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Biomedical subjects

I Liberzon

Publications and source records attributed to I Liberzon.

At least 19 recordsLinked to original sources

Neural correlates of social and nonsocial emotions: An fMRI study.

Common theories of emotion emphasize valence and arousal dimensions or alternatively, specific emotions, and the search for the underlying neurocircuitry is underway. However, it is likely that other important dimensions for emotional neurocircuitry exist, and one of them is sociality. A social dimension may code whether emotions are addressing an individual's biological/visceral need versus more remote social goals involving semantic meaning or intentionality. Thus, for practical purposes, social emotions may be distinguished from nonsocial emotions based in part on the presence of human forms. In the current fMRI study, we aimed to compare regional coding of the sociality dimension of emotion (nonsocial versus social) versus the valence dimension of emotion (positive versus negative). Using a novel fMRI paradigm, film and picture stimuli were combined to induce and maintain four emotions varying along social and valence dimensions. Nonsocial emotions of positively valenced appetite and negatively valenced disgust and social emotions of positively valenced joy/amusement and negatively valenced sadness were studied. All conditions activated the thalamus. Appetite and disgust activated posterior insula and visual cortex, whereas joy/amusement and sadness activated extended amygdala, superior temporal gyrus, hippocampus, and posterior cingulate. Activations within the anterior cingulate, nucleus accumbens, orbitofrontal cortex, and amygdala were modulated by both social and valence dimensions. Overall, these findings highlight that sociality has a key role in processing emotional valence, which may have implications for patient populations with social and emotional deficits.

Adult↗

Differential subjective and psychophysiological responses to socially and nonsocially generated emotional stimuli.

Sociality may determine the subjective experience and physiological response to emotional stimuli. Film segments induced socially and nonsocially generated emotions. Comedy (social positive), bereavement (social negative), pizza scenes (nonsocial positive), and wounded bodies (nonsocial negative) elicited four distinct emotional patterns. Per subjective report, joy, sadness, appetite, and disgust were elicited by the targeted stimulus condition. The social/nonsocial dimension influenced which emotional valence(s) elicited a skin conductance response, a finding that could not be explained by differences in subjective arousal. Heart rate deceleration was more responsive to nonsocially generated emotions. Taken together, these findings suggest that sociality affects the physiological profile of responses to emotional valence.

Adult↗

Summary of a National Institute of Mental Health workshop: developing animal models of anxiety disorders.

RATIONALE: There exists a wide range of animal models and measures designed to assess anxiety or fearfulness. However, the relationship between these models and clinical anxiety symptoms and syndromes is unclear. The National Institute of Mental Health convened a workshop to discuss the relationship between existing behavioral models of anxiety and the clinical profile of anxiety disorders. A second goal of this workshop was to outline various approaches towards modeling components of anxiety disorders. OBJECTIVES: To briefly describe epidemiological and behavioral manifestations of clinical anxiety syndromes and how they relate to commonly employed animal models of anxiety. To describe approaches and considerations for developing, improving, and adapting anxiety models to better understand the neurobiology of anxiety. METHODS: Clinicians, psychiatrists and clinical and basic neuroscientists presented data exemplifying different approaches towards understanding anxiety and the role of animal models. Panel members outlined what they considered to be critical issues in developing and employing animal models of anxiety. RESULTS: This review summarizes the discussions and conclusions of the workshop including recommendations for improving upon existing models and strategies for developing novel models. CONCLUSIONS: The probability of developing comprehensive animal models that accurately reflect the relative influences of factors contributing to anxiety disorder syndromes is quite low. However, ample opportunity remains to better define and extend existing models and behavioral measures related to specific processes that may be disrupted in anxiety disorders and to develop new models that consider the impact of combined factors in determining anxious behaviors.

Animals↗

Posttraumatic stress disorder and pregnancy complications.

