Temporal control of Wnt signaling is required for habenular neuron diversity and brain asymmetry.

Precise temporal coordination of signaling processes is pivotal for cellular differentiation during embryonic development. A vast number of secreted molecules are produced and released by cells and tissues, and travel in the extracellular space. Whether they induce a signaling pathway and instruct cell fate, however, depends on a complex network of regulatory mechanisms, which are often not well understood. The conserved bilateral left-right asymmetrically formed habenulae of the zebrafish are an excellent model for investigating how signaling control facilitates the generation of defined neuronal populations. Wnt signaling is required for habenular neuron type specification, asymmetry and axonal connectivity. The temporal regulation of this pathway and the players involved have, however, have remained unclear. We find that tightly regulated temporal restriction of Wnt signaling activity in habenular precursor cells is crucial for the diversity and asymmetry of habenular neuron populations. We suggest a feedback mechanism whereby the tumor suppressor Wnt inhibitory factor Wif1 controls the Wnt dynamics in the environment of habenular precursor cells. This mechanism might be common to other cell types, including tumor cells.

Altered topological characteristics of morphological brain network relate to language impairment in high genetic risk subjects and schizophrenia patients.

OBJECTIVE: Evidence suggests relationships between abnormalities in various cortical and subcortical brain structures and language dysfunction in individuals with schizophrenia, and to some extent in those with increased genetic risk for this diagnosis. The topological features of the structural brain network at the systems-level and their impact on language function in schizophrenia and in those at high genetic risk has been less well studied. METHOD: Single-subject morphological brain network was constructed in a total of 71 subjects (20 patients with schizophrenia, 19 individuals at high genetic risk for schizophrenia, and 32 controls). Among these 71 subjects, 56 were involved in our previous neuroimaging studies. Graphic Theoretical Techniques was applied to calculate the global and nodal topological characteristics of the morphological brain network of each participant. Index scores for five language-related cognitive tests were also attained from each participant. RESULTS: Significantly smaller nodal degree in bilateral superior occipital gyri (SOG) were observed in individuals with schizophrenia, as compared to the controls and those at high risk; while significantly reduced nodal betweenness centrality (quantifying the level of a node in connecting other nodes in the network) in right middle frontal gyrus (MFG) was found in the high-risk group, relative to controls. The right MFG nodal efficiency and hub capacity (represented by both nodal degree and betweenness centrality) of the morphological brain network were negatively associated with the wide range achievement test (WRAT) standard performance score; while the right SOG nodal degree was positively associated with the WRAT standard performance score, in the entire study sample. CONCLUSIONS: These findings enhance the understanding of structural brain abnormalities at the systems-level in individuals with schizophrenia and those at high genetic risk, which may serve as critical neural substrates for the origin of the language-related impairments and symptom manifestations of schizophrenia.

The CACNA1C risk allele rs1006737 is associated with age-related prefrontal cortical thinning in bipolar I disorder.

Calcium channels control the inflow of calcium ions into cells and are involved in diverse cellular functions. The CACNA1C gene polymorphism rs1006737 A allele has been strongly associated with increased risk for bipolar disorder (BD) and with modulation of brain morphology. The medial prefrontal cortex (mPFC) has been widely associated with mood regulation in BD, but the role of this CACNA1C polymorphism in mPFC morphology and brain aging has yet to be elucidated. One hundred seventeen euthymic BD type I subjects were genotyped for CACNA1C rs1006737 and underwent 3 T three-dimensional structural magnetic resonance imaging scans to determine cortical thickness of mPFC components (superior frontal cortex (sFC), medial orbitofrontal cortex (mOFC), caudal anterior cingulate cortex (cACC) and rostral anterior cingulate cortex (rACC)). Carriers of the CACNA1C allele A exhibited greater left mOFC thickness compared to non-carriers. Moreover, CACNA1C A carriers showed age-related cortical thinning of the left cACC, whereas among A non-carriers there was not an effect of age on left cACC cortical thinning. In the sFC, mOFC and rACC (left or right), a negative correlation was observed between age and cortical thickness, regardless of CACNA1C rs1006737 A status. Further studies investigating the direct link between cortical thickness, calcium channel function, apoptosis mechanism and their underlying relationship with aging-associated cognitive decline in BD are warranted.

Ancestral Exposure to Stress Generates New Behavioral Traits and a Functional Hemispheric Dominance Shift.

