History of childhood maltreatment augments dorsolateral prefrontal processing of emotional valence in PTSD

Posttraumatic stress disorder (PTSD) is characterized by conflicting findings of both increased and decreased amygdala and prefrontal reactivity to threat or trauma stimuli. Childhood maltreatment (CM), a potent risk factor for PTSD, exerts long-lasting influences on threat processing and prefrontal-amygdala function. This suggests that CM history may influence PTSD neural phenotypes related to threat processing. Here, we adapt a well-characterized emotional conflict paradigm to investigate CM effects on both emotional conflict and emotional valence processing within PTSD stratified by task relevance. Forty-two individuals with PTSD (22 reporting extensive CM history (PTSD-CM)) and 20 trauma-exposed healthy controls (TEHCs) underwent functional magnetic resonance imaging while identifying affect of emotional faces (fear and happy) overlaid with a goal-irrelevant emotional distractor word (“FEAR” or “HAPPY”). We examined effects of CM on conflict, conflict adaptation, valence-related activation (fear vs. happy) for goal-relevant (face) and goal-irrelevant stimuli (word), and valence effects in interaction with goal-relevancy (face vs. word). Though no activation differences between groups were observed for conflict contrasts nor for valence effects in the amygdala, CM status interacted with valence processing differences as a function of goal relevance in the left dorsolateral prefrontal cortex (dlPFC). Here, PTSD-CM displayed greater activation relative to PTSD to negative valence when stimuli were goal-irrelevant. CM history also moderated relationships between activation abnormalities and PTSD re-experiencing symptoms. These findings provide initial evidence that CM history augments dorsolateral prefrontal bias to implicitly processed stimulus valence in PTSD.     

The relative involvement of anterior cingulate and prefrontal cortex in attentional control depends on nature of conflict.

While numerous studies have implicated both anterior cingulate and prefrontal cortex in attentional control, the nature of their involvement remains a source of debate. Here we determine the extent to which their relative involvement in attentional control depends upon the levels of processing at which the conflict occurs (e.g., response, non-response). Using a combination of blocked and rapid presentation event-related functional magnetic resonance imaging techniques, we compared neural activity during incongruent Stroop trial types that produce conflict at different levels of processing. Our data suggest that the involvement of anterior cingulate and right prefrontal cortex in attentional control is primarily limited to situations of response conflict, while the involvement of left prefrontal cortex extends to the occurrence of conflict at non-response levels.     

Functional roles and cultural modulations of the medial prefrontal and parietal activity associated with causal attribution

Causal understanding of physical events is culturally universal. However, behavioral studies suggest that how we perceive causality is culturally sensitive, with East Asian culture emphasizing contextual factors and Western culture emphasizing dispositional factors guiding causal relationships. The present study investigated potential neural substrates of the cultural difference in causal attribution of physical events. Using functional magnetic resonance imaging, Experiment 1 scanned Chinese subjects during causality or motion direction judgments when viewing animations of object collisions and identified a causal-attribution related neural circuit consisting of the medial/lateral prefrontal cortex, left parietal/temporal cortex, and cerebellum. Moreover, by manipulating the task demand of causal inference and the complexity of contextual information in physical events, we showed that the medial prefrontal activity was modulated by the demand to infer causes of physical events whereas the left parietal activity was modulated by contextual complexity of physical events. Experiment 2 investigated cultural differences in the medial prefrontal and left parietal activity associated with causal attribution of physical events by scanning two independent groups of American and Chinese subjects. We found that, while the medial prefrontal activity involved in causality judgments was comparable in the two cultural groups, the left parietal activity associated with causality judgments was stronger in Chinese than in Americans regardless of whether the contextual information was attended. Our findings suggest that causal inference in the medial prefrontal cortex is universally implicated in causal reasoning whereas contextual processing in the left parietal cortex is sensitive to cultural differences in causality perception.     

