Differential effects of inactivation of the orbitofrontal cortex on strategy set-shifting and reversal learning

Different subregions of the rodent prefrontal cortex (PFC) mediate dissociable types of behavioral flexibility. For example, lesions of the medial or orbitofrontal (OFC) regions of the PFC impair extradimensional shifts and reversal learning, respectively, when novel stimuli are used during different phases of the task. In the present study, we assessed the effects of inactivation of the OFC on strategy set-shifting and reversal learning, using a maze based set-shifting task mediated by the medial PFC. Long–Evans rats were trained initially on a visual-cue discrimination to obtain food. On the subsequent day, rats had to shift to using a response strategy (e.g., always turn left). On Day 3 (reversal), rats were required to reverse the direction of their turn (e.g., always turn right). Infusions of the local anesthetic bupivacaine into the OFC did not impair initial visual discrimination learning, nor did it impair performance on the set-shift. In contrast, inactivation of the OFC did impair reversal learning; yet, these rats ceased using the previously acquired response rule as readily as controls. Instead, rats receiving OFC inactivations made a disproportionate number of erroneous arm entries towards the visual-cue, suggested that these animals reverted back to using the original visual-cue based strategy. These findings, in addition to previous data, further support the notion that the OFC and medial PFC play dissociable roles in reversal learning and set-shifting. Furthermore, the lack of effect of OFC inactivations on the set-shift indicates that this type of behavioral flexibility does not require cognitive operations related to reversal learning.     

Contribution of Ventrolateral Prefrontal Cortex to the Acquisition and Extinction of Conditioned Fear in Rats

The ventrolateral, agranular insular portion of prefrontal cortex (PFC) in rats is involved in visceral functions and has been shown to be involved in emotional processes. However, its contribution to aversive learning has not been well defined. Classical fear conditioning has been a powerful tool for illuminating some of the primary neural structures involved in aversive emotional learning. We measured both the acquisition and the extinction of conditioned fear following lesions of the ventrolateral PFC of rats. Lesions reduced fear reactivity to contextual stimuli associated with conditioning without affecting CS acquisition, and had no effect on response extinction. Ventrolateral PFC may normally be involved in the processing of contextual information while not being directly involved in extinction processes within the aversive domain.     

Learning representations in a gated prefrontal cortex model of dynamic task switching

The prefrontal cortex is widely believed to play an important role in facilitating people's ability to switch performance between different tasks. We present a biologically‐based computational model of prefrontal cortex (PFC) that explains its role in task switching in terms of the greater flexibility conferred by activation‐based working memory representations in PFC, as compared with more slowly adapting weight‐based memory mechanisms. Specifically we show that PFC representations can be rapidly updated when a task switches via a dynamic gating mechanism based on a temporal‐differences reward‐prediction learning mechanism. Unlike prior models of this type, the present model develops all of its internal representations via learning mechanisms as shaped by the demands of continuous periodic task switching. This advance opens up a new domain of research into the interactions between working memory task demands and the representations that develop to meet them. Results on a version of the Wisconsin card sorting task are presented for the full model and a number of comparison networks that test the importance of various model features. Furthermore, we show that a lesioned model produces perseverative errors like those seen in frontal patients.     

Inhibition and the right inferior frontal cortex

It is controversial whether different cognitive functions can be mapped to discrete regions of the prefrontal cortex (PFC). The localisationist tradition has associated one cognitive function - inhibition - by turns with dorsolateral prefrontal cortex (DLPFC), inferior frontal cortex (IFC), or orbital frontal cortex (OFC). Inhibition is postulated to be a mechanism by which PFC exerts its effects on subcortical and posterior-cortical regions to implement executive control. We review evidence concerning inhibition of responses and task-sets. Whereas neuroimaging implicates diverse PFC foci, advances in human lesion-mapping support the functional localization of such inhibition to right IFC alone. Future research should investigate the generality of this proposed inhibitory function to other task domains, and its interaction within a wider network.     