In a continuously stressful environment, the effects of recurrent prenatal stress (PS) accumulate across generations and generate new behavioral traits in the absence of genetic variation. Here, we investigated if PS or multigenerational PS across 4 generations differentially affect behavioral traits, laterality, and hemispheric dominance in male and female rats. Using skilled reaching and skilled walking tasks, 3 findings support the formation of new behavioral traits and shifted laterality by multigenerational stress. First, while PS in the F1 generation did not alter paw preference, multigenerational stress in the F4 generation shifted paw preference to favor left-handedness only in males. Second, multigenerational stress impaired skilled reaching and skilled walking movement abilities in males, while improving these abilities in females beyond the levels of controls. Third, the shift toward left-handedness in multigenerationally stressed males was accompanied by increased dendritic complexity and greater spine density in the right parietal cortex. Thus, cumulative multigenerational stress generates sexually dimorphic left-handedness and dominance shift toward the right hemisphere in males. These findings explain the origins of apparently heritable behavioral traits and handedness in the absence of DNA sequence variations while proposing epigenetic mechanisms.

Estimating the Heritability of Structural and Functional Brain Connectivity in Families Affected by Attention-Deficit/Hyperactivity Disorder.

IMPORTANCE: Despite its high heritability, few risk genes have been identified for attention-deficit/hyperactivity disorder (ADHD). Brain-based phenotypes could aid gene discovery. There is a myriad of structural and functional connections that support cognition. Disruption of such connectivity is a key pathophysiologic mechanism for ADHD, and identifying heritable phenotypes within these connections could provide candidates for genomic studies. OBJECTIVE: To identify the structural and functional connections that are heritable and pertinent to ADHD. DESIGN, SETTING, AND PARTICIPANTS: Members of extended multigenerational families enriched for ADHD were evaluated. Structural connectivity was defined by diffusion tensor imaging (DTI) of white matter tract microstructure and functional connectivity through resting-state functional magnetic resonance imaging (rsfMRI). Heritability and association with ADHD symptoms were estimated in 24 extended multigenerational families enriched for ADHD (305 members with clinical phenotyping, 213 with DTI, and 193 with rsfMRI data). Findings were confirmed in 52 nuclear families (132 members with clinical phenotypes, 119 with DTI, and 84 with rsfMRI). The study and data analysis were conducted from April 1, 2010, to September 1, 2016. RESULTS: In the 52 nuclear families, 86 individuals (65.2%) were male and the mean (SD) age at imaging was 20.9 (15.0) years; in the 24 multigenerational extended families, 145 individuals (47.5%) were male and mean age at imaging was 30.4 (19.7) years. Microstructural properties of white matter tracts connecting ipsilateral cortical regions and the corpus callosum were significantly heritable, ranging from total additive genetic heritability (h2) = 0.69 (SE, 0.13; P = .0000002) for radial diffusivity of the right superior longitudinal fasciculus to h2 = 0.46 (SE, 0.15; P = .0009) for fractional anisotropy of the right inferior fronto-occipital fasciculus. Association with ADHD symptoms was found in several tracts, most strongly for the right superior longitudinal fasciculus (t = -3.05; P = .003). Heritable patterns of functional connectivity were detected within the default mode (h2 = 0.36; SE, 0.16; cluster level significance, P < .002), cognitive control (h2 = 0.32; SE, 0.15; P < .002), and ventral attention networks (h2 = 0.36; SE, 0.16; P < .002). In all cases, subregions within each network showed heritable functional connectivity with the rest of that network. More symptoms of hyperactivity/impulsivity (t = -2.63; P = .008) and inattention (t = -2.34; P = .02) were associated with decreased functional connectivity within the default mode network. Some cross-modal correlations were purely phenotypic, such as that between axial diffusivity of the right superior longitudinal fasciculus and heritable aspects of the default mode network (phenotypic correlation, ρp = -0.12; P = .03). A genetic cross-modal correlation was seen between the ventral attention network and radial diffusivity of the right inferior fronto-occipital fasciculus (genetic correlation, ρg = -0.45, P = .02). CONCLUSIONS: Analysis of data on multigenerational extended and nuclear families identified the features of structural and functional connectivity that are both significantly heritable and associated with ADHD. In addition, shared genetic factors account for some phenotypic correlations between functional and structural connections. Such work helps to prioritize the facets of the brain's connectivity for future genomic studies.

