Objective: Widespread functional and structural alterations in the brain have been extensively reported in unaffected relatives (RELs) of patients with bipolar disorder (BD) who are at genetic risk for BD. A sufficiently powered meta-analysis of structural (sMRI) and functional magnetic resonance imaging (fMRI) alterations in RELs is still lacking.Methods: Functional and structural magnetic resonance imaging studies investigating RELs and healthy controls (HCs) published by July 2017 were included in the meta-analyses. Study procedures were conducted in accordance with the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. Random-effects coordinate-based meta-analyses were performed across all the studies per imaging modality using Seed-based d Mapping (SDM). For fMRI studies, meta-analyses were calculated for each task type. For sMRI studies, regional volumetric changes-analyses were estimated using R. Finally, multimodal meta-analyses of structural and functional abnormalities were performed. Results:Sixty-nine imaging studies (2195 RELs and 3169 HCs) were included in the meta-analyses. RELs showed hyperactivation in the fronto-striatal regions as well as parietal hypoactivation during cognition. Also, activation was increased in the amygdala during emotional processing and in the orbitofrontal cortex during reward, respectively. Frontal and superior temporal cortex were hypertrophic in RELs. The right inferior frontal gyrus (rIFG) showed both increased activation during cognitive tasks and greater volume in RELs. Conclusions:Our findings demonstrate that increased brain volume and activation are present in RELs and may represent intermediate phenotypes for the disorder.Furthermore, some neural changes including increased rIFG volume may be associated with the resilience to BD. K E Y W O R D Sbipolar disorders, functional magnetic resonance imaging, intermediate phenotype, metaanalysis, relatives, structural magnetic resonance imaging

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The pathophysiology of migraine as a headache disorder is still undetermined. Diffusion tensor imaging (DTI) has significantly improved our knowledge about brain microstructure in this disease. Here, we aimed to systematically review DTI studies in migraine and survey the sources of heterogeneity by investigating diffusion parameter changes associated with clinical characteristics and migraine subtypes. Microstructural changes, as revealed by widespread alteration of diffusion metrics in white matter (WM) tracts, subcortical and cortical regions, were reported by several migraine DTI studies. Specifically, we reported changes in the corpus callosum, thalamic radiations, corona radiata, and brain stem. These alterations showed high variability across migraine cycle phases. Additionally, migraine associated with depressive/anxiety symptoms revealed significant changes in the corpus callosum, internal capsule, and superior longitudinal fasciculus. No significant WM microstructural differences were observed between migraine patients with and without aura. Overall, differences between chronic and episodic migraine showed inconsistency across studies. Migraine is associated with microstructural changes in widespread regions including thalamic radiations, corpus callosum, and brain stem. These alterations can highlight neuronal damage and neuronal plasticity mechanisms either following pain stimulations occurring in migraine cycle or as a compensatory response to pain in chronic migraine. Longitudinal studies applying advanced modalities may shed new light on the underlying microstructural changes in migraine subtypes.

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