Biological Psychiatry

A brief summary of the articles appearing in this issue of Biological Psychiatry.

2013-06-01

Using a double-blind, placebo-controlled design, Sripada et al. (pages 1045–1053) examined the impact of single-dose pregnenolone, a precursor to the neurosteroid allopregnanolone, on neural responses in healthy males during emotional processing and regulation. They report that pregnenolone, and subsequent allopregnanolone elevation, was associated with decreased amygdala and insula response across conditions and increased dorsomedial prefrontal cortex response during appraisal. These neurocircuits have been shown to be altered in anxiety disorders; thus, these findings invite further investigation of allopregnanolone’s potential use as an anxiolytic pharmacological intervention.

The First Steps on the Path Toward Genomic Predictors of Behavioral Therapy for Posttraumatic Stress Disorder

Mary-Anne Enoch — 2013-06-01

Not everyone who has personally experienced, or has been exposed to, severe trauma develops posttraumatic stress disorder (PTSD). The risk-resilience equation is complex and, as we are becoming increasingly aware, includes both genetic predictors and environmental stressors, starting in early childhood. For example, as Binder and colleagues first showed, FKBP5, a gene influencing activity of the hypothalamic-pituitary-adrenal axis, together with exposure to childhood trauma but not adult stressors, predicted the development of PTSD in a low-income, urban African American sample. There is much to be understood about the etiology of PTSD and equally there is much to be learned about developing new treatment options and improving the rates of response to the current first-line treatment for PTSD: cognitive behavioral therapy (CBT).

Threat-Related Attention Bias in the Early Stages of Cognitive-Behavior Therapy Action for Panic Disorder

Rany Abend, Yair Bar-Haim — 2013-06-01

Cognitive theories of anxiety propose that information-processing biases play a pivotal role in the etiology and maintenance of anxiety disorders . Along with the application of conditioning principles derived from learning theories, such cognitive models inspired the development of cognitive-behavioral therapy (CBT), now considered the first-line treatment for anxiety disorders . But although extensive evidence indicates that automatic attention is biased toward threatening information in anxious individuals , such threat-related attention biases were typically thought to be outside the realm of the direct therapeutic effects of CBT, which focuses primarily on the modification of thoughts, interpretations, and beliefs .

Fear and Anxiety Take a Double Hit From Vagal Nerve Stimulation

Michael S. Fanselow — 2013-06-01

At the forefront of translational research to combat anxiety disorders is the idea of developing neuroscience-based adjuncts to traditional exposure-based treatment such as cognitive/behavioral therapy. The core concept of exposure therapy is Pavlovian extinction, in which an anxiety-triggering stimulus is repeatedly presented so that that the patient learns that the stimulus predicts no negative consequences. This new association acts to inhibit the anxiety normally provoked by the stimulus. On its own, such exposure is quite effective, but it has some limitations. After exposure therapy, fear of the extinguished stimulus may return because of a stressful experience, a long passage of time since encountering the stimulus, or confronting the fear-provoking stimulus in a novel environment . Additionally in some anxiety disorders, notably posttraumatic stress disorder, extinction learning itself is compromised . The idea of neuroscience-based adjuncts given during exposure treatment is to overcome this limitation by either strengthening the extinction learning itself or changing its nature. An example of the strengthening strategy is the use of d-cycloserine (DCS) to facilitate the N-methyl-D-aspartate–mediated plasticity that normally mediates memory formation . To change the nature of extinction, researchers have administered extinction training during periods when the original fear memory lacks stability because it was very recently encoded or reactivated .

