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Guilloux J.-P.,University of Pittsburgh | Guilloux J.-P.,University Paris - Sud | Douillard-Guilloux G.,University of Pittsburgh | Kota R.,University of Pittsburgh | And 6 more authors.
Molecular Psychiatry | Year: 2012

Women are twice as likely as men to develop major depressive disorder (MDD) and are more prone to recurring episodes. Hence, we tested the hypothesis that the illness may associate with robust molecular changes in female subjects, and investigated large-scale gene expression in the post-mortem brain of MDD subjects paired with matched controls (n21 pairs). We focused on the lateral/basolateral/basomedian complex of the amygdala as a neural hub of mood regulation affected in MDD. Among the most robust findings were downregulated transcripts for genes coding for γ-aminobutyric acid (GABA) interneuron-related peptides, including somatostatin (SST), tachykinin, neuropeptide Y (NPY) and cortistatin, in a pattern reminiscent to that previously reported in mice with low brain-derived neurotrophic factor (BDNF). Changes were confirmed by quantitative PCR and not explained by demographic, technical or known clinical parameters. BDNF itself was significantly downregulated at the RNA and protein levels in MDD subjects. Investigating putative mechanisms, we show that this core MDD-related gene profile (including SST, NPY, TAC1, RGS4 and CORT) is recapitulated by complementary patterns in mice with constitutive (BDNF-heterozygous) or activity-dependent (exon IV knockout) decreases in BDNF function, with a common effect on SST and NPY. Together, these results provide both direct (low RNA/protein) and indirect (low BDNF-dependent gene pattern) evidence for reduced BDNF function in the amygdala of female subjects with MDD. Supporting studies in mutant mice models suggest a complex mechanism of low constitutive and activity-dependent BDNF function in MDD, particularly affecting SST/NPY-related GABA neurons, thus linking the neurotrophic and GABA hypotheses of depression. © 2012 Macmillan Publishers Limited All rights reserved.


Mueller S.C.,National Institute of Mental Health NIMH | Mueller S.C.,Ghent University | Aouidad A.,University Pierre and Marie Curie | Gorodetsky E.,Mood and Anxiety Disorders Program NIMH | And 3 more authors.
Journal of the American Academy of Child and Adolescent Psychiatry | Year: 2013

Objective: Minimal research links anxiety disorders in adolescents to regional gray matter volume (GMV) abnormalities and their modulation by genetic factors. Prior research suggests that a brain-derived neurotrophic factor (BNDF) Val66Met polymorphism may modulate such brain morphometry profiles. Method: Using voxel-based morphometry and magnetic resonance imaging, associations of BDNF and clinical anxiety with regional GMVs of anterior cingulate cortex, insula, amygdala, and hippocampus were examined in 39 affected (17 Met allele carriers, 22 Val/Val homozygotes) and 63 nonaffected adolescents (33 Met allele carriers, 41 Val/Val homozygotes). Results: Amygdala and anterior hippocampal GMVs were significantly smaller in patients than in healthy comparison adolescents, with a reverse pattern for the insula. Post-hoc regression analyses indicated a specific contribution of social phobia to the GMV reductions in the amygdala and hippocampus. In addition, insula and dorsal-anterior cingulate cortex (ACC) GMVs were modulated by BDNF genotype. In both regions, and GMVs were larger in the Val/Val homozygote patients than in individuals carrying the Met allele. Conclusions: These results implicate reduced GMV in the amygdala and hippocampus in pediatric anxiety, particularly social phobia. In addition, the data suggest that genetic factors may modulate differences in the insula and dorsal ACC.


Dickstein D.P.,Brown University | Leibenluft E.,National Institute of Mental Health NIMH
Israel Journal of Psychiatry and Related Sciences | Year: 2012

From the mid-1990s through the present, studies have demonstrated a significant rise in the numbers of children and adolescents diagnosed with bipolar disorder (BD). Why is this? The present manuscript reviews several possibilities, most notably ambiguity in the diagnostic criteria for mania and how they may apply to children with functionally-impairing irritability. Furthermore, we discuss ongoing phenomenological and affective neuroscience research approaches to address those children most on the fringes of our current psychiatric nosology. In summary, these studies suggest that BD youths may be distinguished on some measures from those with chronic irritability and severe mood dysregulation, although the two groups also have some shared deficits.


