Cortical Abnormalities Associated With Pediatric and Adult Obsessive-Compulsive Disorder: Findings From the ENIGMA Obsessive-Compulsive Disorder Working Group.

OBJECTIVE: Brain imaging studies of structural abnormalities in OCD have yielded inconsistent results, partly because of limited statistical power, clinical heterogeneity, and methodological differences. The authors conducted meta- and mega-analyses comprising the largest study of cortical morphometry in OCD ever undertaken. METHOD: T1-weighted MRI scans of 1,905 OCD patients and 1,760 healthy controls from 27 sites worldwide were processed locally using FreeSurfer to assess cortical thickness and surface area. Effect sizes for differences between patients and controls, and associations with clinical characteristics, were calculated using linear regression models controlling for age, sex, site, and intracranial volume. RESULTS: In adult OCD patients versus controls, we found a significantly lower surface area for the transverse temporal cortex and a thinner inferior parietal cortex. Medicated adult OCD patients also showed thinner cortices throughout the brain. In pediatric OCD patients compared with controls, we found significantly thinner inferior and superior parietal cortices, but none of the regions analyzed showed significant differences in surface area. However, medicated pediatric OCD patients had lower surface area in frontal regions. Cohen's d effect sizes varied from -0.10 to -0.33. CONCLUSIONS: The parietal cortex was consistently implicated in both adults and children with OCD. More widespread cortical thickness abnormalities were found in medicated adult OCD patients, and more pronounced surface area deficits (mainly in frontal regions) were found in medicated pediatric OCD patients. These cortical measures represent distinct morphological features and may be differentially affected during different stages of development and illness, and possibly moderated by disease profile and medication.

Atypical Structural Asymmetry of the Planum Temporale is Related to Family History of Dyslexia.

Research on the neural correlates of developmental dyslexia indicates atypical anatomical lateralization of the planum temporale, a higher-order cortical auditory region. Yet whether this atypical lateralization precedes reading acquisition and is related to a familial risk for dyslexia is not currently known. In this study, we address these questions in 2 separate cohorts of young children and adolescents with and without a familial risk for dyslexia. Planum temporale surface area was manually labeled bilaterally, on the T1-weighted MR brain images of 54 pre-readers (mean age: 6.2 years, SD: 3.2 months; 33 males) and 28 adolescents (mean age: 14.7 years, SD: 3.3 months; 11 males). Half of the pre-readers and adolescents had a familial risk for dyslexia. In both pre-readers and adolescents, group comparisons of left and right planum temporale surface area showed a significant interaction between hemisphere and family history of dyslexia, with participants who had no family risk for dyslexia showing greater leftward asymmetry of the planum temporale. This effect was confirmed when analyses were restricted to normal reading participants. Altered planum temporale asymmetry thus seems to be related to family history of dyslexia.

Oligodendrocyte abnormalities in layer 5 inthe inferior parietal lobule are associated with lackof insight in schizophrenia: A postmorte mmorphometric study

Background and Objectives: Previously we reported in layer 3 of the inferior parietal lobule a reduction in the numerical density of oligodendrocytes (Nv Ol), oligodendrocyte clusters (Nv OlC) in BA 39, and in the number of perineuronal oligodendrocytes(N PnOl) in BA 39/40 areas in schizophrenia. These changes were associatedwith lack of insight. We hypothesized that similar abnormalities might occur in layer 5 inBA 39/40, and they might be associated with lack of insight. Methods: We estimated the Nv Ol, the Nv OlC by optical disector method and the NPnOl in layer 5 in BA 39/40 in Nissl stained sections from 24 males with schizophrenia and 24 normal male controls from the Stanley Parietal Collection. The schizophrenia group was divided into three subgroups based on level of insight: poor, fair or good. Results: We found a significant deficit in the parameters measured in BA 39 in the schizophrenia group and in the subgroup of subjects having poor insight as compared to the control group. In BA 40 the Nv Ol and the Nv OlC were significantly lower in the schizophrenia group compared to controls, and the N PnOl was not changed. Each insight subgroup showed a decreased the Nv Ol and the Nv OlC compared to controls. There were no subgroup differences in BA 39/40. Conclusions: Schizophrenia is characterized by the reduction in the Nv Ol and the NvOlC in layer 5 of BA 39/40. Oligodendrocyte abnormalities in BA 39 are associated with poor insight in schizophrenia (AU)

Abnormalities of cortical structures in adolescent-onset conduct disorder.

