Andreas Konrad

Disturbed structural connectivity is related to inattention and impulsivity in adult attention deficit hyperactivity disorder.

Inattention and impulsivity are the most prominent clinical features of attention deficit hyperactivity disorder (ADHD) in adulthood. Structural and functional neuroimaging studies of subjects with ADHD have demonstrated abnormalities in several brain areas, including fronto‐striatal and fronto‐cerebellar networks. Mostly, these studies were based on volumetric measurements and have been conducted in children. We investigated white matter (WM) integrity and correlation with measures of attention and impulsivity in adult patients with ADHD adopting diffusion tensor imaging (DTI). N = 37 (21 males) never‐medicated adult patients with ADHD combined subtype and N = 34 (16 males) healthy controls were investigated. ADHD diagnosis (DSM‐IV) was assessed with clinical interviews and rating scales, subjects also underwent a large neuropsychological test battery including tests of attention and impulsivity. DTI was acquired, and group differences of fractional anisotropy (FA) and mean diffusivity (MD) as well as correlation analyses with measures of attentional performance and impulsivity were calculated using voxel‐based analyses. In adult patients with ADHD, we found reduced FA as well as higher MD bilaterally in orbitomedial prefrontal WM and in the right anterior cingulate bundle, while elevated FA was present bilaterally in temporal WM structures. Measures of attention were correlated with DTI parameters in the right superior longitudinal fasciculus, whereas measures of impulsivity were correlated with FA in right orbitofrontal fibre tracts. This is the first DTI study demonstrating disturbed structural connectivity of the frontal‐striatal circuitry in adult patients with ADHD. Moreover, a direct correlation between WM integrity and measures of attention and impulsivity is shown.

ErbB4 Genotype Predicts Left Frontotemporal Structural Connectivity in Human Brain

Diminished left frontotemporal connectivity is among the most frequently reported findings in schizophrenia and there is evidence that altered neuronal myelination may in part account for this deficit. Several investigations have suggested that variations of the genes that encode the Neuregulin 1 (NRG1)–ErbB4 receptor complex are associated with schizophrenia illness. As NRG1-–ErbB4 has been implicated in neuronal myelination, we investigated with diffusion tensor imaging (DTI) whether fractional anisotropy (FA)—a putative measure of neuronal myelination—is predicted by a risk haplotype of the ErbB4 gene. The effects of the ErbB4 genotype were investigated in healthy subjects (N=59; mean age: 22.6±1.8 years). We also measured reaction time (RT) during a selective attention/working memory paradigm (visual oddball). In the schizophrenia risk genotype group, we found lower FA in the temporal lobe white matter (WM) including frontotemporal fiber tracts, predominantly in the left hemisphere. RT was increased in the risk genotype group and correlated with FA in the affected brain region. As FA is considered to index structural integrity of WM, to which neuronal fiber myelination is contributing, our results suggest that variations of the ErbB4 genotype may confer risk for schizophrenia illness via its impact on left frontotemporal connectivity in human brain. Reliability and validity of the result is suggested by our observation that (1) the FA–genotype association was not only obtained in the entire sample but also in both the split halves and (2) a statistical relationship was found among RT, genotype and FA.

White matter abnormalities and their impact on attentional performance in adult attention-deficit/hyperactivity disorder

Inattention is the most important behavioral feature of adult patients with attention-deficit/hyperactivity disorder (ADHD). Neuroimaging studies in ADHD have demonstrated abnormalities primarily in the frontostriatal circuitry and were mostly conducted in children. We investigated white matter (WM) integrity in adult ADHD patients and the correlation of WM microstructure and neuropsychological parameters in 37 (21 men) never-medicated adult ADHD patients and 34 age- and gender-matched healthy controls. All subjects underwent clinical interviews, rating scales, and neuropsychological tests of attentional performance. Diffusion tensor imaging (DTI) was acquired, and 12 WM regions-of-interest (ROIs) within the attentional network were chosen. Group differences of mean fractional anisotropy (FA) and mean diffusivity (MD) values were calculated for each ROI, and patients’ DTI measures were then correlated with measures of attentional performance. FA values in ADHD patients were significantly reduced in the left inferior longitudinal fasciculus (ILF), while MD values were significantly increased in ADHD patients in the frontal portion of the left frontooccipital fasciculus (IFO). In ADHD patients, MD values were negatively correlated with attentional performance in the left ILF. Our findings provide further support for disturbed frontostriatal structural connectivity and also point to an involvement of the left temporal white matter with an impact on attentional performance.

