Dean T. Acheson

Interoceptive sensitivity deficits in women recovered from bulimia nervosa

Self-report studies suggest that patients with bulimia nervosa (BN) evidence difficulties with interoceptive awareness. Indeed, interoceptive deficits may persist after recovery of BN and may be a biological trait that predisposes symptom development in BN. However, no studies to date have directly assessed interoceptive sensitivity, or accuracy in detecting and perceiving internal body cues, in patients with or recovered from BN. Nine women who had recovered from BN and 10 healthy control women completed the Heart Beat Perception Task (HBPT) in which individuals were required to estimate the number of heartbeats between intervals of time. Accuracy scores were compared between groups. Significant differences were found between the groups on the HBPT ((F1,19) = 7.78, p = .013, Cohens d = 1.16) when controlling for age. These results suggest that deficits in interoceptive sensitivity are present in individuals recovered from BN. Thus interoceptive deficits may be one factor that bridges the gap between brain dysfunction and symptom presentation in BN.

Sleep deprivation impairs performance in the 5-choice continuous performance test: similarities between humans and mice

Several groups undergo extended periods without sleep due to working conditions or mental illness. Such sleep deprivation (SD) can deleteriously affect attentional processes and disrupt work and family functioning. Understanding the biological underpinnings of SD effects may assist in developing sleep therapies and cognitive enhancers. Utilizing cross-species tests of attentional processing in humans and rodents would aid in mechanistic studies examining SD-induced inattention. We assessed the effects of 36h of: (1) Total SD (TSD) in healthy male and female humans (n=50); and (2) REM SD (RSD) in male C57BL/6 mice (n=26) on performance in the cross-species 5-choice continuous performance test (5C-CPT). The 5C-CPT includes target trials on which subjects were required to respond and non-target trials on which subjects were required to inhibit from responding. TSD-induced effects on human psychomotor vigilance test (PVT) were also examined. Effects of SD were also examined on mice split into good and poor performance groups based on pre-deprivation scores. In the human 5C-CPT, TSD decreased hit rate and vigilance with trend-level effects on accuracy. In the PVT, TSD slowed response times and increased lapses. In the mouse 5C-CPT, RSD reduced accuracy and hit rate with trend-level effects on vigilance, primarily in good performers. In conclusion, SD induced impaired 5C-CPT performance in both humans and mice and validates the 5C-CPT as a cross-species translational task. The 5C-CPT can be used to examine mechanisms underlying SD-induced deficits in vigilance and assist in testing putative cognitive enhancers.

Fear conditioning, safety learning, and sleep in humans.

Fear conditioning is considered an animal model of post-traumatic stress disorder. Such models have shown fear conditioning disrupts subsequent rapid eye movement sleep (REM). Here, we provide a translation of these models into humans. Using the fear potentiated startle (FPS) procedure, we examined the effects of fear conditioning and safety signal learning on subsequent REM sleep in healthy adults. We also examined the effects of changes in REM sleep on retention of fear and safety learning. Participants (n = 42 normal controls) spent 3 consecutive nights in the laboratory. The first was an adaptation night. Following the second night, we administered a FPS procedure that included pairing a wrist shock with a threat signal and a safety signal never paired with a shock. The next day, we administered the FPS procedure again, with no wrist shocks to any stimulus, to measure retention of fear and safety. Canonical correlations assessed the relationship between FPS response and REM sleep. Results demonstrated that increased safety signal learning during the initial acquisition phase was associated with increased REM sleep consolidation that night, with 28.4% of the variance in increased REM sleep consolidation from baseline accounted for by safety signal learning. Overnight REM sleep was, in turn, related to overnight retention of fear and safety learning, with 22.5% of the variance in startle retention accounted for by REM sleep. These data suggest that sleep difficulties, specifically REM sleep fragmentation, may play a mechanistic role in post-traumatic stress disorder via an influence on safety signal learning and/or threat-safety discrimination.

Reward learning as a potential target for pharmacological augmentation of cognitive remediation for schizophrenia: a roadmap for preclinical development.