Alpha2A-adrenoceptor stimulation improves prefrontal cortical regulation of behavior through inhibition of cAMP signaling in aging animals

The working-memory functions of the prefrontal cortex (PFC) are improved by stimulation of postsynaptic, alpha2A-adrenoceptors, especially in aged animals with PFC cognitive deficits. Thus, the alpha2A-adrenoceptor agonist, guanfacine, greatly improves working-memory performance in monkeys and rats following systemic administration or intra-PFC infusion. Alpha2A-adrenoceptors are generally coupled to Gi, which can inhibit adenylyl cyclases and reduce the production of cAMP. However, no study has directly examined whether the working-memory enhancement observed with guanfacine or other alpha2A-adrenoceptor agonists results from cAMP inhibition. The current study confirmed this hypothesis in both rats and monkeys, showing that treatments that increase cAMP-mediated signaling block guanfacine's beneficial effects. In aged rats, guanfacine was infused directly into the prelimbic PFC and was challenged with co-infusions of the cAMP analog, Sp-cAMPS. In aging monkeys, systemically administered guanfacine was challenged with the phosphodiesterase 4 inhibitor, rolipram, using intramuscular doses known to have no effect on their own. In both studies, agents that mimicked the actions of cAMP (rats) or increased endogenous cAMP (monkeys) completely blocked the enhancing effects of guanfacine on working-memory performance. These results are consistent with alpha2A-adrenoceptor stimulation enhancing PFC working-memory function via inhibition of cAMP-mediated signaling.     

Human trace fear conditioning: right-lateralized cortical activity supports trace-interval processes

Pavlovian conditioning requires the convergence and simultaneous activation of neural circuitry that supports conditioned stimulus (CS) and unconditioned stimulus (US) processes. However, in trace conditioning, the CS and US are separated by a period of time called the trace interval, and thus do not overlap. Therefore, determining brain regions that support associative learning by maintaining a CS representation during the trace interval is an important issue for conditioning research. Prior functional magnetic resonance imaging (fMRI) research has identified brain regions that support trace-conditioning processes. However, relatively little is known about whether this activity is specific to the trace CS, the trace interval, or both periods of time. The present study was designed to disentangle the hemodynamic response produced by the trace CS from that associated with the trace interval, in order to identify learning-related activation during these distinct components of a trace-conditioning trial. Trace-conditioned activity was observed within dorsomedial prefrontal cortex (PFC), dorsolateral PFC, insula, inferior parietal lobule (IPL), and posterior cingulate (PCC). Each of these regions showed learning-related activity during the trace CS, while trace-interval activity was only observed within a subset of these areas (i.e., dorsomedial PFC, PCC, right dorsolateral PFC, right IPL, right superior/middle temporal gyrus, and bilateral insula). Trace-interval activity was greater in right than in left dorsolateral PFC, IPL, and superior/middle temporal gyrus. These findings indicate that components of the prefrontal, cingulate, insular, and parietal cortices support trace-interval processes, as well as suggesting that a right-lateralized fronto-parietal circuit may play a unique role in trace conditioning.     

Cortico-subcortical contributions to executive control

The term "executive functions" refers to a range of cognitive processes, their common feature being the coordination of information processing and action control. Cortico-subcortical circuits which connect the prefrontal cortex (PFC), the basal ganglia and the cerebellum via the thalamus are believed to serve as neuroanatomical substrates of executive processing. This paper focuses on information processing related to executive functions by the PFC and related subcortical regions. Findings are mainly derived from neuropsychological investigations of brain-damaged patients but also from imaging studies in healthy subjects. There is evidence for subtle differences between these regions with respect to the cognitive mechanisms contributing to inhibition of habitual responses, task management/multitasking and set shifting, although the data base is sparse so far.     

Separating sustained from transient aspects of cognitive control during thought suppression

Cognitive theories of how people regulate their thoughts have suggested the involvement of two control processes that occur over different time courses. These cognitive accounts parallel recent neural models of executive control, which suggest that the prefrontal cortex (PFC) mediates sustained changes in the allocation of control processes, whereas the anterior cingulate cortex (ACC) relays a transient need for additional control. Combining these cognitive and neural models of control, we used recently developed analysis techniques to distinguish transient from sustained changes in brain activation while subjects attempted to suppress an unwanted thought. Results were consistent with both models: Dorsolateral PFC demonstrated sustained increases in activation during attempts at thought suppression, whereas bilateral ACC demonstrated transient increases associated with occurrences of unwanted thoughts. These data support proposals regarding the different contributions made by the PFC and ACC to executive control and provide initial neuroimaging support for dual-process models of how individuals regulate their thoughts.     

