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1.  Specific Contributions of Ventromedial, Anterior Cingulate, and Lateral Prefrontal Cortex for Attentional Selection and Stimulus Valuation 
PLoS Biology  2011;9(12):e1001224.
Functional clusters of neurons in the monkey prefrontal and anterior cingulate cortex are involved in guiding attention to the most valuable objects in a scene.
Attentional control ensures that neuronal processes prioritize the most relevant stimulus in a given environment. Controlling which stimulus is attended thus originates from neurons encoding the relevance of stimuli, i.e. their expected value, in hand with neurons encoding contextual information about stimulus locations, features, and rules that guide the conditional allocation of attention. Here, we examined how these distinct processes are encoded and integrated in macaque prefrontal cortex (PFC) by mapping their functional topographies at the time of attentional stimulus selection. We find confined clusters of neurons in ventromedial PFC (vmPFC) that predominantly convey stimulus valuation information during attention shifts. These valuation signals were topographically largely separated from neurons predicting the stimulus location to which attention covertly shifted, and which were evident across the complete medial-to-lateral extent of the PFC, encompassing anterior cingulate cortex (ACC), and lateral PFC (LPFC). LPFC responses showed particularly early-onset selectivity and primarily facilitated attention shifts to contralateral targets. Spatial selectivity within ACC was delayed and heterogeneous, with similar proportions of facilitated and suppressed responses during contralateral attention shifts. The integration of spatial and valuation signals about attentional target stimuli was observed in a confined cluster of neurons at the intersection of vmPFC, ACC, and LPFC. These results suggest that valuation processes reflecting stimulus-specific outcome predictions are recruited during covert attentional control. Value predictions and the spatial identification of attentional targets were conveyed by largely separate neuronal populations, but were integrated locally at the intersection of three major prefrontal areas, which may constitute a functional hub within the larger attentional control network.
Author Summary
To navigate within an environment filled with sensory stimuli, the brain must selectively process only the most relevant sensory information. Identifying and shifting attention to the most relevant sensory stimulus requires integrating information about its sensory features as well as its relative value, that is, whether it's worth noticing. In this study, we describe groups of neurons in the monkey prefrontal cortex that convey signals relating to the value of a stimulus and its defining feature and location at the very moment when attention is shifted to the stimulus. We found that signals conveying information about value were clustered in a ventromedial prefrontal region, and were separated from sensory signals within the anterior cingulate cortex and the lateral prefrontal cortex. The integration of valuation and other “top-down” processes, however, was achieved by neurons clustered at the intersection of ventromedial, anterior cingulate, and lateral prefrontal cortex. We conclude that valuation processes are recruited when attention is shifted, independent of any overt behavior. Moreover, our analysis suggests that valuation processes can bias the initiation of attention shifts, as well as ensure sustained attentional focusing.
doi:10.1371/journal.pbio.1001224
PMCID: PMC3246452  PMID: 22215982
2.  Double dissociation of the roles of the left and right prefrontal cortices in anticipatory regulation of action 
Neuropsychologia  2014;63:215-225.
Recent actions can benefit or disrupt our current actions and the prefrontal cortex (PFC) is thought to play a major role in the regulation of these actions before they occur. The left PFC has been associated with overcoming interference from past events in the context of language production and working memory. The right PFC, and especially the right IFG, has been associated with preparatory inhibition processes. But damage to the right PFC has also been associated with impairment in sustaining actions in motor intentional disorders. Moreover, bilateral dorsolateral PFC has been associated with the ability to maintain task-sets, and improve the performance of current actions based on previous experience. However, potential hemispheric asymmetries in anticipatory regulation of action have not yet been delineated. In the present study, patients with left (n=7) vs. right (n=6) PFC damage due to stroke and 14 aged- and education-matched controls performed a picture naming and a verbal Simon task (participants had to say “right” or “left” depending on the color of the picture while ignoring its position). In both tasks, performance depended on the nature of the preceding trial, but in different ways. In the naming task, performance decreased if previous pictures were from the same rather than from different semantic categories (i.e., semantic interference effect). In the Simon task, performance was better for both compatible (i.e., response matching the position of the stimulus) and incompatible trials when preceded by a trial of the same compatibility (i.e. Gratton effect) relative to sequential trials of different compatibility. Left PFC patients were selectively impaired in picture naming; they had an increased semantic interference effect compared to both right PFC patients and aged-matched controls. Conversely, right PFC patients were selectively impaired in the Simon task compared to controls or left PFC patients; they showed no benefit when sequential trials were compatible (cC vs. iC trials) or a decreased Gratton effect. These results provide evidence for a double dissociation between left and right PFC in the anticipatory regulation of action. Our results are in agreement with a preponderant role of the left PFC in overcoming proactive interference from competing memory representations and provide evidence that the right PFC, plays a role in sustaining goal-directed actions consistent with clinical data in right PFC patients with motor intentional disorders.
doi:10.1016/j.neuropsychologia.2014.08.026
PMCID: PMC4194137  PMID: 25201047
Proactive control; Prefrontal cortex; Hemispheric differences; Semantic Interference effect; Gratton effect
3.  The Function and Organization of Lateral Prefrontal Cortex: A Test of Competing Hypotheses 
PLoS ONE  2012;7(2):e30284.
