The Comparison of Early Hemodynamic Response to Single-Pulse Transcranial Magnetic Stimulation following Inhibitory or Excitatory Theta Burst Stimulation on Motor Cortex.

We present a new study design aiming to enhance the understanding of the mechanism by which continuous theta burst stimulation (cTBS) or intermittent theta burst stimulation (iTBS) paradigms elicit cortical modulation. Using near-infrared spectroscopy (NIRS), we compared the cortical hemodynamics of the previously inhibited (after cTBS) or excited (after iTBS) left primary motor cortex (M1) as elicited by single-pulse TMS (spTMS) in a cross-over design. Mean relative changes in hemodynamics within 6 s of the stimulus were compared using a two-sample t-test (p < 0.05) and linear mixed model between real and sham stimuli and between stimuli after cTBS and iTBS. Only spTMS after cTBS resulted in a significant increase (p = 0.04) in blood volume (BV) compared to baseline. There were no significant changes in other hemodynamic parameters (oxygenated/deoxygenated hemoglobin). spTMS after cTBS induced a larger increase in BV than spTMS after iTBS (p = 0.021) and sham stimulus after cTBS (p = 0.009). BV showed no significant difference between real and sham stimuli after iTBS (p = 0.37). The greater hemodynamic changes suggest increased vasomotor reactivity after cTBS compared to iTBS. In addition, cTBS could decrease lateral inhibition, allowing activation of surrounding areas after cTBS.

Electroencephalographic Signature of Out-of-Body Experiences Induced by Virtual Reality: A Novel Methodological Approach.

Out-of-body experiences (OBEs) are subjective experiences of seeing one's own body and the environment from a location outside the physical body. They can arise spontaneously or in specific conditions, such as during the intake of dissociative drug. Given its unpredictable occurrence, one way to empirically study it is to induce subjective experiences resembling an OBE using technology such as virtual reality. We employed a complex multisensory method of virtual embodiment in a virtual reality scenario with seven healthy participants to induce virtual OBE-like experiences. Participants performed two conditions in a randomly determined order. For both conditions, the participant's viewpoint was lifted out of the virtual body toward the ceiling of the virtual room, and real body movements were (visuo-tactile ON condition) or were not (visuo-tactile OFF condition) translated into movements on the virtual body below-the latter aiming to maintain a feeling of connection with the virtual body. A continuous 128-electrode EEG was recorded. Participants reported subjective experiences of floating in the air and of feeling high up in the virtual room at a strong intensity, but a weak to moderate feeling of being "out of their body" in both conditions. The EEG analysis revealed that this subjective experience was associated with a power shift that manifested in an increase of delta and a decrease of alpha relative power. A reduction of theta complexity and an increase of beta-2 connectivity were also found. This supports the growing body of evidence revealing a prominent role of delta activity during particular conscious states.

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.

Local Sleep Slow-Wave Activity Colocalizes With the Ictal Symptomatogenic Zone in a Patient With Reflex Epilepsy: A High-Density EEG Study.

Background: Slow-wave activity (SWA) during non-rapid eye movement (NREM) sleep reflects synaptic potentiation during preceding wakefulness. Epileptic activity may induce increases in state-dependent SWA in human brains, therefore, localization of SWA may prove useful in the presurgical workup of epileptic patients. We analyzed high-density electroencephalography (HDEEG) data across vigilance states from a reflex epilepsy patient with a clearly localizable ictal symptomatogenic zone to provide a proof-of-concept for the testability of this hypothesis. Methods: Overnight HDEEG recordings were obtained in the patient during REM sleep, NREM sleep, wakefulness, and during a right facial motor seizure then compared to 10 controls. After preprocessing, SWA (i.e., delta power; 1-4 Hz) was calculated at each channel. Scalp level and source reconstruction analyses were computed. We assessed for statistical differences in maximum SWA between the patient and controls within REM sleep, NREM sleep, wakefulness, and seizure. Then, we completed an identical statistical comparison after first subtracting intrasubject REM sleep SWA from that of NREM sleep, wakefulness, and seizure SWA. Results: The topographical analysis revealed greater left hemispheric SWA in the patient vs. controls in all vigilance states except REM sleep (which showed a right hemispheric maximum). Source space analysis revealed increased SWA in the left inferior frontal cortex during NREM sleep and wakefulness. Ictal data displayed poor source-space localization. Comparing each state to REM sleep enhanced localization accuracy; the most clearly localizing results were observed when subtracting REM sleep from wakefulness. Conclusion: State-dependent SWA during NREM sleep and wakefulness may help to identify aspects of the potential epileptogenic zone. Future work in larger cohorts may assess the clinical value of sleep SWA to help presurgical planning.

