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This study aimed to examine the presence of neuropsychological deficits and their relationships with clinical, pharmacological, and neuropsychiatric characteristics in chronic migraine (CM) patients assessed during a headache-free period. We enrolled 39 CM patients (mean age: 45.4 years; male/female ratio: 3/36) and 20 age-, sex-, and education-matched healthy controls (HCs, mean age: 45.5 years; male/female ratio: 2/18) in a case–control study. All CM patients underwent a full and extensive clinical, neuropsychiatric, and neuropsychological evaluation to evaluate cognitive domains, including sustained attention (SA), information processing speed (IPS), visuospatial episodic memory, working memory (WM), and verbal fluency (VF), as well as depressive and anxiety symptoms. CM patients exhibited higher scores than HCs for all clinical and neuropsychiatric measures, but no differences were found in personality characteristics. Although more than half of the CM patients (54%) showed mild-to-severe neuropsychological impairment (NI), with the most frequent impairments occurring in short- and long-term verbal episodic memory and inhibitory control (in approximately 90% of these patients), almost half of the patients (46%) showed no NI. Moreover, the severity of NI was positively associated with the number of pharmacological treatments received. Remarkably, disease-related symptom severity and headache-related disability explained global neuropsychological performance in CM patients. The presence of cognitive and neuropsychiatric dysfunction during the interictal phase occurred in more than half of CM patients, increasing migraine-related disability and possibly exerting a negative impact on health-related quality of life and treatment adherence.

Previous studies have shown that machine-learning (ML) algorithms can “predict” sex based on brain anatomical/ functional features. The high classification accuracy achieved by ML algorithms is often interpreted as revealing large differences between the brains of males and females and as confirming the existence of “male/female brains”. However, classification and estimation are quite different concepts, and using classification metrics as surrogate estimates of between-group differences results in major statistical and interpretative distortions. The present study illustrates these distortions and provides a novel and detailed assessment of multivariate sex differences in gray matter volume (GMVOL) that does not rely on classification metrics. Moreover, modeling and clustering techniques and analyses of similarities (ANOSIM) were used to identify the brain areas that contribute the most to these multivariate differences, and to empirically assess whether they assemble into two sex-typical profiles. Results revealed that multivariate sex differences in GMVOL: 1) are “large” if not adjusted for total intracranial volume (TIV) variation, but “small” when controlling for this variable; 2) differ in size between individuals and also depends on the ML algorithm used for their calculation 3) do not stem from two sex-typical profiles, and so describing them in terms of “male/female brains” is misleading.

Cognitive Reserve (CR) is considered a protective factor during the aging process. However, although CR is a multifactorial construct, it has been operationalized in a unitary way (years of formal education or IQ). In the present study, a validated measure to categorize CR holistically (Cognitive Reserve Index Questionnaire) was used to evaluate the resting-state functional connectivity in 77 cognitively unimpaired participants aged 50 years and over with high and low CR, and matched brain global atrophy levels. The connectivity of networks linked to attentional (Dorsal Attention Network -DAN-) and executive (Frontal-Parietal Control Network -FPCN-) processes were evaluated by the combination of Independent Component Analysis and seed-based approaches, since these networks have been proposed as candidates to underlie the protective effect of CR in the aging context. Participants with high CR showed an increase of the connectivity in the FPCN and a decrease in the DAN with respect to the low CR group, correlating with neuropsychological scores and supporting that high CR is related to a better neurocognitive preservation during aging This study was supported by grants from the Spanish Government, Ministerio de Ciencia e Innovación (PSI2017-89389-C2-R; PID2020-114521RB-C21/C22); the Galician Government (Xunta de Galicia), Axudas para a Consolidación e Estruturación de Unidades de Investigación Competitivas do Sistema Universitario de Galicia: GRC (GI-1807-USC); Ref: ED431-2017/27; ED431C-2021/04; all with ERDF/FEDER fund SI