The present experiment tested three hypotheses regarding the function and organization of lateral prefrontal cortex (PFC). The first account (the information cascade hypothesis) suggests that the anterior-posterior organization of lateral PFC is based on the timing with which cue stimuli reduce uncertainty in the action selection process. The second account (the levels-of-abstraction hypothesis) suggests that the anterior-posterior organization of lateral PFC is based on the degree of abstraction of the task goals. The current study began by investigating these two hypotheses, and identified several areas of lateral PFC that were predicted to be active by both the information cascade and levels-of-abstraction accounts. However, the pattern of activation across experimental conditions was inconsistent with both theoretical accounts. Specifically, an anterior area of mid-dorsolateral PFC exhibited sensitivity to experimental conditions that, according to both accounts, should have selectively engaged only posterior areas of PFC. We therefore investigated a third possible account (the adaptive context maintenance hypothesis) that postulates that both posterior and anterior regions of PFC are reliably engaged in task conditions requiring active maintenance of contextual information, with the temporal dynamics of activity in these regions flexibly tracking the duration of maintenance demands. Activity patterns in lateral PFC were consistent with this third hypothesis: regions across lateral PFC exhibited transient activation when contextual information had to be updated and maintained in a trial-by-trial manner, but sustained activation when contextual information had to be maintained over a series of trials. These findings prompt a reconceptualization of current views regarding the anterior-posterior organization of lateral PFC, but do support other findings regarding the active maintenance role of lateral PFC in sequential working memory paradigms.
doi:10.1371/journal.pone.0030284
PMCID: PMC3280249  PMID: 22355309
4.  The role of the lateral prefrontal cortex in inhibitory motor control 
Research on inhibitory motor control has implicated several prefrontal as well as subcortical and parietal regions in response inhibition. Whether prefrontal regions are critical for inhibition, attention or task-set representation is still under debate. We investigated the influence of the lateral PFC in a response inhibition task by using cognitive electrophysiology in prefrontal lesion patients. Patients and age- and education-matched controls performed in a visual Stop-signal task featuring lateralized stimuli, designed to challenge either the intact or lesioned hemisphere. Participants also underwent a purely behavioral Go/Nogo task, which included a manipulation of inhibition difficulty (blocks with 50 vs. 80 % go-trials) and a Change-signal task that required switching to an alternative response. Patients and controls did not differ in their inhibitory speed (stop-signal and change-signal reaction time, SSRT and CSRT), but patients made more errors in the Go/Nogo task and showed more variable performance. The behavioral data stress the role of the PFC in maintaining inhibitory control but not in actual inhibition. These results support a dissociation between action cancellation and PFC- dependent action restraint. Laplacian transformed event-related potentials (ERPs) revealed reduced parietal activity in PFC patients in response to the stop-signals, and increased frontal activity over the intact hemisphere. This electrophysiological finding supports altered PFC- dependent visual processing of the stop-signal in parietal areas and compensatory activity in the intact frontal cortex. No group differences were found in the mu and beta decrease as measures of response preparation and inhibition at electrodes over sensorimotor cortex. Taken together, the data provide evidence for a central role of the lateral PFC in attentional control in the context of response inhibition.
doi:10.1016/j.cortex.2012.05.003
PMCID: PMC3443703  PMID: 22699024
lateral PFC; lesion; SSRT; stop-signal task; cognitive control
5.  Dynamically Allocated Hub in Task-Evoked Network Predicts the Vulnerable Prefrontal Locus for Contextual Memory Retrieval in Macaques 
PLoS Biology  2015;13(6):e1002177.
Neuroimaging and neurophysiology have revealed that multiple areas in the prefrontal cortex (PFC) are activated in a specific memory task, but severity of impairment after PFC lesions is largely different depending on which activated area is damaged. The critical relationship between lesion sites and impairments has not yet been given a clear mechanistic explanation. Although recent works proposed that a whole-brain network contains hubs that play integrative roles in cortical information processing, this framework relying on an anatomy-based structural network cannot account for the vulnerable locus for a specific task, lesioning of which would bring impairment. Here, we hypothesized that (i) activated PFC areas dynamically form an ordered network centered at a task-specific “functional hub” and (ii) the lesion-effective site corresponds to the “functional hub,” but not to a task-invariant “structural hub.” To test these hypotheses, we conducted functional magnetic resonance imaging experiments in macaques performing a temporal contextual memory task. We found that the activated areas formed a hierarchical hub-centric network based on task-evoked directed connectivity, differently from the anatomical network reflecting axonal projection patterns. Using a novel simulated-lesion method based on support vector machine, we estimated severity of impairment after lesioning of each area, which accorded well with a known dissociation in contextual memory impairment in macaques (impairment after lesioning in area 9/46d, but not in area 8Ad). The predicted severity of impairment was proportional to the network “hubness” of the virtually lesioned area in the task-evoked directed connectivity network, rather than in the anatomical network known from tracer studies. Our results suggest that PFC areas dynamically and cooperatively shape a functional hub-centric network to reallocate the lesion-effective site depending on the cognitive processes, apart from static anatomical hubs. These findings will be a foundation for precise prediction of behavioral impacts of damage or surgical intervention in human brains.
Patterns of whole-brain activity while macaques perform a memory retrieval task show that the task-specific functional hub in the dynamic cortical network predicts the task-specific consequences of brain damage better than a task-invariant structural hub does.
Author Summary
Patients with lesions in the front part of the brain’s frontal lobe—the prefrontal cortex—suffer from severe memory deficits. Neuroimaging and neurophysiology studies have revealed that multiple areas in the prefrontal cortex are activated during a specific memory task. However, the severity of the memory deficit after a lesion in the prefrontal cortex largely depends on which of the activated areas is damaged; lesions in only a fraction of the activated areas actually lead to memory deficits. It is currently unknown why some activated areas are “lesion effective” and others are not. Here, by using functional magnetic resonance imaging (fMRI) to measure macaque whole-brain activity during a memory task, we found that the activated areas and the task-specific functional connectivity among them formed a hierarchical network centered on a hub. The task-specific “functional hub” in this dynamic network accurately corresponds to the well-documented lesion-effective site and avoids the neighboring non-lesion-effective sites. Quantitatively, the predicted severity of memory impairment is proportional to the network “hubness” of the lesioned area in the functional network, rather than in the anatomical network, which is statically determined by axonal projection patterns. Our results suggest that the areas of the prefrontal cortex dynamically shape a hub-centric network, reallocating the lesion-effective site apart from the static anatomical hubs depending on the cognitive requirements of the specific memory task.
doi:10.1371/journal.pbio.1002177
PMCID: PMC4488377  PMID: 26125513
6.  A model of amygdala-hippocampal-prefrontal interaction in fear conditioning and extinction in animals 
Brain and cognition  2012;81(1):10.1016/j.bandc.2012.10.005.
