Tianeptine induces expression of dual specificity phosphatases and evokes rebound emergence of cortical slow wave electrophysiological activity.

BACKGROUND: The precise mechanism governing the antidepressant effects of tianeptine is unknown. Modulation of brain glutamatergic neurotransmission has been however implicated, suggesting potential shared features with rapid-acting antidepressants targeting N-methyl-D-aspartate receptors (NMDAR). Our recent studies suggest that a single subanesthetic dose of NMDAR antagonists ketamine or nitrous oxide (N2O) gradually evoke 1-4 Hz electrophysiological activity (delta-rhythm) of cerebral cortex that is accompanied by molecular signaling associated with synaptic plasticity (e.g. activation of tropomyosin receptor kinase B (TrkB) and inhibition of glycogen synthase kinase 3ß (GSK3ß)). METHODS: We have here investigated the time-dependent effects of tianeptine (30 mg/kg, i.p.) on electrocorticogram, focusing on potential biphasic regulation of the delta-rhythm. Selected molecular markers associated with ketamine's antidepressant effects were analyzed in the medial prefrontal cortex after the treatment using quantitative polymerase chain reaction and western blotting. RESULTS: An acute tianeptine treatment induced changes of electrocorticogram typical for active wakefulness that lasted for 2-2.5 h, which was followed by high amplitude delta-activity rebound. The levels of Arc and Homer1a, but not c-Fos, BdnfIV and Zif268, were increased by tianeptine. Phosphorylation of mitogen-activated protein kinase (MAPK), TrkB and GSK3ß remained unaltered at 2-hours and at 3-hours post-treatment. Notably, tianeptine also increased the level of mRNA of several dual specificity phosphatases (Duspss) - negative regulators of MAPK. CONCLUSION: Tianeptine produces acute changes of electrocorticogram resembling rapid-acting antidepressants ketamine and N2O. Concomitant regulation of Dusps may hamper the effects of tianeptine on MAPK pathway and influence the magnitude of homeostatic emergence of delta-activity and TrkB-GSK3ß signaling.

Excitation of Putative Glutamatergic Neurons in the Rat Parabrachial Nucleus Region Reduces Delta Power during Dexmedetomidine but not Ketamine Anesthesia.

BACKGROUND: Parabrachial nucleus excitation reduces cortical delta oscillation (0.5 to 4 Hz) power and recovery time associated with anesthetics that enhance γ-aminobutyric acid type A receptor action. The effects of parabrachial nucleus excitation on anesthetics with other molecular targets, such as dexmedetomidine and ketamine, remain unknown. The hypothesis was that parabrachial nucleus excitation would cause arousal during dexmedetomidine and ketamine anesthesia. METHODS: Designer Receptors Exclusively Activated by Designer Drugs were used to excite calcium/calmodulin-dependent protein kinase 2α-positive neurons in the parabrachial nucleus region of adult male rats without anesthesia (nine rats), with dexmedetomidine (low dose: 0.3 µg · kg-1 · min-1 for 45 min, eight rats; high dose: 4.5 µg · kg-1 · min-1 for 10 min, seven rats), or with ketamine (low dose: 2 mg · kg-1 · min-1 for 30 min, seven rats; high dose: 4 mg · kg-1 · min-1 for 15 min, eight rats). For control experiments (same rats and treatments), the Designer Receptors Exclusively Activated by Designer Drugs were not excited. The electroencephalogram and anesthesia recovery times were recorded and analyzed. RESULTS: Parabrachial nucleus excitation reduced delta power in the prefrontal electroencephalogram with low-dose dexmedetomidine for the 150-min analyzed period, excepting two brief periods (peak median bootstrapped difference [clozapine-N-oxide - saline] during dexmedetomidine infusion = -6.06 [99% CI = -12.36 to -1.48] dB, P = 0.007). However, parabrachial nucleus excitation was less effective at reducing delta power with high-dose dexmedetomidine and low- and high-dose ketamine (peak median bootstrapped differences during high-dose [dexmedetomidine, ketamine] infusions = [-1.93, -0.87] dB, 99% CI = [-4.16 to -0.56, -1.62 to -0.18] dB, P = [0.006, 0.019]; low-dose ketamine had no statistically significant decreases during the infusion). Recovery time differences with parabrachial nucleus excitation were not statistically significant for dexmedetomidine (median difference for [low, high] dose = [1.63, 11.01] min, 95% CI = [-20.06 to 14.14, -20.84 to 23.67] min, P = [0.945, 0.297]) nor low-dose ketamine (median difference = 12.82 [95% CI: -3.20 to 39.58] min, P = 0.109) but were significantly longer for high-dose ketamine (median difference = 11.38 [95% CI: 1.81 to 24.67] min, P = 0.016). CONCLUSIONS: These results suggest that the effectiveness of parabrachial nucleus excitation to change the neurophysiologic and behavioral effects of anesthesia depends on the anesthetic's molecular target.

