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Abstract

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.

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... Such a large volume difference should be replicable in vivo with modern neuroimaging techniques. A systematic review of the literature on structural changes of the hypothalamus in MDD and BD found no evidence to the contrary (41). The exception was that volume reductions were not found by histological studies of the two hypothalamic nuclei studied so far (12,30,31). ...
... The volume loss of the hypothalamus in BD, observed postmortem (32), is supported by neuroimaging findings of a dilated third ventricle adjacent to the hypothalamus (41,(46)(47)(48). Interestingly, in BD, HPA axis hyperactivity is associated with manic and mixed states, but not the depressive state (5). ...
... We can reasonably reject two other explanations for the larger hypothalamus volumes in MDD and BD, relative to controls. Adult neurogenesis in the hypothalamus (77) or disrupted neuronal apoptosis during fetal development (70) would require a correlation between neuron numbers and hypothalamus volumes, which does not appear to be the case for candidate nuclei (41). ...
Article
Objective The purpose of this study was to determine, in vivo, whether the hypothalamus volume is reduced in patients with mood disorders. Methods The cross‐sectional study included 20 unmedicated (MDDu) and 20 medicated patients with major depressive disorder, 21 patients with bipolar disorder, and 23 controls. Twenty of the controls were matched to the MDDu. Seven Tesla, T1‐weighted magnetic resonance images were acquired and processed using methods specifically developed for high‐precision volumetry of the hypothalamus. Results An overall group difference was observed for the left hypothalamus volume corrected for intracranial volume. Planned contrasts identified that the left hypothalamus was approximately 5% larger in each patient group compared with the control group. A paired t‐test with the 20 matched pairs of MDDu and controls and without correction for covariates confirmed the larger left hypothalamus volume in MDDu. Conclusions Contrary to our expectations, the hypothalamus volume was increased in patients with uni‐ and bipolar affective disorders. The effect was left‐sided and independent of medication status or statistical correction for covariates. Supported by emerging evidence that the stress response may be related to structural and functional asymmetry in the brain, our finding suggests a crucial role of the hypothalamus in mood disorders.
... Major depressive disorder (MDD) is the leading global cause of years of health lost to disease in both men and women (WHO 2014), belongs to the most common mental disorders with lifetime prevalence of up to 20% ( Kessler et al. 2005 ) and shows high mortality rates of 10% ( Wulsin et al. 1999 ). Effort on the knowledge of the neurobiology and improvement in treatment effi ciency in MDD has led to the detection of various molecular and structural changes within the brain ( Kern et al. 2012 ;Sacher et al. 2012 ;Schindler et al. 2012 ;Lichtblau et al. 2013 ). Both neuronal and glial alterations are regarded to have pathogenic impact on the onset and course of the disorder ( Rajkowska 2000 ;Rajkowska and Stockmeier, 2013 ). ...
... Since neuronal loss is described for specifi c brain regions in MDD ( Sacher et al. 2012 ;Schindler et al. 2012 ) and NSE is found nearly ubiquitous throughout the brain, elevations of NSE in the CSF may result from a release from neuronal cytoplasms following neuronal cell death, as seen for stroke or haemorrhage ( B ö hmer et al. 2011 ;Ahmad et al. 2012 ). In contrast, since NSE was found to have neurotrophic and neuroprotective properties, elevations could, on the other hand, display or be part of a counter-regulation against neuronal depletion, the literature. ...
Article
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Objectives. Alterations in neuronal and glial integrity are considered to be of pathogenic impact on major depressive disorder (MDD). For MDD, data on cerebrospinal fluid (CSF) levels of neuron-specific enolase (NSE) are lacking and scarce for glial protein S100B. Methods. We measured CSF levels of NSE and S100B in 31 patients with MDD and 32 mentally healthy controls using electrochemiluminescence immunoassays (ECLIA). Results. Adjusted means of NSE were significantly elevated in the MDD patients (11.73 ng/ml (9.95-13.52 95% CI) compared to the controls (6.17 ng/ml (4.55-7.78), F = 9.037, P = 0.004. Effect size for adjusted mean group difference of 5.57 ng/ml was found invariably high (Cohen's d = 1.23). Differentiating MDD from controls, a NSE cut-off of 7.94 ng/ml showed sensitivity of 81% (95% CI 63.7-90.8) and specificity of 75% (95% CI 57.9-86.7). Adjusted levels of S100B did not differ significantly between the two groups (1.12 ng/ml (0.77-1.48) in MDD, 0.97 ng/ml (0.64-1.30) in controls). Conclusions. Our results of elevated CSF-NSE levels support neuronal pathology in MDD and the potential use of CSF-NSE as marker in clinical diagnostics. Missing group differences in S100B do not promote a specific glial pathology in depressive disorders.
... While, to the best of our knowledge, our study is the rst to explicitly report no volumetric differences in the HTH between autistic and non-autistic individuals, it should be noted that from a formal perspective whole-brain VBM is a method that does not depend on a prior spatial hypothesis, so that VBM studies in ASD that found no abnormalities in the HTH could be considered nonsigni cant results with respect to this structure. However, as previously pointed out by Schindler et al. (2012) [65], the sensitivity of VBM to changes in structures as small as the HTH depends largely on the hypothesisdependent parameter settings. Hence, a lack of discussion of the HTH in previous studies does not automatically imply a lack of effect in this region. ...
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Background Oxytocin (OXT) is known to modulate social behavior and cognition and has, thus, been expected to be a potential therapeutic agent for individuals with autism spectrum disorder (ASD). However, the underlying neurobiology is far from clear. For instance, relatively little is known about the association between OXT levels and brain structural differences in autistic people. An accumulating body of evidence indicates the hypothalamus to be of particular importance in this regard. Methods Here we used region of interest (ROI)- based voxel-based morphometry (VBM) approach to investigate hypothalamic gray matter volume (GMV) in autistic and non-autistic adults. T1-weighted MRI images were obtained from autistic adults without intellectual impairment (n = 29, age 36.03 ± 11.0) and matched non-autistic controls (n = 27, age 30.96 ± 11.2). Peripheral plasma OXT levels and the autism quotient for autistic traits were used for correlation analyses. Results GMV of the hypothalamus did not differ between groups. However, the groups showed significant differences in the link between hypothalamic GMV with peripheral OXT levels, such that a positive correlation was found for the ASD group. In addition, hypothalamic GMV showed a positive correlation with autistic traits in the ASD group, while no such correlation was observed in the comparison group. Limitations : The relatively small sample size and the wide age range of the participants warrant caution when interpreting the results. Results could be confounded by the use of various psychiatric medications among our autistic participants. At the same time, this adequately represents the adult autistic population in terms of a naturalistic study design. Conclusion The results provide new evidence for a potentially important role of the HTH in ASD and its relationship to the OXT system, but also point towards the importance of interindividual differences.
... More recently, optogenetic studies in animals clearly demonstrated that hypothalamic neurons can actively control socioemotional behavior such as fear and defensive responses [6][7][8][9][10]. Furthermore, hypothalamic peptides such as oxytocin and arginine-vasopressin have recently attracted great interest for their implications in typical and atypical socioemotional behavior [11][12][13][14][15][16][17]. A large number of controlled trials demonstrated that exogenous oxytocin or arginine-vasopressin administration can significantly influence human socioemotional responses. ...
Article
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There exist extensive animal research and lesion studies in humans demonstrating a tight association between the hypothalamus and socioemotional behavior. However, human neuroimaging literature in this direction is still rather limited. In order to reexamine the functional role of this region in regulating human social behavior, we here provided a synthesis of neuroimaging studies showing hypothalamic activation during affiliative, cooperative interactions, and in relation to ticklish laughter and humor. In addition, studies reporting involvement of the hypothalamus during aggressive and antisocial interactions were also considered. Our systematic review revealed a growing number of investigations demonstrating that the evolutionary conserved hypothalamic neural circuity is involved in multiple and diverse aspects of human socioemotional behavior. On the basis of the observed heterogeneity of hypothalamus-mediated socioemotional responses, we concluded that the hypothalamus might play an extended functional role for species survival and preservation, ranging from exploratory and approaching behaviors promoting social interactions to aggressive and avoidance responses protecting and defending the established social bonds.
... The second study by Pinilla [46], using an exploratory whole-brain voxel-wise analysis in healthy controls and patients with major depression, claimed to have found a significant volume decrease in the patient group with peak differences in the hypothalamus (coordinates (x, y, z) -6, 2, -9 in the left and 9, 2, -9 in the right hemisphere). A reanalysis of the data (reviewed in [52]), however, found the peak difference to lie in the white matter with the lentiform nucleus as the nearest gray matter structure. ...
Article
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The hypothalamus and its subdivisions are involved in many neuropsychiatric conditions such as affective disorders, schizophrenia, or narcolepsy, but parcellations of hypothalamic subnuclei have hitherto been feasible only with histological techniques in postmortem brains. In an attempt to map subdivisions of the hypothalamus in vivo, we analyzed the directionality information from high-resolution diffusion-weighted magnetic resonance images of healthy volunteers. We acquired T1-weighted and diffusion-weighted scans in ten healthy subjects at 3 T. In the T1-weighted images, we manually delineated an individual mask of the hypothalamus in each subject and computed in the co-registered diffusion-weighted images the similarity of the principal diffusion direction for each pair of mask voxels. By clustering the similarity matrix into three regions with a k-means algorithm, we obtained an anatomically coherent arrangement of subdivisions across hemispheres and subjects. In each hypothalamus mask, we found an anterior region with dorsoventral principal diffusion direction, a posteromedial region with rostro-caudal direction, and a lateral region with mediolateral direction. A comparative analysis with microstructural hypothalamus parcellations from the literature reveals that each of these regions corresponds to a specific group of hypothalamic subnuclei as defined in postmortem brains. This is to our best knowledge the first in vivo study that attempts a delineation of hypothalamic subdivisions by clustering diffusion-weighted magnetic resonance imaging data. When applied in a larger sample of neuropsychiatric patients, a structural analysis of hypothalamic subnuclei should contribute to a better understanding of the pathogenesis of neuropsychiatric conditions such as affective disorders.
... The second study by Pinilla [46], using an exploratory whole-brain voxel-wise analysis in healthy controls and patients with major depression, claimed to have found a significant volume decrease in the patient group with peak differences in the hypothalamus (coordinates (x, y, z) -6, 2, -9 in the left and 9, 2, -9 in the right hemisphere). A reanalysis of the data (reviewed in [52]), however, found the peak difference to lie in the white matter with the lentiform nucleus as the nearest gray matter structure. ...
Conference Paper
Introduction The hypothalamus is involved in many aspects of behavioral responses but parcellations of hypothalamic subnuclei have only been feasible in post-mortem brains. Thus it would be-from a clinical point of view-highly desirable if hypothalamic subnuclei could be delineated also noninvasively in living subjects. This study is a first step in this direction: We exploited the directionality information inherent in high-resolution DTI data to map subregions of the hypothalamus in healthy volunteers. directionality information using DTI data to map subregions of the hypothalamus. Methods We scanned 10 subjects with a Siemens 3 T scanner, acquired DTI and T1 scans. We computed the similarity of fiber orientations between all voxels and subjects, and clustered the similarity matrix in 3 regions using a k-means algorithm. Results The diffusion images showed anisotropic tissue orientation within the hypothalamus which was consistent across subjects. The clustering in 3 regions resulted in an anatomically coherent arrangement of clusters across hemispheres and subjects. In each ROI, we found an anterior, a posteromedial, and a lateral subdivision with consistent microscopic tissue orientations across subjects. Conclusion This is to our best knowledge the first study that demonstrates the fine-grained microstructural organization within the human hypothalamus noninvasively in living subjects.
