Cerebral perfusion changes in untreated schizophrenic patients: A CASL-study at 3 Tesla

Purpose: Schizophrenia is a serious mental disorder with a usual onset in early adulthood. It is characterized by positive symptoms, including delusion, hallucination and thought disorder, and negative symptoms, like lack of initiative and affective flattening and cognitive disturbances, including impairment of attention and memory. Even though the etiology of the disorder is still not fully understood, numerous studies have identified a number of features which distinguish brains of schizophrenic patients from brains of healthy controls. Neuropathological and structural brain imaging studies have reported morphological alterations in a variety of brain regions, in particular in the frontal and temporal lobe. Functional imaging studies have investigated blood flow, metabolism at rest and brain activation during a variety of cognitive tasks. Focussing on these, a recent meta-analysis concluded that the most robust difference between schizophrenic patients and healthy controls is an impaired activation of the frontal lobe during cognitive tasks and a reduced cerebral blood flow and metabolism at rest ('hypofrontality'). Because it is well known that medication can change local perfusion patterns, we examined drug-naïve and currently untreated schizophrenic patients to test the hypofrontality hypothesis in this patient group with the absence of any drug influence using continuous arterial spin labeling (CASL) at 3T.

Methods: Within the last three years we examined 11 unmedicated schizophrenic patients (men/woman: 3/8, mean age: 32±5 years) as well as 25 healthy volunteers (men/woman: 12 / 13, mean age: 30±6 years) using our standard clinical CASL-protocol. 8 of the 11 patients were drug-naive and 3 unmedicated within the last two weeks before imaging. All examinations were performed on a Philips 3T-Achieva whole body system using an 8 element coil. The scanning protocol was as follows: sequence: single-shot EPI SE-CASL, TR/TE/Flip: 4200 / 38 / 90, labeling delay: 800 ms, slice thickness: 8mm, FOV: 240, matrix: 64×64, 40 dynamics. The calculation of the cerebral blood flow maps, motion correction of the data, smoothing, and 'normalisation' of the data were performed with an in house developed software package, which partially utilizes SPM2-preprocessing routines (Luke's CASL-Toolbox, LCQP-CASLTools). The statistical analysis included a voxel by voxel based group comparison between the patient population and the group of volunteers (SPM2), an automated region of interest based analysis (Luke's CASL-Toolbox, LCQP-CASLTools) using the 116 ROIs of the 'AAL'-template provided by Chris Rodens MRIcro as well as a voxel by voxel correlation analysis between the local cerebral perfusion and the sum score of the Positive and Negative Symptom Scale (PANSS), a clinical measure of schizophrenia symptoms. The latter was exclusively analyzed for the patient group.

Results: The voxel by voxel based analysis revealed a bilateral hypoperfusion of the medial frontal lobe, parietal lobe as well as the a hypoperfusion of the medial and posterior part of the cingulate gyrus for the patient group. In addition, we found a hyperperfusion of the regional cerebral blood flow in the amygdala, the thalamus and the cerebellum for the patient group. The region of interest analysis confirmed these results and additionally showed that almost all medial frontal and prefrontal regions are hypoperfused in the patient group. The correlation analysis showed a negative correlation between PANSS total score and the local perfusion in the subgenual cingulate cortex as well as a positive correlation between the local perfusion and PANS total score for the patient group.

Conclusion: The findings confirm the hypofrontality hypothesis and show the capabilities of CASL as an completely non invasive technique for assessing regional brain perfusion.