Empirical research has shown that the amygdala, hippocampus, and ventromedial prefrontal cortex (vmPFC) are involved in fear conditioning. However, the functional contribution of each brain area and the nature of their interactions are not clearly understood. Here, we extend existing neural network models of the functional roles of the hippocampus in classical conditioning to include interactions with the amygdala and prefrontal cortex. We apply the model to fear conditioning, in which animals learn physiological (e.g. heart rate) and behavioral (e.g. freezing) responses to stimuli that have been paired with a highly aversive event (e.g. electrical shock). The key feature of our model is that learning of these conditioned responses in the central nucleus of the amygdala is modulated by two separate processes, one from basolateral amygdala and signaling a positive prediction error, and one from the vmPFC, via the intercalated cells of the amygdala, and signaling a negative prediction error. In addition, we propose that hippocampal input to both vmPFC and basolateral amygdala is essential for contextual modulation of fear acquisition and extinction. The model is sufficient to account for a body of data from various animal fear conditioning paradigms, including acquisition, extinction, reacquisition, and context specificity effects. Consistent with studies on lesioned animals, our model shows that damage to the vmPFC impairs extinction, while damage to the hippocampus impairs extinction in a different context (e.g., a different conditioning chamber from that used in initial training in animal experiments). We also discuss model limitations and predictions, including the effects of number of training trials on fear conditioning.
doi:10.1016/j.bandc.2012.10.005
PMCID: PMC3808183  PMID: 23164732
fear conditioning; computational model; hippocampus; amygdala; ventromedial prefrontal cortex; extinction
7.  Electrophysiological evidence for aging effects on local contextual processing 
We used event-related potentials to investigate how aging affects local contextual processing. Local context was defined as the occurrence of a short predictive series of visual stimuli before delivery of a target event. Stimuli were presented to either the left or right visual field and consisted of 15% targets (downward facing triangle) and 85% of equal numbers of three types of standards (triangles facing left, upwards and right). Recording blocks consisted of targets preceded by either randomized sequences of standards or by sequences including a three-standard predictive sequence signaling the occurrence of a subsequent target event. Subjects pressed a button in response to targets. Predictive local context affected target detection by reducing the duration of stimulus evaluation compared to detection of non-predictive random targets comparably for both young and older adults, as shown by a P3b latency shift. The peak of an earlier latency context positivity, which was seen only in the predicted compared to the random target condition, was prolonged in the older population compared to young adults. Finally, older subjects elicited a late sustained positivity in the predictive condition, not seen in the younger subjects. Taken together, theses findings suggest that local contextual effects on target detection processes are altered with age.
doi:10.1016/j.cortex.2009.05.007
PMCID: PMC2826523  PMID: 19559410
aging; context; P3b; EEG; context positivity
8.  False Recall Is Reduced by Damage to the Ventromedial Prefrontal Cortex: Implications for Understanding the Neural Correlates of Schematic Memory 
The Journal of Neuroscience  2014;34(22):7677-7682.
Schematic memory, or contextual knowledge derived from experience (Bartlett, 1932), benefits memory function by enhancing retention and speeding learning of related information (Bransford and Johnson, 1972; Tse et al., 2007). However, schematic memory can also promote memory errors, producing false memories. One demonstration is the “false memory effect” of the Deese–Roediger–McDermott (DRM) paradigm (Roediger and McDermott, 1995): studying words that fit a common schema (e.g., cold, blizzard, winter) often produces memory for a nonstudied word (e.g., snow). We propose that frontal lobe regions that contribute to complex decision-making processes by weighting various alternatives, such as ventromedial prefrontal cortex (vmPFC), may also contribute to memory processes by weighting the influence of schematic knowledge. We investigated the role of human vmPFC in false memory by combining a neuropsychological approach with the DRM task. Patients with vmPFC lesions (n = 7) and healthy comparison participants (n = 14) studied word lists that excluded a common associate (the critical item). Recall and recognition tests revealed expected high levels of false recall and recognition of critical items by healthy participants. In contrast, vmPFC patients showed consistently reduced false recall, with significantly fewer intrusions of critical items. False recognition was also marginally reduced among vmPFC patients. Our findings suggest that vmPFC increases the influence of schematically congruent memories, a contribution that may be related to the role of the vmPFC in decision making. These novel neuropsychological results highlight a role for the vmPFC as part of a memory network including the medial temporal lobes and hippocampus (Andrews-Hanna et al., 2010).
doi:10.1523/JNEUROSCI.0119-14.2014
PMCID: PMC4035527  PMID: 24872571
9.  The role of rostral prefrontal cortex in prospective memory: A voxel-based lesion study 
Neuropsychologia  2011;49(8):2185-2198.
Highlights
► Prospective memory (PM) is a key cognitive component required in multitasking. ► This lesion study examines the critical regions for event- and time-based PM ► We show that the right rostral prefrontal cortex is necessary for time-based PM. ► Distinct prefrontal regions are associated with deficits in event- and time-based PM. ► The PM deficit of rostral patients might explain their deficit in multitasking situations.