Wakefulness-Promoting Effects of Lateral Hypothalamic Area-Deep Brain Stimulation in Traumatic Brain Injury-Induced Comatose Rats: Upregulation of α1-Adrenoceptor Subtypes and Downregulation of Gamma-Aminobutyric Acid ß Receptor Expression Via the Orexins Pathway.

OBJECTIVE: Previous studies have shown that deep brain stimulation (DBS) can improve the level of consciousness of comatose patients with traumatic brain injuries (TBIs). However, the most suitable targets for DBS are unknown, and the mechanisms underlying recovery remain to be determined. The aim of the present study was to assess the effects of lateral hypothalamic area-DBS (LHA-DBS) in comatose rats with TBIs. METHODS: A total of 55 Sprague-Dawley rats were randomly assigned to 5 groups: the control group, TBI group, stimulated (TBI+LHA-DBS) group, antagonist (TBI+SB334867+LHA-DBS) group, and antagonist control (TBI+saline+LHA-DBS) group. The rats in the control group had undergone a sham operation and anesthesia, without coma induction. Coma was induced using a free-fall drop method. The rats in the stimulated group received bilateral LHA stimulation (frequency, 200 Hz; voltage, 2-4 V; pulse width, 0.1 ms) for 1 hour, with 5-minute intervals between subsequent stimulations, which were applied alternately to the left and right sides of the lateral hypothalamus. The comatose rats in the antagonist group received an intracerebroventricular injection with an orexins receptor type 1 (OX1R) antagonist (SB334867) and then received LHA-DBS. A I-VI consciousness scale and electroencephalography were used to assess the level of consciousness in each group of rats after LHA-DBS. Western blotting and immunofluorescence were used to detect OX1R expression in the LHA and α1-adrenoceptor (α1-AR) subtype and gamma-aminobutyric acid ß receptor (GABABR) expression in the prefrontal cortex. RESULTS: In the TBI, stimulated, antagonist, and antagonist control groups, 5, 10, 6, and 9 rats were awakened. The electroencephalographic readings indicated that the proportion of δ waves was lower in the stimulated group than in the TBI and antagonist groups (P < 0.05). Western blotting and immunofluorescence analysis showed that OX1R expression was greater in the stimulated group than in the TBI group (P < 0.05). The expression of α1-AR was also greater in the stimulated group than in the TBI and antagonist groups (P < 0.05). In contrast, the GABABR levels in the stimulated group were lower than those in the TBI and antagonist groups (P < 0.05). A statistically significant difference was found between the antagonist and antagonist control groups. CONCLUSIONS: Taken together, these results suggest that LHA-DBS promotes the recovery of consciousness in comatose rats with TBIs. Upregulation of α1-AR expression and downregulation of GABABR expression in the prefrontal cortex via the orexins and OX1R pathways might be involved in the wakefulness-promoting effects of LHA-DBS.

The administration of the opioid buprenorphine decreases motivational error signals.

While opioid addiction has reached pandemic proportions, we still lack a good understanding of how the administration of opioids interacts with cognitive functions. Error processing - the ability to detect erroneous actions and correct one's behaviour afterwards - is one such cognitive function that might be susceptible to opioidergic influences. Errors are hypothesised to induce aversive negative arousal, while opioids have been suggested to reduce aversive arousal induced by unpleasant and stressful stimuli. Thus, this study investigated whether the acute administration of an opioid would affect error processing. In a double-blind between-subject study, 42 male volunteers were recruited and received either 0.2 mg buprenorphine (a partial µ-opioid receptor agonist and κ-opioid receptor antagonist) or a placebo pill before they performed a stimulus-response task provoking errors. Electroencephalograms (EEG) were recorded while participants performed the task. We observed no group differences in terms of reaction times, error rates, and affective state ratings during the task between buprenorphine and control participants. Additional measures of adaptive control, however, showed interfering effects of buprenorphine administration. On the neural level, decreased Pe (Error Positivity) amplitudes were found in buprenorphine compared to control participants following error commission. Further, frontal delta oscillations were decreased in the buprenorphine group after all responses. Our neural results jointly demonstrate a general reduction in error processing in those participants who received an opioid before task completion, thereby suggesting that opioids might have indeed the potential to dampen motivational error signals. Importantly, the effects of the opioid were evident in more elaborate error processing stages, thereby impacting on processes of conscious error appraisal and evidence accumulation.