... As a part of the limbic system it connects the cerebral cortex with the visceral system and hence is deemed a 'mediator between the mind and the body' – both affected in psychiatric diseases. Structural correlates have been described for example with mood disorders [1,2], schizophrenia [3,4], anxiety [5], borderline personality disorder [6], narcolepsy [7,8] , and frontotemporal dementia [9]. Since the hypothalamic region is less than 4 cm 3 in size, and hard to distinguish from its surroundings, submillimeter magnetic resonance imaging (MRI) is essential for its in vivo structural investigation. ...
Article
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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 Dice's 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.
... Further, rGMV of the hypothalamus is enlarged in patients with borderline personality disorders ( Kuhlmann et al. 2013), which are characterized by aggressiveness ( Látalová and Praško 2010). However, an association between the structure of the hypothalamus and mood disorders has also been shown (Turner and Schönknecht 2012). As for the findings regarding the precentral gyrus and postcentral gyrus, longitudinal neuroimaging pediatric studies have shown that developmental increases in motor skills are negatively correlated with changes in cortical thickness in the left precentral gyrus (children with a greater improvement in motor skills showed greater thinning of gray matter structures in the precentral gyrus) ( Lu et al. 2007). ...
Article
Television (TV) viewing is known to affect children's verbal abilities and other physical, cognitive, and emotional development in psychological studies. However, the brain structural development associated with TV viewing has never been investigated. Here we examined cross-sectional correlations between the duration of TV viewing and regional gray/white matter volume (rGMV/rWMV) among 133 boys and 143 girls as well as correlations between the duration of TV viewing and longitudinal changes that occurred a few years later among 111 boys and 105 girls. After correcting for confounding factors, we found positive effects of TV viewing on rGMV of the frontopolar and medial prefrontal areas in cross-sectional and longitudinal analyses, positive effects of TV viewing on rGMV/rWMV of areas of the visual cortex in cross-sectional analyses, and positive effects of TV viewing on rGMV of the hypothalamus/septum and sensorimotor areas in longitudinal analyses. We also confirmed negative effects of TV viewing on verbal intelligence quotient (IQ) in cross-sectional and longitudinal analyses. These anatomical correlates may be linked to previously known effects of TV viewing on verbal competence, aggression, and physical activity. In particular, the present results showed effects of TV viewing on the frontopolar area of the brain, which has been associated with intellectual abilities.
... Studies also differed notably in age-composition with mean-ages varying from #30 years [20,22,23,34] to .60 years [17,27]. The relevance of these clinical variables was demonstrated by a review of Schindler et al. [35] and meta-analyses of Lai et al. [6] and Bora et al. [3]. E.g., older age, male sex as well as the lack of medication was correlated with ACC gray matter deficits. ...
Article
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Background Major depressive disorder is a serious psychiatric illness with a highly variable and heterogeneous clinical course. Due to the lack of consistent data from previous studies, the study of morphometric changes in major depressive disorder is still a major point of research requiring additional studies. The aim of the study presented here was to characterize and quantify regional gray matter abnormalities in a large sample of clinically well-characterized patients with major depressive disorder. Methods For this study one-hundred thirty two patients with major depressive disorder and 132 age- and gender-matched healthy control participants were included, 35 with their first episode and 97 with recurrent depression. To analyse gray matter abnormalities, voxel-based morphometry (VBM8) was employed on T1 weighted MRI data. We performed whole-brain analyses as well as a region-of-interest approach on the hippocampal formation, anterior cingulate cortex and amygdala, correlating the number of depressive episodes. Results Compared to healthy control persons, patients showed a strong gray-matter reduction in the right anterior insula. In addition, region-of-interest analyses revealed significant gray-matter reductions in the hippocampal formation. The observed alterations were more severe in patients with recurrent depressive episodes than in patients with a first episode. The number of depressive episodes was negatively correlated with gray-matter volume in the right hippocampus and right amygdala. Conclusions The anterior insula gray matter structure appears to be strongly affected in major depressive disorder and might play an important role in the neurobiology of depression. The hippocampal and amygdala volume loss cumulating with the number of episodes might be explained either by repeated neurotoxic stress or alternatively by higher relapse rates in patients showing hippocampal atrophy.
... The hypothalamus is a highly compartmentalized structure consisting of clusters of functionally specialized cells (Schindler et al., 2012), each type of which could have diverse responses to TCDD. The tissue samples we analyzed are derived from the whole hypothalamus. ...
Article
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In some mammals, halogenated aromatic hydrocarbon (HAH) exposure causes wasting syndrome, defined as significant weight loss associated with lethal outcomes. The most potent HAH in causing wasting is 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD), which exerts its toxic effects through the aryl hydrocarbon receptor (AHR). Since TCDD toxicity is thought to predominantly arise from dysregulation of AHR-transcribed genes, it was hypothesized that wasting syndrome is a result of to TCDD-induced dysregulation of genes involved in regulation of food-intake. As the hypothalamus is the central nervous systems' regulatory center for food-intake and energy balance. Therefore, mRNA abundances in hypothalamic tissue from two rat strains with widely differing sensitivities to TCDD-induced wasting syndrome: TCDD-sensitive Long–Evans rats and TCDD-resistant Han/Wistar rats, 23 h after exposure to TCDD (100 μg/kg) or corn oil vehicle. TCDD exposure caused minimal transcriptional dysregulation in the hypothalamus, with only 6 genes significantly altered in Long–Evans rats and 15 genes in Han/Wistar rats. Two of the most dysregulated genes were Cyp1a1 and Nqo1, which are induced by TCDD across a wide range of tissues and are considered sensitive markers of TCDD exposure. The minimal response of the hypothalamic transcriptome to a lethal dose of TCDD at an early time-point suggests that the hypothalamus is not the predominant site of initial events leading to hypophagia and associated wasting. TCDD may affect feeding behaviour via events upstream or downstream of the hypothalamus, and further work is required to evaluate this at the level of individual hypothalamic nuclei and subregions.
... The second study by Pinilla [46], using an exploratory whole-brain voxel-wise analysis in healthy controls and patients with major depression, claimed to have found a significant volume decrease in the patient group with peak differences in the hypothalamus (coordinates (x, y, z)-6, 2,-9 in the left and 9, 2,-9 in the right hemisphere). A reanalysis of the data (reviewed in [52]), however, found the peak difference to lie in the white matter with the lentiform nucleus as the nearest gray matter structure. ...
... In general, the hypothalamus is considered a key brain site for the regulation of numerous homeostatic functions (Lechan and Toni, 2008). Many researchers have indicated clinical significance for hypothalamic dysfunction both developmentally and in adulthood (Schindler et al., 2012;Swaab 2004;Caqueret et al., 2005;Michaud, 2001). Interestingly, some evidence suggests that developmental analyses of human hypothalamic anatomy may provide better comparisons with other species (Koutcherov et al., 2002;. ...
Article
The involvement of key factors operating independently or in cooperation with others contributes to physical and physiological mechanisms to help engineer a vertebrate hypothalamus. The actions of these key factors influence developmental mechanisms including neurogenesis, cell migration, cell differentiation, cell death, axon guidance, and synaptogenesis. On a molecular level, there are several ways to categorize the actions of factors that drive brain development. These range from the actions of transcription factors in cell nuclei that regulate the expression of developmental genes, to external factors in the cellular environment that mediate interactions and cell placements, and to effector molecules that contribute to signaling from one cell to another. Sexual dimorphism is a hallmark of the vertebrate hypothalamus that may arise as a direct consequence of hormone actions or gene actions. These actions may work through any of the mechanisms outlined above. Given the arrangement of cells in groups within the hypothalamus, cell migration may be one particularly important target for early molecular actions that help build the bases for appropriate functions. Supplemental Videos: Video 4.1: http://goo.gl/mCyqY Video 4.2: http://goo.gl/9GrPZ Table of Contents: Acknowledgments / Introduction / Compartments in the Diencephalon / Building a Hypothalamus: Neurogenesis, Cell Survival, and Cell Death / Building a Hypothalamus: Cell Migration / The Long and Winding Road of GnRH Neuronal Migration / Formation of Cell Groups / Connectivity / Rebuilding the Hypothalamus / Conclusion / Bibliography / Author Biographies / Series of Related Interest
... The enhanced cell proliferation and increased numbers of nestin+ NPCs in the hypothalamus and habenula in response to chronic FLX treatment represent a potential mechanism whereby FLX could modulate the activity of these structures, an effect that could have important implications for depressionand anxiety-like behaviors. Interestingly, patients with major depression and bipolar disorder have been reported to exhibit smaller habenula volumes than healthy controls (Ranft et al., 2010;, as well as smaller hypothalamic volumes and/or larger third ventricles (Schindler et al., 2012). In addition, dysregulation of the hypothalamic-pituitary-adrenal axis is commonly observed in psychiatric populations (Pariante and Lightman, 2008). ...
Article
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Chronic treatment with antidepressants has been shown to enhance neurogenesis in the adult mammalian brain. Although this effect was initially reported to be restricted to the hippocampus, recent work has suggested that fluoxetine, a selective serotonin reuptake inhibitor, also promotes neurogenesis in the cortex. However, whether antidepressants target neural progenitor cells in other brain regions has not been examined. Here, we used BrdU labeling and immunohistochemistry with a transgenic mouse line in which nestin+ neural progenitor cells can be inducibly labeled with the fluorescent protein, Tomato, following tamoxifen administration. We investigated the effects of chronic fluoxetine on cell proliferation and nestin+ progenitor cells in periventricular areas in the medial hypothalamus and medial habenula, two brain areas involved in stress and anxiety responses. Our data provide the first in vivo evidence that fluoxetine promotes cell proliferation and neurogenesis and increases the mRNA levels of BDNF in the hypothalamus and habenula. By identifying novel cellular targets of fluoxetine, our results may provide new insight into the mechanisms underlying antidepressant responses. © The Author 2015. Published by Oxford University Press on behalf of CINP.
... This is because the technique to delineate the hypothalamus in MRI is not well established, likely due to difficulties in determining the anatomical borders of the hypothalamus. Nevertheless, a decrease in the hypothalamic volume using structural MRI has been shown in studies of individuals with schizophrenia, affective disorders, and in behavioralvariant frontotemporal dementia [31,32,33,34,35,36,37]. However, the variability of the estimated size of the hypothalamic volumes between studies is high, probably due to different methodological approaches, including discrepancies in defining the hypothalamic region. ...
Article
Huntington disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. Non-motor symptoms and signs such as psychiatric disturbances, sleep problems and metabolic dysfunction are part of the disease manifestation. These aspects may relate to changes in the hypothalamus, an area of the brain involved in the regulation of emotion, sleep and metabolism. Neuropathological and imaging studies using both voxel-based morphometry (VBM) of magnetic resonance imaging (MRI) as well as positron emission tomography (PET) have demonstrated pathological changes in the hypothalamic region during early stages in symptomatic HD. In this investigation, we aimed to establish a robust method for measurements of the hypothalamic volume in MRI in order to determine whether the hypothalamic dysfunction in HD is associated with the volume of this region. Using T1-weighted imaging, we describe a reproducible delineation procedure to estimate the hypothalamic volume which was based on the same landmarks used in histologically processed postmortem hypothalamic tissue. Participants included 36 prodromal HD (pre-HD), 33 symptomatic HD (symp-HD) and 33 control participants who underwent MRI scanning at baseline and 18 months follow-up as part of the IMAGE-HD study. We found no evidence of cross-sectional or longitudinal changes between groups in hypothalamic volume. Our results suggest that hypothalamic pathology in HD is not associated with volume changes.