Disturbed brain activation during a working memory task in drug-naive adult patients with ADHD.

Neuroimaging studies in attention-deficit/hyperactivity disorder (ADHD) have shown abnormalities in several brain areas including the frontostriatal circuitry and were mostly conducted in children and adolescents. We investigated 30 never-medicated adult ADHD patients (16 males) and 30 matched healthy control individuals. Functional magnetic resonance imaging was acquired during a working memory paradigm (n-back). Group activation maps and group differences of activation were calculated using voxel-based analyses. The generic activation pattern was more extended in the control group. In ADHD patients, significantly decreased activation was found in the right inferior parietal cortex. Disturbed parietal brain function may particularly contribute to inattention and working memory impairment in ADHD patients.

An investigation of a genomewide supported psychosis variant in ZNF804A and white matter integrity in the human brain.

ZNF804A, a genomewide supported susceptibility gene for schizophrenia and bipolar disorder, has been associated with task-independent functional connectivity between the left and right dorsolateral prefrontal cortices. Several lines of evidence have converged on the hypothesis that this effect may be mediated by structural connectivity. We tested this hypothesis using diffusion tensor magnetic resonance imaging in three samples: one German sample of 50 healthy individuals, one Scottish sample of 83 healthy individuals and one Scottish sample of 84 unaffected relatives of bipolar patients. Voxel-based analysis and tract-based spatial statistics did not detect any fractional anisotropy (FA) differences between minor allele carriers and individuals homozygous for the major allele at rs1344706. Similarly, region-of-interest analyses and quantitative tractography of the genu of the corpus callosum revealed no significant FA differences between the genotype groups. Examination of effect sizes and confidence intervals indicated that this negative finding is very unlikely to be due to a lack of statistical power. In summary, despite using various analysis techniques in three different samples, our results were strikingly and consistently negative. These data therefore suggest that it is unlikely that the effects of genetic variation at rs1344706 on functional connectivity are mediated by structural integrity differences in large, long-range white matter fiber connections.

Correlation of Brain White Matter Diffusion Anisotropy and Mean Diffusivity with Reaction Time in an Oddball Task

Background: Reaction time (RT) is a frequently used measure of information processing speed, but the underlying physiological and anatomical conditions are not yet fully understood. A correlation between measures of white matter (WM) ultrastructural properties and RT is expected – particularly for those WM tracts that are involved in the attentional system of the brain. Methods: Diffusion tensor imaging data were acquired in 43 unrelated healthy subjects (age: 22.7 ± 1.8 years), and RT was measured during an attention-requiring visual oddball task in the same scanning session. Voxel-by-voxel and region of interest analyses were performed for the large association tracts. A linear regression model was used to correlate fractional anisotropy (FA) and mean diffusivity (MD) values with mean RT. Results: Our analyses revealed significant positive correlations between RT and MD in several WM association tracts, predominantly in the right hemisphere. To a lesser extent, significant negative correlations were found between RT and FA in right temporal WM. Conclusion: These findings suggest that subcortical ultrastructural properties of the dorsal and ventral visual stream are relevant with regard to information processing speed. Furthermore, MD appears to be more sensitive than FA in detecting functionally relevant ultrastructural variations in WM tracts.

Broad Disruption of Brain White Matter Microstructure and Relationship with Neuropsychological Performance in Male Patients with Severe Alcohol Dependence

