Differences in DNA methylation between human neuronal and glial cells are concentrated in enhancers and non-CpG sites.

We applied Illumina Human Methylation450K array to perform a genomic-scale single-site resolution DNA methylation analysis in neuronal and nonneuronal (primarily glial) nuclei separated from the orbitofrontal cortex of postmortem human brain. The findings were validated using enhanced reduced representation bisulfite sequencing. We identified thousands of sites differentially methylated (DM) between neuronal and nonneuronal cells. The DM sites were depleted within CpG-island-containing promoters but enriched in predicted enhancers. Classification of the DM sites into those undermethylated in neurons (neuronal type) and those undermethylated in nonneuronal cells (glial type), combined with findings of others that methylation within control elements typically negatively correlates with gene expression, yielded large sets of predicted neuron-specific and non-neuron-specific genes. These sets of predicted genes were in excellent agreement with the available direct measurements of gene expression in human and mouse. We also found a distinct set of DNA methylation patterns that were unique for neuronal cells. In particular, neuronal-type differential methylation was overrepresented in CpG island shores, enriched within gene bodies but not in intergenic regions, and preferentially harbored binding motifs for a distinct set of transcription factors, including neuron-specific activity-dependent factors. Finally, non-CpG methylation was substantially more prevalent in neurons than in nonneuronal cells.

Report of the American Psychiatric Association Task Force on Treatment of Gender Identity Disorder.

Both the diagnosis and treatment of Gender Identity Disorder (GID) are controversial. Although linked, they are separate issues and the DSM does not evaluate treatments. The Board of Trustees (BOT) of the American Psychiatric Association (APA), therefore, formed a Task Force charged to perform a critical review of the literature on the treatment of GID at different ages, to assess the quality of evidence pertaining to treatment, and to prepare a report that included an opinion as to whether or not sufficient credible literature exists for development of treatment recommendations by the APA. The literature on treatment of gender dysphoria in individuals with disorders of sex development was also assessed. The completed report was accepted by the BOT on September 11, 2011. The quality of evidence pertaining to most aspects of treatment in all subgroups was determined to be low; however, areas of broad clinical consensus were identified and were deemed sufficient to support recommendations for treatment in all subgroups. With subjective improvement as the primary outcome measure, current evidence was judged sufficient to support recommendations for adults in the form of an evidence-based APA Practice Guideline with gaps in the empirical data supplemented by clinical consensus. The report recommends that the APA take steps beyond drafting treatment recommendations. These include issuing position statements to clarify the APA's position regarding the medical necessity of treatments for GID, the ethical bounds of treatments of gender variant minors, and the rights of persons of any age who are gender variant, transgender or transsexual.

Frontotemporal thalamic connectivity in schizophrenia and schizotypal personality disorder.

Schizotypal personality disorder (SPD) resembles schizophrenia, but with attenuated brain abnormalities and the absence of psychosis. The thalamus is integral for processing and transmitting information across cortical regions and widely implicated in the neurobiology of schizophrenia. Comparing thalamic connectivity in SPD and schizophrenia could reveal an intermediate schizophrenia-spectrum phenotype to elucidate neurobiological risk and protective factors in psychosis. We used rsfMRI to investigate functional connectivity between the mediodorsal nucleus (MDN) and pulvinar, and their connectivity with frontal and temporal cortical regions, respectively in 43 healthy controls (HCs), and individuals in the schizophrenia-spectrum including 45 psychotropic drug-free individuals with SPD, and 20 individuals with schizophrenia-related disorders [(schizophrenia (n = 10), schizoaffective disorder (n = 8), schizophreniform disorder (n = 1) and psychosis NOS (n = 1)]. Individuals with SPD had greater functional connectivity between the MDN and pulvinar compared to individuals with schizophrenia. Thalamo-frontal (i.e., between the MDN and rostral middle frontal cortex) connectivity was comparable in SPD and HCs; in SPD greater connectivity was associated with less symptom severity. Individuals with schizophrenia had less thalamo-frontal connectivity and thalamo-temporal (i.e., pulvinar to the transverse temporal cortex) connectivity compared with HCs. Thalamo-frontal functional connectivity may be comparable in SPD and HCs, but abnormal in schizophrenia, and that this may be protective against psychosis in SPD.