... Major depressive disorder (MDD) is characterized by neuropsychological changes which suggest a dysregulation of different neurotransmitters (Werner and Coveñas, 2013). Hypothalamic neurotransmitter dysfunction as well as structural and functional disturbances in the hypothalamic-pituitary-adrenal-axis were supposed to have a major impact on the pathogenesis of depressive disorders (Swaab et al., 2005;Himmerich et al., 2007;Schindler et al., 2012;Savitz et al., 2013). ...
Article
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In preclinical studies, the hypothalamic polypeptide melanin-concentrating hormone (MCH) has been shown to be involved in depression-like behavior and modulations of MCH and MCH-receptors were proposed as potential new antidepressant drug targets. For the first time, MCH serum levels were explored in 30 patients with major depressive disorder (MDD) prior to (T1) and after 2 (T2) and 4 weeks (T3) of antidepressant treatment and in 30 age- and sex-matched healthy controls by applying a fluorescence immunoassay. Levels of MCH did not differ significantly between un-medicated patients (444.11±174.63pg/mL SD) and controls (450.68±210.03pg/mL SD). In MDD patients, MCH levels significantly decreased from T1 to T3 (F=4.663; p=0.013). Post-hoc analyses showed that these changes were limited to patients treated with mirtazapine but not escitalopram and female but not male patients. MCH-levels showed high correlations from T1 to T3 (r≥0.964, p<0.001) and were found to correlate significantly with parameters of sleep within the controls. Small sample size. No follow-up measures were performed within the control group. Our findings suggest peripheral MCH-levels not to be altered in depression but possibly reflecting depression-related state properties that can be modulated by sleep, medication and sex. Copyright © 2015 Elsevier B.V. All rights reserved.
... Through its multiple nuclei, the hypothalamus subserves many critical brain functions in coordinating endocrinal and autonomic activities that are important for human emotions and temper. Most findings on macrostructural abnormalities of the hypothalamus were based on postmortem studies, thus providing a 'retrospective perspective' [10], useful as a groundwork for MRI studies. Nonetheless, in-vivo research on the hypothalamus is still imperative, but the location and the relatively small size of the hypothalamus present methodological challenges for MRI [11]. ...
Article
The hypothalamus is a brain structure containing multiple nuclei that mediate essential behavioral, autonomic, and endocrine functions including oxytocin synthesis. Oxytocin is a neuropeptide linked to complex social cognition and behaviors necessary for an effective social interaction. Oxytocinergic system dysfunction has been linked to social deficits in autism spectrum disorders (ASD). Limited studies have been carried out on the hypothalamus because of its small size and methodological constraints in current technologies. This neuroimaging study examines hypothalamic atrophy in ASD in comparison with a typically developing population (a) by directly measuring gray matter (GM) density with a region-of-interest analysis using voxel-based morphometry in a homogenous sample of participants controlled for age and intelligence quotient; (b) for generalization, by measuring third ventricular volume, on the basis of its position bilaterally surrounded by the hypothalamus, using Freesurfer in a heterogeneous sample of participants. A voxel-based morphometry analysis of cerebrospinal fluid density on the first sample provides a link between GM density and third ventricle volume. Our results show decreased hypothalamic GM density and increased third ventricle volume in ASD compared with typically developing patients. Our findings provide neuroanatomical insights into social deficits in ASD within the hypothalamus that might be relevant for other psychiatric conditions.
... They observed that 4 months of androgen treatment in FtMs increased hypothalamus volume and decreased lateral and third ventricle volumes, whereas anti-androgen and estrogen therapy in MtFs had the opposite effect. Although interesting and promising, we refrained from performing an additional volumetric analysis of our data given the significant challenges and shortcomings of MRI investigations on hypothalamus volume in vivo (Schindler et al. 2012). First, ventricular dilation and volume changes of surrounding structures may affect the reliability of hypothalamus volume measurements (Hulshoff-Pol et al. 2006). ...
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Diffusion-weighted imaging (DWI) is used to measure gray matter tissue density and white matter fiber organization/directionality. Recent studies show that DWI also allows for assessing neuroplastic adaptations in the human hypothalamus. To this end, we investigated a potential influence of testosterone replacement therapy on hypothalamic microstructure in female-to-male (FtM) transgender individuals. 25 FtMs were measured at baseline, 4 weeks, and 4 months past treatment start and compared to 25 female and male controls. Our results show androgenization-related reductions in mean diffusivity in the lateral hypothalamus. Significant reductions were observed unilaterally after 1 month and bilaterally after 4 months of testosterone treatment. Moreover, treatment induced increases in free androgen index and bioavailable testosterone were significantly associated with the magnitude of reductions in mean diffusivity. These findings imply microstructural plasticity and potentially related changes in neural activity by testosterone in the adult human hypothalamus and suggest that testosterone replacement therapy in FtMs changes hypothalamic microstructure towards male proportions.
... Although there are no reports of SCN structural abnormalities in mood disorders, there is evidence of reduced hypothalamic volume and dilation of the third ventricle in mood disorders [104,105]. Furthermore, some neuroanatomical differences have been found in direct targets of the SCN. Several studies showed alterations in the size and function of the PVN in subjects with mood disorders [106][107][108][109][110]. Functionally, the SCN to PVN circuit is important for the control of pituitary hormones and melatonin secretion from the pineal gland (as reviewed in [111]). ...
Article
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Circadian rhythm disturbances are a common symptom among individuals with mood disorders. The suprachiasmatic nucleus (SCN), in the ventral part of the anterior hypothalamus, orchestrates physiological and behavioral circadian rhythms. The SCN consists of self-sustaining oscillators and receives photic and nonphotic cues, which entrain the SCN to the external environment. In turn, through synaptic and hormonal mechanisms, the SCN can drive and synchronize circadian rhythms in extra-SCN brain regions and peripheral tissues. Thus, genetic or environmental perturbations of SCN rhythms could disrupt brain regions more closely related to mood regulation and cause mood disturbances. Here, we review clinical and preclinical studies that provide evidence both for and against a causal role for the SCN in mood disorders.
... Therefore, an influence of sex steroid hormones on hypothalamic structure could be assumed. Furthermore, it has been found that hypothalamic volumes show variations in affective disorders (Schindler et al., 2012;Schindler et al., 2019). Mood disorders are known to have different prevalence rates in males and females, which in part might be influenced by hormones (Salk et al., 2017). ...
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Sex steroid hormones influence hypothalamic micro- and macrostructure in humans and animal models. Neuroimaging studies have suggested that estrogen and anti-androgen treatment decreases volumes of multiple cortical and subcortical brain areas in transgender individuals, including total hypothalamus volume. Here, we aim to further explore potential effects of gender-affirming hormone treatment (GHT) in transgender individuals on hypothalamic volume by providing additional information on hypothalamic subfields. 38 transgender men (TM) and 15 transgender women (TW), with gender dysphoria (DSM-5), as well as 32 cisgender women (CW) and 21 cisgender men (CM) underwent two magnetic resonance imaging (MRI) measurements with an interval of at least four months (median interval TM= 134.5 days (interquartile range (IQR): 126-152.25); TW= 149 days (IQR: 126-178.5); CW= 147 days (IQR: 139.75-170.5); CM= 146 days (IQR: 132-247)) between both sessions. In transgender individuals GHT, consisting of estrogen and anti-androgen treatment in TW and testosterone treatment in TM, was initiated directly after the first measurement. To assess how GHT interacts with hypothalamic structures, the hypothalamus and its subunits were segmented using FreeSurfer. Subject group x time interaction effects were evaluated using repeated measures ANCOVA models. The Bonferroni method was used to correct for multiple comparisons. Significant decreases of total hypothalamic volume and associated subunits were detected in TW after estrogen and anti-androgen treatment compared to cisgender groups. Effects were found in the total hypothalamus volume (p corr = 0.001), the left and right hypothalamus (p corr = 0.002), the inferior tubular subunit bilaterally (right: p corr = 0.001; left: p corr = 0.001), the left superior tubular subunit (p corr = 0.003) the right anterior inferior subunit (p corr = 0.002), as well as the right anterior superior subunit (p corr = 0.0002) of the hypothalamus. Here, we observed significant volumetric effects on the adult human hypothalamus after an interval of at least four months of estrogen and anti-androgen treatment in TW and added knowledge on associated subfields. Further studies investigating influences of sex steroid hormones on brain structure and functional connections are still needed.
... Pre-post changes in the thalamus and negative associations between the hypothalamus and brainstem and mood were also observed, suggesting that lower metabolic function was associated with endorsement of higher levels of depression, irritability, and anxiety. While the role of the hypothalamus in integrating limbic functions is well characterized [54], the association with more subtle changes in self-endorsed mood has not been previously reported. Testosterone has been shown to have an anxiolytic effect in animals, and our results suggest a connection between the hypothalamus and mood symptoms. ...
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Objective: Androgen deprivation therapy (ADT) is a common treatment option for men with biochemical relapse from prostate cancer. ADT is associated with changes in mood, cognition, and quality of life, and most recently with increased risk for Alzheimer's disease (AD). This study examined changes in brain metabolism using positron emission tomography (PET) in men undergoing intermittent ADT. Methods: Nine men with prostate cancer and a rising PSA (biochemical recurrence) without evidence of metastases were treated with intermittent ADT consisting of 9 months of complete androgen blockade achieved with combined leuprolide acetate and flutamide. Patients underwent resting [Fuorine-18] fluorodeoxyglucose PET (18F-FDGPET) at baseline (before treatment) and again after 9 months of ADT. Results: Whole-brain mapping analysis after 9 months of androgen deprivation compared to pretreatment baseline revealed decreased regional cerebral glucose metabolism in the cerebellum, posterior cingulate, and medial thalamus bilaterally. Associations of brain metabolism with measurements of cognition and mood while on androgen deprivation revealed positive correlations between the posterior cingulate, left inferior parietal lobule (BA40), and left mid temporal gyrus (BA39) and spatial reasoning and a negative correlation between left inferior parietal lobule and verbal memory. Several mood indices were negatively correlated with hypothalamus and brainstem. Conclusion: These findings suggest that complete androgen deprivation may result in changes in regional brain metabolism associated with variation in mood, verbal memory, and spatial performance. Brain regions that were impacted from ADT are similar and overlap with brain regions with metabolic decline found in early AD and diabetes, suggesting possible common mechanisms.
... In vivo studies yielded conflicting results. While Dupont et al. (1995) reported normal hypothalamus volumes in MDD, Pinilla (2009) did find reductions in depression (reviewed in Schindler et al. 2012). Concerning hypothalamic nuclei, it has been found that PVN, SON and SCN volumes are normal (Bernstein et al. 1998a(Bernstein et al. , 2005a(Bernstein et al. , b, 2017b, while MB volume reductions were found in MDD (Bernstein et al. 2012a, b). ...
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The past decades have witnessed an explosion of knowledge on brain structural abnormalities in schizophrenia and depression. Focusing on the hypothalamus, we try to show how postmortem brain microscopy has contributed to our understanding of mental disease-related pathologic alterations of this brain region. Gross anatomical abnormalities (volume changes of the third ventricle, the hypothalamus, and its nuclei) and alterations at the cellular level (loss of neurons, increased or decreased expression of hypothalamic peptides such as oxytocin, vasopressin, corticotropin-releasing hormone, and other regulatory factors as well as of enzymes involved in neurotransmitter and neuropeptide metabolism) have been reported in schizophrenia and/or depression. While histologic research has mainly concentrated on neurons, little is currently known about the impact of non-neuronal cells for hypothalamus pathology in mental disorders. Their study would be a rewarding task for the future.
