Decrease In Gamma Power Research Articles

Sex Differences in the Neural and Behavioral Effects of Acute High-Dose Edible Cannabis Consumption in Rats.

The consumption of Δ9-tetrahydrocannabinol (THC)- or cannabis-containing edibles has increased in recent years; however, the behavioral and neural circuit effects of such consumption remain unknown, especially in the context of ingestion of higher doses resulting in cannabis intoxication. We examined the neural and behavioral effects of acute high-dose edible cannabis consumption (AHDECC). Sprague-Dawley rats (six males, seven females) were implanted with electrodes in the prefrontal cortex (PFC), dorsal hippocampus (dHipp), cingulate cortex (Cg), and nucleus accumbens (NAc). Rats were provided access to a mixture of Nutella (6 g/kg) and THC-containing cannabis oil (20 mg/kg) for 10 minutes, during which they voluntarily consumed all of the provided Nutella and THC mixture. Cannabis tetrad and neural oscillations were examined 2, 4, 8, and 24 hours after exposure. In another cohort (16 males, 15 females), we examined the effects of AHDECC on learning and prepulse inhibition and serum and brain THC and 11-hydroxy-THC concentrations. AHDECC resulted in higher brain and serum THC and 11-hydroxy-THC levels in female rats over 24 hours. AHDECC also produced: 1) Cg, dHipp, and NAc gamma power suppression, with the suppression being greater in female rats, in a time-dependent manner; 2) hypolocomotion, hypothermia, and antinociception in a time-dependent manner; and 3) learning and prepulse inhibition impairments. Additionally, most neural activity and behavior changes appear 2 hours after ingestion, suggesting that interventions around this time might be effective in reversing/reducing the effects of AHDECC. SIGNIFICANCE STATEMENT: The effects of high-dose edible cannabis on behavior and neural circuitry are poorly understood. We found that the effects of acute high-dose edible cannabis consumption (AHDECC), which include decreased gamma power, hypothermia, hypolocomotion, analgesia, and learning and information processing impairments, are time and sex dependent. Moreover, these effects begin 2 hours after AHDECC and last for at least 24 hours, suggesting that treatments should target this time window in order to be effective.

Altered age-related alpha and gamma prefrontal-occipital connectivity serving distinct cognitive interference variants

The presence of conflicting stimuli adversely affects behavioral outcomes, which could either be at the level of stimulus (Flanker), response (Simon), or both (Multisource). Briefly, flanker interference involves conflicting stimuli requiring selective attention, Simon interference is caused by an incongruity between the spatial location of the task-relevant stimulus and prepotent motor mapping, and multisource is combination of both. Irrespective of the variant, interference resolution necessitates cognitive control to filter irrelevant information and allocate neural resources to task-related goals. Though previously studied in healthy young adults, the direct quantification of changes in oscillatory activity serving such cognitive control and associated inter-regional interactions in healthy aging are poorly understood. Herein, we used an adapted version of the multisource interference task and magnetoencephalography to investigate age-related alterations in the neural dynamics governing both divergent and convergent cognitive interference in 78 healthy participants (age range: 20-66 years). We identified weaker alpha connectivity between bilateral visual and right dorsolateral prefrontal cortices (DLPFC) and left dorsomedial prefrontal cortices (dmPFC), as well as weaker gamma connectivity between bilateral occipital regions and the right dmPFC during flanker interference with advancing age. Further, an age-related decrease in gamma power was observed in the left cerebellum and parietal region for Simon and differential interference effects (i.e., flanker-Simon), respectively. Moreover, the superadditivity model showed decreased gamma power in the right temporoparietal junction (TPJ) with increasing age. Overall, our findings suggest age-related declines in the engagement of top-down attentional control secondary to reduced alpha and gamma coupling between prefrontal and occipital cortices.

Neural substrates of cognitive impairment in a NMDAR hypofunction mouse model of schizophrenia and partial rescue by risperidone.