Patients with lesions in rostral prefrontal cortex (PFC) often experience problems in everyday-life situations requiring multitasking. A key cognitive component that is critical in multitasking situations is prospective memory, defined as the ability to carry out an intended action after a delay period filled with unrelated activity. The few functional imaging studies investigating prospective memory have shown consistent activation in both medial and lateral rostral PFC but also in more posterior prefrontal regions and non-frontal regions. The aim of this study was to determine regions that are necessary for prospective memory performance, using the human lesion approach. We designed an experimental paradigm allowing us to assess time-based (remembering to do something at a particular time) and event-based (remembering to do something in a particular situation) prospective memory, using two types of material, words and pictures. Time estimation tasks and tasks controlling for basic attention, inhibition and multiple instructions processing were also administered. We examined brain-behaviour relationships with a voxelwise lesion method in 45 patients with focal brain lesions and 107 control subjects using this paradigm. The results showed that lesions in the right polar prefrontal region (in Brodmann area 10) were specifically associated with a deficit in time-based prospective memory tasks for both words and pictures. This deficit could not be explained by impairments in basic attention, detection, inhibition or multiple instruction processing, and there was also no deficit in event-based prospective memory conditions. In addition to their prospective memory difficulties, these polar prefrontal patients were significantly impaired in time estimation ability compared to other patients. The same region was found to be involved using both words and pictures, suggesting that right rostral PFC plays a material nonspecific role in prospective memory. This is the first lesion study showing that rostral PFC is crucial for time-based prospective memory. The findings suggest that time-based and event-based prospective memory might be supported at least in part by distinct brain regions. Two particularly plausible explanations for the deficit rest upon a possible role for polar prefrontal structures in supporting in time estimation, and/or in retrieving an intention to act. More broadly, the results are consistent with the view that the deficit of rostral patients in multitasking situations might at least in part be explained by a deficit in prospective memory.
doi:10.1016/j.neuropsychologia.2011.02.045
PMCID: PMC3128701  PMID: 21371485
Human; Lesion study; Neuropsychology; Rostral prefrontal cortex; Prospective memory
10.  Phasic activation of ventral tegmental neurons increases response and pattern similarity in prefrontal cortex neurons 
eLife  2014;3:e02726.
Dopamine is critical for higher neural processes and modifying the activity of the prefrontal cortex (PFC). However, the mechanism of dopamine contribution to the modification of neural representation is unclear. Using in vivo two-photon population Ca2+ imaging in awake mice, this study investigated how neural representation of visual input to PFC neurons is regulated by dopamine. Phasic stimulation of dopaminergic neurons in the ventral tegmental area (VTA) evoked prolonged Ca2+ transients, lasting ∼30 s in layer 2/3 neurons of the PFC, which are regulated by a dopamine D1 receptor-dependent pathway. Furthermore, only a conditioning protocol with visual sensory input applied 0.5 s before the VTA dopaminergic input could evoke enhanced Ca2+ transients and increased pattern similarity (or establish a neural representation) of PFC neurons to the same sensory input. By increasing both the level of neuronal response and pattern similarity, dopaminergic input may establish robust and reliable cortical representation.
DOI: http://dx.doi.org/10.7554/eLife.02726.001
eLife digest
Around 120 years ago, Ivan Pavlov unintentionally sparked a new field of psychology research. He did so by noting that his dogs had learned to associate the sound of the bell that he rang before feeding them with the food itself, such that they would salivate upon hearing the bell even when there was no food present. This form of learning—now known as associative learning—has since been demonstrated in species from honeybees to humans.
For the brain to associate two events, such as the sound of a bell and the delivery of food, it must encode the first event and keep that information available or ‘on-line’ until the occurrence of the second event, at which point the two can be linked together. This process takes place in part of the brain called the prefrontal cortex, but the mechanism by which it occurs is largely unclear.
Now, Iwashita has obtained new insights into the molecular basis of associative learning by studying how the activity of the prefrontal cortex is affected by the activity of a second region of the brain. This second region, called the ventral tegmental area, is part of the brain's reward circuit: it becomes active whenever an animal experiences a desirable event, such as receiving food, and supplies a neurotransmitter called dopamine to its target areas, which include the prefrontal cortex.
Electrodes were used to mimic the changes in brain activity that occur when a mouse learns to associate a visual stimulus with a reward: this involved repeatedly activating the visual cortex in a conscious mouse, followed by activation of the ventral tegmental area. Short-lived increases in calcium levels were seen in the prefrontal cortex, raising the possibility that these ‘calcium transients’ are the signal that enables the brain to link two events. Moreover, blocking proteins called dopamine D1 receptors in the prefrontal cortex reduced the calcium transients, which is consistent with existing evidence that dopamine from the ventral tegmental area is required for associative learning.
Intriguingly, the calcium transients lasted for roughly 30 s, which is also the maximum length of time by which a stimulus and a reward can be separated and still be associated. Given that the calcium transients could not be detected in anesthetized mice, a full understanding of the mechanisms underlying associative learning may require studies of the conscious brain.
DOI: http://dx.doi.org/10.7554/eLife.02726.002
doi:10.7554/eLife.02726
PMCID: PMC4206826  PMID: 25269147
dopamine; prefrontal cortex; neuronal representation; mouse
11.  Ventromedial Prefrontal Cortex Encodes Emotional Value 
The Journal of Neuroscience  2013;33(27):11032-11039.
The ventromedial prefrontal cortex (vmPFC) plays a critical role in processing appetitive stimuli. Recent investigations have shown that reward value signals in the vmPFC can be altered by emotion regulation processes; however, to what extent the processing of positive emotion relies on neural regions implicated in reward processing is unclear. Here, we investigated the effects of emotion regulation on the valuation of emotionally evocative images. Two independent experimental samples of human participants performed a cognitive reappraisal task while undergoing fMRI. The experience of positive emotions activated the vmPFC, whereas the regulation of positive emotions led to relative decreases in vmPFC activation. During the experience of positive emotions, vmPFC activation tracked participants' own subjective ratings of the valence of stimuli. Furthermore, vmPFC activation also tracked normative valence ratings of the stimuli when participants were asked to experience their emotions, but not when asked to regulate them. A separate analysis of the predictive power of vmPFC on behavior indicated that even after accounting for normative stimulus ratings and condition, increased signal in the vmPFC was associated with more positive valence ratings. These results suggest that the vmPFC encodes a domain-general value signal that tracks the value of not only external rewards, but also emotional stimuli.
doi:10.1523/JNEUROSCI.4317-12.2013
PMCID: PMC3718369  PMID: 23825408
12.  Stress-Induced Impairment of a Working Memory Task: Role of Spiking Rate and Spiking History Predicted Discharge 
PLoS Computational Biology  2012;8(9):e1002681.
