Tonya White

Gyrification abnormalities in childhood- and adolescent-onset schizophrenia

BACKGROUNDnGyrification is an important index of brain development. We used magnetic resonance scanning technology to compare brain surface morphology and measures of gyrification in children and adolescents with a schizophrenia spectrum disorder and in age-equivalent healthy controls.nnnMETHODSnMagnetic resonance scans were obtained from 42 patients and 24 healthy controls, mean age 17.7 years for both groups. We employed novel quantitative measures of brain morphology, including cortical thickness and a variety of indices of sulcal and gyral curvature. We examined these measures in the whole brain and in the frontal, temporal, parietal, and occipital lobes.nnnRESULTSnThere were significant decreases in cortical thickness in the patients. This was most pronounced in the cortical tissue that underlies the sulci. The patient group had significantly more flattened curvature in the sulci and more steeped or peaked curvature in the gyri.nnnCONCLUSIONSnThis study quantitatively examines cortical thickness and surface morphology in children and adolescents with schizophrenia. Patients with schizophrenia demonstrated patterns of brain morphology that were distinctly different from healthy controls. In light of current theories of the formation of gyri and sulci, these changes may reflect aberrations in cerebral and subcortical connectivity.

Developmental changes in dopamine neurotransmission in adolescence: behavioral implications and issues in assessment.

Adolescence is characterized by increased risk-taking, novelty-seeking, and locomotor activity, all of which suggest a heightened appetitive drive. The neurotransmitter dopamine is typically associated with behavioral activation and heightened forms of appetitive behavior in mammalian species, and this pattern of activation has been described in terms of a neurobehavioral system that underlies incentive-motivated behavior. Adolescence may be a time of elevated activity within this system. This review provides a summary of changes within cortical and subcortical dopaminergic systems that may account for changes in cognition and affect that characterize adolescent behavior. Because there is a dearth of information regarding neurochemical changes in human adolescents, models for assessing links between neurochemical activity and behavior in human adolescents will be described using molecular genetic techniques. Furthermore, we will suggest how these techniques can be combined with other methods such as pharmacology to measure the impact of dopamine activity on behavior and how this relation changes through the lifespan.

Diffusion tensor imaging in psychiatric disorders

Objectives Since the development of diffusion tensor imaging (DTI) nearly a decade ago, it has been extensively applied to a number of different psychiatric disorders. Its rapid assimilation into psychiatric research has stemmed from its unique property to measure the coherence and direction of neuronal fiber tracts. The goal of this article is to provide an overview of DTI and its application to psychiatric disorders. Methods We performed an extensive literature review of articles using DTI to study psychiatric disorders. To date, most DTI studies have been performed on individuals with schizophrenia. However, recent studies have emerged that evaluate white matter (WM) integrity in major depressive disorder, anxiety disorders, obsessive-compulsive disorder, attention deficit disorder, autism, and personality disorders. Results There is tremendous heterogeneity in the results of DTI studies of patients with psychiatric disorders. In schizophrenia, which currently has more than 50 studies using DTI, brain regions such as the cingulate bundle, corpus callosum, and regions within the frontal and temporal WM have a proportionally larger number of positive findings across the studies. Studies of other psychiatric disorders have findings that overlap with those seen in schizophrenia. Conclusions There is converging evidence that a number of psychiatric disorders are associated with WM abnormalities. However, the considerable heterogeneity of results, both within and between existing studies, will require future work within and across psychiatric disorders to better delineate the neurobiological underpinnings of these white matter abnormalities.

Anatomic and functional variability: the effects of filter size in group fMRI data analysis.

In the analysis of group fMRI scans, an optimal spatial filter should be large enough to accurately blend functionally homologous anatomic regions, yet small enough not to blur the functionally distinct regions. Hanning filters varying from 0.0 to 18.0 mm were evaluated in a group analysis of six healthy controls performing a simple finger-tapping paradigm. Test-retest reliability and Talairach-based measurements of the sensorimotor region were used to explore the optimal filter size. Two distinct regions of functional activation were noted in the sensorimotor cortex in group images (n = 6) at both time 1 and time 2. These regions merge once the filter size exceeds approximately 6.0 mm. The original hypothesis that these represented a motor and sensory activation was rejected on the basis of structural and functional variability. A discussion of the inherent difficulties in choosing an appropriate filter size is presented.

