Characterizing effects of age, sex and psychosis symptoms on thalamocortical functional connectivity in youth

Abstract

The thalamus is composed of multiple nuclei densely connected with the cortex in an organized manner, forming parallel thalamocortical networks critical to sensory, motor, and cognitive functioning. Thalamocortical circuit dysfunction has been implicated in multiple neurodevelopmental disorders, including schizophrenia, which also often exhibit sex differences in prevalence, clinical characteristics, and neuropathology. However, very little is known about developmental and sex effects on thalamocortical networks in youth. The present study characterized the effects of age, sex and psychosis symptomatology in anatomically constrained thalamocortical networks in a large community sample of youth (n = 1100, aged 8-21) from the Philadelphia Neurodevelopmental Cohort (PNC). Cortical functional connectivity of seven anatomically defined thalamic nuclear groups were examined: anterior, mediodorsal, ventral lateral, ventral posterolateral, pulvinar, medial and lateral geniculate nuclear groups. Age and sex effects were characterized using complementary thalamic region-of-interest (ROI) to cortical ROI and voxel-wise analyses. Effects of clinical symptomatology were analyzed by separating youth into three groups based on their clinical symptoms; typically developing youth (n = 298), psychosis spectrum youth (n = 320), and youth with other psychopathologies (n = 482). As an exploratory analysis, association with PRIME scores were used as a dimensional measure of psychopathology. Age effects were broadly characterized by decreasing connectivity with sensory/motor cortical areas, and increasing connectivity with heteromodal prefrontal and parietal cortical areas. This pattern was most pronounced for thalamic motor and sensory nuclei. Females showed greater connectivity between multiple thalamic nuclear groups and the visual cortex compared to males, while males showed greater connectivity with the inferior frontal and orbitofrontal cortices. Youth with psychosis spectrum symptoms showed a subtle decrease in thalamic connectivity with the premotor and prefrontal cortices. Across all youth, greater PRIME scores were associated with lower connectivity between the prefrontal cortex and mediodorsal thalamus. By characterizing typical development in anatomically constrained thalamocortical networks, this study provides an anchor for conceptualizing disruptions to the integrity of these networks observed in neurodevelopmental disorders.

Keywords: Adolescence; Development; Psychosis spectrum; Resting state; Thalamocortical connectivity; Thalamus.

Fig. 1.

Age (A), Sex (B) and Group (C) effects in predefined thalamocortical networks across the whole sample. The seven networks tested were prefrontal cortex–mediodorsal nucleus (PFC–MD), motor cortex–ventrolateral nuclear group (MTR–VL), somatosensory cortex–ventral posterolateral nucleus (SS–VPL), temporal cortex–medial geniculate nucleus (TMP–MGN), hippocampus–anterior nuclear group (HIPP–AN), parietal cortex–pulvinar (PAR–PU), occipital cortex–lateral geniculate nucleus (OCC–LGN). † indicates p < .05, uncorrected.

Fig. 2.

Voxelwise age and sex effects in thalamic association nuclear groups. Freesurfer segmented mediodorsal, pulvinar and anterior nuclear groups were used in a seed-based voxelwise functional connectivity analyses. Linear age, quadratic age and sex effects were masked to only include cortical voxels and thresholded at a cluster level p = .05 FWE corrected, and voxelwise p = .001 uncorrected.

Fig. 3.

Voxelwise age and sex effects in thalamic sensory/motor nuclear groups. Freesurfer segmented ventral lateral, ventral posterolateral, medial geniculate and lateral geniculate nuclear groups were used in seed-based voxelwise functional connectivity analyses. Linear age, quadratic age and sex effects were masked to only include cortical voxels and thresholded at a cluster level p = .05 FWE corrected, and voxelwise p = .001 uncorrected.

Fig. 4.

Effects of diagnostic groups in thalamic association nuclear groups. FreeSurfer segmented mediodorsal, pulvinar and anterior nuclear groups were used in seed-based voxelwise functional connectivity analyses. Connectivity in typically developing youth (TD) and youth with other psychopathologies (OP) were compared with psychosis spectrum youth (PS). Maps were restricted to the cortex and thresholded at a cluster level p = .05 FWE corrected, and voxelwise p = .001 uncorrected.

Fig. 5.

Effects of diagnostic groups in thalamic sensory/motor nuclear groups. FreeSurfer segmented ventral lateral, ventral posterolateral, medial geniculate and lateral geniculate nuclear groups were used in seed-based voxel-wise functional connectivity analyses. Connectivity in typically developing youth (TD) and youth with other psychopathologies (OP) were compared with psychosis spectrum youth (PS). Maps were restricted to the cortex and thresholded at a cluster level p = .05 FWE corrected, and voxelwise p = .001 uncorrected.