Brady A. Riedner

Arm immobilization causes cortical plastic changes and locally decreases sleep slow wave activity

Sleep slow wave activity (SWA) is thought to reflect sleep need, increasing after wakefulness and decreasing after sleep. We showed recently that a learning task involving a circumscribed brain region produces a local increase in sleep SWA. We hypothesized that increases in cortical SWA reflect synaptic potentiation triggered by learning. To further investigate the link between synaptic plasticity and sleep, we asked whether a procedure leading to synaptic depression would cause instead a decrease in sleep SWA. We show here that if a subjects arm is immobilized during the day, motor performance deteriorates and both somatosensory and motor evoked potentials decrease over contralateral sensorimotor cortex, indicative of local synaptic depression. Notably, during subsequent sleep, SWA over the same cortical area is markedly reduced. Thus, cortical plasticity is linked to local sleep regulation without learning in the classical sense. Moreover, when synaptic strength is reduced, local sleep need is also reduced.

Breakdown in cortical effective connectivity during midazolam-induced loss of consciousness

By employing transcranial magnetic stimulation (TMS) in combination with high-density electroencephalography (EEG), we recently reported that cortical effective connectivity is disrupted during early non-rapid eye movement (NREM) sleep. This is a time when subjects, if awakened, may report little or no conscious content. We hypothesized that a similar breakdown of cortical effective connectivity may underlie loss of consciousness (LOC) induced by pharmacologic agents. Here, we tested this hypothesis by comparing EEG responses to TMS during wakefulness and LOC induced by the benzodiazepine midazolam. Unlike spontaneous sleep states, a subject’s level of vigilance can be monitored repeatedly during pharmacological LOC. We found that, unlike during wakefulness, wherein TMS triggered responses in multiple cortical areas lasting for >300 ms, during midazolam-induced LOC, TMS-evoked activity was local and of shorter duration. Furthermore, a measure of the propagation of evoked cortical currents (significant current scattering, SCS) could reliably discriminate between consciousness and LOC. These results resemble those observed in early NREM sleep and suggest that a breakdown of cortical effective connectivity may be a common feature of conditions characterized by LOC. Moreover, these results suggest that it might be possible to use TMS-EEG to assess consciousness during anesthesia and in pathological conditions, such as coma, vegetative state, and minimally conscious state.

Reduced Sleep Spindle Activity in Schizophrenia Patients

OBJECTIVE High-density EEG during sleep represents a powerful new tool to reveal potential abnormalities in rhythm-generating mechanisms while avoiding confounding factors associated with waking activities. As a first step in this direction, the authors employed high-density EEG to explore whether sleep rhythms differ between schizophrenia subjects, healthy individuals, and a psychiatric control group with a history of depression. METHOD Healthy comparison subjects (N=17), medicated schizophrenia patients (N=18), and subjects with a history of depression (N=15) were recruited. Subjects were recorded during the first sleep episode of the night with a 256-electrode high-density EEG. Recordings were analyzed for changes in EEG power spectra, power topography, and sleep-specific cortical oscillations. RESULTS The authors found that the schizophrenia group had a significant reduction in centroparietal EEG power, from 13.75 to 15.00 Hz, in relation to both the comparison and depression groups. No significant difference in EEG power between the comparison and depression groups was identified. The authors also found a decrease in sleep spindle number, amplitude, duration, and integrated spindle activity in schizophrenia patients. Furthermore, integrated spindle activity had an effect size corresponding to 93.0% or 90.2% separation of the schizophrenia from the comparison or depression group. CONCLUSIONS Sleep spindles are generated by the thalamic reticular nucleus in conjunction with specific thalamic nuclei and are modulated by corticothalamic and thalamocortical connections. The deficit in sleep spindles in schizophrenia subjects may reflect dysfunction in thalamic-reticular and thalamocortical mechanisms and could represent a biological marker of illness.

Triggering sleep slow waves by transcranial magnetic stimulation

During much of sleep, cortical neurons undergo near-synchronous slow oscillation cycles in membrane potential, which give rise to the largest spontaneous waves observed in the normal electroencephalogram (EEG). Slow oscillations underlie characteristic features of the sleep EEG, such as slow waves and spindles. Here we show that, in sleeping subjects, slow waves and spindles can be triggered noninvasively and reliably by transcranial magnetic stimulation (TMS). With appropriate stimulation parameters, each TMS pulse at <1 Hz evokes an individual, high-amplitude slow wave that originates under the coil and spreads over the cortex. TMS triggering of slow waves reveals intrinsic bistability in thalamocortical networks during non-rapid eye movement sleep. Moreover, evoked slow waves lead to a deepening of sleep and to an increase in EEG slow-wave activity (0.5–4.5 Hz), which is thought to play a role in brain restoration and memory consolidation.

