Brodmann area analysis of white matter anisotropy and age in schizophrenia.

Diffusion tensor and structural MRI images were acquired on ninety-six patients with schizophrenia (69 men and 27 women) between the ages of 18 and 79 (mean=39.83, SD=15.16 DSM-IV diagnosis of schizophrenia according to the Comprehensive Assessment of Symptoms and History). The patients reported a mean age of onset of 23 years (range=13-38, SD=6). Patients were divided into an acute subgroup (duration ≤3 years, n=25), and a chronic subgroup (duration >3 years, n=64). Ninety-three mentally normal comparison subjects were recruited; 55 men and 38 women between the ages of 18 and 82 (mean=35.77, SD=18.12). The MRI images were segmented by Brodmann area, and the fractional anisotropy (FA) for the white matter within each Brodmann area was calculated. The FA in white matter was decreased in patients with schizophrenia broadly across the entire brain, but to a greater extent in white matter underneath frontal, temporal and cingulate cortical areas. Both normals and patients with schizophrenia showed a decrease in anisotropy with age but patients with schizophrenia showed a significantly greater rate of decrease in FA in Brodmann area 10 bilaterally, 11 in the left hemisphere and 34 in the right hemisphere. When the effect of age was removed, patients ill more than three years showed lower anisotropy in frontal motor and cingulate white matter in comparison to acute patients ill three years or less, consistent with an ongoing progression of the illness.

Diffusion tensor anisotropy in the cingulate gyrus in schizophrenia.

It has been proposed that schizophrenia results partly from altered brain connectivity. The anterior cingulate cortex in particular has been demonstrated to be affected in schizophrenia, with studies reporting reduced volume, altered neuronal arrangement, decreased anisotropy in diffusion tensor images, and hypometabolism. We used a 3T Siemens scanner to acquire structural and diffusion tensor imaging in age-and sex-matched groups of 41 adults with chronic schizophrenia, 6 adults with recent-onset schizophrenia, and 38 healthy control subjects. We manually traced the anterior and posterior cingulate gyri on all subjects and then compared the volume and anisotropy across groups for the left and right anterior and posterior cingulate gyri. The anterior cingulate gyrus was divided axially into six equal segments, and the posterior cingulate gyrus into two segments. Volume was calculated for the anterior and posterior gyri, and average anisotropy was then calculated for each individual segment, looking separately at gray and white matter. We found decreased overall relative left and right gray matter volume in the anterior cingulate gyrus in persons with schizophrenia compared with healthy controls. Additionally, in both gray and white matter of the cingulate, we found that recent-onset patients had the highest anisotropy, chronic patients had the lowest, and controls were intermediate. These results provide additional evidence for the presence of both white and gray matter abnormalities in the cingulate gyrus, which has been implicated in schizophrenia.

FDG-PET and MRI imaging of the effects of sertindole and haloperidol in the prefrontal lobe in schizophrenia.

Sertindole, a 2nd generation antipsychotic with low movement disorder side effects, was compared with haloperidol in a 6-week crossover study. Fifteen patients with schizophrenia (mean age=42.6, range=22-59, 11 men and 4 women) received sertindole (12-24 mg) or haloperidol (4-16 mg) for 6 weeks and then received a FDG-PET scan and an anatomical MRI. Patients were then crossed to the other treatment and received a second set of scans at week 12. Dose was adjusted by a physician blind to the medication type. Brodmann areas were identified stereotaxically using individual MRI templates applied to the coregistered FDG-PET image. Sertindole administration was associated with higher dorsolateral prefrontal cortex metabolic rates than haloperidol and lower orbitofrontal metabolic rates than haloperidol. This effect was greatest for gray matter of the dorsolateral Brodmann areas 8, 9, 10, 44, 45, and 46. Patients were further contrasted with an approximately age and sex-matched group of 33 unmedicated patients with schizophrenia and with a group of 55 normal volunteers. Sertindole administration was associated with greater change toward normal values and away from the values found in the unmedicated comparison group for dorsolateral prefrontal cortex gray matter and white matter underlying medial prefrontal and cingulate cortex. These results are consistent with the low motor side-effect profile of sertindole, greater improvement on prefrontal cognitive tasks with sertindole than haloperidol, and with the tendency of 2nd generation antipsychotic drugs to have greater frontal activation than haloperidol.

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Previous studies have reported continued focal gray matter loss after the clinical onset of schizophrenia. Longitudinal assessments in chronic illness, of white matter in particular, have been less conclusive.We used diffusion-tensor and structural magnetic resonance imaging in 16 healthy subjects and 49 chronic schizophrenia patients, subdivided into good-outcome (n=23) and poor-outcome (n=26) groups, scanned twice 4 years apart. Fractional anisotropy, gray matter and white matter volumes were parcellated into the Brodmann's areas and entered into multiway ANCOVAs.At baseline, schizophrenia patients had 1) lower anisotropy in frontoparietal white matter, 2) larger posterior frontal white matter volumes, and 3) smaller frontal, temporal, and parietal gray matter volumes. On follow-up, healthy subjects showed a more pronounced 1) decline in anisotropy, 2) expansion of regional white matter volumes, and 3) reduction in regional gray matter volumes than schizophrenia patients. Good-outcome patients showed a more pronounced decline in white matter anisotropy and a less pronounced increase in white matter volumes than poor-outcome patients. Poor-outcome patients displayed a greater gray matter loss throughout the brain than good-outcome patients.In the chronic phase of the illness, longitudinal changes in both gray and white matter are in the direction of an effacement of between-group differences among schizophrenia patients and healthy subjects. Similarly, preexisting white matter differences between good-outcome and poor-outcome patients diminish over time. In contrast, gray matter volumes in poor-outcome patients continue to decline more rapidly than in patients with good outcome. These patterns are consistent with earlier onset of aging-associated changes in schizophrenia.

