Maria Strauß

Structural studies of the hypothalamus and its nuclei in mood disorders

A large body of evidence indicates that the hypothalamus is involved in pathogenetic mechanisms of mood disorders. It has been suggested that functional abnormalities of the hypothalamus are associated with structural hypothalamic changes. Structural neuroimaging allows in vivo investigation of the hypothalamus that may shed light on the underlying pathogenetic mechanisms of unipolar and bipolar disorder. Clearly, the detection of subtle structural cerebral changes depends on the limitations of the neuroimaging technique used. Making a comprehensive database search, we reviewed the literature on hypothalamic macrostructure in affective disorders, addressing the specific question of what structural magnetic resonance imaging might be expected to show. Studies with convincing methodology, although rare, suggest a global volume decrease in the hypothalamus in affective disorders, a decrease which is not shown by the two specific nuclei investigated, the paraventricular and supraoptic nuclei. We discuss the implications of these findings and provide directions for future research.

CSF-hypocretin-1 levels in patients with major depressive disorder compared to healthy controls.

Depressive patients exhibit symptoms of impaired regulation of wakefulness with hyperarousal and agitation as well as difficulties to falling asleep and preserving sleep continuity. Changes in hypocretin (hcrt) levels as polypeptides with impact on arousal and sleep-wake-regulation have been discussed in affective disorders but have not been investigated in patients with solely unipolar depression in comparison to healthy controls. In the present study, cerebrospinal fluid (CSF) levels of hcrt-1 for the first time were analyzed in patients with major depressive disorder (MDD) without psychiatric comorbidities and compared with levels in healthy controls. In 17 inpatients with MDD (mean Hamilton Depression Rating Scale 13.9 ± 7.4) and 10 healthy controls, CSF-hcrt-1 levels were measured using a fluorescence immunoassay (FIA). The mean hcrt-1 CSF levels in patients with MDD (74.3 ± 17.8pg/ml) did not differ compared to that of healthy controls (82.8 ± 22.1pg/ml). Hcrt-1 levels did not correlate with the severity of depressive episode, the symptoms of depression or the number of episodes. Although autonomic and neurohumoral signs of hyperarousal are common in MDD, hcrt-1 levels in CSF were not found to be altered in MDD compared to healthy controls. Whether hcrt-1 levels are altered in depressive patients exhibiting impaired vigilance regulation has to be investigated in further studies combining measures of CSF-hcrt-1 with electroencephalography.

Development and evaluation of an algorithm for the computer-assisted segmentation of the human hypothalamus on 7-Tesla magnetic resonance images.

Post mortem studies have shown volume changes of the hypothalamus in psychiatric patients. With 7T magnetic resonance imaging this effect can now be investigated in vivo in detail. To benefit from the sub-millimeter resolution requires an improved segmentation procedure. The traditional anatomical landmarks of the hypothalamus were refined using 7T T1-weighted magnetic resonance images. A detailed segmentation algorithm (unilateral hypothalamus) was developed for colour-coded, histogram-matched images, and evaluated in a sample of 10 subjects. Test-retest and inter-rater reliabilities were estimated in terms of intraclass-correlation coefficients (ICC) and Dices coefficient (DC). The computer-assisted segmentation algorithm ensured test-retest reliabilities of ICC≥.97 (DC≥96.8) and inter-rater reliabilities of ICC≥.94 (DC = 95.2). There were no significant volume differences between the segmentation runs, raters, and hemispheres. The estimated volumes of the hypothalamus lie within the range of previous histological and neuroimaging results. We present a computer-assisted algorithm for the manual segmentation of the human hypothalamus using T1-weighted 7T magnetic resonance imaging. Providing very high test-retest and inter-rater reliabilities, it outperforms former procedures established at 1.5T and 3T magnetic resonance images and thus can serve as a gold standard for future automated procedures.

Habenula volume increases with disease severity in unmedicated major depressive disorder as revealed by 7T MRI

The habenula is a paired epithalamic structure involved in the pathogenesis of major depressive disorder (MDD). Evidence comes from its impact on the regulation of serotonergic and dopaminergic neurons, the role in emotional processing and studies on animal models of depression. The present study investigated habenula volumes in 20 unmedicated and 20 medicated MDD patients and 20 healthy controls for the first time by applying a triplanar segmentation algorithm on 7 Tesla magnetic resonance (MR) whole-brain T1 maps. The hypothesis of a right-side decrease of habenula volumes in the MDD patients was tested, and the relationship between volumetric abnormalities and disease severity was exploratively investigated. Absolute and relative total and hemispheric habenula volumes did not differ significantly between the three groups. In the patients with short duration of disease for which medication effects could be ruled out, significant correlations were found between bilateral habenula volumes and HAMD-17- and BDI-II-related severities. In the medicated patients, this positive relationship disappeared. Our findings suggest an involvement of habenula pathology in the beginning of MDD, while general effects independent of severity or stage of disease did not occur. Our findings warrant future combined tractographic and functional investigation using ultra-high-resolution in vivo MR imaging.

