Faculty Bibliography

BACKGROUND: Structural and functional abnormalities have been found in language-related brain regions in patients with schizophrenia. We previously reported findings pointing to differences in word processing between people with schizophrenia and individuals who are at high-risk for schizophrenia using a voxel-based (whole brain) fMRI approach. We now extend this finding to specifically examine functional activity in three language related cortical regions using a larger cohort of individuals. METHOD: A visual lexical discrimination task was performed by 36 controls, 21 subjects at high genetic-risk for schizophrenia, and 20 patients with schizophrenia during blood oxygenation level dependent (BOLD) fMRI scanning. Activation in bilateral inferior frontal gyri (Brodmann's area 44-45), bilateral inferior parietal lobe (Brodmann's area 39-40), and bilateral superior temporal gyri (Brodmann's area 22) was investigated. For all subjects, two-tailed Pearson correlations were calculated between the computed laterality index and a series of cognitive test scores determining language functioning. RESULTS: Regional activation in Brodmann's area 44-45 was left lateralized in normal controls, while high-risk subjects and patients with schizophrenia or schizoaffective disorder showed more bilateral activation. No significant differences among the three diagnostic groups in the other two regions of interest (Brodmann's area 22 or areas 39-40) were found. Furthermore, the apparent reasons for loss of leftward language lateralization differed between groups. In high-risk subjects, the loss of lateralization was based on reduced left hemisphere activation, while in the patient group, it was due to increased right side activation. Language ability related cognitive scores were positively correlations with the laterality indices obtained from Brodmann's areas 44-45 in the high-risk group, and with the laterality indices from Brodmann's areas 22 and 44-45 in the patient group. CONCLUSIONS: This study reinforces previous language related imaging studies in high-risk subjects and patients with schizophrenia suggesting that reduced functional lateralization in language related frontal cortex may be a vulnerability marker for schizophrenia. Future studies will determine whether it is predictive of who develops illness

CONTEXT: There is increasing evidence that schizophrenia is characterized by abnormalities in white matter. OBJECTIVE: To investigate the integrity of white matter tracts in adolescents with schizophrenia. DESIGN: Cross-sectional, case-control, whole-brain, voxel-based analysis and fiber tractography using diffusion tensor magnetic resonance imaging. SETTING: University research institute. PARTICIPANTS: Forty-four individuals (age range, 11-18 years), 23 with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder and 21 demographically similar healthy controls. MAIN OUTCOME MEASURES: Fractional anisotropy, trace, and radial diffusivity of diffusion tensor and quantitative tractography. RESULTS: Voxelwise analysis revealed that adolescents with schizophrenia had reduced fractional anisotropy within the left inferior temporal (P < .001) and occipital (P < .001) regions. Tractography was performed to extract the left and the right inferior longitudinal fasciculi (ILF). Measuring the mean diffusion indices along the left ILF, patients had significantly reduced fractional anisotropy (P < .001) as well as significantly increased radial diffusivity (P < .001) and trace (P = .003) after adjusting for differences in a measure thought to reflect premorbid intelligence, Wide Range Achievement Test 3 reading scores. Exploratory analyses revealed that patients with a history of visual hallucinations had lower fractional anisotropy in the left ILF (P = .02) than patients without visual hallucinations. CONCLUSION: Our findings, which benefited from greater image resolution and methodological control than previous studies conducted in adolescents with schizophrenia, provide strong evidence for lower white matter integrity in the left ILF, particularly for patients with a history of visual hallucinations

BACKGROUND: This study tested the hypothesis that microstructural white matter abnormalities in frontostriatal-limbic tracts are associated with poor response inhibition on the Stroop task in depressed elders. METHOD: Fifty-one elders with major depression participated in a 12-week escitalopram trial. Diffusion tensor imaging was used to determine fractional anisotropy (FA) in white matter regions. Executive function (response inhibition) was assessed with the Stroop task. Voxelwise correlational analysis was used to examine the relationship between Stroop performance and fractional anisotropy. RESULTS: Significant associations between FA and Stroop color word interference were evident in multiple frontostriatal-limbic regions, including white matter lateral to the anterior and posterior cingulate cortex and white matter in prefrontal, insular, and parahippocampal regions. CONCLUSIONS: These findings suggest that microstructural white matter abnormalities of frontostriatal-limbic networks are associated with executive dysfunction of late-life depression. This observation provides the rationale for examination of specific frontostriatal-limbic pathways in the pathophysiology of geriatric depression.