Wallace G.L.,National Institute of Mental Health NIMH | Wallace G.L.,George Washington University | Eisenberg I.W.,National Institute of Mental Health NIMH | Robustelli B.,National Institute of Mental Health NIMH | And 4 more authors.
Journal of the American Academy of Child and Adolescent Psychiatry | Year: 2015

Objective Prior reports suggest that autism spectrum disorder (ASD) is associated with atypically excessive early brain growth. Recent cross-sectional studies suggest that later cortical development during adolescence/adulthood might also be aberrant, although longitudinal designs are required to evaluate atypical growth trajectories. The present study sought to examine longitudinal changes in cortical thickness and surface area among adolescents and young adults with ASD. Method Two high-resolution anatomic magnetic resonance imaging scans approximately 2 years apart were acquired from 17 adolescents with ASD and 18 typically developing (TD) adolescents, matched on age (range = 14-24 years), IQ, sex ratio, and handedness (70 scans total). The FreeSurfer image analysis suite was used to quantify longitudinal changes in cortical thickness and surface area. Results Accelerated cortical thinning for the ASD group as compared to the TD group was found in 2 areas in the left hemisphere, the posterior portion of ventral temporal cortex and superior parietal cortex (cluster corrected p <.01). For ventral temporal cortex, cortical thinning was associated with everyday executive function impairments, and thinner cortex at time 2 was correlated with ASD social symptoms. Differences in surface area changes were not detected. Conclusion The present longitudinal study extends prior cross-sectional research by demonstrating increased cortical thinning (in portions of temporal and parietal cortex) but comparable surface area growth rates in participants with ASD compared to TD controls during adolescence and into young adulthood. These findings provide further evidence for atypical cortical development beyond the early years in ASD, marked by increased cortical thinning in late adolescence/young adulthood. © Published by Elsevier Inc. on behalf of the American Academy of Child and Adolescent Psychiatry.


News Article | January 27, 2017
Site: www.techtimes.com

Researchers from the University of Texas Health Science Center at Houston have made an amazing discovery, which could be a potential game changer for the treatment and diagnosis of bipolar disorder and other mental health issues. Bipolar disorder, otherwise known as manic-depressive illness, is a brain condition that causes drastic shifts in a person's mood, energy, and activity. These mood swings are basically classified into three categories: manic episodes (feeling extremely ecstatic and energized), depressive episodes (feeling miserable, hopeless, and suicidal), and hypomanic episodes (less severe manic episode). These radical changes in mood can greatly affect a person's sleep, activities, and way of thinking, and often inhibit them from having a normal life. The exact reason why bipolar disorder occurs in people is still unknown, although experts believe that several factors can trigger the illness or increase one's risk, These include genetics, family history, and brain structure and functioning. Using a combination of magnetic resonance imaging and an advanced segmentation approach, researchers evaluated the differences in the volumes of subfields of the hippocampus, the seahorse-shaped region in the brain's medial temporal lobe. The hippocampus, an essential part of the limbic system, controls our memories and emotional behavior. The researchers discovered that the study participants with bipolar disorder had volume reduction in certain parts of their hippocampus. The portion of the tail, two cellular layers, and subfield 4 of the cornu ammonis all displayed lower volumes. The reduced volume was more pronounced in subjects with bipolar I disorder than those with other mood disorders. Additionally, the researchers found that patients with bipolar I disorder displayed lower volumes of certain hippocampus areas the longer the period of their illness became. Volumes of other CA areas and hippocampal tail, on the other hand, decreased more in subjects with more manic episodes. The entirety of the study can be found in the journal Molecular Psychiatry. Bo Cao, first and corresponding author of the study and a post-doctoral fellow in the Department of Psychiatry and Behavioral Sciences at McGovern Medical School at UTHealth, is hopeful that the results of their study, funded partly through a grant from the National Institute of Mental Health NIMH), will pave the way for further in-depth research aimed at more accurate diagnosis and positive treatment response of the puzzling brain disorder. "Our study is one of the first to locate possible damage of bipolar disorder in specific subfields within the hippocampus," Cao stated. "This is something that researchers have been trying to answer. The theory was that different subfields of the hippocampus may have different functions and may be affected differently in different mood disorders, such as bipolar disorder and major depression disorder." © 2017 Tech Times, All rights reserved. Do not reproduce without permission.