Slow Waves Promote Sleep-Dependent Plasticity and Functional Recovery after Stroke.

Functional recovery after stroke is associated with a remapping of neural circuits. This reorganization is often associated with low-frequency, high-amplitude oscillations in the peri-infarct zone in both rodents and humans. These oscillations are reminiscent of sleep slow waves (SW) and suggestive of a role for sleep in brain plasticity that occur during stroke recovery; however, direct evidence is missing. Using a stroke model in male mice, we showed that stroke was followed by a transient increase in NREM sleep accompanied by reduced amplitude and slope of ipsilateral NREM sleep SW. We next used 5 ms optical activation of Channelrhodopsin 2-expressing pyramidal neurons, or 200 ms silencing of Archeorhodopsin T-expressing pyramidal neurons, to generate local cortical UP, or DOWN, states, respectively, both sharing similarities with spontaneous NREM SW in freely moving mice. Importantly, we found that single optogenetically evoked SW (SWopto) in the peri-infarct zone, randomly distributed during sleep, significantly improved fine motor movements of the limb corresponding to the sensorimotor stroke lesion site compared with spontaneous recovery and control conditions, while motor strength remained unchanged. In contrast, SWopto during wakefulness had no effect. Furthermore, chronic SWopto during sleep were associated with local axonal sprouting as revealed by the increase of anatomic presynaptic and postsynaptic markers in the peri-infarct zone and corresponding contralesional areas to cortical circuit reorganization during stroke recovery. These results support a role for sleep SW in cortical circuit plasticity and sensorimotor recovery after stroke and provide a clinically relevant framework for rehabilitation strategies using neuromodulation during sleep.SIGNIFICANCE STATEMENT Brain stroke is one of the leading causes of death and major disabilities in the elderly worldwide. A better understanding of the pathophysiological mechanisms underlying spontaneous brain plasticity after stroke, together with an optimization of rehabilitative strategies, are essential to improve stroke treatments. Here, we investigate the role of optogenetically induced sleep slow waves in an animal model of ischemic stroke and identify sleep as a window for poststroke intervention that promotes neuroplasticity and facilitates sensorimotor recovery.

Decreased Evoked Slow-Activity After tDCS in Disorders of Consciousness.

Due to life-saving medical advances, the diagnosis and treatment of disorders of consciousness (DOC) has become a more commonly occurring clinical issue. One recently developed intervention option has been non-invasive transcranial direct current stimulation. This dichotomy of patient responders may be better understood by investigating the mechanism behind the transcranial direct current stimulation (tDCS) intervention. The combination of transcranial magnetic stimulation and electroencephalography (TMS-EEG) has been an important diagnostic tool in DOC patients. We therefore examined the neural response using TMS-EEG both before and after tDCS in seven DOC patients (four diagnosed as in a minimally conscious state and three with unresponsive wakefulness syndrome). tDCS was applied over the dorsolateral prefrontal cortex, while TMS pulses were applied to the premotor cortex. None of the seven patients showed relevant behavioral change after tDCS. We did, however, find that the overall evoked slow activity was reduced following tDCS intervention. We also found a positive correlation between the strength of the slow activity and the amount of high-frequency suppression. However, there was no significant pre-post tDCS difference in high frequencies. In the resting-state EEG, we observed that both the incidence of slow waves and the positive slope of the wave were affected by tDCS. Taken together, these results suggest that the tDCS intervention can reduce the slow-wave activity component of bistability, but this may not directly affect high-frequency activity. We hypothesize that while reduced slow activity may be necessary for the recovery of neural function, especially consciousness, this alone is insufficient.

