Age-Normative Pathways of Striatal Connectivity Related to Clinical Symptoms in the General Population

Abstract

Background: Altered striatal development contributes to core deficits in motor and inhibitory control, impulsivity, and inattention associated with attention-deficit/hyperactivity disorder and may likewise play a role in deficient reward processing and emotion regulation in psychosis and depression. The maturation of striatal connectivity has not been well characterized, particularly as it relates to clinical symptomatology.

Methods: Resting-state functional connectivity with striatal subdivisions was examined for 926 participants (8-22 years of age, 44% male) from the general population who had participated in two large cross-sectional studies. Developing circuits were identified and growth charting of age-related connections was performed to obtain individual scores reflecting relative neurodevelopmental attainment. Associations of clinical symptom scales (attention-deficit/hyperactivity disorder, psychosis, depression, and general psychopathology) with the resulting striatal connectivity age-deviation scores were then tested using elastic net regression.

Results: Linear and nonlinear developmental patterns occurred across 231 striatal age-related connections. Both unique and overlapping striatal age-related connections were associated with the four symptom domains. Attention-deficit/hyperactivity disorder severity was related to age-advanced connectivity across several insula subregions, but to age-delayed connectivity with the nearby inferior frontal gyrus. Psychosis was associated with advanced connectivity with the medial prefrontal cortex and superior temporal gyrus, while aberrant limbic connectivity predicted depression. The dorsal posterior insula, a region involved in pain processing, emerged as a strong contributor to general psychopathology as well as to each individual symptom domain.

Conclusions: Developmental striatal pathophysiology in the general population is consistent with dysfunctional circuitry commonly found in clinical populations. Atypical age-normative connectivity may thereby reflect aberrant neurodevelopmental processes that contribute to clinical risk.

Keywords: ADHD; Depression; Development; General psychopathology; Psychosis; Striatum.

Figure 1.

Significant age effects (p<1.67×10⁻⁴) for the six striatal seeds: Dorsal Caudate Right (DCR), Ventral Striatum superior Right (VSsR), Ventral Striatum inferior Right (VSiR), Dorsal Rostral Putamen Right (DRPR), Dorsal Caudal Putamen Right (DCPR), Ventral Rostral Putamen Right (VRPR). Positive linear age effects are in red. Negative linear age effects are in blue. Nonlinear age² effects are in green. The striatal seed is in yellow. The top row displays the three caudate seeds and the bottom row displays the three putamen seeds.

Figure 2.

Significant age effects (p<1.67×10⁻⁴) and growth charts for two example striatal seeds: Ventral Striatum inferior Right (VSiR) and Dorsal Rostral Putamen Right (DRPR). The top row shows significant age effects for VSiR and DRPR. Positive linear age effects are in red. Negative linear age effects are in blue. Nonlinear age² effects are in green. The striatal seed is in yellow. The bottom row shows the growth charts for several of the Age-Related Connections (ARCs): the three on the left display VSiR ARCs and the three on the right display DRPR ARCs. Each green dot represents one participant; open, dark green dots are females and closed, light green dots are males. The sold blue line is the age 50^th percentile, age-normative fit line and the dashed lines represent the 2.5^th, 5^th, 10^th, 25^th, 75^th, 90^th, 95^th, and 97.5^th percentile fits.

Figure 3.

Connections with symptom associations. The peak ARCs with non-zero βs in the Elastic Net (EN) models are shown on the top row. Those ARCs in which greater symptom severity is associated with age-accelerated connectivity are displayed in green, while those ARCs in which greater symptom severity is associated with age-delayed connectivity are displayed in red. The ARC labels and the age-adjusted βs from the optimal EN model are shown in the bottom row.

Figure 4.

Association between the actual dimensional symptom scores and the Elastic Net (EN) fitted values. The EN fit accounts for 10.0%, 6.0%, 13.0% and 8.3 % of the variance for ADHD, psychosis, depression, and general psychopathology, respectively.