Sleep and emotion processing in paediatric posttraumatic stress disorder: A pilot investigation.

Emotion processing abnormalities and sleep pathology are central to the phenomenology of paediatric posttraumatic stress disorder, and sleep disturbance has been linked to the development, maintenance and severity of the disorder. Given emerging evidence indicating a role for sleep in emotional brain function, it has been proposed that dysfunctional processing of emotional experiences during sleep may play a significant role in affective disorders, including posttraumatic stress disorder. Here we sought to examine the relationship between sleep and emotion processing in typically developing youth, and youth with a diagnosis of posttraumatic stress disorder . We use high-density electroencephalogram to compare baseline sleep with sleep following performance on a task designed to assess both memory for and reactivity to negative and neutral imagery in 10 youths with posttraumatic stress disorder, and 10 age- and sex-matched non-traumatized typically developing youths. Subjective ratings of arousal to negative imagery (ΔArousal = post-sleep minus pre-sleep arousal ratings) remain unchanged in youth with posttraumatic stress disorder following sleep (mean increase 0.15, CI -0.28 to +0.58), but decreased in TD youth (mean decrease -1.0, 95% CI -1.44 to -0.58). ΔArousal, or affective habituation, was negatively correlated with global change in slow-wave activity power (ρ = -0.58, p = .008). When considered topographically, the correlation between Δslow-wave activity power and affective habituation was most significant in a frontal cluster of 27 electrodes (Spearman, ρ = -0.51, p = .021). Our results highlight the importance of slow-wave sleep for adaptive emotional processing in youth, and have implications for symptom persistence in paediatric posttraumatic stress disorder. Impairments in slow-wave activity may represent a modifiable risk factor in paediatric posttraumatic stress disorder.

Self-regulated critical brain dynamics originate from high frequency-band activity in the MEG.

Brain function requires the flexible coordination of billions of neurons across multiple scales. This could be achieved by scale-free, critical dynamics balanced at the edge of order and disorder. Criticality has been demonstrated in several, often reduced neurophysiological model systems. In the intact human brain criticality has yet been only verified for the resting state. A more direct link between the concept of criticality and oscillatory brain physiology, which is strongly related to cognition, is yet missing. In the present study we therefore carried out a frequency-specific analysis of criticality in the MEG, recorded while subjects were in a defined cognitive state through mindfulness meditation. In a two-step approach we assessed whether the macroscopic neural avalanche dynamics is scale-free by evaluating the goodness of a power-law fits of cascade size and duration distributions of MEG deflections in different frequency bands. In a second step we determined the closeness of the power-law exponents to a critical value of -1.5. Power-law fitting was evaluated by permutation testing, fitting of alternative distributions, and cascade shape analysis. Criticality was verified by defined relationships of exponents of cascade size and duration distributions. Behavioral relevance of criticality was tested by correlation of indices of criticality with individual scores of the Mindful Attention Awareness Scale. We found that relevant scale-free near-critical dynamics originated only from broad-band high-frequency (> 100 Hz) MEG activity, which has been associated with action potential firing, and therefore links criticality on the macroscopic level of MEG to critical spike avalanches on a microscopic level. Whereas a scale-free dynamics was found under mindfulness meditation and rest, avalanche dynamics shifted towards a critical point during meditation by reduction of neural noise. Together with our finding that during mindfulness meditation avalanches show differences in topography relative to rest, our results show that self-regulated attention as required during meditation can serve as a control parameter of criticality in scale-free brain dynamics.

Increased lucid dream frequency in long-term meditators but not following MBSR training.