Polygenic Risk of Psychosis and Ventral Striatal Activation During Reward Processing in Healthy Adolescents.

IMPORTANCE: Psychotic disorders are characterized by attenuated activity in the brain's valuation system in key reward processing areas, such as the ventral striatum (VS), as measured with functional magnetic resonance imaging. OBJECTIVE: To examine whether common risk variants for psychosis are associated with individual variation in the VS. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study of a large cohort of adolescents from the IMAGEN study (a European multicenter study of reinforcement sensitivity in adolescents) was performed from March 1, 2008, through December 31, 2011. Data analysis was conducted from October 1, 2015, to January 9, 2016. Polygenic risk profile scores (RPSs) for psychosis were generated for 1841 healthy adolescents. Sample size and characteristics varied across regression analyses, depending on mutual information available (N = 1524-1836). MAIN OUTCOMES AND MEASURES: Reward-related brain function was assessed with blood oxygen level dependency (BOLD) in the VS using the monetary incentive delay (MID) task, distinguishing reward anticipation and receipt. Behavioral impulsivity, IQ, MID task performance, and VS BOLD were regressed against psychosis RPS at 4 progressive P thresholds (P < .01, P < .05, P < .10, and P < .50 for RPS models 1-4, respectively). RESULTS: In a sample of 1841 healthy adolescents (mean age, 14.5 years; 906 boys and 935 girls), we replicated an association between increasing psychosis RPS and reduced IQ (matrix reasoning: corrected P = .003 for RPS model 2, 0.4% variance explained), supporting the validity of the psychosis RPS models. We also found a nominally significant association between increased psychosis RPS and reduced MID task performance (uncorrected P = .03 for RPS model 4, 0.2% variance explained). Our main finding was a positive association between psychosis RPS and VS BOLD during reward anticipation at all 4 psychosis RPS models and for 2 P thresholds for reward receipt (RPS models 1 and 3), correcting for the familywise error rate (0.8%-1.9% variance explained). CONCLUSIONS AND RELEVANCE: These findings support an association between psychosis RPS and VS BOLD in adolescents. Genetic risk for psychosis may shape an individual's response to rewarding stimuli.

The changes of c-Fos expression by motor cortex stimulation in the deafferentation pain model.

The effect of motor cortex stimulation (MCS) therapy for deafferentation pain was evaluated based on c-Fos, a known pain marker. Nineteen mature cats weighing 1.5-3.5 kg were used. Cats were divided into three groups: a deafferentation pain group in which the left trigeminal ganglion was destroyed, an MCS group in which MCS was used following destruction of the trigeminal ganglion, and a control group. Sites and levels of c-Fos expression were examined immunohistochemically. The percentage of c-Fos-positive cells in the left spinal nucleus of the trigeminus, the bilateral insula, and the bilateral operculum increased in both the deafferentation pain and the MCS groups. There were no statistically significant differences between these groups. In the cingulate gyrus, the percentage of c-Fos-positive cells increased bilaterally in the deafferentation pain group and the MCS group, but the increase was greater in the MCS group. The increase in c-Fos-positive cells in the left spinal nucleus of the trigeminus in the deafferentation group may reflect reported electrical hyperactivity. The cingulate gyrus, insula, and parietal operculum were activated after deafferentation. This change (increase in c-Fos positive cells) is related to the development of deafferentation pain. Pain relief due to MCS is not dependent on the suppression of the activated left spinal nucleus of the trigeminus or the descending analgesic mechanism of the brain stem. Activation of the cingulate gyrus appears to be a factor in the analgesic mechanism of MCS.

A multicenter tractography study of deep white matter tracts in bipolar I disorder: psychotic features and interhemispheric disconnectivity.