Neurophenomenology of near-death experience memory in hypnotic recall: a within-subject EEG study.

The neurobiological basis of near-death experiences (NDEs) is unknown, but a few studies attempted to investigate it by reproducing in laboratory settings phenomenological experiences that seem to closely resemble NDEs. So far, no study has induced NDE-like features via hypnotic modulation while simultaneously measuring changes in brain activity using high-density EEG. Five volunteers who previously had experienced a pleasant NDE were invited to re-experience the NDE memory and another pleasant autobiographical memory (dating to the same time period), in normal consciousness and with hypnosis. We compared the hypnosis-induced subjective experience with the one of the genuine experience memory. Continuous high-density EEG was recorded throughout. At a phenomenological level, we succeeded in recreating NDE-like features without any adverse effects. Absorption and dissociation levels were reported as higher during all hypnosis conditions as compared to normal consciousness conditions, suggesting that our hypnosis-based protocol increased the felt subjective experience in the recall of both memories. The recall of a NDE phenomenology was related to an increase of alpha activity in frontal and posterior regions. This study provides a proof-of-concept methodology for studying the phenomenon, enabling to prospectively explore the NDE-like features and associated EEG changes in controlled settings.

Sleep as a model to understand neuroplasticity and recovery after stroke: Observational, perturbational and interventional approaches.

Our own experiences with disturbances to sleep demonstrate its crucial role in the recovery of cognitive functions. This importance is likely enhanced in the recovery from stroke; both in terms of its physiology and cognitive abilities. Decades of experimental research have highlighted which aspects and mechanisms of sleep are likely to underlie these forms of recovery. Conversely, damage to certain areas of the brain, as well as the indirect effects of stroke, may disrupt sleep. However, only limited research has been conducted which seeks to directly explore this bidirectional link between both the macro and micro-architecture of sleep and stroke. Here we describe a series of semi-independent approaches that aim to establish this link through observational, perturbational, and interventional experiments. Our primary aim is to describe the methodology for future clinical and translational research needed to delineate competing accounts of the current data. At the observational level we suggest the use of high-density EEG recording, combined analysis of macro and micro-architecture of sleep, detailed analysis of the stroke lesion, and sensitive measures of functional recovery. The perturbational approach attempts to find the causal links between sleep and stroke. We promote the use of transcranial magnetic stimulation combined with EEG to examine the cortical dynamics of the peri-infarct stroke area. Translational research should take this a step further using optogenetic techniques targeting more specific cell populations. The interventional approach focuses on how the same clinical and translational perturbational techniques can be adapted to influence long-term recovery of function.

Differentiation Analysis of Continuous Electroencephalographic Activity Triggered by Video Clip Contents.

While viewing a video clip, we experience a wide variety of contents, from low-level features of the images to high-level ideas such as the storyline. Each change in our experience must be supported by some corresponding change in neurophysiological activity. Differentiation analysis, which quantifies the differences in brain activity by measuring the distances between observed brain states, was applied here to continuous high-density electroencephalographic data recorded while participants watched short video clips. These clips were manipulated in various ways to change the degree of meaningfulness of their contents. We found that neurophysiological differentiation mirrored that of phenomenal differentiation, being higher for meaningful clips and lower for phase-scrambled versions or random noise. The distinction between meaningful and meaningless clips was present even at the individual level, and moreover, differentiation values correlated with individual subjective reports of meaningfulness. Spatial and spectral breakdowns of the overall effect showed frontal and posterior ROIs and highlighted specific roles for different spectral bands. Comparing the results with a multivariate decoding approach reveals that the two methods are capturing different aspects of brain activity and highlights a crucial theoretical distinction between the level and pattern of activity. In future applications, differentiation analysis may be used to evaluate the subjective meaningfulness of stimuli when behavioral responses may be inadequate, as with disorders of consciousness.

