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BACKGROUND: Structural income inequality - the uneven income distribution across regions or countries - could affect brain structure and function, beyond individual differences. However, the impact of structural income inequality on the brain dynamics and the roles of demographics and cognition in these associations remains unexplored. METHODS: Here, we assessed the impact of structural income inequality, as measured by the Gini coefficient on multiple EEG metrics, while considering the subject-level effects of demographic (age, sex, education) and cognitive factors. Resting-state EEG signals were collected from a diverse sample (countries = 10; healthy individuals = 1394 from Argentina, Brazil, Colombia, Chile, Cuba, Greece, Ireland, Italy, Turkey and United Kingdom). Complexity (fractal dimension, permutation entropy, Wiener entropy, spectral structure variability), power spectral and aperiodic components (1/f slope, knee, offset), as well as graph-theoretic measures were analysed. FINDINGS: Despite variability in samples, data collection methods, and EEG acquisition parameters, structural inequality systematically predicted electrophysiological brain dynamics, proving to be a more crucial determinant of brain dynamics than individual-level factors. Complexity and aperiodic activity metrics captured better the effects of structural inequality on brain function. Following inequality, age and cognition emerged as the most influential predictors. The overall results provided convergent multimodal metrics of biologic embedding of structural income inequality characterised by less complex signals, increased random asynchronous neural activity, and reduced alpha and beta power, particularly over temporoposterior regions. CONCLUSION: These findings might challenge conventional neuroscience approaches that tend to overemphasise the influence of individual-level factors, while neglecting structural factors. Results pave the way for neuroscience-informed public policies aimed at tackling structural inequalities in diverse populations.

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Brain clocks, which quantify discrepancies between brain age and chronological age, hold promise for understanding brain health and disease. However, the impact of diversity (including geographical, socioeconomic, sociodemographic, sex and neurodegeneration) on the brain-age gap is unknown. We analyzed datasets from 5,306 participants across 15 countries (7 Latin American and Caribbean countries (LAC) and 8 non-LAC countries). Based on higher-order interactions, we developed a brain-age gap deep learning architecture for functional magnetic resonance imaging (2,953) and electroencephalography (2,353). The datasets comprised healthy controls and individuals with mild cognitive impairment, Alzheimer disease and behavioral variant frontotemporal dementia. LAC models evidenced older brain ages (functional magnetic resonance imaging: mean directional error = 5.60, root mean square error (r.m.s.e.) = 11.91; electroencephalography: mean directional error = 5.34, r.m.s.e. = 9.82) associated with frontoposterior networks compared with non-LAC models. Structural socioeconomic inequality, pollution and health disparities were influential predictors of increased brain-age gaps, especially in LAC (R² = 0.37, F² = 0.59, r.m.s.e. = 6.9). An ascending brain-age gap from healthy controls to mild cognitive impairment to Alzheimer disease was found. In LAC, we observed larger brain-age gaps in females in control and Alzheimer disease groups compared with the respective males. The results were not explained by variations in signal quality, demographics or acquisition methods. These findings provide a quantitative framework capturing the diversity of accelerated brain aging.

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Brain clocks, which quantify discrepancies between brain age and chronological age, hold promise for understanding brain health and disease. However, the impact of multimodal diversity (geographical, socioeconomic, sociodemographic, sex, neurodegeneration) on the brain age gap (BAG) is unknown. Here, we analyzed datasets from 5,306 participants across 15 countries (7 Latin American countries -LAC, 8 non-LAC). Based on higher-order interactions in brain signals, we developed a BAG deep learning architecture for functional magnetic resonance imaging (fMRI=2,953) and electroencephalography (EEG=2,353). The datasets comprised healthy controls, and individuals with mild cognitive impairment, Alzheimer's disease, and behavioral variant frontotemporal dementia. LAC models evidenced older brain ages (fMRI: MDE=5.60, RMSE=11.91; EEG: MDE=5.34, RMSE=9.82) compared to non-LAC, associated with frontoposterior networks. Structural socioeconomic inequality and other disparity-related factors (pollution, health disparities) were influential predictors of increased brain age gaps, especially in LAC (R2=0.37, F2=0.59, RMSE=6.9). A gradient of increasing BAG from controls to mild cognitive impairment to Alzheimer's disease was found. In LAC, we observed larger BAGs in females in control and Alzheimer's disease groups compared to respective males. Results were not explained by variations in signal quality, demographics, or acquisition methods. Findings provide a quantitative framework capturing the multimodal diversity of accelerated brain aging.

