Functional connectivity of cognition-related brain networks in adults with fetal alcohol syndrome

Background: Fetal Alcohol Syndrome (FAS) can result in substantial cognitive dysfunction. Many of the cognitive functions affected are subserved by few functional brain networks. Functional connectivity (FC) in these networks can be assessed with resting state functional MRI (rs-fMRI). Alterations of FC have been reported in children and adolescents prenatally exposed to alcohol. However, previous reports varied substantially regarding which exact cognitive networks were affected, their interactions, and the directionalities of FC alterations. Despite persisting deficits, no previous studies have examined FC in older individuals. Purpose of this rs-fMRI study was to assess FC within and between cognition-related networks in young adults with FAS. Methods: Cross-sectional study in patients with FAS (n = 39, age: 20.9 +- 3.4 years) and controls without prenatal alcohol exposure (n = 44, age: 22.2 +- 3.4 years). FC was calculated as correlation between cortical regions in ten cognition-related sub-networks. Subsequent modelling of overall FC was based on two-tailed t-tests comparing FC between FAS and controls. Results were subjected to a hierarchical statistical testing approach, first determining whether there is any alteration of FC in FAS (compared with controls) in the full cognitive connectome, subsequently resolving these findings to the level of either FC within each network or between networks, and finally to individual connections. The overall and network-level tests are based on the Higher Criticism (HC) approach for the detection of rare and week effects in high dimensional data. In an additional exploratory time-resolved FC analysis, potential group differences of dynamic FC states were assessed. Results: Comparing FAS subjects with controls, we observed altered FC of cognition-related brain regions globally, within 7 out of 10 networks, and between networks employing the HC statistic. This was most obvious in the dorsal attention A sub-network, followed by the salience / ventral attention A subnetwork. Findings also spanned subcomponents of the fronto-parietal control and default mode networks. None of the single FC alterations within these networks yielded statistical significance in the final high-resolution analysis. The exploratory time-resolved FC analysis did not show significant group differences in the temporal behavior of FC states. Conclusions: FC in cognition-related brain networks was altered in adults with FAS. Effects were widely distributed across these networks, potentially reflecting the diversity of cognitive deficits in these individuals. Findings were pronounced in attention-related networks in line with attentional deficits previously reported. An additional exploratory time-resolved FC analysis did not reveal altered dynamic FC patterns. ### Competing Interest Statement Christian Mathys: consulting and lecturing for Siemens on behalf of the employer (Evangelisches Krankenhaus Oldenburg). The other authors declare that they have no known competing financial interests or personal relationships that could appear to have influenced the work reported in this paper. ### Funding Statement Data acquisition in a subgroup of the control subjects overlapped with a sister project which was financially supported by Merck-Serono, Darmstadt, Germany. The sponsor had no influence on any aspects of the study including design, recruitment. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of the University of Muenster and the Westphalian Chamber of Physicians gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes On request to the authors, further intermediate data on a level independent from the individual subjects can be shared. Due to German data protection regulations and to safeguard subject confidentiality, data on the level of individual subjects cannot be made available.