Richard W. Morris

Effects of Bed Nucleus of the Stria Terminalis Lesions on Conditioned Anxiety: Aversive Conditioning With Long-Duration Conditional Stimuli and Reinstatement of Extinguished Fear

Four experiments investigated the effects of lesions of the bed nucleus of the stria terminalis (BNST) on conditioned fear and anxiety. Though BNST lesions did not disrupt fear conditioning with a short-duration conditional stimulus (CS; Experiments 1 and 3), the lesion attenuated conditioning with a longer duration CS (Experiments 1 and 2). Experiment 3 found that lesions attenuated reinstatement of extinguished fear, which relies on contextual conditioning. Experiment 4 confirmed that the lesion reduced unconditioned anxiety in an elevated zero maze. The authors suggest that long-duration CSs, whether explicit cues or contexts, evoke anxiety conditioned responses, which are dissociable from fear responses to shorter CSs. Results are consistent with behavioral and anatomical distinctions between fear and anxiety and with a behavior-systems view of defensive conditioning.

Emotional face processing in schizophrenia

PURPOSE OF REVIEWnRecent studies of face processing deficits in people with schizophrenia have begun to shed light on the answers to four important questions: What is the major component of the deficit? Does it have a neurobiological basis? When does it appear in development? Can it be remediated?nnnRECENT FINDINGSnEye contact is especially important for recognizing fearful expressions. Patients with schizophrenia avoid gazing at important facial feature regions (especially eyes) and are particularly impaired in recognizing fear. Patients were thought to exhibit decreased amygdala activity when viewing fearful faces; however, more recent studies have revealed limbic hyperactivity in patients when viewing nonfearful and fearful faces compared with baseline. Amygdala hyperactivity can also be detected when people with schizophrenia fail to appropriately recognize fear faces. Studies indicate that there are developmental changes in amygdala activation, including limbic hyperactivity to fear faces during adolescence, a critical time for the onset of schizophrenia. New treatment strategies can increase gaze to the eye region, which could improve emotional recognition in patients.nnnSUMMARYnThese findings suggest that there may soon be more options for overcoming specific problems in emotional face evaluation in people who have schizophrenia.

Disambiguating ventral striatum fMRI-related BOLD signal during reward prediction in schizophrenia.

Reward detection, surprise detection and prediction-error signaling have all been proposed as roles for the ventral striatum (vStr). Previous neuroimaging studies of striatal function in schizophrenia have found attenuated neural responses to reward-related prediction errors; however, as prediction errors represent a discrepancy in mesolimbic neural activity between expected and actual events, it is critical to examine responses to both expected and unexpected rewards (URs) in conjunction with expected and UR omissions in order to clarify the nature of ventral striatal dysfunction in schizophrenia. In the present study, healthy adults and people with schizophrenia were tested with a reward-related prediction-error task during functional magnetic resonance imaging to determine whether schizophrenia is associated with altered neural responses in the vStr to rewards, surprise prediction errors or all three factors. In healthy adults, we found neural responses in the vStr were correlated more specifically with prediction errors than to surprising events or reward stimuli alone. People with schizophrenia did not display the normal differential activation between expected and URs, which was partially due to exaggerated ventral striatal responses to expected rewards (right vStr) but also included blunted responses to unexpected outcomes (left vStr). This finding shows that neural responses, which typically are elicited by surprise, can also occur to well-predicted events in schizophrenia and identifies aberrant activity in the vStr as a key node of dysfunction in the neural circuitry used to differentiate expected and unexpected feedback in schizophrenia.

The effect of yohimbine on the extinction of conditioned fear: A role for context.

Six experiments with rat subjects examined the effect of yohimbine, an alpha-2 adrenergic autoreceptor antagonist, on the extinction of conditioned fear to a tone. Experiments 1 and 2 demonstrated that systemic administration of yohimbine (1.0 mg/kg) facilitated a long-term decrease in freezing after extinction, and this depended on pairing drug administration with extinction training. However, Experiments 3 and 4 demonstrated that yohimbine did not eradicate the original fear learning: Freezing was renewed when the tone was tested outside of the extinction context. Experiments 5 and 6 found that the contextually specific attenuation of fear produced by yohimbine transferred to another extinguished conditional stimulus (CS) and not to a nonextinguished CS. The results suggest that yohimbine, when administered in the presence of a neutral context, creates a form of inhibition in that context that allows that specific context to reduce fear of an extinguished CS.

