Coordinated cortical thickness alterations across six neurodevelopmental and psychiatric disorders.

Neuropsychiatric disorders are increasingly conceptualized as overlapping spectra sharing multi-level neurobiological alterations. However, whether transdiagnostic cortical alterations covary in a biologically meaningful way is currently unknown. Here, we studied co-alteration networks across six neurodevelopmental and psychiatric disorders, reflecting pathological structural covariance. In 12,024 patients and 18,969 controls from the ENIGMA consortium, we observed that co-alteration patterns followed normative connectome organization and were anchored to prefrontal and temporal disease epicenters. Manifold learning revealed frontal-to-temporal and sensory/limbic-to-occipitoparietal transdiagnostic gradients, differentiating shared illness effects on cortical thickness along these axes. The principal gradient aligned with a normative cortical thickness covariance gradient and established a transcriptomic link to cortico-cerebello-thalamic circuits. Moreover, transdiagnostic gradients segregated functional networks involved in basic sensory, attentional/perceptual, and domain-general cognitive processes, and distinguished between regional cytoarchitectonic profiles. Together, our findings indicate that shared illness effects occur in a synchronized fashion and along multiple levels of hierarchical cortical organization.

Influence of DAT1 and COMT variants on neural activation during response inhibition in adolescents with attention-deficit/hyperactivity disorder and healthy controls.

BACKGROUND: Impairment of response inhibition has been implicated in attention-deficit/hyperactivity disorder (ADHD). Dopamine neurotransmission has been linked to the behavioural and neural correlates of response inhibition. The current study aimed to investigate the relationship of polymorphisms in two dopamine-related genes, the catechol-O-methyltransferase gene (COMT) and the dopamine transporter gene (SLC6A3 or DAT1), with the neural and behavioural correlates of response inhibition. METHOD: Behavioural and neural measures of response inhibition were obtained in 185 adolescents with ADHD, 111 of their unaffected siblings and 124 healthy controls (mean age 16.9 years). We investigated the association of DAT1 and COMT variants on task performance and whole-brain neural activation during response inhibition in a hypothesis-free manner. Additionally, we attempted to explain variance in previously found ADHD effects on neural activation during response inhibition using these DAT1 and COMT polymorphisms. RESULTS: The whole-brain analyses demonstrated large-scale neural activation changes in the medial and lateral prefrontal, subcortical and parietal regions of the response inhibition network in relation to DAT1 and COMT polymorphisms. Although these neural activation changes were associated with different task performance measures, no relationship was found between DAT1 or COMT variants and ADHD, nor did variants in these genes explain variance in the effects of ADHD on neural activation. CONCLUSIONS: These results suggest that dopamine-related genes play a role in the neurobiology of response inhibition. The limited associations between gene polymorphisms and task performance further indicate the added value of neural measures in linking genetic factors and behavioural measures.

[Neural activation and connectivity during response inhibition in adolescents with ADHD]. / Neurale activatie en connectiviteit tijdens responsinhibitie bij adolescenten met ADHD.

BACKGROUND: We studied the neural correlates of response inhibition in a large cohort of adolescents with ADHD, their unaffected siblings and controls. Response inhibition is a key executive function deficit of attentiondeficit/hyperactivity disorder (ADHD). AIM: To obtain new insight into the biological nature of response inhibition deficits in adolescents with ADHD. METHOD: We studied the neural correlates of response inhibition in a large cohort of adolescents with ADHD (n = 185), their siblings unaffected by ADHD (n = 111) and controls (n = 126). We took fmri measurement while the subjects performed the stop-task; this allowed us to investigate neural activation and neural connectivity. RESULTS: Our results indicate that adolescents with ADHD show reduced brain activation and reduced connectivity in their response inhibition network. Our neural measurements correlated with subjects' performance on the stop-task and with the number of ADHD symptoms in the adolescents with ADHD. Unaffected siblings showed similar but less severe neural deviations but no cognitive deficits; unaffected siblings also showed unique patterns of compensatory connectivity. CONCLUSION: These results provide new insights into the biological background of response inhibition and of ADHD. Neural measurements can give us a better understanding of the familial patterns of biological alterations, even if no behavioral deficits could be detected in the unaffected siblings. These neural correlates can also help to explain part of the ADHD phenotype.