William Byne

Evidence for a decrease in basilar dendrites of pyramidal cells in schizophrenic medial prefrontal cortex

A variety of lines of converging evidence implicates the prefrontal cortex (PFC) in schizophrenia. Previous neuroanatomical studies have shown schizophrenia-associated changes in neuron density, soma size and spine number. We recently demonstrated a schizophrenia-associated decrease in microtubule-associated protein 2 (MAP2) immunostaining in laminae III and V of medial prefrontal area 32 and interpreted that finding as suggestive of a loss of dendritic material. We now present data from medial prefrontal area 32 of 11 schizophrenics and 11 comparison subjects. In Golgi-stained material, we describe a significant decrease in the number of both primary (29%) and secondary (46%) basilar dendrites on pyramidal neurons in layer V. Similarly, in layer III there was also a decrease in both primary (17%) and secondary (15%) basilar dendrites. These findings suggest a decrease in synaptic surface area which could lead to aberrant information processing.

The interstitial nuclei of the human anterior hypothalamus: an investigation of variation with sex, sexual orientation, and HIV status.

The interstitial nuclei of the human anterior hypothalamus (INAH1-4) have been considered candidates for homology with the sexually dimorphic nucleus of the preoptic area of the rat. Volumetric sexual dimorphism has been described for three of these nuclei (INAH1-3), and INAH3 has been reported to be smaller in homosexual than heterosexual men. The current study measured the INAH in Nissl-stained coronal sections in autopsy material from 34 presumed heterosexual men (24 HIV- and 10 HIV+), 34 presumed heterosexual women (25 HIV- and 9 HIV+), and 14 HIV+ homosexual men. HIV status significantly influenced the volume of INAH1 (8% larger in HIV+ heterosexual men and women relative to HIV- individuals), but no other INAH. INAH3 contained significantly more neurons and occupied a greater volume in presumed heterosexual males than females. No sex difference in volume was detected for any other INAH. No sexual variation in neuronal size or density was observed in any INAH. Although there was a trend for INAH3 to occupy a smaller volume in homosexual men than in heterosexual men, there was no difference in the number of neurons within the nucleus based on sexual orientation.

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.

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.

Subcortical oligodendrocyte- and astrocyte-associated gene expression in subjects with schizophrenia, major depression and bipolar disorder

Deficits in the expression of oligodendrocyte and myelin genes have been described in numerous cortical regions in schizophrenia and affective disorders; however, relatively little attention has been paid to subcortical structures. Here we employed quantitative real time PCR to examine the mRNA expression of 17 genes that are expressed by oligodendrocyte precursors (OLPs) and their derivatives, including astrocytes. Four subcortical regions were examined (the anteroventral (AV) and mediodorsal thalamic nuclei (MDN), internal capsule (IC) and putamen (Put)) in postmortem material from subjects (age 25-68 at time of death) with no known psychiatric history (NCs) as well as in subjects with schizophrenia (SZ), major depressive disorder (MDD), and bipolar disorder (BPD). In all regions examined, genes expressed after the terminal differentiation of oligodendrocytes tended to have lower levels of mRNA expression in subjects with SZ compared to NCs. These differences were statistically significant across regions for four genes (CNP, GALC, MAG and MOG) and approached significance for TF. No genes were under expressed in MDD. Only TF was under expressed in BPD and only in the IC. In contrast, two astrocyte-associated genes (GFAP and ALDH1L1) had higher mean expression levels across regions in all psychiatric groups relative to NCs. These differences reached statistical significance for SZ and MDD relative to NCs. There were no age by diagnosis interactions. The majority of age regressions had negative slopes for the expression of oligodendrocyte-associated genes. GFAP but not ALDH1L1 expression was significantly and positively correlated with age in the MDN, AV and Put. Across subject groups the expression of both astrocyte genes was highly correlated with cumulative neuroleptic exposure in all regions except the Put. Significant positive correlations were also observed in some regions between cumulative neuroleptic exposure and the expression of genes associated with mature oligodendrocytes as well as with bipotential OLPs. Multiple negative correlations were observed between the mRNA expression of astrocyte genes and genes expressed by terminally differentiated oligodendrocytes. These data are discussed in the context of myelin turnover and potential effects of psychiatric illness as well as medications on the developmental fate of OLPs.