Lahat A.,McMaster University | Lamm C.,University of New Orleans | Chronis-Tuscano A.,University of Maryland College Park | Pine D.S.,National Institute of Mental Health NIMH | And 2 more authors.
Journal of the American Academy of Child and Adolescent Psychiatry | Year: 2014

Objective Behavioral inhibition (BI) is an early childhood temperament characterized by fearful responses to novelty and avoidance of social interactions. During adolescence, a subset of children with stable childhood BI develop social anxiety disorder and concurrently exhibit increased error monitoring. The current study examines whether increased error monitoring in 7-year-old, behaviorally inhibited children prospectively predicts risk for symptoms of social phobia at age 9 years. Method A total of 291 children were characterized on BI at 24 and 36 months of age. Children were seen again at 7 years of age, when they performed a Flanker task, and event-related potential (ERP) indices of response monitoring were generated. At age 9, self- and maternal-report of social phobia symptoms were obtained. Results Children high in BI, compared to those low in BI, displayed increased error monitoring at age 7, as indexed by larger (i.e., more negative) error-related negativity (ERN) amplitudes. In addition, early BI was related to later childhood social phobia symptoms at age 9 among children with a large difference in amplitude between ERN and correct-response negativity (CRN) at age 7. Conclusions Heightened error monitoring predicts risk for later social phobia symptoms in children with high BI. Research assessing response monitoring in children with BI may refine our understanding of the mechanisms underlying risk for later anxiety disorders and inform prevention efforts.


Garrett A.S.,The Interdisciplinary Center | Reiss A.L.,The Interdisciplinary Center | Howe M.E.,The Interdisciplinary Center | Kelley R.G.,The Interdisciplinary Center | And 4 more authors.
Journal of the American Academy of Child and Adolescent Psychiatry | Year: 2012

Objective: Previous functional magnetic resonance imaging (fMRI) studies in pediatric bipolar disorder (BD) have reported greater amygdala and less dorsolateral prefrontal cortex (DLPFC) activation to facial expressions compared to healthy controls. The current study investigates whether these differences are associated with the early or late phase of activation, suggesting different temporal characteristics of brain responses. Method: A total of 20 euthymic adolescents with familial BD (14 male) and 21 healthy control subjects (13 male) underwent fMRI scanning during presentation of happy, sad, and neutral facial expressions. Whole-brain voxelwise analyses were conducted in SPM5, using a three-way analysis of variance (ANOVA) with factors group (BD and healthy control [HC]), facial expression (happy, sad, and neutral versus scrambled), and phase (early and late, corresponding to the first and second half of each block of faces). Results: There were no significant group differences in task performance, age, gender, or IQ. Significant activation from the main effect of group included greater DLPFC activation in the HC group, and greater amygdala/hippocampal activation in the BD group. The interaction of Group × Phase identified clusters in the superior temporal sulcus/insula and visual cortex, where activation increased from the early to late phase of the block for the BD but not the HC group. Conclusions: These findings are consistent with previous studies that suggest deficient prefrontal cortex regulation of heightened amygdala response to emotional stimuli in pediatric BD. Increasing activation over time in superior temporal and visual cortices suggests difficulty processing or disengaging attention from emotional faces in BD. © 2012 American Academy of Child and Adolescent Psychiatry.


