A pilot investigation of differential neuroendocrine associations with fronto-limbic activation during semantically-cued list learning in mood disorders.

BACKGROUND: Decreased volume and disrupted function in neural structures essential for memory formation (e.g. medial temporal lobe and prefrontal cortex) are common among individuals with depression. Hypothalamic-pituitary-axis function, as reflected by measurement of cortisol levels, is linked to neural activity during memory encoding in healthy people. However, it is not as well understood whether cortisol is associated with alterations in fronto-temporal recruitment during memory encoding in depression. METHODS: In this pilot study, we evaluated associations between cortisol and neural activation during memory encoding in 62 adults (18-65 years) with mood disorders (MD; n = 39, 66.7% female), including major depression (n = 28) and bipolar I disorder (n = 11), and healthy controls (HC; n = 23, 43.5% female). Participants provided salivary cortisol samples before and after completing a semantically-cued list-learning task during 3-Tesla fMRI. Links between pre-scan cortisol (and cortisol change) and activation during encoding were evaluated using block and event-related models. RESULTS: Overall, pre-scan cortisol level was positively associated with greater engagement of fronto-limbic activation during the encoding block. However, in MD, pre-scan cortisol was associated with attenuated activation during encoding in medial frontal, superior and middle temporal gyri, insula, lingual gyrus, and claustrum relative to HCs. Cortisol-related attenuation of activation in MD was also observed during encoding of words subsequently recalled in the ventral anterior cingulate, hypothalamus, and middle temporal gyrus. By and large, cortisol change (pre/post scan) predicted the same pattern of findings in both block and event-related contrasts. LIMITATIONS: Although analyses accounted for variations in scanner time of day, circadian alterations in cortisol may have introduced variability into the results. CONCLUSIONS: Pre-scan cortisol may selectively interfere with recruitment of important fronto-temporal memory circuitry in mood disorders. The inverted associations between cortisol and neural function in MD relative to HC also elucidate potentially unique pathophysiological markers of mood disorders.

Shifted inferior frontal laterality in women with major depressive disorder is related to emotion-processing deficits.

BACKGROUND: Facial emotion perception (FEP) is a critical human skill for successful social interaction, and a substantial body of literature suggests that explicit FEP is disrupted in major depressive disorder (MDD). Prior research suggests that weakness in FEP may be an important phenomenon underlying patterns of emotion-processing challenges in MDD and the disproportionate frequency of MDD in women. Method Women with (n = 24) and without (n = 22) MDD, equivalent in age and education, completed a FEP task during functional magnetic resonance imaging. RESULTS: The MDD group exhibited greater extents of frontal, parietal and subcortical activation compared with the control group during FEP. Activation in the inferior frontal gyrus (IFG) appeared shifted from a left >right pattern observed in healthy women to a bilateral pattern in MDD women. The ratio of left to right suprathreshold IFG voxels in healthy controls was nearly 3:1, whereas in the MDD group, there was a greater percentage of suprathreshold IFG voxels bilaterally, with no leftward bias. In MDD, relatively greater activation in right IFG compared with left IFG (ratio score) was present and predicted FEP accuracy (r = 0.56, p < 0.004), with an inverse relationship observed between FEP and subgenual cingulate activation (r = - 0.46, p = 0.02). CONCLUSIONS: This study links, for the first time, disrupted IFG activation laterality and increased subgenual cingulate activation with deficient FEP in women with MDD, providing an avenue for imaging-to-assessment translational applications in MDD.

Elevated cortisol levels in Cushing's disease are associated with cognitive decrements.

OBJECTIVE: The objective of this study was to use Cushing's disease as a unique human model to elucidate the cognitive deficits resulting from exposure to chronic stress-level elevations of endogenous cortisol. METHODS: Forty-eight patients with a first episode of acute, untreated Cushing's disease and 38 healthy control subjects were studied. RESULTS: Scores for four of five verbal IQ subtests were significantly lower in patients with Cushing's disease; their scores were significantly lower for only one nonverbal performance IQ subtest (block design). Verbal, but not visual, learning and delayed recall at 30 minutes were significantly decreased among patients with Cushing's disease. Although verbal delayed recall was significantly lower in these patients, the retention index (percentage), which compares the amount of initially learned material to that recalled after the delay, was not significantly decreased. There was no significant association between depression scores and cognitive performance. A higher degree of cortisol elevation was associated with poorer performance on several subtests of learning, delayed recall, and visual-spatial ability. CONCLUSIONS: Chronically elevated levels of glucocorticoids have deleterious effects on particular domains of cognition. Verbal learning and other verbal functions seem more vulnerable than nonverbal functions. The results suggest that both the neocortex and hippocampus are affected.