Allopregnanolone Elevations Following Pregnenolone Administration Are Associated with Enhanced Activation of Emotion Regulation Neurocircuits

2013-01-23

Background: The neurosteroid allopregnanolone is a potent allosteric modulator of the gamma-aminobutyric acid type A receptor with anxiolytic properties. Exogenous administration of allopregnanolone reduces anxiety, and allopregnanolone blockade impairs social and affective functioning. However, the neural mechanism whereby allopregnanolone improves mood and reduces anxiety is unknown. In particular, brain imaging has not been used to link neurosteroid effects to emotion regulation neurocircuitry.Methods: To investigate the brain basis of allopregnanolone’s impact on emotion regulation, participants were administered 400 mg of pregnenolone (n=16) or placebo (n=15) and underwent 3T functional magnetic resonance imaging while performing the shifted-attention emotion appraisal task, which probes emotional processing and regulation.Results: Compared with placebo, allopregnanolone was associated with reduced activity in the amygdala and insula across all conditions. During the appraisal condition, allopregnanolone increased activity in the dorsal medial prefrontal cortex and enhanced connectivity between the amygdala and dorsal medial prefrontal cortex, an effect that was associated with reduced self-reported anxiety.Conclusions: These results demonstrate that in response to emotional stimuli, allopregnanolone reduces activity in regions associated with generation of negative emotion. Furthermore, allopregnanolone may enhance activity in regions linked to regulatory processes. Aberrant activity in these regions has been linked to anxiety psychopathology. These results thus provide initial neuroimaging evidence that allopregnanolone may be a target for pharmacologic intervention in the treatment of anxiety disorders and suggest potential future directions for research into neurosteroid effects on emotion regulation neurocircuitry.

D-Cycloserine Enhancement of Fear Extinction is Specific to Successful Exposure Sessions: Evidence from the Treatment of Height Phobia

2013-01-18

Background: Whereas some studies have shown clear evidence for an augmentation effect of D-cycloserine (DCS) on exposure therapy for anxiety disorders, other studies have shown weak effects or no effect at all. Some preclinical data suggest that the DCS augmentation effect is moderated by the success of extinction learning. Therefore, we conducted a reanalysis of existing data to examine whether the effects of DCS on clinical outcome would vary as a function of response to the exposure session (i.e., exposure success).Methods: In a clinical trial, patients with height phobia received two sessions involving 30 minutes of virtual reality exposure therapy and were randomly assigned to a pill placebo (n = 14) or 50 mg of DCS (n = 15) immediately after each session.Results: Mixed-effects regression analysis showed that the effects of DCS administration on clinical improvement was moderated by the level of fear experienced just before concluding exposure sessions. Patients receiving DCS exhibited significantly greater improvement in symptoms relative to patients who received placebo when fear was low at the end of the exposure. In contrast, when end fear was still elevated, patients receiving DCS improved less compared with those receiving placebo.Conclusions: D-cycloserine appears to enhance the benefits of exposure treatment when applied after a successful session, but it seems to have detrimental effects when administered after inadequate/unsuccessful exposure sessions.

The Brain-Derived Neurotrophic Factor Val66Met Polymorphism Predicts Response to Exposure Therapy in Posttraumatic Stress Disorder

2013-01-10

Background: The most effective treatment for posttraumatic stress disorder (PTSD) is exposure therapy, which aims to facilitate extinction of conditioned fear. Recent evidence suggests that brain-derived neurotrophic factor (BDNF) facilitates extinction learning. This study assessed whether the Met-66 allele of BDNF, which results in lower activity-dependent secretion, predicts poor response to exposure therapy in PTSD.Methods: Fifty-five patients with PTSD underwent an 8-week exposure-based cognitive behavior therapy program and provided mouth swabs or saliva to extract genomic DNA to determine their BDNF Val66Met genotype (30 patients with the Val/Val BDNF allele, 25 patients with the Met-66 allele). We examined whether BDNF genotype predicted reduction in PTSD severity following exposure therapy.Results: Analyses revealed poorer response to exposure therapy in the PTSD patients with the Met-66 allele of BDNF compared with patients with the Val/Val allele. Pretreatment Clinician Administered PTSD Scale severity and BDNF Val66Met polymorphism predicted response to exposure therapy using hierarchical regression.Conclusions: This study provides the first evidence that the BDNF Val66Met genotype predicts response to cognitive behavior therapy in PTSD and is in accord with evidence that BDNF facilitates extinction learning.