IMPORTANCE: Tractography studies investigating white matter (WM) abnormalities in patients with bipolar disorder have yielded heterogeneous results owing to small sample sizes. The small size limits their generalizability, a critical issue for neuroimaging studies of biomarkers of bipolar I disorder (BPI). OBJECTIVES: To study WM abnormalities using whole-brain tractography in a large international multicenter sample of BPI patients and to compare these alterations between patients with or without a history of psychotic features during mood episodes. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional, multicenter, international, Q-ball imaging tractography study comparing 118 BPI patients and 86 healthy control individuals. In addition, among the patient group, we compared those with and without a history of psychotic features. University hospitals in France, Germany, and the United States contributed participants. INTERVENTIONS: Participants underwent assessment using the Diagnostic Interview for Genetic Studies at the French sites or the Structured Clinical Interview for DSM-IV at the German and US sites. Diffusion-weighted magnetic resonance images were acquired using the same acquisition parameters and scanning hardware at each site. We reconstructed 22 known deep WM tracts using Q-ball imaging tractography and an automatized segmentation technique. MAIN OUTCOMES AND MEASURES: Generalized fractional anisotropy values along each reconstructed WM tract. RESULTS: Compared with controls, BPI patients had significant reductions in mean generalized fractional anisotropy values along the body and the splenium of the corpus callosum, the left cingulum, and the anterior part of the left arcuate fasciculus when controlling for age, sex, and acquisition site (corrected for multiple testing). Patients with a history of psychotic features had a lower mean generalized fractional anisotropy value than those without along the body of the corpus callosum (corrected for multiple testing). CONCLUSIONS AND RELEVANCE: In this multicenter sample, BPI patients had reduced WM integrity in interhemispheric, limbic, and arcuate WM tracts. Interhemispheric pathways are more disrupted in patients with than in those without psychotic symptoms. Together these results highlight the existence of an anatomic disconnectivity in BPI and further underscore a role for interhemispheric disconnectivity in the pathophysiological features of psychosis in BPI.

Language laterality, handedness and empathy in a sample of parents of children with autism spectrum disorder.

BACKGROUND: First-order relatives of persons with Autism Spectrum Disorder (ASD) exhibit a cognitive pattern which is part of a broader autism phenotype. METHOD: The purpose of the present study was to evaluate whether some neuropsychological features related to the autism phenotype are present in parents of ASD children. To this end, the exploration included a dichotic listening task, handedness and the Empathy Quotient (EQ-60). RESULTS: The scores obtained by the total sample (fathers plus mothers) were similar to those of the general population, although there were differences in some parameters of the dichotic listening task depending on the gender. Contrary to expectations, only in fathers, the negative correlation between data from both ears was not statistically significant, which could be evidence of a lack of hemispheric interdependence. CONCLUSIONS: These results support the possible existence of a genetic susceptibility to an aberrant language asymmetry pattern. Moreover, possible unknown epigenetic factors could act on a vulnerable genotype in some ASD subjects. Nevertheless, due to the small sample size, the present research must be considered a pilot study.

Decreased left middle temporal gyrus volume in antipsychotic drug-naive, first-episode schizophrenia patients and their healthy unaffected siblings.

BACKGROUND: The shared neuropathological characteristics of patients with schizophrenia and their siblings might represent intermediate phenotypes that could be used to investigate genetic susceptibility to the illness. We sought to discover gray matter volume differences in patients with schizophrenia and their unaffected siblings with voxel-based morphometry (VBM). METHODS: We recruited antipsychotic drug-naive, first-episode schizophrenia (FES) patients, their unaffected siblings and age-, sex- and handedness-matched healthy controls. We used VBM to investigate differences in gray matter volume among the 3 groups. RESULTS: There were significant gray matter volumetric differences among the 3 groups in bilateral hippocampal and parahippocampal gyri, bilateral middle temporal gyri, and superior temporal gyri (FDR p<0.05). Patients had significant regional gray matter reduction in all regions listed above compared with healthy volunteers, and their gray matter volume in the right hippocampus and parahippocampus was also lower than the sibling group. The sibling group had significantly lower volumes compared to healthy individuals only in the left middle temporal gyrus, and volume of this region was not different between siblings and patients. CONCLUSIONS: Our findings confirm and extend previous VBM analyses in schizophrenia and it indicate that schizophrenia may be characterized by an abnormal development of cerebral lateralization. Furthermore, these data argue that patients and their unaffected siblings might share decreases in the gray matter volume of the left middle temporal gyrus, and this regional reduction might be a potential endophenotype for schizophrenia.

Complementary hemispheric specialization for language production and visuospatial attention.