Strong conceptual and theoretical connections have been made between meditation practice, mindfulness and lucid dreaming. However, only a handful of empirical studies have evaluated the relationship between lucid dreaming and meditation, and conclusions remain tempered by methodological limitations. Here we evaluate the relationship between meditation, mindfulness and lucid dream frequency using several complementary methods. First, using a cross-sectional design, we evaluate differences in lucid dream frequency between long-term meditators and meditation naïve individuals. Second, we evaluate the relationship between lucid dream frequency and specific facets of trait mindfulness in both meditators and non-meditators. Third, using a blinded randomized-controlled design, we evaluate the impact of an 8-week mindfulness course on lucid dreaming frequency. Our results show that lucid dreaming is more frequent in long-term meditators compared to meditation naïve individuals. Additionally, lucid dream frequency in meditation-naïve individuals was associated with a capacity to verbalize experience, while lucid dream frequency in long-term meditators was associated with observational and decentering facets of trait mindfulness. However, an 8-week mindfulness course did not increase the frequency of lucid dreams. Together these results support a continuity between increased awareness of waking and sleeping states, provide a novel form of evidence linking meditation training to meta-awareness, and support an association between meditation practice and lucid dreaming, but leave open the specific nature of this connection.

Closed-loop system to enhance slow-wave activity.

OBJECTIVE: Recent evidence reports cognitive, metabolic, and sleep restoration benefits resulting from the enhancement of sleep slow-waves using auditory stimulation. Our objective is to make this concept practical for consumer use by developing and validating an electroencephalogram (EEG) closed-loop system to deliver auditory stimulation during sleep to enhance slow-waves. APPROACH: The system automatically detects slow-wave sleep with 74% sensitivity and 97% specificity and optimally delivers stimulation in the form of 50 ms-long tones separated by a constant one-second inter-tone interval at a volume that is dynamically modulated such that louder tones are delivered when sleep is deeper. The system was tested in a study involving 28 participants (18F, 10M; 36.9 ± 7.3 years old; median age: 40 years old) who used the system for ten nights (five nights in a sham condition and five in a stimulation condition). Four nights in each condition were recorded at-home and the fifth one in-lab. MAIN RESULTS: The analysis in two age groups defined by the median age of participants in the study shows significant slow wave activity enhancement (+16.1%, p < 0.01) for the younger group and absence of effect on the older group. However, the older group received only a fraction (57%) of the stimulation compared to the younger group. Changes in sleep architecture and EEG properties due to aging have influenced the amount of stimulation. The analysis of the stimulation timing suggests an entrainment-like phenomenon where slow-waves align to the stimulation periodicity. In addition, enhancement of spindle power in the stimulation condition was found. SIGNIFICANCE: We show evidence of the viability of delivering auditory stimulation during sleep, at home, to enhance slow wave activity. The system ensures the stimulation delivery to be at the right time during sleep without causing disturbance.

Acute effects of meditation training on the waking and sleeping brain: Is it all about homeostasis?

Our recent finding of a meditation-related increase in low-frequency NREM sleep EEG oscillatory activities peaking in the theta-alpha range (4-12 Hz) was not predicted. From a consolidated body of research on sleep homeostasis, we would expect a change peaking in slow wave activity (1-4 Hz) following an intense meditation session. Here we compared these changes in sleep with the post-meditation changes in waking rest scalp power to further characterize their functional significance. High-density EEG recordings were acquired from 27 long-term meditators (LTM) on three separate days at baseline and following two 8-hr sessions of either mindfulness or compassion-and-loving-kindness meditation. Thirty-one meditation-naïve participants (MNP) were recorded at the same time points. As a common effect of meditation practice, we found increases in low and fast waking EEG oscillations for LTM only, peaking at eight and 15 Hz respectively, over prefrontal, and left centro-parietal electrodes. Paralleling our previous findings in sleep, there was no significant difference between meditation styles in LTM as well as no difference between matched sessions in MNP. Meditation-related changes in wakefulness and NREM sleep were correlated across space and frequency. A significant correlation was found in the EEG low frequencies (<12 Hz). Since the peak of coupling was observed in the theta-alpha oscillatory range, sleep homeostatic response to meditation practice is not sufficient to explain our findings. Another likely phenomenon into play is a reverberation of meditation-related processes during subsequent sleep. Future studies should ascertain the interplay between these processes in promoting the beneficial effects of meditation practice.

