Brain Mechanisms of Social Threat Effects on Working Memory.

Social threat can have adverse effects on cognitive performance, but the brain mechanisms underlying its effects are poorly understood. We investigated the effects of social evaluative threat on working memory (WM), a core component of many important cognitive capabilities. Social threat impaired WM performance during an N-back task and produced widespread reductions in activation in lateral prefrontal cortex and intraparietal sulcus (IPS), among other regions. In addition, activity in frontal and parietal regions predicted WM performance, and mediation analyses identified regions in the bilateral IPS that mediated the performance-impairing effects of social threat. Social threat also decreased connectivity between the IPS and dorsolateral prefrontal cortex, while increasing connectivity between the IPS and the ventromedial prefrontal cortex, a region strongly implicated in the generation of autonomic and emotional responses. Finally, cortisol response to the stressor did not mediate WM impairment but was rather associated with protective effects. These results provide a basis for understanding interactions between social and cognitive processes at a neural systems level.

Hypothalamic-pituitary adrenal response to cholecystokinin-B receptor agonism is resistant to cortisol feedback inhibition.

Intravenous injection of the cholecystokinin (CCK)-B receptor agonist, pentagastrin, produces robust, dose-dependent release of adrenocorticotropin (ACTH) and cortisol, supporting the hypothesis that CCK-B agonists pharmacologically activate the hypothalamic-pituitary-adrenal (HPA) axis. The mechanism of activation and its physiological relevance remain uncertain. Preliminary data suggest that the ACTH response to pentagastrin may be differentiated from the response to exogenous corticotropin releasing hormone (CRH) by its relative resistance to cortisol feedback inhibition. To more directly test the relationship between cortisol levels and ACTH response to pentagastrin, this study examined responses to pentagastrin (a) during a peak (8 a.m.) and a nadir (4 p.m.) period of endogenous cortisol secretion and (b) when cortisol levels were artificially reduced to low levels by administration of metyrapone. ACTH responses to pentagastrin were identical in the morning and afternoon, despite substantial differences in basal cortisol levels. Suppression of cortisol with metyrapone had little impact on ACTH response to pentagastrin. These data support the hypothesis that CCK-B receptor mediated activation of the HPA axis is relatively resistant to cortisol feedback inhibition. This differentiates it from CRH-mediated activation and raises the possibility that CCK could contribute to acute activation of the HPA axis even in the face of elevated basal cortisol levels, such as those seen in chronic stress or some psychiatric disorders.

Persistent respiratory irregularity in patients with panic disorder.

BACKGROUND: Dysregulated respiratory control may play a role in the pathophysiology of panic disorder. This could be due to abnormalities in brain stem respiratory nuclei or to dysregulation at higher brain levels. Results from previous studies using the doxapram model of panic have yielded an unclear picture. A brief cognitive manipulation reduced doxapram-induced hyperventilation in patients, suggesting that higher level inputs can substantially alter their respiratory patterns. However, respiratory abnormalities persisted, including a striking irregularity in breathing patterns. METHODS: To directly study respiratory irregularity, breath-by-breath records of tidal volume (V(t)) and frequency (f) from previously studied subjects were obtained. Irregularity was quantified using von Neumann's statistic and calculation of "sigh" frequency in 16 patients and 16 matched control subjects. Half of each group received a standard introduction to the study and half received a cognitive intervention designed to reduce anxiety/distress responses to the doxapram injection. RESULTS: Patients had significantly greater V(t) irregularity relative to control subjects. Neither the cognitive intervention nor doxapram-induced hyperventilation produced significant changes in V(t) irregularity. The V(t) irregularity was attributable to a sighing pattern of breathing that was characteristic of panic patients but not control subjects. Patients also had somewhat elevated f irregularity relative to control subjects. CONCLUSIONS: The irregular breathing patterns in panic patients appear to be intrinsic and stable, uninfluenced by induced hyperventilation or cognitive manipulation. Further study of V(t) irregularity and sighs are warranted in efforts to localize dysregulated neural circuits in panic to brain stem or midbrain levels.

Dose response of arginine vasopressin to the CCK-B agonist pentagastrin.

Cholecystokinin (CCK) is a peptide neurotransmitter that modulates hypothalamic-pituitary-adrenal (HPA) axis activity and may be involved in fear or anxiety states. Arginine vasopressin (AVP) also modulates HPA axis activity and may play a role in fear conditioning. Few human studies have examined interactions between CCK and AVP systems. To explore relationships between CCK-B receptor activation, the HPA axis response, and AVP release, a dose-response study using the CCK-B receptor agonist pentagastrin was conducted. Adrenocorticotropin (ACTH) and cortisol results have been previously reported and AVP data is presented here. Thirty-five healthy subjects were randomly assigned to receive placebo, or 0.2, 0.4, 0.6, or 0.8 microg/kg doses of pentagastrin. AVP release appeared to increase with increasing doses of the CCK-B agonist. However, this may have been due to a greater percentage of subjects releasing AVP in the higher dose groups, rather than a direct effect of dose on magnitude of response. AVP and ACTH responses were correlated, but AVP response alone could not account for the magnitude of the ACTH response. AVP release was significantly correlated with anxiety symptom responses. These findings suggest a possible role for the CCK-B receptor in AVP release, which may be at least partially separate from its role in modulation of the HPA axis. Further work is needed to determine whether these are physiologically meaningful interactions and to determine their functional implications.