BACKGROUND: Previous MRI studies of healthy children have reported age-related white matter (WM) changes in language and motor areas of the brain. The authors investigated WM development in healthy adolescent males through age-associated changes in fractional anisotropy (FA), radial (lambda( perpendicular)) and axial (lambda(||)) diffusivity. METHODS: Twenty-four healthy adolescent males (mean age=16.6, SD=2.5 years) were divided into two groups with an age split of 16.9 years and underwent a whole-brain voxelwise analysis. RESULTS: At a threshold of p<0.001 and extent threshold of 100 contiguous voxels, several clusters with increased FA and axial diffusivity and no differences in radial diffusivity were observed in older adolescents compared to the younger adolescents in the left arcuate fasciculus, bilateral posterior internal capsule/thalamic radiation, bilateral prefrontal gyrus, right superior temporal gyrus, and posterior corpus callosum. Increased FA and lambda(||) of several clusters along the arcuate fasciculus significantly correlated with a test of language and semantic memory. CONCLUSIONS: These results suggest ongoing maturational changes especially in the arcuate fasiculus during late adolescence. Increased FA and lambda(||) with no changes in radial diffusivity may reflect a developmental pattern of reduced tortuousity toward more straightened fibers and/or increased axonal fiber organization during late adolescence

BACKGROUND: Abnormalities in language processing and the related brain structures have been reported in people with schizophrenia. It has been proposed that the brain pathways for language processing are anomalous in these individuals and form the underlying basis for the positive symptoms of the illness. If language pathway abnormalities can be detected early in people at high-risk for schizophrenia prior to the onset of symptoms, early treatment can ensue. METHODS: Fifteen young adults at high genetic risk for developing schizophrenia were compared with 15 of their siblings with schizophrenia or schizoaffective disorder and 15 age and sex matched individuals at low risk for schizophrenia using a visual lexical decision task during fMRI. The data were analyzed by contrasting activation obtained during a real word-pseudoword discrimination task to activation obtained during a nonlinguistic discrimination task, and the differential activations were examined. RESULTS: Patterns of brain activation while reading and discriminating between real and pseudowords differed across groups, with more bilateral activation in schizophrenia patients and their high-risk siblings than controls. In control subjects discrimination of words from psuedowords significantly activated Brodmann's area 44 more strongly than when non-linguistic symbols were discriminated. However, high-risk subjects and their siblings with schizophrenia activated this region similarly for both language and non-language tasks. CONCLUSIONS: Normal individuals can be distinguished from subjects at high genetic risk for schizophrenia and patients with schizophrenia by their more lateralized and stronger activation of Brodmann's area 44 to word compared with symbol discrimination tasks. Thus, evaluation of language processing by fMRI may be a valuable tool for use in the prediction of individual risk for developing schizophrenia

A novel magnetic resonance imaging method was used to determine whether it is feasible to detect early signs of cortical atrophy among individuals who are at high risk for developing schizophrenia. Fifteen individuals at high-risk for schizophrenia and 15 of their first degree relatives diagnosed with schizophrenia were compared with controls (n=25) who did not have a family history of psychiatric illness or psychiatric hospitalizations. On the basis of a voxelwise analysis of apparent diffusion coefficient (ADC) maps derived from diffusion weighted magnetic resonance imaging, these individuals showed evidence of deficits in four separate regions of the brain, all on the left side only: parahippocampal gyrus, lingual gyrus, superior frontal gyrus, and middle frontal gyrus. However, conventional volumetric quantification of ventricular space to detect atrophy failed to reveal differences between high-risk subjects and controls. It is concluded that ADC may be a more sensitive measure than ventricular volume assessments for use in future studies of early prediction of schizophrenia

Patients with schizophrenia show deficits in several neurocognitive domains. However, the relationship between white matter integrity and performance in these domains is poorly understood. The authors conducted neurocognitive testing and diffusion tensor imaging in 25 patients with schizophrenia. Performance was examined for tests of verbal declarative memory, attention, and executive function. Relationships between fractional anisotropy and cognitive performance were examined by using voxelwise correlational analyses. In each case, better performance on these tasks was associated with higher levels of fractional anisotropy in task-relevant regions

Analyses were performed on brain MRI scans from individuals who were frequent cannabis users (N = 10; 9 males, 1 female, mean age 21.1 +/- 2.9, range: 18-27) in adolescence and similar age and sex matched young adults who never used cannabis (N = 10; 9 males, 1 female, mean age of 23.0 +/- 4.4, range: 17-30). Cerebral atrophy and white matter integrity were determined using diffusion tensor imaging (DTI) to quantify the apparent diffusion coefficient (ADC) and the fractional anisotropy (FA). Whole brain volumes, lateral ventricular volumes, and gray matter volumes of the amygdala-hippocampal complex, superior temporal gyrus, and entire temporal lobes (excluding the amygdala-hippocampal complex) were also measured. While differences existed between groups, no pattern consistent with evidence of cerebral atrophy or loss of white matter integrity was detected. It is concluded that frequent cannabis use is unlikely to be neurotoxic to the normal developing adolescent brain