Measuring the effects of first antiepileptic medication in Temporal Lobe Epilepsy: Predictive value of quantitative-EEG analysis.

OBJECTIVE: To determine the quantitative EEG responses in a population of drug-naïve patients with Temporal Lobe Epilepsy (TLE) after Levetiracetam (LEV) initiation as first antiepileptic drug (AED). We hypothesized that the outcome of AED treatment can be predicted from EEG data in patients with TLE. METHODS: Twenty-three patients with TLE and twenty-five healthy controls were examined. Clinical outcome was dichotomized into seizure-free (SF) and non-seizure-free (NSF) after two years of LEV. EEG parameters were compared between healthy controls and patients with TLE at baseline (EEGpre) and after three months of AED therapy (EEGpre-post) and between SF and NSF patients. Receiver Operating Characteristic curves models were built to test whether EEG parameters predicted outcome. RESULTS: AED therapy induces an increase in EEG power for Alpha (p = 0.06) and a decrease in Theta (p < 0.05). Connectivity values were lower in SF compared to NSF patients (p < 0.001). Quantitative EEG predicted outcome after LEV treatment with an estimated accuracy varying from 65.2% to 91.3% (area under the curve [AUC] = 0.56-0.93) for EEGpre and from 69.9% to 86.9% (AUC = 0.69-0.94) for EEGpre-post. CONCLUSIONS: AED therapy induces EEG modifications in TLE patients, and such modifications are predictive of clinical outcome. SIGNIFICANCE: Quantitative EEG may help understanding the effect of AEDs in the central nervous system and offer new prognostic biomarkers for patients with epilepsy.

Post-exposure environment modulates long-term developmental ethanol effects on behavior, neuroanatomy, and cortical oscillations.

Developmental exposure to ethanol has a wide range of anatomical, cellular, physiological and behavioral impacts that can last throughout life. In humans, this cluster of effects is termed fetal alcohol spectrum disorder and is highly prevalent in western cultures. The ultimate expression of the effects of developmental ethanol exposure however can be influenced by post-exposure experience. Here we examined the effects of developmental binge exposure to ethanol (postnatal day 7) in C57BL/6By mice on a specific cohort of inter-related long-term outcomes including contextual memory, hippocampal parvalbumin-expressing neuron density, frontal cortex oscillations related to sleep-wake cycling including delta oscillation amplitude and sleep spindle density, and home-cage behavioral activity. When assessed in adults that were raised in standard housing, all of these factors were altered by early ethanol exposure compared to saline controls except home-cage activity. However, exposure to an enriched environment and exercise from weaning to postnatal day 90 reversed most of these ethanol-induced impairments including memory, CA1 but not dentate gyrus PV+ cell density, delta oscillations and sleep spindles, and enhanced home-cage behavioral activity in Saline- but not EtOH-treated mice. The results are discussed in terms of the inter-dependence of diverse developmental ethanol outcomes and potential mechanisms of post-exposure experiences to regulate those outcomes.

Delta oscillations are a robust biomarker of dopamine depletion severity and motor dysfunction in awake mice.

Delta oscillations (0.5-4 Hz) are a robust feature of basal ganglia pathophysiology in patients with Parkinson's disease (PD) in relationship to tremor, but their relationship to other parkinsonian symptoms has not been investigated. While delta oscillations have been observed in mouse models of PD, they have only been investigated in anesthetized animals, suggesting that the oscillations may be an anesthesia artifact and limiting the ability to relate them to motor symptoms. Here, we establish a novel approach to detect spike oscillations embedded in noise to provide the first study of delta oscillations in awake, dopamine-depleted mice. We find that approximately half of neurons in the substantia nigra pars reticulata (SNr) exhibit delta oscillations in dopamine depletion and that these oscillations are a strong indicator of dopamine loss and akinesia, outperforming measures such as changes in firing rate, irregularity, bursting, and synchrony. These oscillations are typically weakened, but not ablated, during movement. We further establish that these oscillations are caused by the loss of D2-receptor activation and do not originate from motor cortex, contrary to previous findings in anesthetized animals. Instead, SNr oscillations precede those in M1 at a 100- to 300-ms lag, and these neurons' relationship to M1 oscillations can be used as the basis for a novel classification of SNr into two subpopulations. These results give insight into how dopamine loss leads to motor dysfunction and suggest a reappraisal of delta oscillations as a marker of akinetic symptoms in PD.NEW & NOTEWORTHY This work introduces a novel method to detect spike oscillations amidst neural noise. Using this method, we demonstrate that delta oscillations in the basal ganglia are a defining feature of awake, dopamine-depleted mice and are strongly correlated with dopamine loss and parkinsonian motor symptoms. These oscillations arise from a loss of D2-receptor activation and do not require motor cortex. Similar oscillations in human patients may be an underappreciated marker and target for Parkinson's disease (PD) treatment.