Cerebrospinal fluid hypocretin-1 (orexin A) levels in mania compared to unipolar depression and healthy controls.

BACKGROUND Impairment of sleep-wake cycles and circadian rhythm are found in human narcolepsy which is characterized by deficiency of hypocretin (hcrt) or its receptors. A disturbed electroencephalography (EEG) based vigilance regulation is also found in affective disorders such as major depressive disorder (MDD) and mania. For the first time, in the present study hcrt levels were investigated in patients with a manic episode and compared with age-matched patients with MDD and controls. METHODS 15 subjects were enrolled in the study after admission to hospital: 5 manic (mean YMRS 15.6+/-2.9) and 5 age-matched patients with MDD (mean HDRS 11.6+/-8.0), and 5 age-matched controls without any neurological or psychiatric disorder. Cerebrospinal fluid (CSF) hcrt levels were measured in all three groups using a fluorescence immunoassay (FIA). RESULTS Mean hcrt-1 level in manic patients (77.3+/-20.7 pg/ml) did not differ significantly compared to patients with MDD (75.6+/-15.7 pg/ml MDD) or controls (74.9+/-19.3 pg/ml). Hcrt levels and severity of disease did not show a significant association. CONCLUSION In the present study, for the first time hcrt-1 levels in manic patients were investigated but did not reveal significant differences neither compared to age-matched patients with MDD nor healthy controls without any psychiatric or neurological disorder.

Fast versus slow onset of depressive episodes: a clinical criterion for subtyping patients with major depression.

PURPOSE The speed of onset of depressive episodes is a clinical aspect of affective disorders that has not been sufficiently investigated. Thus, we aimed to explore whether patients with fast onset of the full-blown depressive symptomatology (≤7 days) differ from those with slow onset (>7 days) with regard to demographic and clinical aspects. SUBJECTS AND METHODS Data were obtained within an observational study conducted in outpatients with major depression who were treated with duloxetine (30-120 mg/day). Onset of depression (without any preceding critical life event) was fast in 416 (less than one week) and slower in 2220 patients. RESULTS Compared to patients with slow onset, those with fast onset of depression had more suicide attempts in the previous 12 months (2.7% versus 1.3%, P=0.046) and less somatic comorbidity (61.7% versus 74.1%, P<0.0001). In addition, they were slightly younger at onset of depression (mean±SD 40.2±14.6 versus 42.8±14.2 years, P<0.001) and used analgesics at baseline significantly less frequently (22.8% versus 33.4%, P<0.0001). DISCUSSION AND CONCLUSION The speed of onset of depression has to be regarded as a relevant clinical characteristic in patients with unipolar depression.

Brain arousal regulation in adults with attention-deficit/hyperactivity disorder (ADHD)

The main aim of the current study was to test the hypothesis that adult patients with attention-deficit/hyperactivity disorder (ADHD) have less stable brain arousal regulation than healthy controls. We objectively assessed brain arousal regulation using the Vigilance Algorithm Leipzig (VIGALL 2.1) to analyze 15-min resting EEG data of thirty-three ADHD patients and thirty-five matched controls. Based on automatically classified 1-s segments we computed mean EEG-vigilance (indexing arousal level) and arousal stability score (indexing arousal regulation). Adult ADHD patients showed significantly lower arousal levels and significantly less stable brain arousal regulation than controls. Multiple regression analysis indicated that arousal regulation (i.e., arousal stability score) predicted the retrospectively-assessed severity of childhood ADHD symptoms, supporting the trait aspect of brain arousal regulation. Our findings support the arousal regulation model of ADHD, which interprets hyperactivity and sensation seeking as an autoregulatory reaction to an unstable regulation of brain arousal. EEG-based arousal parameters may be candidate biomarkers for adult ADHD.

The association between in vivo central noradrenaline transporter availability and trait impulsivity

The brain noradrenaline (NA) system, particularly NA transporters (NAT), are thought to play an important role in modulating impulsive behavior. Impaired impulsivity is implicated in a variety of neuropsychiatric conditions; however, an in vivo link between central NAT availability and human impulsivity has not been shown. Using positron emission tomography (PET) and S,S-[11C]O-methylreboxetine (MRB), we tested whether NAT availability is associated with this basic behavioral trait based on the Barratt Impulsiveness Scale (BIS-11) in twenty healthy individuals (12 females, 33.8±9.3, 21-52 years of age) with a body mass index (BMI) ranging from 21.7kg/m2 to 47.8kg/m2. Applying both voxel-wise and volume-of-interest (VOI) based analyses, we found that distribution volume ratios (DVR) used as PET outcome measures negatively correlated with BIS-11 total scores in the orbitofrontal cortex (OFC) and in the hippocampus as well as in parts of the cerebellar cortex. These associations however did not remain after correction for multiple testing. Thus, although it appears that low NAT availability is associated with greater scores of impaired behavioral control, this needs to be confirmed in a larger series of individuals with highly impulsive behavior.