Pathogenic effects of central nervous system hyperarousal

Summary Circadian dynamics are genetically modulated cellular reactions to endogenous and exogenous stimuli that reflect states of arousal and homeostatic regulation. Sleep and activity patterns provide reflections of complex cellular and neurotransmitter interactions that occur through the progression of the sleep–wake cycle. These patterns of circadian rhythmicity represent biomarkers indicative of endophenotypic states of neuromodulation and neural efficiency. Circadian instability associated with irritability and mood instability is observed in aging populations as well as in many psychiatric and neurodegenerative disorders. It is proposed that circadian patterns and instability reflect pathophysiological states and/or processes that represent significant developmentally sensitive pathogenic potential. In this view, circadian instability associated with chronic irritability and mood dysregulation in children, adolescents and young adults are neuropsychiatric equivalents of fever, in that, both reflect and contribute to pathological processes. The circadian contributions and/or responses to chronic hyperarousal influence and degrade neural development and function. Neural plasticity, characteristic of young brains, is, under these conditions, vulnerable to the development of abnormal circuitry, abnormal sensitivities and further degradation of neural resilience. Neural plasticity present in early development may, in dysregulated states, allocate resources to hyper-activated circuits, compensatory neural recovery and system stability at the cost of higher order development. Age related reductions of neural plasticity and the cumulative effects of hyperarousal would then be further revealed as development continues and neuronal resilience and capacity to compensate is reduced or overwhelmed. The implications of this hypothesis include its significance related to early intervention and developmental windows of risk and opportunity; the potential for neuroprotection and prevention of chronicity and/or a reduction of severity in neuropsychiatric conditions; the value of circadian measurements and systematic treatment response measurement and monitoring; and, the strategic use of pharmacological agents aimed at modulation of arousal-circadian and stress-response modulation pathologies.