Differential brain activity during emotional versus nonemotional reversal learning

The ability to change an established stimulus-behavior association based on feedback is critical for adaptive social behaviors. This ability has been examined in reversal learning tasks, where participants first learn a stimulus-response association (e.g., select a particular object to get a reward) and then need to alter their response when reinforcement contingencies change. Although substantial evidence demonstrates that the OFC is a critical region for reversal learning, previous studies have not distinguished reversal learning for emotional associations from neutral associations. The current study examined whether OFC plays similar roles in emotional versus neutral reversal learning. The OFC showed greater activity during reversals of stimulus-outcome associations for negative outcomes than for neutral outcomes. Similar OFC activity was also observed during reversals involving positive outcomes. Furthermore, OFC activity is more inversely correlated with amygdala activity during negative reversals than during neutral reversals. Overall, our results indicate that the OFC is more activated by emotional than neutral reversal learning and that OFC's interactions with the amygdala are greater for negative than neutral reversal learning.     

Cognitive sequence learning in Parkinson's disease and amnestic mild cognitive impairment: Dissociation between sequential and non-sequential learning of associations

Evidence suggests that dopaminergic mechanisms in the basal ganglia (BG) are important in the learning of sequential associations. To test the specificity of this hypothesis, we assessed never-medicated patients with Parkinson's disease (PD) and amnestic mild cognitive impairment (aMCI) using a chaining task. In the training phase of the chaining task, each link in a sequence of stimuli leading to reward is trained step-by-step using feedback after each decision, until the complete sequence is learned. In the probe phase of the chaining task, the context of stimulus-response associations must be used (the position of the associations in the sequence). Results revealed that patients with PD showed impaired learning during the training phase of the chaining task, but their performance was spared in the probe phase. In contrast, patients with aMCI with prominent medial temporal lobe (MTL) dysfunctions showed intact learning during the training phase of the chaining task, but their performance was impaired in the probe phase of the chaining task. These results indicate that when dopaminergic mechanisms in the BG are dysfunctional, series of stimulus-response associations are less efficiently acquired, but their sequential manner is maintained. In contrast, MTL dysfunctions may result in a non-sequential learning of associations, which may indicate a loss of contextual information.     

Orbitofrontal inactivation impairs reversal of Pavlovian learning by interfering with ‘disinhibition’ of responding for previously unrewarded cues

Orbitofrontal cortex (OFC) is critical for reversal learning. Reversal deficits are typically demonstrated in complex settings that combine Pavlovian and instrumental learning. Yet recent work has implicated the OFC specifically in behaviors guided by cues and the features of the specific outcomes they predict. To test whether the OFC is important for reversing such Pavlovian associations in the absence of confounding instrumental requirements, we trained rats on a simple Pavlovian task in which two auditory cues were presented, one paired with a food pellet reward and the other presented without reward. After learning, we reversed the cue–outcome associations. For half the rats, OFC was inactivated prior to each reversal session. Inactivation of OFC impaired the ability of the rats to reverse conditioned responding. This deficit reflected the inability of inactivated rats to develop normal responding for the previously unrewarded cue; inactivation of OFC had no impact on the ability of the rats to inhibit responding to the previously rewarded cue. These data show that OFC is critical to reversal of Pavlovian responding, and that the role of OFC in this behavior cannot be explained as a simple deficit in response inhibition. Furthermore, the contrast between the normal inhibition of responding, reported here, and impaired inhibition of responding during Pavlovian over‐expectation, reported previously, suggests the novel hypothesis that OFC may be particularly critical for learning (or behavior) when it requires the subject to generate predictions about outcomes by bringing together or integrating disparate pieces of associative information.     

