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Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults.

ABSTRACT: Prefrontal dopamine levels are relatively increased in adolescence compared to adulthood. Genetic variation of COMT (COMT Val158Met) results in lower enzymatic activity and higher dopamine availability in Met carriers. Given the dramatic changes of synaptic dopamine during adolescence, it has been suggested that effects of COMT Val158Met genotypes might have oppositional effects in adolescents and adults. The present study aims to identify such oppositional COMT Val158Met effects in adolescents and adults in prefrontal brain networks at rest. Resting state functional connectivity data were collected from cross-sectional and multicenter study sites involving 106 healthy young adults (mean age 24 ± 2.6 years), gender matched to 106 randomly chosen 14-year-olds. We selected the anterior medial prefrontal cortex (amPFC) as seed due to its important role as nexus of the executive control and default mode network. We observed a significant age-dependent reversal of COMT Val158Met effects on resting state functional connectivity between amPFC and ventrolateral as well as dorsolateral prefrontal cortex, and parahippocampal gyrus. Val homozygous adults exhibited increased and adolescents decreased connectivity compared to Met homozygotes for all reported regions. Network analyses underscored the importance of the parahippocampal gyrus as mediator of observed effects. Results of this study demonstrate that adolescent and adult resting state networks are dose-dependently and diametrically affected by COMT genotypes following a hypothetical model of dopamine function that follows an inverted U-shaped curve. This study might provide cues for the understanding of disease onset or dopaminergic treatment mechanisms in major neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder.

SUBMITTER: Meyer BM

PROVIDER: S-EPMC4667398 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults.

Meyer Bernhard M BM Huemer Julia J Rabl Ulrich U Boubela Roland N RN Kalcher Klaudius K Berger Andreas A Banaschewski Tobias T Barker Gareth G Bokde Arun A Büchel Christian C Conrod Patricia P Desrivières Sylvane S Flor Herta H Frouin Vincent V Gallinat Jurgen J Garavan Hugh H Heinz Andreas A Ittermann Bernd B Jia Tianye T Lathrop Mark M Martinot Jean-Luc JL Nees Frauke F Rietschel Marcella M Smolka Michael N MN Bartova Lucie L Popovic Ana A Scharinger Christian C Sitte Harald H HH Steiner Hans H Friedrich Max H MH Kasper Siegfried S Perkmann Thomas T Praschak-Rieder Nicole N Haslacher Helmuth H Esterbauer Harald H Moser Ewald E Schumann Gunter G Pezawas Lukas L

Brain structure & function 20141016 1

Prefrontal dopamine levels are relatively increased in adolescence compared to adulthood. Genetic variation of COMT (COMT Val158Met) results in lower enzymatic activity and higher dopamine availability in Met carriers. Given the dramatic changes of synaptic dopamine during adolescence, it has been suggested that effects of COMT Val158Met genotypes might have oppositional effects in adolescents and adults. The present study aims to identify such oppositional COMT Val158Met effects in adolescents ...[more]

PMID: 25319752

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Project description:BACKGROUND:Although dysfunction of amygdala-related circuits is centrally implicated in major depressive disorder (MDD), little is known about how this dysfunction differs between adult and adolescent MDD patients. METHODS:Voxel-wise meta-analyses of abnormal amygdala resting-state functional connectivity (rsFC) were conducted in adult and adolescent groups separately, followed by a quantitative meta-analytic comparison of the two groups. FINDINGS:Nineteen studies that included 665 MDD patients (392 adults and 273 adolescents) and 546 controls (341 adults and 205 adolescents) were identified in the current study. Adult-specific abnormal amygdala rsFC in MDD patients compared to that in controls was located mainly within the affective network, including increased connectivity with the right hippocampus/parahippocampus and bilateral ventromedial orbitofrontal cortex and decreased connectivity with the bilateral insula and the left caudate. Adolescent MDD patients specifically demonstrated decreased amygdala rsFC within the cognitive control network encompassing the left dorsolateral prefrontal cortex and imbalanced amygdala rsFC within the default mode network, which was manifested as hyperconnectivity in the right precuneus and hypoconnectivity in the right inferior temporal gyrus. Additionally, direct comparison between the two groups showed that adult patients had strengthened amygdala rsFC with the right hippocampus/parahippocampus as well as the right inferior temporal gyrus and weakened amygdala rsFC with the bilateral insula compared to that in adolescent patients. INTERPRETATION:Distinct impairments of amygdala-centered rsFC in adult and adolescent patients were related to different network dysfunctions in MDD. Adult-specific amygdala rsFC dysfunction within the affective network presumably reflects emotional dysregulation in MDD, whereas adolescent-specific amygdala rsFC abnormalities in networks involved in cognitive control might reflect the neural basis of affective cognition deficiency that is characteristic of adolescent MDD. FUND: This study was supported by a grant from the National Natural Science Foundation of China (81671669) and by a Sichuan Provincial Youth Grant (2017JQ0001).

Project description:ObjectiveWomen with anorexia nervosa (AN) have been shown to demonstrate differences in functional connectivity in brain regions associated with cognitive control, somatosensory processing, and emotion regulation. However, previous studies have been conducted on small samples and have inconsistent findings. Therefore, this study aimed to identify aberrant brain networks related to the core clinical symptoms of AN and to explore the longitudinal association with clinical outcome in a large population of adolescents experiencing their first episode of AN.MethodsFunctional MRI (fMRI) of brain resting-state functional connectivity (RS-FC) of female adolescents with first-onset AN (n = 56) were compared to age- and education-matched typically developing (TD) adolescents (n = 64). To account for the severity of underweight, separate analyses were performed to investigate differences in RS-FC between underweight AN participants and TD adolescents, as well as between underweight (n = 30) and weight-restored AN (n = 26) participants. Clinical outcomes, i.e. body mass index and eating disorder (ED) symptoms, were assessed at baseline and one-year follow-up. Independent component analyses (ICA) were used to extract the brain networks of interest: the default mode (DMN), left and right frontoparietal (FPN), and the insular (IN) networks. Linear regression analyses were conducted to assess differences in RS-FC between AN and TD participants, as well as to assess whether RS-FC was associated with clinical symptoms at baseline and at one-year of follow-up. Two statistical models were used: model 1 adjusted for age and socioeconomic status (SES), and model 2 additionally adjusted for baseline anxiety and depressive symptoms.ResultsUnderweight AN participants had lower RS-FC between the DMN-IN, as well as between the FPN-IN compared to the TD adolescents. After correction for multiple testing, no significant differences in RS-FC were found between underweight AN participants and weight-restored AN participants, as well as between the whole AN group and the TD group. RS-FC was not associated with the severity of clinical symptoms at baseline nor at one-year of follow-up.ConclusionAN is associated with changes in RS-FC between the FPN-IN and DMN-IN during the underweight state. These changes in RS-FC were no longer observed in weight-restored AN participants, emphasizing the impact of underweight on RS-FC in AN. Changes in these brain networks may partly explain the impaired cognitive control and difficulties with emotion and behavioral regulation in individuals with AN during the underweight state.

Dataset Information

Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults.

Publications

Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults.

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