Stress, pervasive in society, contributes to over half of all work place accidents a year and over time can contribute to a variety of psychiatric disorders including depression, schizophrenia, and post-traumatic stress disorder. Stress impairs higher cognitive processes, dependent on the prefrontal cortex (PFC) and that involve maintenance and integration of information over extended periods, including working memory and attention. Substantial evidence has demonstrated a relationship between patterns of PFC neuron spiking activity (action-potential discharge) and components of delayed-response tasks used to probe PFC-dependent cognitive function in rats and monkeys. During delay periods of these tasks, persistent spiking activity is posited to be essential for the maintenance of information for working memory and attention. However, the degree to which stress-induced impairment in PFC-dependent cognition involves changes in task-related spiking rates or the ability for PFC neurons to retain information over time remains unknown. In the current study, spiking activity was recorded from the medial PFC of rats performing a delayed-response task of working memory during acute noise stress (93 db). Spike history-predicted discharge (SHPD) for PFC neurons was quantified as a measure of the degree to which ongoing neuronal discharge can be predicted by past spiking activity and reflects the degree to which past information is retained by these neurons over time. We found that PFC neuron discharge is predicted by their past spiking patterns for nearly one second. Acute stress impaired SHPD, selectively during delay intervals of the task, and simultaneously impaired task performance. Despite the reduction in delay-related SHPD, stress increased delay-related spiking rates. These findings suggest that neural codes utilizing SHPD within PFC networks likely reflects an additional important neurophysiological mechanism for maintenance of past information over time. Stress-related impairment of this mechanism is posited to contribute to the cognition-impairing actions of stress.
Author Summary
When faced with stressful situations, normal thought processes can be impaired including the ability to focus attention or make decisions requiring deep thought. These effects can result in accidents at the workplace and in combat, jeopardizing the lives of others. To date, the effect of stress on the way neurons communicate and represent cognitive functions is poorly understood. Differing theories have provided opposing predictions regarding the effects of stress-related chemical changes in the brain on neuronal activity of the prefrontal cortex (PFC). In this study, we show that stress increases the discharge rate of PFC neurons during planning and assessment phases of a task requiring the PFC. Additionally, using a point process model of neuronal activity we show that stress, nonetheless, impairs the ability of PFC neurons to retain representations of past events over time. Together these findings suggest that stress-related impairment of cognitive function may involve deficits in the ability of PFC neurons to retain information about past events beyond changes in neuronal firing rates. We believe that this advancement provides new insight into the neural codes of higher cognitive function that may lead to the development of novel treatments for stress-related diseases and conditions involving PFC-dependent cognitive impairment.
doi:10.1371/journal.pcbi.1002681
PMCID: PMC3441423  PMID: 23028279
13.  Prefrontal and Medial Temporal Lobe Activity at Encoding Predicts Temporal Context Memory 
The Journal of Neuroscience  2010;30(46):15558-15565.
One of the defining features of episodic long-term memory is that it includes information about the temporal context in which an event occurred. Little is known about the regions that support the encoding of temporal information in the human brain, although previous work has suggested a role for the lateral prefrontal cortex (PFC) and medial temporal lobes (MTL). Here we used event-related fMRI to examine the relationship between activity at encoding and subsequent memory for temporal context. Participants were scanned while performing a serial order working memory task with pictures of common objects and were later tested for temporal memory at two different timescales. In the coarse temporal memory test, participants viewed one object from each trial and indicated approximately when during the course of the experiment it had appeared. In the fine temporal memory test, participants were shown the remaining objects from each trial and asked to recall the order in which they had been originally presented. Activity in the parahippocampal cortex predicted subsequent fine temporal accuracy, whereas coarse temporal accuracy was predicted by activity in several regions of the PFC, as well as in the hippocampus. Additional multivoxel pattern analyses revealed evidence implicating the rostrolateral PFC in the representation of time-varying contextual states in a manner similar to that proposed by computational theories of temporal context memory. These results highlight MTL and PFC contributions to temporal memory at the time of encoding and suggest a particular role for the rostrolateral PFC in encoding coarse temporal context.
doi:10.1523/JNEUROSCI.1337-10.2010
PMCID: PMC3842495  PMID: 21084610
14.  Ventromedial prefrontal cortex damage alters resting blood flow to the bed nucleus of stria terminalis 
The ventromedial prefrontal cortex (vmPFC) plays a key role in modulating emotional responses, yet the precise neural mechanisms underlying this function remain unclear. vmPFC interacts with a number of subcortical structures involved in affective processing, including the amygdala, hypothalamus, periaqueductal gray, ventral striatum, and bed nucleus of stria terminalis (BNST). While a previous study of non-human primates shows that vmPFC lesions reduce BNST activity and anxious behavior, no such causal evidence exists in humans. In this study, we used a novel application of MRI in neurosurgical patients with focal, bilateral vmPFC damage to determine whether vmPFC is indeed critical for modulating BNST function in humans. Relative to neurologically healthy subjects, who exhibited robust rest-state functional connectivity between vmPFC and BNST, the vmPFC lesion patients had significantly lower resting-state perfusion of the right BNST. No such perfusion differences were observed for the amygdala, striatum, hypothalamus, or periaqueductal gray. This study thus provides unique data on the relationship between vmPFC and BNST, suggesting that vmPFC serves to promote BNST activity in humans. This finding is relevant for neural circuitry models of mood and anxiety disorders.
doi:10.1016/j.cortex.2014.11.013
PMCID: PMC4346536  PMID: 25569763
Prefrontal Cortex; Bed Nucleus of Stria Terminalis; Emotion; Lesion; Anxiety
15.  Closing the gate in the limbic striatum: prefrontal suppression of hippocampal and thalamic inputs 
Neuron  2013;78(1):181-190.
