Prefrontal Cortex Lesions Research Articles

Effects of focal prefrontal cortex lesions on electrophysiological indices of executive attention and action control

The human capacity to maintain an overarching control over mental states and behavior relies on multiple, distributed and dynamically interacting brain networks, in which prefrontal cortex (PFC) plays a critical role. PFC exerts top-down executive control over subcortical and posterior cortical areas via extensive reciprocal connections. The orbital, lateral, and medial PFC subdivisions are associated with distinct executive functions, but their precise roles in large-scale neural networks remain to be determined. The main objective of our research program is to specify cognitive and neural mechanisms that govern executive control functions. We study effects of focal PFC lesions on behavioral and electrophysiological correlates of attention and action control utilizing experiments that relate to real-life requirements for executive control. We provide a selective review of studies on the impact of lesions to PFC subregions on novelty processing, anticipatory attention, and action preparation and motor inhibition. The studies provide evidence for the contribution of both lateral, dorsomedial and orbital PFC in novelty processing and dynamic contextual updating. We also report evidence for a role of lateral PFC in motor preparation and anticipatory attention. In contrast to the common view that orbitofrontal cortex plays a general role in inhibitory control, we report findings indicating an involvement in action outcome monitoring rather than in behavioral inhibition as such. We argue that improved understanding of how basic aspects of attentional control and inhibition is regulated in the brain, will shed light on the complex behavioral, cognitive and emotional problems experienced by patients with executive dysfunction.

Arrested development: early prefrontal lesions impair the maturation of moral judgement

Learning to make moral judgements based on considerations beyond self-interest is a fundamental aspect of moral development. A deficit in such learning is associated with poor socialization and criminal behaviour. The neural systems required for the acquisition and maturation of moral competency are not well understood. Here we show in a unique sample of neurological patients that focal lesions involving ventromedial prefrontal cortex, acquired during development, result in an abnormally egocentric pattern of moral judgement. In response to simple hypothetical moral scenarios, the patients were more likely than comparison participants to endorse self-interested actions that involved breaking moral rules or physically harming others in order to benefit themselves. This pattern (which we also found in subjects with psychopathy) differs from that of patients with adult-onset ventromedial prefrontal cortex lesions--the latter group showed normal rejection of egocentric rule violations. This novel contrast of patients with ventromedial prefrontal cortex lesions acquired during development versus during adulthood yields new evidence suggesting that the ventromedial prefrontal cortex is a critical neural substrate for the acquisition and maturation of moral competency that goes beyond self-interest to consider the welfare of others. Disruption to this affective neural system early in life interrupts moral development.

Virtual lesions of the inferior parietal cortex induce fast changes of implicit religiousness/spirituality

Religiousness and spirituality (RS) are two ubiquitous aspects of human experience typically considered impervious to scientific investigation. Nevertheless, associations between RS and frontoparietal neural activity have been recently reported. However, much less is known about whether such activity is causally involved in modulating RS or just epiphenomenal to them. Here we combined two-pulse (10 Hz) Transcranial Magnetic Stimulation (TMS) with a novel, ad-hoc developed RS-related, Implicit Association Test (IAT) to investigate whether implicit RS representations, although supposedly rather stable, can be rapidly modified by a virtual lesion of inferior parietal lobe (IPL) and dorsolateral prefrontal cortex (DLPFC). A self-esteem (SE) IAT, focused on self-concepts nonrelated to RS representations, was developed as control. A specific increase of RS followed inhibition of IPL demonstrating its causative role in inducing fast plastic changes of religiousness/spirituality. In contrast, DLPFC inhibition had more widespread effects probably reflecting a general role in the acquisition or maintenance of task-rules or in controlling the expression of self-related representations not specific to RS.

6-Hydroxydopamine lesions in the medial prefrontal cortex of rats exposed to a peak-interval procedure.