BACKGROUND: Converging evidence has revealed both functional and structural abnormalities in adolescents with early-onset conduct disorder (EO-CD). The neurological abnormalities underlying EO-CD may be different from that of adolescent-onset conduct disorder (AO-CD) patients. However, the cortical structure in AO-CD patients remains largely unknown. The aim of the present study was to investigate the cortical alterations in AO-CD patients. METHOD: We investigated T1-weighted brain images from AO-CD patients and age-, gender- and intelligence quotient-matched controls. Cortical structures including thickness, folding and surface area were measured using the surface-based morphometric method. Furthermore, we assessed impulsivity and antisocial symptoms using the Barratt Impulsiveness Scale (BIS) and the Antisocial Process Screening Device (APSD). RESULTS: Compared with the controls, we found significant cortical thinning in the paralimbic system in AO-CD patients. For the first time, we observed cortical thinning in the precuneus/posterior cingulate cortex (PCC) in AO-CD patients which has not been reported in EO-CD patients. Prominent folding abnormalities were found in the paralimbic structures and frontal cortex while diminished surface areas were shown in the precentral and inferior temporal cortex. Furthermore, cortical thickness of the paralimbic structures was found to be negatively correlated with impulsivity and antisocial behaviors measured by the BIS and APSD, respectively. CONCLUSIONS: The present study indicates that AO-CD is characterized by cortical structural abnormalities in the paralimbic system, and, in particular, we highlight the potential role of deficient structures including the precuneus and PCC in the etiology of AO-CD.

Small biparietal diameter and head circumference are part of the phenotype instead of independent prognostic markers in fetuses with spinal dysraphism.

OBJECTIVE: The aim of this retrospective study was to assess the fetal biparietal diameter (BPD) and head circumference (HC) in the second trimester of pregnancy in fetuses with open spinal dysraphism. METHODS: BPD and HC were measured at 16-26 weeks in 74 fetuses with open spinal dysraphism and compared with reference values. RESULTS: BPD was smaller in fetuses with open spinal dysraphism. Of all cases with open spinal dysraphism, 62.2% had a BPD <3rd percentile and 79.7% had a BPD <10th percentile. Of all patients, 54.1% had an HC <3rd percentile and 74.3% had an HC <10th percentile. CONCLUSION: Almost all fetuses with open neural tube defects have a smaller BPD and HC at 16-26 weeks compared with reference values, which implicates that this is part of the phenotype of children with open spinal dysraphism instead of an independent prognostic marker for a poor cognitive outcome.

[Tourette syndrome and reading disorder in a boy with left parietofrontal tract disruption]. / Trastorno de Tourette y de la lectura en un niño con disrupción del tracto parietofrontal izquierdo.

We present the case of a nine-year-old boy with Tourette syndrome and reading disorder with a history of a severe infectious process in the late neonatal period. Brain MRI showed a left parietal malacotic cavity and diffusion tensor imaging and tractography showed a striking disruption of the white matter bundle that joins the left parietal region with the ipsilateral frontal region with involvement of the left superior longitudinal fasciculus and of the left arcuate fasciculus. Although Tourette syndrome and reading disorder are fundamentally hereditary neuropsychiatric disorders, they can also occur secondary to cerebral alterations like those existing in this boy. The introduction of modern neuroimaging techniques in patients with neuropsychiatric disorders (or the risk of developing them) can be very useful in the diagnosis and prognosis in the future.

Abnormalities in oligodendrocyte clusters inthe inferior parietal cortex in schizophreniaare associated with insight