Age and diffusion tensor anisotropy in adolescent and adult patients with schizophrenia.

Findings of white matter pathology as indicated by diffusion tensor anisotropy values in schizophrenia are well established, but the differences in this measure between the onset of the disease and the chronic state are not well known. To investigate the differences between these states in the progression of the disease of schizophrenia we acquired 1.5 T diffusion tensor anisotropy images on 35 adult patients with schizophrenia and schizoaffective disorder, 23 adolescents having their first psychotic episode, and age and sex matched controls (33 adults and 15 adolescents). Regions of interest in major cortical white matter tracts chosen as salient to the prefrontal executive deficit in schizophrenia were assessed using stereotaxic coordinates from the Talairach and Tournoux atlas. Regions of each tract along anterior-posterior and/or inferior-superior directions in both hemispheres were evaluated in multiway ANOVA. Tracts between the frontal lobe and other brain regions, but not temporal, occipital and interhemispheric tracts, showed a differential aging pattern in normals and patients indicating that the white matter pathology in these regions is not stable between the onset and the chronic state in schizophrenia. This suggests that tracts involved in the connectivity of the temporal lobe white matter deficits were already well in place in adolescent patients, while frontal lobe pathology continues to develop from adolescence to adulthood.

Cortical gray and white matter volume in unmedicated schizotypal and schizophrenia patients.

Magnetic resonance imaging (MRI) studies have revealed fronto-temporal cortical gray matter volume reductions in schizophrenia. However, to date studies have not examined whether age- and sex-matched unmedicated schizotypal personality disorder (SPD) patients share some or all of the structural brain-imaging characteristics of schizophrenia patients. We examined cortical gray/white matter volumes in a large sample of unmedicated schizophrenia-spectrum patients (n=79 SPD, n=57 schizophrenia) and 148 healthy controls. MRI images were reoriented to standard position parallel to the anterior-posterior commissure line, segmented into gray and white matter tissue types, and assigned to Brodmann areas (BAs) using a postmortem-histological atlas. Group differences in regional volume of gray and white matter in the BAs were examined with MANOVA. Schizophrenia patients had significantly reduced gray matter volume widely across the cortex but more marked in frontal and temporal lobes. SPD patients had reductions in the same regions but only about half that observed in schizophrenia and sparing in key regions including BA10. In schizophrenia, greater fronto-temporal volume loss was associated with greater negative symptom severity and in SPD, greater interpersonal and cognitive impairment. Overall, our findings suggest that increased prefrontal volume in BA10 and sparing of volume loss in temporal cortex (BAs 22 and 20) may be a protective factor in SPD which reduces vulnerability to psychosis.

The effect of doxapram on brain imaging in patients with panic disorder.

Administration of doxapram hydrochloride, a respiratory stimulant, is experienced by panic disorder patients to be similar to panic attacks but has reduced emotional effect in normal volunteers, thus providing a laboratory model of panic for functional imaging. Six panic patients and seven normal control subjects underwent positron emission tomography with (18)F-deoxyglucose imaging after a single-blinded administration of either doxapram or a placebo saline solution. Saline and doxapram were administered on separate days in counterbalanced order. Patients showed a greater heart rate increase on doxapram relative to saline than controls, indicating differential response. On the saline placebo day, patients had greater prefrontal relative activity than controls. In response to doxapram, patients tended to decrease prefrontal activity more than controls, and increased cingulate gyrus and amygdala activity more than controls. This suggests that panic disorder patients activate frontal inhibitory centers less than controls, a tendency that may lower the threshold for panic.

Diffusion tensor anisotropy in adolescents and adults.

We acquired diffusion tensor images on 33 normal adults aged 22-64 and 15 adolescents aged 14-21. We assessed relative anisotropy in stereotaxically located regions of interest in the internal capsule, corpus callosum, anterior thalamic radiations, frontal anterior fasciculus, fronto-occipital fasciculus, temporal lobe white matter, cingulum bundle, frontal inferior longitudinal fasciculus, frontal superior longitudinal fasciculus, and optic radiations. All of these structures except the optic radiations, corpus callosum, and frontal inferior longitudinal fasciculus exhibited differences in anisotropy between adolescents and adults. Areas with anisotropy increasing with age included the anterior limb of the internal capsule, superior levels of the frontal superior longitudinal fasciculus and the inferior portion of the temporal white matter. Areas with anisotropy decreasing with age included the posterior limb of the internal capsule, anterior thalamic radiations, fronto-occipital fasciculus, anterior portion of the frontal anterior fasciculus, inferior portion of the frontal superior longitudinal fasciculus, cingulum bundle and superior portion of the temporal axis. Sex differences were found in the majority of areas but were most marked in the cingulum bundle and internal capsule. These results suggest continuing white matter development between adolescence and adulthood.