Impaired temporal control is symptomatic of several neurological disorders; recently, it has been implicated in schizophrenia. An animal model of schizophrenia using 6-hydroxydopamine (6-OHDA) infused to the medial pre-frontal cortex (mPFC) was employed to examine its effects on temporal control. Twelve rats were trained on a peak-interval procedure (PIP) until stable patterns of behavior were obtained. Rats infused with 6-OHDA responded less during peak trials and their peak functions were flatter than sham rats. These results are consistent with similar studies with transgenic mice with increased striatal dopamine D2 receptor activity. Lesions in the mPFC decreased motivation to respond in a PIP. These effects may be considered analogous to negative symptoms of schizophrenia.

Perseveration in the presence of punishment: The effects of chronic cocaine exposure and lesions to the prefrontal cortex

Perseveration is the repetition of a previously appropriate response in a manner, or context, which is detrimental to the individual. Although both cocaine exposure and prefrontal cortex (PFC) dysfunctions have been implicated in perseverative-like behaviours, the underlying nature of the impairments has been debated.The current study tested whether chronic cocaine exposure and PFC lesions induce perseverative-like behaviours by causing insensitivity to punishment. Food-restricted male Sprague-Dawley rats were trained to respond for sucrose on concurrent schedules of reinforcement. After initial training, rats received either a sensitizing regimen of cocaine exposure, or excitotoxic lesions to subregions of the PFC. The test of perseveration involved a choice of responding between two levers associated with fixed ratio and progressive ratio (PR) schedules. Responding on the PR lever was punished by a 1min timeout period. It was found that, unlike control subjects, those exposed to chronic cocaine, or with lesions to the medial prefrontal cortex, were significantly slower in adapting their responding to avoid punishment.The current study provides evidence that both cocaine exposure and lesions to the prefrontal cortex can increase perseverative-like responding, although the magnitude and permanence of these effects are contingent on the nature of the task.

P 140. Virtual lesions of the inferior parietal and prefrontal cortex alter implicit religiousness and spirituality in healthy individuals

Belief in a higher power constitutes a core feature of religiousness and spirituality (RS), two ubiquitous aspects of human experience and behaviour that have long been considered impervious to scientific investigation. Recently, however, cognitive neuroscience studies have shown an association between RS experiences and neural activity in fronto-parietal regions. Much less is known on whether activity in the above areas is causally involved in modulating RS experiences or just epiphenomenal to them. Here we combined two-pulse (10 Hz) transcranial magnetic stimulation (TMS) with a novel, ad hoc developed RS-related, implicit Association Test (IAT) to investigate whether implicit RS representations, although supposedly rather stable, can be modified in the short-term by a virtual lesion of inferior parietal lobe (IPL) and dorsolateral prefrontal cortex (DLPFC). A self-esteem (SE) IAT, focused on self-concepts non related to RS representations, was developed as control. The results show that inhibiting the IPL induced a specific increase in RS. In contrast, interfering with the left DLPFC induced a marginal increase of difficulty in controlling automatic associations of the self with both RS and SE dimensions. Thus, suppression of neural activity in parietal regions seems causally involved in the specific induction of fast RS increase. Conversely, the DLPFC appears to contribute to RS in relation to attentional processes or activation of self-related concepts.

Behavioral control by the orbital prefrontal cortex: reversal of fortune

A study shows that selective lesions of the orbital prefrontal cortex in macaques spare behavioral flexibility and emotional processing but impair a test of outcome expectation, suggesting that some psychiatric disorders ascribed to a disrupted orbital prefrontal cortex may instead be caused by more widespread dysfunction.