Deciding between conflicting motivations: what mice make of their prefrontal cortex

We investigated the contribution of the mouse prefrontal cortex and, more specifically, the prelimbic area, to a learning task that highlights a choice between two conflicting motivations, the one for food seeking and the one for novelty exploration. We used a learning paradigm in a cross maze task that targets first motivation conflict and second flexible rule adaptation following environmental changes. We show that mice with prelimbic lesions, which showed normal spatial learning, exhibit impairment in switching from one type of reward - food retrieval - to another type - novelty exploration - and sustained difficulties in adapting their behaviour when the rule is changing repeatedly. Mice, like other mammals, possess a prefrontal cortex that participates in the control of the flexible switch between concurrent natural motivations and in the rapid and flexible adaptation to external changes. These results open a way to study in mice models motivation conflict and cognitive adaptation, brain functions known to be compromised in several psychiatric conditions in humans in which the prefrontal cortex functioning is altered.     

Role of the hippocampus in contextual modulation of fear extinction

Fear extinction is an important form of emotional learning, and affects neural plasticity. Cue fear extinction is a classical form of inhibitory learning that can be used as an exposure-based treatment for phobia, because the long-term extinction memory produced during cue fear extinction can limit the over-expression of fear. The expression of this inhibitory memory partly depends on the context in which the extinction learning occurs. Studies such as transient inhibition, electrophysiology and brain imaging have proved that the hippocampus - an important structure in the limbic system - facilitates memory retrieval by contextual cues. Mediation of the hippocampus-medial prefrontal lobe circuit may be the neurobiological basis of this process. This article has reviewed the role of the hippocampus in the learning and retrieval of fear extinction. Contextual modulation of fear extinction may rely on a neural network consisting of the hippocampus, the medial prefrontal cortex and the amygdala.     

Neural activity associated with episodic memory for emotional context

To address the question of which brain regions subserve retrieval of emotionally-valenced memories, we used event-related fMRI to index neural activity during the incidental retrieval of emotional and non-emotional contextual information. At study, emotionally neutral words were presented in the context of sentences that were either negatively, neutrally or positively valenced. At test, fMRI data were obtained while participants discriminated between studied and unstudied words. Recognition of words presented in emotionally negative relative to emotionally neutral contexts was associated with enhanced activity in right dorsolateral prefrontal cortex, left amygdala and hippocampus, right lingual gyrus and posterior cingulate cortex. Recognition of words from positive relative to neutral contexts was associated with increased activity in bilateral prefrontal and orbitofrontal cortices, and left anterior temporal lobe. These findings suggest that neural activity mediating episodic retrieval of contextual information and its subsequent processing is modulated by emotion in at least two ways. First, there is enhancement of activity in networks supporting episodic retrieval of neutral information. Second, regions known to be activated when emotional information is encountered in the environment are also active when emotional information is retrieved from memory.     

The cerebellum mediates conflict resolution

Regions within the frontal and parietal cortex have been implicated as important neural correlates for cognitive control during conflict resolution. Despite the extensive reciprocal connectivity between the cerebellum and these putatively critical cortical areas, a role for the cerebellum in conflict resolution has never been identified. We used a task-switching paradigm that separates processes related to task-set switching and the management of response conflict independent of motor processing. Eleven patients with chronic, focal lesions to the cerebellum and 11 healthy controls were compared. Patients were slower and less accurate in conditions involving conflict resolution. In the absence of response conflict, however, tasks-witching abilities were not impaired in our patients. The cerebellum may play an important role in coordinating with other areas of cortex to modulate active response states. These results are the first demonstration of impaired conflict resolution following cerebellar lesions in the presence of an intact prefrontal cortex.     

Observed and self-experienced conflict induce similar behavioral and neural adaptation

In adapting our behavior to a rapidly changing environment, we also tune our behavior to that of others. To investigate the neural bases of such adaptive mechanisms, we examined how individuals adjust their actions after decision-conflicts observed in others compared to self-experienced conflicts. Participants responded to the color of a stimulus, while its spatial position elicited either a conflicting or a congruent action. Participants were required either to respond to stimuli themselves or to observe the response of another participant. We studied the difference between interference effects following conflicting or congruent stimuli, an effect known as conflict adaptation. Consistent with earlier reports, we found that the implementation of reactive control, following congruent trials, was accompanied by activation of the right inferior frontal cortex. Individual differences in the efficacy of response inhibition covaried with the level of activation in that region. Sustaining proactive control, following incongruent trials, activated the left lateral prefrontal cortex. Most importantly, adaptive controls induced by decision-conflicts observed in others, as well as the associated prefrontal activations, were comparable to those induced by self-experienced conflicts. We show that in both behavioral and neural terms we adapt to conflicts happening to others just as if they happened to us.     