SUMMARY
Many brain circuits control behavior by integrating information arising from separate inputs onto a common target neuron. Neurons in the ventral striatum (VS) receive converging excitatory afferents from the prefrontal cortex (PFC), hippocampus (HP), and thalamus, among other structures, and the integration of these inputs is critical for shaping goal-directed behaviors. Although HP inputs have been described as gating PFC throughput in the VS, recent data reveal that the VS desynchronizes from the HP during epochs of burst-like PFC activity related to decision-making. It is therefore possible that PFC inputs locally attenuate responses to other glutamatergic inputs to the VS. Here, we found that delivering trains of stimuli to the PFC suppresses HP- and thalamus-evoked synaptic responses in the VS, in part through activation of inhibitory processes. This interaction may enable the PFC to exert influence on basal ganglia loops during decision-making instances with minimal disturbance from ongoing contextual inputs.
doi:10.1016/j.neuron.2013.01.032
PMCID: PMC3627185  PMID: 23583113
16.  DETESTABLE OR MARVELOUS? -- NEUROANATOMICAL CORRELATES OF CHARACTER JUDGMENTS 
Neuropsychologia  2010;48(6):1789-1801.
As we learn new information about the social and moral behaviors of other people, we form and update character judgments of them, and this can profoundly influence how we regard and act towards others. In the study reported here, we capitalized on two interesting neurological patient populations where this process of complex “moral updating” may go awry: patients with bilateral damage to ventromedial prefrontal cortex (vmPFC) and patients with bilateral damage to hippocampus (HC). We predicted that vmPFC patients, who have impaired emotion processing, would exhibit reduced moral updating, and we also investigated how moral updating might be affected by severe declarative memory impairment in HC patients. The vmPFC, HC, and brain-damaged comparison (BDC) participants made moral judgments about unfamiliar persons before and after exposure to social scenarios depicting the persons engaged in morally good, bad, or neutral behaviors. In line with our prediction, the vmPFC group showed the least amount of change in moral judgments, and interestingly, the HC group showed the most amount of change. These results suggest that the vmPFC and hippocampus play critical but complementary roles in updating moral character judgments about others: the vmPFC may attribute emotional salience to moral information, whereas the hippocampus may provide necessary contextual information from which to make appropriate character judgments.
doi:10.1016/j.neuropsychologia.2010.03.001
PMCID: PMC2862792  PMID: 20211193
ventromedial; hippocampus; moral; social cognition; memory
17.  Role of the thalamic nucleus reuniens in mediating interactions between the hippocampus and medial prefrontal cortex during spatial working memory 
Despite decades of research, the neural mechanisms of spatial working memory remain poorly understood. Although the dorsal hippocampus is known to be critical for memory-guided behavior, experimental evidence suggests that spatial working memory depends not only on the hippocampus itself, but also on the circuit comprised of the hippocampus and the medial prefrontal cortex (mPFC). Disruption of hippocampal-mPFC interactions may result in failed transfer of spatial and contextual information processed by the hippocampus to the circuitry in mPFC responsible for decision making and goal-directed behavior. Oscillatory synchrony between the hippocampus and mPFC has been shown to increase in tasks with high spatial working memory demand. However, the mechanisms and circuitry supporting hippocampal-mPFC interactions during these tasks is unknown. The midline thalamic nucleus reuniens (RE) is reciprocally connected to both the hippocampus and the mPFC and has been shown to be critical for a variety of working memory tasks. Therefore, it is likely that hippocampal-mPFC oscillatory synchrony is modulated by RE activity. This article will review the anatomical connections between the hippocampus, mPFC and RE along with the behavioral studies that have investigated the effects of RE disruption on working memory task performance. The article will conclude with suggestions for future directions aimed at identifying the specific role of the RE in regulating functional interactions between the hippocampus and the PFC and investigating the degree to which these interactions contribute to spatial working memory.
doi:10.3389/fnsys.2015.00029
PMCID: PMC4354269  PMID: 25805977
reuniens; working memory; hippocampus; medial prefrontal cortex; oscillatory synchrony
18.  GABAAα1-Mediated Plasticity in the Orbitofrontal Cortex Regulates Context-Dependent Action Selection 
Neuropsychopharmacology  2014;40(4):1027-1036.
An essential aspect of goal-directed action selection is differentiating between behaviors that are more, or less, likely to be reinforced. Habits, by contrast, are stimulus-elicited behaviors insensitive to action–outcome contingencies and are considered an etiological factor in several neuropsychiatric disorders. Thus, isolating the neuroanatomy and neurobiology of goal-directed action selection on the one hand, and habit formation on the other, is critical. Using in vivo viral-mediated gene silencing, we knocked down Gabra1 in the orbitofrontal prefrontal cortex (oPFC) in mice, decreasing oPFC GABAAα1 expression, as well as expression of the synaptic marker PSD-95. Mice expressing Green Fluorescent Protein or Gabra1 knockdown in the adjacent M2 motor cortex served as comparison groups. Using instrumental response training followed by action–outcome contingency degradation, we then found that oPFC GABAAα1 deficiency impaired animals' ability to differentiate between actions that were more or less likely to be reinforced, though sensitivity to outcome devaluation and extinction were intact. Meanwhile, M2 GABAAα1 deficiency enhanced sensitivity to action–outcome relationships. Behavioral abnormalities following oPFC GABAAα1 knockdown were rescued by testing mice in a distinct context relative to that in which they had been initially trained. Together, our findings corroborate evidence that chronic GABAAα1 deficiency remodels cortical synapses and suggest that neuroplasticity within the healthy oPFC gates the influence of reward-related contextual stimuli. These stimuli might otherwise promote maladaptive habit-based behavioral response strategies that contribute to—or exacerbate—neuropsychiatric illness.
doi:10.1038/npp.2014.292
PMCID: PMC4330518  PMID: 25348603
19.  Ventromedial prefrontal cortex modulates fatigue after penetrating traumatic brain injury 
Neurology  2010;74(9):749-754.
Background:
Fatigue is a common and disabling symptom in neurologic disorders including traumatic penetrating brain injury (PBI). Despite fatigue's prevalence and impact on quality of life, its pathophysiology is not understood. Studies on effort perception in healthy subjects, animal behavioral paradigms, and recent evidence in different clinical populations suggest that ventromedial prefrontal cortex could play a significant role in fatigue pathophysiology in neurologic conditions.