Metabolomic analysis of mouse prefrontal cortex reveals upregulated analytes during wakefulness compared to sleep.

By identifying endogenous molecules in brain extracellular fluid metabolomics can provide insight into the regulatory mechanisms and functions of sleep. Here we studied how the cortical metabolome changes during sleep, sleep deprivation and spontaneous wakefulness. Mice were implanted with electrodes for chronic sleep/wake recording and with microdialysis probes targeting prefrontal and primary motor cortex. Metabolites were measured using ultra performance liquid chromatography-high resolution mass spectrometry. Sleep/wake changes in metabolites were evaluated using partial least squares discriminant analysis, linear mixed effects model analysis of variance, and machine-learning algorithms. More than 30 known metabolites were reliably detected in most samples. When used by a logistic regression classifier, the profile of these metabolites across sleep, spontaneous wake, and enforced wake was sufficient to assign mice to their correct experimental group (pair-wise) in 80-100% of cases. Eleven of these metabolites showed significantly higher levels in awake than in sleeping mice. Some changes extend previous findings (glutamate, homovanillic acid, lactate, pyruvate, tryptophan, uridine), while others are novel (D-gluconate, N-acetyl-beta-alanine, N-acetylglutamine, orotate, succinate/methylmalonate). The upregulation of the de novo pyrimidine pathway, gluconate shunt and aerobic glycolysis may reflect a wake-dependent need to promote the synthesis of many essential components, from nucleic acids to synaptic membranes.

Reduced sleep spindle activity point to a TRN-MD thalamus-PFC circuit dysfunction in schizophrenia.

Sleep disturbances have been reliably reported in patients with schizophrenia, thus suggesting that abnormal sleep may represent a core feature of this disorder. Traditional electroencephalographic studies investigating sleep architecture have found reduced deep non-rapid eye movement (NREM) sleep, or slow wave sleep (SWS), and increased REM density. However, these findings have been inconsistently observed, and have not survived meta-analysis. By contrast, several recent EEG studies exploring brain activity during sleep have established marked deficits in sleep spindles in schizophrenia, including first-episode and early-onset patients, compared to both healthy and psychiatric comparison subjects. Spindles are waxing and waning, 12-16Hz NREM sleep oscillations that are generated within the thalamus by the thalamic reticular nucleus (TRN), and are then synchronized and sustained in the cortex. While the functional role of sleep spindles still needs to be fully established, increasing evidence has shown that sleep spindles are implicated in learning and memory, including sleep dependent memory consolidation, and spindle parameters have been associated to general cognitive ability and IQ. In this article we will review the EEG studies demonstrating sleep spindle deficits in patients with schizophrenia, and show that spindle deficits can predict their reduced cognitive performance. We will then present data indicating that spindle impairments point to a TRN-MD thalamus-prefrontal cortex circuit deficit, and discuss about the possible molecular mechanisms underlying thalamo-cortical sleep spindle abnormalities in schizophrenia.

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.

Responses in Rat Core Auditory Cortex are Preserved during Sleep Spindle Oscillations.

STUDY OBJECTIVES: Sleep is defined as a reversible state of reduction in sensory responsiveness and immobility. A long-standing hypothesis suggests that a high arousal threshold during non-rapid eye movement (NREM) sleep is mediated by sleep spindle oscillations, impairing thalamocortical transmission of incoming sensory stimuli. Here we set out to test this idea directly by examining sensory-evoked neuronal spiking activity during natural sleep. METHODS: We compared neuronal (n = 269) and multiunit activity (MUA), as well as local field potentials (LFP) in rat core auditory cortex (A1) during NREM sleep, comparing responses to sounds depending on the presence or absence of sleep spindles. RESULTS: We found that sleep spindles robustly modulated the timing of neuronal discharges in A1. However, responses to sounds were nearly identical for all measured signals including isolated neurons, MUA, and LFPs (all differences < 10%). Furthermore, in 10% of trials, auditory stimulation led to an early termination of the sleep spindle oscillation around 150-250 msec following stimulus onset. Finally, active ON states and inactive OFF periods during slow waves in NREM sleep affected the auditory response in opposite ways, depending on stimulus intensity. CONCLUSIONS: Responses in core auditory cortex are well preserved regardless of sleep spindles recorded in that area, suggesting that thalamocortical sensory relay remains functional during sleep spindles, and that sensory disconnection in sleep is mediated by other mechanisms.