Overexpression of CXC chemokines by an adrenocortical carcinoma: a novel clinical syndrome.

A patient with adrenocortical carcinoma presented with fever, leukocytosis, and increased acute phase reactants. The tumor was infiltrated with neutrophils. Immunohistochemical staining of the tumor showed positive signal for epithelial neutrophil-activating protein-78, an angiogenic and chemotactic CXC chemokine. Conditioned medium from tumor-derived cells (RL-251) showed high concentration of IL-8, epithelial neutrophil-activating protein-78, Gro alpha, and Gro gamma, angiogenic CXC chemokines with a potential role in tumorigenesis. An adrenal cancer/severe combined immunodeficiency mouse chimera was developed. Mice grew tumors rapidly, and circulating levels of IL-8 and epithelial neutrophil-activating protein-78 were detected. In contrast, animals transplanted with NCI-H295 cells, a nonchemokine-secreting cell line, grew tumors more slowly and did not have detectable chemokine levels. Similar to the patient, mice with RL-251 tumors developed marked leukocytosis and neutrophilia, and their tumors were infiltrated with neutrophils. Mice were passively immunized with epithelial neutrophil-activating protein-78 antisera. A marked decrease in tumor growth was observed. Potential for chemokine production by other adrenocortical tumors was investigated by RT-PCR in archival material. Six of seven adrenal carcinomas and one of three adenomas had cDNA for IL-8; six of seven carcinomas and the three adenomas had cDNA for epithelial neutrophil-activating protein-78. We concluded that the clinical presentation of this case resulted from increased tumor production of chemotactic chemokines. Through their angiogenic and chemotactic properties these chemokines may play an important role in adrenal tumorigenesis.

Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing's disease.

BACKGROUND: Decreased hippocampal volume is observed in patients with Cushing's syndrome and other conditions associated with elevated cortisol levels, stress, or both. Reversibility of hippocampal neuronal atrophy resulting from stress occurs in animals. Our study investigated the potential for reversibility of human hippocampal atrophy. METHODS: The study included 22 patients with Cushing's disease. Magnetic resonance brain imaging was performed prior to transsphenoidal microadenomectomy and again after treatment. RESULTS: Following treatment, hippocampal formation volume (HFV) increased by up to 10%. The mean percent change (3.2 +/- 2.5) was significantly greater (p < .04) than that of the comparison structure, caudate head volume (1.5 +/- 3.4). Increase in HFV was significantly associated with magnitude of decrease in urinary free cortisol (r = -.61, p < .01). This relationship strengthened after adjustments for age, duration of disease, and months elapsed since surgery (r = -.70, p < .001). There was no significant correlation between caudate head volume change and magnitude of cortisol decrease. CONCLUSIONS: Changes in human HFV associated with sustained hypercortisolemia are reversible, at least in part, once cortisol levels decrease. While many brain regions are likely affected by hypercortisolemia, the human hippocampus exhibits increased sensitivity to cortisol, affecting both volume loss and recovery.

The effect of elevated systemic cortisol levels on plasma catecholamines in Cushing's syndrome patients with and without depressed mood.

This study explored the effect of elevated systemic cortisol levels on plasma epinephrine and norepinephrine, and hemodynamic variables, in patients with active Cushing's syndrome; ratings of depressed mood were also obtained. Norepinephrine levels were significantly negatively correlated with 24 h urinary free cortisol levels. Cushing's patients without depressed mood showed more robust negative correlations than those with depressed mood. The inverse relationship between norepinephrine and cortisol is consistent with data obtained previously in acute studies of normal subjects. Mechanisms which might explain these relationships include changes in control of catecholamine production, release, and or metabolic clearance in Cushing's patients. The decrease in the strength of association in depressed Cushing's patients is consistent with prior studies that suggest abnormal relationships between hypothalamic-pituitary-adrenocortical activity and noradrenergic function in major depressive disorder.

