Early-life adversity and neurological disease: age-old questions and novel answers

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Neurological illnesses, including cognitive impairment, memory decline and dementia, affect over 50 million people worldwide, imposing a substantial burden on individuals and society. These disorders arise from a combination of genetic, environmental and experiential factors, with the latter two factors having the greatest impact during sensitive periods in development. In this Review, we focus on the contribution of adverse early-life experiences to aberrant brain maturation, which might underlie vulnerability to cognitive brain disorders. Specifically, we draw on recent robust discoveries from diverse disciplines, encompassing human studies and experimental models. These discoveries suggest that early-life adversity, especially in the perinatal period, influences the maturation of brain circuits involved in cognition. Importantly, new findings suggest that fragmented and unpredictable environmental and parental signals comprise a novel potent type of adversity, which contributes to subsequent vulnerabilities to cognitive illnesses via mechanisms involving disordered maturation of brain ‘wiring’.

Key points

  • A strong association exists between neurocognitive disorders and early-life adversity, and experimental animal models support a causal relationship, in addition to the critical effects of genetics and gene–environment interactions.

  • The emotional aspects of adversity, including unpredictability of environmental and parental signals, most profoundly influence cognitive outcomes.

  • Mechanistically, early-life adversity might disrupt the normal maturation of the brain circuits that underlie cognitive functions by modulating synaptic maturation and pruning.

  • Novel cross-species imaging and epigenomic technologies hold promise for identifying mechanisms, biomarkers and mechanism-based preventive approaches and interventions.

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Fig. 1: Do aberrant patterns of environmental signals to the developing brain constitute early-life adversity?
Fig. 2: Connectomic analysis reveals sex-specific development and maturation of brain circuits.


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The authors’ work has been supported by NIH grants NS28912, NS35439, NS108296, MH73136 and MH096889, and by the Hewitt Foundation for Biomedical Research.

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Nature Reviews Neurology thanks R. Herringa and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Both authors researched data for the article, wrote the article and reviewed and edited the manuscript before submission.

Correspondence to Tallie Z. Baram.

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