EEG Differentiation Analysis and Stimulus Set Meaningfulness.

A set of images can be considered as meaningfully different for an observer if they can be distinguished phenomenally from one another. Each phenomenal difference must be supported by some neurophysiological differences. Differentiation analysis aims to quantify neurophysiological differentiation evoked by a given set of stimuli to assess its meaningfulness to the individual observer. As a proof of concept using high-density EEG, we show increased neurophysiological differentiation for a set of natural, meaningfully different images in contrast to another set of artificially generated, meaninglessly different images in nine participants. Stimulus-evoked neurophysiological differentiation (over 257 channels, 800 ms) was systematically greater for meaningful vs. meaningless stimulus categories both at the group level and for individual subjects. Spatial breakdown showed a central-posterior peak of differentiation, consistent with the visual nature of the stimulus sets. Temporal breakdown revealed an early peak of differentiation around 110 ms, prominent in the central-posterior region; and a later, longer-lasting peak at 300-500 ms that was spatially more distributed. The early peak of differentiation was not accompanied by changes in mean ERP amplitude, whereas the later peak was associated with a higher amplitude ERP for meaningful images. An ERP component similar to visual-awareness-negativity occurred during the nadir of differentiation across all image types. Control stimulus sets and further analysis indicate that changes in neurophysiological differentiation between meaningful and meaningless stimulus sets could not be accounted for by spatial properties of the stimuli or by stimulus novelty and predictability.

Altered sleep homeostasis correlates with cognitive impairment in patients with focal epilepsy.

In animal studies, both seizures and interictal spikes induce synaptic potentiation. Recent evidence suggests that electroencephalogram slow wave activity during sleep reflects synaptic potentiation during wake, and that its homeostatic decrease during the night is associated with synaptic renormalization and its beneficial effects. Here we asked whether epileptic activity induces plastic changes that can be revealed by high-density electroencephalography recordings during sleep in 15 patients with focal epilepsy and 15 control subjects. Compared to controls, patients with epilepsy displayed increased slow wave activity power during non-rapid eye movement sleep over widespread, bilateral scalp regions. This global increase in slow wave activity power was positively correlated with the frequency of secondarily generalized seizures in the 3-5 days preceding the recordings. Individual patients also showed local increases in sleep slow wave activity power at scalp locations matching their seizure focus. This local increase in slow wave activity power was positively correlated with the frequency of interictal spikes during the last hour of wakefulness preceding sleep. By contrast, frequent interictal spikes during non-rapid eye movement sleep predicted a reduced homeostatic decrease in the slope of sleep slow waves during the night, which in turn predicted reduced daytime learning. Patients also showed an increase in sleep spindle power, which was negatively correlated with intelligence quotient. Altogether, these findings suggest that both seizures and interictal spikes may induce long-lasting changes in the human brain that can be sensitively detected by electroencephalographic markers of sleep homeostasis. Furthermore, abnormalities in sleep markers are correlated with cognitive impairment, suggesting that not only seizures, but also interictal spikes can have negative consequences.

Functional split brain in a driving/listening paradigm.

We often engage in two concurrent but unrelated activities, such as driving on a quiet road while listening to the radio. When we do so, does our brain split into functionally distinct entities? To address this question, we imaged brain activity with fMRI in experienced drivers engaged in a driving simulator while listening either to global positioning system instructions (integrated task) or to a radio show (split task). We found that, compared with the integrated task, the split task was characterized by reduced multivariate functional connectivity between the driving and listening networks. Furthermore, the integrated information content of the two networks, predicting their joint dynamics above and beyond their independent dynamics, was high in the integrated task and zero in the split task. Finally, individual subjects' ability to switch between high and low information integration predicted their driving performance across integrated and split tasks. This study raises the possibility that under certain conditions of daily life, a single brain may support two independent functional streams, a "functional split brain" similar to what is observed in patients with an anatomical split.

Optimizing detection and analysis of slow waves in sleep EEG.

