Lesions Of Orbital Prefrontal Cortex Research Articles

Targeted Stimulation of Human Orbitofrontal Networks Disrupts Outcome-Guided Behavior.

Outcome-guided behavior requires knowledge about the current value of expected outcomes. Such behavior can be isolated in the reinforcer devaluation task, which assesses the ability to infer the current value of specific rewards after devaluation. Animal lesion studies demonstrate that orbitofrontal cortex (OFC) is necessary for normal behavior in this task, but a causal role for human OFC in outcome-guided behavior has not been established. Here, we used sham-controlled, non-invasive, continuous theta-burst stimulation (cTBS) to temporarily disrupt human OFC network activity by stimulating a site in the lateral prefrontal cortex that is strongly connected to OFC prior to devaluation of food odor rewards. Subjects in the sham group appropriately avoided Pavlovian cues associated with devalued food odors. However, subjects in the stimulation group persistently chose those cues, even though devaluation of food odors themselves was unaffected by cTBS. This behavioral impairment was mirrored in changes in resting-state functional magnetic resonance imaging (rs-fMRI) activity such that subjects in the stimulation group exhibited reduced OFC network connectivity after cTBS, and the magnitude of this reduction was correlated with choices after devaluation. These findings demonstrate the feasibility of indirectly targeting the human OFC with non-invasive cTBS and indicate that OFC is specifically required for inferring the value of expected outcomes.

Evidence of a role for orbital prefrontal cortex in preventing over-generalization to moderate predictors of biologically significant events

The mammalian brain is specialized to acquire information about environmental predictors of biologically significant events. However, environments contain an array of stimuli from which animals must ascertain which ones are meaningful in the current situation. This kind of uncertainty is inherent in the discriminative fear conditioning to context task (DFCTC) during which rats are trained to associate one context with foot-shock and another distinct context with no event. Although the contexts differ on several dimensions, they also share similarities making some cues perfect predictors, but others moderate predictors. Appropriate responding requires animals to determine which cues are relevant in the current situation and the ability to constrain their responses only to those perfect predictors. The orbital prefrontal cortex (OPFC) is thought to modulate this function as OPFC lesions result in over-generalization during DFCTC. Two experiments were conducted; the first was intended to dissociate the role of the OPFC in acquisition and expression of DFCTC, and the second intended to determine if the OPFC will also function to constrain responses during an appetitive version of DFCTC. We found that inactivation of the OPFC prior to assessment measures resulted in generalized responses on the appetitive and aversive task, however, these effects may be more prominent during the aversive task. Despite generalization during activity testing, rats were able to discriminate between the two contexts during preference. These results point to a broader role for the OPFC constraining responses to perfect predictors of biologically significant events in uncertain contexts.

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.

Selective Ablations Reveal That Orbital and Lateral Prefrontal Cortex Play Different Roles in Estimating Predicted Reward Value

Subregions of prefrontal cortex are important for estimating reward values and using these values to guide behavior. The present studies directly tested whether orbital prefrontal cortex (O-PFC) and lateral prefrontal cortex (L-PFC) are necessary for evaluating trial-to-trial changes in the reward values predicted by visual cues. We have compared intact rhesus monkeys, those with bilateral O-PFC lesions (n = 3), and those with bilateral L-PFC lesions (n = 3). We used three versions of a visually cued color discrimination task: we varied reward size, delay to reward, or both. O-PFC lesions altered estimations of predicted reward value in all versions of the task. L-PFC lesions disrupted performance only when both reward size and delay to reward were varied together. Neither lesion directly affected basic internal drive states (satiation curves). Our results suggest that O-PFC is essential for establishing independent, context-specific scales with which predicted reward values are measured. L-PFC appears necessary for integration of predicted reward value across these different scales.