Corticostriatal Control of Goal-Directed Action Is Impaired in Schizophrenia

BACKGROUNDnGoal-directed actions depend on our capacity to integrate the anticipated consequences of an action with the value of those consequences, with the latter derived from direct experience or inferred from predictive stimuli. Schizophrenia is associated with poor goal-directed performance, but whether this reflects a deficit in experienced or predicted value or in integrating these values with action-outcome information is unknown, as is the locus of any associated neuropathology.nnnMETHODSnWe assessed the contribution of these sources of value to goal-directed actions in people with schizophrenia (SZ) (n = 18) and healthy adults (n = 18). Participants learned to use specific actions to liberate snack foods from a vending machine. They also learned about the reward value of the foods, changes in reward value, and the relationship between various predictive stimuli and food delivery. We then evaluated the ability of subjects to use experienced or predicted value to guide goal-directed actions while undergoing functional magnetic resonance imaging.nnnRESULTSnAcquisition and sensitivity to experienced changes in outcome value did not differ in SZ and healthy adults. The SZ were, however, deficient in their ability to integrate action-outcome learning with outcome values to guide choice, more so when actions were guided by experienced than by predicted values. These effects were differentially associated with reductions in activity in caudate and limbic structures, respectively.nnnCONCLUSIONSnThis novel assessment of goal-directed learning revealed dysfunction in corticostriatal control associated with a profound deficit in integrating changes in experienced value with the action-outcome association in schizophrenia.

Lack of cortico-limbic coupling in bipolar disorder and schizophrenia during emotion regulation

Bipolar disorder (BD) and schizophrenia (Sz) share dysfunction in prefrontal inhibitory brain systems, yet exhibit distinct forms of affective disturbance. We aimed to distinguish these disorders on the basis of differential activation in cortico-limbic pathways during voluntary emotion regulation. Patients with DSM-IV diagnosed Sz (12) or BD-I (13) and 15 healthy control (HC) participants performed a well-established emotion regulation task while undergoing functional magnetic resonance imaging. The task required participants to voluntarily upregulate or downregulate their subjective affect while viewing emotionally negative images or maintain their affective response as a comparison condition. In BD, abnormal overactivity (hyperactivation) occurred in the right ventrolateral prefrontal cortex (VLPFC) during up- and downregulation of negative affect, relative to HC. Among Sz, prefrontal hypoactivation of the right VLPFC occurred during downregulation (opposite to BD), whereas upregulation elicited hyperactivity in the right VLPFC similar to BD. Amygdala activity was significantly related to subjective negative affect in HC and BD, but not Sz. Furthermore, amygdala activity was inversely coupled with the activity in the left PFC during downregulation in HC (r=−0.76), while such coupling did not occur in BD or Sz. These preliminary results indicate that differential cortico-limbic activation can distinguish the clinical groups in line with affective disturbance: BD is characterized by ineffective cortical control over limbic regions during emotion regulation, while Sz is characterized by an apparent failure to engage cortical (hypofrontality) and limbic regions during downregulation.

Attention to Irrelevant Cues Is Related to Positive Symptoms in Schizophrenia

Many modern learning theories assume that the amount of attention to a cue depends on how well that cue predicted important events in the past. Schizophrenia is associated with deficits in attention and recent theories of psychosis have argued that positive symptoms such as delusions and hallucinations are related to a failure of selective attention. However, evidence demonstrating that attention to irrelevant cues is related to positive symptoms in schizophrenia is lacking. We used a novel method of measuring attention to nonpredictive (and thus irrelevant) cues in a causal learning test (Le Pelley ME, McLaren IP. Learned associability and associative change in human causal learning. Q J Exp Psychol B. 2003;56:68–79) to assess whether healthy adults and people with schizophrenia discriminate previously predictive and nonpredictive cues. In a series of experiments with independent samples, we demonstrated: (1) when people with schizophrenia who had severe positive symptoms successfully distinguished between predictive and nonpredictive cues during training, they failed to discriminate between predictive and nonpredictive cues relative to healthy adults during subsequent testing and (2) learning about nonpredictive cues was correlated with more severe positive symptoms scores in schizophrenia. These results suggest that positive symptoms of schizophrenia are related to increased attention to nonpredictive cues during causal learning. This deficit in selective attention results in learning irrelevant causal associations and may be the basis of positive symptoms in schizophrenia.

