Maternal stimulation in infancy predicts hypothalamic–pituitary–adrenal axis reactivity in young men

Evidence from animal research has demonstrated the effect of early maternal care on the offspring’s endocrine and behavioral stress response in adulthood. The present prospective study investigates, in humans, the long-term impact of maternal responsiveness and stimulation during early mother–child interaction on adrenocorticotropic hormone (ACTH) and cortisol response to a psychosocial laboratory stressor in adulthood. The data are from an epidemiological cohort study of the long-term outcome of early risk factors assessed at birth. At age 3 months, mothers and infants were videotaped during a 10-min standardized nursing and playing situation and evaluated by trained raters for maternal stimulation and infant and maternal responsiveness. At age 19 years, 270 participants (146 females, 124 males) completed the Trier Social Stress Test. The results indicated that less maternal stimulation during early interaction at age 3 months predicted diminished plasma ACTH and cortisol increase in response to acute psychosocial stress in male, but not female offspring. In contrast, maternal responsiveness was found to be unrelated to hypothalamic–pituitary–adrenal (HPA) reactivity. In accordance with the findings from animal research, the present study provides prospective evidence in humans of a long-term association between early maternal interaction behavior and the offspring’s hormonal stress response in young adulthood, suggesting that poor maternal stimulation in early infancy may result in reduced HPA axis reactivity to an acute psychosocial stressor in males.     

Adjunctive high-frequency right prefrontal repetitive transcranial magnetic stimulation (rTMS) was not effective in obsessive–compulsive disorder but improved secondary depression

BackgroundThere is preliminary evidence that repetitive transcranial magnetic stimulation (rTMS) may be useful in obsessive–compulsive disorder (OCD) patients.MethodsOur objective was to examine efficacy of adjunctive right prefrontal high-frequency (rapid) rTMS treatment in OCD patients. 42 patients with OCD were randomly assigned to 10 sessions of add-on high-frequency right prefrontal active rTMS (10 Hz, 110% of motor threshold, 4 s per train, 20 trains per session) or sham stimulation. They were rated on Yale Brown Obsessive Compulsive Scale (YBOCS), Hamilton Rating Scale for Depression (HAM-D), Hamilton Rating Scale for Anxiety (HAM-A) and Clinical Global Impression-Severity of Illness (CGI-S) at baseline, day 14 and day 28. The dose of antiobsessive drug was kept constant throughout the period of assessment.ResultsFor YBOCS scores, repeated measures ANOVA showed significant main effect of treatment, but no effect of treatment over time (Pillai's Trace F = 1.39, p = .262). However, significant effect of treatment over time as shown by interaction effect for both HAM-D (Pillai's Trace F = 3.67, p = .035, η² = .158) and HAM-A scores (Pillai's Trace F = 5.22, p = .01, η² = .211) were seen.ConclusionAdjunctive high-frequency right prefrontal rTMS does not have any significant effect in the treatment of OCD. However, it is modestly effective in the treatment of comorbid depressive symptoms in patients with OCD.     

High-frequency repetitive transcranial magnetic stimulation to the left dorsolateral prefrontal cortex of patients with Parkinson’s disease and treatment-resistant depression: a pilot study

An increasing amount of evidence is showing the therapeutic effects of rTMS on PD-related non-motor functions neuroanatomically linked to the DLPFC. This presents an ongoing need to apply an optimal combination of stimulation parameters to clinically heterogeneous patient populations, including those with neuropsychiatric problems and other comorbidities along with the neurodegenerative process. In this prospective pilot study, six patients with PD and treatment-resistant depression were thoroughly assessed and carefully monitored before, during, and after each stimulation procedure. The results can provide the basis for developing an extended rTMS protocol that is both effective and safe.     

Can sleep disturbance in depression predict repetitive transcranial magnetic stimulation (rTMS) treatment response?