Prefrontal cortical contributions during discriminative fear conditioning, extinction, and spontaneous recovery in rats

This research examined the roles played by the ventromedial orbital prefrontal cortex (OPFC) and the infralimbic/prelimbic prefrontal cortex (I/P PFC) during discriminative fear conditioning. The first experiment included nine rats with bilateral lesions to the I/P PFC, an additional nine with OPFC lesions, and eight sham lesion controls. Behavioural analysis was conducted using a discriminative fear conditioning to context task 10 days after surgery. Results indicate that lesions to ventromedial orbital prefrontal cortex result in generalized fear and impaired extinction. In contrast, infralimbic/prelimbic cortical lesioned animals exhibit appropriate fear response patterns and extinction, but show a specific impairment in spontaneous recovery. To ascertain why I/P PFC lesion rats did not exhibit spontaneous recovery, a second experiment was conducted. All procedures in the second experiment were identical to the first except a decay period was employed in place of extinction training. Results from the second experiment indicate that the difficulty retrieving the extinguished association is related to extinction processes and not decay. Taken together, these findings suggest that OPFC and I/P PFC have distinct roles in associative processes necessary for discriminative fear conditioning, extinction, and spontaneous recovery. These results further implicate OPFC and I/P PFC in the pathology underlying generalized anxiety disorder.

Difficulty Overcoming Learned Non‐reward during Reversal Learning in Rats with Ibotenic Acid Lesions of Orbital Prefrontal Cortex

Behavioral flexibility is a concept often invoked when describing the function of the prefrontal cortex. However, the psychological substrate of behavioral flexibility is complex. Its key components are allocation of attention, goal-directedness, planning, working memory, and response selection. Furthermore, there is evidence that different regions of the prefrontal cortex might be implicated in these different components. In rule-switching tasks, a distinction is made between errors that are perseverative (difficulty switching from a previously rewarded strategy) and errors due to learned-irrelevance (difficulty switching to a strategy previously uncorrelated with reward). A similar distinction might be made for reversal learning, which involves inhibition of a previously rewarded response and activation of a previously unrewarded response. Damage to the orbital prefrontal cortex (OPFC) results in a deficit in reversal learning. The present study was designed to examine whether one or both of either perseveration or learned non-reward might account for the deficit. Rats with bilateral ibotenic acid-induced lesions of the OPFC were not impaired in acquisition of discriminations. They were impaired, relative to controls, only when they had to overcome learned non-reward. They did not show enhanced perseveration. We conclude that an inability to overcome learned non-reward significantly contributes to OPFC lesion-induced deficits in behavioral flexibility.

Neurotoxic Lesions of the Medial Mediodorsal Nucleus of the Thalamus Disrupt Reinforcer Devaluation Effects in Rhesus Monkeys

The mediodorsal thalamus is a major input to the prefrontal cortex and is thought to modulate cognitive functions of the prefrontal cortex. Damage to the medial, magnocellular part of the mediodorsal thalamus (MDmc) impairs cognitive functions dependent on prefrontal cortex, including memory. The contribution of MDmc to other aspects of cognition dependent on prefrontal cortex has not been determined. The ability of monkeys to adjust their choice behavior in response to changes in reinforcer value, a capacity impaired by lesions of orbital prefrontal cortex, can be tested in a reinforcer devaluation paradigm. In the present study, rhesus monkeys with bilateral neurotoxic MDmc lesions were tested in the devaluation procedure. Monkeys learned visual discrimination problems in which each rewarded object is reliably paired with one of two different food rewards and then were given choices between pairs of rewarded objects, one associated with each food. Selective satiation of one of the food rewards reduces choices of objects associated with that food in normal monkeys. Monkeys with bilateral neurotoxic lesions of MDmc learned concurrently presented visual discrimination problems as quickly as unoperated control monkeys but showed impaired reinforcer devaluation effects. This finding suggests that the neural circuitry for control of behavioral choice by changes in reinforcer value includes MDmc.

Rhesus Monkeys with Orbital Prefrontal Cortex Lesions Can Learn to Inhibit Prepotent Responses in the Reversed Reward Contingency Task

Monkeys with lesions of the orbital prefrontal cortex (PFo) are impaired on behavioral tasks that require the ability to respond flexibly to changes in reward contingency (e.g., object reversal learning and extinction). These and related findings in rodents and humans have led to the suggestion that PFo is critical for the inhibitory control needed to overcome prepotent responses. To test this idea, we trained rhesus monkeys with PFo lesions and unoperated controls on acquisition of the reversed reward contingency task. In this task, selecting the smaller of 2 food quantities (1 half peanut [1P]) leads to receipt of the larger quantity (4 half peanuts [4P]) and vice versa. Choice of a larger quantity of food is a reliable prepotent response, and, accordingly, all monkeys initially selected 4P rather than one. With experience, however, all monkeys learned to select 1P in order to receive 4. Surprisingly, monkeys with PFo lesions learned as quickly as unoperated controls. Thus, PFo lesions do not yield a deficit in all tests that require the inhibition of a prepotent response.