Synaptic refinement during development and its effect on slow-wave activity: a computational study.

Recent evidence suggests that synaptic refinement, the reorganization of synapses and connections without significant change in their number or strength, is important for the development of the visual system of juvenile rodents. Other evidence in rodents and humans shows that there is a marked drop in sleep slow-wave activity (SWA) during adolescence. Slow waves reflect synchronous transitions of neuronal populations between active and inactive states, and the amount of SWA is influenced by the connection strength and organization of cortical neurons. In this study, we investigated whether synaptic refinement could account for the observed developmental drop in SWA. To this end, we employed a large-scale neural model of primary visual cortex and sections of the thalamus, capable of producing realistic slow waves. In this model, we reorganized intralaminar connections according to experimental data on synaptic refinement: during prerefinement, local connections between neurons were homogenous, whereas in postrefinement, neurons connected preferentially to neurons with similar receptive fields and preferred orientations. Synaptic refinement led to a drop in SWA and to changes in slow-wave morphology, consistent with experimental data. To test whether learning can induce synaptic refinement, intralaminar connections were equipped with spike timing-dependent plasticity. Oriented stimuli were presented during a learning period, followed by homeostatic synaptic renormalization. This led to activity-dependent refinement accompanied again by a decline in SWA. Together, these modeling results show that synaptic refinement can account for developmental changes in SWA. Thus sleep SWA may be used to track noninvasively the reorganization of cortical connections during development.

Short Meditation Trainings Enhance Non-REM Sleep Low-Frequency Oscillations.

STUDY OBJECTIVES: We have recently shown higher parietal-occipital EEG gamma activity during sleep in long-term meditators compared to meditation-naive individuals. This gamma increase was specific for NREM sleep, was present throughout the entire night and correlated with meditation expertise, thus suggesting underlying long-lasting neuroplastic changes induced through prolonged training. The aim of this study was to explore the neuroplastic changes acutely induced by 2 intensive days of different meditation practices in the same group of practitioners. We also repeated baseline recordings in a meditation-naive cohort to account for time effects on sleep EEG activity. DESIGN: High-density EEG recordings of human brain activity were acquired over the course of whole sleep nights following intervention. SETTING: Sound-attenuated sleep research room. PATIENTS OR PARTICIPANTS: Twenty-four long-term meditators and twenty-four meditation-naïve controls. INTERVENTIONS: Two 8-h sessions of either a mindfulness-based meditation or a form of meditation designed to cultivate compassion and loving kindness, hereafter referred to as compassion meditation. MEASUREMENTS AND RESULTS: We found an increase in EEG low-frequency oscillatory activities (1-12 Hz, centered around 7-8 Hz) over prefrontal and left parietal electrodes across whole night NREM cycles. This power increase peaked early in the night and extended during the third cycle to high-frequencies up to the gamma range (25-40 Hz). There was no difference in sleep EEG activity between meditation styles in long-term meditators nor in the meditation naïve group across different time points. Furthermore, the prefrontal-parietal changes were dependent on meditation life experience. CONCLUSIONS: This low-frequency prefrontal-parietal activation likely reflects acute, meditation-related plastic changes occurring during wakefulness, and may underlie a top-down regulation from frontal and anterior parietal areas to the posterior parietal and occipital regions showing chronic, long-lasting plastic changes in long-term meditators.

Phase-locked loop for precisely timed acoustic stimulation during sleep.