... pain, sweating, and temperature sensation) [25]. The hypothalamus is a limbic structure responsible for the production of many hormones which thermoregulation and other functions in a human body [26,27]. Results of RSFC analysis between the hypothalamus and insula propose the possibility that the two regions are involved in the brain-endocrine interaction through a shared neural circuit, such as cortical-limbic system [28], and the hypothalamus mediates the functional changes induced by the insular in MDD patients [29]. ...
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The hypothalamus is a limbic structure involved in the emergence and persistence of major depressive disorder symptoms. Previous studies have indicated that major depressive disorder patients exhibited dysregulation between the hypothalamus and cerebral regions. However, it is still unclear about the exact hypothalamic functional connectivity patterns with other brain regions based on resting-state functional MRI in major depressive disorder. Here, we investigated the whole-brain voxel-based hypothalamic resting-state functional connectivity in 55 patients with major depressive disorder and 40 age sex-matched healthy controls. The results showed that major depressive disorder patients had a significant decrease in resting-state functional connectivity of the bilateral hypothalamus with the right insula, superior temporal gyrus, inferior frontal gyrus, and Rolandic operculum compared with healthy controls. This study suggests that the pathophysiology of major depressive disorder might be associated with the abnormal hypothalamic resting-state functional connectivity.
... Our finding that hypothalamus volume was related to a psychobehavioral construct (ie. caregiving style) has some foundation in previous research, which has linked structural differences in the hypothalamus to brain function and behavior. Multiple studies showed differences in hypothalamus volume for individuals with a mood disorder as opposed to healthy controls (Schindler et al., 2018; also see Schindler et al., 2012 for an overview). Furthermore, cellular-level structural changes in the hypothalamus were linked to differences in hypothalamus function, (Hatton, 1997) lending credibility to the idea that structural differences detectable via MRI (such as volume) may underly functional changes which, in turn, could promote differential behavioral phenotypes in constructs such as caregiving style. ...
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Most studies on mammalian caregiving and attachment have focused on the mother-child relationship, particularly in humans. Yet, changing societal roles of male caregivers have highlighted the necessity for research with fathers. In this study, we examined the volume of the hypothalamus, an important subcortical brain area for caregiving and attachment, in a sample of N=50 fathering (child age 5-6 years) and N=45 nonfathering men using a novel technique to identify the human hypothalamus in 3T MRI. Furthermore, we employed three self-report measures to assess interindividual differences in adult attachment style across all men and caregiving beliefs in fathers. While we did not observe any significant difference in hypothalamus volume between fathers and non-fathers or associations between hypothalamus volume and self-reported adult attachment style across all men, self-reported caregiving beliefs were positively related to total hypothalamus volume in fathers. A follow-up analysis showed that fathers’ self-reported belief that a father’s role is important to child development was specifically related to tuberal hypothalamus volume, while self-reported enjoyment of spending time with the child was not associated with volume in hypothalamus sub-regions. Together, these findings suggest that interindividual variability in self reported caregiving beliefs in fathers is related to brain structure, warranting further research.
... Despite this and its central role in stress regulation, the hypothalamus is not studied often volumetrically in MDD due to its amorphous, heterogeneous structure leading to difficulty in segmentation. A few studies have examined group differences in volume in both in vivo and post-mortem contexts that were discrepant due to methodological limitations (Schindler et al., 2012). Post-mortem studies (using the same patient sample) found bilaterally smaller volumes of the hypothalamus in MDD (Bielau et al., 2005;Bernstein et al., 2012). ...
Article
Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is considered one of the mechanisms underlying the development of major depressive disorder (MDD), but the exact nature of this dysfunction is unknown. We investigated the relationship between hypothalamus volume (HV) and blood-derived DNA methylation in MDD. We obtained brain MRI, clinical and molecular data from 181 unmedicated MDD and 90 healthy control (HC) participants. MDD participants received a 16-week standardized antidepressant treatment protocol, as part of the first Canadian Biomarker Integration Network in Depression (CAN-BIND) study. We collected bilateral HV measures via manual segmentation by two independent raters. DNA methylation and RNA sequencing were performed for three key HPA axis-regulating genes coding for the corticotropin-binding protein (CRHBP), glucocorticoid receptor (NR3C1) and FK506 binding protein 5 (FKBP5). We used elastic net regression to perform variable selection and assess predictive ability of methylation variables on HV. Left HV was negatively associated with duration of current episode (ρ = -0.17, p = 0.035). We did not observe significant differences in HV between MDD and HC or any associations between HV and treatment response at weeks 8 or 16, overall depression severity, illness duration or childhood maltreatment. We also did not observe any differentially methylated CpG sites between MDD and HC groups. After assessing functionality by correlating methylation levels with RNA expression of the respective genes, we observed that the number of functionally relevant CpG sites differed between MDD and HC groups in FKBP5 (χ2 = 77.25, p < 0.0001) and NR3C1 (χ2 = 7.29, p = 0.007). Cross-referencing functionally relevant CpG sites to those that were highly ranked in predicting HV in elastic net modeling identified one site from FKBP5 (cg03591753) and one from NR3C1 (cg20728768) within the MDD group. Stronger associations between DNA methylation, gene expression and HV in MDD suggest a novel putative molecular pathway of stress-related sensitivity in depression. Future studies should consider utilizing the epigenome and ultra-high field MR data which would allow the investigation of HV sub-fields.
... The current research considers the hypothalamo-pituitaryadrenal (HPA) axis, which mediates stress responses, one major pathway for depressive symptomatology (Schindler et al., 2012). HPA axis activity is governed by the secretion of adrenocorticotropic hormone-releasing factor (CRF) and vasopressin (AVP) from the hypothalamus, which, in turn, activates the secretion of adrenocorticotropic hormone (ACTH) from the pituitary, which ultimately stimulates the secretion of glucocorticoids from the adrenal cortex (Nemeroff, 1996). ...
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Hypothalamic communication with the rest of the brain is critical for accomplishing a wide variety of physiological and psychological functions, including the maintenance of neuroendocrine circadian rhythms and the management of affective processes. Evidence has shown that major depressive disorder (MDD) patients exhibit increased functioning of the hypothalamic-pituitary-adrenal (HPA) axis. Neurofibrillary tangles are also found in the hypothalamus of Alzheimer’s disease (AD) patients, and AD patients exhibit abnormal changes in the HPA. However, little is known of how the hypothalamus interacts with other brain regions in AD patients with depression (D-AD). Functional connectivity (FC) analysis explores the connectivity between brain regions that share functional properties. Here, we used resting-state (rs) magnetic resonance imaging (MRI) technology and the FC method to measure hypothalamic connectivity across the whole brain in 22 D-AD patients and 21 non-depressed AD patients (nD-AD). Our results showed that D-AD patients had reduced FC among the hypothalamus, the right middle temporal gyrus (MTG) and the right superior temporal gyrus (STG) compared with the FC of nD-AD patients, suggesting that the abnormal FC between the hypothalamus and the temporal lobe may play a key role in the pathophysiology of depression in AD patients.
... During the formation periods of alcohol preference, the following regions were involved: NAc, OT, VTA, IC, Hypo, SNC, Au, DB, Hipp, VLPO, and THA. Among these changes, several different systems were included, such as addiction and reward association (NAc, IC, OT, VTA, Hypo) [28][29][30][31], mood regulation (Hypo, DB, IC, AU, Tha) [32][33][34], wake-sleep cycles (VLPO, DB, SNC, Hypo) [35], memory (Hipp, DB, IC) [36,37], and motor activity (SNC, DB, VLPO, Tha) [38][39][40][41]. ...
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Alcohol addiction is regarded as a series of dynamic changes to neural circuitries. A comparison of the global network during different stages of alcohol addiction could provide an efficient way to understand the neurobiological basis of addiction. Two animal models (P-rats screened from an alcohol preference family, and NP-rats screened from an alcohol non-preference family) were trained for alcohol preference with a two-bottle free choice method for 4 weeks. To examine the changes in the neural response to alcohol during the development of alcohol preference and acute stimulation, different trials were studied with resting-state fMRI methods during different periods of alcohol preference. The correlation coefficients of 28 regions in the whole brain were calculated, and the results were compared for alcohol preference related to the genetic background/training association. The variety of coherence patterns was highly related to the state and development of alcohol preference. We observed significant special brain connectivity changes during alcohol preference in P-rats. The comparison between the P- and NP-rats highlighted the role of genetic background in alcohol preference. The results of this study support the alterations of the neural network connection during the formation of alcohol preference and confirm that alcohol preference is highly related to the genetic background. This study could provide an effective approach for understanding the neurobiological basis of alcohol addiction.
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The proposed pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) mainly includes ischemia and neuroinflammation mechanisms. Protein encoded by Proteoglycan 2 (PRG2) mRNA is involved in the immune process related to eosinophils, also being found in the placenta and peripheral blood of pregnant women. We evaluated the correlation between PRG2 and NPSLE for the first time and found that PRG2 protein is overexpressed in the serum of patients with NPSLE and correlated with the SLE disease activity index (SLEDAI) subset scores of psychosis. Moreover, we investigated the correlation between hippocampal PRG2 level and hippocampally dependent learning and memory ability in MRL/lpr mice, and discovered that the number of PRG2⁺GFAP⁺ astrocytes in the cortex and hypothalamus and the number of PRG2⁺IBA-1⁺ microglia in the hippocampus and cortex significantly increased in the MRL/lpr mice. These data provided a reference for the follow-up exploration of the role of PRG2 in SLE or other diseases.
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This paper presents a computational framework for whole brain segmentation of 7 Tesla magnetic resonance images able to handle ultra-high resolution data. The approach combines multi-object topology-preserving deformable models with shape and intensity atlases to encode prior anatomical knowledge in a computationally efficient algorithm. Experimental validation on simulated and real brain images shows accuracy and robustness of the method and demonstrates the benefits of an increased processing resolution.
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Background: Morphometric studies demonstrated wide-ranging distribution of brain structural abnormalities in major depressive disorder (MDD). Objective: This study explored the progressive gray matter volume (GMV) changes pattern of structural network in 108 MDD patients throughout the illness duration by using voxel-based morphometric analysis. Methods: The causal structural covariance network method was applied to map the causal effects of GMV alterations between the original source of structural changes and other brain regions as the illness duration prolonged in MDD. This was carried out by utilizing the Granger causality analysis to T1-weighted data ranked based on the disease progression information. Results: With greater illness duration, the GMV reduction was originated from the right insula and progressed to the frontal lobe, and then expanded to the occipital lobe, temporal lobe, dorsal striatum (putamen and caudate) and the cerebellum. Importantly, results revealed that the right insula was the prominent node projecting positive causal influences (i.e., GMV decrease) to frontal lobe, temporal lobe, postcentral gyrus, putamen, and precuneus. While opposite causal effects were detected from the right insula to the angular, parahippocampus, supramarginal gyrus and cerebellum. Conclusions: This work may provide further information and vital evidence showing that MDD is associated with progressive brain structural alterations.