Opposing effects of amygdala and orbital prefrontal cortex lesions on the extinction of instrumental responding in macaque monkeys

Extinction is a well-known behavioural phenomenon that allows organisms to respond flexibly to a changing environment. Although recent work implicates the amygdala and orbital prefrontal cortex (PFo) in extinction of Pavlovian conditioned fear and aversion, much less is known about the neural bases of instrumental extinction. To explore the contribution of the macaque amygdala to flexible responding in the face of changing reward contingency, we tested the effects of selective, excitotoxic lesions of the amygdala on extinction of an instrumental response. For comparison, we evaluated the effects of ablation of PFo on the same task. Amygdala lesions facilitated the extinction of instrumental responses, whereas lesions of PFo had the opposite effect.

Comparison of the Effects of Bilateral Orbital Prefrontal Cortex Lesions and Amygdala Lesions on Emotional Responses in Rhesus Monkeys

The present study examines the effects of bilateral orbital prefrontal cortex (PFo) lesions on monkeys' emotional responses in two different contexts: in the presence of a rubber snake and in the presence of a human intruder. For comparison, we also assessed the responses of rhesus monkeys with selective amygdala lesions on these same tasks. Monkeys with PFo lesions, like those with amygdala lesions, displayed blunted emotional responses to the fake snake. Unlike monkeys with amygdala lesions, however, monkeys with PFo lesions displayed more mild aggression than controls in the presence of a human intruder. The findings support the idea that the PFo helps integrate sensory signals in the service of choosing among competing responses. In addition, they point to a divergence of the roles of the PFo and amygdala in responding to a social stimulus, the human intruder.

Rapid Associative Encoding in Basolateral Amygdala Depends on Connections with Orbitofrontal Cortex

Certain goal-directed behaviors depend upon interactions between basolateral amygdala (ABL) and orbitofrontal cortex (OFC). Here we describe neurophysiological evidence of this cooperative function. We recorded from ABL in intact and OFC-lesioned rats during learning of odor discrimination problems and reversals. During learning, rats with ipsilateral OFC lesions exhibited a marked decline in the proportion of ABL neurons that fired differentially during cue sampling both before and after reversal and in the proportion of neurons that reversed odor preference when the odor-outcome associations were reversed. This decline appeared to reflect a loss of rapid flexibility in cue selectivity that characterized activity in intact rats. In addition, lesioned rats had fewer neurons that fired in anticipation of the predicted outcome during a delay period after responding but before outcome delivery. These findings support a role for OFC in facilitating the encoding of information about expected outcomes in ABL.

Bilateral orbital prefrontal cortex lesions in rhesus monkeys disrupt choices guided by both reward value and reward contingency.

The orbital prefrontal cortex (PFo) operates as part of a network involved in reward-based learning and goal-directed behavior. To test whether the PFo is necessary for guiding behavior based on the value of expected reward outcomes, we compared four rhesus monkeys with two-stage bilateral PFo removals and six unoperated controls for their responses to reinforcer devaluation, a task that assesses the monkeys' abilities to alter choices of objects when the value of the underlying food has changed. For comparison, the same monkeys were tested on a standard test of flexible stimulus-reward learning, namely object reversal learning. Relative to controls, monkeys with bilateral PFo removals showed a significant attenuation of reinforcer devaluation effects on each of two separate assessments, one performed shortly after surgery and the other approximately 19 months after surgery; the operated monkeys were also impaired on object reversal learning. The same monkeys, however, were unimpaired in acquisition of object discrimination learning problems and responded like controls when allowed to choose foods alone, either on a food preference test among six different foods or after selective satiation. Thus, satiety mechanisms and the ability to assign value to familiar foods appear to be intact in monkeys with PFo lesions. The pattern of results suggests that the PFo is critical for response selection based on predicted reward outcomes, regardless of whether the value of the outcome is predicted by affective signals (reinforcer devaluation) or by visual signals conveying reward contingency (object reversal learning).