OBJECTIVE: To assess the associations between specific pregnancy complications and posttraumatic stress disorder based on neurobiologic and behavioral characteristics, using Michigan Medicaid claims data from 1994-1996. METHODS: Two thousand, two hundred nineteen female recipients of Michigan Medicaid who were of childbearing age had posttraumatic stress disorder on the basis of International Classification of Diseases, 9th Revision (ICD-9) codes. Twenty percent (n = 455) of those recipients and 30% of randomly selected comparison women with no mental health diagnostic codes (n = 638; P <.001) had ICD-9 diagnostic codes for pregnancy complications. We used multiple logistic regression to investigate associations between specific pregnancy complications and posttraumatic stress disorder, controlling for demographic and psychosocial variables. Obstetric complications were hypothesized based on high-risk behaviors and neurobiologic alterations in stress axis function in posttraumatic stress disorder. RESULTS: After controlling for demographic and psychosocial factors, women with posttraumatic stress disorder had higher odds ratios (ORs) for ectopic pregnancy (OR 1.7, 95% confidence interval [CI] 1.1, 2.8), spontaneous abortion (OR 1.9, 95% CI 1.3, 2.9), hyperemesis (OR 3.9, 95% CI 2.0, 7.4), preterm contractions (OR 1.4, 95% CI 1.1, 1.9), and excessive fetal growth (OR 1.5, 95% CI 1.0, 2.2). Hypothesized labor differences were not confirmed and no differences were found for complications not thought to be related to traumatic stress. CONCLUSIONS: Pregnant women with posttraumatic stress disorder might be at higher risk for certain conditions, and assessment and treatment for undiagnosed posttraumatic stress might be warranted for women with those obstetric complications. Prospective studies are needed to confirm present findings and to determine potential biologic mechanisms. Treatment of traumatic stress symptoms might improve pregnancy morbidity and maternal mental health.

Adult↗

The effect of graded aversive stimuli on limbic and visual activation.

Activation studies have shown that in response to evocative visual stimuli, brain activity increases in the visual cortex and limbic areas. However, non-affective characteristics of these images, such as color composition and visual complexity, confound the interpretation of these results. To address this issue, we had subjects rate over 100 images on aversive intensity (facial mutilation, dead bodies) and semantic complexity (number of objects subjects could name). From these images, we assembled digitized image sets of non-aversive, mild and strong intensity, balanced on semantic complexity and content (human faces and figures), and adjusted for color composition. A fourth condition consisted of a fixation cross on a blank screen. Thirteen subjects underwent eight positron emission tomography scans using the [(15)O] water methodology. Measurement of skin conductance was recorded simultaneously. All picture conditions, relative to the blank screen, activated the amygdalae and bilateral orbitofrontal cortex, while we found activation trends associated with increasing aversive content in the sub-lenticular region. Skin conductance increased during all picture conditions. Relative to the non-aversive pictures, aversive image content caused modulation of occipital and occipital-temporal cortex. These results demonstrated activation of the amygdala to salient, arousing stimuli, and not just aversive stimuli. In addition, they suggest that pictorial complexity, as indexed by our semantic measure, does not account for the modulation of visual cortex by aversive, emotional stimuli.

Adult↗

Limbic activation and psychophysiologic responses to aversive visual stimuli. Interaction with cognitive task.

We mapped regional brain activity and peripheral psychophysiologic responses, occurring in response to evocative emotional stimuli, and examined whether task instructions could modulate limbic activation. Ten subjects viewed pictures with neutral or aversive emotional content during simultaneous measurement of peripheral psychophysiology and brain activity with [15O]water positron emission tomography (PET). Cognitive task was manipulated by having the subjects rate the pictures or perform a recognition memory task. Aversive pictures, relative to neutral pictures, increased cerebral activity in bilateral amygdala, thalamic/hypothalamic area, midbrain, and left lateral prefrontal cortex, along with greater skin conductance responses (SCR). Voxel-by-voxel correlation coefficients between regional brain activity and SCR showed significant positive correlation peaks in the thalamus and right amygdala. Limbic activation was significantly greater during the rating condition compared to the recognition condition, suggesting that when task demands modify emotional responses, this modulation can occur at the level of limbic activity.

Adult↗

Serotonin 1A receptor messenger RNA regulation in the hippocampus after acute stress.

BACKGROUND: When rats are subjected to chronic stress for 2 weeks, a significant decrease in hippocampal serotonin (5-HT)1A messenger RNA (mRNA) is observed. We wanted to investigate whether stress, administered for shorter periods of time, would result in decreases in 5-HT1A gene expression in hippocampus. METHODS: In one experiment, rats were either stressed daily for 1 week or implanted with two corticosterone pellets to produce elevated corticosterone levels. In another experiment, rats were subjected to a severe acute stressor and sacrificed 1 day or 1 week after the stressor. RESULTS: We found that 24 hours after the acute stress, rats showed a significant decrease in 5-HT1A mRNA levels in CA1 and the dentate gyrus compared to controls. No significant changes in 5-HT1A mRNA levels were detected in any of the other groups. CONCLUSIONS: Although 1 week of chronic stress is not sufficient to cause significant decreases in hippocampal 5-HT1A mRNA levels, a severe and prolonged acute stress is capable of down-regulating, at least transiently, 5-HT1A mRNA gene expression in hippocampus.