Effects of the adenosine A2A antagonist istradefylline on cognitive performance in rats with a 6-OHDA lesion in prefrontal cortex

Altered cognitive function is a common feature of both the early and later stages of Parkinson's disease (PD) that involves alterations in cortical dopamine content. Adenosine A2A antagonists, such as istradefylline, improve motor function in PD, but their effect on cognitive impairment has not been determined. The present study investigated whether impairment of working memory due to the loss of dopaminergic input into the prefrontal cortex (PFC) is reversed by administration of istradefylline. We also evaluated whether A2A antagonist administration modulates dopamine levels in the PFC. Bilateral lesions of the dopaminergic input to the PFC were produced in rats using 6-hydroxydopamine (6-OHDA). Cognitive performance was evaluated using an object recognition task and delayed alternation task. The effects of istradefylline, donepezil and methamphetamine on cognitive performance were examined. In addition, the effect of istradefylline on extracellular dopamine levels in the PFC was studied. PFC dopamine levels and cognitive performance were significantly reduced by 6-OHDA lesioning. Istradefylline, donepezil and methamphetamine improved cognitive performance of PFC-lesioned rats. Istradefylline increased dopamine levels in the PFC in both normal and PFC-lesioned rats. PFC dopaminergic input plays an important role in working memory performance. Blockade of A2A receptors using istradefylline reverses the changes in cognitive function, and this may be due to an increase in PFC dopamine content. Adenosine A2A receptor antagonists not only improve motor performance in PD but may also lead to improved cognition.

Transgenic expression of the FTDP-17 tauV337M mutation in brain dissociates components of executive function in mice

Frontotemporal lobe dementia (FTD) is a heterogeneous range of disorders, a subset of which arise from fully penetrant, autosomal dominant point mutations in the gene coding for the microtubule associated protein tau. These genetic tauopathies are associated with complex behavioural/cognitive disturbances, including compromised executive function. In the present study, we modelled the effects of the FTD with Parkinsonism linked to chromosome 17 (FTDP-17) tauV337M mutation (known as the Seattle Family A mutation) expressed in mice on executive processes using a novel murine analogue of the Stroop task. Employing biconditional discrimination procedures, Experiment 1 showed that normal mice, but not mice with excitotoxic lesions of the medial prefrontal cortex, were able to use context cues to resolve response conflict generated by incongruent stimulus compounds. In contrast to predictions, response conflict resolution was not disrupted by the tauV337M mutation (Experiment 2). However, while context appropriate actions were goal-directed in wild-type mice, performance of tauV337M mice was not goal-directed (Experiment 3). The results indicate that the tauV337M mutation in mice disrupts, selectively, a subset of processes related to executive function.

A Novel Translational Assay of Response Inhibition and Impulsivity: Effects of Prefrontal Cortex Lesions, Drugs Used in ADHD, and Serotonin 2C Receptor Antagonism

Animal models are making an increasing contribution to our understanding of the psychology and brain mechanisms underlying behavioral inhibition and impulsivity. The aim here was to develop, for the first time, a mouse analog of the stop-signal reaction time task with high translational validity in order to be able to exploit this species in genetic and molecular investigations of impulsive behaviors. Cohorts of mice were trained to nose-poke to presentations of visual stimuli. Control of responding was manipulated by altering the onset of an auditory 'stop-signal' during the go response. The anticipated systematic changes in action cancellation were observed as stopping was made more difficult by placing the stop-signal closer to the execution of the action. Excitotoxic lesions of medial prefrontal cortex resulted in impaired stopping, while the clinically effective drugs methylphenidate and atomoxetine enhanced stopping abilities. The specific 5-HT2C receptor antagonist SB242084 also led to enhanced response control in this task. We conclude that stop-signal reaction time task performance can be successfully modeled in mice and is sensitive to prefrontal cortex dysfunction and drug treatments in a qualitatively similar manner to humans and previous rat models. Additionally, using this model we show novel and highly discrete effects of 5-HT2C receptor antagonism that suggest manipulation of 5-HT2C receptor function may be of use in correcting maladaptive impulsive behaviors and provide further evidence for dissociable contributions of serotonergic transmission to response control.

