Philip R. Szeszko

Brain-derived neurotrophic factor Val66met polymorphism and volume of the hippocampal formation

Magnetic resonance (MR) imaging studies have identified hippocampal structural alterations in the pathogenesis of schizophrenia. Brain-derived neurotrophic factor (BDNF) is one of the neurotrophins that is widely expressed in the hippocampal formation and has been implicated in the neurobiology of schizophrenia. Polymorphisms in the BDNF gene may therefore confer risk for schizophrenia through hippocampal pathogenesis and/or making the hippocampus more susceptible to environmental insults. In this study, we investigated whether val66met, a functional and abundant missense polymorphism in the coding region of the BDNF gene, was associated with the volume of the hippocampal formation in 19 patients with first-episode schizophrenia and 25 healthy volunteers. A total of 124 contiguous T1-weighted coronal MR images (slice thickness=1.5 mm) were acquired through the whole head using a 3D Fast SPGR IR Prep sequence on a 1.5 T GE imaging system. Volumes of the right and left hippocampal formation were measured manually by an operator blind to group status and genotype. All participants were genotyped for the BDNF val66met locus. Mixed model analyses revealed a main effect of BDNF val66met genotype such that in the combined sample of patients and healthy volunteers, val/val homozygotes (N=27) had larger volumes of the hippocampal formation compared to val/met heterozygotes (N=17). In separate analyses by group, however, val66met genotype accounted for a greater proportion of the variance in the volume of the hippocampal formation in patients compared to healthy volunteers. These findings implicate genetic involvement of BDNF in variation of human hippocampal volume and suggest that this effect may be greater among patients compared to healthy volunteers.

Attention-deficit/hyperactivity disorder: A preliminary diffusion tensor imaging study

BACKGROUND The purpose of this study was to explore whether there are white matter (WM) abnormalities in children with attention-deficit/hyperactivity disorder (ADHD) using diffusion tensor imaging. Based upon the literature, we predicted decreased fractional anisotropy (FA) findings in the frontal and cerebellar regions. METHODS Eighteen patients with ADHD and 15 age- and gender-matched healthy volunteers received DTI assessments. Fractional anisotropy maps of WM were compared between groups with a voxelwise analysis after intersubject registration to Talairach space. RESULTS Children with ADHD had decreased FA in areas that have been implicated in the pathophysiology of ADHD: right premotor, right striatal, right cerebral peduncle, left middle cerebellar peduncle, left cerebellum, and left parieto-occipital areas. CONCLUSIONS These preliminary data support the hypothesis that alterations in brain WM integrity in frontal and cerebellar regions occur in ADHD. The pattern of decreased FA might implicate the corticopontocerebellar circuit in the pathophysiology of ADHD.

Regional specificity of hippocampal volume reductions in first-episode schizophrenia

Hippocampal volume reductions are widely observed in schizophrenia. Some studies suggest anterior hippocampal regions are more susceptible and associated with frontal lobe dysfunctions, while others implicate posterior regions. Using high-resolution MR images and novel computational image analysis methods, we identified the hippocampal subregions most vulnerable to disease processes in 62 (45 m/17 f) first-episode schizophrenia patients compared to 60 (30 m/30 f) healthy controls, similar in age. The hippocampi were traced on coronal brain slices and hemispheric volumes were compared between diagnostic groups. Regional structural abnormalities were identified by comparing distances, measured from homologous hippocampal surface points to the central core of each individuals hippocampal surface model, between groups in 3D. CSF concentrations were also compared statistically at homologous hippocampal surface points to localize corresponding gray matter reductions. Significant bilateral hippocampal volume reductions were observed in schizophrenia irrespective of brain size corrections. Statistical mapping results, confirmed by permutation testing, showed pronounced left hemisphere shape differences in anterior and midbody CA1 and CA2 regions in patients. Significant CSF increases surrounding the hippocampus were observed in a similar spatial pattern in schizophrenia. Results confirm that hippocampal volume reductions are a robust neuroanatomical correlate of schizophrenia and are present by first episode. Mid- to antero-lateral hippocampal regions show pronounced volume changes and complementary increases in peri-hippocampal CSF, suggesting that these hippocampal regions are more susceptible to disease processes in schizophrenia. Targeting regional hippocampal abnormalities may help dissociate schizophrenia patients from other groups exhibiting global hippocampal volume changes, and better focus systems-level pathophysiological hypotheses.

White matter development during late adolescence in healthy males: a cross-sectional diffusion tensor imaging study.

