Detection of the acute effects of hydrocortisone in the hippocampus using pharmacological fMRI

Impaired hippocampal function is believed to be important in the pathogenesis of depression. The hippocampus contains a high concentration of both mineralocorticoid (MR) and glucocorticoid receptors (GR), and the experimental administration of corticosteroids has been reported to mimic memory impairments seen in depression. Using pharmacological functional magnetic resonance imaging (phMRI) we investigated whether hippocampal function is altered after acute administration of hydrocortisone. Changes in BOLD signal following infusion of 100 mg hydrocortisone given as a rapid intravenous bolus were measured in 14 healthy volunteers in a within-subject placebo-controlled crossover design. Subsequently, subjects completed an n-back task during an fMRI scan. Hydrocortisone infusion caused a significant, time-dependent increase in fMRI BOLD signal in hippocampus reaching a maximal effect at 11–19 min. The n-back task increased BOLD signal in prefrontal and parietal cortical areas and decreased it in the hippocampus. After hydrocortisone the left hippocampal decrease in BOLD signal was attenuated with the magnitude of attenuation correlating with the increase seen after hydrocortisone infusion. No difference in behavioural task performance was observed. The results suggest acute hydrocortisone has rapid direct and modulatory influences on hippocampal function, probably acting through non-genomic GR or MR signalling. Hydrocortisone infusion phMRI may be a useful tool to investigate hippocampal corticosteroid receptor function in depression.     

Effect of sub-chronic hydrocortisone on responses to amphetamine in normal male volunteers

Rationale Enhancement of dopamine (DA) release by corticosteroids may be of aetiological importance in substance misuse.Objectives To examine the effect of sub-chronic administration of hydrocortisone on the response to amphetamine in healthy male volunteers.Methods Following baseline assessment, 20 volunteers were pretreated for 7 days with 20 mg of hydrocortisone or placebo at 0800 hours and 2000 hours in a double-blind, random order, cross-over design prior to receiving 0.15 mg/kg metamphetamine intravenously. Blood samples for cortisol and prolactin were taken every 15 min. Subjects also underwent tests of neuropsychological function including sustained attention using the rapid visual information processing test (RVIP), which has been shown to be sensitive to changes in DA function.Results Metamphetamine produced a substantial reduction in prolactin levels, and increased subjective mood ratings of "mind-race" and "buzz". Sub-chronic hydrocortisone administration had no effect on these neuroendocrine responses, subjective mood changes or neurocognitive performance on a task of sustained attention (RVIP).Conclusions Despite measurable changes in neuroendocrine and affective functioning in response to metamphetamine, pretreatment with hydrocortisone did not significantly affect any of the variables measured. This suggests that this model of DA function is not affected by this regimen of corticosteroid administration.     

Altering cortisol level does not change the pleasurable effects of methamphetamine in humans.

Preclinical studies have linked corticosteroid secretion and levels with drug self-administration by animals. In a double-blind, cross-over study, subjective, physiological, and endocrine responses to intravenous doses of methamphetamine 0.5 mg/kg or placebo were assessed in eight methamphetamine-experienced subjects after three cortisol-modifying premedication conditions: augmenting cortisol level with oral hydrocortisone 50 mg, blocking cortisol response with the corticosteroid synthesis inhibitor metyrapone 1500 mg orally, or no premedication. Although the pharmacologic manipulations produced the expected hormonal changes, subjective response to the methamphetamine showed few differences. Diminishing cortisol response by pharmacologic blockade did not alter the pleasurable effects of methamphetamine. Hydrocortisone did increase self-reported 'bad drug effect' and decreased craving after saline placebo relative to the period following methamphetamine. Metyrapone was associated with significant premature ventricular complexes in two subjects during methamphetamine administration and may not be safe for those who use methamphetamine.     

Glucocorticoid-Related Molecular Signaling Pathways Regulating Hippocampal Neurogenesis

Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. We, therefore, investigated the molecular signaling pathways mediating the effects of cortisol on proliferation, neuronal differentiation, and astrogliogenesis, in an immortalized human hippocampal progenitor cell line. In addition, we examined the molecular signaling pathways activated in the hippocampus of prenatally stressed rats, characterized by persistently elevated glucocorticoid levels in adulthood. In human hippocampal progenitor cells, we found that low concentrations of cortisol (100 nM) increased proliferation (+16%), decreased neurogenesis into microtubule-associated protein 2 (MAP2)-positive neurons (−24%) and doublecortin (Dcx)-positive neuroblasts (−21%), and increased differentiation into S100β-positive astrocytes (+23%). These effects were dependent on the mineralocorticoid receptor (MR) as they were abolished by the MR antagonist, spironolactone, and mimicked by the MR-agonist, aldosterone. In contrast, high concentrations of cortisol (100 μM) decreased proliferation (−17%) and neuronal differentiation into MAP2-positive neurons (−22%) and into Dcx-positive neuroblasts (−27%), without regulating astrogliogenesis. These effects were dependent on the glucocorticoid receptor (GR), blocked by the GR antagonist RU486, and mimicked by the GR-agonist, dexamethasone. Gene expression microarray and pathway analysis showed that the low concentration of cortisol enhances Notch/Hes-signaling, the high concentration inhibits TGFβ-SMAD2/3-signaling, and both concentrations inhibit Hedgehog signaling. Mechanistically, we show that reduced Hedgehog signaling indeed critically contributes to the cortisol-induced reduction in neuronal differentiation. Accordingly, TGFβ-SMAD2/3 and Hedgehog signaling were also inhibited in the hippocampus of adult prenatally stressed rats with high glucocorticoid levels. In conclusion, our data demonstrate novel molecular signaling pathways that are regulated by glucocorticoids in vitro, in human hippocampal progenitor cells, and by stress in vivo, in the rat hippocampus.     

Hippocampal subfield morphology in monozygotic twins discordant for affective disorders

Unipolar and bipolar disorders aggregate in families and have been associated with a reduced gray-matter volume in hippocampal and prefrontal cortex. Here we used structural MRI to clarify whether abnormalities in hippocampal subfield and prefrontal cortical morphology are associated with familial vulnerability (i.e., changes present both in patients and unaffected relatives compared to healthy individuals), resilience (i.e., changes differentiating unaffected relatives and patients), or sequalae of illness in a sample of monozygotic twins. We investigated regional differences in gray-matter volume extracted using FreeSurfer 6.0 between remitted affected twins (AT) with either unipolar or bipolar disorder (n = 67), unaffected discordant co-twins (UT, n = 39), and low-risk twins (LT, n = 31) with no personal or first-degree family history of affective disorders. The UT showed greater bilateral hippocampal volumes compared to AT. Between group differences in left hippocampal volume were driven by greater cornu ammonis 1–3 and 4, subiculum and subfield of dentate gyrus. For the right hippocampus, differences were driven by greater hippocampal tail and subiculum. There was a trend for UT having a larger left hippocampus than LT, but no significant differences in hippocampal volumes between AT and LT. Outside the hippocampus, AT showed a smaller volume of left dorsomedial prefrontal cortex compared to LT. Our results suggest that larger volume of specific hippocampal subfields may be associated with resilience in healthy relatives of patients with an affective illness. Moreover, a smaller volume of left dorsomedial prefrontal cortex may reflect a sequalae of illness.Subject terms: Depression, Predictive markers, Depression     

Effects of hydrocortisone administration on cognitive function in the elderly

Previous studies have found adverse effects of both acute and chronic elevations of corticosteroids on cognitive function in humans and that cortisol levels may predict cognitive decline in elderly subjects. However, no previous studies have directly investigated the effects of hydrocortisone on cognitive functioning in the healthy elderly. Sixteen healthy elderly subjects took part in a placebo-controlled, double-blind, cross-over trial. Hydrocortisone 20 mg or placebo was administered twice, 12 h and 1 h before cognitive testing. On each occasion, a battery of neuropsychological tests was performed which included tests of attention, working memory, declarative memory and executive function. Salivary cortisol levels at the time of testing were elevated approximately 10-fold following hydrocortisone compared with placebo. No significant effects were found on memory or a range of other cognitive functions. The lack of effect of this regime of hydrocortisone is in contrast to studies in younger subjects. The elderly may be less sensitive to cognitive effects of short-term increases in cortisol levels, possibly due to an age-related downregulation of hippocampal glucocorticoid receptors.     

Hippocampal to pituitary volume ratio: a specific measure of reciprocal neuroendocrine alterations in alcohol dependence.