Diurnal rhythm of plasma delta-sleep-inducing peptide in humans: evidence for positive correlation with body temperature and negative correlation with rapid eye movement and slow wave sleep.

Since delta-sleep-inducing peptide (DSIP) was isolated in 1977, numerous reports have suggested that this nonapeptide stimulates delta-sleep [slow wave sleep (SWS)]. Although DSIP-like immunoreactivity (DSIP-LI) has been found in the serum of many animals and man, its diurnal rhythm and relation to sleep stages have not been well defined. We hypothesized that circulating levels of this putative sleep hormone would be highest at night and would probably be elevated before or during episodes of SWS. We, therefore, measured plasma DSIP-LI levels every 30 min for 24 h in 12 normal volunteers in whom we obtained simultaneous polygraphic recordings. We found a distinct diurnal rhythm for plasma DSIP-LI levels, with the maximum at 1500 h and the minimum at 0100 h. DSIP-LI levels were substantially lower in rapid eye movement sleep (P < 0.005) and somewhat lower in SWS (P < 0.05) compared to awake values. DSIP-LI levels did not rise before, during, or after a significant percentage of episodes of SWS. We found, however, that the diurnal rhythm of DSIP-LI closely followed that of body temperature with a high degree of correlation (r2 = 0.66; P < 0.0001). We conclude that endogenous elevations of circulating DSIP may be associated with suppression of slow wave and rapid eye movement sleep, and that the circadian rhythm of this peptide is coupled directly or indirectly to that of body temperature.

Sleep architecture and sleep apnea in patients with Cushing's disease.

Patients with Cushing's syndrome (CS) frequently have sleep complaints. We evaluated sleep polysomnographically in 22 patients, including 17 with pituitary-ACTH-dependent Cushing's disease (CD) and five with CS from an adrenal tumor. Data were compared to healthy controls of comparable age. Seven patients (32%) demonstrated at least mild sleep apnea (> or = 9.4 events/hour), and four of 22 (18%) had > or = 17.5 events/hour. The apneic CD and CS patients had a trend for a greater complaint of excessive daytime sleepiness. Both apneic and nonapneic groups had considerable snoring and obesity. The electroencephalographic (EEG) sleep of nonapneic patients was compared to that of normal subjects. Nonapneic CD patients differed strikingly from healthy volunteers in sleep continuity and architecture, demonstrating lighter, fragmented sleep. Rapid eye movement (REM) sleep in CD patients bore many similarities to the sleep of patients with major depression, with REM latency being significantly shortened and REM density significantly increased. Continued examination of EEG sleep in CD patients may shed light on similarities in pathophysiology between CD and major depression, disorders which are characterized by both a dysfunction of the hypothalamic-pituitary-adrenal axis and alterations in mood.

Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing's syndrome.

Patients with chronic hypercortisolemia due to Cushing's syndrome (CS) exhibit cognitive dysfunction. Because glucocorticoid excess is associated with hippocampal damage in animals, and the hippocampus participates in learning and memory, we explored the relationships between hippocampal formation (HF) volume, memory dysfunction, and cortisol levels in 12 patients with CS. After magnetic resonance imaging, HF volume was determined using digital sum of track ball traces of dentate gyrus, hippocampus proper and subiculum, correcting for total intracranial volume. For 27% of the patients, HF volume fell outside the 95% confidence intervals for normal subject volume given in the literature. In addition, there were significant and specific correlations between HF volume and scores for verbal paired associate learning, verbal recall, and verbal recall corrected for full-scale IQ (r = 0.57 to 0.70, p < 0.05). HF volume was negatively correlated with plasma cortisol levels (r = -0.73, p < 0.05). These studies suggest an association between reduced HF volume, memory dysfunction, and elevated cortisol in patients with CS.

Discordant changes in plasma ACTH and beta-lipotropin/beta-endorphin levels in Cushing's disease patients with depression.