How we use rules to select actions: A review of evidence from cognitive neuroscience

Much of our behavior is guided by rules, or prescribed guides for action. In this review, I consider the current state of knowledge of how rules are learned, stored in the brain, and retrieved and used as the need arises. The focus is primarily on studies in humans, but the review is informed by relevant studies in nonhuman primates. Ventrolateral prefrontal cortex (VLPFC) has been implicated in rule learning, retrieval from long-term memory, and on-line maintenance during task preparation. Interactions between VLPFC and temporal cortex are required for rule retrieval in nonhuman primates, and brain imaging findings in humans suggest that rule knowledge is stored in the posterior middle temporal gyrus. Dorsolateral PFC appears to be more closely related to rule-based response selection than to rule retrieval. An important task for the future is to explain how PFC, basal ganglia, and temporal, parietal, and motor cortices interact to produce rule-guided behavior.     

Memory for temporal order of new and familiar spatial location sequences: role of the medial prefrontal cortex

Rats with medial prefrontal cortex or sham control lesions were tested on an eight-arm radial maze task to examine memory for the temporal order of a variable and a constant sequence of spatial locations as a function of temporal distance. During the study phase of each trial, rats were allowed to visit each of eight arms once in an order that was randomly selected or fixed for that trial. The test phase required the rats to choose which of two arms occurred earlier in the sequence of arms visited during the study phase. The arms selected as test arms varied according to temporal distance (0, 2, 4, or 6) or the number of arms that occurred between the two test arms in the study phase. For the variable sequences based on new information, control rats showed an increasing temporal distance function. Relative to control rats, medial prefrontal cortex-lesioned rats displayed a temporal order memory deficit across all distances. For the constant sequence based on familiar information, control rats performed well across all distances. Relative to controls, the medial prefrontal cortex-lesioned rats displayed a performance deficit. The results support the idea that the medial prefrontal cortex contributes to mnemonic operations associated with temporal order for new and familiar spatial location information.     

Frontal pole cortex: encoding ends at the end of the endbrain

Considerable neuroimaging research in humans indicates that the frontal pole cortex (FPC), also known as Brodmann area 10, contributes to many aspects of cognition. Despite these findings, however, its fundamental function and mechanism remain unclear. Recent neurophysiological results from the FPC of monkeys have implications about both. Neurons in the FPC seem to encode chosen goals at feedback time and nothing else. Goals, the places and objects that serve as targets for action, come in many forms and arise from many cognitive processes. The FPC's signal, although surprisingly simple for neurons at the apex of a prefrontal hierarchy, could promote learning about which kinds of goals and goal-generating processes produce particular costs and benefits, thereby improving future choices.     

Prefrontal cortex and the mediation of proactive interference in working memory

Mediating proactive interference (PI), the deleterious effect of antecedent information on current memory representations, is believed to be a key function of prefrontal cortex (PFC). Item-specific PI results when an invalid probe matches a memorandum from the preceding trial; item-nonspecific PI is produced by the accumulation of no-longer-relevant items from previous trials. We tested the hypothesis that these two types of PI are mediated by common PFC-based processes with an fMRI study of a delayed-recognition task designed to produce both types of PI. Our results indicated that the fMRI correlates of both effects were restricted both to Brodmann’s area 45 in the left hemisphere and to the memory probe epoch of the trial. These results suggest that a unification of the literatures and approaches that have independently studied these phenomena might offer a fruitful new perspective from which to study the relations between working memory, executive control, and the PFC.     