Cingulate and temporal lobe fractional anisotropy in schizotypal personality disorder.

BACKGROUND: Consistent with the clinical picture of milder symptomatology in schizotypal personality disorder (SPD) than schizophrenia, morphological studies indicate SPD abnormalities in temporal lobe regions but to a much lesser extent in prefrontal regions implicated in schizophrenia. Lower fractional anisotropy (FA), a measure of white-matter integrity within prefrontal, temporal, and cingulate regions has been reported in schizophrenia but has been little studied in SPD. AIMS: The study aim was to examine temporal and prefrontal white matter FA in 30 neuroleptic-naïve SPD patients and 35 matched healthy controls (HCs). We hypothesized that compared with HCs, SPD patients would exhibit lower FA in temporal lobe and anterior cingulum regions but relative sparing in prefrontal regions. METHOD: We acquired diffusion tensor imaging (DTI) in all participants and examined FA in the white matter underlying Brodmann areas (BAs) in dorsolateral prefrontal (BAs 44, 45, and 46), temporal lobe (BAs 22, 21, and 20), and cingulum (BAs 25, 24, 31, 23, and 29) regions with a series of analyses using multivariate analysis of variance. RESULTS: Compared with HCs, the SPD group had significantly lower FA in the left temporal lobe but not prefrontal regions. In the cingulum, FA was lower in the SPD group in the posterior regions (BAs 31 and 23), higher in the anterior (BA 25) regions and lower overall in the right but not the left cingulum. Among the SPD group, lower FA in the cingulum was associated with more severe negative symptoms (e.g., odd speech). CONCLUSIONS: Similar to schizophrenia, our results indicate cingulum-temporal lobe FA abnormalities in SPD and suggest that cingulum abnormalities are associated with negative symptoms.

Correlations between ventricular enlargement and gray and white matter volumes of cortex, thalamus, striatum, and internal capsule in schizophrenia.

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.

Clinical features and psychiatric comorbidities in military veterans with schizophrenia with or without suicidality.

Suicide is currently among the leading causes of death among individuals with schizophrenia. Reducing mortality from suicide remains a major clinical challenge in the care of veterans with schizophrenia. There is a need to increase our understanding of what elevates suicide risk in veterans with schizophrenia as a first step towards the future development of suicide prevention interventions. This study compared demographic and clinical features of military veterans with schizophrenia with vs. without suicidality to determine specific risk factors for suicidality. The sample consisted of two groups of veterans with schizophrenia: suicide ideators and/or attempters (SIA) and individuals without a history of suicidal ideation or attempts (no-SIA). Participants were interviewed using the Structured Clinical Interview for DSM-5 Axis I disorders (SCID-I), Positive and Negative Syndrome Scale for Schizophrenia (PANSS), Hamilton Depression Rating Scale (HDRS), and Schizotypal Personality Questionnaire (SPQ). In bivariate analyses, the PANSS-Positive Symptom scores, PANSS-General Psychopathology scores, HDRS total score, HDRS-Paranoid symptoms item score, and SPQ total scores were higher among SIA compared with no-SIA patients. In this unique clinical sample of veterans with schizophrenia, SIA patients were more likely to have mood disorders, post-traumatic stress disorder (PTSD), and/or alcohol use disorder in comparison to the no-SIA group. Logistic regression analysis indicated that the HDRS total score and presence/absence of comorbid mood disorder drive the difference between the groups. These results indicate that suicide risk assessment in veterans with schizophrenia should include identifying individuals with comorbid mood disorders/symptoms, PTSD, alcohol use disorder, marked positive symptoms, and schizotypal features.

Behavioral and neurobiological effects of GnRH agonist treatment in mice-potential implications for puberty suppression in transgender individuals.