Cushing's Disease is often associated with a depressive syndrome, with mood, vegetative, and cognitive abnormalities of variable severity. In 11 patients with (pituitary ACTH-dependent) Cushing's disease (10 women, 1 man), we studied the relationship between severity of the depressive syndrome and concordance of changes in ACTH and beta-lipotropin/beta-endorphin (beta-LPH/beta-E) levels at baseline and in response to metyrapone and dexamethasone. For each condition, blood samples were drawn at 0800h, 1200h, 1600h, and 2200h. Six patients were categorized as mildly depressed (mean [+/- SD] depressed mood score = 0.17 +/- 0.4; modified Hamilton Depression scale score = 7.6 +/- 4.5) and five as severely depressed (mean depressed mood score = 2.4 +/- 0.5; modified Hamilton Depression scale score = 15 +/- 5.6) (p < 0.05). ACTH and beta-LPH/beta-E were measured by radioimmunoassay. For each experimental condition, changes in levels were scored as concordant if the two peptides moved in parallel between sampling points. There was a relationship between greater severity of depression and more frequent discordant changes in ACTH and beta-LPH/beta-E levels: The six patients with mild depression exhibited 23 concordant and 3 discordant change patterns, while the five patients with severe depression showed 8 concordant and 15 discordant patterns. The mean percentage of concordant patterns per patient differed significantly between the two groups (mildly depressed = 90.0 +/- 16.7; severely depressed = 34.6 +/- 8.7 (p < 0.001). When each study condition was examined separately, differences in the frequency of concordance between the groups reached significance during the post-metyrapone phase and with 8.0 mg dexamethasone administration.(ABSTRACT TRUNCATED AT 250 WORDS)

EEG sleep in Cushing's disease and Cushing's syndrome: comparison with patients with major depressive disorder.

Because patients with Cushing' syndrome (CS) and Major depressive disorder (MDD) share features of hypercortisolism and the depressive syndrome, we compared electro-encephalographic (EEG) sleep in patients with pituitary-ACTH-dependent Cushing's syndrome (Cushing's disease, CD), patients with ACTH-independent Cushing's syndrome (AICS), patients with major depressive disorder (MDD), and normal subjects. There were substantial similarities in the abnormal polysomnography profiles of patients with CD, AICS, and MDD. All three patient groups demonstrated poorer sleep continuity, shortened rapid eye movement (REM) latency, and increased first REM period density compared with normal subjects. In addition, AICS patients and MDD patients had elevated REM activity and density. These findings are discussed in terms of models of pathophysiology that relate abnormalities in sleep, mood, and hypothalamic-pituitary-adrenal function.

Peripheral catecholamine levels and the symptoms of anxiety: studies in patients with and without pheochromocytoma.

We studied the correlation of plasma and urinary epinephrine (E) and norepinephrine (NE) levels with anxiety symptoms in three patient groups: 1) pheochromocytoma (PH+) (n = 17); 2) hypertensives with elevated catecholamine levels shown not to have a PH (PH-) (n = 25); and 3) patients with panic disorder (PD) (n = 23). Structured interviews and four self-rated anxiety scales were used: the SCL-90R Anxiety and Phobic Anxiety scales, and the Spielberger State/Trait Anxiety Inventories. The SCL-90R Somatization scale (which measures 12 somatic symptoms) was also utilized. None of the PH+ patients met DSM-III criteria for PD. Two met criteria for generalized anxiety disorder (GAD). Of the PH- patients, two had PD, two had GAD, and three had both. Urinary and plasma E did not show significant positive correlations with any of the four anxiety scales in any of the three patient groups. In both the PH+ and PH- groups, E was significantly correlated with the SCL-90R Somatization scale. NE was not significantly correlated with any of the four anxiety scales in the PH+ group. In contrast, in the PH- group, plasma NE was significantly correlated with anxiety on all anxiety scales (r = +0.55 to +0.77, p less than 0.05). Furthermore, in the PH- group, plasma NE was significantly correlated with those items of the SCL-90R Anxiety scale measuring the cognitive rather than the noncognitive symptoms of anxiety. In the PD group as well, plasma NE showed a significant correlation with the SCL-90R Anxiety Scale (r = +0.67, p less than 0.05). Taken together, our observations suggest that: 1) the effects of catecholamines in the periphery derived from a source independent of nervous system control (such as a PH) are not sufficient to elicit an anxiety disorder meeting DSM-III criteria; and 2) in patients without an autonomous source of peripheral catecholamines, NE in the periphery results from sympathetic nervous system activation and probably reflects, rather than causes, anxiety.