Sources of openness/intellect: cognitive and neuropsychological correlates of the fifth factor of personality

We characterize Openness/Intellect as motivated cognitive flexibility, or cognitive exploration, and develop a neuropsychological model relating it to dopaminergic function and to the functions of the prefrontal cortex (PFC). Evidence is reviewed for sources of Openness/Intellect shared with Extraversion and sources unique to Openness/Intellect. The hypothesis that the cognitive functions of the dorsolateral PFC are among the latter was tested using standard measures of cognitive ability and a battery of tasks associated with dorsolateral PFC function (N=175). Dorsolateral PFC function, as well as both fluid and crystallized cognitive ability, was positively related to Openness/Intellect but no other personality trait. Additionally, facet level analysis supported the characterization of Openness/Intellect as a primarily cognitive trait.     

Neuroimaging studies of working memory:

We performed meta-analyses on 60 neuroimaging (PET and fMRI) studies of working memory (WM), considering three types of storage material (spatial, verbal, and object), three types of executive function (continuous updating of WM, memory for temporal order, and manipulation of information in WM), and interactions between material and executive function. Analyses of material type showed the expected dorsal-ventral dissociation between spatial and nonspatial storage in the posterior cortex, but not in the frontal cortex. Some support was found for left frontal dominance in verbal WM, but only for tasks with low executive demand. Executive demand increased right lateralization in the frontal cortex for spatial WM. Tasks requiring executive processing generally produce more dorsal frontal activations than do storage-only tasks, but not all executive processes show this pattern. Brodmann’s areas (BAs) 6, 8, and 9, in the superior frontal cortex, respond most when WM must be continuously updated and when memory for temporal order must be maintained. Right BAs 10 and 47, in the ventral frontal cortex, respond more frequently with demand for manipulation (including dual-task requirements or mental operations). BA 7, in the posterior parietal cortex, is involved in all types of executive function. Finally, we consider a potential fourth executive function: selective attention to features of a stimulus to be stored in WM, which leads to increased probability of activating the medial prefrontal cortex (BA 32) in storage tasks.     

Meta-analytic evidence for a superordinate cognitive control network subserving diverse executive functions

Classic cognitive theory conceptualizes executive functions as involving multiple specific domains, including initiation, inhibition, working memory, flexibility, planning, and vigilance. Lesion and neuroimaging experiments over the past two decades have suggested that both common and unique processes contribute to executive functions during higher cognition. It has been suggested that a superordinate fronto–cingulo–parietal network supporting cognitive control may also underlie a range of distinct executive functions. To test this hypothesis in the largest sample to date, we used quantitative meta-analytic methods to analyze 193 functional neuroimaging studies of 2,832 healthy individuals, ages 18–60, in which performance on executive function measures was contrasted with an active control condition. A common pattern of activation was observed in the prefrontal, dorsal anterior cingulate, and parietal cortices across executive function domains, supporting the idea that executive functions are supported by a superordinate cognitive control network. However, domain-specific analyses showed some variation in the recruitment of anterior prefrontal cortex, anterior and midcingulate regions, and unique subcortical regions such as the basal ganglia and cerebellum. These results are consistent with the existence of a superordinate cognitive control network in the brain, involving dorsolateral prefrontal, anterior cingulate, and parietal cortices, that supports a broad range of executive functions.     

The impact of Parkinson's disease on sequence learning: perceptual pattern learning and executive function

The current study examined the contribution of brain areas affected by Parkinson's disease (PD) to sequence learning, with a specific focus on response-related processes, spatial attentional control, and executive functioning. Patients with mild PD, patients with moderate PD, and healthy age-matched participants performed three tasks-a sequence learning task with a spatial pattern that was incidental to response selection, a spatial cuing task, and neuropsychological tests of executive function. Whereas moderate PD patients failed to show significant sequence learning, mild PD patients performed comparably with controls. Neither group of PD patients was impaired in the control of spatial attention. Sequence learning was correlated with neuropsychological measures of executive function but not with the ability to control spatial attention. These results suggest that the contribution of the brain areas affected by PD to sequence learning extends beyond motor learning to include the learning of perceptual patterns and involves executive function, including cognitive flexibility and set shifting.     

