Technical feasibility of using auditory phase-targeted stimulation after pediatric severe traumatic brain injury in an intensive care setting.

BACKGROUND: Supplementary treatment options after pediatric severe traumatic brain injury (TBI) are needed to improve neurodevelopmental outcome. Evidence suggests enhancement of brain delta waves via auditory phase-targeted stimulation might support neuronal reorganization, however, this method has never been applied in analgosedated patients on the pediatric intensive care unit (PICU). Therefore, we conducted a feasibility study to investigate this approach: In a first recording phase, we examined feasibility of recording over time and in a second stimulation phase, we applied stimulation to address tolerability and efficacy. METHODS: Pediatric patients (> 12 months of age) with severe TBI were included between May 2019 and August 2021. An electroencephalography (EEG) device capable of automatic delta wave detection and sound delivery through headphones was used to record brain activity and for stimulation (MHSL-SleepBand version 2). Stimulation tolerability was evaluated based on report of nurses, visual inspection of EEG data and clinical signals (heart rate, intracranial pressure), and whether escalation of therapy to reduce intracranial pressure was needed. Stimulation efficacy was investigated by comparing EEG power spectra of active stimulation versus muted stimulation (unpaired t-tests). RESULTS: In total, 4 out of 32 TBI patients admitted to the PICU (12.5%) between 4 and 15 years of age were enrolled in the study. All patients were enrolled in the recording phase and the last one also to the stimulation phase. Recordings started within 5 days after insult and lasted for 1-4 days. Overall, 23-88 h of EEG data per patient were collected. In patient 4, stimulation was enabled for 50 min: No signs of patient stress reactions were observed. Power spectrums between active and muted stimulation were not statistically different (all P > .05). CONCLUSION: Results suggests good feasibility of continuously applying devices needed for auditory stimulation over multiple days in pediatric patients with TBI on PICU. Very preliminary evidence suggests good tolerability of auditory stimuli, but efficacy of auditory stimuli to enhance delta waves remains unclear and requires further investigation. However, only low numbers of severe TBI patients could be enrolled in the study and, thus, future studies should consider an international multicentre approach.

Thalamic Influence on Slow Wave Slope Renormalization During Sleep.

OBJECTIVE: Slow waves are thought to mediate an overall reduction in synaptic strength during sleep. The specific contribution of the thalamus to this so-called synaptic renormalization is unknown. Thalamic stroke is associated with daytime sleepiness, along with changes to sleep electroencephalography and cognition, making it a unique "experiment of nature" to assess the relationship between sleep rhythms, synaptic renormalization, and daytime functions. METHODS: Sleep was studied by polysomnography and high-density electroencephalography over 17 nights in patients with thalamic (n = 12) and 15 nights in patients with extrathalamic (n = 11) stroke. Sleep electroencephalographic overnight slow wave slope changes and their relationship with subjective daytime sleepiness, cognition, and other functional tests were assessed. RESULTS: Thalamic and extrathalamic patients did not differ in terms of age, sleep duration, or apnea-hypopnea index. Conversely, overnight slope changes were reduced in a large cluster of electrodes in thalamic compared to extrathalamic stroke patients. This reduction was related to increased daytime sleepiness. No significant differences were found in other functional tests between the 2 groups. INTERPRETATION: In patients with thalamic stroke, a reduction in overnight slow wave slope change and increased daytime sleepiness was found. Sleep- and wake-centered mechanisms for this relationship are discussed. Overall, this study suggests a central role of the thalamus in synaptic renormalization. ANN NEUROL 2021;90:821-833.

Changes in cross-frequency coupling following closed-loop auditory stimulation in non-rapid eye movement sleep.

Regional changes of non-rapid eye movement (NREM) sleep delta and sigma activity, and their temporal coupling have been related to experience-dependent plastic changes during previous wakefulness. These sleep-specific rhythms seem to be important for brain recovery and memory consolidation. Recently, it was demonstrated that by targeting slow waves in a particular region at a specific phase with closed-loop auditory stimulation, it is possible to locally manipulate slow-wave activity and interact with training-induced neuroplastic changes. In our study, we tested whether closed-loop auditory stimulation targeting the up-phase of slow waves might not only interact with the main sleep rhythms but also with their coupling within the circumscribed region. We demonstrate that while closed-loop auditory stimulation globally enhances delta, theta and sigma power, changes in cross-frequency coupling of these oscillations were more spatially restricted. Importantly, a significant increase in delta-sigma coupling was observed over the right parietal area, located directly posterior to the target electrode. These findings suggest that closed-loop auditory stimulation locally modulates coupling between delta phase and sigma power in a targeted region, which could be used to manipulate sleep-dependent neuroplasticity within the brain network of interest.