Khanum Ridler

Fronto-cerebellar systems are associated with infant motor and adult executive functions in healthy adults but not in schizophrenia

Delineating longitudinal relationships between early developmental markers, adult cognitive function, and adult brain structure could clarify the pathogenesis of neurodevelopmental disorders such as schizophrenia. We aimed to identify brain structural correlates of infant motor development (IMD) and adult executive function in nonpsychotic adults and to test for abnormal associations between these measures in people with schizophrenia. Representative samples of nonpsychotic adults (n = 93) and people with schizophrenia (n = 49) were drawn from the Northern Finland 1966 general population birth cohort. IMD was prospectively assessed at age 1 year; executive function testing and MRI were completed at age 33–35 years. We found that earlier motor development in infancy was correlated with superior executive function in nonpsychotic subjects. Earlier motor development was also normally associated with increased gray matter density in adult premotor cortex, striatum, and cerebellum and increased white matter density in frontal and parietal lobes. Adult executive function was normally associated with increased gray matter density in a fronto-cerebellar system that partially overlapped, but was not identical to, the gray matter regions normally associated with IMD. People with schizophrenia had relatively delayed IMD and impaired adult executive function in adulthood. Furthermore, they demonstrated no normative associations between fronto-cerebellar structure, IMD, or executive function. We conclude that frontal cortico-cerebellar systems correlated with adult executive function are anatomically related to systems associated with normal infant motor development. Disruption of this anatomical system may underlie both the early developmental and adult cognitive abnormalities in schizophrenia.

Widespread anatomical abnormalities of grey and white matter structure in tuberous sclerosis.

Background. Neuroimaging studies of tuberous sclerosis complex (TSC) have previously focused mainly on tubers or subependymal nodules. Subtle pathological changes in the structure of the brain have not been studied in detail. Computationally intensive techniques for reliable morphometry of brain structure are useful in disorders like TSC, where there is little prior data to guide selection of regions of interest. Methods. Dual-echo, fast spin-echo MRI data were acquired from 10 TSC patients of normal intelligence and eight age-matched controls. Between-group dierences in grey matter, white matter and cerebrospinal fluid were estimated at each intracerebral voxel after registration of these images in standard space; a permutation test based on spatial statistics was used for inference. CSF-attenuated FLAIR images were acquired for neuroradiological rating of tuber number. Results. Significant deficits were found in patients, relative to comparison subjects, of grey matter volume bilaterally in the medial temporal lobes, posterior cingulate gyrus, thalamus and basal ganglia, and unilaterally in right fronto-parietal cortex (patients fi20%). We also found significant and approximately symmetrical deficits of central white matter involving the longitudinal fasciculi and other major intrahemispheric tracts (patients fi21%); and a bilateral cerebellar region of relative white matter excess (patients ›28%). Within the patient group, grey matter volume in limbic and subcortical regions of deficit was negatively correlated with tuber count. Conclusions. Neuropathological changes associated with TSC may be more extensive than hitherto suspected, involving radiologically normal parenchymal structures as well as tubers, although these two aspects of the disorder may be correlated.

Morphometric Brain Abnormalities in Schizophrenia in a Population-Based Sample: Relationship to Duration of Illness

Biased recruitment and sample selection may cause variability in neuroimaging studies. Epidemiologically principled population-based magnetic resonance imaging (MRI) studies of schizophrenia are very rare. We gathered structural MRI data on 154 subjects from the Northern Finland 1966 Birth Cohort, aged 33-35 (100 controls, 54 schizophrenia patients). Regional differences in density of gray matter, white matter, and cerebrospinal fluid (CSF) were identified between groups using nonparametric statistical analysis, and the relationship of the regional differences to duration of illness was explored. Gray matter reductions were found bilaterally in the cerebellum, thalamus, basal ganglia, middle frontal gyrus, inferior frontal gyrus, precentral gyrus, insula, superior temporal gyrus, fusiform gyrus, parahippocampal gyrus, cuneus, and lingual gyrus; in the left posterior cingulate, superior frontal gyrus, transverse temporal gyrus, and precuneus; and in the right postcentral gyrus. Gray matter excesses were observed bilaterally in the basal ganglia, anterior cingulate, and medial orbitofrontal cortices. There were white matter deficits in an extensive network including inter- and intrahemispheric tracts bilaterally in the frontal, temporal, parietal, and occipital lobes, subcortical structures, cerebellum, and brain stem. CSF excesses were found bilaterally in the lateral ventricles, third ventricle, interhemispheric, and left Sylvian fissure. We replicated the previous findings of structural brain abnormalities in schizophrenia on a general population level. Gray and white matter deficits were associated with duration of illness suggesting either that developmental brain deficits relate to an earlier age of onset or that brain abnormalities in schizophrenia are progressive in nature.