Rationale: Impaired cognitive abilities are a key characteristic of schizophrenia. Although currently approved pharmacological treatments have demonstrated efficacy for positive symptoms, to date no pharmacological treatments successfully reverse cognitive dysfunction in these patients. Cognitively-based interventions such as cognitive remediation (CR) and other psychosocial interventions however, may improve some of the cognitive and functional deficits of schizophrenia. Given that these treatments are time-consuming and labor-intensive, maximizing their effectiveness is a priority. Augmenting psychosocial interventions with pharmacological treatments may be a viable strategy for reducing the impact of cognitive deficits in patients with schizophrenia. Objective: We propose a strategy to develop pharmacological treatments that can enhance the reward-related learning processes underlying successful skill-learning in psychosocial interventions. Specifically, we review clinical and preclinical evidence and paradigms that can be utilized to develop these pharmacological augmentation strategies. Prototypes for this approach include dopamine D1 receptor and α7 nicotinic acetylcholine receptor agonists as attractive targets to specifically enhance reward-related learning during CR. Conclusion: The approach outlined here could be used broadly to develop pharmacological augmentation strategies across a number of cognitive domains underlying successful psychosocial treatment.

Early Adolescent Emergence of Reversal Learning Impairments in Isolation-Reared Rats.

Cognitive impairments appear early in the progression of schizophrenia, often preceding the symptoms of psychosis. Thus, the systems subserving these functions may be more vulnerable to, and mechanistically linked with, the initial pathology. Understanding the trajectory of behavioral and anatomical abnormalities relevant to the schizophrenia prodrome and their sensitivity to interventions in relevant models will be critical to identifying early therapeutic strategies. Isolation rearing of rats is an environmental perturbation that deprives rodents of social contact from weaning through adulthood and produces behavioral and neuronal abnormalities that mirror some pathophysiology associated with schizophrenia, e.g. frontal cortex abnormalities and prepulse inhibition (PPI) of startle deficits. Previously, we showed that PPI deficits in isolation-reared rats emerge in mid-adolescence (4 weeks after weaning; approx. postnatal day 52) but are not present when tested at 2 weeks after weaning (approx. postnatal day 38). Because cognitive deficits are reported during early adolescence, are relevant to the prodrome, and are linked to functional outcome, we examined the putative time course of reversal learning deficits in isolation-reared rats. Separate groups of male Sprague Dawley rats were tested in a two-choice discrimination task at 2 and 8 weeks after weaning, on postnatal day 38 and 80, respectively. The isolation-reared rats displayed impaired reversal learning at both time points. Isolation rearing was also associated with deficits in PPI at 4 and 10 weeks after weaning. The reversal learning deficits in the isolated rats were accompanied by reductions in parvalbumin immunoreactivity, a marker for specific subpopulations of GABAergic neurons, in the hippocampus. Hence, isolation rearing of rats may offer a unique model to examine the ontogeny of behavioral and neurobiological alterations that may be relevant to preclinical models of prodromal psychosis.

Fear learning alterations after traumatic brain injury and their role in development of posttraumatic stress symptoms

It is unknown how traumatic brain injury (TBI) increases risk for posttraumatic stress disorder (PTSD). One potential mechanism is via alteration of fear‐learning processes that could affect responses to trauma memories and cues. We utilized a prospective, longitudinal design to determine if TBI is associated with altered fear learning and extinction, and if fear processing mediates effects of TBI on PTSD symptom change.

Psychophysiology in the study of psychological trauma: where are we now and where do we need to be?

Posttraumatic stress disorder (PTSD) is a major public health concern, which has been seeing increased recent attention partly due to the wars in Iraq and Afghanistan. Historically, research attempting to understand the etiology and treatment of PTSD has made frequent use of psychophysiological measures of arousal as they provide a number of advantages in providing objective, non-self-report outcomes that are closely related to proposed neurobiological mechanisms and provide opportunity for cross-species translation. Further, the ongoing shift in classification of psychiatric illness based on symptom clusters to specific biological, physiological, and behavioral constructs, as outlined in the US National Institute of Mental Health (NIMH) Research Domain Criteria project (RDoC), promises that psychophysiological research will continue to play a prominent role in research on trauma-related illnesses. This review focuses on the current state of the knowledge regarding psychophysiological measures and PTSD with a focus on physiological markers associated with current PTSD symptoms, as well as markers of constructs thought to be relevant to PTSD symptomatology (safety signal learning, fear extinction), and psychophysiological markers of risk for developing PTSD following trauma. Future directions and issues for the psychophysiological study of trauma including traumatic brain injury (TBI), treatment outcome studies, and new wearable physiological monitoring technologies are also discussed.

