Disturbed laterality of non-rapid eye movement sleep oscillations in post-stroke human sleep: a pilot study

Since you didn't create a sleep protocol, nothing here is of any use to survivors trying to recover. Useless! Being a pilot study does not excuse you from providing useful recovery data.

Disturbed laterality of non-rapid eye movement sleep oscillations in post-stroke human sleep: a pilot study

Benjamin K. Simpson^1† Rohit Rangwani^2,3† Aamir Abbasi² Jeffrey M. Chung¹ Chrystal M. Reed^1‡ Tanuj Gulati^1,2,3,4*‡

• ¹Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
• ²Department of Biomedical Sciences, Center for Neural Science and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
• ³Bioengineering Graduate Program, Department of Bioengineering, Henry Samueli School of Engineering, University of California, Los Angeles, Los Angeles, CA, United States
• ⁴Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States

Sleep is known to promote recovery post-stroke. However, there is a paucity of data profiling sleep oscillations in the post-stroke human brain. Recent rodent work showed that resurgence of physiologic spindles coupled to sleep slow oscillations (SOs) and concomitant decrease in pathological delta (δ) waves is associated with sustained motor performance gains during stroke recovery. The goal of this study was to evaluate bilaterality of non-rapid eye movement (NREM) sleep-oscillations (namely SOs, δ-waves, spindles, and their nesting) in post-stroke patients vs. healthy control subjects. We analyzed NREM-marked electroencephalography (EEG) data in hospitalized stroke-patients (n = 5) and healthy subjects (n = 3). We used a laterality index to evaluate symmetry of NREM oscillations across hemispheres. We found that stroke subjects had pronounced asymmetry in the oscillations, with a predominance of SOs, δ-waves, spindles, and nested spindles in affected hemisphere, when compared to the healthy subjects. Recent preclinical work classified SO-nested spindles as restorative post-stroke and δ-wave-nested spindles as pathological. We found that the ratio of SO-nested spindles laterality index to δ-wave-nested spindles laterality index was lower in stroke subjects. Using linear mixed models (which included random effects of concurrent pharmacologic drugs), we found large and medium effect size for δ-wave nested spindle and SO-nested spindle, respectively. Our results in this pilot study indicate that considering laterality index of NREM oscillations might be a useful metric for assessing recovery post-stroke and that factoring in pharmacologic drugs may be important when targeting sleep modulation for neurorehabilitation post-stroke.

Introduction

Stroke is a leading cause of motor disability world-wide. Despite advances in neurorehabilitation, there is a lack of widely adopted therapies that target plasticity post-stroke, and functional outcomes remain inconsistent (1–3). Sleep is known to play a major role in regulating plasticity (4–12) and accordingly, there has been an interest in modulating sleep for stroke motor rehabilitation (13, 14). To optimize efforts for effective sleep modulation, there is a need to better understand neural processing during sleep. Additionally, it is important to consider co-morbidities and concurrent pharmaceuticals that may impact excitatory/inhibitory neural transmission. Previous animal and human studies have shown that sleep can influence motor recovery post-stroke (2, 14–23), however more work is needed to understand how sleep neurophysiology is affected in stroke. This has become all the more important with advances in our understanding of sleep neurophysiology linking nested non-rapid eye movement (NREM) oscillations to plasticity, motor memory consolidation, and motor recovery (4, 6, 14, 24).

Sleep-dependent neural processing is crucial for memory consolidation, which is the process of transferring newly learned information to stable long-term memory (9, 25). Initial investigations looked at sleep’s role in declarative memory (26, 27), but recent studies have underscored sleep’s role in motor skill consolidation (5, 6, 28). Specifically, NREM sleep has been linked to the reactivation of awake motor-practice activity and performance gains in a motor skill after sleep (4–6). There is now a consensus that this consolidation occurs during temporal coupling of sleep spindles (10–16 Hz) to larger amplitude slow oscillations (SOs, 0.1–1 Hz) (6, 25, 29–31). Recent work in rodents has shown that these SOs nested with spindles decline immediately post-stroke and increase during motor recovery (14). This work also showed that delta waves (δ waves, 1–4 Hz), along with δ wave-nested spindles increased post-stroke and reduced during recovery. These two nested oscillations (namely, SO-nested spindles vs. δ wave-nested spindles) were shown to have a competing role during recovery. Pharmacological reduction of tonic γ-aminobutyric acid (GABA) neurotransmission shifted the balance toward restorative SO-nested spindles in the brain and increased the pace of recovery. The chief goal of our study was to see if NREM oscillations and their nesting were affected post-stroke in human patients within a hospital setting. Specifically, we wanted to check for laterality of NREM oscillations’ densities in stroke vs. contralateral hemisphere and compare it to healthy subjects.

Our study showed that, acutely post-stroke, there is an increase in SOs, δ waves, and spindles on stroke electrodes when compared to contralateral hemisphere electrodes, whereas healthy subjects had symmetrical density of these oscillations. Our linear mixed effect model revealed that there were significant fixed effects of stroke vs. contralateral electrodes for SOs and δ waves with overall medium effect sizes, including random effects of concurrent pharmacologic drugs. We also observed a large effect size of the linear mixed model for δ wave-nested spindles. Finally, we found that the proportion of SO-nested spindles to δ-wave-nested spindles was lower in stroke subjects compared to healthy subjects. Our work here in a pilot dataset suggests that laterality of NREM sleep oscillations could be a useful marker for physiological sleep activity post-stroke. Future work that confirms our findings in a larger dataset can inform acute stroke care management that also incorporates pharmacologic drug interactions and their effects on laterality of ‘restorative’ sleep oscillations.

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