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Optic neuritis (ON) is an inflammatory condition of the optic nerve, which leads to retinal ganglion cell (RGC) loss. A subset of RGCs expressing the photopigment melanopsin regulates non-image-forming visual system (NIFVS) functions such as pupillary light reflex (PLR) and circadian rhythms. Melatonin is a chronobiotic agent able to regulate the circadian system. We analyzed the effect of ON on the NIFVS, and the effect of melatonin on the NIFVS alterations induced by ON. For this purpose, optic nerves from male Wistar rats received vehicle or bacterial lipopolysaccharide (LPS), and one group of animals received a subcutaneous pellet of melatonin or a sham procedure. The NIFVS was analyzed in terms of: i) blue light-evoked PLR, ii) the communication between the retina and the suprachiasmatic nuclei (by anterograde transport, and ex vivo magnetic resonance images), iii) locomotor activity rhythm, and iv) Brn3a(+) and melanopsin(+) RGC number (by immunohistochemistry). Experimental ON significantly decreased the blue light-evoked PLR, induced a misconnection between the retina and the suprachiasmatic nuclei, decreased Brn3a(+) RGCs, but not melanopsin(+) RGC number. A bilateral injection of LPS significantly increased the light (but not dark) phase locomotor activity, rhythm periodicity, and time of offset activity. Melatonin prevented the decrease in blue light-evoked PLR, and locomotor activity rhythm alterations induced by ON. These results support that ON provoked alterations of the circadian physiology, and that melatonin could restore the circadian system misalignment.

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Enriched environment (EE) protects the retina from adult rats against ischemia/reperfusion (I/R) injury; however, how the components of EE contribute to the recovery after retinal ischemic damage remains unclear. We analyzed the contribution of social, cognitive, and visual stimulation on functional and histological alterations induced by I/R. Male Wistar rats were submitted to unilateral ischemia by increasing intraocular pressure to 120 mmHg for 40 min. After ischemia, animals were housed in the following conditions: standard environment (SE), enriched environment (EE), novelty environment (NE), standard social environment (SoE), standard visual environment (SVE), or visual environment (VE). In another set of experiments, rats were submitted to bilateral ischemia and housed in SE or EE. At 2 weeks post-ischemia, rats were subjected to electroretinography and histological analysis. EE (but not SoE or NE) afforded functional and histological protection against unilateral ischemia. EE did not induce protection in animals submitted to bilateral ischemia. VE protected retinal function and histology and increased retinal BDNF levels, while a TrkB receptor antagonist prevented the protective effect of VE against I/R damage. In animals submitted to unilateral ischemia, EE and VE induced an increase in c-fos immunoreactivity in the ipsi and contralateral superior colliculus, whereas in animals submitted to bilateral ischemia, no changes in c-fos-immunoreactivity were observed in either superior colliculus from EE-housed animals. These results support that visual stimulation could be a potent stimulus for driving retinal protection in adult rats through a BDNF/TrkB-dependent mechanism, likely involving the superior colliculus.

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Neuroinflammatory diseases are characterized by blood-brain barrier disruption (BBB) and leukocyte infiltration. We investigated the involvement of monocyte recruitment in visual pathway damage provoked by primary optic neuritis (ON) induced by a microinjection of bacterial lipopolysaccharide (LPS) into the optic nerve from male Wistar rats. Increased Evans blue extravasation and cellularity were observed at 6 h post-LPS injection. In WT-GFPþ/WT chimeric rat optic nerves, the presence of GFP(+) neutrophils and GFP(+) monocytes, and in wild-type rat optic nerves, an increase in CD11b+CD45low and CD11b+CD45high cell number, were observed at 24 h post-LPS. Gamma-irradiation did not affect the increase in BBB permeability, but significantly lessened the decrease in pupil light reflex (PLR), and retinal ganglion cell (RGC) number induced by LPS. At 6 h post-LPS, an increase in chemokine (C-C motif) ligand 2 (CCL2) immunoreactivity co-localized with neutrophils (but not microglia/macrophages or astrocytes) was observed, while at 24 h post-injection, an increase in Iba-1-immunoreactivity and its co-localization with CCL2 became evident. The co-injection of LPS with bindarit (a CCL2 synthesis inhibitor) lessened the effect of LPS on PLR, and RGC loss. The treatment with etoposide or gadolinium chloride that significantly decreased peripheral monocyte (but not neutrophil or lymphocyte) percentage decreased the effect of LPS on PLR, and RGC number. Moreover, a negative correlation between PRL and monocyte (but not lymphocyte or neutrophil) percentage was observed at 7 days post-LPS. Taken together, these results support that monocytes are key players in the initial events that take place during primary ON.

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