BACKGROUND: A brain-computer interface could potentially enhance the various benefits of sleep. NEW METHOD: We describe a strategy for enhancing slow-wave sleep (SWS) by stimulating the sleeping brain with periodic acoustic stimuli that produce resonance in the form of enhanced slow-wave activity in the electroencephalogram (EEG). The system delivers each acoustic stimulus at a particular phase of an electrophysiological rhythm using a phase-locked loop (PLL). RESULTS: The PLL is computationally economical and well suited to follow and predict the temporal behavior of the EEG during slow-wave sleep. COMPARISON WITH EXISTING METHODS: Acoustic stimulation methods may be able to enhance SWS without the risks inherent in electrical stimulation or pharmacological methods. The PLL method differs from other acoustic stimulation methods that are based on detecting a single slow wave rather than modeling slow-wave activity over an extended period of time. CONCLUSIONS: By providing real-time estimates of the phase of ongoing EEG oscillations, the PLL can rapidly adjust to physiological changes, thus opening up new possibilities to study brain dynamics during sleep. Future application of these methods hold promise for enhancing sleep quality and associated daytime behavior and improving physiologic function.

Auditory responses and stimulus-specific adaptation in rat auditory cortex are preserved across NREM and REM sleep.

Sleep entails a disconnection from the external environment. By and large, sensory stimuli do not trigger behavioral responses and are not consciously perceived as they usually are in wakefulness. Traditionally, sleep disconnection was ascribed to a thalamic "gate," which would prevent signal propagation along ascending sensory pathways to primary cortical areas. Here, we compared single-unit and LFP responses in core auditory cortex as freely moving rats spontaneously switched between wakefulness and sleep states. Despite robust differences in baseline neuronal activity, both the selectivity and the magnitude of auditory-evoked responses were comparable across wakefulness, Nonrapid eye movement (NREM) and rapid eye movement (REM) sleep (pairwise differences <8% between states). The processing of deviant tones was also compared in sleep and wakefulness using an oddball paradigm. Robust stimulus-specific adaptation (SSA) was observed following the onset of repetitive tones, and the strength of SSA effects (13-20%) was comparable across vigilance states. Thus, responses in core auditory cortex are preserved across sleep states, suggesting that evoked activity in primary sensory cortices is driven by external physical stimuli with little modulation by vigilance state. We suggest that sensory disconnection during sleep occurs at a stage later than primary sensory areas.

Reversal of cortical information flow during visual imagery as compared to visual perception.

The role of bottom-up and top-down connections during visual perception and the formation of mental images was examined by analyzing high-density EEG recordings of brain activity using two state-of-the-art methods for assessing the directionality of cortical signal flow: state-space Granger causality and dynamic causal modeling. We quantified the directionality of signal flow in an occipito-parieto-frontal cortical network during perception of movie clips versus mental replay of the movies and free visual imagery. Both Granger causality and dynamic causal modeling analyses revealed an increased top-down signal flow in parieto-occipital cortices during mental imagery as compared to visual perception. These results are the first direct demonstration of a reversal of the predominant direction of cortical signal flow during mental imagery as compared to perception.

Experienced mindfulness meditators exhibit higher parietal-occipital EEG gamma activity during NREM sleep.

Over the past several years meditation practice has gained increasing attention as a non-pharmacological intervention to provide health related benefits, from promoting general wellness to alleviating the symptoms of a variety of medical conditions. However, the effects of meditation training on brain activity still need to be fully characterized. Sleep provides a unique approach to explore the meditation-related plastic changes in brain function. In this study we performed sleep high-density electroencephalographic (hdEEG) recordings in long-term meditators (LTM) of Buddhist meditation practices (approximately 8700 mean hours of life practice) and meditation naive individuals. We found that LTM had increased parietal-occipital EEG gamma power during NREM sleep. This increase was specific for the gamma range (25-40 Hz), was not related to the level of spontaneous arousal during NREM and was positively correlated with the length of lifetime daily meditation practice. Altogether, these findings indicate that meditation practice produces measurable changes in spontaneous brain activity, and suggest that EEG gamma activity during sleep represents a sensitive measure of the long-lasting, plastic effects of meditative training on brain function.