N-methyl D-aspartate receptor (NMDAR) hypofunction is a pathophysiological mechanism relevant for schizophrenia. Acute administration of the NMDAR antagonist phencyclidine (PCP) induces psychosis in patients and animals while subchronic PCP (sPCP) produces cognitive dysfunction for weeks. We investigated the neural correlates of memory and auditory impairments in mice treated with sPCP and the rescuing abilities of the atypical antipsychotic drug risperidone administered daily for two weeks. We recorded neural activities in the medial prefrontal cortex (mPFC) and the dorsal hippocampus (dHPC) during memory acquisition, short-term, and long-term memory in the novel object recognition test and during auditory processing and mismatch negativity (MMN) and examined the effects of sPCP and sPCP followed by risperidone. We found that the information about the familiar object and its short-term storage were associated with mPFC→dHPC high gamma connectivity (phase slope index) whereas long-term memory retrieval depended on dHPC→mPFC theta connectivity. sPCP impaired short-term and long-term memories, which were associated with increased theta power in the mPFC, decreased gamma power and theta-gamma coupling in the dHPC, and disrupted mPFC-dHPC connectivity. Risperidone rescued the memory deficits and partly restored hippocampal desynchronization but did not ameliorate mPFC and circuit connectivity alterations. sPCP also impaired auditory processing and its neural correlates (evoked potentials and MMN) in the mPFC, which were also partly rescued by risperidone. Our study suggests that the mPFC and the dHPC disconnect during NMDAR hypofunction, possibly underlying cognitive impairment in schizophrenia, and that risperidone targets this circuit to ameliorate cognitive abilities in patients.

Age Differences in Learning-Related Neurophysiological Changes

Abstract: Research in young adults has demonstrated that neurophysiological measures are able to provide insight into learning processes. However, to date, it remains unclear whether neurophysiological changes during learning in older adults are comparable to those in younger adults. The current study addressed this issue by exploring age differences in changes over time in a range of neurophysiological outcome measures collected during visuomotor sequence learning. Specifically, measures of electroencephalography (EEG), skin conductance, heart rate, heart rate variability, respiration rate, and eye-related measures, in addition to behavioral performance measures, were collected in younger ( Mage = 27.24 years) and older adults ( Mage = 58.06 years) during learning. Behavioral responses became more accurate over time in both age groups during visuomotor sequence learning. Yet, older adults needed more time in each trial to enhance the precision of their movement. Changes in EEG during learning demonstrated a stronger increase in theta power in older compared to younger adults and a decrease in gamma power in older adults while increasing slightly in younger adults. No such differences between the two age groups were found on other neurophysiological outcome measures, suggesting changes in brain activity during learning to be more sensitive to age differences than changes in peripheral physiology. Additionally, differences in which neurophysiological outcomes were associated with behavioral performance on the learning task were found between younger and older adults. This indicates that the neurophysiological underpinnings of learning may differ between younger and older adults. Therefore, the current findings highlight the importance of taking age into account when aiming to gain insight into behavioral performance through neurophysiology during learning.

Muscarinic and N-methyl-D-aspartate receptor blockade reveal differences in hippocampal local field potentials in mice with low cholinergic tone.

We hypothesize that hippocampal local field potentials in acetylcholine (ACh)-deficient mutant mice, compared to wild-type (WT) mice, will show lower sensitivity to muscarinic cholinergic antagonist scopolamine (5mg/kg i.p.) but higher sensitivity to NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP, 10mg/kg i.p.). Recordings were made during walk and awake-immobility (IMM) in WT mice, and in mice with forebrain knockout (KO) of the vesicular acetylcholine transporter (VAChT) gene, or heterozygous knockdown of VAChT gene (KD). Scopolamine or CPP did not significantly alter walk theta frequency, which was higher in KD than WT/KO mice. Scopolamine decreased theta power peak rise during walk in WT/KD mice but not in KO mice, while CPP suppressed theta peak rise more in WT/KO mice than KD mice. During IMM, scopolamine decreased gamma1 (γ1, 30-58 Hz) power more in KD/WT mice than KO mice, while delta (1-4Hz) power and delta-gamma cross-frequency coherence (CFC) were increased in all mouse groups during IMM or walk. During walk, scopolamine increased delta and beta (13-30 Hz) power and decreased gamma2 (γ2, 62-100 Hz) power and theta-γ2 CFC more in WT/KD than KO mice. Theta-γ2, but not theta-γ1, CFC increased with theta-peak-frequency in WT/KD mice, and was suppressed by scopolamine at high theta (8-10Hz) frequency; theta-γ2 CFC in KO mice was not significantly altered by scopolamine. CPP decreased beta and gamma power more in KD/KO mice compared to WT mice, while delta power and delta-gamma CFC were increased in all mouse groups. ACh deficiency exacerbates the attenuation of beta and gamma power by CPP. We conclude that both muscarinic and NMDA transmission contribute toward hippocampal theta, beta, and gamma power, and a decrease in gamma power or theta-gamma CFC may be associated with loss of arousal and cognitive functions.

