Transient oscillation dynamics during sleep provide a robust basis for electroencephalographic phenotyping and biomarker identification.

Transient oscillatory events in the sleep electroencephalogram represent short-term coordinated network activity. Of particular importance, sleep spindles are transient oscillatory events associated with memory consolidation, which are altered in aging and in several psychiatric and neurodegenerative disorders. Spindle identification, however, currently contains implicit assumptions derived from what waveforms were historically easiest to discern by eye, and has recently been shown to select only a high-amplitude subset of transient events. Moreover, spindle activity is typically averaged across a sleep stage, collapsing continuous dynamics into discrete states. What information can be gained by expanding our view of transient oscillatory events and their dynamics? In this paper, we develop a novel approach to electroencephalographic phenotyping, characterizing a generalized class of transient time-frequency events across a wide frequency range using continuous dynamics. We demonstrate that the complex temporal evolution of transient events during sleep is highly stereotyped when viewed as a function of slow oscillation power (an objective, continuous metric of depth-of-sleep) and phase (a correlate of cortical up/down states). This two-fold power-phase representation has large intersubject variability-even within healthy controls-yet strong night-to-night stability for individuals, suggesting a robust basis for phenotyping. As a clinical application, we then analyze patients with schizophrenia, confirming established spindle (12-15 Hz) deficits as well as identifying novel differences in transient non-rapid eye movement events in low-alpha (7-10 Hz) and theta (4-6 Hz) ranges. Overall, these results offer an expanded view of transient activity, describing a broad class of events with properties varying continuously across spatial, temporal, and phase-coupling dimensions.

Short-term succinic acid treatment mitigates cerebellar mitochondrial OXPHOS dysfunction, neurodegeneration and ataxia in a Purkinje-specific spinocerebellar ataxia type 1 (SCA1) mouse model.

Mitochondrial dysfunction plays a significant role in neurodegenerative disease including ataxias and other movement disorders, particularly those marked by progressive degeneration in the cerebellum. In this study, we investigate the role of mitochondrial oxidative phosphorylation (OXPHOS) deficits in cerebellar tissue of a Purkinje cell-driven spinocerebellar ataxia type 1 (SCA1) mouse. Using RNA sequencing transcriptomics, OXPHOS complex assembly analysis and oxygen consumption assays, we report that in the presence of mutant polyglutamine-expanded ataxin-1, SCA1 mice display deficits in cerebellar OXPHOS complex I (NADH-coenzyme Q oxidoreductase). Complex I genes are upregulated at the time of symptom onset and upregulation persists into late stage disease; yet, functional assembly of complex I macromolecules are diminished and oxygen respiration through complex I is reduced. Acute treatment of postsymptomatic SCA1 mice with succinic acid, a complex II (succinate dehydrogenase) electron donor to bypass complex I dysfunction, ameliorated cerebellar OXPHOS dysfunction, reduced cerebellar pathology and improved motor behavior. Thus, exploration of mitochondrial dysfunction and its role in neurodegenerative ataxias, and warrants further investigation.