Effects of an Orexin-2 Receptor Antagonist on Sleep and Event-Related Oscillations in Female Rats Exposed to Chronic Intermittent Ethanol During Adolescence.

BACKGROUND: Alcohol use is on the rise among women in the United States which is especially concerning since women who drink have a higher risk of alcohol-related problems. Orexin (hypocretin) receptor antagonists may have some therapeutic value for alcohol-induced insomnia; however, the use of this class of drugs following female adolescent binge drinking is limited. The current study will address whether adolescent intermittent ethanol (AIE) in female rats can result in lasting changes in sleep pathology and whether orexin-targeted treatment can alleviate these deficits. METHODS: Following a 5-week AIE vapor model, young adult rats were evaluated on waking event-related oscillations (EROs) and EEG sleep. Subsequently, AIE rats were treated with orexin receptor 2 (OX2 R) antagonist (MK-1064; 10, 20mg/kg) to test for modifications in sleep pathology and waking ERO. RESULTS: Female AIE rats exhibited lasting changes in sleep compared to controls. This was demonstrated by increased fragmentation of slow wave sleep (SWS) and rapid eye movement sleep, as well as reductions in delta and theta power during SWS. There was no impact of AIE on waking EROs. Acute MK-1064 hastened SWS onset and increased the number of SWS episodes, without increasing sleep fragmentation in AIE and controls. While treatment with MK-1064 did not impact sleep EEG spectra, waking ERO energy was increased in delta, theta, and beta frequency bands. CONCLUSIONS: These results demonstrate that AIE can produce lasting changes in sleep in female rats, highly similar to what we previously found in males. Additionally, while the OX2 R antagonist promoted sleep in both alcohol-exposed and unexposed rats, it did not reverse most of the alcohol-induced disruptions in sleep. Thus, OX2 R antagonism may serve as a potential therapeutic strategy for the treatment of insomnia, but not the specific signs of alcohol-induced insomnia.

Comparison of electroencephalogram between propofol- and thiopental-induced anesthesia for awareness risk in pregnant women.

There have been few comparative studies using electroencephalogram (EEG) spectral characteristics during the induction of general anesthesia for cesarean section. This retrospective study investigated the differences in the depth of anesthesia through EEG analysis between propofol- and thiopental-induced anesthesia. We reviewed data of 42 patients undergoing cesarean section who received either thiopental (5 mg/kg) or propofol (2 mg/kg). EEG data were extracted from the bispectral index (BIS) monitor, and 10-second segments were selected from the following sections: 1) Stage I, BIS below 60 after induction; 2) Stage II, after intubation completion; 3) Stage III, end-tidal sevoflurane above 0 vol%. The risk of awareness was represented by the BIS and entropy measures. In Stage III, the thiopental group (n = 20) showed significantly higher BIS value than the propofol group (n = 22) (67.9 [18.66] vs 44.5 [20.63], respectively, p = 0.002). The thiopental group had decreased slow-delta oscillations and increased beta-oscillations as compared to the propofol group in Stages II and III (p < 0.05). BIS, spectral entropy, and Renyi permutation entropy were also higher in the thiopental group at Stages II and III (p < 0.05). In conclusion, frontal spectral EEG analysis demonstrated that propofol induction maintained a deeper anesthesia than thiopental in pregnant women.

High cortical delta power correlates with aggravated allodynia by activating anterior cingulate cortex GABAergic neurons in neuropathic pain mice.

Patients with chronic pain often report being sensitive to pain at night before falling asleep, a time when the synchronization of cortical activity is initiated. However, how cortical activity relates to pain sensitivity is still unclear. Because sleep is characterized by enhanced cortical delta power, we hypothesized that enhanced cortical delta power may be an indicator of intensified pain. To test this hypothesis, we used pain thresholds tests, EEG/electromyogram recordings, c-Fos staining, and chemogenetic and pharmacological techniques in mice. We found that sleep deprivation or pharmacologic enhancement of EEG delta power by reserpine and scopolamine dramatically decreased mechanical pain thresholds, but not thermal withdrawal latency, in a partial sciatic nerve ligation model of neuropathic pain mice. On the contrary, suppression of EEG delta power using a wake-promoting agent modafinil significantly attenuated mechanical allodynia. Moreover, when EEG delta power was enhanced, c-Fos expression decreased in most regions of the cortex, except the anterior cingulate cortex (ACC), where c-Fos was increased in the somatostatin- and parvalbumin-positive GABAergic neurons. Chemogenetic activation of GABAergic neurons in ACC enhanced EEG delta power and lowered mechanical pain thresholds simultaneously in naive mice. However, chemogenetic inhibition of ACC GABAergic neurons could not block mechanical allodynia. These results provided compelling evidence that elevated EEG delta power is accompanied with aggravated neuropathic pain, whereas decreased delta power attenuated it, suggesting that enhanced delta power can be a specific marker of rising chronic neuropathic pain and that wake-promoting compounds could be used as analgesics in the clinic.