OBJECTIVE: Studies to date provide conflicting views of the relationship between corticosteroids and decreased hippocampal volume in alcoholism. If this were mediated through the hypothalamic-pituitary-adrenal (HPA) axis, enlarged pituitary volumes relative to hippocampal volumes might be expected and be measurable using the hippocampus to pituitary volume (H:P) ratio. METHOD: Using magnetic resonance imaging (MRI), we performed volumetric analysis of the pituitary and hippocampus on 10 subjects with alcohol dependence (AD) and on 10 normal control subjects. RESULTS: Compared to normal controls, AD subjects demonstrated a trend towards decreased hippocampal volume (p < .06) and increased pituitary volume (p < .07). More importantly, H:P ratios were significantly smaller in AD subjects (p < .01). This observation persisted even when covaried for age. CONCLUSIONS: Reduced H:P ratio fits the hypothesis that ethanol stimulates pituitary corticotrophs resulting in elevated corticosteroid levels and possible injury to the hippocampus. If replicated, reduced H:P ratio may serve as a clinical measure of reciprocal neuroendocrine changes in chronic heavy ethanol use.     

Resting-state functional connectivity after hydrocortisone administration in patients with post-traumatic stress disorder and borderline personality disorder

In a previous study, we found that - in contrast to healthy individuals - patients with borderline personality disorder (BPD) and post-traumatic stress disorder (PTSD) showed better memory retrieval performance after hydrocortisone administration compared to placebo. As these results suggest an altered function of corticosteroid receptors in the brain in PTSD and BPD, we examined the effect of hydrocortisone on brain activation in both disorders. We recruited 40 female healthy controls, 20 female unmedicated patients with PTSD and 18 female unmedicated patients with BPD. We conducted a placebo-controlled cross-over study, in which all participants underwent two resting state MRI measurements after they received either a placebo or 10 mg hydrocortisone orally and in randomized order. There was a time interval of one week between the measurements. We analysed resting state functional connectivity (RSFC) with the hippocampus and the amygdala as seed regions. Compared to healthy controls, both patient groups showed reduced hippocampus RSFC to dorsomedial prefrontal cortex (dmPFC). Positive hippocampus dmPFC RSFC correlated negatively with childhood trauma (r = -0.47) and with severity of clinical symptoms, measured with the Borderline Symptom List (r = -0.44) and the Posttraumatic Stress Diagnostic Scale (r = -0.45). We found neither differences in amygdala RSFC nor an effect of hydrocortisone administration. Childhood trauma might lead to decreased positive hippocampus dmPFC RSFC. This might explain symptoms of PTSD and BPD that are characterized by dysfunctional fear regulation.     

A pilot study of hippocampal volume and N-acetylaspartate (NAA) as response biomarkers in riluzole-treated patients with GAD

Anxiolytic benefit following chronic treatment with the glutamate modulating agent riluzole in patients with generalized anxiety disorder (GAD) was previously associated with differential changes in hippocampal NAA concentrations. Here, we investigated the association between hippocampal volume and hippocampal NAA in the context of riluzole response in GAD. Eighteen medication-free adult patients with GAD received 8-week of open-label riluzole. Ten healthy subjects served as a comparison group. Participants underwent magnetic resonance imaging and spectroscopy at baseline and at the end of Week 8. GAD patients who completed all interventions were classified as remitters (n=7) or non-remitters (n=6), based on final Hamilton Anxiety Rating Scale (HAM-A) scores ≤7. At baseline, GAD patients had a significant reduction in total hippocampal volume compared to healthy subjects (F_(1,21)=6.55, p=0.02). This reduction was most pronounced in the remitters, compared to non-remitters and healthy subjects. Delta (final?baseline) hippocampal volume was positively correlated with delta NAA in GAD. This positive association was highly significant in the right hippocampus in GAD [r=0.81, p=0.002], with no significant association in healthy subjects [Fisher r-to-z p=0.017]. Across all GAD patients, delta hippocampal volume was positively associated with improvement in HAM-A (r_spearman=0.62, p=0.03). These preliminary findings support hippocampal NAA and volume as neural biomarkers substantially associated with therapeutic response to a glutamatergic drug.     