Methods:
We enrolled 97 PBI patients and 37 control subjects drawn from the Vietnam Head Injury Study registry. Fatigue was assessed with a self-report questionnaire and a clinician-rated instrument; lesion location and volume were evaluated on CT scans. PBI patients were divided in 3 groups according to lesion location: a nonfrontal lesion group, a ventromedial prefrontal cortex lesion (vmPFC) group, and a dorso/lateral prefrontal cortex (d/lPFC) group. Fatigue scores were compared among the 3 PBI groups and the healthy controls.
Results:
Individuals with vmPFC lesions were significantly more fatigued than individuals with d/lPFC lesions, individuals with nonfrontal lesions, and healthy controls, while these 3 latter groups were equally fatigued. VmPFC volume was correlated with fatigue scores, showing that the larger the lesion volume, the higher the fatigue scores.
Conclusions:
We demonstrated that ventromedial prefrontal cortex lesion (vmPFC) plays a critical role in penetrating brain injury–related fatigue, providing a rationale to link fatigue to different vmPFC functions such as effort and reward perception. The identification of the anatomic and cognitive basis of fatigue can contribute to developing pathophysiology-based treatments for this disabling symptom.
GLOSSARY
= Automated Anatomic Labeling;
= analysis of variance;
= Beck Depression Inventory;
= dorso/lateral prefrontal cortex;
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= Neurobehavioral Rating Scale;
= nonfrontal lesion;
= penetrating brain injury;
= region of interest;
= Structured Clinical Interview for DSM-IV, Axis I;
= Vietnam Head Injury Study;
= ventromedial prefrontal cortex lesion.
doi:10.1212/WNL.0b013e3181d25b6b
PMCID: PMC2836872  PMID: 20194914
20.  Implicit Versus Explicit Local Contextual Processing 
PLoS ONE  2013;8(6):e65914.
We investigated the effects of implicit local contextual processing using behavioral and electrophysiological measures. EEG recording blocks consisted of targets preceded by either randomized sequences of standards or by sequences including a predictive sequence signaling the occurrence of a target event. Subjects performed two sessions: in the first the regularity of the predictive sequence was implicit, while in the second this regularity was made explicit. Subjects pressed a button in response to targets. Both the implicit and explicit sessions showed shorter reaction times and peak P3b latencies for predicted versus random targets, although to a greater extent in the explicit session. In both sessions the middle and last most-informative stimuli of the three-standard predictive sequence induced a significant larger P3b compared with randomized standards. The findings show that local contextual information is processed implicitly, but that this modulation was significantly greater when subjects were explicitly instructed to attend to target-predictive contextual information. The findings suggest that top-down attentional networks have a role in modulating the extent to which contextual information is utilized.
doi:10.1371/journal.pone.0065914
PMCID: PMC3681826  PMID: 23785458
21.  Predictive Features of Persistent Activity Emergence in Regular Spiking and Intrinsic Bursting Model Neurons 
PLoS Computational Biology  2012;8(4):e1002489.
Proper functioning of working memory involves the expression of stimulus-selective persistent activity in pyramidal neurons of the prefrontal cortex (PFC), which refers to neural activity that persists for seconds beyond the end of the stimulus. The mechanisms which PFC pyramidal neurons use to discriminate between preferred vs. neutral inputs at the cellular level are largely unknown. Moreover, the presence of pyramidal cell subtypes with different firing patterns, such as regular spiking and intrinsic bursting, raises the question as to what their distinct role might be in persistent firing in the PFC. Here, we use a compartmental modeling approach to search for discriminatory features in the properties of incoming stimuli to a PFC pyramidal neuron and/or its response that signal which of these stimuli will result in persistent activity emergence. Furthermore, we use our modeling approach to study cell-type specific differences in persistent activity properties, via implementing a regular spiking (RS) and an intrinsic bursting (IB) model neuron. We identify synaptic location within the basal dendrites as a feature of stimulus selectivity. Specifically, persistent activity-inducing stimuli consist of activated synapses that are located more distally from the soma compared to non-inducing stimuli, in both model cells. In addition, the action potential (AP) latency and the first few inter-spike-intervals of the neuronal response can be used to reliably detect inducing vs. non-inducing inputs, suggesting a potential mechanism by which downstream neurons can rapidly decode the upcoming emergence of persistent activity. While the two model neurons did not differ in the coding features of persistent activity emergence, the properties of persistent activity, such as the firing pattern and the duration of temporally-restricted persistent activity were distinct. Collectively, our results pinpoint to specific features of the neuronal response to a given stimulus that code for its ability to induce persistent activity and predict differential roles of RS and IB neurons in persistent activity expression.
Author Summary
Memory, referred to as the ability to retain, store and recall information, represents one of the most fundamental cognitive functions in daily life. A significant feature of memory processes is selectivity to particular events or items that are important to our survival and relevant to specific situations. For long-term memory, the selectivity to a specific stimulus is seen both at the behavioral as well as the cellular level. For working memory, a type of short-term memory involved in decision making and attention processes, stimulus selectivity has been observed in vivo using spatial working memory tasks. In addition, persistent activity, which is the cellular correlate of working memory, is also selective to specific stimuli for each neuron, suggesting that each neuron has a ‘memory field’. Our study proposes that both the location of incoming inputs onto the neuronal dendritic tree and specific temporal features of the neuronal response can be used to predict the emergence of persistent activity in two neuron models with different firing patterns, revealing possible mechanisms for generating and propagating stimulus-selectivity in working memory processes. The study also reveals that neurons with different firing patterns may have different roles in persistent activity expression.
doi:10.1371/journal.pcbi.1002489
PMCID: PMC3343116  PMID: 22570601
22.  Learning-dependent Changes in the Neuronal Correlates of Response Inhibition in the Prefrontal Cortex and Hippocampus 
Experimental Neurobiology  2014;23(2):178-189.
