Individual variations in ‘brain age’ relate to early-life factors more than to longitudinal brain change

Brain age is a widely used index for quantifying individuals’ brain health as deviation from a normative brain aging trajectory. Higher-than-expected brain age is thought partially to reflect above-average rate of brain aging. Here, we explicitly tested this assumption in two independent large test datasets (UK Biobank [main] and Lifebrain [replication]; longitudinal observations ≈ 2750 and 4200) by assessing the relationship between cross-sectional and longitudinal estimates of brain age. Brain age models were estimated in two different training datasets (n ≈ 38,000 [main] and 1800 individuals [replication]) based on brain structural features. The results showed no association between cross-sectional brain age and the rate of brain change measured longitudinally. Rather, brain age in adulthood was associated with the congenital factors of birth weight and polygenic scores of brain age, assumed to reflect a constant, lifelong influence on brain structure from early life. The results call for nuanced interpretations of cross-sectional indices of the aging brain and question their validity as markers of ongoing within-person changes of the aging brain. Longitudinal imaging data should be preferred whenever the goal is to understand individual change trajectories of brain and cognition in aging.

History of Mental Disorders

Writing the history of mental disorders is an unfinishable task. Each historical period is expected to write its own, and in a style designed to satisfy its own conceptual and social needs. In the 21st century such a historical account seems to be one that conceives of mental disorders as natural kinds, that is, as entities that for their meaning and ontology require to be related to a brain change. However, being aware that, after all, concepts are just instruments in the hands of humans opens up the possibility of writing a more comprehensive history of mental disorders, one based on their historical epistemology, that is, on the manner in which madness has been culturally reconfigured throughout the ages. This approach should be more fruitful in regard to finding ways of helping people with mental sufferings, a task which is about the only justification for the existence of the discipline called psychiatry.

Intranasal oxytocin modulates very early visual processing of emotional faces

Functional imaging and behavioural studies have shown that the neuropeptide oxytocin influences processing of emotional faces. However, it is not clear whether these effects reflect modulation at an early or late stage of affective processing. We investigated the effects of oxytocin administration on early and late visual evoked potentials (VEP) in response to faces with neutral, fearful and happy expressions. In addition, we measured multifocal VEP and its associated nonlinearities to ascertain whether any changes observed in electrophysiology were indicative of a generalised effect or of one tied strictly to emotional processing. In a randomized, double-blind, cross-over design, 27 healthy male participants self-administered a nasal spray of either oxytocin (24 IU) or placebo. At very early latencies (40-60ms), oxytocin reduced right-temporal responses to fearful faces (d = .51), and central responses to both fearful (d = .48) and neutral faces (d = .54). For left occipito-temporal electrode sites, oxytocin decreased P100 reactivity to fearful expressions (d = 0.72). Oxytocin also decreased the amplitudes of the vertex positive potential (140-180ms) and late positive potential (400-600ms), regardless of whether the faces had fearful, happy or neutral expressions. The mfVEP showed no signs of selective magno-or parvo-cellular peak modulation comparing OXT with placebo with either low or high contrast stimulation. These results suggest that at early stages of visual processing, nasal oxytocin modulates responses to facial emotions, whereas at later stages of visual processing, it appears to influence more general face processing mechanisms. In addition, the measurable effects of OXT appear to be not a result of generalized brain change, but systematically related to emotional processing.

Maternally regulated gastrulation as a source of variation contributing to cavefish forebrain evolution

Sequential developmental events, starting from the moment of fertilization, are crucial for the acquisition of animal body plan. Subtle modifications in such early events are likely to have major impacts in later morphogenesis, bringing along morphological diversification. Here, comparing the blind cave and the surface morphotypes of Astyanax mexicanus fish, we found heterochronies during gastrulation that produce organizer and axial mesoderm tissues with different properties (including differences in the expression of dkk1b) that may have contributed to cavefish brain evolution. These variations observed during gastrulation depend fully on maternal factors. The developmental evolution of retinal morphogenesis and hypothalamic patterning are among those traits that retained significant maternal influence at larval stages. Transcriptomic analysis of fertilized eggs from both morphotypes and reciprocal F1 hybrids showed a strong and specific maternal signature. Our work strongly suggests that maternal effect genes and developmental heterochronies that occur during gastrulation have impacted morphological brain change during cavefish evolution.

Concluding discussion

This chapter looks at potential common underlying factors linking MMN/MMNm deficiency to the broad range of heterogeneous clinical conditions outlined in the book. Several promising clinical applications of MMN/MMNm are summarized, including the prediction of conversion to psychosis among clinically at-risk individuals, the prediction of the recovery of consciousness and cognitive capabilities in patients in a comatose or persistent vegetative state, the early detection of perceptual deficits in developmental brain disorders, and the early identification of the presence of Mild Cognitive Impairment (MCI). Furthermore, the evaluation of the cognitive decline occurring in different brain disorders, as well as the prediction of cognitive recovery after the occurrence of a stroke or other brain injury, and the objective monitoring of age-related cognitive brain change and potential countermeasures to slow down this age-related cognitive decline are discussed.

Maternally-regulated gastrulation as a source of variation contributing to cavefish forebrain evolution

Sequential developmental events, starting from the moment of fertilization, are crucial for the acquisition of animal body plan. Subtle modifications in such early events are likely to have a major impact in later morphogenesis, bringing along morphological diversification. Here, comparing the blind cave and the surface morphotypes of Astyanax mexicanus fish, we found heterochronies during gastrulation, producing organizer and axial mesoderm tissues with different properties, including differences in expression of dkk1b, that may have contributed to cavefish brain evolution. These variations observed during gastrulation depend fully on maternal factors, whereas later phenotypic differences in neural development became progressively hidden when zygotic genes take the control over development. Transcriptomic analysis of fertilized eggs from both morphotypes and reciprocal F1 hybrids showed a strong and specific maternal signature. Our work strongly suggests that maternal effect genes and developmental heterochronies occurring during gastrulation have impacted morphological brain change during cavefish evolution.