BACKGROUND Previous MRI studies of healthy children have reported age-related white matter (WM) changes in language and motor areas of the brain. The authors investigated WM development in healthy adolescent males through age-associated changes in fractional anisotropy (FA), radial (lambda( perpendicular)) and axial (lambda(||)) diffusivity. METHODS Twenty-four healthy adolescent males (mean age=16.6, SD=2.5 years) were divided into two groups with an age split of 16.9 years and underwent a whole-brain voxelwise analysis. RESULTS At a threshold of p<0.001 and extent threshold of 100 contiguous voxels, several clusters with increased FA and axial diffusivity and no differences in radial diffusivity were observed in older adolescents compared to the younger adolescents in the left arcuate fasciculus, bilateral posterior internal capsule/thalamic radiation, bilateral prefrontal gyrus, right superior temporal gyrus, and posterior corpus callosum. Increased FA and lambda(||) of several clusters along the arcuate fasciculus significantly correlated with a test of language and semantic memory. CONCLUSIONS These results suggest ongoing maturational changes especially in the arcuate fasiculus during late adolescence. Increased FA and lambda(||) with no changes in radial diffusivity may reflect a developmental pattern of reduced tortuousity toward more straightened fibers and/or increased axonal fiber organization during late adolescence.

Clinical and Neuropsychological Correlates of White Matter Abnormalities in Recent Onset Schizophrenia

The objective of this study was to investigate the clinical and neuropsychological correlates of white matter abnormalities in patients with schizophrenia studied early in the course of illness. A total of 33 (21 male/12 female) patients with recent onset schizophrenia and 30 (18 male/12 female) healthy volunteers completed structural and diffusion tensor imaging exams. Patients also received clinical and neuropsychological assessments. Fractional anisotropy (FA) maps were compared between groups in the white matter using a voxelwise analysis following intersubject registration to Talairach space and correlated with functional indices. Compared to healthy volunteers, patients demonstrated significantly (p<0.001, cluster size ⩾100) lower FA within temporal lobe white matter regions corresponding approximately to the right and left uncinate fasciculus, left inferior fronto-occipital fasciculus, and left superior longitudinal fasciculus. There were no areas of significantly higher FA in patients compared to healthy volunteers. Lower FA in the bilateral uncinate fasciculus correlated significantly with greater severity of negative symptoms (alogia and affective flattening), and worse verbal learning/memory functioning. In addition, higher FA in the inferior fronto-occipital fasciculus correlated significantly with greater severity of delusions and hallucinations. White matter abnormalities are evident in patients with schizophrenia early in the course of illness, appearing most robust in left temporal regions. These abnormalities have clinical and neuropsychological correlates, which may be useful in further characterizing structure–function relations in schizophrenia and constraining neurobiological models of the disorder.

Cortical thinning in cingulate and occipital cortices in first episode schizophrenia

BACKGROUND Postmortem studies examining discrete regions show reduced cortical thickness in schizophrenia. Computational image analysis methods allow spatially detailed cortical thickness measurements across the entire cortex in 3D, but have not addressed thickness changes in cingulate or other cortices bordering the medial walls of the cerebral hemispheres in first episode schizophrenia. METHODS Magnetic resonance images and cortical pattern matching methods were used to compare gray matter thickness, measured at sub-voxel resolution at thousands of spatially equivalent locations on the medial hemispheric surfaces, between 72 (51m/21f) first episode schizophrenia patients and 78 (37m/41f) healthy controls similar in age. Group differences were mapped in 3D, and their overall significance was confirmed by permutation testing. RESULTS Patients with little or no prior antipsychotic medication treatment showed significant cortical thinning within cingulate, occipital and frontopolar cortices with no significant increases in any cortical location. Regional sex differences were observed with pronounced thinning in the left paracentral lobule and right posterior cingulate in male and female patients respectively compared to same sex controls. CONCLUSIONS Cortical thinning may correspond to cytoarchitectural and neurochemical abnormalities observed in similar anatomic locations and may underlie systems-wise disturbances that include heteromodal association cortices, where cortical thinning has been previously observed in first episode schizophrenia.

Reduced frontal white matter integrity in early-onset schizophrenia: a preliminary study.

