Major depressive disorder.

Major depressive disorder (MDD) is a debilitating disease that is characterized by depressed mood, diminished interests, impaired cognitive function and vegetative symptoms, such as disturbed sleep or appetite. MDD occurs about twice as often in women than it does in men and affects one in six adults in their lifetime. The aetiology of MDD is multifactorial and its heritability is estimated to be approximately 35%. In addition, environmental factors, such as sexual, physical or emotional abuse during childhood, are strongly associated with the risk of developing MDD. No established mechanism can explain all aspects of the disease. However, MDD is associated with alterations in regional brain volumes, particularly the hippocampus, and with functional changes in brain circuits, such as the cognitive control network and the affective-salience network. Furthermore, disturbances in the main neurobiological stress-responsive systems, including the hypothalamic-pituitary-adrenal axis and the immune system, occur in MDD. Management primarily comprises psychotherapy and pharmacological treatment. For treatment-resistant patients who have not responded to several augmentation or combination treatment attempts, electroconvulsive therapy is the treatment with the best empirical evidence. In this Primer, we provide an overview of the current evidence of MDD, including its epidemiology, aetiology, pathophysiology, diagnosis and treatment.

Response to induced relaxation during pregnancy: comparison of women with high versus low levels of anxiety.

Relaxation exercises have become a standard intervention for individuals with anxiety disorders but little is known about their potential for anxiety relief during pregnancy. The purpose of this study was to examine psychoendocrine (i) baseline differences and (ii) changes after a standardized relaxation period in pregnant women with high versus low levels of anxiety. Thirty-nine third-trimester high and low anxious pregnant women performed active or passive relaxation while levels of anxiety, hypothalamic-pituitary-adrenal (HPA) axis and sympathetic-adrenal-medullary (SAM) system activity were assessed before and after the relaxation period. In women with high levels of trait anxiety, state anxiety (F(1,36) = 8.3, p = .007) and negative affect (F(1,36) = 7.99, p = .008) as well as ACTH (F(1,35) = 9.24, p = .002) remained elevated over the entire course of the experimental procedure, the last indicating increased HPA axis activity. In addition, norepinephrine showed a constricted decrease of relaxation reflecting lower response of the SAM-system (F(1,37) = 4.41, p = .043). Although relaxation exercises have become a standard intervention for individuals with anxiety, pregnant women with high levels of trait anxiety benefited less than women with low levels from a single standardized relaxation period.

The use of imagery to manipulate challenge and threat appraisal States in athletes.

The present study investigated whether imagery could manipulate athletes' appraisal of stress-evoking situations (i.e., challenge or threat) and whether psychological and cardiovascular responses and interpretations varied according to cognitive appraisal of three imagery scripts: challenge, neutral, and threat. Twenty athletes (M(age) = 20.85; SD = 1.76; 10 female, 10 male) imaged each script while heart rate, stroke volume, and cardiac output were obtained using Doppler echocardiography. State anxiety and self-confidence were assessed following each script using the Immediate Anxiety Measures Scale. During the imagery, a significant increase in heart rate, stroke volume, and cardiac output occurred for the challenge and threat scripts (p < .05). Although there were no differences in physiological response intensities for both stress-evoking scripts, these responses, along with anxiety symptoms, were interpreted as facilitative during the challenge script and debilitative during the threat script. Results support using imagery to facilitate adaptive stress appraisal.

Inherited tertiary hypothyroidism in Sprague-Dawley rats.

Thyroid hormones (THs) are important in the development and maturation of the central nervous system (CNS). The significant actions of THs during CNS development occur at the time when TH levels are lower than those in the mother and the hypothalamic-thyroid (HPT) axis is not fully functional. In the developing rat nervous system, primarily the cerebellum, the first three postnatal weeks represent a period of significant sensitivity to thyroid hormones. This study presents a spontaneous, inherited recessive hypothyroidism in Sprague-Dawley rats with devastating functional consequences to the development of the CNS. The clinical signs develop around 14 day's postnatal (dpn) and are characterized by ataxia, spasticity, weight loss and hypercholesterolemia. The afflicted rats died at 30 days due to severe neurological deficits. The deterioration affects the entire CNS and is characterized by progressive neuronal morphological and biochemical changes, demyelination and astrogliosis. The cerebellum, brain stem, neocortex, hippocampus and adrenal gland medulla appear to be most affected. Thyroid Stimulating Hormone (TSH), T3 and T4 levels were significantly lower in hypothyroid rats than control. Immunohistochemistry and RT-PCR demonstrated a reduction of Thyrotropin Releasing Hormone (TRH) in the hypothalamus of hypothyroid rats. The weight of both thyroid and pituitary glands were significantly less in hypothyroid rats than the corresponding normal littermate controls. Transmission electron microscopy demonstrates consistent postsynaptic dendritic, synaptic and spine alterative changes in the brain of hypothyroid rats. These data suggest that we discovered a tertiary form of inherited hypothyroidism involving the hypothalamus.