BACKGROUND: Analysis of individual slow waves in EEG recording during sleep provides both greater sensitivity and specificity compared to spectral power measures. However, parameters for detection and analysis have not been widely explored and validated. NEW METHOD: We present a new, open-source, Matlab based, toolbox for the automatic detection and analysis of slow waves; with adjustable parameter settings, as well as manual correction and exploration of the results using a multi-faceted visualization tool. RESULTS: We explore a large search space of parameter settings for slow wave detection and measure their effects on a selection of outcome parameters. Every choice of parameter setting had some effect on at least one outcome parameter. In general, the largest effect sizes were found when choosing the EEG reference, type of canonical waveform, and amplitude thresholding. COMPARISON WITH EXISTING METHOD: Previously published methods accurately detect large, global waves but are conservative and miss the detection of smaller amplitude, local slow waves. The toolbox has additional benefits in terms of speed, user-interface, and visualization options to compare and contrast slow waves. CONCLUSIONS: The exploration of parameter settings in the toolbox highlights the importance of careful selection of detection METHODS: The sensitivity and specificity of the automated detection can be improved by manually adding or deleting entire waves and or specific channels using the toolbox visualization functions. The toolbox standardizes the detection procedure, sets the stage for reliable results and comparisons and is easy to use without previous programming experience.

The occurrence of individual slow waves in sleep is predicted by heart rate.

The integration of near-infrared spectroscopy and electroencephalography measures presents an ideal method to study the haemodynamics of sleep. While the cortical dynamics and neuro-modulating influences affecting the transition from wakefulness to sleep is well researched, the assumption has been that individual slow waves, the hallmark of deep sleep, are spontaneously occurring cortical events. By creating event-related potentials from the NIRS recording, time-locked to the onset of thousands of individual slow waves, we show the onset of slow waves is phase-locked to an ongoing oscillation in the NIRS recording. This oscillation stems from the moment to moment fluctuations of light absorption caused by arterial pulsations driven by the heart beat. The same oscillating signal can be detected if the electrocardiogram is time-locked to the onset of the slow wave. The ongoing NIRS oscillation suggests that individual slow wave initiation is dependent on that signal, and not the other way round. However, the precise causal links remain speculative. We propose several potential mechanisms: that the heart-beat or arterial pulsation acts as a stimulus which evokes a down-state; local fluctuations in energy supply may lead to a network effect of hyperpolarization; that the arterial pulsations lead to corresponding changes in the cerebral-spinal-fluid which evokes the slow wave; or that a third neural generator, regulating heart rate and slow waves may be involved.

The Roles of Dopamine and Hypocretin in Reward: A Electroencephalographic Study.

The proper functioning of the mesolimbic reward system is largely dependent on the neurotransmitter dopamine. Recent evidence suggests that the hypocretin system has significant projections to this reward system. We examined the distinct effects of reduced dopamine or reduced hypocretin levels on reward activity in patients with Parkinson's disease, dopamine deficient, as well as patients with narcolepsy-cataplexy, hypocretin depleted, and healthy controls. Participants performed a simple game-like task while high-density electroencephalography was recorded. Topography and timing of event-related potentials for both reward cue, and reward feedback was examined across the entire dataset. While response to reward cue was similar in all groups, two distinct time points were found to distinguish patients and controls for reward feedback. Around 160 ms both patient groups had reduced ERP amplitude compared to controls. Later at 250 ms, both patient groups also showed a clear event-related potential (ERP), which was absent in controls. The initial differences show that both patient groups show a similar, blunted response to reward delivery. The second potential corresponds to the classic feedback-related negativity (FRN) potential which relies on dopamine activity and reflects reward prediction-error signaling. In particular the mismatch between predicted reward and reward subsequently received was significantly higher in PD compared to NC, independent of reward magnitude and valence. The intermediate FRN response in NC highlights the contribution of hypocretin in reward processing, yet also shows that this is not as detrimental to the reward system as in Parkinson's. Furthermore, the inability to generate accurate predictions in NC may explain why hypocretin deficiency mediates cataplexy triggered by both positive and negative emotions.

The effects of theta-burst stimulation on sleep and vigilance in humans.