In the United States, ~1.4 million individuals identify as transgender. Many transgender adolescents experience gender dysphoria related to incongruence between their gender identity and sex assigned at birth. This dysphoria may worsen as puberty progresses. Puberty suppression by gonadotropin-releasing hormone agonists (GnRHa), such as leuprolide, can help alleviate gender dysphoria and provide additional time before irreversible changes in secondary sex characteristics may be initiated through feminizing or masculinizing hormone therapy congruent with the adolescent's gender experience. However, the effects of GnRH agonists on brain function and mental health are not well understood. Here, we investigated the effects of leuprolide on reproductive function, social and affective behavior, cognition, and brain activity in a rodent model. Six-week-old male and female C57BL/6J mice were injected daily with saline or leuprolide (20 µg) for 6 weeks and tested in several behavioral assays. We found that leuprolide increases hyperlocomotion, changes social preference, and increases neuroendocrine stress responses in male mice, while the same treatment increases hyponeophagia and despair-like behavior in females. Neuronal hyperactivity was found in the dentate gyrus (DG) of leuprolide-treated females, but not males, consistent with the elevation in hyponeophagia and despair-like behavior in females. These data show for the first time that GnRH agonist treatment after puberty onset exerts sex-specific effects on social- and affective behavior, stress regulation, and neural activity. Investigating the behavioral and neurobiological effects of GnRH agonists in mice will be important to better guide the investigation of potential consequences of this treatment for youth experiencing gender dysphoria.

Toward Optimizing Mental Health Care for Sexual and Gender Minority Veterans.

Studies examining physicians' knowledge, attitudes, and perceptions of their clinical competence have revealed that many are, or perceive themselves to be, poorly prepared to address the needs of sexual and gender minority (SGM) patients as well as military veterans. In this article, the authors examine these findings as they pertain to mental health care and identify the areas of cultural and clinical competence necessary for psychiatrists and other mental health professionals to provide high-quality care for SGM veterans.

Gender Dysphoria in Adults: An Overview and Primer for Psychiatrists.

(Copyright © William Byne et al. 2018; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.).

The thalamus and schizophrenia: current status of research.

The thalamus provides a nodal link for multiple functional circuits that are impaired in schizophrenia (SZ). Despite inconsistencies in the literature, a meta analysis suggests that the volume of the thalamus relative to that of the brain is decreased in SZ. Morphometric neuroimaging studies employing deformation, voxel-based and region of interest methodologies suggest that the volume deficit preferentially affects the thalamic regions containing the anterior and mediodorsal nuclei, and the pulvinar. Postmortem design-based stereological studies have produced mixed results regarding volume and neuronal deficits in these nuclei. This review examines those aspects of thalamic circuitry and function that suggest salience to SZ. Evidence for anomalies of thalamic structure and function obtained from postmortem and neuroimaging studies is then examined and directions for further research proposed.

Effects of mental illness and aging in two thalamic nuclei.

We previously reported a schizophrenia associated reduction of neuronal and oligodendrocyte number in the anterior principal thalamic nucleus (APN) in a cohort of severely impaired elderly subjects with schizophrenia (SZ) relative to age matched nonpsychiatric controls (NCs). The present study was undertaken to determine 1) if those findings could be replicated in an independent sample of less chronically impaired subjects with SZ and NCs stratified across a broader age range; 2) if the findings are specific to SZ or are also seen in unipolar major depressive (MDD) or bipolar disorder (BPD); and 3) if the findings are specific to the APN or also seen in another thalamic nucleus. Computer assisted stereological methods were employed to determine the number of neurons and oligodendrocytes in the APN and centromedian nucleus (CMN) of the Nissl-stained thalamic sections maintained by the Stanley Foundation Brain Bank. This collection includes specimens from NCs and age matched subjects with diagnoses of SZ, MDD, or BPD who died between the ages of 25 and 68. Data were analyzed by mixed-effects linear regressions adjusting for demographic variables and known history of exposure to psychotropic medications. Oligodendrocyte number was decreased in both nuclei relative to NCs in subjects with SZ and in that subset of subjects with BPD who had experienced psychotic episodes. Compared to NCs both of these patient groups also exhibited an attenuation of an age-related increase in the number of oligodendrocytes. Contrary to our previous report, we did not detect a SZ-associated deficit in neuronal number in the APN. A history of exposure to neuroleptics, however, was associated with a decrease in neuronal number in both nuclei, but this decrease did not vary in relation to cumulative lifetime neuroleptic exposure in fluphenazine equivalents. Among subjects with psychiatric diagnoses, exposure to lithium was associated with an increase in the number of oligodendrocytes. No effects were detected for exposure to anticonvulsants or for abuse of alcohol or other substances.