The brain structural disposition to social interaction.

Social reward dependence (RD) in humans is a stable pattern of attitudes and behaviour hypothesized to represent a favourable disposition towards social relationships and attachment as a personality dimension. It has been theorized that this long‐term disposition to openness is linked to the capacity to process primary reward. Using brain structure measures from magnetic resonance imaging, and a measure of RD from Cloninger’s temperament and character inventory, a self‐reported questionnaire, in 41 male subjects sampled from a general population birth cohort, we investigated the neuro‐anatomical basis of social RD. We found that higher social RD in men was significantly associated with increased gray matter density in the orbitofrontal cortex, basal ganglia and temporal lobes, regions that have been previously shown to be involved in processing of primary rewards. These findings provide evidence for a brain structural disposition to social interaction, and that sensitivity to social reward shares a common neural basis with systems for processing primary reward information.

Standardized whole brain mapping of tubers and subependymal nodules in tuberous sclerosis complex.

Tuberous sclerosis complex is associated with radiologically visible abnormalities of brain structure, principally tubers and subependymal nodules. We reviewed the literature on neuroimaging of tubers and subependymal nodules and found qualitative evidence of bilateral, predominantly frontal distribution of tubers and bilateral, predominantly subcortical distribution of subependymal nodules in prior studies of pediatric samples. We studied 25 high-functioning adults with tuberous sclerosis complex and normal IQ, acquiring both dual spin-echo and fluid-attenuated inversion recovery magnetic resonance imaging sequences to optimize radiologic diagnosis of tubers and nodules. Individual lesion maps were then coregistered in a standard stereotactic space to facilitate construction of lesion density maps and estimation of lesion density in cortical and subcortical regions reliably defined by a parcellated template image. We found the highest frequency of tubers in frontal lobes and the highest density of tubers in parietal regions. There was significant regional variation in tuber density but no significant lateralization of frequently bilateral tubers. Nodules were located predominantly in the caudate nucleus and were not significantly lateralized. Tuber and nodule volumes were significantly positively correlated. Tuber volume was larger, on average, in patients with a lifetime history of epilepsy, but there was no correlation between IQ and these measures of lesion load. Contemporary image processing tools can be used to enhance quantitative, whole brain analysis of lesion load in patients with tuberous sclerosis complex. (J Child Neurol 2004; 19:658-665).

Association between duration of untreated psychosis and brain morphology in schizophrenia within the Northern Finland 1966 Birth Cohort

BACKGROUND Duration of untreated psychosis (DUP) has been linked with poor prognosis and changes in the brain structure in schizophrenia at least at the beginning of the disease, but it is still unknown whether DUP relates to brain morphometry in the longer term. Our aim was to analyze the relation between DUP and the brain structure in schizophrenia in the general population, after several years of illness. METHODS Brains of subjects with psychosis from the Northern Finland 1966 Birth Cohort (NFBC 1966) were scanned with MRI during 1999-2001 after an 11-year follow-up. DUP was assessed from medical records and regressed against global and local tissue density measurements. The brain morphometric and the DUP information were available for 46 subjects with DSM-III-R schizophrenia. RESULTS The DUP did not correlate with volumes of the total gray or white matter or the cerebrospinal fluid. The length of DUP associated positively with reduced densities of the right limbic area and the right hippocampus. CONCLUSIONS Long DUP was slightly associated with reductions of gray matter densities in the limbic area and especially the hippocampus after several years follow-up, supporting the hypothesis that, compared to short DUP, long DUP might be a marker of different disease trajectories including subtle morphometric changes.

Structural brain changes in patients with recurrent major depressive disorder presenting with anxiety symptoms.

Major depressive disorder (MDD) presents with extensive clinical heterogeneity. In particular, overlap with anxiety symptoms is common during depressive episodes and as a comorbid disorder. The aim of this study was to test for morphological brain differences between patients having a history of recurrent MDD with, and without, anxiety symptoms (MDD+A and MDD−A).