Background and Objectives: Deficits in oligodendrocytes have been consistentlyreported in the brains of patients with schizophrenia and include alterations in theclustering pattern of oligodendrocytes. Recently it has been shown that oligodendrocyteprogenitors proliferate in the adult mammalian brain to form oligodendrocyte clusters(OlC). We previously found a deficit of oligodendrocytes in layer 3 of the inferior parietallobule (IPL) in subjects with schizophrenia with poor insight into disorder. We hypothesizedthat the number of OlC might be reduced in schizophrenia subjects with poor insight.Methods: Nissl-stained sections from the Stanley “Parietal Collection” from maleschizophrenia subjects (n = 24) that have poor, fair, or good insight into their disorder andnormal matched controls (n = 24) were studied. The numerical density (Nv) of OlC wasestimated in layer 3 of BA 39 and BA 40 by optical disector method.Results: The Nv of OlC was 23% lower in BA 39 and 30% lower in BA40 in the schizophreniagroup compared to the control group (p<0.01). Normal hemispheric differences inthe Nv of OlC in BA 39 were absent in the schizophrenia group. The Nv of OlC was significantlydecreased in BA39 in the subgroup with poor insight and in BA40 in the subgroupswith fair and good insight as compared to controls. In BA40 lower Nv of OlC (-40%,p<0.01) was found in the subgroup with adolescent onset of disease as compared to controls.Conclusions: The deficit of OlC may be associated with altered proliferation and/ormaturation of oligodendrocyte progenitors in schizophrenia (AU)

First trimester screening for holoprosencephaly with choroid plexus morphology ('butterfly' sign) and biparietal diameter.

OBJECTIVE: The aim of this study was to determine whether choroid plexus morphology ('butterfly' sign) and biparietal diameter (BPD) are effective sonographic screening tools for holoprosencephaly (HPE) in the first trimester. METHODS: An axial view of the fetal head was obtained routinely to determine the presence of the 'butterfly' sign in pregnancies presenting for sonographic screening at 11-13 weeks of gestation. The same view was also used to obtain BPD measurements. The definitive diagnosis of HPE was established by the sonographic demonstration of an anterior cerebral monoventricular cavity and thalamic fusion. RESULTS: During a 9-year study period, 11 068 live fetuses were screened. There were 11 cases of HPE (prevalence 1/1006); all of them were detected by demonstration of an absent 'butterfly' sign with no false-positive cases. The BPD was less than the 5th percentile in 40% of the cases. CONCLUSIONS: The 'butterfly' sign appears to be a highly sensitive marker for HPE in the first trimester. On the other hand, BPD measurements had a lower sensitivity, implying that microcephaly is not a prominent first-trimester feature in these cases. Incorporation of the 'butterfly' sign into the first trimester anatomy scan is simple and can facilitate the identification of the vast majority of fetuses with HPE in the first trimester.

Frontoparietal connectivity in substance-naïve youth with and without a family history of alcoholism.

Frontoparietal connections underlie key executive cognitive functions. Abnormalities in the frontoparietal network have been observed in chronic alcoholics and associated with alcohol-related cognitive deficits. It remains unclear whether neurobiological differences in frontoparietal circuitry exist in substance-naïve youth who are at-risk for alcohol use disorders. This study used functional connectivity magnetic resonance imaging and diffusion tensor imaging to examine frontoparietal connectivity and underlying white matter microstructure in 20 substance-naïve youth with a family history of alcohol dependence and 20 well-matched controls without familial substance use disorders. Youth with a family history of alcohol dependence showed significantly less functional connectivity between posterior parietal and dorsolateral prefrontal seed regions (ps<.05), as compared to family history negative controls; however, they did not show differences in white matter architecture within tracts subserving frontoparietal circuitry (ps>.34). Substance-naïve youth with a family history of alcohol dependence show less frontoparietal functional connectivity in the absence of white matter microstructural abnormalities as compared to youth with no familial risk. This may suggest a potential neurobiological marker for the development of substance use disorders.

Aberrant diffusion and geometric properties in the left arcuate fasciculus of developmentally delayed children: a diffusion tensor imaging study.

