Cortical Tonic Inhibition Gates the Expression of Spike-and-Wave Discharges Associated with Absence Epilepsy.

OBJECTIVE: Absence seizures result from aberrant thalamocortical processing that confers synchronous, bilateral spike-and-wave discharges (SWDs) and behavioral arrest. Previous work has demonstrated that SWDs can result from enhanced thalamic tonic inhibition, consistent with the mechanism of first-line antiabsence drugs that target thalamic low-voltage-activated calcium channels. However, nearly half of patients with absence epilepsy are unresponsive to first-line medications. In this study we evaluated the role of cortical tonic inhibition and its manipulation on absence seizure expression. METHODS: We used video-electroencephalogram (EEG) monitoring to show that mice with a γ-aminobutyric acid type A (GABAA) receptor mutation (γ2R43Q) display absence seizures. Voltage-clamp recordings in brain slices from wild type and γ2R43Q mice were used to evaluate the amount of tonic inhibition and its selective pharmacological modulation. Finally, we determined whether modulating tonic inhibition controls seizure expression. RESULTS: γ2R43Q mice completely lack tonic inhibition in principal neurons of both layer 2/3 cortex and ventrobasal thalamus. Blocking cortical tonic inhibition in wild type mice is sufficient to elicit SWDs. Tonic inhibition in slices from γ2R43Q mice could be rescued in a dose-dependent fashion by the synthetic neurosteroid ganaxolone. Low-dose ganaxolone suppressed seizures in γ2R43Q mice. CONCLUSIONS: Our data suggest that reduced cortical tonic inhibition promotes absence seizures and that normal function can be restored via selective pharmacological rescue. These results, together with previous findings, suggest that deviations of tonic inhibition either above or below an optimal set point can contribute to absence epilepsy. Returning the thalamocortical system to this set point may provide a novel treatment for refractory absence epilepsy.

Aging Does Not Affect Beta Modulation during Reaching Movements.

During movement, modulation of beta power occurs over the sensorimotor areas, with a decrease just before its start (event-related desynchronization, ERD) and a rebound after its end (event-related synchronization, ERS). We have recently found that the depth of ERD-to-ERS modulation increases during practice in a reaching task and the following day decreases to baseline levels. Importantly, the magnitude of the beta modulation increase during practice is highly correlated with the retention of motor skill tested the following day. Together with other evidence, this suggests that the increase of practice-related modulation depth may be the expression of sensorimotor cortex's plasticity. Here, we determine whether the practice-related increase of beta modulation depth is equally present in a group of younger and a group of older subjects during the performance of a 30-minute block of reaching movements. We focused our analyses on two regions of interest (ROIs): the left sensorimotor and the frontal region. Performance indices were significantly different in the two groups, with the movements of older subjects being slower and less accurate. Importantly, both groups presented a similar increase of the practice-related beta modulation depth in both ROIs in the course of the task. Peak latency analysis revealed a progressive delay of the ERS peak that correlated with the total movement time. Altogether, these findings support the notion that the depth of beta modulation in a reaching movement task does not depend on age and confirm previous findings that only ERS peak latency but not ERS magnitude is related to performance indices.

Extended Visual Sequence Learning Leaves a Local Trace in the Spontaneous EEG.

We have previously demonstrated that, in rested subjects, extensive practice in a motor learning task increased both electroencephalographic (EEG) theta power in the areas involved in learning and improved the error rate in a motor test that shared similarities with the task. A nap normalized both EEG and performance changes. We now ascertain whether extensive visual declarative learning produces results similar to motor learning. Thus, during the morning, we recorded high-density EEG in well rested young healthy subjects that learned the order of different visual sequence task (VSEQ) for three one-hour blocks. Afterward, a group of subjects took a nap and another rested quietly. Between each VSEQ block, we recorded spontaneous EEG (sEEG) at rest and assessed performance in a motor test and a visual working memory test that shares similarities with VSEQ. We found that after the third block, VSEQ induced local theta power increases in the sEEG over a right temporo-parietal area that was engaged during the task. This local theta increase was preceded by increases in alpha and beta power over the same area and was paralleled by performance decline in the visual working memory test. Only after the nap, VSEQ learning rate improved and performance in the visual working memory test was restored, together with partial normalization of the local sEEG changes. These results suggest that intensive learning, like motor learning, produces local theta power increases, possibly reflecting local neuronal fatigue. Sleep may be necessary to resolve neuronal fatigue and its effects on learning and performance.