Recurrent insulin-induced hypoglycemia causes site-specific patterns of habituation or amplification of CNS neuronal genomic activation.

Antecedent hypoglycemia is a primary factor in hypoglycemia-associated autonomic failure, a pathophysiological condition characterized by impaired glucose counterregulatory function. Conventional therapeutic strategies involving administration of intermediate dosage-release formulations of insulin in the management of insulin-dependent diabetes mellitus result in frequent iatrogenic hypoglycemia. This study investigated the neuroanatomical location, direction, and magnitude of CNS neuronal genomic activation by singular versus repeated induction of hypoglycemic bouts of greater than 6 h duration achieved by administration of the intermediate-acting insulin, humulin neutral protamine Hagedorn (NPH). Adult male rats injected subcutaneously with Humulin NPH exhibited robust immunolabeling for the nuclear transcription factor, Fos, in discrete telencephalic, diencephalic, midbrain, and caudal hindbrain loci in a pattern that was not identical to that described for regular insulin. Administration of four doses of insulin on as many days significantly diminished or extinguished Fos immunostaining within the parvocellular hypothalamic paraventricular nucleus, lateral hypothalamic area, dorsomedial hypothalamic nucleus, thalamic paraventricular nucleus, nucleus tractus solitarius, and area postrema, but did not modify labeling of other metabolic loci. However, numbers of Fos-immunoreactivity-positive magnocellular neurons in the hypothalamic paraventricular and supraoptic nuclei were significantly increased after the second and fourth insulin doses, relative to the single-dose group. Concurrent observations of exacerbated hypoglycemia and modified patterns of glucoregulatory hormone secretion after serial injections of intermediate-acting insulin suggest that central mechanisms governing compensatory endocrine responses, specifically glucagon, become habituated to repetitive hypoglycemia of extended duration. Resultant alterations in CNS-islet and -adrenomedullary output and hypothalamic-pituitary-adrenal activity may reflect diminished neuronal activation within one or more of the brain loci characterized here by nonuniform transcriptional activation. The current studies provide a neuroanatomical foundation for further investigation of the neurochemical phenotypes and interconnectivity of functionally adaptive neurons, underlying cellular and molecular mechanisms of diminished or enhanced activation, as well as the impact of these modified cellular responses on glucose counterregulation during administration of intermediate-acting insulin.

Role of glucocorticoids in mediating effects of fasting and diabetes on hypothalamic gene expression.

BACKGROUND: Fasting and diabetes are characterized by elevated glucocorticoids and reduced insulin, leptin, elevated hypothalamic AGRP and NPY mRNA, and reduced hypothalamic POMC mRNA. Although leptin replacement can reverse changes in hypothalamic gene expression associated with fasting and diabetes, leptin also normalizes corticosterone; therefore the extent to which the elevated corticosterone contributes to the regulation of hypothalamic gene expression in fasting and diabetes remains unclear. To address if elevated corticosterone is necessary for hypothalamic responses to fasting and diabetes, we assessed the effects of adrenalectomy on hypothalamic gene expression in 48-hour-fasted or diabetic mice. To assess if elevated corticosterone is sufficient for the hypothalamic responses to fasting and diabetes, we assessed the effect of corticosterone pellets implanted for 48 hours on hypothalamic gene expression. RESULTS: Fasting and streptozotocin-induced diabetes elevated plasma glucocorticoid levels and reduced serum insulin and leptin levels. Adrenalectomy prevented the rise in plasma glucocorticoids associated with fasting and diabetes, but not the associated reductions in insulin or leptin. Adrenalectomy blocked the effects of fasting and diabetes on hypothalamic AGRP, NPY, and POMC expression. Conversely, corticosterone implants induced both AGRP and POMC mRNA (with a non-significant trend toward induction of NPY mRNA), accompanied by elevated insulin and leptin (with no change in food intake or body weight). CONCLUSION: These data suggest that elevated plasma corticosterone mediate some effects of fasting and diabetes on hypothalamic gene expression. Specifically, elevated plasma corticosterone is necessary for the induction of NPY mRNA with fasting and diabetes; since corticosterone implants only produced a non-significant trend in NPY mRNA, it remains uncertain if a rise in corticosterone may be sufficient to induce NPY mRNA. A rise in corticosterone is necessary to reduce hypothalamic POMC mRNA with fasting and diabetes, but not sufficient for the reduction of hypothalamic POMC mRNA. Finally, elevated plasma corticosterone is both necessary and sufficient for the induction of hypothalamic AGRP mRNA with fasting and diabetes.