It has been suggested that the hippocampus and the prefrontal cortex (PFC) play key roles in representing contextual memory and utilizing contextual information for flexible response selection. During response selection, a correct response should be facilitated and an incorrect response should be inhibited flexibly in association with a cueing stimulus. However, it is poorly understood how the hippocampal and PFC networks behave during such flexible control of facilitation and inhibition of behavioral responses. To find neural correlates of context-cued flexible response selection, the current study employed an object-place paired-associate (OPPA) task in which object A is only rewarded in place 1 and object B is associated with reward in place 2 while recording single units simultaneously from the hippocampus and PFC. During the task, response inhibition in front of a contextually wrong object is required for successful performance and such inhibitory responses were observed before the rat learned the task. A significant proportion of neurons that fired differentially depending on the existence of inhibitory behavior in the PFC was observed during the pre-learning stage. By contrast, the proportion of such neurons in the hippocampus was significantly greater than chance during post-learning stage. The results suggest that the development of inhibitory behavior is a critical behavioral marker that foretells an upcoming acquisition of the task and the hippocampus and PFC are involved in learning contextual response selection by learning how to control the inhibition of behavior as learning progresses.
doi:10.5607/en.2014.23.2.178
PMCID: PMC4065833  PMID: 24963284
hippocampus; prefrontal cortex; electrophysiology; object; context; memory; learning
23.  Ventromedial prefrontal cortex regulates depressive-like behavior and rapid eye movement sleep in the rat 
Neuropharmacology  2014;86:125-132.
Major depressive disorder (MDD) is a debilitating disease with symptoms like persistent depressed mood and sleep disturbances. The prefrontal cortex (PFC) has been implicated as an important structure in the neural circuitry of MDD, with pronounced abnormalities in blood flow and metabolic activity in PFC subregions, including the subgenual cingulate cortex (sgACC, or Brodmann area 25). In addition, deep brain stimulation in the sgACC has recently been shown to alleviate treatment-resistant depression. Depressed patients also show characteristic changes in sleep: insomnia, increased rapid-eye-movement (REM) sleep and shortened REM sleep latency. We hypothesized that sleep changes and depressive behavior may be a consequence of the abnormal PFC activity in MDD. The rat ventromedial PFC (vmPFC, prelimbic and infralimbic cortices) is considered to be the homolog of the human sgACC, so we examined the effect of excitotic lesions in the vmPFC on sleep-wake and depressive behavior. We also made lesions in the adjacent dorsal region (dmPFC) to compare the effect of this similar but distinct mPFC region. We found that both dmPFC and vmPFC lesions led to increased REM sleep, but only vmPFC-lesioned animals displayed increased sleep fragmentation, shortened REM latency and increased immobility in the forced swim test. Anatomic tracing suggests that the mPFC projects to the pontine REM-off neurons that interact with REM-on neurons in the dorsal pons. These results support our hypothesis that neuronal loss in the rat vmPFC resembles several characteristics of MDD and may be a critical area for modulating both mood and sleep.
doi:10.1016/j.neuropharm.2014.07.005
PMCID: PMC4188719  PMID: 25036609
Ibotenic acid; REM sleep latency; forced swim test; neural circuit
24.  Alterations of attention and emotional processing following childhood-onset damage to the prefrontal cortex 
Behavioral neuroscience  2013;128(1):1-11.
The prefrontal cortex (PFC), especially the medial sector, plays a crucial role in emotional processing. Damage to this region results in impaired processing of emotional information, perhaps due to an inability to initiate and maintain attention toward emotional materials, a process that is normally automatic. Childhood onset damage to the PFC impairs emotional processing more than adult-onset PFC damage. The aim of this work was to study the involvement of the PFC in attention to emotional stimuli, and to explore how age at lesion onset affects this involvement. To address these issues, we studied both the emotional and attentional modulation of the startle reflex. Our sample was composed of 4 patients with childhood-onset PFC damage, 6 patients with adult-onset PFC damage, and 10 healthy comparison participants. Subjects viewed 54 affective pictures; acoustic startle probes were presented at 300 ms after picture onset in 18 pictures (as an index of attentional modulation) and at 3,800 ms after picture onset in 18 pictures (as an index of emotional modulation). Childhood-onset PFC patients did not show attentional or emotional modulation of the response, in contrast to adult-onset PFC damage and comparison participants. Early-onset damage to the PFC results, therefore, in more severe dysfunction in the processing of affective stimuli than adult-onset PFC damage, perhaps reflecting limited plasticity in the neural systems that support these processes.
doi:10.1037/a0035415
PMCID: PMC4324722  PMID: 24377423
Emotion; Attention; Prefrontal cortex; Childhood-onset brain damage; Startle reflex; Prepulse inhibition
25.  Distinct roles for lateral and medial rostral prefrontal cortex in source monitoring of perceived and imagined events 
Neuropsychologia  2008;46(5):1442-1453.
Rostral prefrontal cortex (PFC) is known to be involved in source memory, the ability to recollect contextual information about an event. However it is unclear whether subregions of rostral PFC may be differentially engaged during the recollection of different kinds of source detail. We used event related functional MRI to contrast two forms of source recollection: (1) recollection of whether stimuli had previously been perceived or imagined, and (2) recollection of which of two temporally distinct lists those stimuli had been presented in. Lateral regions of rostral PFC were activated in both tasks. However medial regions of rostral PFC were activated only when participants were required to recollect source information for self-generated, “imagined” stimuli, indicating a specific role in self-referential processing. In addition, reduced activity in a region of medial ventro-caudal PFC/basal forebrain was associated with making “imagined-to-perceived” confabulation errors. These results suggest that whilst the processing resources supported by some regions of lateral rostral PFC play a general role in source recollection, those supported by medial rostral PFC structures may be more specialised in their contributions.
doi:10.1016/j.neuropsychologia.2007.12.029
PMCID: PMC2697314  PMID: 18294660
Functional magnetic resonance imaging (fMRI); Cognitive control; Source memory; Reality monitoring; Self-referential processing; Confabulation

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