AIMS In the last years, refined magnetic resonance diffusion tensor imaging (DTI) methods have become available to study microstructural alterations in the human brain. We investigated to what extent white matter tissue abnormalities are present in male patients after chronic, excessive alcohol consumption and if these alterations are correlated with measures of alcohol consumption and neuropsychological performance. METHODS Twenty-four detoxified adult male patients with severe alcohol dependence and 23 healthy male control subjects were included in the study. Neuropsychological tests were assessed for executive function, attention, memory and visuospatial function. DTI was acquired and preprocessing of the data was performed using tract-based spatial statistics. Group differences of fractional anisotropy (FA) as well as correlation analyses with neuropsychological measures and drinking history were calculated. RESULTS Performance in alcoholic patients was significantly poorer in tests of non-verbal reasoning and attention. In detoxified alcoholic patients, lower FA was primarily found in the body of the corpus callosum, but these findings did not correlate directly with behavioral measures. However, executive and psychomotor performance (Trail-Making Test) correlated significantly with FA in right anterior cingulate and left motor areas. CONCLUSION These findings provide further evidence for reduced integrity of interhemispheric connections in male patients with severe alcohol dependence, and neurocognitive performance was in part correlated with FA.

Vbm-dti correlates of verbal intelligence: A potential link to broca's area

Human brain lesion studies first investigated the biological roots of cognitive functions including language in the late 1800s. Neuroimaging studies have reported correlation findings with general intelligence predominantly in fronto-parietal cortical areas. However, there is still little evidence about the relationship between verbal intelligence and structural properties of the brain. We predicted that verbal performance is related to language regions of Brocas and Wernickes areas. Verbal intelligence quotient (vIQ) was assessed in 30 healthy young subjects. T1-weighted MRI and diffusion tensor imaging data sets were acquired. Voxel-wise regression analyses were used to correlate fractional anisotropy (FA) and mean diffusivity values with vIQ. Moreover, regression analyses of regional brain volume with vIQ were performed adopting voxel-based morphometry (VBM) and ROI methodology. Our analyses revealed a significant negative correlation between vIQ and FA and a significant positive correlation between vIQ and mean diffusivity in the left-hemispheric Brocas area. VBM regression analyses did not show significant results, whereas a subsequent ROI analysis of Brocas area FA peak cluster demonstrated a positive correlation of gray matter volume and vIQ. These findings suggest that cortical thickness in Brocas area contributes to verbal intelligence. Diffusion parameters predicted gray matter ratio in Brocas area more sensitive than VBM methodology.

229 – ERBB4 genotype effects on human brain structure

Background:Disturbed functional and structural brain connectivity in schizophrenia has been shown in a large number of studies. There is evidence from several neuroimaging and post mortem studies that altered neuronal myelination may in part account for this deficit. Recent investigations have suggested that variations of the genes that encode the Neuregulin 1 (NRG1) ErbB4 receptor complex might be associated with schizophrenia illness. As NRG1 and ErbB4 have been implicated in myelination and neuronal proliferation. We investigated whether cerebral micro and macrostructure is predicted by two risk haplotypes of the ErbB4 gene. Methods: The effects of two single-nucleotide polymorphisms (SNPs) rs2289086 and rs4673628 were investigated by diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) analysis in 51 healthy subjects (mean age 22.6±1.8 years). Reaction time (RT) was measured during an attentional paradigm (visual oddball). Results: For both rs2289086 and rs4673628, we found higher fractional anisotropy (FA) in the A/A genotype group in left temporal lobe white matter. In addition, higher FA in the rs4673628 A/A genotype group was demonstrated in the subventricular zone. Conclusions: As FA is considered to index structural integrity of WM, to which neuronal fiber myelination is contributing, our results suggest that variations of the ErbB4 genotype may confer risk for schizophrenia illness via its impact on structural connectivity in human brain. References: Konrad A, Winterer G (2007). Schizophr Bull (online). Nicodemus KK, et al. (2006). Mol Psychiatry 11(12): 1062–5. Silberberg G, et al. (2006). Am J Med Genet B Neuropsychiatr Genet 141(2): 142–8.

93. Structural brain abnormalities in attention-deficit/hyperactivity disorder: A voxel-based MRI study in adult patients

tivity disorder: A voxel-based MRI study in adult patients—A. Konrad , T.F. Dielentheis , M. Bayerl , D. El Masri , T. Bauermann , G. Vucurevic , P. Stoeter , G. Winterer 3 ( Johannes Gutenberg-Universität, Klinik für Psychiatrie und Psychotherapie, Mainz, Germany, 2 Johannes Gutenberg-Universität Mainz, Institut für Neuroradiologie, Mainz, Germany, 3 Heinrich-HeineUniversität Düsseldorf, Klinik für Psychiatrie, Düsseldorf, Germany)