Schizophrenia and sex associated differences in the expression of neuronal and oligodendrocyte-specific genes in individual thalamic nuclei.

Considerable evidence based on the study of postmortem brain tissue suggests deficits in both neuronal and myelin systems in schizophrenia (SZ). To date, the majority of the biochemical and molecular biological studies have focused on the cerebral cortex. Most information traveling to or from the cortex is relayed or synaptically gated through the thalamus, and numerous studies suggest structural and functional abnormalities in interconnected regions of the thalamus and cortex in SZ. The present study extends our gene expression studies of neuronal and myelin systems to the thalamus. Quantitative PCR was employed to assess the expression of 10 genes in 5 divisions of the thalamus which were precisely harvested using Laser Capture Microdissection. The divisions studied were present on coronal sections at the level of the centromedian nucleus (CMN) taken from 14 schizophrenic and 16 normal control postmortem brains. The genes examined were specific for oligodendrocytes (MAG, CNP, MBP), neurons (ENO2), glutamatergic neurons (VGlut1, VGlut2, PV, CB) or GABAergic neurons (GAD65, GAD67). Expression levels for each of these markers were quantitated and compared between diagnoses, between sexes, and across nuclei. CB was much more highly expressed in the CMN in SZs compared to NCs. No other diagnosis related differences in gene expression were observed. The expression levels of CNP and MAG, but not MBP, were highly correlated with one another and both, but not MBP, were much more highly expressed in females than in males in all thalamic divisions examined. All markers were differentially expressed across nuclei.

Ionotropic glutamate receptor mRNA expression in the human thalamus: absence of change in schizophrenia.

Abnormalities in glutamate neurotransmission are thought to be among the major contributing factors to the pathophysiology of schizophrenia. Although schizophrenia has been regarded mostly as a disorder of higher cortical function, the cortex and thalamus work as a functional unit. Existing data regarding alterations of glutamate receptor subunit expression in the thalamus in schizophrenia remain equivocal. This postmortem study examined mRNA expression of ionotropic glutamate receptor (iGluR) subunits and PSD95 in 5 precisely defined and dissected thalamic subdivisions (medial and lateral sectors of the mediodorsal nucleus; and the ventral lateral posterior, ventral posterior, and centromedian nuclei) of persons with schizophrenia and matched controls using quantitative PCR with normalization to multiple endogenous controls. Among 15 genes examined (NR1 and NR2A-D subunits of the NMDA receptor; GluR1-4 subunits of the AMPA receptor; GluR5-7 and KA1-2 subunits of the kainate receptor; PSD95), all but two (GluR4 and KA1) were expressed at quantifiable levels. Differences in iGluR gene expression were seen between different thalamic nuclei but not between diagnostic groups. The relative abundance of transcripts was: NR1>>NR2A>NR2B>NR2D>NR2C for NMDA, GluR2>GluR1>GluR3 for AMPA, and KA2>GluR5>GluR7>GluR6 for kainate receptors. The expression of PSD95 correlated with the expression of NR1, NR2A, NR2B, NR2D and GluR6 in all nuclei. These results provide detailed and quantitative information on iGluR subunit expression in multiple nuclei of the human thalamus but suggest that alterations in their expression are not a prominent feature of schizophrenia.

A unique role for DNA (hydroxy)methylation in epigenetic regulation of human inhibitory neurons.