Acute Disease↗

Brain activation in PTSD in response to trauma-related stimuli.

BACKGROUND: Repetitive recall of traumatic memories and chronic intermittent hyperarousal are characteristic of posttraumatic stress disorder (PTSD). Hyperarousal and memory dysfunction implicates "limbic" brain regions, including the amygdaloid complex, hippocampal formation, and limbic cortex, such as the orbitofrontal and anterior cingulate areas. To investigate the neurobiologic role of these brain regions in PTSD, we measured regional cerebral blood flow in PTSD with single photon emission computerized tomography (SPECT) during a symptom provocation paradigm. METHODS: Fourteen Vietnam veterans with PTSD, 11 combat control subjects, and 14 normal control subjects were studied with [99mTc]HMPAO in two sessions 48 hours apart: one session after exposure to white noise and the other following exposure to combat sounds. Skin conductance, heart rate, and subjective experience were recorded at the time of the studies. RESULTS: Activation for all three groups occurred in the anterior cingulate/middle prefrontal gyrus. Activation in the region of the left amygdala/nucleus accumbens was found in PTSD patients only. Deactivation was found in all three groups in the left retrosplenial region. CONCLUSIONS: These findings implicate regions of the "limbic" brain, which may mediate the response to aversive stimuli in healthy individuals and in patients suffering from PTSD.

Arousal↗

Dose response of adrenocorticotropin and cortisol to the CCK-B agonist pentagastrin.

Cholecystokinin (CCK) is an abundant neurotransmitter in brain. Its functional significance in humans is incompletely understood, but it may modulate activity in the hypothalamic-pituitary-adrenal (HPA) axis. To explore this hypothesis, we examined the effects of varying doses (0 to 0.8 microgram/kg) of the CCK-B agonist pentagastrin on adrenocorticotropin (ACTH) and cortisol release in healthy human subjects. We also examined anxiety, heart rate (HR), and blood pressure (BP) responses. Pentagastrin induced large (up to 520% increase over baseline), significant and very rapid, dose-dependent elevations in ACTH and cortisol levels. Significant elevations in HR and BP were seen at all doses, without clear dose-response relationships. Anxious distress and symptom responses were also somewhat dose dependent; but hormonal responses were more robustly linked to pentagastrin dose than to these subjective measures. The HPA axis response to the CCK-B agonist pentagastrin may be a direct pharmacological effect. Further work is needed to determine the mechanisms and the physiological significance of CCK-mediated modulation of the human neuroendocrine stress axis.

Adolescent↗

Neuroendocrine and psychophysiologic responses in PTSD: a symptom provocation study.

Biological research on post-traumatic stress disorder (PTSD) has focused on autonomic, sympatho-adrenal, and hypothalamo-pituitary-adrenal (HPA) axis systems. Interactions among these response modalities have not been well studied and may be illuminating. We examined subjective, autonomic, adrenergic, and HPA axis responses in a trauma-cue paradigm and explored the hypothesis that the ability of linked stress-response systems to mount integrated responses to environmental threat would produce strong correlations across systems. Seventeen veterans with PTSD, 11 veteran controls without PTSD, and 14 nonveteran controls were exposed to white noise and combat sounds on separate days. Subjective distress, heart rate, skin conductance, plasma catecholamines, ACTH, and cortisol, at baseline and in response to the auditory stimuli, were analyzed for group differences and for patterns of interrelationships. PTSD patients exhibited higher skin conductance, heart rate, plasma cortisol, and catecholamines at baseline, and exaggerated responses to combat sounds in skin conductance, heart rate, plasma epinephrine, and norepinephrine, but not ACTH. The control groups did not differ on any measure. In canonical correlation analyses, no significant correlations were found between response systems. Thus, PTSD patients showed heightened responsivity to trauma-related cues in some, but not all, response modalities. The data did not support the integrated, multisystem stress response in PTSD that had been hypothesized. Individual response differences or differing pathophysiological processes may determine which neurobiological system is affected in any given patient.

Acoustic Stimulation↗

Differential regulation of hippocampal glucocorticoid receptors mRNA and fast feedback: relevance to post-traumatic stress disorder.