Observed and self-experienced conflict induce similar behavioral and neural adaptation

In adapting our behavior to a rapidly changing environment, we also tune our behavior to that of others. To investigate the neural bases of such adaptive mechanisms, we examined how individuals adjust their actions after decision-conflicts observed in others compared to self-experienced conflicts. Participants responded to the color of a stimulus, while its spatial position elicited either a conflicting or a congruent action. Participants were required either to respond to stimuli themselves or to observe the response of another participant. We studied the difference between interference effects following conflicting or congruent stimuli, an effect known as conflict adaptation. Consistent with earlier reports, we found that the implementation of reactive control, following congruent trials, was accompanied by activation of the right inferior frontal cortex. Individual differences in the efficacy of response inhibition covaried with the level of activation in that region. Sustaining proactive control, following incongruent trials, activated the left lateral prefrontal cortex. Most importantly, adaptive controls induced by decision-conflicts observed in others, as well as the associated prefrontal activations, were comparable to those induced by self-experienced conflicts. We show that in both behavioral and neural terms we adapt to conflicts happening to others just as if they happened to us.     

Neural basis of individualistic and collectivistic views of self

Individualism and collectivism refer to cultural values that influence how people construe themselves and their relation to the world. Individualists perceive themselves as stable entities, autonomous from other people and their environment, while collectivists view themselves as dynamic entities, continually defined by their social context and relationships. Despite rich understanding of how individualism and collectivism influence social cognition at a behavioral level, little is known about how these cultural values modulate neural representations underlying social cognition. Using cross‐cultural functional magnetic resonance imaging (fMRI), we examined whether the cultural values of individualism and collectivism modulate neural activity within medial prefrontal cortex (MPFC) during processing of general and contextual self judgments. Here, we show that neural activity within the anterior rostral portion of the MPFC during processing of general and contextual self judgments positively predicts how individualistic or collectivistic a person is across cultures. These results reveal two kinds of neural representations of self (eg, a general self and a contextual self) within MPFC and demonstrate how cultural values of individualism and collectivism shape these neural representations. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.     

Movement‐related activity during goal‐directed hand actions in the monkey ventrolateral prefrontal cortex

Grasping actions require the integration of two neural processes, one enabling the transformation of object properties into corresponding motor acts, and the other involved in planning and controlling action execution on the basis of contextual information. The first process relies on parieto‐premotor circuits, whereas the second is considered to be a prefrontal function. Up to now, the prefrontal cortex has been mainly investigated with conditional visuomotor tasks requiring a learned association between cues and behavioural output. To clarify the functional role of the prefrontal cortex in grasping actions, we recorded the activity of ventrolateral prefrontal (VLPF) neurons while monkeys (Macaca mulatta) performed tasks requiring reaching–grasping actions in different contextual conditions (in light and darkness, memory‐guided, and in the absence of abstract learned rules). The results showed that the VLPF cortex contains neurons that are active during action execution (movement‐related neurons). Some of them showed grip selectivity, and some also responded to object presentation. Most movement‐related neurons discharged during action execution both with and without visual feedback, and this discharge typically did not change when the action was performed with object mnemonic information and in the absence of abstract rules. The findings of this study indicate that a population of VLPF neurons play a role in controlling goal‐directed grasping actions in several contexts. This control is probably exerted within a wider network, involving parietal and premotor regions, where the role of VLPF movement‐related neurons would be that of activating, on the basis of contextual information, the representation of the motor goal of the intended action (taking possession of an object) during action planning and execution.     