Cushing's syndrome after treatment: changes in cortisol and ACTH levels, and amelioration of the depressive syndrome.

Twenty-three patients with pituitary adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome were studied before and after treatment. The relationship between the amelioration of the depressive syndrome and changes in cortisol and ACTH levels was investigated. There was a significant difference in mean change in 24-hour urinary free cortisol (UFC) excretion for changes in the depressed mood score from first to last visit. There were also significant correlations between decreases in UFC and decreases in both the depressed mood score and the modified Hamilton depression score. These relationships were not found for ACTH. Furthermore, with cortisol decreased to normal levels, continued high ACTH levels did not prevent improvement in depressed mood. The possibility that cortisol may also play a role in the pathogenesis and/or maintenance of the mood disorder in psychiatric patients is discussed.

Anxiety in patients with pheochromocytomas.

Anxiety has been considered an important clinical feature of patients with pheochromocytomas. We studied 17 patients with active pheochromocytoma to determine whether they experienced anxiety that met criteria of the Diagnostic and Statistical Manual of Mental Disorders, third edition, for either panic disorder or generalized anxiety disorder. Fifty-two patients with primary anxiety disorders were used as a comparison group. Six patients with pheochromocytomas had norepinephrine-secreting tumors and 11 had mixed-secretion tumors, with elevated levels of both epinephrine and norepinephrine. None of the 17 patients described the severe apprehension or fear characteristic of panic attacks and none described agoraphobia. One patient received a diagnosis of possible panic disorder, two met criteria for generalized anxiety disorder, and two met criteria for major depressive episode. Thus, the elevated levels of catecholamines secreted by pheochromocytomas are not sufficient to elicit an anxiety disorder.

Pseudocyesis: psychologic and neuroendocrine interrelationships.

There is a paucity of information concerning the interrelationship of psychiatric and neuroendocrine abnormalities in pseudocyesis. We have studied two patients using a multimodal investigatory approach, with particular attention to the association of depression and alterations in endocrine secretory patterns. Both patients had abnormal growth hormone secretory patterns, as demonstrated by lack of sleep-associated peaks and the absence of a response to L-dopa administration. Both patients had elevated testosterone and estradiol levels and normal prolactin levels. Only the patient who met DSM III criteria for a major depressive episode had abnormally elevated luteinizing hormone (LH) levels and large LH pulse amplitudes. These findings, together with a review of cases reported in the literature, suggest that no single neuroendocrine profile is common to all patients with pseudocyesis.

Impact of psychodynamic factors on the course and management of patients with pseudocyesis.

Comparing and contrasting two patients with pseudocyesis made it clear that differing psychodynamic factors specific to each patient resulted in divergent ways in which they sought out and used medical care. The propensity of these patients to distort reality was observed to interfere with the usefulness of sonography in convincing them that they were not pregnant. Management recommendations are suggested to aid the obstetrician in designing a treatment approach to assist the patient in accepting the diagnosis, giving up the symptom, and preventing future recurrences.

Neuropsychiatric manifestations of patients with Cushing's syndrome. Relationship to cortisol and adrenocorticotropic hormone levels.

Thirty-five consecutive patients with Cushing's syndrome were studied prospectively before treatment. A consistent constellation of neuropsychiatric disturbances was found, including impairments in affect (depressed mood and crying), cognitive functions (decreased libido and insomnia). Thirty-four percent of patients were rated as having a mild, 26% a moderate, 29% a severe, and 11% a very severe psychiatric disability. A statistically significant relationship was found between the overall neuropsychiatric disability rating and cortisol and adrenocorticotropic hormone (ACTH) levels. Patients with adrenal adenomas with high cortisol but low ACTH levels did not have as severe a neuropsychiatric disability.