Pre-surgical training ameliorates orbitofrontal-mediated impairments in spatial reversal learning

We recently reported that orbitofrontal cortical (OFC) lesions impaired reversal learning of an instrumental two-lever spatial discrimination task, a deficit manifested as increased perseveration on the pre-potent response. Here we examine whether exposure to reversal learning test pre-operatively may have a beneficial effect for future reversal learning of OFC-lesioned animals. Rats were trained on a novel instrumental two-lever spatial discrimination and reversal learning task, measuring both 'cognitive flexibility' and constituent processes including response inhibition. Both levers were presented, only one of which was reinforced. The rat was required to respond on the reinforced lever under a fixed ratio 3 schedule of reinforcement. Following attainment of criterion, two reversals were introduced. Rats were then matched according to their reversal performance and subjected to bilateral excitotoxic OFC lesions. Following recovery, a series of four reversals was presented. OFC lesions impaired neither retention nor reversal phases. These data, together with the previously reported reversal deficit following OFC lesions, suggest that OFC is not needed when task experience has been gained but it is necessary when task demands are relatively high.     

Distinct hippocampal and basal ganglia contributions to probabilistic learning and reversal

The hippocampus and the basal ganglia are thought to play fundamental and distinct roles in learning and memory, supporting two dissociable memory systems. Interestingly, however, the hippocampus and the basal ganglia have each, separately, been implicated as necessary for reversal learning-the ability to adaptively change a response when previously learned stimulus-outcome contingencies are reversed. Here, we compared the contribution of the hippocampus and the basal ganglia to distinct aspects of learning and reversal. Amnesic subjects with selective hippocampal damage, Parkinson subjects with disrupted basal ganglia function, and healthy controls were tested on a novel probabilistic learning and reversal paradigm. In this task, reversal can be achieved in two ways: Subjects can reverse a previously learned response, or they can select a new cue during the reversal phase, effectively "opting out" of the reversal. We found that both patient groups were intact at initial learning, but differed in their ability to reverse. Amnesic subjects failed to reverse, and continued to use the same cue and response learned before the reversal. Parkinson subjects, by contrast, opted out of the reversal by learning a new cue-outcome association. These results suggest that both the hippocampus and the basal ganglia support reversal learning, but in different ways. The basal ganglia are necessary for learning a new response when a previously learned response is no longer rewarding. The failure of the amnesic subjects to reverse their response or to learn a new cue is consistent with a more general role for the hippocampus in configural learning, and suggests it may also support the ability to respond to changes in cue-outcome contingencies.     

Reward-related reversal learning after surgical excisions in orbito-frontal or dorsolateral prefrontal cortex in humans

Neurophysiological studies in primates and neuroimaging studies in humans suggest that the orbito-frontal cortex is involved in representing the reward value of stimuli and in the rapid learning and relearning of associations between visual stimuli and rewarding or punishing outcomes. In the present study, we tested patients with circumscribed surgical lesions in different regions of the frontal lobe on a new visual discrimination reversal test, which, in an fMRI study (O'Doherty, Kringelbach, Rolls, Hornak, & Andrews, 2001), produced bilateral orbito-frontal cortex activation in normal subjects. In this task, touching one of two simultaneously presented patterns produced reward or loss of imaginary money delivered on a probabilistic basis to minimize the usefulness of verbal strategies. A number of types of feedback were present on the screen. The main result was that the group of patients with bilateral orbito-frontal cortex lesions were severely impaired at the reversal task, in that they accumulated less money. These patients often failed to switch their choice of stimulus after a large loss and often did switch their choice although they had just received a reward. The investigation showed that bilateral lesions were required for this deficit, since patients with unilateral orbito-frontal cortex (or medial prefrontal cortex) lesions were not impaired in the probabilistic reversal task. The task ruled out a simple motor disinhibition as an explanation of the deficit in the bilateral orbito-frontal cortex patients, in that the patients were required to choose one of two stimuli on each trial. A comparison group of patients with dorsolateral prefrontal cortex lesions was in some cases able to do the task, and in other cases, was impaired. Posttest debriefing showed that all the dorsolateral prefrontal patients who were impaired at the task had failed to pay attention to the crucial feedback provided on the screen after each trial about the amount won or lost on each trial. In contrast, all dorsolateral patients who paid attention to this crucial feedback performed normally on the reversal task. Further, it was confirmed that the bilateral orbito-frontal cortex patients had also paid attention to this crucial feedback, but in contrast had still performed poorly at the task. The results thus show that the orbital prefrontal cortex is required bilaterally for monitoring changes in the reward value of stimuli and using this to guide behavior in the task; whereas the dorsolateral prefrontal cortex, if it produces deficits in the task, does so for reasons related to executive functions, such as the control of attention. Thus, the ability to determine which information is relevant when making a choice of pattern can be disrupted by a dorsolateral lesion on either side, whereas the ability to use this information to guide behavior is not disrupted by a unilateral lesion in either the left or the right orbito-frontal cortex, but is severely impaired by a bilateral lesion in this region. Because both abilities are important in many of the tasks and decisions that arise in the course of daily life, the present results are relevant to understanding the difficulties faced by patients after surgical excisions in different frontal brain regions.     