Treatment for depression is not effective in all patients and it is therefore important to identify factors that can be used to tailor treatments. One potential factor is insomnia. Several repetitive transcranial magnetic stimulation (rTMS) studies have reported on this symptom, however, they did not take into account the presence of hypersomnia or that insomnia was related to their outcome measure. Our aim was to investigate whether baseline sleep disruption was related to rTMS treatment response. We pooled data from four clinical trials using rTMS to treat depression, including 139 subjects in data analysis. Insomnia was measured using the Hamilton Depression Rating Scale (HamD) sleep questions and hypersomnia from the Beck Depression Inventory (BDI). To reduce the possible impact of insomnia on our treatment response outcome we created an adjusted HamD score which omitted sleep items. Sleep disturbances were common in our study: 66% had insomnia and 38% hypersomnia. Using regression analysis with our adjusted HamD score we found no relation between baseline insomnia or hypersomnia and rTMS treatment response. Our data are consistent with previous studies; however, this is the first rTMS study to our knowledge that has attempted to dissociate baseline insomnia from the HamD outcome measure and to report no relationship between hypersomnia and rTMS outcome.     

Differences in hypothalamic–pituitary–adrenal axis functioning among children with ADHD predominantly inattentive and combined types

Some evidence suggests that the HPA axis may be dysfunctional in children with attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to investigate whether a different pattern of HPA axis activity is found between the inattentive (I) and combined (C) subtypes of ADHD, in comparison with healthy control children. A total of 100 prepubertal subjects [52 children with ADHD combined type (ADHD-C), 23 children with ADHD predominantly inattentive type (ADHD-I), and 25 healthy control subjects] were studied. The effects of stress were studied by comparing cortisol responses to a psychosocial stressor, consisting of a public speaking task. Children with ADHD-I showed an elevated cortisol response to the psychosocial stressor, in contrast to children with ADHD-C who showed a blunted cortisol response to the psychosocial stressor. When a distinction was made between responders and non-responders (a subject was classified as a responder when there was an increase in cortisol reactivity), hyperactivity symptoms were clearly related to a lower cortisol reactivity to stress. The results indicate that a low-cortisol responsivity to stress may be a neurobiological marker for children with ADHD-C, but not for those with ADHD-I. Directions for future research and clinical implications are discussed.     

Effects of low-frequency repetitive transcranial magnetic stimulation on electroencephalogram and seizure frequency in 15 patients with temporal lobe epilepsy following dipole source localization*★

BACKGROUND： Low-frequency repetitive transcranial magnetic stimulation （rTMS） has been shown to significantly reduce epileptiform discharges and control clinical seizures in intractable epilepsy patients. The location of epileptic foci and magnetic stimulation sites remain uncertain. The effects of rTMS on electroencephalogram and seizure remain unclear in epileptic patients following dipole source localization. OBJECTIVE： To investigate the effects of low-frequency rTMS on electroencephalogram and seizure in temporal lobe epilepsy patients after dipole source localization. DESIGN, TIME AND SETTING： The randomized, controlled study was performed at the outpatient clinic Department of Neurology, Hospital Affiliated to North Sichuan Medical College from December 2003 to February 2007. PARTICIPANTS： A total of 30 temporal lobe epilepsy patients, comprising 19 males and 11 females, aged 1749 years, presented with epileptiform discharges and were enrolled for this study. Disease course ranged between 1-6 years, with 1-5 seizures per month. Imaging examinations revealed 11 patients with structural changes in the brain. The patients were randomly and equally assigned into drug treatment and transcranial magnetic stimulation （TMS） groups. METHODS： Patients in the drug treatment group were orally treated with carbamazepine. Patients in the TMS group received oral carbamazepine treatment of and TMS. A Maglite-r25 magnetic stimulator （Dantec Dynamics, Denmark） was used to stimulate epileptic foci in the temporal lobe following electroencephalogram dipole localization （1 Hz, 90% threshold intensity, at a stimulation frequency of 500 times, once a day, for 7 days）. MAIN OUTCOME MEASURES： At 30 days after TMS, seizure frequency and rate of epileptiform discharges were observed in patients from both groups. Therapeutic safety was investigated during treatment. RESULTS： Within 30 days of treatment, there were no significant differences in seizure frequency between the TMS group （1.5 ± 0.3） seiz     

Role of hypothalamic corticotropin-releasing factor in mediating alcohol-induced activation of the rat hypothalamic–pituitary–adrenal axis