In pursuit of a sensitive EEG functional connectivity outcome measure for clinical trials in Alzheimer's disease.

OBJECTIVE: In clinical trials in Alzheimer's Disease (AD), an improvement of impaired functional connectivity (FC) could provide biological support for the potential efficacy of the drug. Electroencephalography (EEG) analysis of the SAPHIR-trial showed a treatment induced improvement of global relative theta power but not of FC measured by the phase lag index (PLI). We compared the PLI with the amplitude envelope correlation with leakage correction (AEC-c), a presumably more sensitive FC measure. METHODS: Patients with early AD underwent 12 weeks of placebo or treatment with PQ912, a glutaminylcyclase inhibitor. Eyes-closed task free EEG was measured at baseline and follow-up (PQ912 n = 47, placebo n = 56). AEC-c and PLI were measured in multiple frequency bands. Change in FC was compared between treatment groups by using two models of covariates. RESULTS: A significant increase in global AEC-c in the alpha frequency band was found with PQ912 treatment compared to placebo (p = 0.004, Cohen's d = 0.58). The effect remained significant when corrected for sex, country, ApoE ε4 carriage, age, baseline value (model 1; p = 0.006) and change in relative alpha power (model 2; p = 0.004). CONCLUSIONS: Functional connectivity in early AD, measured with AEC-c in the alpha frequency band, improved after PQ912 treatment. SIGNIFICANCE: AEC-c may be a robust and sensitive FC measure for detecting treatment effects.

Region-specific adenosinergic modulation of the slow-cortical rhythm in urethane-anesthetized rats.

Slow cortical rhythm (SCR) is a rhythmic alternation of UP and DOWN states during sleep and anesthesia. SCR-associated slow waves reflect homeostatic sleep functions. Adenosine accumulating during prolonged wakefulness and sleep deprivation (SD) may play a role in the delta power increment during recovery sleep. NREM sleep is a local, use-dependent process of the brain. In the present study, direct effect of adenosine on UP and DOWN states was tested by topical application to frontal, somatosensory and visual cortices, respectively, in urethane-anesthetized rats. Local field potentials (LFPs) were recorded using an electrode array inserted close to the location of adenosine application. Multiple unit activity (MUA) was measured from layer V-VI in close proximity of the recording array. In the frontal and somatosensory cortex, adenosine modulated SCR with slow kinetics on the LFP level while MUA remained mostly unaffected. In the visual cortex, adenosine modulated SCR with fast kinetics. In each region, delta power increment was based on the increased frequency of state transitions as well as increased height of UP-state associated slow waves. These results show that adenosine may directly modulate SCR in a complex and region-specific manner which may be related to the finding that restorative processes may take place with varying duration and intensity during recovery sleep in different cortical regions. Adenosine may play a direct role in the increment of the slow wave power observed during local sleep, furthermore it may shape the region-specific characteristics of the phenomenon.

δ-Oscillation Correlates of Anesthesia-induced Unconsciousness in Large-scale Brain Networks of Human Infants.

BACKGROUND: Functional brain connectivity studies can provide important information about changes in brain-state dynamics during general anesthesia. In adults, γ-aminobutyric acid-mediated agents disrupt integration of information from local to the whole-brain scale. Beginning around 3 to 4 months postnatal age, γ-aminobutyric acid-mediated anesthetics such as sevoflurane generate α-electroencephalography oscillations. In previous studies of sevoflurane-anesthetized infants 0 to 3.9 months of age, α-oscillations were absent, and power spectra did not distinguish between anesthetized and emergence from anesthesia conditions. Few studies detailing functional connectivity during general anesthesia in infants exist. This study's aim was to identify changes in functional connectivity of the infant brain during anesthesia. METHODS: A retrospective cohort study was performed using multichannel electroencephalograph recordings of 20 infants aged 0 to 3.9 months old who underwent sevoflurane anesthesia for elective surgery. Whole-brain functional connectivity was evaluated during maintenance of a surgical state of anesthesia and during emergence from anesthesia. Functional connectivity was represented as networks, and network efficiency indices (including complexity and modularity) were computed at the sensor and source levels. RESULTS: Sevoflurane decreased functional connectivity at the δ-frequency (1 to 4 Hz) in infants 0 to 3.9 months old when comparing anesthesia with emergence. At the sensor level, complexity decreased during anesthesia, showing less whole-brain integration with prominent alterations in the connectivity of frontal and parietal sensors (median difference, 0.0293; 95% CI, -0.0016 to 0.0397). At the source level, similar results were observed (median difference, 0.0201; 95% CI, -0.0025 to 0.0482) with prominent alterations in the connectivity between default-mode and frontoparietal regions. Anesthesia resulted in fragmented modules as modularity increased at the sensor (median difference, 0.0562; 95% CI, 0.0048 to 0.1298) and source (median difference, 0.0548; 95% CI, -0.0040 to 0.1074) levels. CONCLUSIONS: Sevoflurane is associated with decreased capacity for efficient information transfer in the infant brain. Such findings strengthen the hypothesis that conscious processing relies on an efficient system of integrated information transfer across the whole brain.