Amygdala–Hippocampal Connectivity Changes During Acute Psychosocial Stress: Joint Effect of Early Life Stress and Oxytocin

Previous evidence shows that acute stress changes both amygdala activity and its connectivity with a distributed brain network. Early life stress (ELS), especially emotional abuse (EA), is associated with altered reactivity to psychosocial stress in adulthood and moderates or even reverses the stress-attenuating effect of oxytocin (OXT). The neural underpinnings of the interaction between ELS and OXT remain unclear, though. Therefore, we here investigate the joint effect of ELS and OXT on transient changes in amygdala-centered functional connectivity induced by acute psychosocial stress, using a double-blind, randomized, placebo-controlled, within-subject crossover design. Psychophysiological interaction analysis in the placebo session revealed stress-induced increases in functional connectivity between amygdala and medial prefrontal cortex, posterior cingulate cortex, putamen, caudate and thalamus. Regression analysis showed that EA was positively associated with stress-induced changes in connectivity between amygdala and hippocampus. Moreover, hierarchical linear regression showed that this positive association between EA and stress-induced amygdala–hippocampal connectivity was moderated after the administration of intranasal OXT. Amygdala–hippocampal connectivity in the OXT session correlated negatively with cortisol stress responses. Our findings suggest that altered amygdala-hippocampal functional connectivity during psychosocial stress may have a crucial role in the altered sensitivity to OXT effects in individuals who have experienced EA in their childhood.     

Abnormal Structure of Fear Circuitry in Pediatric Post-Traumatic Stress Disorder

Structural brain studies of adult post-traumatic stress disorder (PTSD) show reduced gray matter volume (GMV) in fear regulatory areas including the ventromedial prefrontal cortex (vmPFC) and hippocampus. Surprisingly, neither finding has been reported in pediatric PTSD. One possibility is that they represent age-dependent effects that are not fully apparent until adulthood. In addition, lower-resolution MRI and image processing in prior studies may have limited detection of such differences. Here we examine fear circuitry GMV, including age-related differences, using higher-resolution MRI in pediatric PTSD vs healthy youth. In a cross-sectional design, 3 T anatomical brain MRI was acquired in 27 medication-free youth with PTSD and 27 healthy non-traumatized youth of comparable age, sex, and IQ. Voxel-based morphometry was used to compare GMV in a priori regions including the medial prefrontal cortex and amygdala/hippocampus. Compared with healthy youth, PTSD youth had reduced GMV but no age-related differences in anterior vmPFC (BA 10/11, Z=4.5), which inversely correlated with PTSD duration. In contrast, although there was no overall group difference in hippocampal volume, a group × age interaction (Z=3.6) was present in the right anterior hippocampus. Here, age positively predicted hippocampal volume in healthy youth but negatively predicted volume in PTSD youth. Within the PTSD group, re-experiencing symptoms inversely correlated with subgenual anterior cingulate cortex (sgACC, Z=3.7) and right anterior hippocampus (Z=3.5) GMV. Pediatric PTSD is associated with abnormal structure of the vmPFC and age-related differences in the hippocampus, regions important in the extinction and contextual gating of fear. Reduced anterior vmPFC volume may confer impaired recovery from illness, consistent with its role in the allocation of attentional resources. In contrast, individual differences in sgACC volume were associated with re-experiencing symptoms, consistent with the role of the sgACC in fear extinction. The negative relationship between age and hippocampal volume in youth with PTSD may suggest an ongoing neurotoxic process over development, which further contributes to illness expression. Future studies employing a longitudinal design would be merited to further explore these possibilities.     

Stress-System Genes and Life Stress Predict Cortisol Levels and Amygdala and Hippocampal Volumes in Children

Depression has been linked to increased cortisol reactivity and differences in limbic brain volumes, yet the mechanisms underlying these alterations are unclear. One main hypothesis is that stress causes these effects. This is supported by animal studies showing that chronic stress or glucocorticoid administration can lead to alterations in hippocampal and amygdala structures. Relatedly, life stress is cited as one of the major risk factors for depression and candidate gene studies have related variation in stress-system genes to increased prevalence and severity of depression. The present study tested the hypothesis that genetic profile scores combining variance across 10 single nucleotide polymorphisms from four stress-system genes (CRHR1, NR3C2, NR3C1, and FKBP5) and early life stress would predict increases in cortisol levels during laboratory stressors in 120 preschool-age children (3–5 years old), as well as hippocampal and amygdala volumes assessed with MRI in these same children at school age (7–12 years old). We found that stress-system genetic profile scores positively predicted cortisol levels while the number of stressful/traumatic life events experienced by 3–5 years old negatively predicted cortisol levels. The interaction of genetic profile scores and early life stress predicted left hippocampal and left amygdala volumes. Cortisol partially mediated the effects of genetic variation and life stress on limbic brain volumes, particularly on left amygdala volume. These results suggest that stress-related genetic and early environmental factors contribute to variation in stress cortisol reactivity and limbic brain volumes in children, phenotypes associated with depression in adulthood.     