Alcohol stimulates the hypothalamic–pituitary–adrenal (HPA) axis through brain-based mechanisms in which endogenous corticotropin-releasing factor (CRF) plays a major role. This review first discusses the evidence for this role, as well as the possible importance of intermediates such as vasopressin, nitric oxide and catecholamines. We then illustrate the long-term influence exerted by alcohol on the HPA axis, such as the ability of a first exposure to this drug during adolescence, to permanently blunt neuroendocrine responses to subsequent exposure of the drug. In view of the role played by CRF in addiction, it is likely that a better understanding of the mechanisms through which this drug stimulates the HPA axis may lead to the development of new therapies used in the treatment of alcohol abuse, including clinically relevant CRF antagonists.     

Stress,seizures, and hypothalamic–pituitary–adrenal axis targets for the treatment of epilepsy

Epilepsy is a heterogeneous condition with varying etiologies including genetics, infection, trauma, vascular, neoplasms, and toxic exposures. The overlap of psychiatric comorbidity adds to the challenge of optimal treatment for people with epilepsy. Seizure episodes themselves may have varying triggers; however, for decades, stress has been commonly and consistently suspected to be a trigger for seizure events. This paper explores the relationship between stress and seizures and reviews clinical data as well as animal studies that increasingly corroborate the impact of stress hormones on neuronal excitability and seizure susceptibility. The basis for enthusiasm for targeting glucocorticoid receptors for the treatment of epilepsy and the mixed results of such treatment efforts are reviewed. In addition, this paper will highlight recent findings identifying a regulatory pathway controlling the body's physiological response to stress which represents a novel therapeutic target for modulation of the hypothalamic–pituitary–adrenal (HPA) axis. Thus, the HPA axis may have important clinical implications for seizure control and imply use of anticonvulsants that influence this neuronal pathway.This article is part of a Special Issue entitled “The Future of Translational Epilepsy Research”.     

Cholinergic dysfunction and amnesia in patients with Wernicke–Korsakoff syndrome: a transcranial magnetic stimulation study

The specific neurochemical substrate underlying the amnesia in patients with Wernicke–Korsakoff syndrome (WKS) is still poorly defined. Memory impairment has been linked to dysfunction of neurons in the cholinergic system. A transcranial magnetic stimulation (TMS) protocol, the short latency afferent inhibition (SAI), may give direct information about the function of some cholinergic pathways in the human motor cortex. In the present study, we measured SAI in eight alcoholics with WKS and compared the data with those from a group of age-matched healthy individuals; furthermore, we correlated the individual SAI values of the WKS patients with memory and other cognitive functions. Mean SAI was significantly reduced in WKS patients when compared with the controls. SAI was increased after administration of a single dose of donezepil in a subgroup of four patients. The low score obtained in the Rey Complex Figure delayed recall test, the Digit Span subtest of the Wechsler Adult Intelligence Scale—Revised (WAIS-R) and the Corsi’s Block Span subtest of the WAIS-R documented a severe impairment in the anterograde memory and short-term memory. None of the correlations between SAI values and these neuropsychological tests reached significance. We provide physiological evidence of cholinergic involvement in WKS. However, this putative marker of central cholinergic activity did not significantly correlate with the memory deficit in our patients. These findings suggest that the cholinergic dysfunction does not account for the memory disorder and that damage to the cholinergic system is not sufficient to cause a persisting amnesic syndrome in WKS.     

The use of slow-frequency transcranial magnetic stimulation in the treatment of depression at Brasília University Hospital: preliminary findings

This paper reports the use of slow frequency transcranial magnetic stimulation of the right pre-frontal cortex in three patients with a diagnosis of major depressive episode according to the DSM-IV classification. There was a significant improvement in two patients, with a decrease of over 50% in the Hamilton Scale scores- 17 items. Possible indications and limitations of this therapeutic tool are discussed, as well as socio-economic aspects of this new treatment.     

Vagus nerve stimulation: Can it be used in adolescents or children with treatment-resistant depression?