Delineating Prefrontal Cortex Region Contributions to Crossmodal Object Recognition in Rats

In the present study, we assessed the involvement of the prefrontal cortex (PFC) in the ability of rats to perform crossmodal (tactile-to-visual) object recognition tasks. We tested rats with 3 different types of bilateral excitotoxic lesions: (1) Large PFC lesions, including the medial PFC (mPFC) and ventral and lateral regions of the orbitofrontal cortex (OFC); (2) selective mPFC lesions; and (3) selective OFC lesions. Rats were tested on 2 versions of crossmodal object recognition (CMOR): (1) The original CMOR task, which uses a tactile-only sample phase and a visual-only choice phase; and (2) a "multimodal pre-exposure" version (PE/CMOR), in which simultaneous pre-exposure to the tactile and visual features of an object facilitates CMOR performance over longer memory delays. Inclusive PFC lesions disrupted performance on both versions of CMOR, whereas selective mPFC damage had no effect. Lesions limited to the OFC caused delay-dependent deficits on the CMOR task, but failed to reverse the enhancement produced by multimodal object pre-exposure. This pattern of functional dissociations suggests complex, multidimensional contributions of the PFC and its subregions to crossmodal cognition.

Differential effects of amygdala, orbital prefrontal cortex, and prelimbic cortex lesions on goal-directed behavior in rhesus macaques.

We assessed the involvement of the orbital prefrontal cortex (PFo), the prelimbic region of the medial prefrontal cortex (PL), and the amygdala in goal-directed behavior. Rhesus monkeys were trained on a task in which two different instrumental responses were linked to two different outcomes. One response, called "tap," required the monkeys to repeatedly touch a colored square on a video monitor to produce one kind of food reward. The other response, called "hold," required persistent contact of an identical stimulus, and it produced a different kind of food reward. After training, we assessed the effects of sensory-specific reinforcer devaluation as a way to probe each monkey's use of goal-directed behavior. In this procedure, monkeys were allowed to consume one of the two foods to satiety and were then tested for tap/hold preference under extinction. Unoperated control monkeys showed a reduction in the response associated with obtaining the devalued food, called the "devaluation effect," a hallmark of goal-directed behavior. Monkeys with bilateral lesions of PFo or the amygdala exhibited significantly reduced devaluation effects. Results from monkeys with PL lesions were equivocal. We conclude that both PFo and the amygdala play a significant role in goal-directed behavior in monkeys. Notably, the findings for PFo challenge the idea that orbital and medial prefrontal regions are exclusively dedicated to object- and action-based processes, respectively.

Dissociation between memory retention across a delay and pattern separation following medial prefrontal cortex lesions in the touchscreen TUNL task

The neural structures that support the retention of memories over time has been a subject of intense research in cognitive neuroscience. However, recently much attention has turned to pattern separation, the putative process by which memories are stored as unique representations that are resistant to confusion. It remains unclear, however, to what extent these two processes can be neurally dissociated. The trial-unique delayed nonmatching-to-location (TUNL) task was developed to assess spatial working memory and pattern separation function using trial-unique locations on a touch-sensitive screen (Talpos, McTighe, Dias, Saksida, & Bussey, 2010). Using this task, Talpos et al. (2010) showed that lesions of the hippocampus led to both impairments with a 6s delay, and impairments in pattern separation. The present study shows that lesions of the medial prefrontal cortex lead to a different pattern of effects: impairment at the same, 6s delay, but no hint of impairment in pattern separation. In addition, rats with medial prefrontal lesions were more susceptible to interference in this task. When compared with previously published results, these data show that whereas the prefrontal cortex and hippocampus likely interact in the service of working memory across a delay, only the hippocampus and not the medial prefrontal cortex is essential for pattern separation.