Reinforcement and reversal learning in first-episode psychosis

Background: Abnormalities in reinforcement learning and reversal learning have been reported in psychosis, possibly secondary to subcortical dopamine abnormalities. Methods: We studied simple discrimination (SD) learning and reversal learning in a sample of 119 first-episode psychosis patients from the Cambridge early psychosis service (CAMEO) and 107 control participants. We used data on reinforcement learning and reversal learning extracted from the Cambridge Neuropsychological Test Automated Battery Intradimensional-Extradimensional shift task, which measures cognitive flexibility but also involves simple reinforcement learning (SD learning) and reversal learning stages. We also gathered diagnostic information to examine whether there were any differences between patients ultimately diagnosed with schizophrenia-spectrum disorders and those diagnosed with affective psychosis. Results: Psychosis patients demonstrated deficits in simple reinforcement learning (SD learning) and in reversal learning, with no differences between affective psychosis and schizophrenia-spectrum psychosis. There was a significant modest correlation between reversal errors and negative symptoms (Spearman rho = 0.3, P = .02). Conclusions: There are reinforcement learning abnormalities in first-episode psychosis, which correlate with negative symptoms, suggesting a possible role for orbitofrontal cortex and ventral striatal pathology in the pathogenesis of motivational deficits in psychosis.     

Discrimination, reversal, and shift learning in Huntington's disease: mechanisms of impaired response selection

In a series of three experiments, we investigated different aspects of response selection in early-stage clinically symptomatic Huntington's disease (HD) patients in the context of discrimination learning. A series of structurally related response selection tasks involving discrimination, reversal, and shift learning were employed. In Experiment 1, the mechanisms of our previously reported [37] finding of impaired extra-dimensional shift learning were explored. The results suggested that impaired shift learning in HD is a result of perseverative responding. In Experiment 2, performance on a concurrent-pair (CP) discrimination and reversal task was examined. HD patients showed no deficits in CP discrimination learning or reversal. In Experiment 3, the performance of HD patients on a probabilistic discrimination and reversal task was examined. HD patients were impaired in the learning of a probabilistic discrimination, and also its reversal. This reversal deficit was again the result of perseverative responding. In addition, there was a strong correlation between HD patients' activities of daily living scores and reversal errors. The result are consistent with current theories of the role of the basal ganglia in cognition, and suggest specific impairments in response selection mechanisms in HD, in particular, in overcoming selection biases based on prior reinforcement.     