Effects of Multisensory Distractor Interference on Attentional Driving

Distracted driving refers to multisensory integration and attention shifts between attentional driving and different interferences from different modalities, including visual and auditory stimuli. Here, we compared the behavioral performance with interacting multisensory distractors during attentional driving. Then, the independent component analysis (ICA) and event-related spectral perturbation (ERSP) were applied to investigate the neural oscillation changes. The behavioral results showed that the response times (RTs) increased when distractors appeared in response to attentional driving. Moreover, the RTs were longer when the distractor interference was presented in the auditory modality compared with the visual modality. Eye movement intervals showed shorter tracking saccades under distractor interference. These results may indicate that attentional driving performance was impaired under the exposure to multisensory distractor interference. The ERSPs under visual and auditory distraction exposure showed decreased beta power in the frontal area, increased theta and delta power in the central area, and decreased alpha power in the parietal area. During this process, distracted driving under cross-modal sensory interference required more neural oscillation involvement. Moreover, the visual modality showed increased gamma power in the frontal, central, parietal and occipital areas, while the auditory modality showed decreased gamma power in the frontal area, indicating that auditory interference could intervene in top-down attentional processing.

Neuroprotective Effects of Electrical Stimulation Following Ischemic Stroke in Non-Human Primates.

Brain stimulation has emerged as a novel therapy for ischemic stroke, a major cause of brain injury that often results in lifelong disability. Although past works in rodents have demonstrated protective effects of stimulation following stroke, few of these results have been replicated in humans due to the anatomical differences between rodent and human brains and a limited understanding of stimulation-induced network changes. Therefore, we combined electrophysiology and histology to study the neuroprotective mechanisms of electrical stimulation following cortical ischemic stroke in non-human primates. To produce controlled focal lesions, we used the photothrombotic method to induce targeted vasculature damage in the sensorimotor cortices of two macaques while collecting electrocorticography (ECoG) signals bilaterally. In another two monkeys, we followed the same lesioning procedures and applied repeated electrical stimulation via an ECoG electrode adjacent to the lesion. We studied the protective effects of stimulation on neural dynamics using ECoG signal power and coherence. In addition, we performed histological analysis to evaluate the differences in lesion volume. In comparison to controls, the ECoG signals showed decreased gamma power across the sensorimotor cortices in stimulated animals. Meanwhile, Nissl staining revealed smaller lesion volumes for the stimulated group, suggesting that electrical stimulation may exert neuroprotection by suppressing post-ischemic neural activity. With the similarity between NHP and human brains, this study paves the path for developing effective stimulation-based therapy for acute stroke in clinical studies.

Impaired spike-gamma coupling of area CA3 fast-spiking interneurons as the earliest functional impairment in the AppNL-G-F mouse model of Alzheimer\u2019s disease

In Alzheimer’s disease (AD) the accumulation of amyloid-β (Aβ) correlates with degradation of cognition-relevant gamma oscillations. The gamma rhythm relies on proper neuronal spike-gamma coupling, specifically of fast-spiking interneurons (FSN). Here we tested the hypothesis that decrease in gamma power and FSN synchrony precede amyloid plaque deposition and cognitive impairment in AppNL-G-F knock-in mice (AppNL-G-F). The aim of the study was to evaluate the amyloidogenic pathology progression in the novel AppNL-G-F mouse model using in vitro electrophysiological network analysis. Using patch clamp of FSNs and pyramidal cells (PCs) with simultaneous gamma oscillation recordings, we compared the activity of the hippocampal network of wild-type mice (WT) and the AppNL-G-F mice at four disease stages (1, 2, 4, and 6 months of age). We found a severe degradation of gamma oscillation power that is independent of, and precedes Aβ plaque formation, and the cognitive impairment reported previously in this animal model. The degradation correlates with increased Aβ1-42 concentration in the brain. Analysis on the cellular level showed an impaired spike-gamma coupling of FSN from 2 months of age that correlates with the degradation of gamma oscillations. From 6 months of age PC firing becomes desynchronized also, correlating with reports in the literature of robust Aβ plaque pathology and cognitive impairment in the AppNL-G-F mice. This study provides evidence that impaired FSN spike-gamma coupling is one of the earliest functional impairment caused by the amyloidogenic pathology progression likely is the main cause for the degradation of gamma oscillations and consequent cognitive impairment. Our data suggests that therapeutic approaches should be aimed at restoring normal FSN spike-gamma coupling and not just removal of Aβ.

