Raquel E. Gur

An improved framework for confound regression and filtering for control of motion artifact in the preprocessing of resting-state functional connectivity data.

Several recent reports in large, independent samples have demonstrated the influence of motion artifact on resting-state functional connectivity MRI (rsfc-MRI). Standard rsfc-MRI preprocessing typically includes regression of confounding signals and band-pass filtering. However, substantial heterogeneity exists in how these techniques are implemented across studies, and no prior study has examined the effect of differing approaches for the control of motion-induced artifacts. To better understand how in-scanner head motion affects rsfc-MRI data, we describe the spatial, temporal, and spectral characteristics of motion artifacts in a sample of 348 adolescents. Analyses utilize a novel approach for describing head motion on a voxelwise basis. Next, we systematically evaluate the efficacy of a range of confound regression and filtering techniques for the control of motion-induced artifacts. Results reveal that the effectiveness of preprocessing procedures on the control of motion is heterogeneous, and that improved preprocessing provides a substantial benefit beyond typical procedures. These results demonstrate that the effect of motion on rsfc-MRI can be substantially attenuated through improved preprocessing procedures, but not completely removed.

Impact of In-Scanner Head Motion on Multiple Measures of Functional Connectivity: Relevance for Studies of Neurodevelopment in Youth

It has recently been reported (Van Dijk et al., 2011) that in-scanner head motion can have a substantial impact on MRI measurements of resting-state functional connectivity. This finding may be of particular relevance for studies of neurodevelopment in youth, confounding analyses to the extent that motion and subject age are related. Furthermore, while Van Dijk et al. demonstrated the effect of motion on seed-based connectivity analyses, it is not known how motion impacts other common measures of connectivity. Here we expand on the findings of Van Dijk et al. by examining the effect of motion on multiple types of resting-state connectivity analyses in a large sample of children and adolescents (n=456). Following replication of the effect of motion on seed-based analyses, we examine the influence of motion on graphical measures of network modularity, dual-regression of independent component analysis, as well as the amplitude and fractional amplitude of low frequency fluctuation. In the entire sample, subject age was highly related to motion. Using a subsample where age and motion were unrelated, we demonstrate that motion has marked effects on connectivity in every analysis examined. While subject age was associated with increased within-network connectivity even when motion was accounted for, controlling for motion substantially attenuated the strength of this relationship. The results demonstrate the pervasive influence of motion on multiple types functional connectivity analysis, and underline the importance of accounting for motion in studies of neurodevelopment.

Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia.

Recent molecular genetics studies implicate neuregulin 1 (NRG1) and its receptor erbB in the pathophysiology of schizophrenia. Among NRG1 receptors, erbB4 is of particular interest because of its crucial roles in neurodevelopment and in the modulation of N-methyl-D-aspartate (NMDA) receptor signaling. Here, using a new postmortem tissue–stimulation approach, we show a marked increase in NRG1-induced activation of erbB4 in the prefrontal cortex in schizophrenia. Levels of NRG1 and erbB4, however, did not differ between schizophrenia and control groups. To evaluate possible causes for this hyperactivation of erbB4 signaling, we examined the association of erbB4 with PSD-95 (postsynaptic density protein of 95 kDa), as this association has been shown to facilitate activation of erbB4. Schizophrenia subjects showed substantial increases in erbB4–PSD-95 interactions. We found that NRG1 stimulation suppresses NMDA receptor activation in the human prefrontal cortex, as previously reported in the rodent cortex. NRG1-induced suppression of NMDA receptor activation was more pronounced in schizophrenia subjects than in controls, consistent with enhanced NRG1-erbB4 signaling seen in this illness. Therefore, these findings suggest that enhanced NRG1 signaling may contribute to NMDA hypofunction in schizophrenia.

Facial emotion discrimination: II. Behavioral findings in depression

The facial discrimination tasks described in part I (Erwin et al., 1992) were administered to a sample of 14 patients with depression and 14 normal controls matched for sex (12 women, 2 men) and balanced for age and sociodemographic characteristics. Patients performed more poorly on measures of sensitivity for happy discrimination and specificity for sad discrimination, and had a higher negative bias across tasks. Severity of negative affect was correlated with poorer performance for patients. The results suggest that depression is associated with an impaired ability to recognize facial displays of emotion.

Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia

Eleven studies now report significant associations between schizophrenia and certain haplotypes of single-nucleotide polymorphisms in the gene encoding dysbindin-1 at 6p22.3. Dysbindin-1 is best known as dystrobrevin-binding protein 1 (DTNBP1) and may thus be associated with the dystrophin glycoprotein complex found at certain postsynaptic sites in the brain. Contrary to expectations, however, we found that when compared to matched, nonpsychiatric controls, 73-93% of cases in two schizophrenia populations displayed presynaptic dysbindin-1 reductions averaging 18-42% (P = 0.027-0.0001) at hippocampal formation sites lacking neuronal dystrobrevin (i.e., beta-dystrobrevin). The reductions, which were not observed in the anterior cingulate of the same schizophrenia cases, occurred specifically in terminal fields of intrinsic, glutamatergic afferents of the subiculum, the hippocampus proper, and especially the inner molecular layer of the dentate gyrus (DGiml). An inversely correlated increase in vesicular glutamate transporter-1 (VGluT-1) occurred in DGiml of the same schizophrenia cases. Those changes occurred without evidence of axon terminal loss or neuroleptic effects on dysbindin-1 or VGluT-1. Our findings indicate that presynaptic dysbindin-1 reductions independent of the dystrophin glycoprotein complex are frequent in schizophrenia and are related to glutamatergic alterations in intrinsic hippocampal formation connections. Such changes may contribute to the cognitive deficits common in schizophrenia.

