D2/D3 Dopamine Receptor Binding With [F-18] Fallypride Correlates of Executive Function in Medication-Naïve Patients With Schizophrenia

Document Type

Conference Proceeding

Publication Date

12-6-2016

Abstract

Background: Converging evidence indicates that the prefrontal cortex is critically involved in executive control and that executive dysfunction is implicated in schizophrenia. Reduced dopamine D2/D3 binding potential has been reported in schizophrenia, and the correlations with neuropsychological test scores have been positive and negative for different tasks. The aim of this study was to examine D2/D3 dopamine correlates with frontal cortical related cognitive task performance in schizophrenia.

Methods: Resting-state 18F-fallypride positron emission tomography was performed on 20 medication-naïve and 5 previously medicated (for brief earlier periods) patients with schizophrenia and 19 age- and sex-matched normal controls. Striatal and extra-striatal dopamine D2/D3 receptor levels were quantified as binding potential using fallypride imaging. Magnetic resonance images in standard Talairach position and segmented into gray and white matter were co-registered to the fallypride images, and the AFNI stereotaxic atlas was applied. Two neuropsychological tasks known to activate frontal and temporal lobe function were chosen, the Wisconsin Card Sorting Test (WCST) and the California Verbal Learning Test (CVLT).

Results: Images of the voxel-by-voxel correlation coefficient between Fallypride binding and WCST and CVLT performance showed predominantly negative correlations in patients in contrast to positive correlations in healthy volunteers. This was especially marked for the temporal lobe, Brodmann areas 46 and 47, striatum, and thalamus. Examination of the distribution of correlation coefficients between neuropsychological scores and binding potential in regions of interest showed healthy volunteer correlations significantly more positive correlations with a more positive skewed distribution. Patients with schizophrenia had a negative skew to the distribution. Permutation analysis is used to confirm correlation differences, addressing the issue of regional intercorrelations.

Conclusions: The results of this study demonstrate that lower Fallypride binding potential in patients with schizophrenia may be associated with better performance and consistent with previous studies that failed to find cognitive improvement with typical dopamine-blocking medications.

Our findings in this study reinforce the concept of distributed influence of dopamine on performance involving both striatal and extrastriatal regions. These influences are trait-like in nature extending across cognitive tasks in healthy subjects. Patients with schizophrenia show relationships between performance and binding potential that are anomalous and likely heterogeneous, leaving a disturbed distribution of regional binding potential versus performance correlations. Our findings are also consistent with the widely interconnected network patterns observed in fMRI connectivity studies rather than with a restricted network of several small, localized, and specialized neural loci.

Comments

Presented at the American College of Neuropsychopharmacology (ACNP) annual meeting, Hollywood, FL, December 4-8, 2016.


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