Vagus nerve stimulation (VNS) therapy has been approved by the US Food and Drug Administration for treatment-resistant depression in patients 18 years of age and older and for intractable epilepsy. Long-term studies suggest VNS has an antidepressant effect in adults. This paper reviews the available clinical data for VNS therapy. Its potential application for treatment-resistant depression in adolescents and children is also discussed.     

Dissection of glucocorticoid receptor-mediated inhibition of the hypothalamic–pituitary–adrenal axis by gene targeting in mice

Negative feedback regulation of glucocorticoid (GC) synthesis and secretion occurs through the function of glucocorticoid receptor (GR) at sites in the hypothalamic–pituitary–adrenal (HPA) axis, as well as in brain regions such as the hippocampus, prefrontal cortex, and sympathetic nervous system. This function of GRs in negative feedback coordinates basal glucocorticoid secretion and stress-induced increases in secretion that integrate GC production with the magnitude and duration of the stressor. This review describes the effects of GR loss along major sites of negative feedback including the entire brain, the paraventricular nucleus of the hypothalamus (PVN), and the pituitary. In genetic mouse models, we evaluate circadian regulation of the HPA axis, stress-stimulated neuroendocrine response and behavioral activity, as well as the integrated response of organism metabolism. Our analysis provides information on contributions of region-specific GR-mediated negative feedback to provide insight in understanding HPA axis dysregulation and the pathogenesis of psychiatric and metabolic disorders.     

The social buffering of the hypothalamic–pituitary–adrenocortical axis in humans: Developmental and experiential determinants

Social buffering, a subset of social support, is the process through which the availability of a conspecific reduces the activity of stress-mediating neurobiological systems. While its role in coping and resilience is significant, we know little about its developmental history in humans. This brief review presents an integrative developmental account of the social buffering of hypothalamic–pituitary–adrenocortical (HPA) stress reactivity in humans, from infancy to adulthood. During infancy, parents are powerful stress-regulators for children, but child temperament also plays a role and interacts with parenting quality to predict the magnitude of stress responses to fear or pain stimuli. Recent work indicates that parental support remains a potent stress buffer into late childhood, but that it loses its effectiveness as a buffer of the HPA axis by adolescence. Puberty may be the switch that alters the potency of parental buffering. Beginning in middle childhood, friends may serve as stress buffers, particularly when other peers are the source of stress. By adulthood, romantic partners assume this protective role, though studies often reveal sex differences that are currently not well understood. Translational research across species will be critical for developing a mechanistic understanding of social buffering and the processes involved in developmental changes noted in this review.     

Hypothalamic–pituitary–thyroid (HPT) axis functioning in anxiety disorders. A systematic review

Depression has repeatedly been linked to subclinical hypothyroidism, and thyroid hormones have successfully been used to augment antidepressant treatment. By contrast, the extent of thyroid dysfunction in anxiety disorders remains less clear. This is surprising, given that anxiety-related symptoms (e.g., nervousness, palpitations, increased perspiration) are highly prevalent in hyperthyroidism. The present study was undertaken to synthesize the literature on hypothalamic–pituitary–thyroid (HPT) axis functioning in anxiety disorders. The PubMed and PsycINFO databases were systematically searched. Three types of studies were included: (1) “comorbidity studies” assessing the prevalence of thyroid disorders in individuals with anxiety disorders, (2) “case-control studies” comparing HPT parameters between patients and controls, and (3) “correlational studies” assessing self-reported anxiety levels and HPT parameters. Risk of bias was assessed via a standardized quality rating. Twenty studies were eligible. Nearly all found the comorbidity between anxiety and thyroid disorders was significant. Half of the studies additionally supported the notion of subtle thyroid dysfunction in that thyroid-stimulating hormone (TSH) responses to the administration of thyrotropin-releasing hormone (TRH) were blunted and an inverse relationship was observed between self-reported anxiety levels and TSH. Overall, HPT assessments were well conducted, but several studies failed to adjust their analyses for smoking, body mass index (BMI), and depression. The findings resonate well with clinical recommendations to routinely screen for thyroid disorders in patients with anxiety disorders, and with what is known from basic research about thyroid–brain interactions. The results of the risk of bias assessment underscore the importance of further high-quality experimental and longitudinal epidemiological research.