M. Mehmet Haznedar

MRI white matter diffusion anisotropy and PET metabolic rate in schizophrenia

A disturbance in the frontal–striatal–thalamic circuitry has been proposed for schizophrenia, but this concept has been based primarily on indirect evidence from psychopharmacology and analogies with animal research. Diffusion tensor imaging, a new MRI technique that permits direct assessment of the large axon masses stretching from the prefrontal cortex to the striatum, was used to study white matter axon bundles. Diffusion tensor images, high-resolution structural MRI and positron emission tomography scans with 18-fluorodexoyglucose were obtained on five patients with schizophrenia and six age- and sex-matched normal controls. Significantly lower diffusion anisotropy in the white matter of the prefrontal cortex in schizophrenic patients than in normal controls was observed in statistical probability maps. Co-registered PET scans revealed significantly lower correlation coefficients between metabolic rates in the prefrontal cortex and striatum in patients than in controls. These twin findings provide convergent evidence for diminished fronto–striatal connectivity in schizophrenia.

Striatal Volume on Magnetic Resonance Imaging and Repetitive Behaviors in Autism

BACKGROUND The repetitive behaviors seen in autism phenotypically resemble those seen in obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), disorders in which structural and functional abnormalities of the basal ganglia (BG) are present and correspond to the severity of repetitive behaviors. METHODS Seventeen subjects with autism by DSM-IV and Autism Diagnostic Interview (ADI) and 17 matched controls completed a 1.5 T magnetic resonance image (MRI) of the brain. Two blinded researchers, with good inter-rater reliability, outlined the right and left caudate and putamen. Autistic and control BG volumes covaried for total brain volume were compared using analysis of covariance. BG volumes within the autistic group were correlated with the ADI Repetitive Behavior scores (ADI-C domain). RESULTS Right caudate volume controlled for total brain volume was significantly larger in autistic subjects than in controls. In addition, right caudate and total putamen volumes correlated positively with repetitive behavior scores on the ADI-C domain, particularly the higher order OCD-like repetitive behaviors. CONCLUSIONS Increased right caudate volume in autism is of interest, since this has also been observed in OCD patients. Increased volume of the right caudate and total putamen positively correlated with greater repetitive behaviors, supporting the hypothesis of BG dysfunction associated with repetitive behaviors in autistic adults.

Amygdala-prefrontal disconnection in borderline personality disorder.

Abnormal fronto-amygdala circuitry has been implicated in impulsive aggression, a core symptom of borderline personality disorder (BPD). We examined relative glucose metabolic rate (rGMR) at rest and after m-CPP (meta-chloropiperazine) with 18fluorodeoxyglucose (FDG) with positron emission tomography (PET) in 26 impulsive aggressive (IED)-BPD patients and 24 controls. Brain edges/amygdala were visually traced on MRI scans co-registered to PET scans; rGMR was obtained for ventral and dorsal regions of the amygdala and Brodmann areas within the prefrontal cortex (PFC). Correlation coefficients were calculated between rGMR for dorsal/ventral amygdala regions and PFC. Additionally, amygdala volumes and rGMR were examined in BPD and controls. Correlations PFC/amygdala Placebo: Controls showed significant positive correlations between right orbitofrontal (OFC) and ventral, but not dorsal, amygdala. Patients showed only weak correlations between amygdala and the anterior PFC, with no distinction between dorsal and ventral amygdala. Correlations PFC/amygdala: m-CPP response: Controls showed positive correlations between OFC and amygdala regions, whereas patients showed positive correlations between dorsolateral PFC and amygdala. Group differences between interregional correlational matrices were highly significant. Amygdala volume/metabolism: No group differences were found for amygdala volume, or metabolism in the placebo condition or in response to meta-chloropiperazine (m-CPP). We demonstrated a tight coupling of metabolic activity between right OFC and ventral amygdala in healthy subjects with dorsoventral differences in amygdala circuitry, not present in IED-BPD. We demonstrated no significant differences in amygdala volumes or metabolism between BPD patients and controls.

Reduced anterior and posterior cingulate gray matter in borderline personality disorder.

BACKGROUND Structural abnormalities in prefrontal and cingulate gyrus regions-important in affective processing, impulse control and cognition may contribute to the psychopathology of borderline personality disorder (BPD). Previous MRI studies examining volume have reported that compared with healthy controls, BPD patients have decreases in right anterior cingulate, no differences in dorsolateral prefrontal cortex, and mixed findings for prefrontal cortex. We extended this investigation by examining gray and white matter volume of frontal and cingulate gyrus Brodmann areas (BAs) in a large group of patients and healthy controls. METHODS MRI scans were acquired in 50 BPD patients (n = 13 with comorbid diagnosis of BPD and Schizotypal Personality Disorder (SPD) and n = 37 without SPD) and 50 healthy controls, and gray/white matter volume in cingulate gyrus and frontal lobe BAs were assessed. Normal BPD and BPD subgroup comparisons were conducted. RESULTS Compared with controls, BPD patients showed reduced gray matter volume in BA 24 and 31 of the cingulate. BPD patients without comorbid SPD had isolated gray matter volume loss in BA 24, but were spared for BA 31 in contrast to BPD patients with SPD. There were no group differences in whole cingulate or frontal lobe volume. CONCLUSIONS The finding of more pervasive cingulate shrinkage in the patients with BPD and SPD comorbidity resembles recent observations with the same methods in patients with schizophrenia. The pattern of reduced anterior and posterior cingulate gray matter volume in BPD patients, particularly those comorbid for SPD is consistent with the affective and attentional deficits observed in these personality disorders.