Neural fatigue due to intensive learning is reversed by a nap but not by quiet waking.

Do brain circuits become fatigued due to intensive neural activity or plasticity? Is sleep necessary for recovery? Well-rested subjects trained extensively in a visuo-motor rotation learning task (ROT) or a visuo-motor task without rotation learning (MOT), followed by sleep or quiet wake. High-density electroencephalography showed that ROT training led to broad increases in EEG power over a frontal cluster of electrodes, with peaks in the theta (mean ± SE: 24% ± 6%, p = 0.0013) and beta ranges (10% ± 3%, p = 0.01). These traces persisted in the spontaneous EEG (sEEG) between sessions (theta: 42% ± 8%, p = 0.0001; beta: 35% ± 7%, p = 0.002) and were accompanied by increased errors in a motor test with kinematic characteristics and neural substrates similar to ROT (81.8% ± 0.8% vs. 68.2% ± 2.3%; two-tailed paired t-test: p = 0.00001; Cohen's d = 1.58), as well as by score increases of subjective task-specific fatigue (4.00 ± 0.39 vs. 5.36 ± 0.39; p = 0.0007; Cohen's d = 0.60). Intensive practice with MOT did not affect theta sEEG or the motor test. A nap, but not quiet wake, induced a local sEEG decrease of theta power by 33% (SE: 8%, p = 0.02), renormalized test performance (70.9% ± 2.9% vs 79.1% ± 2.7%, p = 0.018, Cohen's d = 0.85), and improved learning ability in ROT (adaptation rate: 71.2 ± 1.2 vs. 73.4 ± 0.9, p = 0.024; Cohen's d = 0.60). Thus, sleep is necessary to restore plasticity-induced fatigue and performance.

Effects of anesthesia on the response to sleep deprivation.

STUDY OBJECTIVE: Slow wave activity (SWA) during NREM sleep is the best characterized marker of sleep homeostasis, and the occurrence of sleep slow waves is necessary to reduce sleep need. Recent evidence suggests that sleep slow waves may mediate several beneficial effects of sleep on performance, from the prevention of cognitive impairments to memory consolidation. However, slow waves are also triggered by low doses of many anesthetics, but very few reports have examined whether anesthesia-mediated slow waves affect the homeostatic regulation of sleep. Moreover, no study has examined how sleep is affected by higher doses of anesthetics, which lead to a predominantly "isoelectric" EEG tracing without slow waves. DESIGN: We studied in rats whether 1 hour of a dose of isoflurane or desflurane able to induce almost continuous slow waves (ISO-sw, DES-sw), and of a dose of desflurane resulting in a predominantly isoelectric EEG (DES-iso) reduces the sleep pressure caused by 4 h of sleep deprivation. Anesthesia was compared to a mock condition in which rats were only anesthetized for 2-3 min. SETTING: Basic sleep research laboratory. PATIENTS OR PARTICIPANTS: Male WKY rats (n=31). INTERVENTIONS: Total sleep deprivation by exposure to novel objects starting at light onset, followed by one hour of anesthesia or mock anesthesia. MEASUREMENTS AND RESULTS: One hour of anesthesia (sw or iso) did not affect either sleep duration or the overall sleep pattern. Anesthesia with ISO-sw or DES-sw, both associated with the occurrence of almost continuous slow waves, reduced the SWA rebound expected following 4 h of sleep deprivation. One hour of anesthesia with DES-iso, associated with isoelectric EEG and few slow waves, also reduced the SWA rebound after sleep deprivation, and did so to an extent similar to that observed after DES-sw. However, in contrast to DES-sw, SWA after DES-iso remained chronically lower than in baseline, resulting in reduced slow wave energy (SWE, SWA × time) for at least 2 days. CONCLUSION: The blunted SWA rebound after ISO-sw and DES-sw suggests that anesthesia slow waves may substitute for sleep slow waves. The reduced SWA rebound after DES-iso may reflect a pathological condition that results in a chronic decrease in SWA, or may suggest that anesthesia slow waves are not an absolute requirement to discharge sleep pressure.