Source modeling sleep slow waves

Slow waves are the most prominent electroencephalographic (EEG) feature of sleep. These waves arise from the synchronization of slow oscillations in the membrane potentials of millions of neurons. Scalp-level studies have indicated that slow waves are not instantaneous events, but rather they travel across the brain. Previous studies of EEG slow waves were limited by the poor spatial resolution of EEGs and by the difficulty of relating scalp potentials to the activity of the underlying cortex. Here we use high-density EEG (hd-EEG) source modeling to show that individual spontaneous slow waves have distinct cortical origins, propagate uniquely across the cortex, and involve unique subsets of cortical structures. However, when the waves are examined en masse, we find that there are diffuse hot spots of slow wave origins centered on the lateral sulci. Furthermore, slow wave propagation along the anterior−posterior axis of the brain is largely mediated by a cingulate highway. As a group, slow waves are associated with large currents in the medial frontal gyrus, the middle frontal gyrus, the inferior frontal gyrus, the anterior cingulate, the precuneus, and the posterior cingulate. These areas overlap with the major connectional backbone of the cortex and with many parts of the default network.

Thalamic dysfunction in schizophrenia suggested by whole-night deficits in slow and fast spindles

OBJECTIVE Slow waves and sleep spindles are the two main oscillations occurring during non-REM sleep. While slow oscillations are primarily generated and modulated by the cortex, sleep spindles are initiated by the thalamic reticular nucleus and regulated by thalamo-reticular and thalamo-cortical circuits. In a recent high-density EEG study, the authors found that 18 medicated schizophrenia patients had reduced sleep spindles, compared with healthy and depressed subjects, during the first non-REM episode. In the present study, the authors investigated whether spindle deficits were present in a larger sample of schizophrenia patients, were consistent across the night, were related to antipsychotic medications, and were suggestive of impairments in specific neuronal circuits. METHOD Whole-night high-density EEG recordings were performed in 49 schizophrenia patients, 20 nonschizophrenia patients receiving antipsychotic medication, and 44 healthy subjects. In addition to sleep spindles, several parameters of slow waves were assessed. RESULTS Schizophrenia patients had whole-night deficits in spindle power (12-16 Hz) and in slow (12-14 Hz) and fast (14-16 Hz) spindle amplitude, duration, number, and integrated activity in the prefrontal, centroparietal, and temporal regions. Integrated spindle activity and spindle number had the largest effect sizes (effect size: ≥ 2.21). In contrast, no slow wave deficits were found in schizophrenia patients. CONCLUSIONS These results indicate that spindle deficits can be reliably established in schizophrenia, are stable across the night, are unlikely to be due to antipsychotic medications, and point to deficits in the thalamic reticular nucleus and thalamo-reticular circuits.

Reduced evoked gamma oscillations in the frontal cortex in schizophrenia patients: a TMS/EEG study.

OBJECTIVE Transcranial magnetic stimulation (TMS) combined with high-density electroencephalography (EEG) can be used to directly examine the properties of thalamocortical circuits in the brain without engaging an individual in cognitive or motor tasks. The authors investigated EEG responses in schizophrenia patients and healthy comparison subjects following the application of TMS to the premotor cortex. METHOD Sixteen schizophrenia patients and 14 healthy comparison subjects were recruited to participate in the study. Participants underwent three to five TMS/high-density EEG sessions at various TMS doses. The following three aspects of TMS-evoked responses were analyzed: amplitude, synchronization, and source localization. RESULTS Relative to healthy comparison subjects, schizophrenia patients had a marked decrease in evoked gamma oscillations that occurred within the first 100 msec after TMS, particularly in a cluster of electrodes located in a fronto-central region. These oscillations were significantly reduced in amplitude (calculated using global-mean field power and event-related spectral perturbation analysis) and synchronization (measured using intertrial coherence). Furthermore, source modeling analysis revealed that the TMS-evoked brain activation underlying these gamma oscillations in patients with schizophrenia did not propagate (as it did in healthy comparison subjects) and was mostly confined to the stimulated brain region. CONCLUSIONS Schizophrenia patients showed a decrease in EEG-evoked responses in the gamma band when TMS was applied to directly stimulate the frontal cortex while these responses were recorded. Since EEG responses to direct cortical stimulation are not affected by an individuals motivation, attention, or cognitive capacity and are not relayed through peripheral afferent pathways, these findings suggest that there might be an intrinsic dysfunction in frontal thalamocortical circuits in individuals with schizophrenia.