Sleep deprivation and Modafinil affect cortical sources of resting state electroencephalographic rhythms in healthy young adults.

OBJECTIVE: It has been reported that sleep deprivation affects the neurophysiological mechanisms underpinning the vigilance. Here, we tested the following hypotheses in the PharmaCog project (www.pharmacog.org): (i) sleep deprivation may alter posterior cortical delta and alpha sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms in healthy young adults; (ii) after the sleep deprivation, a vigilance enhancer may recover those rsEEG source markers. METHODS: rsEEG data were recorded in 36 healthy young adults before (Pre-sleep deprivation) and after (Post-sleep deprivation) one night of sleep deprivation. In the Post-sleep deprivation, these data were collected after a single dose of PLACEBO or MODAFINIL. rsEEG cortical sources were estimated by eLORETA freeware. RESULTS: In the PLACEBO condition, the sleep deprivation induced an increase and a decrease in posterior delta (2-4 Hz) and alpha (8-13 Hz) source activities, respectively. In the MODAFINIL condition, the vigilance enhancer partially recovered those source activities. CONCLUSIONS: The present results suggest that posterior delta and alpha source activities may be both related to the regulation of human brain arousal and vigilance in quiet wakefulness. SIGNIFICANCE: Future research in healthy young adults may use this methodology to preselect new symptomatic drug candidates designed to normalize brain arousal and vigilance in seniors with dementia.

Asenapine maleate normalizes low frequency oscillatory deficits in a neurodevelopmental model of schizophrenia.

Asenapine maleate (AM) is an atypical antipsychotic that, unlike many other antipsychotics, shows some efficacy in treating cognitive dysfunction in schizophrenia. Normal cognitive function has long since been associated with high frequency neuronal oscillations. However, recent research has highlighted the potential importance of low frequency oscillations. Here, the impact of AM on low frequency neural oscillatory activity was evaluated in the methylazoxymethanol acetate (MAM) rat model system used for the study schizophrenia, and the oscillatory signatures compared to those of haloperidol (HAL) and clozapine (CLZ). AM and CLZ normalized low frequency spectral power deficits in the prefrontal cortex, while HAL and AM reversed corticostriatal and corticocortical delta coherence deficits. However, only chronic AM administration normalized corticostriatal and corticocortical delta coherence deficits between 3-4 Hz. These findings support the idea that antipsychotic-induced amelioration of both delta coherence and power may be important for therapeutic efficacy in treating the cognitive deficits inherent in schizophrenia.

TAK-071, a muscarinic M1 receptor positive allosteric modulator, attenuates scopolamine-induced quantitative electroencephalogram power spectral changes in cynomolgus monkeys.

Activation of the muscarinic M1 receptor is a promising approach to improve cognitive deficits associated with cholinergic dysfunction in Alzheimer's disease, dementia with Lewy bodies, and schizophrenia. TAK-071 is an M1-selective positive allosteric modulator that improves cognitive deficits induced by scopolamine, a non-selective muscarinic receptor antagonist, with reduced side effects on gastrointestinal function in rats. In this study, we explored changes in quantitative electroencephalography (qEEG) power bands, with or without scopolamine challenge, as a non-invasive translational biomarker for the effect of TAK-071 in cynomolgus monkeys. Scopolamine has been reported to increase theta and delta power bands and decrease alpha power band in healthy volunteers. In line with the clinical observations, scopolamine (25-100 µg/kg, subcutaneous administration [s.c.]) increased theta and delta power bands in cynomolgus monkeys in a dose-dependent manner, whereas it had the opposite effect on alpha power band. The effects of TAK-071 on scopolamine (25 µg/kg, s.c.)-induced qEEG spectral changes were examined using an acetylcholinesterase inhibitor donepezil and a muscarinic M1/M4 receptor agonist xanomeline as comparative cholinomimetics. TAK-071 (0.3-3 mg/kg, oral administration [p.o.]), donepezil (3 mg/kg, p.o.), and xanomeline (1 mg/kg, s.c.) suppressed the scopolamine-induced increases in alpha, theta, and delta power bands. These results suggest that changes in specific qEEG power bands, in particular theta and delta power bands in the context of scopolamine challenge, could be used as translational biomarkers for the evaluation of TAK-071 in clinical studies.