Effects of orbitofrontal, infralimbic and prelimbic cortical lesions on serial spatial reversal learning in the rat

BACKGROUND: Recent evidence suggests that the neural correlates of reversal learning are localised to the orbitofrontal cortex whereas studies on the contribution of the medial prefrontal cortex to this capacity have produced equivocal results. This study examines the behavioural effects of selective lesions centred on orbitofrontal, infralimbic and prelimbic cortex on serial spatial reversal learning in the rat. METHODS: Rats were trained on a novel instrumental two-lever spatial discrimination and reversal learning task, measuring both 'cognitive flexibility' and constituent processes including response inhibition. Both levers were presented, only one of which was reinforced. The rat was required to respond on the reinforced lever under a fixed ratio 3 schedule of reinforcement. Following attainment of criterion, a series of reversals was presented. RESULTS: Bilateral excitotoxic lesions of the orbitofrontal cortex did not affect retention of a preoperatively acquired spatial discrimination but did impair reversal learning. This deficit manifested as increased perseverative responding on the previously correct lever. Although impairments were evident during reversal 1, OFC-lesioned animals performed significantly better than controls on reversal 2. There were no significant effects of infralimbic and prelimbic lesions on the retention of a spatial discrimination or reversal learning. CONCLUSIONS: These results indicate that the orbitofrontal cortex is critical for flexible responding in serial spatial reversal learning. The present findings may be relevant to deficits in reversal learning and response inhibition in such neuropsychiatric disorders as obsessive-compulsive disorder.     

Orbital prefrontal cortex mediates reversal learning and not attentional set shifting in the rat

It has been demonstrated previously that lesions to medial prefrontal cortex in rats impair the shifting of attentional set between perceptual features of complex stimuli [J. Neurosci. 20 (2000) 4320], a result that mirrors the deficit found in humans and monkeys [Nature 380 (1996) 69; Behav. Neurosci. 110 (1996) 872; J. Neurosci. 17 (1997) 9285; Neuropsychologia 29 (1991) 993]. These data imply functional homology between rat medial prefrontal cortex and primate prefrontal cortex.In marmoset monkeys, there is a double dissociation between the effects of lesions of lateral prefrontal cortex, which impair shifting of attentional set, and lesions of orbital prefrontal cortex, which result in impairments of reversal of stimulus-reward contingencies, leaving attentional set-shifting capacities intact [Nature 380 (1996) 69; Behav. Neurosci. 110 (1996) 872; J. Neurosci. 17 (1997) 9285]. The present investigation examined whether lesions to rat orbital prefrontal cortex would produce deficits in reversal learning in the absence of deficits in shifting attentional set, as seen in monkeys. Rats were trained to perform an attentional set-shifting task that is formally the same as that used in monkeys and humans. In a single session, rats performed a series of discriminations, including acquisitions and reversals. Damage to orbital prefrontal cortex in the rats did not disrupt the ability to acquire, maintain or shift attentional set. We report here the same selective impairment in reversal learning in rats as seen in primates with orbital prefrontal cortex lesions.     

The role of the orbitofrontal cortex in human discrimination learning

Several lines of evidence implicate the prefrontal cortex in learning but there is little evidence from studies of human lesion patients to demonstrate the critical role of this structure. To this end, we tested patients with lesions of the frontal lobe (n = 36) and healthy controls (n = 35) on two learning tasks: the weather prediction task (WPT), and an eight-pair concurrent visual discrimination task (‘Choose’). Performance of both tasks was previously shown to be disrupted in patients with Parkinson's disease; the Choose deficit was only present when patients were medicated. Patients with damage to the orbitofrontal cortex (OFC) were significantly impaired on Choose, compared to both healthy controls and non-OFC lesion patients. The OFC lesion patients showed a mild deficit on the first 50 trials of the WPT, compared to the control subjects but not non-OFC lesion patients. The selective deficit in the OFC patients on Choose performance could not be attributed to the larger lesion size in this group, and the deficit was not correlated with the volume of damage to adjacent prefrontal subregions (e.g. anterior cingulate cortex). These data support the notion that the OFC play a role in normal discrimination learning, and suggest qualitative similarities in learning performance of patients with OFC damage and medicated PD patients.     

