Exploring the local field potential signal from the subthalamic nucleus for phase-targeted auditory stimulation in Parkinson's disease.

BACKGROUND: Enhancing slow waves, the electrophysiological (EEG) manifestation of non-rapid eye movement (NREM) sleep, could potentially benefit patients with Parkinson's disease (PD) by improving sleep quality and slowing disease progression. Phase-targeted auditory stimulation (PTAS) is an approach to enhance slow waves, which are detected in real-time in the surface EEG signal. OBJECTIVE: We aimed to test whether the local-field potential of the subthalamic nucleus (STN-LFP) can be used to detect frontal slow waves and assess the electrophysiological changes related to PTAS. METHODS: We recruited patients diagnosed with PD and undergoing Percept™ PC neurostimulator (Medtronic) implantation for deep brain stimulation of STN (STN-DBS) in a two-step surgery. Patients underwent three full-night recordings, including one between-surgeries recording and two during rehabilitation, one with DBS+ (on) and one with DBS- (off). Surface EEG and STN-LFP signals from Percept PC were recorded simultaneously, and PTAS was applied during sleep in all three recording sessions. RESULTS: Our results show that during NREM sleep, slow waves of the cortex and STN are time-locked. PTAS application resulted in power and coherence changes, which can be detected in STN-LFP. CONCLUSION: Our findings suggest the feasibility of implementing PTAS using solely STN-LFP signal for slow wave detection, thus without a need for an external EEG device alongside the implanted neurostimulator. Moreover, we propose options for more efficient STN-LFP signal preprocessing, including different referencing and filtering to enhance the reliability of cortical slow wave detection in STN-LFP recordings.

Wake EEG oscillation dynamics reflect both sleep need and brain maturation across childhood and adolescence.

An objective measure of brain maturation is highly insightful for monitoring both typical and atypical development. Slow wave activity, recorded in the sleep electroencephalogram (EEG), reliably indexes changes in brain plasticity with age, as well as deficits related to developmental disorders such as attention-deficit hyperactivity disorder (ADHD). Unfortunately, measuring sleep EEG is resource-intensive and burdensome for participants. We therefore aimed to determine whether wake EEG could likewise index developmental changes in brain plasticity. We analyzed high-density wake EEG collected from 163 participants 3-25 years old, before and after a night of sleep. We compared two measures of oscillatory EEG activity, amplitudes and density, as well as two measures of aperiodic activity, intercepts and slopes. Furthermore, we compared these measures in patients with ADHD (8-17 y.o., N=58) to neurotypical controls. We found that wake oscillation amplitudes behaved the same as sleep slow wave activity: amplitudes decreased with age, decreased after sleep, and this overnight decrease decreased with age. Oscillation densities were also substantially age-dependent, decreasing overnight in children and increasing overnight in adolescents and adults. While both aperiodic intercepts and slopes decreased linearly with age, intercepts decreased overnight, and slopes increased overnight. Overall, our results indicate that wake oscillation amplitudes track both development and sleep need, and overnight changes in oscillation density reflect some yet-unknown shift in neural activity around puberty. No wake measure showed significant effects of ADHD, thus indicating that wake EEG measures, while easier to record, are not as sensitive as those during sleep.

The Theta Paradox: 4-8 Hz EEG Oscillations Reflect Both Sleep Pressure and Cognitive Control.

Human electroencephalographic (EEG) oscillations characterize specific behavioral and vigilance states. The frequency of these oscillations is typically sufficient to distinguish a given state; however, theta oscillations (4-8 Hz) have instead been found in near-opposite conditions of drowsiness during sleep deprivation and alert cognitive control. While the latter has been extensively studied and is often referred to as "frontal midline theta," (fmTheta) the former has been investigated far less but is considered a marker for sleep pressure during wake. In this study we investigated to what extent theta oscillations differed during cognitive tasks and sleep deprivation. We measured high-density EEG in 18 young healthy adults (nine female) performing six tasks under three levels of sleep deprivation. We found both cognitive load and sleep deprivation increased theta power in medial prefrontal cortical areas; however, sleep deprivation caused additional increases in theta in many other, predominantly frontal, areas. The sources of sleep deprivation theta (sdTheta) were task dependent, with a visual-spatial task and short-term memory (STM) task showing the most widespread effects. Notably, theta was highest in supplementary motor areas during passive music listening, and highest in the inferior temporal cortex (responsible for object recognition) during a spatial game. Furthermore, while changes in task performance were correlated with increases in theta during sleep deprivation, this relationship was not specific to the EEG of the same task and did not survive correction for multiple comparisons. Altogether, these results suggest that both during sleep deprivation and cognition theta oscillations may preferentially occur in cortical areas not involved in ongoing behavior.SIGNIFICANCE STATEMENT Electroencephalographic (EEG) research in sleep has often remained separate from research in cognition. This has led to two incompatible interpretations of the function of theta brain oscillations (4-8 Hz): that they reflect local sleep events during sleep deprivation, or that they reflect cognitive processing during tasks. With this study, we found no fundamental differences between theta oscillations during cognition and theta during sleep deprivation that would suggest different functions. Instead, our results indicate that in both cases, theta oscillations are generated by cortical areas not required for ongoing behavior. Therefore, at least in humans, theta may reflect either cortical disengagement or inhibition.