Neurobehavioral Evidence for Changes in Dopamine System Activity During Adolescence

Human adolescence has been characterized by increases in risk-taking, emotional lability, and deficient patterns of behavioral regulation. These behaviors have often been attributed to changes in brain structure that occur during this developmental period, notably alterations in gray and white matter that impact synaptic architecture in frontal, limbic, and striatal regions. In this review, we provide a rationale for considering that these behaviors may be due to changes in dopamine system activity, particularly overactivity, during adolescence relative to either childhood or adulthood. This rationale relies on animal data due to limitations in assessing neurochemical activity more directly in juveniles. Accordingly, we also present a strategy that incorporates molecular genetic techniques to infer the status of the underlying tone of the dopamine system across developmental groups. Implications for the understanding of adolescent behavioral development are discussed.

Effects of olanzapine on cerebellar functional connectivity in schizophrenia measured by fMRI during a simple motor task.

BACKGROUNDnAccording to current theories, schizophrenia results from altered connectivity in brain circuits for fundamental cognitive operations. Consequently, the poorly understood mechanisms of neuroleptic treatment may be explainable by altered functional interactions within such networks. The cognitive dysmetria model hypothesizes that one key structure in these circuits is the cerebellum. To investigate the effects of olanzapine on cerebellar functional connectivity (CFC), a seed-voxel correlation analysis (SVCA) was used in a functional magnetic resonance imaging (fMRI) study of a simple finger-tapping task.nnnMETHODSnfMRI scans were obtained from six schizophrenic patients under both drug-free and olanzapine-treated conditions and from a matched control group of six healthy subjects at corresponding time points. SVCAs were performed for anatomically and functionally standardized seed voxels in the anterior cerebellum. SVCA results were then processed by three different randomization analyses.nnnRESULTSnThe analyses revealed that olanzapine caused widespread changes of CFC, including prominent changes in prefrontal cortex and mediodorsal thalamus. Significant changes in motor structures were found after subtractions within both groups and may thus indicate repetition effects rather than drug effects. Olanzapine normalized the patients CFC patterns for the right, but not for the left cerebellum.nnnCONCLUSIONnEven for a simple motor task, olanzapine affects functional interactions between the cerebellum and many non-motor brain regions, including elements of the cognitive dysmetria circuit. Altogether, our findings suggest that olanzapine has a stronger differential effect on neural activity in prefrontal cortex and thalamus than in motor structures.

Global White Matter Abnormalities in Schizophrenia: A Multisite Diffusion Tensor Imaging Study

BACKGROUNDnEmerging evidence implicates white matter (WM) abnormalities in the pathophysiology of schizophrenia. However, there is considerable heterogeneity in the presentation of WM abnormalities in the existing studies. The object of this study was to evaluate WM integrity in a large sample of patients with first-episode (FE) and chronic schizophrenia in comparison to matched control groups. Our goal was to assess whether WM findings occurred early in the illness or whether these abnormalities developed with the illness over time.nnnMETHODSnParticipants included 114 patients with schizophrenia (31 FE and 83 chronic patients) and 138 matched controls. High-resolution structural and diffusion tensor images were obtained on all participants. Measures of fractional anisotropy (FA) were calculated for the 4 cortical lobes and the cerebellum and brain stem.nnnRESULTSnFA was significant lower in patients vs controls in the whole brain and individually in the frontal, parietal, occipital, and temporal lobes. FA was not significantly different in the brain stem or cerebellum. FA differences were significant only in patients with chronic schizophrenia and not in the FE group.nnnCONCLUSIONSnWe found global differences in the WM microstructure in patients with chronic but not FE schizophrenia. These findings suggest progressive alterations in WM microstructure.