A new splicing variant for human tyrosine hydroxylase in the adrenal medulla.

It has been reported that several mRNA isoforms of tyrosine 3-monooxygenase (tyrosine hydroxylase; TH) occur only in primates. New TH isoforms produced by skipping of exon 3 in the adrenal medulla of patients with progressive supranuclear palsy (PSP) have recently been reported, J. Neurochem. 67 (1996) 19. Here, we looked for the presence of new TH isoforms in control brains and adrenal medulla and in brains from patients with PSP. We found a novel type of TH mRNA in the adrenal medulla from one of the control subjects. The mRNA lacked exon 4, resulting in a premature stop codon at amino acid 147. This result suggests the importance of alternative splicing in the regulation of TH activity.

Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome.

OBJECTIVE: The author's goal was to develop a pathophysiological model for neuroleptic malignant syndrome with greater explanatory power than the alternative hypotheses of hypothalamic dopamine antagonism (elevated set point) and direct myotoxicity (malignant hyperthermia variant). METHOD: Published clinical findings on neuroleptic malignant syndrome were integrated with data from human and animal studies of muscle physiology, thermoregulation, and autonomic nervous system function. RESULTS: The data show that the sympathetic nervous system's latent capacity for autonomous activity is expressed when tonic inhibitory inputs from higher central nervous system centers are disrupted. These tonic inhibitory inputs are relayed to preganglionic sympathetic neurons by way of dopaminergic hypothalamospinal tracts. The sympathetic nervous system mediates hypothalamic coordination of thermoregulatory activity and is a primary regulator of muscle tone and thermogenesis, augmenting both of these when stimulated. In addition, the sympathetic nervous system modulates all of the other end-organs that function abnormally in neuroleptic malignant syndrome. CONCLUSIONS: There is substantial evidence to support the hypothesis that dysregulated sympathetic nervous system hyperactivity is responsible for most, if not all, features of neuroleptic malignant syndrome. A predisposition to more extreme sympathetic nervous system activation and/or dysfunction in response to emotional or psychological stress may constitute a trait vulnerability for neuroleptic malignant syndrome, which, when coupled with state variables such as acute psychic distress or dopamine receptor antagonism, produces the clinical syndrome of neuroleptic malignant syndrome. This hypothesis provides a more comprehensive explanation for existing clinical data than do the current alternatives.

Chronic life stress alters sympathetic, neuroendocrine, and immune responsivity to an acute psychological stressor in humans.

OBJECTIVE: Life stress is hypothesized to alter the dynamic regulation of the autonomic, neuroendocrine, and immune systems. This study examined the effects of antecedent chronic life stress on psychological and physiological responsivity after acute challenge with a psychological stressor. METHOD: Using a within-subject mixed design, male volunteers with (N = 12) and without chronic life stress (N = 11) were administered a 12-minute laboratory stressor (mental arithmetic) vs a video control. RESULTS: Acute psychological stress induced subjective distress, increases of circulating concentrations of epinephrine, norepinephrine, beta-endorphin, adrenocorticotropic hormone (ACTH), and cortisol, and a selective redistribution of natural killer (NK) cells into the peripheral blood as compared with the video control condition. Although the two groups were almost identical at baseline in psychological, sympathetic, neuroendocrine, and immune domains, the chronic stress group showed greater subjective distress, higher peak levels of epinephrine, lower peak levels of beta-endorphin and of NK cell lysis, and a more pronounced redistribution of NK cells in response to the acute psychological challenge than the controls. Furthermore, the acute stressor induced a protracted decline in NK lysis per NK cell in the chronic stress group but had no effect in the controls. CONCLUSIONS: In summary, when persons who are undergoing chronic life stress are confronted with an acute psychological challenge, an exaggerated psychologic and peak sympathomedullary reactivity occurs that is associated with decrements in individual NK cell function and is protracted beyond termination of the stressor and sympathomedullary recovery.