Task-related fronto-striatal functional connectivity during working memory performance in schizophrenia

Working memory (WM) deficits and associated brain dysfunction are among the most well replicated candidate endophenotypic processes in schizophrenia. However, previous studies demonstrate inconsistent over- and under-activation of dorsolateral and ventrolateral prefrontal cortices (DLPFC; VLPFC), inferior parietal lobule (IPL) during WM performance, as well as subcortical structures including the striatum, and dysfunctional connectivity among fronto-striatal regions in schizophrenia. However, no previous study has investigated task-related functional connectivity (FC) of DLPFC and striatal regions using a seed-based method; here we employed this method to assess patterns of cortical and subcortical functional connectivity among WM structures during a standard 2-back WM task performed by 28 schizophrenia (SZ) and 28 healthy controls (HC). Initial group comparisons of blood oxygenation level dependent (BOLD) responses during the WM task revealed significantly greater bilateral activity in the striatum in SZ relative to HC, but there was no significant group difference in WM cortical activity (right DLPFC, VLPFC or IPL). Analyses of FC within the cortico-subcortical WM network in the HC group revealed positive performance-related FC between the right DLPFC and the right caudate, and between the right VLPFC and the right IPL; this pattern was absent in SZ. In contrast, SZ patients showed negative performance-related functional connectivity between the left putamen and the right VLPFC. Direct group comparisons in functional connectivity showed significantly greater performance-related FC between the VLPFC and bilateral putamen, as well as unilaterally between the VLPFC and the right IPL, in HC. Results suggest a critical dysfunction of cortico-striatal connectivity underpinning information retrieval for SZ patients during WM performance.

Translational studies of goal-directed action as a framework for classifying deficits across psychiatric disorders

The ability to learn contingencies between actions and outcomes in a dynamic environment is critical for flexible, adaptive behavior. Goal-directed actions adapt to changes in action-outcome contingencies as well as to changes in the reward-value of the outcome. When networks involved in reward processing and contingency learning are maladaptive, this fundamental ability can be lost, with detrimental consequences for decision-making. Impaired decision-making is a core feature in a number of psychiatric disorders, ranging from depression to schizophrenia. The argument can be developed, therefore, that seemingly disparate symptoms across psychiatric disorders can be explained by dysfunction within common decision-making circuitry. From this perspective, gaining a better understanding of the neural processes involved in goal-directed action, will allow a comparison of deficits observed across traditional diagnostic boundaries within a unified theoretical framework. This review describes the key processes and neural circuits involved in goal-directed decision-making using evidence from animal studies and human neuroimaging. Select studies are discussed to outline what we currently know about causal judgments regarding actions and their consequences, action-related reward evaluation, and, most importantly, how these processes are integrated in goal-directed learning and performance. Finally, we look at how adaptive decision-making is impaired across a range of psychiatric disorders and how deepening our understanding of this circuitry may offer insights into phenotypes and more targeted interventions.

Recent exposure to a dangerous context impairs extinction and reinstates lost fear reactions

Rats were shocked in a context and then exposed to that context in the absence of shock. Shorter intervals between these extinction trials produced more long-term freezing than did longer ones, and shorter intervals between the final extinction trial and test produced more freezing than did longer ones. A short interval between a context extinction trial and test with an extinguished conditioned stimulus (CS) produced more freezing than did a longer one, and a short interval between a nonreinforced context exposure and an extinguished CS reinstated freezing when the CS was tested 24 hr later. The results suggest that recent fear acts to favor subsequent retrieval of the memory formed at conditioning rather than extinction and to render the retrieved memory more salient.