The effect of orbital prefrontal cortex lesions on performance on a progressive ratio schedule: implications for models of inter-temporal choice

In a previous experiment [Kheramin S, Body S, Mobini S, Ho M-Y, Velazquez-Martinez DN, Bradshaw CM, et al. Effects of quinolinic acid-induced lesions of the orbital prefrontal cortex on inter-temporal choice: a quantitative analysis. Psychopharmacology 2002;165: 9–17], destruction of the orbital prefrontal cortex (OPFC) in rats altered choice between two delayed food reinforcers, enhancing preference for the larger reinforcer. Theoretical analysis based on a quantitative model of inter-temporal choice [Ho M-Y, Mobini S, Chiang T-J, Bradshaw CM, Szabadi E. Theory and method in the quantitative analysis of ‘impulsive choice’ behaviour: implications for psychopharmacology. Psychopharmacology 1999;146:362–72] indicated that the lesion had increased the relative value of the larger of the two reinforcers due to a general reduction of absolute reinforcer value. The present experiment tested this hypothesis using a reinforcement schedule that did not entail either explicit choice or delayed reinforcement. Ten rats received quinolinic acid-induced lesions of the OPFC, and ten rats received sham lesions. The rats were trained under a progressive-ratio schedule of food reinforcement for 60 daily sessions. Response rates in successive ratios were a bitonic (inverted-U) function of ratio size. Analysis of the data using a three-parameter equation derived from a quantitative model of ratio schedule performance [Killeen PR. Mathematical principles of reinforcement. Behav. Brain Sci. 1994;17:105–72] revealed that the parameter specifying hypothetical reinforcer value was significantly lower in the OPFC-lesioned group than in the sham-lesioned group, consistent with the hypothesis that destruction of the OPFC resulted in devaluation of the food reinforcer.

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.

Role of the orbital prefrontal cortex in choice between delayed and uncertain reinforcers: a quantitative analysis.

'Inter-temporal choice' refers to choice between two or more outcomes that differ with respect to their sizes, delays, and/or probabilities of occurrence. According to the multiplicative hyperbolic model of inter-temporal choice, the value of a reinforcer increases as a hyperbolic function of its size, and decreases as a hyperbolic function of its delay and the odds against its occurrence. These functions, each of which contains a single discounting parameter, are assumed to combine multiplicatively to determine the overall value of the reinforcer. The model gives rise to a quantitative methodology for analysing inter-temporal choice, based on a family of linear null equations which describe performance under conditions of indifference, when the values of the reinforcers are assumed to be equal. This approach was used to examine the effect of lesions of the orbital prefrontal cortex (OPFC) on inter-temporal choice in rats. Under halothane anaesthesia, rats received injections of the excitotoxin quinolinate into the OPFC or sham lesions. They were trained to press two levers (A and B) for food-pellet reinforcers in discrete-trials schedules. In free-choice trials, a press on A resulted in delivery of a pellet after a delay d(A) with a probability P=0.5; a press on B resulted in delivery of a pellet with a probability P=1 after a delay d(B). d(B) was increased progressively across successive blocks of six trials in each session, while d(A) was manipulated systematically across phases of the experiment. The indifference delays, d(B(50)) (value of d(B) corresponding to 50% choice of B) was estimated for each rat in each phase. Linear functions of d(B(50)) versus d(A) were derived, and the parameters of the function compared between the groups. In both groups, d(B(50)) increased linearly with d(A). The slope of the linear function was significantly steeper in the lesioned group than in the sham-lesioned group, whereas the intercept did not differ significantly between the groups. Analysis based on the relevant null equation indicated that the lesion of the OPFC increased the rate of both delay and odds discounting. Possible implications of the results for interpreting the effects of OPFC lesions on inter-temporal choice behaviour in man are discussed.