Sex differences in the structural connectome of the human brain

Significance Sex differences are of high scientific and societal interest because of their prominence in behavior of humans and nonhuman species. This work is highly significant because it studies a very large population of 949 youths (8–22 y, 428 males and 521 females) using the diffusion-based structural connectome of the brain, identifying novel sex differences. The results establish that male brains are optimized for intrahemispheric and female brains for interhemispheric communication. The developmental trajectories of males and females separate at a young age, demonstrating wide differences during adolescence and adulthood. The observations suggest that male brains are structured to facilitate connectivity between perception and coordinated action, whereas female brains are designed to facilitate communication between analytical and intuitive processing modes. Sex differences in human behavior show adaptive complementarity: Males have better motor and spatial abilities, whereas females have superior memory and social cognition skills. Studies also show sex differences in human brains but do not explain this complementarity. In this work, we modeled the structural connectome using diffusion tensor imaging in a sample of 949 youths (aged 8–22 y, 428 males and 521 females) and discovered unique sex differences in brain connectivity during the course of development. Connection-wise statistical analysis, as well as analysis of regional and global network measures, presented a comprehensive description of network characteristics. In all supratentorial regions, males had greater within-hemispheric connectivity, as well as enhanced modularity and transitivity, whereas between-hemispheric connectivity and cross-module participation predominated in females. However, this effect was reversed in the cerebellar connections. Analysis of these changes developmentally demonstrated differences in trajectory between males and females mainly in adolescence and in adulthood. Overall, the results suggest that male brains are structured to facilitate connectivity between perception and coordinated action, whereas female brains are designed to facilitate communication between analytical and intuitive processing modes.

Emotion recognition deficit in schizophrenia: association with symptomatology and cognition.

BACKGROUND Previous investigations have found impaired recognition of facial affect in schizophrenia. Controversy exists as to whether this impairment represents a specific emotion recognition deficit when compared with other face recognition control tasks. Regardless of whether the emotion processing deficit is differential, it may uniquely influence other manifestations of schizophrenia. We compared patients and healthy control subjects on computerized tasks of emotion and age recognition. Performances on emotion and age recognition tasks were correlated with cognitive functioning and with symptomatology. METHODS Thirty-five patients with schizophrenia and 45 healthy people underwent computerized testing for emotion and age recognition. Participants were assessed neuropsychologically, and patients were rated for positive and negative symptoms. RESULTS The patients with schizophrenia performed worse than control subjects on emotion and age recognition without differential deficit. In both groups, we found higher error rates for identification of emotion in female faces and for identification of sad versus happy faces. In schizophrenic patients, emotion but not age recognition correlated with severity of negative and positive symptoms. In healthy control subjects, neither task correlated with cognitive functions. In schizophrenic patients, emotion but not age recognition correlated with attention, verbal and spatial memory, and language abilities. CONCLUSIONS This study did not reveal a specific deficit for emotion recognition in schizophrenia; however, our findings lend support to the concept that emotion recognition is uniquely associated in schizophrenia with core symptomatology and cognitive domains.

Sex differences in regional cerebral glucose metabolism during a resting state

Positron emission tomography was used to evaluate the regional distribution of cerebral glucose metabolism in 61 healthy adults at rest. Although the profile of metabolic activity was similar for men and women, some sex differences and hemispheric asymmetries were detectable. Men had relatively higher metabolism than women in temporal-limbic regions and cerebellum and relatively lower metabolism in cingulate regions. In both sexes, metabolism was relatively higher in left association cortices and the cingulate region and in right ventro-temporal limbic regions and their projections. These results are consistent with the hypothesis that differences in cognitive and emotional processing have biological substrates.

COMPARE: Classification of Morphological Patterns Using Adaptive Regional Elements

This paper presents a method for classification of structural brain magnetic resonance (MR) images, by using a combination of deformation-based morphometry and machine learning methods. A morphological representation of the anatomy of interest is first obtained using a high-dimensional mass-preserving template warping method, which results in tissue density maps that constitute local tissue volumetric measurements. Regions that display strong correlations between tissue volume and classification (clinical) variables are extracted using a watershed segmentation algorithm, taking into account the regional smoothness of the correlation map which is estimated by a cross-validation strategy to achieve robustness to outliers. A volume increment algorithm is then applied to these regions to extract regional volumetric features, from which a feature selection technique using support vector machine (SVM)-based criteria is used to select the most discriminative features, according to their effect on the upper bound of the leave-one-out generalization error. Finally, SVM-based classification is applied using the best set of features, and it is tested using a leave-one-out cross-validation strategy. The results on MR brain images of healthy controls and schizophrenia patients demonstrate not only high classification accuracy (91.8% for female subjects and 90.8% for male subjects), but also good stability with respect to the number of features selected and the size of SVM kernel used

Neuropsychological evidence supporting a neurodevelopmental model of schizophrenia: a longitudinal study

The stability of neuropsychological performance in schizophrenia and its relationship to clinical change was contrasted between 60 patients with schizophrenia (30 first-episode, 30 previously treated) and 38 healthy controls using a comprehensive neuropsychological battery and clinical scales administered at intake and at a 19-month follow-up. Consistent with the neurodevelopmental model of schizophrenia, patients demonstrated deficits in cognitive performance at initial testing and did not show decline at follow-up. There were no differences in neuropsychological performance over time between first-episode and previously treated patients, nor between male and female patients or controls. As expected, patients improved clinically with treatment with respect to both positive and negative symptoms. First-episode patients improved more on the positive symptoms of hallucination and delusion; male and female patients showed equivalent clinical improvement. Clinical improvement correlated positively with neuropsychological change, with improved negative symptomatology accounting for most of the significant correlations.