Repetitive transcranial magnetic stimulation (TMS) has become a popular tool to modulate neuronal networks and associated brain functions in both clinical and basic research. Yet few studies have examined the potential effects of cortical stimulation on general levels of vigilance. In this exploratory study, we used theta-burst protocols, both continuous (cTBS) and intermittent (iTBS) patterns, to examine whether inhibition or excitation of the left dorso-lateral prefrontal cortex (dlPFC) was able to induce reliable and acute changes to vigilance measures, compared to the left dorso-lateral associative visual cortex (dlAVC) as a control site in line with previous work. Partially sleep restricted participants underwent four separate sessions in a single day, in a between subjects design for TBS stimulation type and within subjects for locaton, each consisting of maintenance of wakefulness test (MWT), a sleep latency test, and a psychomotor vigilance task (PVT). TBS significantly affected measures of sleep consolidation, namely latency to sleep stage 2 and sleep efficiency, but had no effects on sleep drive or psychomotor vigilance levels for either TBS type or location. Contrary to our initial hypothesis of the dlAVC as a control site, stimulation to this region resulted in the largest differential effects between stimulation types. Moreover, the effect of TBS was found to be consistent throughout the day. These data may provide the basis for further investigation into therapeutic applications of TBS in sleep disorders.

Humor as a reward mechanism: event-related potentials in the healthy and diseased brain.

Humor processing involves distinct processing stages including incongruity detection, emotional response, and engagement of mesolimbic reward regions. Dysfunctional reward processing and clinical symptoms in response to humor have been previously described in both hypocretin deficient narcolepsy-cataplexy (NC) and in idiopathic Parkinson disease (PD). For NC patients, humor is the strongest trigger for cataplexy, a transient loss of muscle tone, whereas dopamine-deficient PD-patients show blunted emotional responses to humor. To better understand the role of reward system and the various contributions of hypocretinergic and dopaminergic mechanisms to different stages of humor processing we examined the electrophysiological response to humorous and neutral pictures when given as reward feedback in PD, NC and healthy controls. Humor compared to neutral feedback demonstrated modulation of early ERP amplitudes likely corresponding to visual processing stages, with no group differences. At 270 ms post-feedback, conditions showed topographical and amplitudinal differences for frontal and left posterior electrodes, in that humor feedback was absent in PD patients but increased in NC patients. We suggest that this effect relates to a relatively early affective response, reminiscent of increased amygdala response reported in NC patients. Later ERP differences, corresponding to the late positive potential, revealed a lack of sustained activation in PD, likely due to altered dopamine regulation in reward structures in these patients. This research provides new insights into the temporal dynamics and underlying mechanisms of humor detection and appreciation in health and disease.

Time perception in narcolepsy in comparison to patients with Parkinson's disease and healthy controls - an exploratory study.

The striatum and the prefrontal cortex play an important role in cognitive time processing, and time perception depends on sustained attention. Narcolepsy patients are unable to maintain sustained attention, due probably to deficient hypocretin signalling. Impaired time perception has been found in Parkinson's disease (PD) and attributed to a dysfunctional dopaminergic striatal pacemaker. We aimed to assess time perception in patients with narcolepsy and PD and to compare the outcome to healthy control participants. Seventeen narcolepsy patients, 12 PD patients and 15 healthy controls performed a short time production task, where they had to produce an interval of 1, 2 or 5 s. The accuracy of time production differed significantly according to task target duration, and there was a trend towards a group difference with narcolepsy patients tending to overproduce all target durations. Absolute variability was significantly different between groups, with narcolepsy patients showing higher absolute variability in comparison to controls and PD patients. The analysis of the temporal course of time estimation showed more pronounced overproduction of each target duration at the end of each trial in narcolepsy patients, whereas performance was more or less stable in controls and PD patients. Overproduction and higher variability of all time durations in narcolepsy indicate impaired short interval timing in the seconds range, while the scalar property of timing was preserved. The time-course of accuracy and variability of time production within sessions indicate an attention-related mechanism of impaired interval timing.