Transplantation and surgical treatment of parkinsonian syndromes.

Neurosurgical attempts to correct parkinsonism use strategies aimed either at alleviating the underlying dopamine deficiency or at correcting abnormal compensatory effects in neural circuits within the basal ganglia. During the review period, clinical trials of four different neurosurgical approaches were reported. These approaches are intracerebral transplantation of fetal dopamine neurons, intracerebral transplantation of adrenal medullary tissue, tremor-reducing surgical lesions in the ventrolateral thalamus, and ventroposterior pallidotomy aimed at reducing akinesia and rigidity. Experimental studies in rats and monkeys designed to explore mechanisms of graft actions were also reported.

[Activity of plasma dopamine-beta-hydroxylase and urine excretion of catecholamines in patients with deficiency-cold and deficiency-heat syndromes].

Spectrophotometric assay of plasma dopamine-beta-hydroxylase (D beta H) activity and fluorospectrophotometric assay of urine catecholamines (CA) were performed in 30 patients and 21 normal persons. According to TCM, the patients were divided into two groups, 16 cases of deficiency-cold syndrome (DCD), and 14 cases of deficiency-heat syndrome (DHD). The results showed that in the patients with DCD, the activity of D beta H and the levels of CA were lower than those of the normal, whereas the activity of D beta H and the levels of CA of the patients with DHD were higher than those of the normal (P less than 0.01, P less than 0.05). Variations of the involved visceral organs determined in the traditional way made no difference to the above-mentioned changes. D beta H and CA correlated significantly to each other. The authors also took the canonical correlation analysis to the cases, the result showed that the heat syndrome correlated with D beta H and CA positively. These results showed hyperfunctioning of the sympathetic-adrenomedullary system in DHD and hypofunctioning of this system in DCD.

[Effect of qigong on sympathetico-adrenomedullary function in patients with liver yang exuberance hypertension].

By using the differential diagnosis of traditional Chinese medicine to determine the types of hypertension, using the diagnosis of western medicine (WM) to determine the phases of hypertension, 61 inpatients of Liver Yang exuberance type hypertension were randomly divided into Qigong group and WM group. The patients in the Qigong group were treated with both Qigong and antihypertensive drugs at low dosage, but those in the WM group were treated with the drugs alone. Several laboratory tests concerning sympathetico-adrenomedullary functions were conducted twice respectively at 1st and 9th week after hospitalization of the patients. The results indicated that the Qigong group after treatment of 9 weeks had more cases with normal sympathetico-adrenomedullary functions than it had before the treatment, and that their urinary CA, E, NE decreased, MHPG-SO4 increased, plasma cAMP and cGMP got down, but cAMP/cGMP ratio got up. It suggested that Qigong could modulate the sympathetico-adrenomedullary functions of patients with Liver Yang exuberance type hypertension.

Epinephrine exacerbates arthritis by an action at presynaptic B2-adrenoceptors.

Sympathetic efferents contribute to the severity of joint injury in experimental arthritis in the rat, [Levine J. D. et al. (1986) J. Neurosci. 6, 3423-3429] and beta 2-adrenergic receptor antagonists suppress the disease [Levine J. D. et al. (1988) Proc. natn. Acad. Sci. U.S.A. 85, 4553-4556]. The present study was directed at determining the endogenous ligand for, and target of, the beta 2-receptor contribution to arthritis. We report that adrenal medullectomy significantly reduced joint injury in experimental arthritis, but that severe joint injury was re-established in adrenal medullectomized rats chronically treated with epinephrine or the beta 2-agonist, salbutamol. The ability of these two drugs to enhance joint injury in adrenal medullectomized rats was blocked by sympathectomy. These data suggest that adrenal medulla-derived epinephrine acts at beta 2-adrenoceptors on sympathetic efferent nerve terminals, to contribute to the severity of experimental arthritis.