Positron emission tomography imaging of dopamine D2/3 receptors in the human cortex with [11C]FLB 457: Reproducibility studies

In a recent PET study, we demonstrated the ability to measure amphetamine‐induced DA release in the human cortex with the relatively high affinity dopamine D2/3 radioligand [11C]FLB 457 (Narendran et al., [2009] Synapse 63:447–461). The aim of this study was to evaluate the reproducibility and reliability of [11C]FLB 457 in the same imaging paradigm we used to measure amphetamine‐induced DA transmission. Six healthy human subjects (three males/three females) were studied twice with [11C]FLB 457, once at baseline and again 3 h following the end of the baseline scan. D2/3 receptor binding parameters were estimated using a two‐tissue compartment kinetic analysis in the cortical regions of interest and cerebellum (reference region). The test–retest variability and intraclass correlation coefficient were assessed for distribution volume (VT), binding potential relative to plasma concentration (BPP), and binding potential relative to nondisplaceable uptake (BPND) of [11C]FLB 457. The test–retest variability of [11C]FLB 457 VT, BPP, and BPND were ≤15%, consistent with the published test–retest variability for this ligand in other brain regions (Sudo et al., [2001] Nucl Med Commun 22:1215–1221; Vilkman et al., [2000] Eur J Nucl Med 27:1666–1673). In addition, no significant decrease in [11C]FLB 457 BPND was observed in the second scan compared to the first one. This suggests that the contribution of carryover mass of [11C]FLB 457 to the measured reduction in [11C]FLB 457 BPND following amphetamine was relatively low. These data support the further validation of [11C]FLB 457 as a tool to measure amphetamine‐induced dopamine release in the human cortex. Synapse 65:35–40, 2011.

Neuregulin-1 genotype is associated with structural differences in the normal human brain

The human neuregulin-1 (NRG-1) gene is highly expressed in the brain, is implicated in numerous functions associated with neuronal development, and is a leading candidate gene for schizophrenia. The T allele of SNP8NRG243177, part of a risk haplotype for schizophrenia, has been previously associated with decreases in white matter in the right anterior internal capsule and the left anterior thalamic radiation. To our knowledge no studies have described the effects of SNP8NRG243177 on grey matter volume at a voxelwise level. We assessed associations between this SNP and brain structure in 79 general population volunteers from the Northern Finland 1966 Birth Cohort (NFBC 1966). We show, for the first time, that genetic variation in SNP8NRG243177 is associated with variation in frontal brain structure in both grey and white matter. T allele carriers showed decreased grey matter volume in several frontal gyri, including inferior, middle and superior frontal gyri and the anterior cingulate gyrus, as well as decreased white matter volume in the regions of the genu and body of the corpus callosum, anterior and superior corona radiata, anterior limb of the internal capsule and external capsule regions traversed by major white matter tracts of the anterior thalamic radiation, and the inferior fronto-occipital fasciculus. These results suggest that this genetic variant may mediate risk for schizophrenia, in part, through its effect on brain structure in these regions.

Characterization of in vivo pharmacological properties and sensitivity to endogenous serotonin of [11C] P943: A positron emission tomography study in Papio anubis

[11C] P943 is a recently developed PET radiotracer for serotonin 5‐HT1B receptors. We characterized a number of its in vivo pharmacokinetic properties, including the evaluation of its two stereo‐isomers, saturability of specific binding, selectivity for 5‐HT1B and 5‐HT1D receptors, and vulnerability to pharmacologically induced increases in endogenous 5‐HT levels. Six isoflurane‐anesthetized baboons were scanned with [11C] P943 at baseline, and following various pharmacological manipulations. The interventions included the administration of pharmacological doses of P943, SB‐616234‐S (a 5‐HT1B selective antagonist), SB‐714786 (a 5‐HT1D selective antagonist), as well as the administration of 5‐HT releasing agents (fenfluramine, amphetamine) and 5‐HT reuptake inhibitor (citalopram). [11C] P943 was observed to bind saturably and specifically to 5‐HT1B receptors and to be sensitive to all three challenges known to alter 5‐HT levels in the proximity of receptors. [11C] P943 shows promise as a tracer to image serotonin function in healthy subjects as well as subjects with psychiatric or neurologic conditions. Synapse, 2011.