Processing of time within the prefrontal cortex: Recent time engages posterior areas whereas distant time engages anterior areas

Studies of prefrontal cortex (PFC) lesion patients suggest that information conveying high immediacy, certainty, or tangibility engages the more posterior part of the PFC, whereas information that is more abstract or complex engages the anterior part. We examined whether the anterior and posterior subdivisions of the PFC have distinct roles in processing temporal information during decision making in healthy individuals. We hypothesized that the more the locus of activation is in the posterior (as opposed to anterior) PFC, the more the decision maker will be affected by recent information at the expense of past outcomes. Participants performed a complex decision task while their PFC activity was monitored using fMRI. Results indicate that individual differences in the effect of recent outcomes correspond to differences in the locus of activation, with elevated recency associated with more posterior loci of activation.

Medial prefrontal cortex lesions impair decision-making on a rodent gambling task: Reversal by D1 receptor antagonist administration

Decision-making is a complex cognitive process that is impaired in a number of psychiatric disorders. In the laboratory, decision-making is frequently assessed using “gambling” tasks that are designed to simulate real-life decisions in terms of uncertainty, reward and punishment. Here, we investigate whether lesions of the medial prefrontal cortex (PFC) cause impairments in decision-making using a rodent gambling task (rGT). In this task, rats have to decide between 1 of 4 possible options: 2 options are considered “advantageous” and lead to greater net rewards (food pellets) than the other 2 “disadvantageous” options. Once rats attained stable levels of performance on the rGT they underwent sham or excitoxic lesions of the medial PFC and were allowed to recover for 1 week. Following recovery, rats were retrained for 5 days and then the effects of a dopamine D1-like receptor antagonist (SCH23390) or a D2-like receptor antagonist (haloperidol) on performance were assessed. Lesioned rats exhibited impaired decision-making: they made fewer advantageous choices and chose the most optimal choice less frequently than did sham-operated rats. Administration of SCH23390 (0.03mg/kg), but not haloperidol (0.015–0.03mg/kg) attenuated the lesion-induced decision-making deficit. These results indicate that the medial PFC is important for decision-making and that excessive signaling at D1 receptors may contribute to decision-making impairments.

The interaction between the dopaminergic forebrain projections and the medial prefrontal cortex is critical for memory of objects: Implications for Parkinson's disease

Neuropsychological and neuroimaging studies have implicated the dopaminergic nigrostriatal pathway and the prefrontal cortex in learning and memory deficits in patients with Parkinson's disease. However, little is known about how these two brain regions interact in the processing of learning and memory. We employed a disconnection procedure to test whether interaction of these regions contributes to performance in various memory tasks. Male rats received either a unilateral injection of 6-hydroxydopamine into the nigro-striatal tract or a unilateral NMDA lesion in the medial prefrontal cortex, or both these lesions combined in either the same or opposite hemispheres. Spontaneous object exploration, spatial working memory, locomotor, emotional and sensorimotor tests were administered. Only the group with both lesions placed in opposite hemispheres failed to show object recognition memory. None of the groups treated with 6-hydroxydopamine showed intact temporal order memory, whereas only the groups that received combined lesions failed to show object-in-place and spatial recognition memory. No differences between groups were found in the spatial working memory test. Our data indicate that locomotor, emotional and sensorimotor factors are not likely to confound the results of the memory tests. Thus, the interaction between the dopaminergic forebrain projections, particularly the nigrostriatal dopamine, and the medial prefrontal cortex is critical for object recognition memory but not for spatial working memory in rats.

Metacognitive and online error awareness deficits after prefrontal cortex lesions

Awareness of deficits after brain injury represents a significant clinical and theoretical challenge, but relatively little is known about the neuroanatomical correlates of specific types of deficit awareness. We examined the awareness correlates of left versus right prefrontal cortex lesions in comparison to left and right posterior lesions including two types of awareness measures—metacognitive and online error monitoring. Frontal lobe frontal lesion patients exhibited impaired metacognitive awareness and also showed deficits in monitoring errors as they occurred. In addition, frontal lobe lesion patients also showed reduced autonomic response to aware errors. Online and metacognitive awareness were not, however, significantly correlated, suggesting that distinct neuroanatomical systems may underpin these two types of awareness deficit. We hypothesize that while metacognitive awareness depends on both left and right frontal regions, accurate moment-to-moment processing of errors depends more on the right than on the left prefrontal cortex.