Changes in Automatic Threat Processing Precede and Predict Clinical Changes with Exposure-Based Cognitive-Behavior Therapy for Panic Disorder

Andrea Reinecke, Lara Waldenmaier, Myra J. Cooper, Catherine J. Harmer — 2013-03-18

Background: Cognitive behavioral therapy (CBT) is an effective treatment for emotional disorders such as anxiety or depression, but the mechanisms underlying successful intervention are far from understood. Although it has been a long-held view that psychopharmacological approaches work by directly targeting automatic emotional information processing in the brain, it is usually postulated that psychological treatments affect these processes only over time, through changes in more conscious thought cycles. This study explored the role of early changes in emotional information processing in CBT action.Methods: Twenty-eight untreated patients with panic disorder were randomized to a single session of exposure-based CBT or waiting group. Emotional information processing was measured on the day after intervention with an attentional visual probe task, and clinical symptoms were assessed on the day after intervention and at 4-week follow-up.Results: Vigilance for threat information was decreased in the treated group, compared with the waiting group, the day after intervention, before reductions in clinical symptoms. The magnitude of this early effect on threat vigilance predicted therapeutic response after 4 weeks.Conclusions: Cognitive behavioral therapy rapidly affects automatic processing, and these early effects are predictive of later therapeutic change. Such results suggest very fast action on automatic processes mediating threat sensitivity, and they provide an early marker of treatment response. Furthermore, these findings challenge the notion that psychological treatments work directly on conscious thought processes before automatic information processing and imply a greater similarity between early effects of pharmacological and psychological treatments for anxiety than previously thought.

Rapid Remission of Conditioned Fear Expression with Extinction Training Paired with Vagus Nerve Stimulation

David F. Peña, Navzer D. Engineer, Christa K. McIntyre — 2012-12-14

Background: Fearful experiences can produce long-lasting and debilitating memories. Extinction of conditioned fear requires consolidation of new memories that compete with fearful associations. In human subjects, as well as rats, posttraining stimulation of the vagus nerve enhances memory consolidation. Subjects with posttraumatic stress disorder show impaired extinction of conditioned fear. The objective of this study was to determine whether vagus nerve stimulation (VNS) can enhance the consolidation of extinction of conditioned fear.Methods: Male Sprague-Dawley rats were trained on an auditory fear conditioning task followed by 1 to 10 days of extinction training. Treatment with vagus nerve or sham stimulation was administered concurrently with exposure to the fear conditioned stimulus. Another group was given VNS and extinction training but the VNS was not paired with exposure to conditioned cues. Retention of fear conditioning was tested 24 hours after each treatment.Results: Vagus nerve stimulation paired with exposure to conditioned cues enhanced the extinction of conditioned fear. After a single extinction trial, rats given VNS stimulation demonstrated a significantly lower level of freezing, compared with that of sham control rats. When extinction trials were extended to 10 days, paired VNS accelerated extinction of the conditioned response.Conclusions: Extinction paired with VNS is more rapid than extinction paired with sham stimulation. As it is currently approved by the Federal Food and Drug Administration for depression and seizure prevention, VNS is a readily available and promising adjunct to exposure therapy for the treatment of severe anxiety disorders.

Chronic Antidepressant Treatment Impairs the Acquisition of Fear Extinction

2012-12-20

Background: Like fear conditioning, the acquisition phase of extinction involves new learning that is mediated by the amygdala. During extinction training, the conditioned stimulus is repeatedly presented in the absence of the unconditioned stimulus, and the expression of previously learned fear gradually becomes suppressed. Our previous study revealed that chronic treatment with a selective serotonin reuptake inhibitor (SSRI) impairs the acquisition of auditory fear conditioning. To gain further insight into how SSRIs affect fear learning, we tested the effects of chronic SSRI treatment on the acquisition of extinction.Methods: Rats were treated chronically (22 days) or subchronically (9 days) with the SSRI citalopram (10 mg/kg/day) before extinction training. The results were compared with those after chronic and subchronic treatment with tianeptine (10 mg/kg/day), an antidepressant with a different method of action. The expression of the NR2B subunit of the N-methyl-D-aspartate receptor in the amygdala was examined after behavioral testing.Results: Chronic but not subchronic administration of citalopram impaired the acquisition of extinction and downregulated the NR2B subunit of the N-methyl-D-aspartate receptor in the lateral and basal nuclei of the amygdala. Similar behavioral and molecular changes were found with tianeptine treatment.Conclusions: These results provide further evidence that chronic antidepressant treatment can impair amygdala-dependent learning. Our findings are consistent with a role for glutamatergic neurotransmission in the final common pathway of antidepressant treatment.