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Emerging evidence suggests that the nervous system is involved in tumor development in the periphery, however, the role of central nervous system remains largely unknown. Here, by combining genetic, chemogenetic, pharmacological and electrophysiological approaches, we show that hypothalamic oxytocin (Oxt)-producing neurons modulate colitis-associated cancer (CAC) progression in mice. Depletion or activation of Oxt neurons could augment or suppress CAC progression. Importantly, brain treatment with celastrol, a pentacyclic triterpenoid, excites Oxt neurons and inhibits CAC progression, and this anti-tumor effect was significantly attenuated in Oxt neuron-lesioned mice. Furthermore, brain treatment with celastrol suppresses sympathetic neuronal activity in the celiac-superior mesenteric ganglion (CG-SMG), and activation of β2 adrenergic receptor abolishes the anti-tumor effect of Oxt neuron activation or centrally administered celastrol. Taken together, these findings demonstrate that hypothalamic Oxt neurons regulate CAC progression by modulating the neuronal activity in the CG-SMG. Stimulation of Oxt neurons using chemicals, eg. celastrol, might be a novel strategy for colorectal cancer treatment.
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In recent years, the hypothalamus, amygdala and hippocampus have attracted increased interest with regard to the effects of stress on neurobiological systems in individuals with depression and suicidal behaviour. A large body of evidence indicates that these subcortical regions are involved in the pathogenetic mechanisms of mood disorders and suicide. The current neuroimaging techniques inadequately resolve the structural components of small and complex brain structures. In previous studies, our group was able to demonstrate a structural and neuronal pathology in mood disorders. However, the impact of suicide remains unclear. In the current study we used volumetric measurements of serial post-mortem sections with combined Nissl-myelin staining to investigate the hypothalamus, amygdala and hippocampus in suicide victims with mood disorders (n = 11), non-suicidal mood disorder patients (n = 9) and control subjects (n = 23).Comparisons between the groups by using an ANCOVA showed a significant overall difference for the hypothalamus(p = 0.001) with reduced volumes in non-suicidal patients compared to suicide victims (p = 0.018) and controls (p = 0.006). To our surprise, the volumes between the suicide victims and controls did not differ significantly. For the amygdala and hippocampus no volume changes between the groups could be detected (all p values were n. s.). In conclusion our data suggest a structural hypothalamic pathology in non-suicidal mood disorder patients. The detected differences between suicidal and non-suicidal patients suggest that suicidal performances might be related to the degree of structural deficits.
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Advert for Cogent Psychology Publish your Policy Brief rapidly today and inspire change for tomorrow. Banner advert for Australian Journal of Psychology, now open access Full Article Figures & data References Citations Metrics Reprints & Permissions Get access Accepted author version Abstract Most studies on mammalian caregiving and attachment have focused on the mother-child relationship, particularly in humans. Yet, changing societal roles of male caregivers have highlighted the necessity for research with fathers. In this study, we examined the volume of the hypothalamus, an important subcortical brain area for caregiving and attachment, in a sample of N=50 fathering (child age 5-6 years) and N=45 non-fathering men using a novel technique to identify the human hypothalamus in 3T MRI. Furthermore, we employed three self-report measures to assess interindividual differences in adult attachment style across all men and caregiving beliefs in fathers. While we did not observe any significant difference in hypothalamus volume between fathers and non-fathers or associations between hypothalamus volume and self-reported adult attachment style across all men, self-reported caregiving beliefs were positively related to total hypothalamus volume in fathers. A follow-up analysis showed that fathers’ self-reported belief that a father’s role is important to child development was specifically related to tuberal hypothalamus volume, while self-reported enjoyment of spending time with the child was not associated with volume in hypothalamus sub-regions. Together, these findings suggest that interindividual variability in self-reported caregiving beliefs in fathers is related to brain structure, warranting further research.
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Approximately 45 million people worldwide are diagnosed with bipolar disorder (BD). While there are many known risk factors and models of the pathologic processes influencing BD, the exact neurologic underpinnings of BD are unknown. We attempt to integrate the existing literature and create a unifying hypothesis regarding the pathophysiology of BD with the hope that a concrete model may potentially facilitate more specific diagnosis, prevention, and treatment of BD in the future. We hypothesize that dysfunctional signaling from the parvocellular neurons of the paraventricular hypothalamic nucleus (PVN) results in the clinical presentation of BD. Functional damage to this nucleus and its signaling pathways may be mediated by myriad factors (e.g. immune dysregulation and auto-immune processes, polygenetic variation, dysfunctional interhemispheric connections, and impaired or overactivated hypothalamic axes) which could help explain the wide variety of clinical presentations along the BD spectrum. The neurons of the PVN regulate ultradian rhythms, which are observed in cyclic variations in healthy individuals, and mediate changes in functional hemispheric lateralization. Theoretically, dysfunctional PVN signaling results in prolonged functional hemispheric dominance. In this model, prolonged right hemispheric dominance leads to depressive symptoms, whereas left hemispheric dominance correlated to the clinical picture of mania. Subsequently, physiologic processes that increase signaling through the PVN (hypothalamic-pituitaryadrenal axis, hypothalamic- pituitary-gonadal axis, and hypothalamic-pituitary-thyroid axis activity, suprachiasmatic nucleus pathways) as well as, neuro-endocrine induced excito-toxicity, auto-immune and inflammatory flairs may induce mood episodes in susceptible individuals. Potentially, ultradian rhythms slowing with age, in combination with changes in hypothalamic axes and maturation of neural circuitry, accounts for BD clinically presenting more frequently in young adulthood than later in life.
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Diurnal preference (morningness-eveningness) is known to be associated with several individual characteristics that are important in the fields of sociology, education, and psychiatry. Despite this importance, the anatomical correlates of individual differences in morningness-eveningness are unknown, and these were investigated in the present study. We used voxel-based morphometry and a questionnaire to determine individual morningness-eveningness and its association with brain structures in 432 healthy men and 344 healthy women (age, 20.7 ± 1.8 years). We demonstrated that morningness (less eveningness) was associated with (a) lower regional gray matter density (rGMD) in the precuneus and adjacent areas, (b) lower rGMD in the left posterior parietal cortex and adjacent areas, and (c) higher rGMD in the bilateral orbitofrontal cortex. Further, our exploratory analyses revealed that (d) higher rGMD in hypothalamic areas around the bilateral suprachiasmatic nuclei was associated with morningness. These findings demonstrate that variations in morningness-eveningness reflect the GM structures of focal regions across the cortex, and suggest a structural basis for individual morningness-eveningness and its association with a wide range of psychological variables distributed across different GM areas of the brain. Copyright © 2015. Published by Elsevier Inc.
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Sibling and friend relationships have significant impact on socio-emotional development. Hypothalamic supraoptic nucleus (SON) and paraventricular nucleus (PVN) are viable candidates in the formation and maintenance of these relationships through the synthesis and secretion of neuropeptides associated with attachment behaviors, including oxytocin. Here, using fMRI, we investigate the implication of these two hypothalamic nuclei in the processing of personally known faces. Faces of same-sex sibling, best friend, celebrity and unknown person appear in the middle of the screen while participants perform a task requiring a button click each time a central white dot turns red. Ratings of familiarity (time spent together) and emotionality (feelings toward individual) towards the four individuals are recorded. Local activation within the hypothalamus is assessed via two complementary methods: 1) Voxel-based analyses within inclusive mask of the hypothalamus; 2) Region-of-interest (ROI) analysis of partial hypothalamic volumes using SON and PVN as center of mass coordinates, with percent signal change (PSC) extracted and analyzed within these ROIs. Results suggest that the SON responds to all familiar individuals while the PVN has increased response to sibling compared to friend faces, and is correlated to familiarity but not emotionality. These findings support differential involvement of local hypothalamic substructures SON and PVN in response to faces of individuals with different social relationships.
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Mammillary bodies are relay nuclei within limbic and extralimbic connections. Whereas other subcortical brain structures have been found to be altered in depression, no current information exists regarding the pathomorphology of mammillary bodies in affective disorders. We studied the postmortem brains of 19 human subjects with mood disorders (9 with major depressive disorder and 10 with bipolar I disorder) and 20 control individuals and assessed the mammillary body and fornix volumes, number of neurons and neuronal densities. We found that male control subjects have significantly larger mammillary bodies compared with females. In addition, control subjects of both sexes with the diagnosis/cause of death of "heart failure/insufficiency" had significantly smaller mammillary body volumes compared with non-psychiatric patients who died from other causes. When estimating the mammillary bodies volumes of patients with depression compared with control subjects, a significant reduction of the left mammillary body volume was found in patients with bipolar disorder, but not in patients with major depression. However, significant depression-associated mammillary body volume reductions were found between the control subjects who did not die of heart failure and patients with major depression and bipolar disorder. Moreover, the MB volumes of control subjects who died of heart failure were in the range exhibited by subjects with depression. There was no significant influence of suicidal behavior on mammillary volumes observed. Moreover, no significant group differences in the total neuronal number or neuronal density were found between the controls, subjects with major depression and subjects with bipolar disorder. Furthermore, the fornix volumes were significantly reduced only in the control subjects with heart failure. Taken together, these results show that the mammillary bodies are compromised in depression.
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Behavioral-variant frontotemporal dementia (bvFTD) is a progressive neurodegenerative brain disorder, clinically characterized by changes in cognition, personality, and behavior. Marked disturbances in eating behavior, such as overeating and preference for sweet foods, are also commonly reported. The hypothalamus plays a critical role in feeding regulation, yet the relation between pathology in this region and eating behavior in FTD is unknown. This study aimed to address this issue using 2 complementary approaches. First, 18 early stage bvFTD patients and 16 healthy controls underwent high-resolution structural magnetic resonance imaging and assessment of eating behavior. Hypothalamic volumes were traced manually on coronal images. Second, postmortem analyses of 12 bvFTD cases and 6 matched controls were performed. Fixed hypothalamic tissue sections were stained for a cell marker and for peptides regulating feeding behaviors using immunohistochemistry. Stereological estimates of the hypothalamic volume and the number of neurons and glia were performed. Significant atrophy of the hypothalamus in bvFTD was present in both analyses. Patients with high feeding disturbance exhibited significant atrophy of the posterior hypothalamus. Neuronal loss, which was observed only in bvFTD cases with Tar DNA protein-43 deposition, was also predominant posteriorly. In contrast, orexin (hypocretin), neuropeptide Y, cocaine- and amphetamine-regulating transcript, and vasopressin-containing neurons that regulate appetite were spared in posterior nuclei known to participate in feeding regulation. Degeneration and consequent dysregulation within the hypothalamus relates to significant feeding disturbance in bvFTD. These findings provide a basis for the development of therapeutic models.
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Morphometric analysis of the human hypothalamus revealed that the volume of the suprachiasmatic nucleus (SCN) in homosexual men is 1.7 times as large as that of a reference group of male subjects and contains 2.1 times as many cells. In another hypothalamic nucleus which is located in the immediate vicinity of the SCN, the sexually dimorphic nucleus (SDN), no such differences in either volume or cell number were found. The SDN data indicate the selectivity of the enlarged SCN in homosexual men, but do not support the hypothesis that homosexual men have a 'female hypothalamus'.