Dissociable Deficits in the Decision-Making Cognition of Chronic Amphetamine Abusers, Opiate Abusers, Patients with Focal Damage to Prefrontal Cortex, and Tryptophan-Depleted Normal Volunteers: Evidence for Monoaminergic Mechanisms

We used a novel computerized decision-making task to compare the decision-making behavior of chronic amphetamine abusers, chronic opiate abusers, and patients with focal lesions of orbital prefrontal cortex (PFC) or dorsolateral/medial PFC. We also assessed the effects of reducing central 5-hydroxytryptamine (5-HT) activity using a tryptophan-depleting amino acid drink in normal volunteers. Chronic amphetamine abusers showed sub-optimal decisions (correlated with years of abuse), and deliberated for significantly longer before making their choices. The opiate abusers exhibited only the second of these behavioral changes. Importantly, both sub-optimal choices and increased deliberation times were evident in the patients with damage to orbitofrontal PFC but not other sectors of PFC. Qualitatively, the performance of the subjects with lowered plasma tryptophan was similar to that associated with amphetamine abuse, consistent with recent reports of depleted 5-HT in the orbital regions of PFC of methamphetamine abusers. Overall, these data suggest that chronic amphetamine abusers show similar decision-making deficits to those seen after focal damage to orbitofrontal PFC. These deficits may reflect altered neuromodulation of the orbitofrontal PFC and interconnected limbic-striatal systems by both the ascending 5-HT and mesocortical dopamine (DA) projections.

Gonadal hormones and sex differences in nonreproductive behaviors in rodents: Organizational and activational influences

Sex differences in many nonreproductive behaviors have been described in rodents. Among the behaviors that are sexually dimorphic in the rat are activity, aggression, pain, and taste sensitivity, food intake and body weight regulation, the learning and retention of certain kinds of mazes, avoidance responses, taste aversion, and performance on certain schedules of reinforcement. Gonadal hormones seem to be responsible, in part, for sex differences in these behaviors, but their contribution varies greatly with the behavior in question. Frequently, these sexually dimorphic behaviors are influenced both by organizational and activational actions of sex hormones. In other instances (e.g., maze learning and the acquisition of shuttle-box avoidance responses) organizational influences predominate. And while there is no sexually dimorphic behavior surveyed that can be shown to be influenced only by activational effects, wheel-running activity is clearly more strongly subject to activational than to organizational effects of the gonadal hormones. In general, only rudimentary information exists regarding the temporal limits of the period in development when organizational influences on nonsexual behaviors occur. The suggestion can be made that organizational influences often occur outside of the critical period for differentiation of the neuroendocrine system regulating cyclic release of gonadotrophins. Even for behaviors where organizational effects usually occur during a roughly delimited period of development, data for other behavioral systems suggest that the time limits during which organizational effects can occur are not rigidly fixed. Very little information exists regarding biochemical or neural mechanisms by which organizational or activational effects on sexually dimorphic nonreproductive behaviors are expressed. It is important to recognize for many of the sexually dimorphic behaviors in the rat that differences between the sexes are neither large nor absolute. This is especially true of several kinds of learning situations where groups of males and females typically differ in average levels of performance. Ostensibly minor variations in test procedure can abolish or accentuate the average difference in performance between the sexes. We are a long way from an adequate understanding of what factors are important, but such information could be quite helpful in estimating whether sex differences in certain laboratory learning tasks have any adaptive significance. Sex differences in nonreproductive behaviors may be influenced by many factors other than hormonal status. This greatly complicates a comparative analysis, but such an analysis will ultimately be necessary. What limited data exist on rodents suggest that: (1) Sexually dimorphic responses in the rat are often not similarly differentiated in the hamster, the gerbil, or the mouse; and (2) major differences exist among rodent species in hormonal effects on such responses. Over the last decade it has become clear that the behavioral effects of deliberate neurological insult are not necessarily the same in male and female rats (or in one case, in rhesus monkeys). Sex differences in the behavioral effects of ventromedial hypothalamic, lateral hypothalamic, septal, and striatal lesions in the rat and of orbital prefrontal cortex lesions in the monkey have been described. While information regarding hormonal modulation of these differences in response to brain damage is very limited, available data suggest both organizational and activational effects of sex hormones may be involved. It is too early to tell where this line of research may ultimately lead, but rather striking sex differences in the incidence of certain neurological disorders in humans suggest that further research may have both practical and theoretical significance.