Thalamic dopamine D2-receptor availability in schizophrenia: a study on antipsychotic-naive patients with first-episode psychosis and a meta-analysis

Abstract

Pharmacological and genetic evidence support a role for an involvement of the dopamine D2-receptor (D2-R) in the pathophysiology of schizophrenia. Previous molecular imaging studies have suggested lower levels of D2-R in thalamus, but results are inconclusive. The objective of the present study was to use improved methodology to compare D2-R density in whole thalamus and thalamic subregions between first-episode psychosis patients and healthy controls. Differences in thalamocortical connectivity was explored based on the D2-R results. 19 antipsychotic-naive first-episode psychosis patients and 19 age- and sex-matched healthy controls were examined using high-resolution Positron Emission Tomography (PET) and the high-affinity D2-R radioligand [¹¹C]FLB457. The main outcome was D2-R binding potential (BP_ND) in thalamus, and it was predicted that patients would have lower binding. Diffusion tensor imaging (DTI) was performed in a subgroup of 11 patients and 15 controls. D2-R binding in whole thalamus was lower in patients compared with controls (Cohen's dz = -0.479, p = 0.026, Bayes Factor (BF) > 4). Among subregions, lower BP_ND was observed in the ROI representing thalamic connectivity to the frontal cortex (Cohen's dz = -0.527, p = 0.017, BF > 6). A meta-analysis, including the sample of this study, confirmed significantly lower thalamic D2-R availability in patients. Exploratory analyses suggested that patients had lower fractional anisotropy values compared with controls (Cohen's d = -0.692, p = 0.036) in the inferior thalamic radiation. The findings support the hypothesis of a dysregulation of thalamic dopaminergic neurotransmission in schizophrenia, and it is hypothesized that this could underlie a disturbance of thalamocortical connectivity.

Fig. 1. Average BP_ND values and thalamic ROIs.

Upper panel: average BP_ND image values for first-episode psychosis patients and matched control subjects. Lower panel: ROIs for thalamic subregions shown on a template T1 MR image, based on their connectivity to cortical brain regions. Blue = THA-PFC (projections to prefrontal cortex), red = THA-TC (temporal cortex), gray = THA-M1 (primary motor cortex), green = THA-PreMC (premotor cortex), orange = THA-PPC (posterior parietal cortex).

Fig. 2. Patient-control differences in [¹¹C]FLB 457 BP_ND in the whole thalamus and subthalamic regions.

There was a significant difference between groups in the whole thalamus as well as the subregion corresponding to prefrontal cortex connectivity.

Fig. 3. Meta-analyses of thalamic D2-R availability differences between patients and controls.

A Patients show significantly overall lower D2-R levels in whole thalamus compared with healthy control subjects. B Meta-analysis only including studies which used the two high-affinity radioligands [¹¹C]FLB457 and [¹⁸F]Fallypride. Additional meta-analyses excluding studies with partially overlapping samples, and funnel plots can be found in the supplementary information.