Conserved functional connectivity but impaired effective connectivity of thalamocortical circuitry in schizophrenia.

Schizophrenia is a severe mental illness with neurobiological bases that remain elusive. One hypothesis emphasizes disordered thalamic function. We previously used concurrent single pulse transcranial magnetic stimulation (spTMS) and functional magnetic resonance imaging (fMRI) to show that individuals with schizophrenia have a decreased spTMS-evoked response in the thalamus, and decreased effective connectivity between thalamus and insula and thalamus and superior frontal gyrus. To better understand the factors that may accompany or account for these findings, we investigated, in the same participants, resting state functional connectivity, white matter structural connectivity, and grey matter integrity. Patients with schizophrenia did not differ from healthy control subjects in resting state functional- or white matter structural connectivity, although they did show decreased measures of grey matter integrity in the insula. However, in this region, the spTMS-evoked response did not differ between groups. In a region of the thalamus that also had grey matter intensity abnormalities, although not at a level that survived correction for multiple comparisons, the spTMS-evoked response in patients was deficient. These results suggest that measures of structure and function are not necessarily complementary. Further, given its sensitivity for identifying deficits not evident with traditional imaging methods, these results highlight the utility of spTMS-fMRI, a method that directly and causally probes effective connectivity, as a tool for studying brain-based disorders.

Connectivity changes underlying spectral EEG changes during propofol-induced loss of consciousness.

The mechanisms underlying anesthesia-induced loss of consciousness remain a matter of debate. Recent electrophysiological reports suggest that while initial propofol infusion provokes an increase in fast rhythms (from beta to gamma range), slow activity (from delta to alpha range) rises selectively during loss of consciousness. Dynamic causal modeling was used to investigate the neural mechanisms mediating these changes in spectral power in humans. We analyzed source-reconstructed data from frontal and parietal cortices during normal wakefulness, propofol-induced mild sedation, and loss of consciousness. Bayesian model selection revealed that the best model for explaining spectral changes across the three states involved changes in corticothalamic interactions. Compared with wakefulness, mild sedation was accounted for by an increase in thalamic excitability, which did not further increase during loss of consciousness. In contrast, loss of consciousness per se was accompanied by a decrease in backward corticocortical connectivity from frontal to parietal cortices, while thalamocortical connectivity remained unchanged. These results emphasize the importance of recurrent corticocortical communication in the maintenance of consciousness and suggest a direct effect of propofol on cortical dynamics.

Reduced natural oscillatory frequency of frontal thalamocortical circuits in schizophrenia.

CONTEXT: Converging evidence from electrophysiological studies suggests that in individuals with schizophrenia, electroencephalographic frontal fast oscillations are reduced. It is still unclear whether this reduction reflects an intrinsic deficit of underlying cortical/thalamocortical circuits and whether this deficit is specific for frontal regions. Recent electrophysiological studies in healthy individuals have established that, when perturbed, different brain regions oscillate at a specific, intrinsically generated dominant frequency, the natural frequency. OBJECTIVE: To assess the natural frequency of the posterior parietal, motor, premotor, and prefrontal cortices in patients with schizophrenia and healthy control subjects. DESIGN: High-density electroencephalographic recordings during transcranial magnetic stimulation of 4 cortical areas were performed. Several transcranial magnetic stimulation­evoked electroencephalographic oscillation parameters, including synchronization, amplitude, and natural frequency, were compared across the schizophrenia and healthy control groups. SETTING: Wisconsin Psychiatric Institute and Clinic, University of Wisconsin­Madison. PARTICIPANTS: Twenty patients with schizophrenia and 20 age-matched healthy control subjects. MAIN OUTCOME MEASURES: High-density electroencephalographic measurements of transcranial magnetic stimulation­evoked activity in 4 cortical areas, scores on the Positive and Negative Syndrome Scale, and performance scores (reaction time, accuracy) on 2 computerized tasks (word memory [Penn Word Recognition Test] and facial memory [Penn Facial Memory Test]). RESULTS: Patients with schizophrenia showed a slowing in the natural frequency of the frontal/prefrontal regions compared with healthy control subjects (from an average of a 2-Hz decrease for the motor area to an almost 10-Hz decrease for the prefrontal cortex). The prefrontal natural frequency of individuals with schizophrenia was slower than in any healthy comparison subject and correlated with both positive Positive and Negative Syndrome Scale scores and reaction time on the Penn Word Recognition Test. CONCLUSIONS: These findings suggest that patients with schizophrenia have an intrinsic slowing in the natural frequency of frontal cortical/thalamocortical circuits, that this slowing is not present in parietal areas, and that the prefrontal natural frequency can predict some of the symptoms as well as the cognitive dysfunctions of schizophrenia.