BACKGROUND AND PURPOSE: One of the neurologic substrates of poor language in children with DD is the abnormal development of perisylvian language networks. We sought to determine whether this manifests as aberrant regional changes in diffusivity or geometry of the left AF. MATERIALS AND METHODS: We performed DTI studies in 16 young (age, 55.4 ± 18.95 months) patients with DD and 11 age- and sex-matched TD children (age, 60.09 ± 21.27 months). All children were right-handed. To detect the malformation of left AF structure in native or standard space, we proposed new methodology consisting of 2 complementary approaches, principal fiber orientation quantification in color-coded anisotropic maps and tract-based morphometry analysis. RESULTS: Patients with DD did not show the typical pattern of age-related maturity of the AP and ML pathways passing through the left AF (R(2) of the AP pathway: DD versus TD = 0.002 versus 0.4542; R(2) of the ML pathway: DD versus TD = 0.002 versus 0.4154). In addition, the patients with DD showed significantly reduced FA in the temporal portion of the AF (mean FA of DD versus TD = 0.37 ± 0.11 versus 0.48 ± 0.06, P < .001), and the AF showed higher curvatures in the parietotemporal junction, resulting in sharper bends to the Wernicke area (mean curvature of DD versus TD = 0.12 ± 0.03 versus 0.06 ± 0.02, P < .001). CONCLUSIONS: The proposed methods successfully revealed regional abnormalities in the axonal integrity of the left AF in the patients with DD. These abnormalities support the notion that the perisylvian language network is malformed in children with DD.

Reduced cortical folding in mental retardation.

BACKGROUND AND PURPOSE: MR is a developmental disorder associated with impaired cognitive functioning and deficits in adaptive behavior. With a 2D region of interest-based GI, a preliminary study reported significantly reduced gyrification in the prefrontal lobe in MR. The purpose of this study was to further investigate the abnormalities of cortical gyrification in MR and to explore the possible causes of these abnormalities. MATERIALS AND METHODS: Thirteen patients with MR and 26 demographically matched healthy controls were included in this study. A 3D surface-based lGI was calculated as a measure to quantify gyrification. Then vertex-by-vertex contrasts of lGI were performed between patients with MR and healthy controls. RESULTS: Statistical analysis showed that patients with MR had significantly reduced lGI in multiple brain regions compared with healthy controls. These regions include the lateral and medial prefrontal cortices, the right superior temporal gyrus, the left superior parietal lobe, the bilateral insular and adjacent cortices, and the visual and motor cortices. CONCLUSIONS: The observed abnormal pattern of cortical gyrification revealed by significant reduction of lGI in multiple brain regions might reflect the developmental disturbance in intracortical organization and cortical connectivities in MR.

Mathematical learning disabilities in children with 22q11.2 deletion syndrome: a review.

Mathematical learning disabilities (MLD) occur frequently in children with specific genetic disorders, like Turner syndrome, fragile X syndrome and neurofibromatosis. This review focuses on MLD in children with chromosome 22q11.2 deletion syndrome (22q11DS). This syndrome is the most common known microdeletion syndrome with a prevalence of at least 1:4000 to 1:6000 live births. Although the clinical presentation of 22q11DS is quite variable, its major characteristics include velopharyngeal abnormalities, congenital cardiac anomalies, mild facial dysmorphism and learning difficulties. Children with 22q11DS show considerable difficulties in mathematics, despite relatively normal reading performance. While fact retrieval seems to be preserved, impairments in procedural calculation and word problem solving are particularly prominent. Children with 22q11DS also have substantial difficulties in understanding and representing numerical quantities, possibly related to poor visuospatial attention, which all might stem from their underlying abnormalities in the inferior parietal cortex. This review ends with a discussion on how research on genetic disorders might aid our understanding of MLD in general.

Effort awareness and sense of volition in schizophrenia.

Contemporary experimental research has emphasised the role of centrally generated signals arising from premotor areas in voluntary muscular force perception. It is therefore generally accepted that judgements of force are based on a central sense, known as the sense of effort, rather than on a sense of intra-muscular tension. Interestingly, the concept of effort is also present in the classical philosophy: to the French philosopher Maine de Biran [Maine de Biran (1805). Mémoire sur la décomposition de la pensée (Tome III), Vrin, Paris (1963)], the sense of effort is the fundamental component of self-experience, the landmark of the exercise of the will. In the present review, after a presentation of the nature and neurophysiological bases of effort sensation, we will examine its possible involvement in the neurocognitive process of agency. We will further focus on delusions of alien control in schizophrenic patients. Experimental data suggest that these patients have an abnormal awareness of effort caused by cerebral anomalies in the frontal and parietal lobes.

Expression of astrocytic markers aquaporin 4 and connexin 43 is altered in brains of subjects with autism.