Cellular Adaptations of Dorsal Raphe Serotonin Neurons Associated with the Development of Active Coping in Response to Social Stress

2013-03-01

Background: Social stress is a risk factor for affective disorders for certain vulnerable individuals. Stress and depression are linked in part through regulation of the dorsal raphe (DR)-serotonin (5-HT) system by the stress-related neuropeptide, corticotropin-releasing factor (CRF). We used a rat social stress model that shows individual differences in coping strategies to determine whether differences in CRF-5-HT interactions underlie individual differences in the vulnerability to social stress.Methods: Rats were exposed to the resident-intruder model of social stress for 5 days. In vivo single-unit recordings assessed DR-5-HT neuronal responses to CRF and immunoelectron microscopy assessed CRF1 and CRF2 cellular localization 24 hours after the last stress.Results: Rats responded to social stress passively, assuming defeat with short latencies (48%), or actively, with proactive behaviors and longer defeat latencies (LL, 52%). Whereas CRF (30 ng, intra-DR) inhibited 5-HT neuronal activity of control and SL rats, it activated 5-HT neurons of LL rats, an effect that was CRF2-mediated. Consistent with this, social stress promoted CRF1 internalization together with CRF2 recruitment to the plasma membrane of DR neurons selectively in LL rats.Conclusions: These data suggest that a proactive coping strategy toward social stress is associated with a redistribution of CRF1 and CRF2 in DR-5-HT neurons that primes the system to be activated by subsequent stress. The lack of this adaptation in passive coping rats may contribute to their depressive-like phenotype. These studies provide a cellular mechanism for individual differences in stress responses and consequences.

Prenatal Stress Affects Network Properties of Rat Hippocampal Neurons

Gayane Grigoryan, Menahem Segal — 2013-03-29

Background: Long-term effects of stress during pregnancy on brain and behavior have been analyzed extensively in recent years. One major problem with these studies is the inability to separate between the net effects of the prenatal stress (PS) and the effects of the stressed mother and siblings on the newborn animals.Methods: To address these issues, we studied morphological and electrophysiological properties of neurons in dissociated cultures of the hippocampus taken from newborn PS rats. We complemented these studies with experiments on behaving rats and recordings from slices taken from PS rats and their control rats.Results: While the density of cultured neurons was not different between PS and control rats, there were fewer glutamic acid decarboxylase-positive neurons in the former cultures. Additionally, cells taken from PS pups developed more extensive dendrites than control animals. These differences were correlated with a higher rate of synchronous activity in the PS cultures and a lower rate of spontaneous miniature inhibitory postsynaptic current activity. There were no differences in the excitatory synaptic currents or the passive and active properties of the recorded neurons in the two groups. Young PS rats were more motile in open field and elevated plus maze than control rats, and they learned faster to navigate in a water maze. Slices taken from hippocampus of PS rats expressed less paired-pulse inhibition than slices from control rats.Conclusions: These results indicate that PS affects network properties of hippocampal neurons, by reducing gamma-aminobutyric acidergic inhibition.

