sparse. In this study, we used iTRAQ (isobaric tag for relative and absolute quantification)-based proteomics and electron microscopy to investigate the molecular composition of a synaptic membrane fraction from adolescent postnatal day (P)34 and P44 and adult (P78) rat medial prefrontal cortex. Differential expression of proteins was most prominent between early adolescence and young adulthood (35%, P34-P78), with an over-representation of cell-membrane proteins during adolescent development (between P34 and P44), and synaptic vesicle proteins between late adolescence and young adulthood (P44-P78). Indicative of the critical period of development, we found that, between P34 and P44, a substantial number of proteins was differentially expressed (14%), much more than during the period after adolescence, i.e. between P44 and P78 (5%). A striking observation was the developmental non-stoichiometric regulation of distinct classes of proteins from the synaptic vesicle and the presynaptic release machinery. Electron microscopy demonstrated a small change in the number of docked vesicles between P34 and P44, but not in the total number of synaptic vesicles and in the size of the vesicle cluster. We conclude that the molecular composition of synapses, and more specifically the synaptic release machinery, of the medial prefrontal cortex changes drastically during adolescent development.     

Anatomical segmentation of the human medial prefrontal cortex

The medial prefrontal areas 32, 24, 14, and 25 (mPFC) form part of the limbic memory system, but little is known about their functional specialization in humans. To add anatomical precision to structural and functional magnetic resonance imaging (MRI) data, we aimed to identify these mPFC subareas in histological preparations of human brain tissue, determine sulci most consistently related with mPFC areal boundaries, and use these sulci to delineate mPFC areas in MRIs. To achieve this, we obtained three‐dimensional MRI data from 11 ex vivo hemispheres and processed them for cyto‐ and myelo‐architectonic analysis. The architectonic boundaries of mPFC areas were identified in histology and cortical surface length and volumes were measured. Unfolded maps of histologically determined boundaries were generated to identify the association of mPFC areal boundaries with sulci across cases. This analysis showed that cingulate and superior rostral were the sulci most consistently related to mPFC areal boundaries. Based on presence/absence and anastomosis between such sulci, 6 sulci patterns in the 11 hemispheres were found. A further analysis of 102 hemispheres of in vivo MRI scans (N = 51 males, mean ± SD 24.1 ± 3.1 years of age) showed similar sulci patterns, which allowed us to delineate the mFPC areas in them. The volumes of mPFC areas across histological, ex vivo and in vivo MRI delineations were comparable and probabilistic maps generated from the MRIs of the102 hemispheres. Probabilistic maps of mPFC areas were registered to MNI space and are available for regional analysis of functional magnetic resonance imaging data.     

Extent and time‐course of competition in visual cortex between emotionally arousing distractors and a concurrent task

Emotionally arousing cues automatically attract attentional resources, which may be at the cost of processing task‐related information. Of central importance is how the visual system resolves competition for processing resources among stimuli differing in motivational salience. Here, we assessed the extent and time‐course of competition between emotionally arousing distractors and task‐related stimuli in a frequency‐tagging paradigm. Steady‐state visual evoked potentials (ssVEPs) were evoked using random‐dot kinematograms that consisted of rapidly flickering (8.57 Hz) dots, superimposed upon emotional or neutral distractor pictures flickering at 12 Hz. The time‐varying amplitude of the ssVEP evoked by the motion detection task showed a significant reduction to the task‐relevant stream while emotionally arousing pictures were presented as distractors. Competition between emotionally arousing pictures and moving dots began 450 ms after picture onset and persisted for an additional 2600 ms. Competitive effects of the overlapping task and picture stream revealed cost effects for the motion detection task when unpleasant pictures were presented as distractors between 450 and 1650 ms after picture onset, where an increase in ssVEP amplitude to the flickering picture stimulus was at the cost of ssVEP amplitude to the flickering dot stimulus. Cost effects were generalized to all emotionally arousing contents between 1850 and 3050 ms after picture onset, where the greatest amount of competition was evident for conditions in which emotionally arousing pictures, compared to neutral, served as distractors. In sum, the processing capacity of the visual system as measured by ssVEPs is limited, resulting in prioritized processing of emotionally relevant cues.     

Accepting unfairness by a significant other is associated with reduced connectivity between medial prefrontal and dorsal anterior cingulate cortex

Conflict is a ubiquitous feature of interpersonal relationships, yet many of these relationships preserve their value following conflict. Our ability to refrain from punishment despite the occurrence of conflict is a characteristic of human beings. Using a combination of behavioral and neuroimaging techniques, we show that prosocial decision-making is modulated by relationship closeness. In an iterated social exchange, participants were more likely to cooperate with their partner compared to an unknown person by accepting unfair exchanges. Importantly, this effect was not influenced by how resources were actually being shared with one’s partner. The medial prefrontal cortex (MPFC) was activated when the partner, rather than the unknown person, behaved unfairly and, in the same context, the MPFC demonstrated greater functional connectivity with the dorsal anterior cingulate cortex (DACC). MPFC–DACC connectivity was inversely associated with participants’ tendency to “forgive” their partner for unfairness as well as performance outside the scanner on a behavioral measure of forgiveness. We conclude that relationship closeness modulates a neural network comprising the MPFC/DACC during economic exchanges.     

Distinct regions of medial rostral prefrontal cortex supporting social and nonsocial functions

While some recent neuroimaging studies have implicated medialrostral prefrontal cortex (MPFC) in ‘mentalizing’and self-reflection, others have implicated this region in attentiontowards perceptual vs self-generated information. In order toreconcile these seemingly contradictory findings, we used fMRIto investigate MPFC activity related to these two functionsin a factorial design. Participants performed two separate tasks,each of which alternated between ‘stimulus-oriented phases’(SO), where participants attended to task-relevant perceptualinformation, and ‘stimulus-independent phases’ (SI),where participants performed the same tasks in the absence ofsuch information. In half of the blocks (‘mentalizingcondition’), participants were instructed that they wereperforming these tasks in collaboration with an experimenter;in other blocks (‘non-mentalizing condition’), participantswere instructed that the experimenter was not involved. In fact,the tasks were identical in these conditions. Neuroimaging datarevealed adjacent but clearly distinct regions of activationwithin MPFC related to (i) mentalizing vs non-mentalizing conditions(relatively caudal/superior) and (ii) SO vs SI attention (relativelyrostral/inferior). These results generalized from one task tothe other, suggesting a new axis of functional organizationwithin MPFC.