Neuroanatomical studies have revealed extensive structural brain abnormalities in subjects with autism. Recently, studies have provided evidence of neuroglial responses and neuroinflammation in autism. The current study investigated whether two astrocytic markers, aquaporin 4 and connexin 43, are altered in brains from subjects with autism. Postmortem brain tissues from Brodmann's Area 40 (BA40, parietal cortex), Brodmann's Area 9 (BA9, superior frontal cortex), and cerebella of subjects with autism and matched controls were subject to SDS-PAGE and western blotting. Connexin 43 expression was increased significantly in BA9. Aquaporin 4 expression was decreased significantly in cerebellum. These data suggest that changes are apparent in markers for abnormal glial-neuronal communication (connexin 43 and aquaporin 4) in brains of subjects with autism.

Bilateral symmetric tonic posturing suggesting propagation to the supplementary motor area in a patient with precuneate cortical dysplasia.

We report a patient manifesting seizures with bilateral symmetric tonic posturing, which were markedly reduced after resection of the left precuneus. A 16-year-old man had sudden onset, complex partial seizures with bilateral symmetric tonic posturing since the age of eight years. Magnetic resonance fluid-attenuated inversion-recovery imaging revealed a hyperintense lesion in left precuneus. In almost all focal seizures recorded during an invasive EEG evaluation, ictal onset was detected from the inferomesial aspect of the lesion, but fast paroxysmal discharges from the ipsilateral supplementary motor area (SMA) were observed just before the clinical onset. After surgical excision of the EEG onset zone, including the lesion, seizure frequency was markedly (> 95%) reduced. By the 20th month after surgery, there were only brief nocturnal seizures involving slight elevation of both shoulders and slight abduction of both arms, with preservation of consciousness occurring once every few days. Invasive EEG findings and surgical outcome suggested that the epileptic activity originating from the epileptogenic zone may have propagated to the symptomatogenic zone including mainly the ipsilateral SMA. In summary, we report an interesting case of bilateral symmetric tonic posturing suggesting propagation to the SMA. MRI and invasive EEG confirmed the epileptogenic focus as a precuneate cortical dysplasia lesion.[Published with video sequences].

Changes in the expression of cation-Cl- cotransporters, NKCC1 and KCC2, during cortical malformation induced by neonatal freeze-lesion.

Focal cortical malformations comprise a heterogeneous group of disturbances in brain development, often associated with intractable epilepsy. A focal freeze-lesion of cerebral cortex in newborn rat produces a cortical malformation that resembles human polymicrogyria, clinical conditions that results from abnormal neuronal migration. The change in GABAergic functions that occurs during early brain development is induced by an alteration in Cl(-) homeostasis and plays important roles in neocortical development by modulating such events as laminar organization and synaptogenesis. We therefore investigated the relationship between pathogenesis of polymicrogyria and ontogeny of Cl(-) homeostasis in developing parietal cortex after creation of a freeze-lesion at P0. We demonstrated, by in situ hybridization histochemistry for cation-Cl(-) cotrtansporters, that NKCC1 mRNA expression was upregulated and KCC2 mRNA expression downregulated at P4 in "bridge" structure (formed in lesion site across the gap in intact exofocal cortex) as compared to exfocal cortex. Immunohistochemical investigation revealed a colocalization of NKCC1 and neuron specific enolase (NSE) within this structure, while BrdU-positive cells express GFAP and NKCC1 appeared beneath it. These results suggest that immature cortical plate neurons might produce "bridge" structure during formation of microgyrus, and that altered neuronal Cl(-) homeostasis might be involved in neuronal migration disorder that ultimately results in cortical malformations.

Interfrontal commissural abnormality in schizophrenia: tractography-assisted callosal parcellation.

Previous studies have indicated abnormal fiber connectivity of the corpus callosum (CC) in schizophrenia. This study investigated whether the interfrontal commissural region of the CC is decreased in schizophrenia, by partitioning the CC using a function-anatomically relevant internal landmark derived from tractographic analysis of diffusion tensor imaging (DTI). T1 weighted and DTI images were acquired by 3T-MRI. Using tractography, the interfrontal commissural region (anterior part) was partitioned from the rest of the CC in 40 schizophrenia patients and 36 healthy controls. Schizophrenia patients showed smaller anterior/total CC length and area rates. These results suggested interfrontal hypoconnectivity in schizophrenia.