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Background: The present paper describes the immunocytochemical and morphometric characteristics of two major cell groups of the suprachiasmatic nucleus (SCN) in the human hypothalamus: the vasopressin (VP) and vasoactive intestinal polypeptide (VIP) neuronal subdivisions. The dimensions (volume and length) and the number of neurons expressing each peptide in the two subdivisions were obtained, as well as the mean diameter of the cell nuclei. All morphometric parameters were studied in relation to sex and age. Methods: Brains of 42 human subjects (22 males and 20 females) ranging in age from 10 to 92 years were obtained at autopsy. The hypothalamic area containing the SCN was dissected from each brain, dehydrated, and embedded in paraffin. Serial sections of 6 microns were cut in a coronal plane and stained with thionin for general orientation. To determine the architectonic boundaries of the VP- and VIP-expressing cell populations every 25th section was immunocytochemically stained by means of antibodies against arginine VP or VIP using the peroxidase-antiperoxidase method. The VP- and VIP-expressing cell numbers in the SCN of each subject were estimated by unilaterally counting the number of nuclear profiles with the aid of a Zeiss microscope under x 500 magnification, using a deconvolution procedure and a correction for section thickness. Results: The main portion of the VP positive neurons is located in the dorsomedial part of the SCN and is rostrocaudally longer in females than in males (1.76 +/- 0.12 mm and 1.40 +/- 0.10 mm, respectively). The volume of the VP subdivision is 0.244 +/- 0.017 mm3 and contains 6,890 +/- 520 VP-immunoreactive neurons, with a mean density of about 29,000 neurons/mm3. No significant sexual dimorphism or age-related alterations in the population of VP neurons is found. The VIP positive neurons are mainly located in the ventral and central part of the SCN and extend rostrocaudally in a similar way in females and males (1.07 +/- 0.08 mm and 1.02 +/- 0.11 mm, respectively). The volume of the VIP subdivision is 0.034 +/- 0.004 mm3 and contains 1,700 +/- 140 VIP-immunoreactive neurons, with a mean density of about 63,000 neurons/mm3. An age-dependent sexual dimorphism is observed in the number of VIP-expressing neurons in the SCN: young males have about twice as many VIP neurons as females of the same age, whereas in middle-aged subjects this sexual difference is reversed, and less robust, with females now having about 1.7 times as many VIP neurons as males. In old subjects the difference in VIP cell number between men and women disappears. Conclusions: The present study clearly shows that the population of VP neurons in the human SCN is considerably larger than the population of VIP neurons. Furthermore, the age-related sexual differences in the VIP cell number reinforces the idea that the SCN is not only involved in the timing of circadian rhythms but also in the temporal organization of reproductive functions.
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The reversible nature of deep brain stimulation (DBS) brought renewed interest on surgery to medically intractable mental illnesses. The explosion of anatomical and functional imaging has allowed the development of new potential targets and the understanding of historical targets. Fifteen patients undergoing stereotactic surgery for movement disorders, at UCLAs interventional MRI operating-room, were studied with fiber tracking. Stereotactic targets and fiber tracking were determined on MRIs using the Schaltenbrand-Wahren atlas for definition in the iPlan software. Cingulate, subcaudate, BA25/CgWM, amygdala, posterior hypothalamus, orbitofrontal cortex, nucleus accumbens, anterior limb of the internal capsule and dorsomedial thalamus were studied. DTI parameters used ranged from 10 to 20mm for voxel size in the x/y/z planes, fiber length was kept constant at 36 mm, and fractional anisotropy (FA) threshold varied from 0.20 to 0.25. Reliable interconnectivity of targets were determined with DTI and related to PET imaging. Mental illness targets were observed with functional and fiber tract maps. This confirmation yields reliability to DTI imaging in order to determine novel targets and enhance the understanding of areas not well understood. Currently available imaging techniques, the reversibility of DBS to modulate targets promises to bring a brighter future for surgery of mental illness.
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Ventricular enlargement is one of the most consistent abnormal structural brain findings in schizophrenia and has been used to infer brain shrinkage. However, whether ventricular enlargement is related to local overlying cortex and/or adjacent subcortical structures or whether it is related to brain volume change globally has not been assessed. We systematically assessed interrelations of ventricular volumes with gray and white matter volumes of 40 Brodmann areas (BAs), the thalamus and its medial dorsal nucleus and pulvinar, the internal capsule, caudate and putamen. We acquired structural MRI ( patients with schizophrenia (n = 64) and healthy controls (n = 56)) and diffusion tensor fractional anisotropy (FA) (untreated schizophrenia n = 19, controls n = 32). Volumes were assessed by manual tracing of central structures and a semi-automated parcellation of BAs. Patients with schizophrenia had increased ventricular size associated with decreased cortical gray matter volumes widely across the brain; a similar but less pronounced pattern was seen in normal controls; local correlations (e.g. temporal horn with temporal lobe volume) were not appreciably higher than non-local correlations (e.g. temporal horn with prefrontal volume). White matter regions adjacent to the ventricles similarly did not reveal strong regional relationships. FA and center of mass of the anterior limb of the internal capsule also appeared differentially influenced by ventricular volume but findings were similarly not regional. Taken together, these findings indicate that ventricular enlargement is globally interrelated with gray matter volume diminution but not directly correlated with volume loss in the immediately adjacent caudate, putamen, or internal capsule. Electronic supplementary material The online version of this article (doi:10.1007/s00406-011-0202-x) contains supplementary material, which is available to authorized users.
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Objective : Sex hormones are not only involved in the formation of reproductive organs, but also induce sexually-dimorphic brain development and organization. Cross-sex hormone administration to transsexuals provides a unique possibility to study the effects of sex steroids on brain morphology in young adulthood. Methods : Magnetic resonance brain images were made prior to, and during, cross-sex hormone treatment to study the influence of anti-androgen + estrogen treatment on brain morphology in eight young adult male-to-female transsexual human subjects and of androgen treatment in six female-to-male transsexuals. Results : Compared with controls, anti-androgen + estrogen treatment decreased brain volumes of male-to-female subjects towards female proportions, while androgen treatment in female-to-male subjects increased total brain and hypothalamus volumes towards male proportions. Conclusions : The findings suggest that, throughout life, gonadal hormones remain essential for maintaining aspects of sex-specific differences in the human brain.
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The neural networks that putatively modulate aspects of normal emotional behavior have been implicated in the pathophysiology of mood disorders by converging evidence from neuroimaging, neuropathological and lesion analysis studies. These networks involve the medial prefrontal cortex (MPFC) and closely related areas in the medial and caudolateral orbital cortex (medial prefrontal network), amygdala, hippocampus, and ventromedial parts of the basal ganglia, where alterations in grey matter volume and neurophysiological activity are found in cases with recurrent depressive episodes. Such findings hold major implications for models of the neurocircuits that underlie depression. In particular evidence from lesion analysis studies suggests that the MPFC and related limbic and striato-pallido-thalamic structures organize emotional expression. The MPFC is part of a larger "default system" of cortical areas that include the dorsal PFC, mid- and posterior cingulate cortex, anterior temporal cortex, and entorhinal and parahippocampal cortex, which has been implicated in self-referential functions. Dysfunction within and between structures in this circuit may induce disturbances in emotional behavior and other cognitive aspects of depressive syndromes in humans. Further, because the MPFC and related limbic structures provide forebrain modulation over visceral control structures in the hypothalamus and brainstem, their dysfunction can account for the disturbances in autonomic regulation and neuroendocrine responses that are associated with mood disorders. This paper discusses these systems together with the neurochemical systems that impinge on them and form the basis for most pharmacological therapies.
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The hypothalamus contains the control systems that are critically involved in many physiological, endocrine, and behavioral processes, such as feeding and drinking, reproduction and the regulation of the sleep-wake cycle, and temperature. This chapter describes the comparative anatomy of the hypothalamus in mammals. In mammals, the pre-optic region of the hypothalamus is implicated in the neural control of endocrine functions and in the temporal organization of a wide spectrum of biological rhythms. The pivotal role of two hypothalamic cell groups has been considered in this context: the sexually dimorphic nucleus (SDN-POA) as part of the neural circuitry underlying masculine sexual behavior and reproductive functions and the suprachiasmatic nucleus (SCN) as the principal component of the central clock mechanism. The observations on the human SCN in relation to photoperiod indeed reveal a marked seasonal variation in the morphology of the human SCN. The complexity of the annual SCN cycle, however, suggests that, in addition to the environmental lighting conditions, other nonphotic signals are involved in generating this phenomenon.
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Vasopressin was determined in CSF and plasma of 243 patients with different neurological and psychiatric disorders, including control patients. CSF vasopressin was significantly higher in patients with high pressure hydrocephalus, intracranial tumour, benign intracranial hypertension, intracranial haemorrhage, ischaemic stroke, and craniocerebral trauma. In patients with primary degenerative dementia, CSF vasopressin was lower than in control patients. Among patients with psychiatric disorders, CSF vasopressin was increased in manic patients, while in patients with depression CSF concentration of this hormone did not differ from that found in controls. However, an increase in CSF vasopressin level was found in patients recovering from a depression. The clinical significance of changes in CSF vasopressin concentrations in groups of patients with neurological and psychiatric disorders is still unknown.
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Many studies have shown subtle neuroanatomical, neurochemical, and neuroendocrinological differences between male and female brains not only in neocortical regions relevant for various cognitive functions but also in limbic and hypothalamic areas, in which basic emotional and vegetative neuronal mechanisms are regulated. This leads to the assumption that the different clinical forms of depression in males and females could be caused - besides psychological and social influences - by different neuropathological correlates. Therefore, the present study analysed in post mortem brains of 20 patients with unipolar or bipolar depression (12 males, 8 females) and 23 control cases without neuropsychiatric disorders the structure volumes of several limbic, di-encephalic, and basal ganglia structures by planimetry of serial sections. Diagnosis-dependent significant volume reduction (smaller in male and female depressives) were found for the nucleus accumbens, hypothalamus, and all parts of the basal ganglia. Gender-dependent but diagnosis-independent differences (smaller volumes in females) were seen for the nc. accumbens and the basal limbic forebrain, a structure situated below the anterior commissure between the posterior orbital cortex and the anterior hypothalamus. There were no significant gender-specific disease effects; this means that the neuropathological changes were the same in male and female depressed patients. Data suggest that the different clinical appearance of depressive syndromes in males and females may be caused by neurochemical, neuroendocrine, or psychosocial factors, but not by structural anomalies detectable at the macroscopic level.
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Background: Cerebrospinal fluid levels of arginine vasopressin (AVP) and oxytocin (OXT) have been found to change in mood disorders. In the present study, the numbers of AVP-immunoreactive (IR) and OXT-IR neurons were determined in the paraventricular nucleus (PVN) of the human hypothalamus.Methods: Postmortem brain tissue was fixed in formalin, embedded in paraffin, and stained for AVP and OXT using immunocytochemical techniques. The number of IR neurons in the PVN was estimated by morphometry in eight depressed patients ranging in age from 21 to 85 years and eight age-matched controls ranging in age from 23 to 88 years.Results: The numbers of AVP-IR and OXT-IR neurons in the PVN of patients with mood disorder were increased by 56% and 23%, respectively. No differences were found in AVP-IR or OXT-IR cell numbers between three patients with major depression and three patients with bipolar depression. The numbers of AVP-IR and OXT-IR neurons in two patients with depression not otherwise specified were within the same range as in the six other patients with a mood disorder.Conclusions: The AVP and OXT neurons were activated in the PVN in patients with major depression or bipolar disorder. This activation may be associated with activation of the hypothalamic-pituitary-adrenal axis in these patients, since both AVP and OXT are known to potentiate the effects of corticotropin-releasing hormone. Because of their central effects, activation of AVP and OXT neurons may also be related to symptoms of major depression or bipolar disorder.