Preserved stimulus-reward and reversal learning after selective neonatal orbital frontal areas 11/13 or amygdala lesions in monkeys

Neither lesions of orbital frontal (OFC) areas 11/13 nor selective amygdala lesions alter the ability to learn stimulus-reinforcer association and reversal discriminations in adult monkeys. Here, we investigated whether the same conclusion will hold true when the same lesions occur in infancy. Infant rhesus monkeys received sham-operations, neurotoxic amygdala lesions, or aspiration OFC 11/13 lesions at 8-15 days of age and were trained on object discrimination reversal (ODR) tasks. Performance on a single pair (1-Pair) ODR was assessed at the age of 3 months and 3 years, and then animals were tested in a 5-Pair ODR task in which they had to concurrently learn and reverse five discrimination problems. The results indicated that the ability to solve a single-pair discrimination problem followed by six reversals appears to be late maturing in monkeys but is spared following selective lesions of either OFC areas 11/13 or amygdala, even with the use of the more challenging 5-object ODR task. Finally, performance in the 1 and 5-Pair ODR at 3 years was comparable to that following adult-onset lesions, indicating that neither OFC areas 11/13 nor amygdala are critical for the development of reversal learning.     

Reduction of lesion-induced deficits in visual reversal learning following cross-modal training

Two experiments examined the effects of postoperative auditory intensity training on serial brightness reversal learning of visual decorticate rats. In Experiment 1 rats learned an avoidance response cued by a high intensity light prior to visual decortication. Six days later the rats were given either avoidance training with an auditory intensity cue, additional training with the preoperative visual cue, or no training. The next day all rats began a series of 8 brightness discrimination reversals. The no-training lesion group failed the early reversals but reached criterion in later reversals. Lesion rats retrained with visual cues failed early reversals with the low intensity light cue but not reversals with the high intensity cue. In contrast, lesion rats given auditory training easily reached criterion in all reversals. Experiment 2 followed a similar training sequence except auditory training was given after the second reversal. All rats showed rapid acquisition of all visual reversals subsequent to auditory training. These data suggest that generalization of a learning set by cross-modal transfer training with an intact modality can reduce reversal learning deficits following brain damage more efficiently than comparable training with the damaged system.     

T-maze discrimination and reversal learning after unilateral temporal or frontal lobe lesions in man.

The interpretation of conditional discrimination and reversal learning as acquisition of declarative knowledge suggests that subjects with temporal lobe/hippocampal lesions are likely to be impaired on such tasks. Patients with unilateral left or right temporal lobectomy (and small hippocampal excisions) and patients with unilateral frontal lobe resections were compared with healthy controls on a discrimination reversal task, embedded in a computer game modelled on T-maze tasks traditionally used in animal experiments. The right temporal group showed a deficit in acquiring an initial conditional discrimination, and the frontal group tended to display a marginal impairment in discrimination reversal. These findings are compared with results from animal studies in terms of the mechanisms underlying reversal learning.     

Orbitofrontal cortex dysfunction in attention-deficit hyperactivity disorder revealed by reversal and extinction tasks

Attention-deficit hyperactivity disorder (ADHD) has been considered a mental illness in which the frontal lobe is dysfunctional. The orbitofrontal cortex (OFC) controls emotional and motivational behaviors which are impaired in ADHD. Patients with OFC damage have shown impaired performance in reversal and extinction tasks in a simple go/no-go paradigm. We assigned ADHD subjects the two tasks to examine a hypothesized dysfunction of OFC. ADHD subjects indeed showed a performance deficit in the tasks, supporting OFC dysfunction in ADHD. Furthermore, a discriminat analysis using the task performance variables correctly classified 89.7% of the participants among ADHD patients and normal controls.     