Posttraumatic Stress Disorder and Impaired Autonomic Modulation in Male Twins

2013-02-25

Background: Posttraumatic stress disorder (PTSD) has been linked to increased morbidity. An inflexibility of the autonomic nervous system might be the underlying mechanism. We aimed to assess whether PTSD and combat trauma exposure are associated with lower heart rate variability (HRV), a measure of autonomic function and a predictor of death.Methods: We measured HRV by power spectral analysis on 24-hour ambulatory electrocardiogram in 459 middle-aged veteran male twins. Combat trauma was assessed with the combat exposure scale, and current and remitted PTSD was assessed with the Structured Clinical Interview for Psychiatry Disorders. Mixed-effects regression models were used to test associations of PTSD and HRV between and within twin pairs.Results: Of all twins, 211 had combat exposure, 31 had current PTSD, and 43 had remitted PTSD. Current PTSD was inversely associated with very-low-frequency and low-frequency HRV both in individual twins and within 20 pairs discordant for current PTSD. Twins with current PTSD had a 49% lower low-frequency HRV than their brothers without PTSD (p<.001). Remitted PTSD was not associated with HRV. Results were robust to adjustment for depression and other risk factors. Combat exposure was inversely associated with most HRV frequencies, but this association mostly diminished after adjustment for current PTSD.Conclusion: In middle-aged veteran men, combat exposure and current PTSD are associated with measures of autonomic inflexibility previously shown to have prognostic significance. The negative health impact of combat exposure on autonomic function is mediated largely through PTSD and might reverse with remission of PTSD.

Abnormal Activity-Dependent Brain Lactate and Glutamate+Glutamine Responses in Panic Disorder

2013-01-21

Background: Prior evidence suggests panic disorder (PD) is characterized by neurometabolic abnormalities, including increased brain lactate responses to neural activation. Increased lactate responses could reflect a general upregulation of metabolic responses to neural activation. However, prior studies in PD have not measured activity-dependent changes in brain metabolites other than lactate. Here we examine activity-dependent changes in both lactate and glutamate plus glutamine (glx) in PD.Methods: Twenty-one PD patients (13 remitted, 8 symptomatic) and 12 healthy volunteers were studied. A single-voxel, J-difference, magnetic resonance spectroscopy editing sequence was used to measure lactate and glx changes in visual cortex induced by visual stimulation.Results: The PD patients had significantly greater activity-dependent increases in brain lactate than healthy volunteers. The differences were significant for both remitted and symptomatic PD patients, who did not differ from each other. Activity-dependent changes in glx were significantly smaller in PD patients than in healthy volunteers. The temporal correlation between lactate and glx changes was significantly stronger in control subjects than in PD patients.Conclusions: The novel demonstration that glx responses are diminished and temporally decoupled from lactate responses in PD contradicts the model of a general upregulation of activity-dependent brain metabolic responses in PD. The increase in activity-dependent brain lactate accumulation appears to be a trait feature of PD. Given the close relationship between lactate and pH in the brain, the findings are consistent with a model of brain metabolic and pH dysregulation associated with altered function of acid-sensitive fear circuits contributing to trait vulnerability in PD.

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2013-06-01

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2013-06-01

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2013-06-01

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2013-06-01

Biological Psychiatry

A brief summary of the articles appearing in this issue of Biological Psychiatry.

The First Steps on the Path Toward Genomic Predictors of Behavioral Therapy for Posttraumatic Stress Disorder

Threat-Related Attention Bias in the Early Stages of Cognitive-Behavior Therapy Action for Panic Disorder

Fear and Anxiety Take a Double Hit From Vagal Nerve Stimulation

Allopregnanolone Elevations Following Pregnenolone Administration Are Associated with Enhanced Activation of Emotion Regulation Neurocircuits

D-Cycloserine Enhancement of Fear Extinction is Specific to Successful Exposure Sessions: Evidence from the Treatment of Height Phobia

The Brain-Derived Neurotrophic Factor Val66Met Polymorphism Predicts Response to Exposure Therapy in Posttraumatic Stress Disorder

Changes in Automatic Threat Processing Precede and Predict Clinical Changes with Exposure-Based Cognitive-Behavior Therapy for Panic Disorder

Rapid Remission of Conditioned Fear Expression with Extinction Training Paired with Vagus Nerve Stimulation

Chronic Antidepressant Treatment Impairs the Acquisition of Fear Extinction

Cellular Adaptations of Dorsal Raphe Serotonin Neurons Associated with the Development of Active Coping in Response to Social Stress

Prenatal Stress Affects Network Properties of Rat Hippocampal Neurons

Posttraumatic Stress Disorder and Impaired Autonomic Modulation in Male Twins

Abnormal Activity-Dependent Brain Lactate and Glutamate+Glutamine Responses in Panic Disorder

Editorial Board Page

Subscribers Page

Table of Contents

Guide for Authors

Manuscript Submission Form