Voxel-based Morphometric Multisite Collaborative Study on Schizophrenia

Regional gray matter (GM) abnormalities are well known to exist in patients with chronic schizophrenia. Voxel-based morphometry (VBM) has been previously used on structural magnetic resonance images (MRI) data to characterize these abnormalities. Two multisite schizophrenia studies, the Functional Biomedical Informatics Research Network and the Mind Clinical Imaging Consortium, which include 9 data collection sites, are evaluating the efficacy of pooling structural imaging data across imaging centers. Such a pooling of data could yield the increased statistical power needed to elucidate effects that may not be seen with smaller samples. VBM analyses were performed to evaluate the consistency of patient versus control gray matter concentration (GMC) differences across the study sites, as well as the effects of combining multisite data. Integration of data from both studies yielded a large sample of 503 subjects, including 266 controls and 237 patients diagnosed with schizophrenia, schizoaffective or schizophreniform disorder. The data were analyzed using the combined sample, as well as analyzing each of the 2 multisite studies separately. A consistent pattern of reduced relative GMC in schizophrenia patients compared with controls was found across all study sites. Imaging center-specific effects were evaluated using a region of interest analysis. Overall, the findings support the use of VBM in combined multisite studies. This analysis of schizophrenics and controls from around the United States provides continued supporting evidence for GM deficits in the temporal lobes, anterior cingulate, and frontal regions in patients with schizophrenia spectrum disorders.

MTHFR 677C --> T genotype disrupts prefrontal function in schizophrenia through an interaction with COMT 158Val --> Met.

Understanding how risk genes cumulatively impair brain function in schizophrenia could provide critical insights into its pathophysiology. Working memory impairment in schizophrenia has been associated with abnormal dopamine signaling in the prefrontal cortex, which is likely under complex genetic control. The catechol-O-methyltransferase (COMT) 158Val → Met polymorphism (rs4680), which affects the availability of prefrontal dopamine signaling, consistently stratifies prefrontal activation during working memory performance. However, the low-dopamine COMT 158Val allele does not confer increased risk for schizophrenia, and its effects on prefrontal function are not specific to the disorder. In the setting of other genetic variants influencing prefrontal dopamine signaling, COMT 158Val → Met genotype may exert disease-specific effects. A second polymorphism, methylenetetrahydrofolate reductase (MTHFR) 677C → T (rs1801133), has been associated with overall schizophrenia risk and executive function impairment in patients, and may influence dopamine signaling through mechanisms upstream of COMT effects. We found that the hypofunctional 677T variant was associated with decreased working memory load-dependent activation in the prefrontal and insular cortices in 79 schizophrenia patients, but not in 75 demographically matched healthy controls. Further, significant MTHFR × COMT genotype interactions were observed, which differed by diagnostic group: Reduced prefrontal activation was associated with the 677T and 158Val alleles in patients, but with 677C/C and 158Met/Met genotype in controls. These findings are consistent with epistatic effects of the COMT and MTHFR polymorphisms on prefrontal dopamine signaling, and suggest that in schizophrenia patients, the MTHFR 677T allele exacerbates prefrontal dopamine deficiency. The findings also suggest the importance of weighing COMT effects on prefrontal function within the context of MTHFR genotype.

Neuropsychological Performance in First-Episode Adolescents with Schizophrenia: A Comparison with First-Episode Adults and Adolescent Control Subjects

BACKGROUNDnThe goal of this study was to compare the extent of cognitive deficits between adolescents and adults early in the course of schizophrenia.nnnMETHODSnA comprehensive neuropsychological battery was performed on 49 adolescents with childhood- or adolescent-onset schizophrenia, 139 adults with adult-onset schizophrenia, 32 healthy adolescent volunteers, and 240 healthy adult volunteers. Both patient groups were assessed early in the course of their illness and were matched to their respective control groups on age and parental education.nnnRESULTSnThe adolescent patients performed significantly worse than the adult patients on tasks of working memory, language, and motor function. The healthy adolescents also performed significantly worse than the healthy adults in working memory and language tasks but were significantly better than the adults in motor function. When accounting for developmental differences in the control group, only motor performance was worse in the adolescent patients compared with the adult patients.nnnCONCLUSIONSnThese findings, when coupled with published retrospective studies reporting greater cognitive deficits in earlier onset schizophrenia, implicate a cessation in development in specific cognitive domains following the onset of schizophrenia in adolescent patients.