Probing thalamic integrity in schizophrenia using concurrent transcranial magnetic stimulation and functional magnetic resonance imaging.

CONTEXT: Schizophrenia is a devastating illness with an indeterminate pathophysiology. Several lines of evidence implicate dysfunction in the thalamus, a key node in the distributed neural networks underlying perception, emotion, and cognition. Existing evidence of aberrant thalamic function is based on indirect measures of thalamic activity, but dysfunction has not yet been demonstrated with a causal method. OBJECTIVE: To test the hypothesis that direct physiological stimulation of the cortex will produce an abnormal thalamic response in individuals with schizophrenia. DESIGN: We stimulated the precentral gyrus with single-pulse transcranial magnetic stimulation (spTMS) and measured the response to this pulse in synaptically connected regions (thalamus, medial superior frontal cortex, insula) using concurrent functional magnetic resonance imaging. The mean hemodynamic response from these regions was fit with the sum of 2 gamma functions, and response parameters were compared across groups. SETTING: Academic research laboratory. PARTICIPANTS: Patients with schizophrenia and sex- and age-matched psychiatrically healthy subjects were recruited from the community. MAIN OUTCOME MEASURE: Peak amplitude of the thalamic hemodynamic response to spTMS of the precentral gyrus. RESULTS: The spTMS-evoked responses did not differ between groups at the cortical stimulation site. Compared with healthy subjects, patients with schizophrenia showed a reduced response to spTMS in the thalamus (P=1.86 × 10(-9)) and medial superior frontal cortex (P=.02). Similar results were observed in the insula. Sham TMS indicated that these results could not be attributed to indirect effects of TMS coil discharge. Functional connectivity analyses revealed weaker thalamus-medial superior frontal cortex and thalamus-insula connectivity in patients with schizophrenia compared with control subjects. CONCLUSIONS: Individuals with schizophrenia showed reduced thalamic activation in response to direct perturbation delivered to the cortex. These results extend prior work implicating the thalamus in the pathophysiology of schizophrenia and suggest that the thalamus contributes to the patterns of aberrant connectivity characteristic of this disease.

A postsleep decline in auditory evoked potential amplitude reflects sleep homeostasis.

OBJECTIVE: It has been hypothesized that slow wave activity, a well established measure of sleep homeostasis that increases after waking and decreases after sleep, may reflect changes in cortical synaptic strength. If so, the amplitude of sensory evoked responses should also vary as a function of time awake and asleep in a way that reflects sleep homeostasis. METHODS: Using 256-channel, high-density electroencephalography (EEG) in 12 subjects, auditory evoked potentials (AEP) and spontaneous waking data were collected during wakefulness before and after sleep. RESULTS: The amplitudes of the N1 and P2 waves of the AEP were reduced after a night of sleep. In addition, the decline in N1 amplitude correlated with low-frequency EEG power during non-rapid eye movement sleep and spontaneous wakefulness, both homeostatically regulated measures of sleep need. CONCLUSIONS: The decline in AEP amplitude after a night of sleep may reflect a homeostatic reduction in synaptic strength. SIGNIFICANCE: These findings provide further evidence for a connection between synaptic plasticity and sleep homeostasis.