Inactivation of the prelimbic, but not infralimbic, prefrontal cortex impairs the contextual control of response conflict in rats

One fundamental function of the prefrontal cortex (PFC) is to guide context-appropriate behaviour in situations of response conflict. Haddon and Killcross recently developed a task in rats which mimics some aspects of response conflict seen in human cognitive paradigms such as the Stroop task. Using this paradigm they demonstrated that large PFC lesions including the prelimbic (PL), infralimbic (IL) and anterior cingulate cortices (ACC) selectively impaired performance on incongruent trials which required the use of task-setting contextual cues to control responding in the face of ambiguous response information. The current experiment was conducted to determine whether specific PFC regions were responsible for the deficit in incongruent performance. Rats were trained on two instrumental biconditional discriminations, one auditory and one visual, in two different contexts. Following acquisition, rats were implanted with guide cannulae aimed at the PL or the IL cortices of the rat prefrontal cortex. Following retraining, rats received microinfusions of the GABA(A) agonist muscimol or artificial cerebrospinal fluid (aCSF) into either the PL or the IL prior to presentations of novel congruent and incongruent audiovisual compounds of the training stimuli in extinction. Results showed that temporary inactivation of the PL cortex led to a selective deficit on incongruent compound trials, but left congruent, and hence biconditional task performance intact. By contrast, IL inactivation had no effect on the accuracy of responding during either congruent or incongruent trials. These results suggest that the PL cortex is necessary for the use of task-setting contextual cues to control responding to conflicting information.     

Neural substrates of approach‐avoidance conflict decision‐making

Animal approach‐avoidance conflict paradigms have been used extensively to operationalize anxiety, quantify the effects of anxiolytic agents, and probe the neural basis of fear and anxiety. Results from human neuroimaging studies support that a frontal–striatal–amygdala neural circuitry is important for approach‐avoidance learning. However, the neural basis of decision‐making is much less clear in this context. Thus, we combined a recently developed human approach‐avoidance paradigm with functional magnetic resonance imaging (fMRI) to identify neural substrates underlying approach‐avoidance conflict decision‐making. Fifteen healthy adults completed the approach‐avoidance conflict (AAC) paradigm during fMRI. Analyses of variance were used to compare conflict to nonconflict (avoid‐threat and approach‐reward) conditions and to compare level of reward points offered during the decision phase. Trial‐by‐trial amplitude modulation analyses were used to delineate brain areas underlying decision‐making in the context of approach/avoidance behavior. Conflict trials as compared to the nonconflict trials elicited greater activation within bilateral anterior cingulate cortex, anterior insula, and caudate, as well as right dorsolateral prefrontal cortex (PFC). Right caudate and lateral PFC activation was modulated by level of reward offered. Individuals who showed greater caudate activation exhibited less approach behavior. On a trial‐by‐trial basis, greater right lateral PFC activation related to less approach behavior. Taken together, results suggest that the degree of activation within prefrontal‐striatal‐insula circuitry determines the degree of approach versus avoidance decision‐making. Moreover, the degree of caudate and lateral PFC activation related to individual differences in approach‐avoidance decision‐making. Therefore, the approach‐avoidance conflict paradigm is ideally suited to probe anxiety‐related processing differences during approach‐avoidance decision‐making. Hum Brain Mapp 36:449–462, 2015. © 2014 Wiley Periodicals, Inc.     

Linking trait-based phenotypes to prefrontal cortex activation during inhibitory control

Inhibitory control is subserved in part by discrete regions of the prefrontal cortex whose functionality may be altered according to specific trait-based phenotypes. Using a unified model of normal range personality traits, we examined activation within lateral and medial aspects of the prefrontal cortex during a manual go/no-go task. Evoked hemodynamic oxygenation within the prefrontal cortex was measured in 106 adults using a 16-channel continuous-wave functional near-infrared spectroscopy system. Within lateral regions of the prefrontal cortex, greater activation was associated with higher trait levels of extraversion, agreeableness and conscientiousness, and lower neuroticism. Higher agreeableness was also related to more activation in the medial prefrontal cortex during inhibitory control. These results suggest that personality traits reflecting greater emotional stability, extraversion, agreeableness and conscientiousness may be associated with more efficient recruitment of control processes subserved by lateral regions of the prefrontal cortex. These findings highlight key links between trait-based phenotypes and neural activation patterns in the prefrontal cortex underlying inhibitory control.     