Acute onset and remission of obsessions and compulsions following medical illnesses and stress.

Obsessive Compulsive Disorder (OCD) is generally chronic. Episodic OCD with complete remission has been rarely reported. Two cases of brief, episodic obsessions and compulsions that appeared for the first time following psychological stress and in the context of medical illness are reported. The possibility of brief episodes of OCD precipitated by stress is illustrated. Exploration of this phenomenon may help us learn more about OCD in general.

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.

Effect of alcohol on social phobic anxiety.

OBJECTIVE: Previous research has demonstrated a greater-than-expected association between social phobia and alcohol use disorders. The purpose of this study was to test the hypothesis that drinking alcohol reduces social phobic anxiety. METHOD: Treatment-seeking individuals with social phobia (N = 40) were asked to give two impromptu speeches. Twenty subjects received a placebo alcoholic drink before both speeches, and 20 subjects received a placebo before the first speech, followed by a moderate dose of alcohol before the second speech. Subjective anxiety ratings, heart rate, and cognitions related to social anxiety were used as measures of anxiety. RESULTS: Repeated measures analyses of variance yielded no significant differences in anxiety (subjective, physiological, cognitive) between the alcohol and placebo groups. Current and past drinking habits did not significantly alter the effect of alcohol on anxiety. The belief that one received alcohol was significantly related to levels of subjective anxiety and negative cognitions. CONCLUSIONS: Alcohol does not directly reduce social phobic anxiety. The belief that one received alcohol may reduce social anxiety.

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.

Defense mechanism changes in successfully treated patients with obsessive-compulsive disorder.

OBJECTIVE: Changes in defense mechanisms after treatment of patients with obsessive-compulsive disorder (OCD) were measured by using an established rating scale. METHOD: Before and after 7-week group behavior therapy, 17 patients with DSM-III-R OCD were assessed with the Defense Style Questionnaire, Yale-Brown Obsessive Compulsive Scale, and Beck Depression Inventory. RESULTS: After behavior therapy the patients evidenced significant decreases in Yale-Brown Obsessive Compulsive Scale scores and significant increases in the use of more adaptive defense mechanisms. There were no significant changes in three maladaptive defense mechanism categories. The improvement in adaptive defenses was independently linked to improvement both in OCD and in depression. CONCLUSIONS: Personality as defined by defense mechanisms may be more amenable to brief behavioral treatment than previously thought. The permanence of these changes must be further assessed.

Adrenocorticotropic hormone and cortisol responses to corticotropin-releasing hormone: changes in panic disorder and effects of alprazolam treatment.

This study applied the corticotropin-releasing hormone (CRH) stimulation test to patients with panic disorder, before and during treatment with alprazolam, and to control subjects. In contrast to some, but not all prior studies, untreated, nondepressed panic disorder patients failed to show blunted adrenocorticotropic hormone or cortisol responses to CRH. In fact, the responses were subtly enhanced in that they were more rapid than those of controls. After 12 weeks of alprazolam treatment, repeat testing gave results that were indistinguishable from those of controls. Inconsistency among reports of CRH testing in panic disorder may be related to interactions among illness mechanisms, concurrent subthreshold depressive symptoms, the chronic stress of the illness, and hyperresponsiveness of panic patients to the acute stress of experimental manipulations. Pretreatment abnormalities in hypothalamic-pituitary-adrenal axis function appear to resolve with alprazolam treatment. Preliminary observations suggest that pretreatment dysregulation of the hypothalamic-pituitary-adrenal system may predict a more difficult or less satisfactory treatment.

Childhood adversity and vulnerability to mood and anxiety disorders.

Based upon epidemiological surveys, adverse childhood events are proposed to be risk factors for adult depressive and anxiety disorders. However, the extent to which these events are seen in clinical patient populations is less clear. We examined the prevalence of a number of proposed risk factors for depression in 650 patients with mood and anxiety disorders at the time of presentation for treatment in an outpatient subspecialty clinic. Emotional abuse, physical abuse, or sexual abuse (childhood adversity) was found in approximately 35% of patients with major depression and panic disorder, was more common in women than men, and was associated with an earlier onset of symptoms. Childhood adversity was also strongly associated with marital discord/divorce, and psychopathology in a parent, suggesting family discord predisposes to childhood abuse. Furthermore, the association of childhood abuse with parental mental illness suggests that genetic and environmental factors are difficult to separate as etiological factors in vulnerability.