BACKGROUND Research suggests that brain frontal white matter (WM) might be qualitatively altered in adolescents with early onset schizophrenia (EOS). Diffusion tensor imaging provides a relatively new approach for quantifying possible connectivity of WM in vivo. METHODS Diffusion tensor imaging was used to examine the WM integrity of frontal regions at seven levels from 25 mm above to 5 mm below the anterior commissure-posterior commissure (AC-PC) plane. Three other regions were examined: the occipital region at the AC-PC plane and the genu and splenium of the corpus callosum. Fractional anisotropy was compared between 12 adolescents (nine male, 3 female) with EOS (onset of psychotic symptoms by age 18 years) and nine age-similar healthy comparison subjects (six male, 3 female). RESULTS Adolescents with EOS had significantly reduced fractional anisotropy in the frontal WM at the AC-PC plane in both hemispheres and in the occipital WM at the AC-PC plane in the right hemisphere. CONCLUSIONS These preliminary data support a hypothesis that alterations in brain WM integrity occur in adolescents with EOS. Abnormalities found in this study were similar to those reported in adults with chronic schizophrenia. Additional studies are needed to assess whether there is progression of WM abnormalities in schizophrenia.

AMYGDALA AND HIPPOCAMPAL VOLUMES IN FAMILIAL EARLY ONSET MAJOR DEPRESSIVE DISORDER

BACKGROUND Abnormalities in the amygdala and hippocampus have been implicated in the pathogenesis of major depressive disorder (MDD). To our knowledge, no prior study has examined amygdala-hippocampus anatomy in pediatric patients with familial MDD (at least one first degree relative with MDD). METHODS Thirty-two psychotropic-naive patients with familial MDD, aged 8-21 years (12 males and 20 females), and 35 group-matched healthy participants (13 males and 22 females) underwent volumetric magnetic resonance imaging in order to evaluate hippocampal and amygdala volumes. RESULTS Patients with familial MDD had significantly smaller left hippocampal (p = .007, effect size [d] = .44) and right hippocampal volumes (p = .025, d = .33) than controls. No differences were noted in amygdala volumes between groups (right: p > .05, left: p > .05). No correlations between hippocampal or amygdala volumes and demographic or clinical variables were noted. CONCLUSIONS Reduced hippocampal volume may be suggestive of a risk factor for developing MDD.

A role for white matter abnormalities in the pathophysiology of bipolar disorder.

Bipolar disorder is a chronically disabling psychiatric disorder characterized by manic states that is often interspersed with periods of depression whose neurobiology remains largely unknown. There is, however, increasing evidence that white matter (WM) abnormalities may play an important role in the neurobiology of the disorder. In this review we critically evaluate evidence for WM abnormalities in bipolar disorder obtained from neuroimaging, neuropathological, and genetic research. Increased rates of white matter hyperintensities, regional volumetric abnormalities, abnormal water diffusion along prefrontal-subcortical tracts, fewer oligodendrocytes in prefrontal WM, and alterations in the expression of myelin- and oligodendrocyte-related genes are among the most consistent findings. Abnormalities converge in the prefrontal WM and, in particular, tracts that connect prefrontal regions and subcortical gray matter structures known to be involved in emotion. Taken together, the evidence supports and clarifies a model of BD that involves disconnectivity in regions implicated in emotion generation and regulation.

White Matter Development in Adolescence: Diffusion Tensor Imaging and Meta-Analytic Results

BACKGROUND In light of the evidence for brain white matter (WM) abnormalities in schizophrenia, study of normal WM maturation in adolescence may provide critical insights relevant to the neurodevelopment of the disorder. Voxel-wise diffusion tensor imaging (DTI) studies have consistently demonstrated increases in fractional anisotropy (FA), a putative measure of WM integrity, from childhood into adolescence. However, the WM tracts that show FA increases have been variable across studies. Here, we aimed to assess which WM tracts show the most pronounced changes across adolescence. METHODS DTI was performed in 78 healthy subjects aged 8-21 years, and voxel-wise analysis conducted using tract-based spatial statistics (TBSS). In addition, we performed the first meta-analysis of TBSS studies on WM development in adolescence. RESULTS In our sample, we observed bilateral increases in FA with age, which were most significant in the left superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and anterior thalamic radiation. These findings were confirmed by the meta-analysis, and FA increase in the bilateral SLF was the most consistent finding across studies. Moreover, in our sample, FA of the bilateral SLF showed a positive association with verbal working memory performance and partially mediated increases in verbal fluency as a function of increasing age. CONCLUSIONS These data highlight increasing connectivity in the SLF during adolescence. In light of evidence for compromised SLF integrity in high-risk and first-episode patients, these data suggest that abnormal maturation of the SLF during adolescence may be a key target in the neurodevelopment of schizophrenia.