Hippocampal glucocorticoid receptors (GR and MR) play an important role in glucocorticoid negative feedback. Abnormalities in negative feedback are found in depression and in post-traumatic stress disorder (PTSD), suggesting that GR and MR might be involved in the pathophysiology of these disorders. Enhanced negative feedback, the PTSD-specific neuroendocrine abnormality, can be induced in animals using a single prolonged stress (SPS) paradigm (a number of different stressors in one prolonged session, 'no stress' interval and a testing session one week later). In the current study, we examined hippocampal GR and MR mRNA distribution in the same animals that exhibited altered negative feedback following the SPS. Seven groups of adult Sprague-Dawley male rats (seven animals each) were used in two studies, comparing unstressed controls to acutely stressed animals (SPS: 24 h group), SPS animals (seven and 14 days), and SPS + chronic stress animals. GR and MR mRNA distribution across hippocampal subfields was studied using in-situ hybridization with 35S-labelled cRNA probes. Acute stress produced down-regulation of GR and MR mRNA across all hippocampal subfields. Seven days later (SPS-7 group), there was a differential recovery, with GR mRNA reaching higher than the prestress levels, and MR mRNA remaining down-regulated. The same differential regulation was present in the 14-day group. Chronically stressed animals that exhibited normal fast feedback also had normalization in their GR and MR mRNA levels. The MR/GR ratio was decreased only in animals that had enhanced fast feedback. These findings suggest that the increase in GR, in hippocampus is involved in the fast feedback hypersensitivity observed in the SPS animals, and might also underlie enhanced dexamethasone sensitivity found in PTSD. Since differential activation of GR and MR can modulate memory, behavioural responsivity, anxiety and fear, change in MR/GR ratio might also explain other PTSD-related phenomena.

Animals↗

Psychophysiologic responsivity in posttraumatic stress disorder: generalized hyperresponsiveness versus trauma specificity.

BACKGROUND: Clinically, subjects with posttraumatic stress disorder (PTSD) are viewed as hyperresponsive to a variety of stimuli. Psychophysiologic studies, however, have demonstrated hyperresponsiveness only to stimuli that are closely related to the original trauma. METHODS: This set of experiments uses a variety of stimuli that vary in trauma-relatedness, arousal level, sensory modality stimulated, and degree of cognitive processing demanded to assess the extent of generalization of physiologic responses. Heart rate (HR), frontal electromyogram (EMG), and skin conductance (EDG) responses were measured during presentation of each stimulus. RESULTS: PTSD subjects (n = 15) had an elevated baseline EDG and increased HR and EMG responses to the trauma-related stimulus (combat sounds) compared to normal control subjects (n = 11) and combat control subjects (n = 10). No significant differences were noted between PTSD and control groups in response to non-trauma-related arousing stimuli. CONCLUSIONS: These results suggest that the physiologic hyperresponsivity of PTSD subjects is limited to stimuli closely associated with the inciting trauma.

Acoustic Stimulation↗

Rorschach patterns of response in Vietnam veterans with posttraumatic stress disorder versus combat and normal controls.

To further evaluate Rorschach indicators of posttraumatic stress disorder (PTSD), test protocols of 16 combat veterans so diagnosed were compared with those of 9 combat controls and 12 noncombat subjects. Results replicated Rorschach abnormalities previously associated with this disorder, including signs of low stress tolerance, poor affect modulation, perceptual distortion, and interpersonal disengagement. However, only two indicators, EB (Erlebnistypus) and CC (combat-related content), differentiated PTSD subjects from controls (P < .05). Examination of negative findings revealed that all three groups similarly deviated from Exner nonpatient norms (Exner, 1993: The Rorschach, Vol 1. New York: John Wiley and Sons) on many Rorschach variables. Possible explanations for these findings are considered, and the need for control subjects in Rorschach investigation is underscored.

Adult↗

Psychophysiologic responses to the Rorschach in PTSD patients, noncombat and combat controls.

While psychophysiologic studies of posttraumatic stress disorder (PTSD) have investigated the effects of trauma-related stimuli on arousal, none have explored the development of intrusive imagery and affect states in the absence of such specific cues. The present study compares autonomic arousal during PTSD-related Rorschach responses in PTSD veterans vs. combat controls and noncombat controls. It was found that Rorshach responses containing traumatic content were found only in the PTSD group, and that these responses showed elevations in skin conductance (SC) and heart rate (HR). Our data also suggest that PTSD patients are more easily hyperaroused, especially under conditions of experienced stress and helplessness. Finally, combat control subjects exhibited lower baseline SC and HR than their counterparts, as well as decelerated HR during trauma- and stress-related Rorschach responses, suggesting a physiologic resilience in this group.