Adrenal demedullation blocks and brain norepinephrine depletion potentiates the hyperglycemic response to a variety of stressors.

The role of adrenal hormones in mediating the increase in blood glucose levels following several stressful stimuli (environmental and pharmacological) was studied. The role for brain norepinephrine systems in the initiation of the BG response to these challenges was investigated as well. There is disagreement as to whether stress-induced increases in blood glucose levels are mediated primarily by hormonal or neural stimulation of the liver. A stressful stimulus probably causes increases in blood glucose levels by activating neural connections from the brain to both the liver and the adrenal medulla. The relative contribution that each of these pathways makes to the overall blood glucose response may be dependent on certain factors, such as the type of preparation used (awake or anesthetized, fasted or fed) and the intensity of the stimulus used to induce hyperglycemia. In the experiments reported here, which were performed in awake male rats, we found that increases in blood glucose levels following brief footshock stress, injection of 2-deoxy-D-glucose, exposure to the odor of a predator, and electrical stimulation of the hypothalamus were almost entirely eliminated by removal of the adrenal medullae, a procedure that does not damage hypothalamic norepinephrine systems or the multi-synaptic neural pathways from the hypothalamus to the liver. Furthermore, rather than having impaired blood glucose responses, rats that were depleted of brain norepinephrine showed normal responses to the injection of adrenergic agonists (including epinephrine), and potentiated responses to stressful stimuli compared to non-depleted controls. We conclude that: (1) rapid changes in blood glucose levels that occur following the stressful stimuli used here are mediated mainly by the release of epinephrine from the adrenal medullae and (2) intact brain norepinephrine systems are not required for these increases in blood glucose to occur.

Temporal adjustments in sympathoadrenal activity in rats with obesity-producing hypothalamic knife cuts.

Sympathoadrenal activity was assessed in adult rats with obesity-producing hypothalamic knife cuts prior to and after the onset of gross obesity by measuring urinary excretion of norepinephrine and epinephrine and by determining rates of norepinephrine turnover in selected organs. Urinary excretion of norepinephrine, as an index of overall sympathetic nervous system activity, was approximately doubled throughout the 4-week study in knife-cut rats, as was intake of the high-fat diet. Three days after knife-cut surgery (before the onset of gross obesity) rates of norepinephrine turnover (ng X organ-1 X hr-1) were 23-33% lower in three of the four organs examined than in the corresponding organs of control rats; rates of norepinephrine turnover were depressed in pancreas, interscapular brown adipose tissue, and abdominal white adipose tissue and unchanged in hearts. Four weeks after surgery when gross obesity was evident, rates of norepinephrine turnover were accelerated in heart (+82%) and pancreas (+63%), but remained low in interscapular brown adipose tissue (-27%) and abdominal white adipose tissue (-28%). Adrenal medullary activity, assessed by urinary excretion of epinephrine, was suppressed within the 1st day after knife-cut surgery and remained suppressed for several weeks. Brown adipose tissue and white adipose tissue appear to be selectively excluded from the generalized activation of the sympathetic nervous system in adult hyperphagic rats with obesity-producing hypothalamic knife cuts. Activation of the sympathetic nervous system was associated with reciprocal suppression of adrenal medullary responses in knife-cut rats.

Sympathetic nervous system involvement in the lateral hypothalamic lesion syndrome.

The role of the sympathetic nervous system in the lateral hypothalamic syndrome of body-weight loss was investigated. Bilateral electrolytic lesions of the lateral hypothalamus (LH) were performed in 90-day-old male albino rats. In experiment 1, the splanchnic nerves were resected at 35 days (right) and 70 days (left) postlesion. In experiment 2, bilateral adrenal demedullations were performed in a second group of rats with LH lesions (LH rats) at 35 days postlesion. The results indicated that lesions of the lateral hypothalamic area lowered body-weight maintenance levels to approximately 87% of nonlesion control values. Bilateral splanchnicetomy produced a significantly greater body-weight loss in nonlesion animals than in LH rats. Following adrenal demedullation, nonlesion rats also reduced body-weight levels whereas LH rats significantly increased weight-maintenance levels. In addition, the adrenal glands of LH rats with sham demedullations weighed significantly more than the adrenals of nonlesion-sham demedullated animals. These data are discussed in relation to metabolic-autonomic mechanisms that may play a role in LH lesion-induced weight loss.