Reliability and procedural validity of UM-CIDI DSM-III-R phobic disorders.

We evaluate the long-term test-retest reliability and procedural validity of phobia diagnoses in the UM-CIDI, the version of the Composite International Diagnostic Interview, used in the US National Co-morbidity Survey (NCS) and a number of other ongoing large-scale epidemiological surveys. Test-retest reliabilities of lifetime diagnoses of simple phobia, social phobia, and agoraphobia over a period between 16 and 34 months were K = 0.46, 0.47, and 0.63, respectively. Concordances with the Structured Clinical Interview for DSM-III-R (SCID) were K = 0.45, 0.62, and 0.63, respectively. Diagnostic discrepancies with the SCID were due to the UM-CIDI under-diagnosing. Post hoc analysis demonstrated that modification of UM-CIDI coding rules could dramatically improve cross-sectional procedural validity for both simple phobia (K = 0.57) and social phobia (K = 0.95). Based on these results, it seems likely that future modification of CIDI questions and coding rules could lead to substantial improvements in diagnostic validity.

Respiratory psychophysiology and anxiety: cognitive intervention in the doxapram model of panic.

UNLABELLED: The goals of this study were to: a) confirm prior evidence that the respiratory stimulant doxapram induces panic attacks and produces excessive hyperventilation in patients with panic disorder and b) explore the impact of cognitive mediators on symptom and respiratory responses. METHOD: Thirty-two subjects (16 patients and 16 controls) received doxapram (0.5 mg/kg) and placebo infusions while symptom, respiratory, and heart rate responses were monitored. Subjects were randomly assigned to receive either a standard introduction or a cognitive intervention designed to reduce the panic responses of panic patients to laboratory challenges. RESULTS: Doxapram was a potent and specific panicogenic agent, inducing panic in 75% of patients and 12.5% of controls. Compared with controls, patients also showed a greater decrease in end tidal carbon dioxide (CO2) and greater increases in minute ventilation, respiratory frequency, and heart rate. The cognitive intervention substantially attenuated the excessive hyperventilatory response of patients but did not fully normalize their breathing patterns. Tidal volume was the only respiratory measure not significantly altered by the cognitive intervention. CONCLUSIONS: In patients with panic disorder, doxapram (0.5 mg/kg) triggers panic attacks about as potently as 7% CO2 and more potently than 5% CO2 or lactate. Psychological factors can modulate the appearance of ventilatory abnormalities in panic patients, but persistent respiratory disturbances were still seen. Psychological factors and respiratory physiology both appear to be important phenomena in laboratory panic.

Neuroendocrine responses to laboratory panic: cognitive intervention in the doxapram model.

Doxapram is a respiratory stimulant that appears to be a potent and specific panicogenic agent. It also elicits an abnormal ventilatory response in patients with panic. A replication study confirmed these findings and demonstrated that behavioral and ventilatory responses to doxapram were significantly modified by a psychological intervention designed to cognitively block panic. The replication study provided an opportunity to simultaneously investigate the neuroendocrine effects of the illness, the drug, the drug-induced panic attacks, and the cognitive intervention. Epinephrine (EPI), norepinephrine (NE), growth hormone (GH), adrenocorticotropin (ACTH), and cortisol were studied in patients with panic and control subjects given placebo and doxapram injections after receiving either standard instructions or a brief cognitive intervention. Patients with panic had elevated levels of EPI, ACTH, and cortisol throughout the study. Doxapram had little or no detectable effects on plasma NE, GH, ACTH, and cortisol. Doxapram-induced panic attacks were not associated with elevations in NE, GH, ACTH, or cortisol. Doxapram led to a rapid and very brief rise in plasma EPI, which was small in subjects who did not panic and pronounced in patients who did panic. The cognitive intervention attenuated the EPI response to doxapram, perhaps through its effect on panic, and modified the temporal pattern of ACTH and cortisol secretion. These results suggest that: (1) further study of catecholamine responses within the first few minutes after panic induction is needed; (2) intense panic can occur without significant activation of the hypothalamic-pituitary-adrenal axis; and (3) cognitive factors can modulate neuroendocrine activity in laboratory studies of patients with panic.

Hypothalamic-pituitary-adrenal axis activity in panic disorder. 24-hour secretion of corticotropin and cortisol.