How does the hippocampal formation mediate memory for stimuli processed by the magnocellular and parvocellular visual pathways? Evidence from the comparison of schizophrenia and amnestic mild cognitive impairment (aMCI)

Paired associates learning is impaired in both schizophrenia and amnestic mild cognitive impairment (aMCI), which may reflect hippocampal pathology. In addition, schizophrenia is characterized by the dysfunction of the retino-geniculo-striatal magnocellular (M) visual pathway. The purpose of this study was to investigate the interaction between visual perceptual and memory dysfunctions. We administered a modified version of the CANTAB paired associates learning task to patients with schizophrenia (n=20), aMCI (n=20), and two groups of matched healthy controls (n=20 for each patient group). The stimuli in the paired associates learning task biased information processing toward the M pathways (low contrast, low spatial frequency) and parvocellular (P) pathways (high contrast, high spatial frequency). Results revealed that patients with schizophrenia exhibited a more pronounced learning deficit for M-biased relative to P-biased stimuli. In aMCI, there were similar memory deficits for both types of stimuli. Orientation discrimination for M- and P-biased stimuli was intact in both groups of patients. The number of errors in the M-biased memory condition significantly and inversely correlated with the volume of the right hippocampus in schizophrenia. These results suggest an interaction between M-biased perceptual processing and short-term relational memory in schizophrenia, which may be associated with the structural alteration of the right hippocampus.     

Dissociation between medial temporal lobe and basal ganglia memory systems in schizophrenia

The purpose of this study was to investigate basal ganglia (BG) and medial temporal lobe (MTL) dependent learning in patients with schizophrenia. Acquired equivalence is a phenomenon in which prior training to treat two stimuli as equivalent (if two stimuli are associated with the same response) increases generalization between them. The learning of stimulus-response pairs is related to the BG, whereas the MTL system participates in stimulus generalization. Forty-three patients with DSM-IV schizophrenia and 28 matched healthy controls participated. Volunteers received the Rutgers acquired equivalence task (face-fish task) by [Myers, C.E., Shohamy, D., Gluck, M.A. et al., 2003. Dissociating hippocampal versus basal ganglia contributions to learning and transfer. J. Cogn. Neurosci. 15, 185-193.], the California Verbal Learning Test (CVLT), and the n-back working memory test. The Rutgers acquired equivalence task investigates BG-dependent processes (stimulus-response learning) and MTL-dependent processes (stimulus generalization) with a single test. Results revealed that patients with schizophrenia showed a selective deficit on stimulus generalization, whereas stimulus-response learning was spared. The stimulus generalization deficit correlated with the CVLT performance (total scores from trials 1-5 and long-delay recall), but not with the n-back test performance. The number of errors during stimulus-response learning correlated with the daily chlorpromazine-equivalent dose of antipsychotics. In conclusion, this is the first study to show that patients with schizophrenia exhibit deficits during MTL-dependent learning, but not during BG-dependent learning within a single task. High-dose first generation antipsychotics may disrupt BG-dependent learning by blocking dopaminergic neurotransmission in the nigro-stiratal system.     

An examination of executive dysfunction associated with frontostriatal circuitry in Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative movement disorder presenting with subcortical pathology and characterized by motor deficits. However, as is frequently reported in the literature, patients with PD can also exhibit cognitive and behavioral (i.e., nonmotor) impairments, cognitive executive deficits and depression being the most prominent. Considerable attention has addressed the role that disruption to frontostriatal circuitry can play in mediating nonmotor dysfunction in PD. The three nonmotor frontostriatal circuits, which connect frontal cortical regions to the basal ganglia, originate from the dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), and orbitofrontal cortex (OFC). The objective of the current study was to use our understanding of frontostriatal circuit function (via literature review) to categorize neuropsychological measures of cognitive and behavioral executive functions by circuit. To our knowledge, such an approach has not been previously attempted in the study of executive dysfunction in PD. Neuropsychological measures of executive functions and self-report behavioral inventories, categorized by circuit function, were administered to 32 nondemented patients with Parkinson's disease (NDPD) and to 29 demographically matched, healthy normal control participants (NC). Our findings revealed significant group differences for each circuit, with the PD group performing worse than the NC group. Among the patients with PD, indices of impairment were greater for tasks associated with DLPFC function than with OFC function. Further, only an index of DLPFC test performance was demonstrated to significantly discriminate individuals with and without PD. In conclusion, our findings suggest that nondemented patients with PD exhibit greater impairment on neuropsychological measures associated with DLPFC than with ACC or OFC circuit function.     