The interstitial nuclei of the human anterior hypothalamus : an investigation of sexual variation in volume and cell size, number and density

The four interstitial nuclei of the anterior hypothalamus (INAH) have been considered as candidate human nuclei for homology with the much studied sexually dimorphic nucleus of the preoptic area of the rat. Assessment of the INAH for sexual dimorphism has produced discrepant results. This study reports the first systematic examination of all four INAH in the human for sexual variation in volume, neuronal number and neuronal size. Serial Nissl-stained coronal sections through the medial preoptic area and anterior hypothalamus were examined from 18 males and 20 females who died between the ages of 17 and 65 without evidence of hypothalamic pathology or infection with the human immunodeficiency virus. A computer-assisted image-analysis system and commercial stereology software package were employed to assess total volume, neuronal number and mean neuronal size for each INAH. INAH3 occupied a significantly greater volume and contained significantly more neurons in males than in females. No sex differences in volume were detected for any of the other INAH. No sexual variation in neuronal size or packing density was observed in any nucleus. The present data corroborate two previous reports of sexual dimorphism of INAH3 but provide no support for previous reports of sexual variation in other INAH.

Thalamic activation during an attention-to-prepulse startle modification paradigm: a functional MRI study

BACKGROUND Prepulse inhibition (PPI) of the startle reflex reflects early stages of information processing and is modulated by selective attention. Animal models indicate medial frontal-thalamic circuitry is important in PPI modulation. We report data from the first functional magnetic resonance imaging (fMRI) study examining whether attending to or ignoring a prepulse differentially activates brain areas within this circuitry. METHODS Ten healthy subjects received structural and functional MRI. During fMRI acquisition, subjects heard intermixed attended and ignored tones serving as prepulses to the startle stimulus. Regions of interest were traced on structural MRI and coregistered to fMRI images. RESULTS Greater amplitude fMRI blood-oxygen-level-dependent response to attended than ignored PPI conditions occurred in the right thalamus, and bilaterally in the anterior and mediodorsal thalamic nuclei, whereas the startle-alone condition showed deactivation. In transitional medial cortex (Brodmann Area 32), which is involved in affective processing of noxious stimuli, the startle-alone condition elicited the greatest response, the attended-PPI condition showed the smallest response, and the ignored-PPI condition was intermediate. CONCLUSIONS These findings extend animal models to humans by indicating thalamic involvement in the modulation of PPI. Further fMRI investigations may elucidate other key structures in the circuitry underlying normal and disordered modulation of PPI.

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.

Astrocyte and Glutamate Markers in the Superficial, Deep, and White Matter Layers of the Anterior Cingulate Gyrus in Schizophrenia

Most studies of the neurobiology of schizophrenia have focused on neurotransmitter systems, their receptors, and downstream effectors. Recent evidence suggests that it is no longer tenable to consider neurons and their functions independently of the glia that interact with them. Although astrocytes have been viewed as harbingers of neuronal injury and CNS stress, their principal functions include maintenance of glutamate homeostasis and recycling, mediation of saltatory conduction, and even direct neurotransmission. Results of studies of astrocytes in schizophrenia have been variable, in part because of the assessment of single and not necessarily universal markers and/or assessment of non-discrete brain regions. We used laser capture microdissection to study three distinct partitions of the anterior cingulate gyrus (layers I–III, IV–VI, and the underlying white matter) in the brains of 18 well-characterized persons with schizophrenia and 21 unaffected comparison controls. We studied the mRNA expression of nine specific markers known to be localized to astrocytes. The expression of astrocyte markers was not altered in the superficial layers or the underlying white matter of the cingulate cortex of persons with schizophrenia. However, the expression of some astrocyte markers (diodinase type II, aquaporin-4, S100β, glutaminase, excitatory amino-acid transporter 2, and thrombospondin), but not of others (aldehyde dehydrogenase 1 family member L1, glial fibrillary acidic protein, and vimentin) was significantly reduced in the deep layers of the anterior cingulate gyrus. These findings suggest that a subset of astrocytes localized to specific cortical layers is adversely affected in schizophrenia and raise the possibility of glutamatergic dyshomeostasis in selected neuronal populations.

The medial preoptic and anterior hypothalamic regions of the rhesus monkey: cytoarchitectonic comparison with the human and evidence for sexual dimorphism

Examination of thionin-stained sections through the hypothalamus of the rhesus monkey revealed nuclei that resemble the first, second and third interstitial nuclei of the anterior hypothalamus (INAH1-3) of the human. Volumetric analysis of these nuclei in a small sample of monkeys suggests that the nucleus that resembles INAH3 is larger in males than in females. INAH1-3 have each been reported to be larger in men than in women and each has been considered as a potential candidate for homology with the much-studied sexually dimorphic nucleus of the preoptic area (SDN-POA) of the rat. Positional and cytoarchitectonic criteria suggest that of these nuclei, INAH3 and its potential counterpart in the rhesus monkey are the best candidates for homology with the SDN-POA. While the criteria employed in the present study may be used to suggest homologies, they are not adequate to confirm them. Confirmation of the homologies suggested here must rely on other considerations such as connectivity, neurotransmitter and peptide content, and function. It is hoped that the present report will stimulate interest in further examinations of the rhesus hypothalamus that will test both the suggested homologies and the evidence for sexual dimorphism.