Evidence for the Involvement of the Rat Prefrontal Cortex in Sustained Attention

Previous studies suggest that, in both humans and rats, the prefrontal cortex (PFC) is involved in both selective and divided attention. We have also shown that the PFC is involved in response selection and that its involvement is modulated by the cognitive effort required by the task. However, the role of the PFC is much less clear when no response selection is required. The purpose of the present experiments was to assess the role of the PFC in attentional functions with a low response-selection demand. We used two tasks in which information processing was effortful but where the demand on a response selection process is low. Moreover, we assessed two different types of visual attentional functions: selective attention (Experiment 1) and sustained attention (Experiment 2). The results showed a differential involvement of the PFC in the two tasks. Selective attention was not impaired by prefrontal lesions when the number of possible positions for the stimulus on which the subjects must focus was restricted to two (Experiment 1). In contrast, prefrontal rats were unable to sustain their attention long enough to detect, and react to, subtle variations in brightness (Experiment 2). This result suggests a dissociation between different types of attentional functions depending upon the integrity of the PFC. More specifically, results in Experiment 2 suggest an involvement of the PFC in sustained attention. Finally, the overall results show that even in tasks involving low demands on response selection the PFC is involved in attentional functions.     

贫困对个体执行功能的影响

已有研究发现,贫困会对个体的执行功能产生消极的影响,这种影响贯穿于个体婴儿期、童年期以及成年期。贫困会影响与执行功能相关的前额叶的结构（如较小的灰质体积）。贫困个体与非贫困个体对额叶区域资源的调用方式不同,贫困个体需要使用额外的补偿资源来监测和抑制对干扰物的反应。贫困会通过压力、认知剥夺以及父母养育等因素直接或间接的影响个体的执行功能。今后该领域的研究应关注贫困影响执行功能的调节变量（如自我肯定、自我调节）,建立贫困影响执行功能的综合模型（如考虑贫困经历时间等）,立足执行功能的可塑性,通过认知干预提高贫困个体的执行功能。     

Do young and older adults rely on different processes in source memory tasks? A neuropsychological study

Source memory has consistently been associated with prefrontal function in both normal and clinical populations. Nevertheless, the exact contribution of this brain region to source memory remains uncertain, and evidence suggests that processes used by young and older adults may differ. The authors explored the extent to which scores on composite measures of neuropsychological tests of frontal and medial temporal function differentially predicted the performance of young and older adults on source memory tasks. Results indicated that a frontal composite measure, consistently associated with source memory performance in older adults, was unrelated to source memory in young adults, although it was sensitive to a demanding working memory task. The memory composite score, however, predicted performance in the young group. In addition, item and source memory were correlated in young but not older people. Findings are discussed in terms of age-related differences in working memory and executive functions, and differential binding processes necessary for item and source memory. The requirement to integrate item and source information at encoding appears to place greater demands on executive or working memory processes in older adults than in younger adults.     

Development of dopaminergic genetic associations with visuospatial,verbal and social working memory

Dopamine transmission in the prefrontal cortex (PFC) supports working memory (WM), the temporary holding, processing and manipulation of information in one's mind. The gene coding the catechol‐O‐methyltransferase (COMT) enzyme, which degrades dopamine, in particular in the PFC, has a common single nucleotide polymorphism leading to two versions of the COMT enzyme which vary in their enzymatic activity. The methionine (Met) allele has been associated with higher WM performance and lower activation of the PFC in executive function tasks than the valine (Val) allele. In a previous study, COMT genotype was associated with performance on verbal and visuospatial WM tasks in adults, as well as with performance on a novel social WM paradigm that requires participants to maintain and manipulate information about the traits of their friends or family over a delay. Here, data collected in children and adolescents (N = 202) were compared to data from the adult sample (N = 131) to investigate possible age differences in genetic associations. Our results replicate and extend previous work showing that the pattern of superior WM performance observed in Met/Met adults emerges during development. These findings are consistent with a decrease in prefrontal dopamine levels during adolescence. Developmentally moderated genetic effects were observed for both visuospatial and social WM, even when controlling for non‐social WM performance, suggesting that the maintenance and manipulation of social information may also recruit the dopamine neurotransmitter system. These findings show that development should be considered when trying to understand the impact of genetic polymorphisms on cognitive function.