Brain function depends on interaction of diverse cell types whose gene expression and identity are defined, in part, by epigenetic mechanisms. Neuronal DNA contains two major epigenetic modifications, methylcytosine (mC) and hydroxymethylcytosine (hmC), yet their cell type-specific landscapes and relationship with gene expression are poorly understood. We report high-resolution (h)mC analyses, together with transcriptome and histone modification profiling, in three major cell types in human prefrontal cortex: glutamatergic excitatory neurons, medial ganglionic eminence-derived γ-aminobutyric acid (GABA)ergic inhibitory neurons, and oligodendrocytes. We detected a unique association between hmC and gene expression in inhibitory neurons that differed significantly from the pattern in excitatory neurons and oligodendrocytes. We also found that risk loci associated with neuropsychiatric diseases were enriched near regions of reduced hmC in excitatory neurons and reduced mC in inhibitory neurons. Our findings indicate differential roles for mC and hmC in regulation of gene expression in different brain cell types, with implications for the etiology of human brain diseases.

Gender Dysphoria in Adults: An Overview and Primer for Psychiatrists.

Regardless of their area of specialization, adult psychiatrists are likely to encounter gender-variant patients; however, medical school curricula and psychiatric residency training programs devote little attention to their care. This article aims to assist adult psychiatrists who are not gender specialists in the delivery of respectful, clinically competent, and culturally attuned care to gender-variant patients, including those who identify as transgender or transsexual or meet criteria for the diagnosis of Gender Dysphoria (GD) as defined by The Diagnostic and Statistical Manual of Mental Disorders (5th edition). The article will also be helpful for other mental health professionals. The following areas are addressed: evolution of diagnostic nosology, epidemiology, gender development, and mental health assessment, differential diagnosis, treatment, and referral for gender-affirming somatic treatments of adults with GD.

Reduction of right medial pulvinar volume and neuron number in schizophrenia.

Several studies have described a reduction of pulvinar volume and/or neuronal number in schizophrenia (SZ). In order to better localize these changes, we assessed volume and neuronal number of the pulvinar and several of its subdivisions in postmortem material from subjects with chronic SZ and subjects with no psychiatric history. Total pulvinar volume and neuronal number were significantly lower in SZ and these differences were significant in only in its medial division. The medial pulvinar interconnects various heteromodal cortical regions suggesting that these deficits may contribute to the abnormalities of higher order integrative functions characteristic of schizophrenia.

DNA Methylation Profiling of Human Prefrontal Cortex Neurons in Heroin Users Shows Significant Difference between Genomic Contexts of Hyper- and Hypomethylation and a Younger Epigenetic Age.

We employed Illumina 450 K Infinium microarrays to profile DNA methylation (DNAm) in neuronal nuclei separated by fluorescence-activated sorting from the postmortem orbitofrontal cortex (OFC) of heroin users who died from heroin overdose (N = 37), suicide completers (N = 22) with no evidence of heroin use and from control subjects who did not abuse illicit drugs and died of non-suicide causes (N = 28). We identified 1298 differentially methylated CpG sites (DMSs) between heroin users and controls, and 454 DMSs between suicide completers and controls (p < 0.001). DMSs and corresponding genes (DMGs) in heroin users showed significant differences in the preferential context of hyper and hypo DM. HyperDMSs were enriched in gene bodies and exons but depleted in promoters, whereas hypoDMSs were enriched in promoters and enhancers. In addition, hyperDMGs showed preference for genes expressed specifically by glutamatergic as opposed to GABAergic neurons and enrichment for axonogenesis- and synaptic-related gene ontology categories, whereas hypoDMGs were enriched for transcription factor activity- and gene expression regulation-related terms. Finally, we found that the DNAm-based "epigenetic age" of neurons from heroin users was younger than that in controls. Suicide-related results were more difficult to interpret. Collectively, these findings suggest that the observed DNAm differences could represent functionally significant marks of heroin-associated plasticity in the OFC.