Boosting Recovery During Sleep by Means of Auditory Stimulation.

Sufficient recovery during sleep is the basis of physical and psychological well-being. Understanding the physiological mechanisms underlying this restorative function is essential for developing novel approaches to promote recovery during sleep. Phase-targeted auditory stimulation (PTAS) is an increasingly popular technique for boosting the key electrophysiological marker of recovery during sleep, slow-wave activity (SWA, 1-4 Hz EEG power). However, it is unknown whether PTAS induces physiological sleep. In this study, we demonstrate that, when applied during deep sleep, PTAS accelerates SWA decline across the night which is associated with an overnight improvement in attentional performance. Thus, we provide evidence that PTAS enhances physiological sleep and demonstrate under which conditions this occurs most efficiently. These findings will be important for future translation into clinical populations suffering from insufficient recovery during sleep.

Neuromodulation by means of phase-locked auditory stimulation affects key marker of excitability and connectivity during sleep.

The propagating pattern of sleep slow waves (high-amplitude oscillations < 4.5 Hz) serves as a blueprint of cortical excitability and brain connectivity. Phase-locked auditory stimulation is a promising tool for the modulation of ongoing brain activity during sleep; however, its underlying mechanisms remain unknown. Here, eighteen healthy young adults were measured with high-density electroencephalography in three experimental conditions; one with no stimulation, one with up- and one with down-phase stimulation; ten participants were included in the analysis. We show that up-phase auditory stimulation on a right prefrontal area locally enhances cortical involvement and promotes traveling by increasing the propagating distance and duration of targeted small-amplitude waves. On the contrary, down-phase stimulation proves more efficient at perturbing large-amplitude waves and interferes with ongoing traveling by disengaging cortical regions and interrupting high synchronicity in the target area as indicated by increased traveling speed. These results point out different underlying mechanisms mediating the effects of up- and down-phase stimulation and highlight the strength of traveling wave analysis as a sensitive and informative method for the study of connectivity and cortical excitability alterations.

Cortical plasticity elicited by acoustically cued monetary losses: an ERP study.

Both human and animal studies have demonstrated remarkable findings of experience-induced plasticity in the cortex. Here, we investigated whether the widely used monetary incentive delay (MID) task changes the neural processing of incentive cues that code expected monetary outcomes. We used a novel auditory version of the MID task, where participants responded to acoustic cues that coded expected monetary losses. To investigate task-induced brain plasticity, we presented incentive cues as deviants during passive oddball tasks before and after two sessions of the MID task. During the oddball task, we recorded the mismatch-related negativity (MMN) as an index of cortical plasticity. We found that two sessions of the MID task evoked a significant enhancement of MMN for incentive cues that predicted large monetary losses, specifically when monetary cue discrimination was essential for maximising monetary outcomes. The task-induced plasticity correlated with the learning-related neural activity recorded during the MID task. Thus, our results confirm that the processing of (loss)incentive auditory cues is dynamically modulated by previously learned monetary outcomes.

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.

The Monetary Incentive Delay (MID) Task Induces Changes in Sensory Processing: ERP Evidence.

Numerous cognitive studies have demonstrated experience-induced plasticity in the primary sensory cortex, indicating that repeated decisions could modulate sensory processing. In this context, we investigated whether an auditory version of the monetary incentive delay (MID) task could change the neural processing of the incentive cues that code expected monetary outcomes. To study sensory plasticity, we presented the incentive cues as deviants during oddball sessions recorded before and after training in the two MID task sessions. We found that after 2 days of training in the MID task, incentive cues evoked a larger P3a (compared with the baseline condition), indicating there was an enhancement of the involuntary attention to the stimuli that predict rewards. At the individual level, the training-induced change of mismatch-related negativity was correlated with the amplitude of the feedback-related negativity (FRN) recorded during the first MID task session. Our results show that the MID task evokes plasticity changes in the auditory system associated with better passive discrimination of incentive cues and with enhanced involuntary attention switching towards these cues. Thus, the sensory processing of incentive cues is dynamically modulated by previous outcomes.

Correlation of cue-locked FRN and feedback-locked FRN in the auditory monetary incentive delay task.

Reflecting the discrepancy between received and predicted outcomes, the reward prediction error (RPE) plays an important role in learning in a dynamic environment. A number of studies suggested that the feedback-related negativity (FRN) component of an event-related potential, known to be associated with unexpected outcomes, encodes RPEs. While FRN was clearly shown to be sensitive to the probability of outcomes, the effect of outcome magnitude on FRN remains to be further clarified. In studies on the neural underpinnings of reward anticipation and outcome evaluation, a monetary incentive delay (MID) task proved to be particularly useful. We investigated whether feedback-locked FRN and cue-locked dN200 responses recorded during an auditory MID task were sensitive to the probability and magnitude of outcomes. The cue-locked dN200 is associated with the update of information about the magnitude of prospective outcomes. Overall, we showed that feedback-locked FRN was modulated by both the magnitude and the probability of outcomes during an auditory version of MID task, whereas no such effect was found for cue-locked dN200. Furthermore, the cue-locked dN200, which is associated with the update of information about the magnitude of prospective outcomes, correlated with the standard feedback-locked FRN, which is associated with a negative RPE. These results further expand our knowledge on the interplay between the processing of predictive cues that forecast future outcomes and the subsequent revision of these predictions during outcome delivery.