Effects of anxiolytic treatment on potentiated startle during aversive image anticipation

Heightened anticipation of future events has been characterized as a feature of certain anxiety disorders. In functional magnetic resonance imaging studies, anticipation of fearful/threatening images has been shown to robustly activate the insular cortex and amygdala in healthy subjects, in subjects with high trait anxiety, and in some with anxiety disorders. Blood oxygenation level dependent activation in response to negative image anticipation is also sensitive to anxiolytic treatment, suggesting that image anticipation probes anxiety systems. It is not clear, however, if behavioral responses to image anticipation are also sensitive to anxiolytics. This study tested the hypothesis that anxiety behaviors during anticipation of negative images are sensitive to anxiolytic treatment.

Oxytocin Enhancement of Fear Extinction: A New Target for Facilitating Exposure-Based Treatments?

It has been more than a decade since Ressler et al. published the first demonstration of facilitation of exposure-based therapy with the N-methyl-D-aspartate co-agonist D-cycloserine (1). Since that pivotal study, there has been a surge of research to identify additional targets that enhance fear extinction for adjunctive treatment strategies. Potential pathways include catecholamines, endocannabinoids, and various neuropeptide systems and epigenetic pathways (1). Among the neuropeptide candidates, oxytocin (OT) has gained attention as a modulator of conditioned fear processes including fear extinction. OT receptors are located on neural circuits mediating fear learning and extinction, and there is substantial preclinical literature supporting modulatory effects of OT receptor signaling on conditioned fear learning, recall, and extinction (2). Furthermore, the putative prosocial effects of OT make it attractive as an adjunctive treatment for behavioral therapies, as it may facilitate patient-therapist alliance and acceptability of treatment. Initial support for the hypothesis that OT may enhance fear extinction in humans came from a study from our laboratory, which found that OT administration before extinction training significantly increased 24-hour extinction recall. However, the mechanism by which OT affects extinction in humans is unknown. In this issue of Biological Psychiatry, Eckstein et al. (3) address the question of neural mechanisms of OT effects on extinction in important ways. They studied 62 healthy men who were randomly assigned to receive either intranasal OT or placebo spray after a fear conditioning procedure. Participants then received fear extinction training 30 min after OT treatment. Compared with men given placebo, participants given OT exhibited increased conditioned fear responses in the early phase of extinction, but by the last training phase they showed significantly lower conditioned fear responses than the placebo group. Despite initial increases in fear responding, the OT-treated group had significantly enhanced extinction learning by the end of training. The authors showed that OT affected activity in neural circuits associated with fear processing, including the prefrontal cortex (PFC) and the amygdala. The findings of Eckstein et al. are intriguing in that they did not implicate OT engagement of the well-known PFC region implicated in extinction, the ventromedial PFC, but instead a dorsal region of the mid-medial PFC. The mid-medial PFC was activated only during initial fear extinction training, when fear responding was significantly higher than in the placebo group, but not during the second phase corresponding to lower fear responses. The dorsolateral PFC is associated with deliberate regulation of responses to conditioned cues, whereas the dorsomedial PFC is more commonly associated with fear

COMT val158met polymorphism links to altered fear conditioning and extinction are modulated by PTSD and childhood trauma

Risk for posttraumatic stress disorder (PTSD) is thought to be mediated by gene × environment (G × E) interactions that affect core cognitive processes such as fear learning. The catechol‐O‐methyltransferase (COMT) val158met polymorphism has been associated with risk for PTSD and impaired fear inhibition. We used a large, relatively homogenous population to (1) replicate previous findings of poor fear inhibition in COMT Met/Met carriers with PTSD; (2) determine if COMT association with fear inhibition is moderated by childhood trauma (CT), an environmental risk factor for PTSD; and (3) determine if COMT is associated with altered fear processes after recent exposure to combat trauma.