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Background: Recent reports in the literature document an association between focal white matter abnormalities in bipolar as well as unipolar mood disorder. The importance of this finding and other associated anatomic differences is uncertain. Methods: We examined the volume of abnormal white matter and other brain volumes using quantitative magnetic resonance imaging analysis. We explored the relationship of these variables with diagnosis, cognitive function, and clinical variables in 36 patients with bipolar disorder, 30 patients with unipolar disorder, and 26 control subjects who were free from significant medical and neurologic illness. Results: Younger patients with bipolar disorder (but not similarly aged patients with unipolar disorder or controls) have an increased volume of abnormal white matter. Data also indicate that the total volume of abnormal white matter may be associated with increased cognitive impairment, increased rate of psychiatric illness in the family, and onset after adolescence. Conclusion: Patients with bipolar disorder demonstrate a pattern of subcortical brain morphologic abnormalities and cognitive impairment.
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Prior magnetic resonance imaging (MRI) studies report both medial and lateral cortical temporal changes and disturbed temporal lobe asymmetries in schizophrenic patients compared with healthy controls. The specificity of temporal lobe (TL) changes in schizophrenia is unknown. We determined the occurrence and specificity of these TL changes. Forty-six schizophrenic patients were compared to 60 normal controls and 27 bipolar subjects on MRI measures of bilateral volumes of anterior and posterior superior temporal gyrus (STG), amygdala, entorhinal cortex, and multiple medial temporal structures, as well as global brain measures. Several regional comparisons distinguished schizophrenia from bipolar disorder. Entorhinal cortex, not previously assessed using MRI in schizophrenia, was bilaterally smaller than normal in schizophrenia but not in bipolar disorder. Schizophrenic but not bipolar patients had an alteration of normal posterior STG asymmetry. Additionally, left anterior STG and right amygdala were smaller than predicted in schizophrenia but not bipolar disorder. Left amygdala was smaller and right anterior STG larger in bipolar disorder but not schizophrenia.
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The cyto- and chemoarchitecture of the human paraventricular hypothalamic nucleus (Pa) was studied with the aid of three-dimensional computer reconstruction. The adult human Pa is a vertically elongated structure that abuts the wall of the third ventricle (3V) medially and is indented dorsolaterally by the descending fornix. Chemoarchitecture revealed the following five subnuclei in the human Pa. The most prominent of these is the magnocellular subnucleus (PaM) occupying the ventrolateral quadrant of the Pa and comprised of a concentration of large arginin-vasopressin (AVP)- and acetylcholinesterase (AChE)-positive cells, and small calbindin (Cb)-positive neurons. Rostrally, the PaM is succeeded by the small anterior parvicellular subnucleus (PaAP), which contains small AChE-, AVP- and tyrosin hydroxylase (TH)-positive cells. Dorsal to the PaM is found the dorsal subnucleus (PaD), containing large spindle-shaped TH-, oxytocin (OXY)-, and AChE-positive cells, as well as a population of small Cb-positive neurons. Abutting the wall of the 3V and medial to PaM and PaD is the parvicellular subnucleus (PaP). The PaP contains small cells immunoreactive for corticotropin-releasing factor (CRF), neuromedin K receptor (NK3), and nonphosphorylated neurofilament protein (SMI32). The posterior subnucleus (PaPo) is situated posterior to the descending column of the fornix; it replaces all above-mentioned subdivisions caudally, and is a chemoarchitectonic amalgam that includes dispersed large AChE-, OXY-, AVP- and TH-positive cells, as well as small NK3-, CRF-, SMI32- and Cb-immunoreactive neurons. The present findings suggest that the human PaM and PaD are homologues to the magnocellular subnuclei of the rat Pa, whereas the human PaP and PaPo correspond to the rat medial parvicellular and posterior subnuclei, respectively. J. Comp. Neurol. 423:299–318, 2000. © 2000 Wiley-Liss, Inc.
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Pituitary volume in humans has been reported to change size in response to experimental manipulations of photoperiod, and to be increased during an episode of non-seasonal major depression. We wanted to determine whether pituitary volume changes either across the seasons or during an episode of winter depression. Nineteen patients with winter-seasonal affective disorder and 19 sex-, age-, height-, and weight-matched controls underwent magnetic resonance imaging of the pituitary gland in both winter and summer. Images were obtained using 0.7-mm contiguous slices and the areas of all slices were summed to compute the final volume for each gland. We found no main effects or interactions involving either diagnosis or season in our primary analysis. In a post-hoc analysis, we found a trend towards a season X gender effect (P = 0.06), such that pituitary volume increased slightly (+4.0%) across seasons in women, whereas it decreased slightly (-4.3%) across seasons in men. The results suggest that neither winter depression nor the change of seasons is associated with a significant change in pituitary size.
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Increased serum cortisol levels and a hyperactive hypothalamo-pituitary-adrenal (HPA) axis have been proposed to play an important role in the pathophysiology of Major Depressive Disorder (MDD). However, there are inconsistent results regarding pituitary gland volume (PGV), which is one of the key elements of the HPA axis evaluated by MRI in depressed patients. In this study, we analyzed the PGV of medication-free moderately depressed MDD patients (N = 34) and age and sex matched healthy controls (N = 39). PGV did not differ between MDD patients and healthy controls [mean volume ± S.D.; 0.76 ± 0.17 cm3 and 0.75 ± 0.14 cm3; ANCOVA, F1,69 = 1.25 p > 0.05; respectively]. Our results confirm that volumetric PGV changes are not crucial for depression pathophysiology among unmedicated, moderately depressed adults.
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At its simplest, voxel-based morphometry (VBM) involves a voxel-wise comparison of the local concentration of gray matter between two groups of subjects. The procedure is relatively straightforward and involves spatially normalizing high-resolution images from all the subjects in the study into the same stereotactic space. This is followed by segmenting the gray matter from the spatially normalized images and smoothing the gray-matter segments. Voxel-wise parametric statistical tests which compare the smoothed gray-matter images from the two groups are performed. Corrections for multiple comparisons are made using the theory of Gaussian random fields. This paper describes the steps involved in VBM, with particular emphasis on segmenting gray matter from MR images with nonuniformity artifact. We provide evaluations of the assumptions that underpin the method, including the accuracy of the segmentation and the assumptions made about the statistical distribution of the data.
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Hypothalamic-pituitary-adrenal (HPA) axis hyperactivity has been demonstrated in both schizophrenia and bipolar disorder, but the mechanisms underlying this abnormality are still unclear. Enlarged pituitary volume has been recently reported in patients with first episode psychosis and been interpreted as a consequence of an increased activation of the HPA axis. The aim of this study was to assess the contribution of familial liability to pituitary volume in schizophrenia and bipolar disorder. Pituitary volume may be an indirect measure of HPA axis activity. MRI brain scans and measurements of pituitary volumes were obtained for 183 subjects: 26 patients with established schizophrenia or schizoaffective disorder, 44 of their unaffected first-degree relatives (22 familial schizophrenia, 22 non-familial schizophrenia), 29 patients with established bipolar disorder, 38 of their unaffected first-degree relatives, and 46 healthy comparison subjects. We found a significantly larger pituitary volume (effect size=0.7) in unaffected relatives of patients with schizophrenia compared with controls (p=0.002); the pituitary was even larger in relatives of patients with familial schizophrenia (effect size=0.8, p=0.005). We did not find a significant difference in pituitary volume when comparing the relatives of bipolar patients with controls. Among patients, those with schizophrenia who were receiving prolactin-elevating antipsychotics had an increased pituitary volume compared with controls (effect size=1.0, p=0.006). These results suggest that the larger pituitary volume previously reported in first episode schizophrenia could be partly due to a genetic susceptibility to over-activate the HPA axis.
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Atlas-based segmentation techniques are often employed to encode anatomical information for the delineation of multiple structures in magnetic resonance images of the brain. One of the primary challenges of these approaches is to efficiently model qualitative and quantitative anatomical knowledge without introducing a strong bias toward certain anatomical preferences when segmenting new images. This paper explores the use of topological information as a prior and proposes a segmentation framework based on both topological and statistical atlases of brain anatomy. Topology can be used to describe continuity of structures, as well as the relationships between structures, and is often a critical component in cortical surface reconstruction and deformation-based morphometry. Our method guarantees strict topological equivalence between the segmented image and the atlas, and relies only weakly on a statistical atlas of shape. Tissue classification and fast marching methods are used to provide a powerful and flexible framework to handle multiple image contrasts, high levels of noise, gain field inhomogeneities, and variable anatomies. The segmentation algorithm has been validated on simulated and real brain image data and made freely available to researchers. Our experiments demonstrate the accuracy and robustness of the method and the limited influence of the statistical atlas.
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To summarize quantitatively the literature comparing hypothalamic-pituitary-adrenal (HPA) axis function between depressed and nondepressed individuals and to describe the important sources of variability in this literature. These sources include methodological differences between studies, as well as demographic or clinical differences between depressed samples. The current study used meta-analytic techniques to compare 671 effect sizes (cortisol, adrenocorticotropic hormone, or corticotropin-releasing hormone) across 361 studies, including 18,454 individuals. Although depressed individuals tended to display increased cortisol (d = 0.60; 95% confidence interval [CI], 0.54-0.66) and adrenocorticotropic hormone levels (d = 0.28; 95% CI, 0.16-0.41), they did not display elevations in corticotropin-releasing hormone (d = 0.02; 95% CI, -0.47-0.51). The magnitude of the cortisol effect was reduced by almost half (d = 0.33; 95% CI, 0.21-0.45) when analyses were limited to studies that met minimal methodological standards. Gender did not significantly modify any HPA outcome. Studies that included older hospitalized individuals reported significantly greater cortisol differences between depressed and nondepressed groups compared with studies with younger outpatient samples. Important cortisol differences also emerged for atypical, endogenous, melancholic, and psychotic forms of depression. The current study suggests that the degree of HPA hyperactivity can vary considerably across patient groups. Results are consistent with HPA hyperactivity as a link between depression and increased risk for conditions, such as diabetes, dementia, coronary heart disease, and osteoporosis. Such a link is strongest among older inpatients who display melancholic or psychotic features of depression.
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The macroscopic extrinsic white matter connectivity and the internal structure of the hypothalamus are still incompletely defined in humans. We investigated whether in-vivo diffusion tensor imaging tractography provides evidence of systematization according to hypothalamic compartmentalization. Six defined hypothalamic macroscopic compartments, preoptic, supraoptic, anteroventral, anterodorsal, lateral and posterior, were probed, within the right and left hemispheres of 14 subjects. Important new insights into the macroscopic structure of hypothalamus and white matter connections were found; the preoptic, anteroventral, lateral and posterior compartments are strongly connected to the cortex. The anteroventral connects particularly to the prefrontal cortex while the preoptic compartment connects mainly to the deep anterior brain. The anterodorsal connects mainly to the medial thalamus and the midline gray matter. There is a rightward frontal trend of hemispheric connectivity for the preoptic, anteroventral and lateral compartments. These findings may aid new neuromodulation applications and understanding in brain connectomics.