Frontal slow wave resting EEG power is higher in individuals at Ultra High Risk for psychosis than in healthy controls but is not associated with negative symptoms or functioning.

Decreased brain activity in the frontal region, as indicated by increased slow wave EEG power measured by electrodes place on the skull over this area, in association with negative symptoms has previously been shown to distinguish ultra-high risk (UHR) individuals who later transitioned to psychosis (UHR-P) from those who did not transition (UHR-NP). The aims of the current study were to: 1) replicate these results and 2) investigate whether similar association between increased frontal slow wave activity and functioning shows any value in the prediction of transition to psychosis in UHR individuals. The brain activity, recorded using EEG, of 44 UHR individuals and 38 healthy controls was included in the analyses. Symptom severity was assessed in UHR participants and functioning was measured in both groups. The power in the theta frequency band in the frontal region of UHR individuals was higher than in controls. However, there was no difference between the UHR-P and the UHR-NP groups, and no change in slow frequency power following transition to psychosis. The correlation between delta frequency power and negative symptoms previously observed was not present in our UHR cohort, and there was no association between frontal delta or theta and functioning in either group. Increased delta power was rather correlated with depressive symptoms in the UHR group. Future research will be needed to better understand when, in the course of the illness, does the slow wave activity in the frontal area becomes impaired.

Chronic Suppression of Hypothalamic Cell Proliferation and Neurogenesis Induces Aging-Like Changes in Sleep-Wake Organization in Young Mice.

Aging is associated with sleep-wake disruption, dampening of circadian amplitudes, and a reduced homeostatic sleep response. Aging is also associated with a decline in hypothalamic cell proliferation. We hypothesized that the aging-related decline in cell-proliferation contributes to the dysfunction of preoptic-hypothalamic sleep-wake and circadian systems and consequent sleep-wake disruption. We determined if cytosine-ß-D-arabinofuranoside (AraC), an antimitotic agent known to suppress hypothalamic cell proliferation and neurogenesis, causes sleep-wake instability in young mice. The sleep-wake profiles were compared during baseline, during 4 weeks of artificial cerebrospinal fluid (aCSF) + 5-bromo-2'-deoxyuridine (BrdU) or AraC+BrdU infusion into the lateral ventricle, and 8 weeks after treatments. The sleep-wake architecture after AraC treatment was further compared with sleep-wake profiles in aged mice. Compared to aCSF+BrdU, 4 weeks of AraC+BrdU infusion significantly decreased (-96%) the number of BrdU+ cells around the third ventricular wall and adjacent preoptic-hypothalamic area and produced a) sleep disruption during the light phase with decreases in non-rapid eye movement (nonREM) (-9%) and REM sleep (-21%) amounts, and increased numbers of shorter (<2 min; 142 versus 98 episodes/12 h) and decreased numbers of longer (>5 min; 19 versus 26 episodes/12 h) nonREM sleep episodes; and b) wake disruption during the dark phase, with increased numbers of shorter (138 versus 91 episodes/12 h) and decreased numbers of longer active waking (17 versus 24 episodes/12 h) episodes. AraC-treated mice also exhibited lower delta activity within nonREM recovery sleep. The sleep-wake architecture of AraC-treated mice was similar to that observed in aged mice. These findings are consistent with a hypothesis that a decrease in hypothalamic cell proliferation/neurogenesis is detrimental to sleep-wake and circadian systems and may underlie sleep-wake disturbance in aging.

Co-existence of Rolandic and 3 Hz Spike-Wave Discharges on EEG in Children with Epilepsy.