Language production and spatial attention are the most salient lateralized cerebral functions, and their complementary specialization has been observed in the majority of the population. To investigate whether the complementary specialization has a causal origin (the lateralization of one function causes the opposite lateralization of the other) or rather is a statistical phenomenon (different functions lateralize independently), we determined the lateralization for spatial attention in a group of individuals with known atypical right hemispheric (RH) lateralization for speech production, based on a previous large-scale screening of left-handers. We show that all 13 participants with RH language dominance have left-hemispheric dominance for spatial attention, and all but one of 16 participants with left-hemispheric language dominance are RH dominant for spatial attention. Activity was observed in the dorsal fronto-parietal pathway of attention, including the inferior parietal sulcus and superior parietal lobule, the frontal eye-movement field, and the inferior frontal sulcus/gyrus, and these regions functionally colateralized in the hemisphere dominant for attention, independently of the side of lateralization. Our results clearly support the Causal hypothesis about the complementary specialization, and we speculate that it derives from a longstanding evolutionary origin. We also suggest that the conclusions about lateralization based on an unselected sample of the population and laterality assessment using coarse functional transcranial Doppler sonography should be interpreted with more caution.

Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder.

OBJECTIVE: The subgenual anterior cingulate cortex is implicated in the pathology and treatment response of major depressive disorder. Low levels of brain-derived neurotrophic factor (BDNF) and reduced markers for GABA function, including in the amygdala, are reported in major depression, but their contribution to subgenual anterior cingulate cortex dysfunction is not known. METHOD: Using polymerase chain reaction, we first assessed the degree to which BDNF controls mRNA expression (defined as BDNF dependency) of 15 genes relating to GABA and neuropeptide functions in the cingulate cortex of mice with reduced BDNF function (BDNF-heterozygous [Bdnf(+/-)] mice and BDNF exon-IV knockout [Bdnf(KIV)] mice). Gene expression was then quantified in the subgenual anterior cingulate cortex of 51 postmortem subjects with major depressive disorder and comparison subjects (total subjects, N=102; 49% were women) and compared with previous amygdala results. RESULTS: Based on the results in Bdnf(+/-) and Bdnf(KIV) mice, genes were sorted into high, intermediate, and no BDNF dependency sets. In postmortem human subjects with major depression, BDNF receptor (TRKB) expression, but not BDNF, was reduced. Postmortem depressed subjects exhibited down-regulation in genes with high and intermediate BDNF dependency, including markers of dendritic targeting interneurons (SST, NPY, and CORT) and a GABA synthesizing enzyme (GAD2). Changes extended to BDNF-independent genes (PVALB and GAD1). Changes were greater in men (potentially because of low baseline expression in women), displayed notable differences from prior amygdala results, and were not explained by demographic or clinical factors other than sex. CONCLUSIONS: These parallel human/mouse analyses provide direct (low TRKB) and indirect (low expression of BDNF-dependent genes) evidence in support of decreased BDNF signaling in the subgenual anterior cingulate cortex in individuals with major depressive disorder, implicate dendritic targeting GABA neurons and GABA synthesis, and, together, suggest a common BDNF-/GABA-related pathology in major depression with sex- and brain region-specific features.

Glutathione S-transferase alpha 1 risk polymorphism and increased bilateral thalamus mean diffusivity in schizophrenia.

Oxidative damage in brain cells is one of the factors hypothesized to be involved in the pathogenesis of schizophrenia. Glutathione S-transferase (GST) A1*B polymorphism, a genotype associated with a higher risk of oxidative damage, is associated with increased frequency of schizophrenia diagnosis. Thus, here we studied Glutathione S-transferase (GST) A1 polymorphism and diffusion tensor imaging-mean diffusivity (MD) data on deep grey matter brain structures in 56 patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revised (DSM-IV-TR) schizophrenia. Clinical diagnosis and psychopathological symptom severity were assessed by using the Structured Clinical Interview for DSM-IV-TR (SCID-P) and the Scales for Assessment of Positive and Negative Symptoms (SAPS and SANS). Results confirmed that patients with schizophrenia who were carriers of the GSTA1 *B risk allele had an increased MD in bilateral thalami and increased severity of auditory and global hallucinations in comparison with non-B carriers. Thus, oxidative stress associated factors may be implicated in specific mechanisms of schizophrenia such as altered microstructure of the thalami and specific psychopathological features of auditory hallucinations.

Interaction of catechol O-methyltransferase and serotonin transporter genes modulates effective connectivity in a facial emotion-processing circuitry.