BACKGROUND: Oversecretion of corticotropin-releasing hormone and/or dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may contribute to pathophysiologic processes in panic disorder, but documentation of HPA axis disturbance in panic has been inconsistent. In the current study we examined HPA axis activity in panic disorder over a full circadian cycle, using frequent blood sampling to provide detailed assessment of corticotropin and cortisol secretion. METHODS: Twenty patients with panic disorder and 12 normal control subjects were studied. Blood samples were drawn every 15 minutes for 24 hours and assayed for corticotropin and cortisol levels. RESULTS: Patients with panic disorder had elevated overnight cortisol secretion and greater amplitude of ultradian secretory episodes. Patients who entered the study through clinical referral channels had greater cortisol secretion than those recruited by advertisements. Patients with panic disorder who had a low frequency of panic attacks had elevated daytime corticotropin levels and elevated corticotropin ultradian amplitude. Patients with a high frequency of attacks had shifted corticotropin circadian cycles. CONCLUSIONS: Patients with panic disorder demonstrate subtle alterations in HPA axis activity, characterized by overnight hypercortisolemia and increased activity in ultradian secretory episodes, but HPA axis alterations in panic are modulated by illness severity and treatment seeking. It remains unclear whether HPA axis dysregulation in panic represents a pathogenic defect within the axis itself. Inconsistencies in prior work may reflect the subtlety of the abnormalities seen, differences in clinical characteristics of patients studied, and the use of different probes and measurement contexts.

Hypothalamic-pituitary-adrenal axis activity in panic disorder: effects of alprazolam on 24 h secretion of adrenocorticotropin and cortisol.

Pre-clinical and some clinical evidence suggests that central overdrive within the hypothalamic-pituitary-adrenal (HPA) axis may play a role in panic disorder, and that the anti-panic efficacy of alprazolam may involve its ability to inhibit this drive. Detailed examination of 24 h secretion of adrenocorticotropin (ACTH) and cortisol in 20 panic patients had revealed subtle HPA axis abnormalities prior to treatment. In order to determine whether these abnormalities resolve with alprazolam therapy, these patients were re-studied over a full circadian cycle after 12 weeks on alprazolam. Alprazolam produced substantial improvement in clinical status which was accompanied by nearly full resolution of pre-treatment hypercortisolemia. The impact of treatment on ACTH was more complex and influenced by symptom severity. The results are consistent with the hypotheses that HPA axis regulation is subtly disturbed in panic disorder and that impact on the HPA axis may play a role in alprazolam's mechanism of efficacy.

Hypothalamic-pituitary-adrenal axis activity in panic disorder: prediction of long-term outcome by pretreatment cortisol levels.

OBJECTIVE: The authors sought to determine whether hypothalamic-pituitary-adrenal (HPA) axis activity in patients before their treatment for panic disorder can predict follow-up functional status. Although baseline HPA axis disturbances in patients with panic disorder appear to attenuate with treatment, there is evidence that they may be linked to poorer long-term outcomes. METHOD: Follow-up clinical data were obtained for 18 of 20 patients with panic disorder who participated in a detailed study of HPA axis activity in panic, both before and during their treatment with alprazolam. HPA axis assessment included monitoring of adrenocorticotropin and cortisol over a full circadian cycle. The relationships between disability and clinical status at 2-year follow-up and HPA axis overactivity at entry were examined. RESULTS: Mean 24-hour cortisol levels before treatment provided a strong, positive predictor of disability scores at follow-up. Those patients who achieved the treatment goal of medication-free remissions had less evidence of HPA axis overactivity at entry than those who were not in remission. CONCLUSIONS: HPA axis activity before treatment did predict outcome 2 years later. This relationship appears robust and reproducible. Further work is needed to define the neuroendocrine mechanisms underlying the HPA axis markers that are linked to long-term functioning and to determine the biological, psychological, and social processes that link HPA axis disturbance to poorer outcomes.

Cholecystokinin in psychiatric research: a time for cautious excitement.

Cholecystokinin (CCK) is a peptide neurotransmitter that was originally isolated from the gastrointestinal system, but which is extensively and abundantly distributed within the central nervous system (CNS). Stimulated by the fairly recent recognition of receptor subtypes (A and B), and the development of receptor-specific antagonists, CCK research has been advancing rapidly; and its potential importance to psychiatric neuroscience has been increasingly recognized. CCK participates in the mediation of satiety; it interacts with dopamine and may modulate psychosis; it interacts with opiate systems and may be an "anti-analgesic": and it appears to play a role in the mediation of anxiety. Highly specific, CCK-B receptor antagonists have reached clinical trials and have potential clinical utility as anxiolytics, antipsychotics, anti-anorexics, or analgesics. There are grounds for excitement, but many obstacles remain to be overcome and clinical potential may not be fulfilled. However, we must not allow clinical disappointments to slow the accelerating pace of scientific progress in CCK research. Regardless of clinical payoffs, the CCK receptor is clearly of great importance to human CNS functioning and deserves ongoing scientific attention.