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Many of the clinical and neuroendocrine features of bipolar disorder involve hypothalamic structures. Although current neuroimaging techniques inadequately resolve the structural components of the hypothalamus, evidence of derangement can be sought by examining the adjacent third ventricle and the functionally related pituitary. To investigate the structure and function of the hypothalamic-pituitary-adrenal axis in euthymic patients with bipolar disorder. Euthymic adult patients with bipolar disorder (n=49) were compared with matched normal control subjects (n=47). Pituitary volume and third ventricle width were assessed on MRI scans. Basal salivary cortisol levels were measured. The width of the third ventricle in patients with bipolar disorder exceeded that of controls (mean +/- SD (in mm): 3.87 +/- 1.96 versus 2.56 +/- 1.34; d=0.76, ANOVA F=12.7, p=0.001), with the greatest differences found in males. Third ventricle width increased with age across the groups (F=16.97, p<0.001). Pituitary volumes did not differ between patients and controls (mean +/- SD (in mm(3)): 632 +/- 176 versus 679 +/- 159). Overall, females had larger pituitaries than males (703 +/- 160 versus 595 +/- 161; d=0.67, F=9.65, p=0.003; all subjects), but female patients had smaller pituitaries compared to female controls (637 +/- 178 versus 756 +/- 126; d=0.65, F=5.04, p=0.03). No difference was found in a comparable analysis of males. Pituitary volume did not differ between patients prescribed and not prescribed antipsychotic drugs. Basal salivary cortisol levels did not differ between patients and controls. In euthymic patients with normal basal cortisol levels, pituitary volume and third ventricle width were found to differ from normal controls. These differences were related to gender, may be important in the pathogenesis of bipolar disorder and could link the vegetative and endocrine abnormalities seen in this condition. Such findings may reflect a trait abnormality or be a consequence of previous episodes.
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Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been reported in bipolar disorder (BD), but previous magnetic resonance imaging (MRI) studies of pituitary gland volume in BD have yielded inconsistent findings. In addition, the contribution of genetic factors to the pituitary changes in BD remains largely unknown. We used MRI to investigate the pituitary volume in 29 remitted patients with BD, 49 of their first-degree relatives (of whom 15 had a diagnosis of Major Depressive Disorder), and 52 age- and gender-matched healthy controls. BD patients had a significantly larger pituitary volume compared with their relatives and healthy controls. Pituitary volume did not differ between controls and healthy relatives or relatives diagnosed with major depression. Direct measures of HPA function (i.e., hormonal levels) were not available. These findings suggest that enlarged pituitary volume is associated with disease expression but not genetic susceptibility to BD.
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Despite effective pharmacological treatments for bipolar disorder, we still lack a comprehensive pathophysiological model of the illness. Recent neurobiological research has implicated a number of key brain regions and neuronal components in the behavioural and cognitive manifestations of bipolar disorder. Dopamine has previously been investigated in some depth in bipolar disorder, but of late has not been a primary focus of attention. This article examines the role of dopamine in bipolar disorder, incorporating recent advances into established models where possible. A critical evaluation of the literature was undertaken, including a review of behavioural, neurochemical, receptor, and imaging studies, as well as genetic studies focusing on dopamine receptors and related metabolic pathways. In addition, pharmacologic manipulation of the central dopaminergic pathways and comparisons with other disease states such as schizophrenia were considered, principally as a means of exploring the hypothesised models. Multiple lines of evidence, including data from pharmacological interventions and structural and functional magnetic resonance imaging studies, suggest that the dopaminergic system may play a central role in bipolar disorder. Future research into the pathophysiological mechanisms of bipolar disorder and the development of new treatments for bipolar disorder should focus on the dopaminergic system.
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The human central nervous system or neuraxis consists of the brain (encephalon) and the spinal cord (medulla spinalis). The brain is encased by the skull; the spinal cord lies within the spinal canal, extending from the foramen magnum to the level of the second lumbar vertebra. Globally, the brain can be subdivided into the cerebrum, the cerebellum and the truncus cerebri or brain stem (Fig. 1.1). On the basis of its ontogeny the brain can be divided into three main parts, the rhombencephalon or hindbrain, the mesencephalon or midbrain and the prosencephalon or forebrain (Fig. 1.2). The rhombencephalon classically includes the medulla oblongata or myelencephalon and the metencephalon. The medulla oblongata represents an expanded rostral extension of the spinal cord. The metencephalon forms a large ventral protrusion, known as the pons, whereas its much expanded dorsal portion is differentiated into the cerebellum.
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The etiology and consistency of findings on normal sexual dimorphisms of the adult human brain are unresolved. In this study, we present a comprehensive evaluation of normal sexual dimorphisms of cortical and subcortical brain regions, using in vivo magnetic resonance imaging, in a community sample of 48 normal adults. The men and women were similar in age, education, ethnicity, socioeconomic status, general intelligence and handedness. Forty-five brain regions were assessed based on T 1 -weighted three-dimensional images acquired from a 1.5 T magnet. Sexual dimorphisms of adult brain volumes were more evident in the cortex, with women having larger volumes, relative to cerebrum size, particularly in frontal and medial paralimbic cortices. Men had larger volumes, relative to cerebrum size, in frontomedial cortex, the amygdala and hypothalamus. A permutation test showed that, compared to other brain areas assessed in this study, there was greater sexual dimorphism among brain areas that are homologous with those identified in animal studies showing greater levels of sex steroid receptors during critical periods of brain development. These findings have implications for developmental studies that would directly test hypotheses about mechanisms relating sex steroid hormones to sexual dimorphisms in humans.
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The relationship between dexamethasone suppression test (DST) results and in vivo pituitary volume was studied in 24 psychiatric inpatients. The principles of systematic stereology were used to measure pituitary volume from 3-mm contiguous sagittal spin-echo magnetic resonance (MR) images of the brain. There was no correlation between pituitary volume and 3 p.m. or 10 p.m. postdexamethasone (post-DEX) plasma cortisol concentrations. However, when multiple regression analysis was performed to relate pituitary volume to gender, age, and post-DEX plasma cortisol concentrations, there was a significant relationship between pituitary volume and age, gender, and 10 p.m. post-DEX cortisol plasma concentration. This is the first study to demonstrate a method that directly measures, rather than estimates, in vivo pituitary volume. Furthermore, it suggests that activation of the hypothalamic-pituitary-adrenal axis in psychiatric patients, as manifested by elevated post-DEX cortisol concentrations, may influence pituitary volume.
Article
The mammalian circadian timing system has three principal components; (1) photoreceptors and visual pathways mediating entrainment; (2) a pacemaker, the suprachiasmatic nucleus of the hypothalamus; and (3) efferent pathways coupling the suprachiasmatic nucleus to effector systems exhibiting circadian function. In most mammals there are two visual entraining pathways, a direct retinohypothalamic pathway terminating in the suprachiasmatic nucleus, for which the transmitter is unknown, and a secondary visual pathway, the geniculohypothalamic tract, from the intergeniculate leaflet of the lateral geniculate to the suprachiasmatic nucleus that is neuropeptide Y-producing. These pathways end in a distinct subdivision of the suprachiasmatic nucleus characterized by the presence of vasoactive intestinal polypeptide neurons. A second suprachiasmatic nucleus division does not receive visual afferents and is characterized by vasopressin neurons. The efferent projections of the suprachiasmatic nucleus are very restricted, predominantly to the hypothalamus. Although we have much less information on the human circadian timing system than on that of other animals, it seems clear that the human conforms to the general animal pattern in most features. There are, however, two significant differences. First, the largest neural component of the human suprachiasmatic nucleus is a population of neurotensin neurons found throughout the nucleus. Few, if any, neurotensin neurons are found in monkey or other mammals. Second, the human suprachiasmatic nucleus contains a large number of neuropeptide Y neurons located where the plexus arising from geniculate neuropeptide Y neurons is found in other mammals. This is unique and suggests that the geniculohypothalamic projection may be bypassed in the human. It also may imply that the functional organization of the human SCN is fundamentally different from that of other mammals. The function of the circadian timing system is to coordinate the activities of a series of homeostatic regulatory mechanisms with the control of behavioral state in a temporal pattern that facilitates adaptive behavior, including reproduction (Fig. 9). The function of this system, then, is to provide the appropriate physiological and behavioral background to facilitate adaptation and survival.
Article
In the present study using magnetic resonance imaging (MRI), age changes in the morphology of the cerebral cortex, greatest in the frontal and parietal convexities, were observed during adolescence. Results suggest that increases in cerebrospinal fluid (CSF) within the sulci of these cortical regions accompany grey matter decreases. Smaller reductions in volume are also observed in subcortical grey matter nuclei. These apparent grey matter volume reductions presumably reflect processes of late brain maturation. The changes may be related to decreasing neural plasticity.
Article
Magnetic resonance images centered at the pituitary stalk were used to measure pituitary gland size in 19 patients with major depression compared with that in age- and sex-matched controls. Depressed patients had significantly greater pituitary cross-sectional area (P = 0.0009) and volume (P = 0.007) than the controls. This difference was particularly prominent in elderly depressed patients compared to elderly controls. These results provide the first demonstration of structural alterations in the pituitary gland in major depression.
Article
The human suprachiasmatic nucleus was analysed by immunohistochemical demonstration of various substances in combination with 3-dimensional computerized reconstruction and video overlay facilities. In the human, the suprachiasmatic nucleus is not as compact as in the rodent. Its boundaries are not easily delineated using conventional stains, and it shows no obvious cytoarchitectonic structure. However, based on its chemoarchitecture, the human suprachiasmatic nucleus can be apportioned into five major subdivisions: Dorsal, comprising a crescent shaped mass of densely packed neurophysin/vasopressin-neurons as well as neurotensin-neurons, and also containing 3-fucosyl-N-acetyl-lactosamine (FAL)-positive neurons in its medial part. Central, occupying the core of the nucleus and consisting precisely of a region devoid of neurophysin/vasopressin neurons but demarcated by calbindin, synaptophysin, and a circumscribed cluster of vasoactive intestinal polypeptide-neurons and containing neurotensin neurons as well. Anteroventrally this division also contains some intermingled neurons positive for neurotensin, neuropeptide Y, somatostatin, and FAL. Ventral, extending from the anterior extreme of the preoptic recess caudolaterally to a field between the optic chiasm and the anteroventral margin of the supraoptic nucleus. This subdivision is specified by synaptophysin, calhindin, and substance P immunoreactivity and is almost free of glial fibrillary acidic protein. From its rostral portion, fibers immunoreactive for calbindin, vasoactive intestinal polypeptide, synaptophysin, and substance P protrude deeply into the optic chiasm. Medial, comprising a thin band between the subependymal zone and the dorsal subdivision, containing scattered somatostatin neurons. External, extending as a band around the dorsal and lateral borders of the nucleus, containing astrocytes expressing the FAL-epitope and scattered neurophysin/vasopressin and neurotensin neurons.
Article
A sexually dimorphic cell group is described in the preoptic area of the human hypothalamus. Morphometric analysis revealed that the volume of this nucleus is 2.5 +/- 0.6 times (mean +/- standard error of the mean) as large in men as in women, and contains 2.2 +/- 0.5 times as many cells. Between the ages of 10 and 93 years, the nucleus decreases greatly in volume and in cell number. Although no function has yet been established for this nucleus, it is located within an area that is essential for gonadotropin release and sexual behavior in other mammals.
Article
The suprachiasmatic nucleus (SCN) is considered to be the endogenous clock of the brain, essential for the ovulation cycle and the temporal organization of sleep-wake patterns, among other things. Immunocytochemical staining with anti-vasopressin as a marker permitted a morphometric study of this nucleus in the human brain, which revealed that the shape of the SCN is sexually dimorphic. The shape of the SCN was elongated in women and more spherical in men. In both sexes a decrease in SCN volume and cell number was observed in senescence (80-100 years). The latter change was especially pronounced in patients with senile dementia of the Alzheimer type (SDAT). This suggests the presence of a structural defect in the SCN which underlies the general disturbance of biological rhythms in senescence and SDAT.