Cortical reactivity and effective connectivity during REM sleep in humans.

We recorded the electroencephalographic (EEG) responses evoked by transcranial magnetic stimulation (TMS) during the first rapid eye movement (REM) sleep episode of the night and compared them with the responses obtained during previous wakefulness and non-REM (NREM) sleep. Confirming previous findings, upon falling into NREM sleep, cortical activations became more local and stereotypical, indicating a significant impairment of the intracortical dialogue. During REM sleep, a state in which subjects regain consciousness but are almost paralyzed, TMS triggered more widespread and differentiated patterns of cortical activation that were similar to the ones observed in wakefulness. Similarly, TMS/high-density EEG may be used to probe the internal dialogue of the thalamocortical system in brain-injured patients that are unable to move and communicate.

Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder

The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant major depressive disorder (MDD). In rats, ketamine selectively increased electroencephalogram (EEG) slow wave activity (SWA) during non-rapid eye movement (REM) sleep and altered central brain-derived neurotrophic factor (BDNF) expression. Taken together, these findings suggest that higher SWA and BDNF levels may respectively represent electrophysiological and molecular correlates of mood improvement following ketamine treatment. This study investigated the acute effects of a single ketamine infusion on depressive symptoms, EEG SWA, individual slow wave parameters (surrogate markers of central synaptic plasticity) and plasma BDNF (a peripheral marker of plasticity) in 30 patients with treatment-resistant MDD. Montgomery-Åsberg Depression Rating Scale scores rapidly decreased following ketamine. Compared to baseline, BDNF levels and early sleep SWA (during the first non-REM episode) increased after ketamine. The occurrence of high amplitude waves increased during early sleep, accompanied by an increase in slow wave slope, consistent with increased synaptic strength. Changes in BDNF levels were proportional to changes in EEG parameters. Intriguingly, this link was present only in patients who responded to ketamine treatment, suggesting that enhanced synaptic plasticity - as reflected by increased SWA, individual slow wave parameters and plasma BDNF - is part of the physiological mechanism underlying the rapid antidepressant effects of NMDA antagonists. Further studies are required to confirm the link found here between behavioural and synaptic changes, as well as to test the reliability of these central and peripheral biomarkers of rapid antidepressant response.

Electrophysiological correlates of behavioural changes in vigilance in vegetative state and minimally conscious state

The existence of normal sleep in patients in a vegetative state is still a matter of debate. Previous electrophysiological sleep studies in patients with disorders of consciousness did not differentiate patients in a vegetative state from patients in a minimally conscious state. Using high-density electroencephalographic sleep recordings, 11 patients with disorders of consciousness (six in a minimally conscious state, five in a vegetative state) were studied to correlate the electrophysiological changes associated with sleep to behavioural changes in vigilance (sustained eye closure and muscle inactivity). All minimally conscious patients showed clear electroencephalographic changes associated with decreases in behavioural vigilance. In the five minimally conscious patients showing sustained behavioural sleep periods, we identified several electrophysiological characteristics typical of normal sleep. In particular, all minimally conscious patients showed an alternating non-rapid eye movement/rapid eye movement sleep pattern and a homoeostatic decline of electroencephalographic slow wave activity through the night. In contrast, for most patients in a vegetative state, while preserved behavioural sleep was observed, the electroencephalographic patterns remained virtually unchanged during periods with the eyes closed compared to periods of behavioural wakefulness (eyes open and muscle activity). No slow wave sleep or rapid eye movement sleep stages could be identified and no homoeostatic regulation of sleep-related slow wave activity was observed over the night-time period. In conclusion, we observed behavioural, but no electrophysiological, sleep wake patterns in patients in a vegetative state, while there were near-to-normal patterns of sleep in patients in a minimally conscious state. These results shed light on the relationship between sleep electrophysiology and the level of consciousness in severely brain-damaged patients. We suggest that the study of sleep and homoeostatic regulation of slow wave activity may provide a complementary tool for the assessment of brain function in minimally conscious state and vegetative state patients.