OBJECTIVE: Benign epilepsy of childhood with central temporal spikes (BECTS) and absence epilepsy are common epilepsy syndromes in children with similar age of onset and favorable prognosis. However, the co-existence of the electrocardiogram (EEG) findings of rolandic spike and 3 Hz generalized spike-wave (GSW) discharges is extremely rare, with few cases reported in the literature. Our objective was to characterize the EEG findings of these syndromes in children in our center and review the electro-clinical features. METHODS: All EEGs at BC Children's Hospital are entered in a database, which include EEG findings and clinical data. Patients with both centro-temporal spikes and 3 Hz GSW discharges were identified from the database and clinical data were reviewed. RESULTS: Among the 43,061 patients in the database from 1992 to 2017, 1426 with isolated rolandic discharges and 528 patients with isolated 3 Hz GSW discharges were identified, and 20 (0.05%) patients had both findings: 3/20 had BECTS, and subsequently developed childhood absence epilepsy and 17/20 had no seizures characteristic for BECTS. At follow-up, 17 (85%) were seizure-free, 1 (5%) had rare, and 2 (10%) had frequent seizures. CONCLUSIONS: This is the largest reported group of patients to our knowledge with the co-existence of rolandic and 3 Hz GSW discharges on EEGs in one institution, not drug-induced. As the presence of both findings is extremely rare, distinct pathophysiological mechanisms are likely. The majority had excellent seizure control at follow-up, similar to what would be expected for each type of epilepsy alone.

OBJECTIF: L'épilepsie bénigne de l'enfance à pointes centro-temporales (ou épilepsie rolandique bénigne [ERB]) et l'absence épileptique sont des syndromes épileptiques communs chez des enfants dont le pronostic est favorable et dont l'apparition des premiers symptômes s'est produite à un âge similaire. Cependant, la coexistence, lors d'EEG, de résultats montrant des décharges rolandiques et des décharges à pointes-ondes continues de 3 Hz demeure extrêmement rare, peu de cas ayant été signalés dans la littérature scientifique. Notre objectif a donc consisté à décrire les résultats d'EEG liés à ces syndromes dans le cas d'enfants fréquentant notre établissement et à examiner leurs caractéristiques électro-cliniques. MÉTHODES: En plus de certaines données cliniques, tous les résultats d'EEG réalisés au BC Children's Hospital sont saisis dans une base de données. Tant les jeunes patients donnant à voir des décharges à pointes centro-temporales que ceux atteints de décharges à pointes-ondes continues de 3 Hz ont été identifiés à partir de cette base de données. Leurs données cliniques ont été ensuite passées en revue. RÉSULTATS: Sur un total de 43 061 jeunes patients présents dans la base de données de 1992 à 2017, nous en avons identifié 1426 avec des décharges rolandiques isolées et 528 avec des décharges isolées à pointes-ondes de 3 Hz. À noter que seulement vingt d'entre eux, soit 0,05 %, étaient concernés par ces deux types de décharge. À cet égard, 3 sur 20 étaient atteints d'ERB et ont développé ultérieurement un syndrome d'absence épileptique; chez les 17 autres, aucune convulsion caractéristique de l'ERB n'a été observée. Lors d'un suivi, 17 (85 %) d'entre eux n'avaient plus de crises convulsives tandis que 1 (5 %) avait exceptionnellement des crises et 2 (10 %), des crises fréquentes. CONCLUSIONS: À notre connaissance, il s'agit là du plus vaste groupe déclaré de patients donnant à voir, lors d'EGG menés au sein d'un seul établissement, une coexistence entre des décharges rolandiques et des décharges à pointes-ondes de 3 Hz, et ce, sans qu'elles n'aient été causées par des médicaments. Considérant que la présence de ces deux phénomènes est particulièrement inhabituelle, le rôle de divers mécanismes pathophysiologiques est fort probable. Fait à souligner, la majorité de ces patients ont pu montrer, au moment de leur suivi, une excellente maîtrise de leurs crises convulsives, maîtrise semblable à celle à laquelle on pourrait s'attendre pour chaque type d'épilepsie pris individuellement.

Mammillary body regulates state-dependent fear by alternating cortical oscillations.

State-dependent memory describes a phenomenon that memory will be efficiently retrieved only when the brain state during retrieval matches the state during encoding. While a variety of psychoactive drugs, such as ethanol, cocaine, morphine and NMDA receptor antagonists, are able to induce state-dependent memory, the biological hallmark of brain state and neural mechanism of its regulation are still unknown. In this study, we found that MK-801 enhanced delta oscillations in awake mice, representing a drug-induced brain state, in which fear memory could only be successfully retrieved when the same drug condition was presented. We identified a key nucleus, mammillary body (MB), which regulates the specific brain state associated with MK-801. Chemogenetic silencing of MB neurons enhanced cortical delta oscillations and generated state-dependent memory. Moreover, optogenetic reconstitution of delta oscillations alone facilitated retrieval of fear memory encoded under MK-801. Our results indicated that delta oscillations in awake animals defined a specific brain state, in which memory formed is inaccessible under the normal condition, shining light on the neural mechanism underlying the fluctuation of memory retrieval and the role of MB in memory encoding and recall.