Imaging genetic studies showed exaggerated blood oxygenation level-dependent response in limbic structures in carriers of low activity alleles of serotonin transporter-linked promoter region (5-HTTLPR) as well as catechol O-methyltransferase (COMT) genes. This was suggested to underlie the vulnerability to mood disorders. To better understand the mechanisms of vulnerability, it is important to investigate the genetic modulation of frontal-limbic connectivity that underlies emotional regulation and control. In this study, we have examined the interaction of 5-HTTLPR and COMT genetic markers on effective connectivity within neural circuitry for emotional facial expressions. A total of 91 healthy Caucasian adults underwent functional magnetic resonance imaging experiments with a task presenting dynamic emotional facial expressions of fear, sadness, happiness and anger. The effective connectivity within the facial processing circuitry was assessed with Granger causality method. We have demonstrated that in fear processing condition, an interaction between 5-HTTLPR (S) and COMT (met) low activity alleles was associated with reduced reciprocal connectivity within the circuitry including bilateral fusiform/inferior occipital regions, right superior temporal gyrus/superior temporal sulcus, bilateral inferior/middle prefrontal cortex and right amygdala. We suggest that the epistatic effect of reduced effective connectivity may underlie an inefficient emotion regulation that places these individuals at greater risk for depressive disorders.

Similar clinical and neuroimaging features in monozygotic twin pair with mutation in progranulin.

OBJECTIVE: To report the phenotypic characterization of monozygotic twins with mutations encoding progranulin (PGRN). METHODS: We studied a twin pair with an exon 4 gene deletion in the PGRN gene. Both twins had clinical and neuropsychological examinations as well as structural MRI and fluorodeoxyglucose PET (FDG-PET) scans. PGRN gene sequencing was performed followed by progranulin ELISA in plasma. RESULTS: Both twins manifested symptoms within 3 years of each other, with early behavioral, language, dysexecutive, and memory problems. MRI and FDG-PET imaging demonstrated a strikingly similar topography of findings with clear left hemisphere predominance. Serum progranulin levels in both were well below those from a normal population sample. CONCLUSIONS: Compared with the heterogeneity seen in many families with PGRN mutations, these monozygotic twins demonstrated strong clinical, neuroimaging, and serum progranulin level similarities, demonstrating the importance of shared genetic profiles beyond environmental influences in the symptomatic expression of the disease.

Breast cancer predisposition and brain hemispheric laterality specification likely share a common genetic cause.

The majority of breast cancer cases seen in women remain unexplained by simple Mendelian genetics. It is generally hypothesized that such non-familial, so-called sporadic cases, result from exposure of the affected individuals to a cancer-causing environment and/or from stochastic cell biological errors. Clearly, adverse environment exposure can cause disease, but is that necessarily the cause of most sporadic cases? Curiously, female breast cancer patients who were selected to prefer right-hand-use reportedly exhibited a higher incidence of reversed-brain hemispheric laterality when compared to that of the public at large. Notably, such a higher level of hemispheric reversal is also found in healthy, left-handed or ambidextrous persons. Based on the association between these disparate traits, a new hypothesis for the etiology of sporadic breast cancer cases is advanced here; breast cancer predisposition and brain laterality development likely share a common genetic cause.

Distinguishing between major depressive disorder and obsessive-compulsive disorder in children by measuring regional cortical thickness.

CONTEXT: Cortical abnormalities have been noted in previous studies of major depressive disorder (MDD). OBJECTIVE: To hypothesize differences in regional cortical thickness among children with MDD, children with obsessive-compulsive disorder (OCD), and healthy controls. DESIGN: Cross-sectional study of groups. SETTING: Children's Hospital of Michigan in Detroit. PARTICIPANTS: A total of 24 psychotropic drug-naive pediatric patients with MDD (9 boys and 15 girls), 24 psychotropic drug-naive pediatric outpatients with OCD (8 boys and 16 girls), and 30 healthy controls (10 boys and 20 girls). INTERVENTION: Magnetic resonance imaging. MAIN OUTCOME MEASURE: Cortical thickness. RESULTS: In the right hemisphere of the brain, the pericalcarine gyrus was thinner in patients with MDD than in outpatients with OCD (P = .002) or healthy controls (P = .04), the postcentral gyrus was thinner in patients with MDD than in outpatients with OCD (P = .002) or healthy controls (P = .02), and the superior parietal gyrus was thinner in patients with MDD than in outpatients with OCD (P = .008) or healthy controls (P = .03). The outpatients with OCD and the healthy controls did not differ in these regions of the brain. The temporal pole was thicker in patients with MDD than in outpatients with OCD (P < .001) or healthy controls (P = .01), both of which groups did not differ in temporal pole thickness. The cuneus was thinner in patients with MDD than in outpatients with OCD (P = .008), but it did not differ from that in healthy controls. In the left hemisphere, the supramarginal gyrus was thinner in both patients with MDD (P = .04) and outpatients with OCD (P = .01) than in healthy controls, and the temporal pole was thicker in patients with MDD than in both healthy controls and outpatients with OCD (P < .001). CONCLUSIONS: To our knowledge, this is the first study to explore cortical thickness in pediatric patients with MDD. Although differences in some regions of the brain would be expected given neurobiological models of MDD, our study highlights some unexpected regions (ie, supramarginal and superior parietal gyri) that merit further investigation. These results underscore the need to expand exploration beyond the frontal-limbic circuit.