Exercise‐induced stress resistance is independent of exercise controllability and the medial prefrontal cortex

Exercise increases resistance against stress-related disorders such as anxiety and depression. Similarly, the perception of control is a powerful predictor of neurochemical and behavioral responses to stress, but whether the experience of choosing to exercise, and exerting control over that exercise, is a critical factor in producing exercise-induced stress resistance is unknown. The current studies investigated whether the protective effects of exercise against the anxiety- and depression-like consequences of stress are dependent on exercise controllability and a brain region implicated in the protective effects of controllable experiences, the medial prefrontal cortex. Adult male Fischer 344 rats remained sedentary, were forced to run on treadmills or motorised running wheels, or had voluntary access to wheels for 6 weeks. Three weeks after exercise onset, rats received sham surgery or excitotoxic lesions of the medial prefrontal cortex. Rats were exposed to home cage or uncontrollable tail shock treatment three weeks later. Shock-elicited fear conditioning and shuttle box escape testing occurred the next day. Both forced and voluntary wheel running, but not treadmill training, prevented the exaggerated fear conditioning and interference with escape learning produced by uncontrollable stress. Lesions of the medial prefrontal cortex failed to eliminate the protective effects of forced or voluntary wheel running. These data suggest that exercise controllability and the medial prefrontal cortex are not critical factors in conferring the protective effects of exercise against the affective consequences of stressor exposure, and imply that exercise perceived as forced may still benefit affect and mental health.

Social Signals in Primate Orbitofrontal Cortex

Primate evolution produced an increased capacity to respond flexibly to varying social contexts as well as expansion of the prefrontal cortex. Despite this association, how prefrontal neurons respond to social information remains virtually unknown. People with damage to their orbitofrontal cortex (OFC) struggle to recognize facial expressions, make poor social judgments, and frequently make social faux pas. Here we test explicitly whether neurons in primate OFC signal social information and, if so, how such signals compare with responses to primary fluid rewards. We find that OFC neurons distinguish images that belong to socially defined categories, such as female perinea and faces, as well as the social dominance of those faces. These modulations signaled both how much monkeys valued these pictures and their interest in continuing to view them. Far more neurons signaled social category than signaled fluid value, despite the stronger impact of fluid reward on monkeys' choices. These findings indicate that OFC represents both the motivational value and attentional priority of other individuals, thus contributing to both the acquisition of information about others and subsequent social decisions. Our results betray a fundamental disconnect between preferences expressed through overt choice, which were primarily driven by the desire for more fluid, and preferential neuronal processing, which favored social computations.

Medial prefrontal cortex lesions in mice do not impair effort-based decision making

The function of the medial prefrontal cortex has previously been determined in the rat to play an important role in effort-based decision making and this, along with functions of other areas, has been assumed largely, to hold true in all rodents. In this study, we attempted to replicate this result in mice and to develop a model for effort-based decision making that could be useful for the study of neurological conditions. Mice were trained on a cost-benefit T-maze paradigm, whereby they chose between a low reward with little effort needed to obtain it or a higher reward, which required increased effort. Following training, the medial prefrontal cortex was lesioned. After surgery, contrary to earlier published rat studies, the performance of the mice did not change. In previous studies, prefrontal cortex lesioned rats chose the low effort/low reward option, but lesioned mice continued to select the high reward/high effort option. However, the other results are in line with previous mouse studies in both the extent of pathology and anxiety-like behaviour. These results illustrate a difference in the functioning of the prefrontal cortex between rats and mice and offer a word of caution on the interpretation of data from studies that employ different species.