Differentiating the effect of antipsychotic medication and illness on brain volume reductions in first-episode psychosis: A Longitudinal,Randomised, Triple-blind,Placebo-controlled MRI Study

Changes in brain volume are a common finding in Magnetic Resonance Imaging (MRI) studies of people with psychosis and numerous longitudinal studies suggest that volume deficits progress with illness duration. However, a major unresolved question concerns whether these changes are driven by the underlying illness or represent iatrogenic effects of antipsychotic medication. In this study, 62 antipsychotic-naïve patients with first-episode psychosis (FEP) received either a second-generation antipsychotic (risperidone or paliperidone) or a placebo pill over a treatment period of 6 months. Both FEP groups received intensive psychosocial therapy. A healthy control group (n = 27) was also recruited. Structural MRI scans were obtained at baseline, 3 months and 12 months. Our primary aim was to differentiate illness-related brain volume changes from medication-related changes within the first 3 months of treatment. We secondarily investigated long-term effects at the 12-month timepoint. From baseline to 3 months, we observed a significant group x time interaction in the pallidum (p < 0.05 FWE-corrected), such that patients receiving antipsychotic medication showed increased volume, patients on placebo showed decreased volume, and healthy controls showed no change. Across the entire patient sample, a greater increase in pallidal grey matter volume over 3 months was associated with a greater reduction in symptom severity. Our findings indicate that psychotic illness and antipsychotic exposure exert distinct and spatially distributed effects on brain volume. Our results align with prior work in suggesting that the therapeutic efficacy of antipsychotic medications may be primarily mediated through their effects on the basal ganglia.Subject terms: Psychosis, Psychosis     

Effect of corticosteroids in the hippocampus on passive avoidance behavior in the rat

The site of action of corticosteroids in avoidance learning was investigated in 110 rats. Injection of cycloheximide, 30 min before one-trial training on a passive avoidance task suppressed corticosteroid secretion in response to footshock, and produced an avoidance deficit in a test 6 days later. However, an additional injection of hydrocortisone, either subcutaneously or intra-hippocampally within 5 min of training, restored the avoidance response in the test. Septal and hypothalamic injections of the hormone were ineffective in reversing the cycloheximide effect, whereas the effect of hormone injection into the amygdala was equivocal because of an increased level of activity. Corticosteroids secreted following an aversive experience appear to act upon the steroid-sensitive neurons in the hippocampus to influence the animal's later performance of passive avoidance response.     

The effects of sub-chronic administration of hydrocortisone on hormonal and psychological responses to L-tryptophan in normal male volunteers

RATIONALE: 5-Hydroxytryptamine(1A) (5-HT(1A)) receptor function has been shown to be attenuated by corticosteroid hormones in a variety of animal experimental paradigms. It has been suggested that this effect may be central to the pathophysiology of severe depressive illness in humans, a condition in which 5-HT(1A) receptor function is reduced and corticosteroid hormone levels are elevated. Evidence suggests that the hormonal response to L-tryptophan ( L-TRP) is mediated by 5-HT(1A) receptors. This response has been shown to be reduced following acute administration of hydrocortisone, and we hypothesised that sub-chronic administration of hydrocortisone would also blunt it. OBJECTIVES: To examine the effects of sub-chronic administration of hydrocortisone on hormonal and psychological responses to L-TRP infusion in healthy male subjects. To ascertain whether cortisol was exerting effects on prolactin release directly at the pituitary rather than via hypothalamic 5-HT(1A) receptors, a thyroid-releasing hormone (TRH) challenge test was performed. METHODS: Fourteen healthy male volunteers took part in a random-order, double-blind, placebo-controlled study, in which 20 mg hydrocortisone or placebo was administered twice daily for 7 days before infusion of L-TRP. A TRH challenge was administered to eight of the subjects following the L-TRP infusion. RESULTS: Pre-treatment with hydrocortisone significantly reduced the growth hormone (GH) and cortisol responses, but not the prolactin (PRL) response to the infusion. TRH administration caused a robust increase in PRL, but this response was not attenuated by hydrocortisone pre-treatment. The TSH response to TRH was blunted. There was no effect of pre-treatment on psychological responses to L-TRP. CONCLUSIONS: The attenuation in GH response following hydrocortisone pre-treatment could indicate a reduction in 5-HT(1A) receptor function, although it is probable that it is attributable to the action of hydrocortisone at the pituitary level. More precise, non-neuroendocrine models of 5-HT(1A) receptor function are necessary to clarify this.