Adult↗

The effect of emotional content on visual recognition memory: a PET activation study.

The emotional content of stimuli can enhance memory for those stimuli. This process may occur via an interaction with systems responsible for perception and memory or via the addition of distinct brain regions specialized for emotion which augment mnemonic processing. We performed an 15O PET study to identify neuroanatomical systems which encode visual stimuli with strong negative emotional valence compared to stimuli with neutral valence. Subjects also performed a recognition memory task for these same images, mixed with distracters of similar emotional valence. The experimental design permitted us to independently test effects of emotional content and recognition memory on regional activity. We found activity in the left amygdaloid complex associated with the encoding of emotional stimuli, although this activation appeared early in the scanning session and was not detectable during recognition memory. Visual recognition memory recruited the right middle frontal gyrus and the superior anterior cingulate cortex for both negative and neutral stimuli. An interaction occurred between emotional content and recognition in the lingual gyrus, where greater activation occurred during recognition of negative images compared to recognition of neutral images. Instead of distinct neuroanatomical systems for emotion augmenting memory, we found that emotionally salient stimuli appeared to enhance processing of early sensory input during visual recognition.

Adult↗

Stress-restress: effects on ACTH and fast feedback.

Glucocorticoid secretion is tightly regulated by negative feedback. Glucocorticoid feedback has been found to be altered in depression and post-traumatic stress disorder (PTSD). While hyposensitive glucocorticoid feedback has been found in depression, hypersensitive or enhanced negative feedback was described in PTSD. Enhanced negative feedback, can be seen as a sensitization of the inhibitory elements of HPA axis, and stress-restress or time dependent sensitization (TDS) model, has been suggested as an animal model for PTSD. We have studied the effects of this model on the HPA axis to determine whether it will produce increased sensitivity to negative feedback as found in PTSD patients. Adult Sprague-Dawley male rats were exposed to a single session of prolonged stress (restraint followed by a forced swim and exposure to ether vapors) and briefly restressed 7 days later. The effects of single prolonged stress on plasma ACTH and corticosterone responses (0, 5, and 30 min) and on glucocorticoid fast feedback (cortisol vs. saline pretreatment) were assessed in two studies. Animals exposed to single prolonged stress showed enhanced negative feedback in comparison to naive animals (F = 4.6371, df = 3, p = .0107), but there was no difference in ACTH or corticosterone responses during the restress. Pretreatment with cortisol, in the first stress session, did not prevent the development of the enhanced fast feedback when restressed. This can be seen as a sensitization of the inhibitory elements of HPA axis, suggesting that stress-restress paradigm might serve as a good animal model for HPA abnormalities found in PTSD patients.

Adrenocorticotropic Hormone↗

Effects of stress and glucocorticoids on CNS oxytocin receptor binding.

Oxytocin receptors in several regions of the limbic system are regulated by gonadal steroids and play an important role in the mediation of maternal, sexual and affiliative behaviors. We have previously reported oxytocin receptor regulation by glucocorticoids in hippocampus and subiculum-neuroanatomical regions implicated in memory and stress regulation. In the current study we examined oxytocin receptor regulation by stress and high glucocorticoid concentration in adrenally intact male rats. Single prolonged stress and chronic non-habituating stress were used as experimental conditions in the first study, and chronic non-habituating and high dose corticosterone implants in the second. Oxytocin receptor concentration was assessed using in vitro receptor autoradiography with [125I]OVTA at the approximate KD concentration. Both stress paradigms increased oxytocin receptor binding (F = 3.7, df = 2, p = .03) across brain regions in the first study. Chronic non-habituating stress and corticosterone implants increased oxytocin receptor binding in the ventral hippocampus only (one-way ANOVA, F = 3.88, df = 2, p < .05). The current studies demonstrate that stress increases oxytocin receptor binding in areas of the CNS that are rich in glucocorticoid receptors, such as hippocampus. This suggests differential regulation of oxytocin receptors in CNS, depending upon their functional role in different regions. Oxytocin receptor modulation could mediate some of the long-term effects of stress on memory, and possibly play a role in the regulation of hypothalamo-pituitary-adrenal stress response. The ability of circulating glucocorticoids to up-regulate these receptors suggests a plausible mechanism for this stress-sensitive regulation.

Adrenalectomy↗