Internal capsule, corpus callosum and long associative fibers in good and poor outcome schizophrenia: a diffusion tensor imaging survey.

BACKGROUND: Prior voxelwise studies of white matter anisotropy found widespread reductions involving all major fiber tracts of the schizophrenic brain. We set out to confirm these exploratory findings and evaluate their relation to illness severity using a hypothesis-driven region-of-interest approach. METHODS: 104 schizophrenia patients (51 with good outcomes, 53 with poor outcomes) and 41 matched comparison subjects participated in the study. Regions of interest were selected on the basis of published voxelwise findings and placed within major fiber tracts using Talairach's stereotaxic coordinates. RESULTS: Fractional anisotropy reductions in schizophrenia patients were confirmed in the left cingulum, anterior thalamic radiation, fronto-occipital and inferior longitudinal fasciculi, as well as bilaterally in the corpus callosum, anterior and posterior limbs of internal capsule, superior longitudinal fasciculus, optic radiation, and frontotemporal extrafascicular white matter. Anisotropy reductions were more extensive in patients with poor outcomes ("Kraepelinian"), particularly in the posterior corpus callosum, fronto-occipital fasciculus, left optic radiation and frontotemporal white matter. Lower anisotropy in the right hemisphere tracts was associated with more prominent positive symptomatology, whereas negative symptoms were inversely associated with anisotropy values in both hemispheres. CONCLUSIONS: These results support a global neural disconnectivity in schizophrenia patients, which is more severe in those with poor clinical outcomes.

Diffusion tensor imaging of frontal lobe white matter tracts in schizophrenia.

We acquired diffusion tensor and structural MRI images on 103 patients with schizophrenia and 41 age-matched normal controls. The vector data was used to trace tracts from a region of interest in the anterior limb of the internal capsule to the prefrontal cortex. Patients with schizophrenia had tract paths that were significantly shorter in length from the center of internal capsule to prefrontal white matter. These tracts, the anterior thalamic radiations, are important in frontal-striatal-thalamic pathways. These results are consistent with findings of smaller size of the anterior limb of the internal capsule in patients with schizophrenia, diffusion tensor anisotropy decreases in frontal white matter in schizophrenia and hypothesized disruption of the frontal-striatal-thalamic pathway system.

Diffusion tensor imaging in schizophrenia.

BACKGROUND: Alignment of white matter axons as inferred from diffusion tensor imaging has indicated changes in schizophrenia in frontal and frontotemporal white matter. METHODS: Diffusion tensor anisotropy and anatomical magnetic resonance images were acquired in 64 patients with schizophrenia and 55 normal volunteers. Anatomical images were acquired with a magnetization prepared rapid gradient echo sequence, and diffusion tensor images used a pulsed gradient spin-echo acquisition. Images were aligned and warped to a standard brain, and anisotropy in normal volunteers and patients was compared using significance probability mapping. RESULTS: Patients showed widespread areas of reduced anisotropy, including the frontal white matter, the corpus callosum, and the frontal longitudinal fasciculus. CONCLUSIONS: These findings, which are consistent with earlier reports of frontal decreases in anisotropy, demonstrate that the effects are most prominent in frontal and callosal areas and are particularly widespread in frontal white matter regions.

White matter fractional anisotropy and outcome in schizophrenia.

OBJECTIVE: Disparate white matter fractional anisotropy (FA) findings have been reported in patients with schizophrenia in recent years. This may in part reflect heterogeneity of subjects in the studies, including differences in outcome and severity of the illness. We examined whether there is a relationship between white matter FA and outcome in patients with schizophrenia. METHOD: Diffusion-tensor images were obtained in 41 normal subjects and 104 patients with schizophrenia, divided into good-outcome (n=51) and poor-outcome (Kraepelinian; n=53) subtypes based on their ability for self-care. White matter FA and its relationship to regional tissue volumes were evaluated across 40 individual Brodmann's areas using a semi-automated parcellation technique. RESULTS: Overall white matter FA was lower in schizophrenia patients than normal subjects, with regional reductions in widespread temporoparietal and selected prefrontal white matter regions. In schizophrenia patients, lower regional white matter FA was associated with lower regional gray matter volumes. In comparison to normal subjects, overall white matter FA was reduced in patients with poor outcomes in both hemispheres, but to a lesser extent and only in the right hemisphere in good-outcome patients. Lower regional FA was associated with larger regional white matter volumes in good-outcome group. CONCLUSIONS: Global FA reductions implicate white matter as tissue type in the pathophysiology of schizophrenia. In contrast to poor outcome, good outcome in schizophrenia patients may be associated with less extensive FA reductions, higher FA in regional frontal and cingulate white matter, and correlated increases in regional white matter volumes, particularly in the left hemisphere.