Prior Practice Affects Movement-Related Beta Modulation and Quiet Wake Restores It to Baseline.

Beta oscillations (13.5-25 Hz) over the sensorimotor areas are characterized by a power decrease during movement execution (event-related desynchronization, ERD) and a sharp rebound after the movement end (event-related synchronization, ERS). In previous studies, we demonstrated that movement-related beta modulation depth (peak ERS-ERD) during reaching increases within 1-h practice. This increase may represent plasticity processes within the sensorimotor network. If so, beta modulation during a reaching test should be affected by previous learning activity that engages the sensorimotor system but not by learning involving other systems. We thus recorded high-density EEG activity in a group of healthy subjects performing three 45-min blocks of motor adaptation task to a visually rotated display (ROT) and in another performing three blocks of visual sequence-learning (VSEQ). Each block of either ROT or VSEQ was followed by a simple reaching test (mov) without rotation. We found that beta modulation depth increased with practice across mov tests. However, such an increase was greater in the group performing ROT over both the left and frontal areas previously involved in ROT. Importantly, beta modulation values returned to baseline values after a 90-min of either nap or quiet wake. These results show that previous practice leaves a trace in movement-related beta modulation and therefore such increases are cumulative. Furthermore, as sleep is not necessary to bring beta modulation values to baseline, they could reflect local increases of neuronal activity and decrease of energy and supplies.

A causal role for brain-derived neurotrophic factor in the homeostatic regulation of sleep.

Slow-wave activity (SWA), the EEG power between 0.5 and 4 Hz during non-rapid eye movement (NREM) sleep, is one of the best characterized markers of sleep need, because it increases as a function of preceding waking duration and decreases during sleep, but the underlying mechanisms remain unknown. We hypothesized that SWA is high at sleep onset because it reflects the occurrence, during the previous waking period, of widespread synaptic potentiation in cortical and subcortical areas. Consistent with this hypothesis, we recently showed that the more rats explore, the stronger is the cortical expression of BDNF during wakefulness, and the larger is the increase in SWA during the subsequent sleep period. There is compelling evidence that BDNF plays a causal role in synaptic potentiation, and exogenous application of BDNF in vivo is sufficient to induce long-term increases in synaptic strength. We therefore performed cortical unilateral microinjections of BDNF in awake rats and measured SWA during the subsequent sleep period. SWA during NREM sleep was higher in the injected hemisphere relative to the contralateral one. The effect was reversible within 2 h, and did not occur during wakefulness or rapid eye movement sleep. Asymmetries in NREM SWA did not occur after vehicle injections. Furthermore, microinjections, during wakefulness, of a polyclonal anti-BDNF antibody or K252a, an inhibitor of BDNF TrkB receptors, led to a local SWA decrease during the following sleep period. These effects were also reversible and specific for NREM sleep. These results show a causal link between BDNF expression during wakefulness and subsequent sleep regulation.

Beta Modulation Depth Is Not Linked to Movement Features.