Schizophrenia-associated reduction of neuronal and oligodendrocyte numbers in the anterior principal thalamic nucleus.

The anterior principal thalamic nucleus provides a nodal link for intralimbic circuits involved in the execution of multiple complex functions that are impaired in schizophrenia (SZ). Using stereologic sampling procedures, we assessed the volume and the number of neurons and oligodendrocytes in this nucleus in well-characterized postmortem material from 23 neuroleptic treated subjects with chronic SZ (SZs) and 12 comparison subjects (Cs) with no psychiatric history. Volume was decreased on average by 17% in SZ, but this difference was not statistically significant. For neuronal number, there was a significant sex by diagnosis interaction with neuronal number being lower in male (p = .002) but not female (p = .374) SZs relative to their respective Cs. For the number of oligodendrocytes, there was a main effect of diagnosis and a diagnosis by sex interaction such that number was significantly reduced in male SZs (p < .001) with a similar trend in female SZs (p = .051) relative to their respective controls. The ratio of oligodendrocytes to neurons was significantly decreased in SZs (p = .045) with no sex by diagnosis interaction. These findings are consistent with a previous report of reduced neuronal number in the anterior principal nucleus of male SZs and add to a growing body of evidence implicating oligodendrocyte abnormalities in SZ.

Metabolic thalamocortical correlations during a verbal learning task and their comparison with correlations among regional volumes.

Methods based on the analysis of metabolic and volumetric interregional correlations have been used in neuroimaging research, yet metabolic and volumetric interregional correlations for identical regions of interest have never been compared in the same group of subjects. Magnetic resonance and [18F]-fluorodeoxyglucose positron emission tomography brain images were acquired in 59 healthy subject. Correlation matrices for relative glucose metabolic rates during a verbal learning task and for relative gray matter volumes were compiled between the manually traced mediodorsal, centromedian, and pulvinar nuclei of the thalamus and 39 cortical Brodmann's areas. Metabolic correlations between the cortex and these thalamic nuclei followed the known patterns of anatomical connectivity in non-human primates. Intercorrelations of the mediodorsal nucleus were widespread with the prefrontal cortex (9 out of 10 Brodmann's areas in the left hemisphere) and temporal lobe (10 out of 11 Brodmann's areas in the left hemisphere) while the pulvinar correlated only with the parietal and occipital cortical areas. Different correlation patterns were observed for the regional gray matter volumes whereby only the pulvinar yielded extensive cortical intercorrelations, primarily with the occipital, parietal, anterior cingulate, and orbitofrontal areas in the right hemisphere. Metabolic thalamocortical correlations were much more extensive for the mediodorsal and centromedian nuclei whereas structural correlations were more extensive for the pulvinar. Therefore, metabolic and volumetric correlational methods are sensitive to different aspects of interregional relations in the brain and their comparison in the same group of subjects may render complementary and only partially overlapping connectivity information.

Correlations between volumes of the pulvinar, centromedian, and mediodorsal nuclei and cortical Brodmann's areas in schizophrenia.

Correlations between the MRI-assessed volumes of the pulvinar, centromedian, and mediodorsal nuclei of the thalamus and 39 cortical Brodmann's areas were evaluated and compared in 41 unmedicated schizophrenia patients and 59 healthy comparison subjects. For the right pulvinar, positive intercorrelations with ipsilateral orbitofrontal and occipital cortices were significantly weaker while negative intercorrelations with dorsolateral prefrontal and temporopolar/entorhinal cortices were stronger in schizophrenia patients compared to healthy subjects. For the centromedian nucleus, positive correlation with the dorsolateral prefrontal area 46 in the right hemisphere was significantly weaker in patients than in healthy subjects. Higher cortical/pulvinar volume ratios for the right frontotemporal regions with stronger negative correlations in patients were associated with better performance on recall and semantic memory tasks. Right pulvinocortical disconnections in patients with schizophrenia may be related to visual attentional deficits whereas stronger-than-normal inverse pulvinar associations with the heteromodal cortical regions may reflect compensatory reliance on alternative information-processing strategies.