Martinowich K.,National Institute of Mental Health NIMH | Schloesser R.J.,National Institute of Mental Health NIMH | Jimenez D.V.,National Institute of Mental Health NIMH | Weinberger D.R.,National Institute of Mental Health NIMH | And 2 more authors.
Molecular Brain | Year: 2011

Background: Sleep homeostasis is characterized by a positive correlation between sleep length and intensity with the duration of the prior waking period. A causal role for brain-derived neurotrophic factor (BDNF) in sleep homeostasis has been suggested, but the underlying mechanisms remain unclear. Cortistatin, a neuropeptide expressed primarily in a subset of cortical GABAergic interneurons, is another molecule implicated in sleep homeostasis. Results: We confirmed that sleep deprivation leads to an increase in cortical cortistatin mRNA expression. Disruption of activity-dependent BDNF expression in a genetically modified mouse line impairs both baseline levels of cortistatin mRNA as well as its levels following sleep deprivation. Disruption of activity-dependent BDNF also leads to a decrease in sleep time during the active (dark) phase. Conclusion: Our studies suggest that regulation of cortistatin-expressing interneurons by activity-dependent BDNF expression may contribute to regulation of sleep behavior. © 2011 Martinowich et al; licensee BioMed Central Ltd.


Lerchner W.,National Institute of Mental Health NIMH | Corgiat B.,National Institute of Mental Health NIMH | Der Minassian V.,National Institute of Mental Health NIMH | Saunders R.C.,National Institute of Mental Health NIMH | Richmond B.J.,National Institute of Mental Health NIMH
Gene Therapy | Year: 2014

We, like many others, wish to use modern molecular methods to alter neuronal functionality in primates. For us, this requires expression in a large proportion of the targeted cell population. Long generation times make germline modification of limited use. The size and intricate primate brain anatomy poses additional challenges. We surved methods using lentiviruses and serotypes of adeno-associated viruses (AAVs) to introduce active molecular material into cortical and subcortical regions of old-world monkey brains. Slow injections of AAV2 give well-defined expression of neurons in the cortex surrounding the injection site. Somewhat surprisingly we find that in the monkey the use of cytomegalovirus promoter in lentivirus primarily targets glial cells but few neurons. In contrast, with a synapsin promoter fragment the lentivirus expression is neuron specific at high transduction levels in all cortical layers. We also achieve specific targeting of tyrosine hydroxlase (TH)-rich neurons in the locus coeruleus and substantia nigra with a lentvirus carrying a fragment of the TH promoter. Lentiviruses carrying neuron specific promoters are suitable for both cortical and subcortical injections even when injected quickly. © 2014 Macmillan Publishers Limited.


DiazGranados N.,National Institute of Mental Health NIMH | Ibrahim L.A.,National Institute of Mental Health NIMH | Brutsche N.E.,National Institute of Mental Health NIMH | Ameli R.,National Institute of Mental Health NIMH | And 4 more authors.
Journal of Clinical Psychiatry | Year: 2010

Objective: Suicidal ideation is a medical emergency, especially when severe. Little research has been done on pharmacologic interventions that could address this problem. Ketamine, an N-methyl-d-aspartate antagonist, has been reported to have antidepressant effects within hours. We examined the effects of a single dose of ketamine on suicidal ideation in subjects with treatment- resistant major depressive disorder (MDD). Method: Thirty-three subjects with DSM-IV-diagnosed MDD received a single open-label infusion of ketamine (0.5 mg/kg) and were rated at baseline and at 40, 80, 120, and 230 minutes postinfusion with the Scale for Suicide Ideation (SSI), the MontgomeryÅ sberg Depression Rating Scale, the Hamilton Depression Rating Scale, and the Beck Depression Inventory. The study was conducted between October 2006 and January 2009. Results: Suicidal ideation scores decreased significantly on the SSI as well as on the suicide subscales of other rating instruments within 40 minutes; these decreases remained significant through the first 4 hours postinfusion (P < .001). Ten subjects (30%) had an SSI score ≥ 4 at baseline; all these scores dropped below 4 (9 dropped by 40 minutes and 1 by 80 minutes). For those patients with a starting score below 4 on the SSI, only 1 reached a score of 4. Depression, anxiety, and hopelessness were significantly improved at all time points (P < .001). Conclusions: Suicidal ideation in the context of MDD improved within 40 minutes of a ketamine infusion and remained improved for up to 4 hours postinfusion. Future studies with ketamine in suicidal ideation are warranted due to the potential impact on public health. Trial Registration: clinicaltrials.gov Identifier: NCT00088699. © Copyright 2010 Physicians Postgraduate Press, Inc.

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