Beta power over the sensorimotor areas starts decreasing just before movement execution (event-related desynchronization, ERD) and increases post-movement (event-related synchronization, ERS). In this study, we determined whether the magnitude of beta ERD, ERS and modulation depth are linked to movement characteristics, such as movement length and velocity. Brain activity was recorded with a 256-channels EEG system in 35 healthy subjects performing fast, uncorrected reaching movements to targets located at three distances. We found that the temporal profiles of velocity were bell-shaped and scaled to the appropriate target distance. However, the magnitude of beta ERD, ERS and modulation depth, as well as their timing, did not significantly change and were not related to movement features.

A Case of Psychosis in a Patient with Secondary Adrenal Insufficiency: A Possible Etiological Role of a Hypocortisolemic-induced Increase in Proinflammatory Cytokines.

Adrenal insufficiency is divided into three types based on the etiology of its development. In primary adrenal insufficiency, pathology resides in end-organ failure at the level of the adrenal cortex, while in secondary and tertiary adrenal insufficiency, impairment rests in the pituitary gland and hypothalamus, respectively. Regardless of etiology, adrenal insufficiency results in a hypocortisolemic condition. While the relationship between neuropsychiatric symptoms, especially psychosis, and hypercortisolemia has been extensively documented, the development of hypocortisolemia-induced psychosis is less common. We present a case of secondary adrenal insufficiency caused by a pituitary tumor. During the course of evaluation and treatment, the patient developed a psychotic episode. We will briefly review the condition of adrenal insufficiency and propose how hypocortisolemia can result in psychosis.

Beta Oscillatory Changes and Retention of Motor Skills during Practice in Healthy Subjects and in Patients with Parkinson's Disease.

Recently we found that modulation depth of beta power during movement increases with practice over sensory-motor areas in normal subjects but not in patients with Parkinson's disease (PD). As such changes might reflect use-dependent modifications, we concluded that reduction of beta enhancement in PD represents saturation of cortical plasticity. A few questions remained open: What is the relation between these EEG changes and retention of motor skills? Would a second task exposure restore beta modulation enhancement in PD? Do practice-induced increases of beta modulation occur within each block? We thus recorded EEG in patients with PD and age-matched controls in two consecutive days during a 40-min reaching task divided in fifteen blocks of 56 movements each. The results confirmed that, with practice, beta modulation depth over the contralateral sensory-motor area significantly increased across blocks in controls but not in PD, while performance improved in both groups without significant correlations between behavioral and EEG data. The same changes were seen the following day in both groups. Also, beta modulation increased within each block with similar values in both groups and such increases were partially transferred to the successive block in controls, but not in PD. Retention of performance improvement was present in the controls but not in the patients and correlated with the increase in day 1 modulation depth. Therefore, the lack of practice-related increase beta modulation in PD is likely due to deficient potentiation mechanisms that permit between-block saving of beta power enhancement and trigger mechanisms of memory formation.

Loss of Sleep Affects the Ultrastructure of Pyramidal Neurons in the Adolescent Mouse Frontal Cortex.

STUDY OBJECTIVE: The adolescent brain may be uniquely affected by acute sleep deprivation (ASD) and chronic sleep restriction (CSR), but direct evidence is lacking. We used electron microscopy to examine how ASD and CSR affect pyramidal neurons in the frontal cortex of adolescent mice, focusing on mitochondria, endosomes, and lysosomes that together perform most basic cellular functions, from nutrient intake to prevention of cellular stress. METHODS: Adolescent (1-mo-old) mice slept (S) or were sleep deprived (ASD, with novel objects and running wheels) during the first 6-8 h of the light period, chronically sleep restricted (CSR) for > 4 days (using novel objects, running wheels, social interaction, forced locomotion, caffeinated water), or allowed to recover sleep (RS) for ∼32 h after CSR. Ultrastructural analysis of 350 pyramidal neurons was performed (S = 82; ASD = 86; CSR = 103; RS = 79; 4 to 5 mice/group). RESULTS: Several ultrastructural parameters differed in S versus ASD, S versus CSR, CSR versus RS, and S versus RS, although the different methods used to enforce wake may have contributed to some of the differences between short and long sleep loss. Differences included larger cytoplasmic area occupied by mitochondria in CSR versus S, and higher number of secondary lysosomes in CSR versus S and RS. We also found that sleep loss may unmask interindividual differences not obvious during baseline sleep. Moreover, using a combination of 11 ultrastructural parameters, we could predict in up to 80% of cases whether sleep or wake occurred at the single cell level. CONCLUSIONS: Ultrastructural analysis may be a powerful tool to identify which cellular organelles, and thus which cellular functions, are most affected by sleep and sleep loss.