Cellular imaging with zif268 expression in the rat nucleus accumbens and frontal cortex further dissociates the neural pathways activated following the retrieval of contextual and cued fear memory

Quantitative in situ hybridization revealed that the expression of the plasticity-associated gene zif268 was increased in specific regions of the rat frontal cortex and nucleus accumbens following fear memory retrieval. Increased expression of zif268 was observed in neurons in the core of the nucleus accumbens during the retrieval of contextual and discrete cued fear associations. In contrast, zif268 expression was additionally induced in neurons of the nucleus accumbens shell and the anterior cingulate cortex during the retrieval of contextual but not cued fear memories. No changes in the expression of this gene were seen in the ventral medial prefrontal cortex or ventral and lateral regions of the orbitofrontal cortex that were correlated specifically with the retrieval of fear memory. These experiments demonstrate the specific and dissociable activation of limbic cortical-ventral striatal regions that accompanies cued and contextual fear. These data, together with those previously published by our laboratory (Hall, J., Thomas, K.L. & Everitt, B.J. (2001) J. Neurosci., 21, 2186-2193), suggest that retrieval of contextual fear memories activates a wider limbic cortical-ventral striatal neural circuitry than does retrieval of cued fear memories. Moreover, the expression of zif268 may contribute to plasticity and reconsolidation of fear memory in these dissociable pathways.     

How does the brain mediate interpretation of incongruent auditory emotions? The neural response to prosody in the presence of conflicting lexico‐semantic cues

We frequently encounter conflicting emotion cues. This study examined how the neural response to emotional prosody differed in the presence of congruent and incongruent lexico-semantic cues. Two hypotheses were assessed: (i) decoding emotional prosody with conflicting lexico-semantic cues would activate brain regions associated with cognitive conflict (anterior cingulate and dorsolateral prefrontal cortex) or (ii) the increased attentional load of incongruent cues would modulate the activity of regions that decode emotional prosody (right lateral temporal cortex). While the participants indicated the emotion conveyed by prosody, functional magnetic resonance imaging data were acquired on a 3T scanner using blood oxygenation level-dependent contrast. Using SPM5, the response to congruent cues was contrasted with that to emotional prosody alone, as was the response to incongruent lexico-semantic cues (for the 'cognitive conflict' hypothesis). The right lateral temporal lobe region of interest analyses examined modulation of activity in this brain region between these two contrasts (for the 'prosody cortex' hypothesis). Dorsolateral prefrontal and anterior cingulate cortex activity was not observed, and neither was attentional modulation of activity in right lateral temporal cortex activity. However, decoding emotional prosody with incongruent lexico-semantic cues was strongly associated with left inferior frontal gyrus activity. This specialist form of conflict is therefore not processed by the brain using the same neural resources as non-affective cognitive conflict and neither can it be handled by associated sensory cortex alone. The recruitment of inferior frontal cortex may indicate increased semantic processing demands but other contributory functions of this region should be explored.     

Theta dynamics reveal domain-specific control over stimulus and response conflict

Cognitive control allows us to adjust to environmental changes. The medial frontal cortex (MFC) is thought to detect conflicts and recruit additional resources from other brain areas including the lateral prefrontal cortices. Here we investigated how the MFC acts in concert with visual, motor, and lateral prefrontal cortices to support adaptations of goal-directed behavior. Physiologically, these interactions may occur through local and long-range synchronized oscillation dynamics, particularly in the theta range (4-8 Hz). A speeded flanker task allowed us to investigate conflict-type-specific control networks for perceptual and response conflicts. Theta power over MFC was sensitive to both perceptual and response conflict. Interareal theta phase synchrony, however, indicated a selective enhancement specific for response conflicts between MFC and left frontal cortex as well as between MFC and the presumed motor cortex contralateral to the response hand. These findings suggest that MFC theta-band activity is both generally involved in conflict processing and specifically involved in linking a neural network controlling response conflict.     

