Analysis of lateralization of brain dopamine function in psychosis: [18F] FDOPA PET imaging study

Abnormal dopamine brain function is a hallmark of psychotic disorders like schizophrenia, and the main pharmacological target for psychotic treatment. However, the functional organization and regulation of the dopamine system are not completely known, due to its complex topology and interplay with other neuroreceptor systems. The primary objective of this research is to comprehend the normal state of dopamine lateralization in the human brain and identify whether dopamine lateralization is altered in schizophrenia. This study considered a dataset of 136 patients with psychosis matched to 143 healthy controls acquired with the [18F] FDOPA PET imaging, a biomarker for measuring dopamine synthesis capacity in vivo in humans. For each subject, neuroimaging metrics from 41 regions of interest (ROIs) were derived using the Desikan-Killiany atlas for each brain hemisphere. For each ROI and each subject, a lateralization index (lx) was computed to compare the dopamine function between the left and right hemispheres. The same metrics were fed into the Random Forest, XGBoost, SVM, KNN, Naïve Bayes, and Logistic Regression classifier models to distinguish patients and controls by exploiting the difference with the best-performing model in brain dopamine lateralization. In normal individuals, brain dopamine is mainly lateralized in the Inferior Parietal (p=0.039) and Transverse Temporal (p=0.004) with a significant effect of age and gender. Moreover, when comparing lateralization between controls and patients, left-biased lateralization in Putamen decreases by 50%, right-biased lateralization in Accumbens decreases by 60%, and right-biased lateralization in Pallidum changes direction and shows a significant increase around 300% in Ki levels. In terms of patient classification, the best performing model was XGBoost with the metrics of 79% accuracy, 79% precision, 79% recall, and 78% f1-score on the test set. Finally, the post hoc model agnostic explainability method SHAP reported the Accumbens, Fusiform, Posterior Cingulate, Thalamus, and Pallidum as the top 5 most salient features which have a significant effect on the decision. In conclusion, healthy controls present a clear lateralization of dopamine function that can change its direction and magnitude in the case of schizophrenia. Further studies should focus to investigate the biological rationale behind these differences and their implication for the stratification of patients with psychosis.