Developmental patterns of sleep slow wave activity and synaptic density in adolescent mice.

STUDY OBJECTIVE: In humans sleep slow wave activity (SWA) declines during adolescence. It has been suggested that this decline reflects the elimination of cortical synapses, but this hypothesis has never been tested directly. DESIGN: We focused on mouse frontal cortex and collected data from early adolescence (∼postnatal day 20, P20) to adulthood (P60) of (1) SWA; (2) expression of synapsin I, a presynaptic marker; and (3) number of dendritic spines in layers I-II. SETTING: Basic sleep research laboratory. PATIENTS OR PARTICIPANTS: YFP-line H mice (n = 70; P15-87, all males) and GFP-line S mice (n = 14; P17-60, 8 females) were used for EEG recording. Forty-five YFP mice (P19-119, 12 females) and 42 GFP-S mice (P20-60, 14 females) were used for in vivo 2-photon imaging and ex vivo confocal microscopy, respectively. Other YGP mice (n = 57, P10-77) were used for western blot analysis of synapsin I. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: As in humans, SWA in mice declined from early adolescence to adulthood. Synapsin I levels increased from P10 to P24, with little change afterwards. Mean spine density in apical dendrites of layer V pyramidal neurons (YFP-H) showed no change from P20 to P60. Spine number in layers I-II apical dendrites, belonging to layer III and V pyramidal neurons (GFP-S), increased slightly from P20 to P30 and decreased from P30 to P60; smaller spines decreased in number from P20 to P60, while bigger spines increased. CONCLUSIONS: In mice, it is unlikely that the developmental decrease in SWA can be accounted for by a net pruning of cortical synapses.

Sleep patterns and homeostatic mechanisms in adolescent mice.

Sleep changes were studied in mice (n = 59) from early adolescence to adulthood (postnatal days P19-111). REM sleep declined steeply in early adolescence, while total sleep remained constant and NREM sleep increased slightly. Four hours of sleep deprivation starting at light onset were performed from ages P26 through adulthood (>P60). Following this acute sleep deprivation all mice slept longer and with more consolidated sleep bouts, while NREM slow wave activity (SWA) showed high interindividual variability in the younger groups, and increased consistently only after P42. Three parameters together explained up to 67% of the variance in SWA rebound in frontal cortex, including weight-adjusted age and increase in alpha power during sleep deprivation, both of which positively correlated with the SWA response. The third, and strongest predictor was the SWA decline during the light phase in baseline: mice with high peak SWA at light onset, resulting in a large SWA decline, were more likely to show no SWA rebound after sleep deprivation, a result that was also confirmed in parietal cortex. During baseline, however, SWA showed the same homeostatic changes in adolescents and adults, declining in the course of sleep and increasing across periods of spontaneous wake. Thus, we hypothesize that, in young adolescent mice, a ceiling effect and not the immaturity of the cellular mechanisms underlying sleep homeostasis may prevent the SWA rebound when wake is extended beyond its physiological duration.

Sleep and waking modulate spine turnover in the adolescent mouse cortex.

Cortical development involves synaptic formation and elimination. Although synaptogenesis predominates in the early stages and pruning in the later stages, the two processes are thought to happen concurrently. In adults, synaptic strength is modulated by behavioral state, and we asked whether synaptic remodeling may be affected by sleep and waking states. Using two-photon microscopy in adolescent mice, we found that waking results in a net increase in cortical spines, whereas sleep is associated with net spine loss.