Contextual modulation of amygdala responsivity to surprised faces

We recently demonstrated a functional relationship between fMRI responses within the amygdala and the medial prefrontal cortex based upon whether subjects interpreted surprised facial expressions positively or negatively. In the present fMRI study, we sought to assess amygdala-medial prefrontal cortex responsivity when the interpretations of surprised faces were determined by contextual experimental stimuli, rather than subjective judgment. Subjects passively viewed individual presentations of surprised faces preceded by either a negatively or positively valenced contextual sentence (e. g., She just found $500 vs. She just lost $500). Negative and positive sentences were carefully matched in terms of length, situations described, and arousal level. Negatively cued surprised faces produced greater ventral amygdala activation compared to positively cued surprised faces. Responses to negative versus positive sentences were greater within the ventrolateral prefrontal cortex, whereas responses to positive versus negative sentences were greater within the ventromedial prefrontal cortex. The present study demonstrates that amygdala response to surprised facial expressions can be modulated by negatively versus positively valenced verbal contextual information. Connectivity analyses identified candidate cortical-subcortical systems subserving this modulation.     

Decomposing interference during Stroop performance into different conflict factors: An event-related fMRI study

In the current event-related functional magnetic resonance imaging (fMRI) study, we sought to trace back Stroop-interference to circumscribed properties of task-irrelevant word information - response-incompatibility, semantic incongruency and task-reference - that we conceive as conflict factors. Thereby, we particularly wanted to disentangle intermingled contributions of semantic conflict and response conflict to the overall Stroop-interference effect. To delineate neural substrates of single factors, we referred to the logics of cognitive subtraction and cognitive conjunction. Moreover, in a second step, we conducted correlation analyses to determine the relationship between neural activations and behavioral interference costs (i.e., conflict-related reaction time (RT) slowing) so as to further elucidate the functional role of the respective brain regions in conflict processing. Response-incompatibility was associated with activation in the left premotor cortex which can be interpreted as indicating motor competition or conflict, i.e., the presence of competing response tendencies. Accordingly, this activation was positively correlated with behavioral conflict costs. Semantic incongruency exhibited specific activation in the anterior cingulate cortex (ACC), the bilateral insula, and thalamus as well as in left somatosensory cortex. As supported by the consistent negative correlation with behavioral conflict costs, these activations most probably reflect strengthened control efforts to overcome interference and to ensure adequate task performance. Finally, task-reference elicited activation in the left temporo-polar cortex (TPC) and the right medial superior as well as in left rostroventral prefrontal cortex (rvPFC, sub-threshold activation). As strongly supported by prior studies' findings, this neural activation pattern may underlie residual semantic processing of the task-irrelevant word information.     

The prefrontal cortex: functional neural development during early childhood.

The prefrontal cortex plays an essential role in various cognitive functions, such as planning and reasoning, yet little is known about how such neural mechanisms develop during childhood, particularly in young children. To better understand this issue, the present article reviews the literature on the development of the prefrontal cortex during early childhood, focusing mainly on the changes in structural architecture, neural activity, and cognitive abilities. Neuroanatomically, the prefrontal cortex undergoes considerable maturation during childhood, including a reduction of synaptic and neuronal density, a growth of dendrites, and an increase in white matter volume, thereby forming distributed neural networks appropriate for complex cognitive processing. Concurrently, behavioral performance of various cognitive tasks improves with age, and intercorrelations among performance on each task become weak through development. Furthermore, the correlation between subcategories of intelligence test decreases as general intellectual efficiency increases. In addition, recent neuroimaging findings suggest that the prefrontal cortex is already functional in 4-year olds and becomes organized into focal, fine-tuned systems through later development. The literature reviewed suggests that fractionation of the functional neural systems plays a key role in the development of prefrontal cortex and such fractionating process has already commenced in preschool children.