Shape and size of the corpus callosum in schizophrenia and schizotypal personality disorder

The size and shape of the corpus callosum were assessed on sagittal section magnetic resonance images in 27 patients with schizophrenia, 13 patients with schizotypal personality disorder (SPD), and 30 healthy volunteers. High-resolution 1.2mm axial SPGR images were acquired and resectioned so that the sagittal plane passed through the anterior and posterior commissures and was parallel to the interhemispheric fissure. The corpus callosum and the whole brain were traced on midsagittal section slices of each brain, and the callosum was divided into 30 anteroposterior sectors. Pixel-by-pixel chi-square and thin-plate spline analyses were used to assess between-group shape differences. Size of the corpus callosum was smaller anteriorly in the genu of the corpus callosum and posteriorly in the splenium in schizophrenic patients than in normal controls. The genu of the corpus callosum was larger in SPD patients than in schizophrenic patients or normal controls. The posterior corpus callosum was largest in normal controls, smaller in SPD patients, and smallest in schizophrenic patients. Shape analysis was consistent with these size comparisons, and suggested a downward bowing of the corpus callosum in schizophrenic and SPD patients. SPD patients also had a region of the callosum just posterior to the genu that was narrower than in the other two groups. The decreases in corpus callosal size in schizophrenia varied directly with length of illness, perhaps indicative of a progressive process. The patient-control differences in callosal size and shape are consistent with a hypothesis of decreased connectivity between the left and the right hemispheres in schizophrenia and SPD.

Prefrontal cortex glucose metabolism and startle eyeblink modification abnormalities in unmedicated schizophrenia patients

Attentional modulation of the startle reflex was studied in 16 unmedicated schizophrenia patients and 15 control individuals during the 18F-2-deoxyglucose uptake period for positron emission tomography. In a task involving attended, ignored, and novel tones that served as prepulses, control individuals showed greater prepulse inhibition (PPI) at 120 ms and greater prepulse facilitation at 4,500 ms during attended than during ignored prepulses; the amount of PPI and facilitation during novel prepulses was intermediate. In contrast, patients failed to show differential PPI at 120 ms and tended to show greater facilitation at 4,500 ms during novel prepulses. For control individuals, greater PPI was associated with higher relative metabolic activity rates in prefrontal (Brodmann Areas 8, 9, and 10 bilaterally) and lower in visual cortex. Patients showed this relationship only for Area 10 on the left. Patients also had low metabolism in superior, middle, and inferior prefrontal cortex. Consistent with animal models, our results demonstrate the importance of the functional integrity of prefrontal cortex to PPI modulation.

Hypofrontality in unmedicated schizophrenia patients studied with PET during performance of a serial verbal learning task.

Previous research indicates that verbal learning and memory deficits are among the most severe cognitive deficits observed in schizophrenia. However, the concomitant patterns of regional brain function associated with these deficits in schizophrenia are not well understood. The present study examined verbal-memory performance and simultaneous relative glucose metabolic rates (rGMR) with FDG PET in 20 unmedicated schizophrenia patients who met stringent memory-performance criteria and 32 age- and sex-matched normal volunteers. On a modified version of the California Verbal Learning Test, patients recalled fewer correct words using a semantic-clustering strategy and exhibited more intrusions compared with normal subjects. However, patients had higher serial-ordering strategy scores, indicating their use of a less efficient organizational strategy. Among patients, greater use of the serial-ordering strategy was associated with decreased rGMR in frontal cortex and increased rGMR in temporal cortex. Patients had lower rGMR primarily in frontal and temporal cortex, but not parietal and occipital lobe regions. Patients also exhibited hypofrontality (lower ratio of frontal to occipital rGMR) compared with normal subjects. Among the patients, more severe hypofrontality was associated with increased perseveration errors.

Ventricular volume and asymmetry in schizotypal personality disorder and schizophrenia assessed with magnetic resonance imaging

Magnetic resonance imaging (MRI) was performed in 12 patients with schizotypal personality disorder (SPD), 11 patients with chronic schizophrenia, and 23 age- and sex-matched normal volunteers. MRI slices were acquired in the axial plane at 1.2-mm intervals, and the ventricles were traced on every other slice. The lateral ventricular system was divided into the anterior horn, temporal horn, and dorsal lateral ventricle. Schizophrenic patients had larger left anterior and temporal horns than the normal volunteers. Size of the left anterior and temporal horn in SPD patients was intermediate between those of normal volunteers and schizophrenic patients and differed significantly from schizophrenic patients. The left-minus-right difference was larger in schizophrenic patients than in normal volunteers or SPD patients. Thus, in their structural brain characteristics, as well as in their clinical symptomatology, SPD patients evidence, in attenuated form, abnormalities resembling those found in full-fledged schizophrenia. The findings suggest that decreased left hemispheric volume, in frontal and temporal regions, may characterize both psychotic and non-psychotic disorders of the schizophrenia spectrum.

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.

Age-related shift in brain region activity during successful memory performance

Coregistered positron emission tomography (PET)/magnetic resonance imaging (MRI) was used to characterize brain function in 70 volunteers, aged 20-87 years, during a verbal memory task. Frontal activity showed an age-related decline that remained significant after statistical control for sulcal atrophy. Analyses of young and old subgroups matched for memory scores revealed that young good performers activated frontal regions, whereas old good performers relied on occipital regions. Although activating different cortical regions, good performers of all ages used the same cognitive strategy semantic clustering. Age-related functional change may reflect dynamic re-allocation in a network of brain areas, not merely anatomically fixed neuronal loss or diminished capacity to perform.