PCSK6 is associated with handedness in individuals with dyslexia.

Approximately 90% of humans are right-handed. Handedness is a heritable trait, yet the genetic basis is not well understood. Here we report a genome-wide association study for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)]. The most highly associated marker, rs11855415 (P = 4.7 × 10(-7)), is located within PCSK6. Two independent cohorts with RD show the same trend, with the minor allele conferring greater relative right-hand skill. Meta-analysis of all three RD samples is genome-wide significant (n = 744, P = 2.0 × 10(-8)). Conversely, in the general population (n = 2666), we observe a trend towards reduced laterality of hand skill for the minor allele (P = 0.0020). These results provide molecular evidence that cerebral asymmetry and dyslexia are linked. Furthermore, PCSK6 is a protease that cleaves the left-right axis determining protein NODAL. Functional studies of PCSK6 promise insights into mechanisms underlying cerebral lateralization and dyslexia.

The impact of the Val158Met catechol-O-methyltransferase genotype on neural correlates of sad facial affect processing in patients with bipolar disorder and their relatives.

BACKGROUND: The Met allele of the catechol-O-methyltransferase (COMT) valine-to-methionine (Val158Met) polymorphism is known to affect dopamine-dependent affective regulation within amygdala-prefrontal cortical (PFC) networks. It is also thought to increase the risk of a number of disorders characterized by affective morbidity including bipolar disorder (BD), major depressive disorder (MDD) and anxiety disorders. The disease risk conferred is small, suggesting that this polymorphism represents a modifier locus. Therefore our aim was to investigate how the COMT Val158Met may contribute to phenotypic variation in clinical diagnosis using sad facial affect processing as a probe for its neural action. METHOD: We employed functional magnetic resonance imaging to measure activation in the amygdala, ventromedial PFC (vmPFC) and ventrolateral PFC (vlPFC) during sad facial affect processing in family members with BD (n=40), MDD and anxiety disorders (n=22) or no psychiatric diagnosis (n=25) and 50 healthy controls. RESULTS: Irrespective of clinical phenotype, the Val158 allele was associated with greater amygdala activation and the Met158 allele with greater signal change in the vmPFC and vlPFC. Signal changes in the amygdala and vmPFC were not associated with disease expression. However, in the right vlPFC the Met158 allele was associated with greater activation in all family members with affective morbidity compared with relatives without a psychiatric diagnosis and healthy controls. CONCLUSIONS: Our results suggest that the COMT Val158Met polymorphism has a pleiotropic effect within the neural networks subserving emotional processing. Furthermore the Met158 allele further reduces cortical efficiency in the vlPFC in individuals with affective morbidity.

The concept of anomalous cerebral lateralization in Klinefelter syndrome.

Klinefelter syndrome (KS) is a genetic disorder in males characterized by the presence of an extra X chromosome. Its most consistent endocrinological manifestations include lower testosterone production and impaired spermatogenesis. KS individuals have a general typical appearance with taller stature, and they demonstrate a characteristic cognitive phenotype involving weaknesses in verbal processing. Anomalous cerebral lateralization involves the inverse or weak dominance of hand, language, and visuospatial abilities and has been associated with the cognitive deficits of KS individuals. This article summarizes the ongoing research in this field, discusses the main findings, and attempts to provide a thorough description of the cause of the observed functional and anatomical cerebral asymmetries associated with the syndrome. Nonetheless, efforts have been directed to incorporate evidence for and against theoretical accounts that explain the experimental findings, to discuss issues involving the implications of the chosen methodology, and present key research areas for future empirical research.