Probabilistic reversal learning impairments in schizophrenia: further evidence of orbitofrontal dysfunction

Impairments in feedback processing and reinforcement learning appear to be prominent aspects of schizophrenia (SZ), which may relate to symptoms of the disorder. Evidence from cognitive neuroscience investigations indicates that disparate brain systems may underlie different kinds of feedback-driven learning. The ability to rapidly shift response tendencies in the face of negative feedback, when reinforcement contingencies are reversed, is an important type of learning thought to depend on ventral prefrontal cortex (PFC). Schizophrenia has long been associated with dysfunction in dorsolateral areas of PFC, but evidence for ventral PFC impairment in more mixed. In order to assess whether SZ patients experience particular difficulty in carrying out a cognitive function commonly linked to ventral PFC function, we administered to 34 patients and 26 controls a modified version of an established probabilistic reversal learning task from the experimental literature [Cools, R., Clark, L., Owen, A.M., Robbins, T.W., 2002. Defining the neural mechanisms of probabilistic reversal learning using event-related functional magnetic resonance imaging. J. Neurosci. 22, 4563-4567]. Although SZ patients and controls performed similarly on the initial acquisition of probabilistic contingencies, patients showed substantial learning impairments when reinforcement contingencies were reversed, achieving significantly fewer reversals [chi(2)(6)=15.717, p=0.008]. Even when analyses were limited to subjects who acquired all probabilistic contingencies initially (22 patients and 20 controls), patients achieved significantly fewer reversals [chi(2)(3)=9.408, p=0.024]. These results support the idea that ventral PFC dysfunction is a prevalent aspect of schizophrenic pathophysiology, which may contribute to deficits in reinforcement learning exhibited by patients. Further studies are required to investigate the roles of dopaminergic systems in these impairments.     

Altered neural function in pediatric bipolar disorder during reversal learning

Dickstein DP, Finger EC, Skup M, Pine DS, Blair JR, Leibenluft E. Altered neural function in pediatric bipolar disorder during reversal learning.
Bipolar Disord 2010: 12: 707–719. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objective: Data documenting the functional impairment associated with the diagnosis of bipolar disorder (BD) in children and adolescents highlight the need for greater understanding of its pathophysiology. Toward that end, we demonstrated previously that BD youth have behavioral deficits on reversal learning tasks. On such tasks, participants must first acquire a stimulus/response relationship through trial‐and‐error learning, and then discern when the stimulus/reward relationship reverses. Here, we use event‐related functional magnetic resonance imaging (fMRI) to elucidate neural correlates of reversal learning deficits in euthymic BD youth compared to typically developing controls. Method: We compared euthymic pediatric BD participants (n = 16) versus age‐, sex‐, and IQ‐matched controls (n = 16). Our main outcome measure was blood oxygen level‐dependent (BOLD) signal measured with fMRI during an event‐related probabilistic reversal task. Results: Pediatric BD participants had significantly greater neural activity than controls in fronto‐parietal regions during the reversal phase, particularly in response to punished reversal errors (p < 0.05 corrected for multiple comparisons). Conclusions: Our current study suggests that during reversal learning, BD youths inefficiently recruit regions associated with processing response conflict and implementing alternative responses, including subdivisions of the frontal cortex and the parietal cortex. Such deficits are present in euthymic BD youth. Further work is necessary to evaluate the specificity of such alterations.