No evidence for theta power as a marker of hypnotic state in highly hypnotizable subjects

EEG spectral-power density was analyzed in a group of nine highly hypnotizable subjects via ten frontal, central, parietal, and occipital electrodes under four conditions: 1) wake state, 2) neutral hypnosis, 3) hypnotic suggestion for altering perception of tones, and 4) post-hypnosis. Results indicate no theta-power changes between conditions, challenging previous findings that increased theta power is a marker of hypnosis. A decrease in gamma power under hypnotic suggestion and an almost significant decrease under neutral hypnosis were observed, compared to post-hypnosis. Anteroposterior power distribution remained stable over all conditions. The results are discussed and compared to earlier studies, which report heterogenous findings.

Blink- and saccade-related suppression effects in early visual areas of the human brain: Intracranial EEG investigations during natural viewing conditions

Blinks and saccades, both ubiquitous in natural viewing conditions, cause rapid changes of visual inputs that are hardly consciously perceived. The neural dynamics in early visual areas of the human brain underlying this remarkable visual stability are still incompletely understood. We used electrocorticography (ECoG) from electrodes directly implanted on the human early visual areas V1, V2, V3d/v, V4d/v and the fusiform gyrus to investigate blink- and saccade-related neuronal suppression effects during non-experimental, free viewing conditions. We found a characteristic, biphasic, broadband gamma power decrease-increase pattern in all investigated visual areas. During saccades, a decrease in gamma power clearly preceded eye movement onset, at least in V1. This may indicate that cortical information processing is actively suppressed in human early visual areas before and during saccades, which then possibly mediates perceptual visual suppression. The following eye movement offset-related increase in gamma power may indicate the recovery of visual perception and the resumption of visual processing.

GABAA receptors in the basal forebrain mediates emergence from propofol anaesthesia in rats

Purpose The aim of the current study was to explore the role of the basal forebrain (BF) in propofol anaesthesia. Methods In the present study, we observed the neural activities of the BF during propofol anaesthesia using calcium fibre photometry recording. Subsequently, ibotenic acid was injected into the BF to verify the role of the BF in propofol anaesthesia. Finally, to test whether GABAA receptors in the BF were involved in modulating propofol anaesthesia, muscimol (GABAA receptor agonist) and gabazine (GABAA receptor antagonist) were microinjected into the BF. Cortical electroencephalogram (EEG), time to loss of righting reflex (LORR), and recovery of righting reflex (RORR) under propofol anaesthesia were recorded and analysed. Results The activity of BF neurons was inhibited during induction of propofol anaesthesia and activated during emergence from propofol anaesthesia. In addition, non-specifical lesion of BF neurons significantly prolonged the time to RORR and increased delta power in the frontal cortex under propofol anaesthesia. Next, microinjection of muscimol into the BF delayed emergence from propofol anaesthesia, increased delta power of the frontal cortex, and decreased gamma power under propofol anaesthesia. Conversely, infusion of gabazine accelerated emergence times and decreased EEG delta power. Conclusions The basal forebrain is involved in modulating frontal cortex delta activity and emergence from propofol anaesthesia. Additionally, the GABAA receptors in the basal forebrain are involved in regulating emergence propofol anaesthesia.

Pharmacologic Characterization of JNJ-42226314, [1-(4-Fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone, a Reversible, Selective, and Potent Monoacylglycerol Lipase Inhibitor.

The serine hydrolase monoacylglycerol lipase (MAGL) is the rate-limiting enzyme responsible for the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) into arachidonic acid and glycerol. Inhibition of 2-AG degradation leads to elevation of 2-AG, the most abundant endogenous agonist of the cannabinoid receptors (CBs) CB1 and CB2. Activation of these receptors has demonstrated beneficial effects on mood, appetite, pain, and inflammation. Therefore, MAGL inhibitors have the potential to produce therapeutic effects in a vast array of complex human diseases. The present report describes the pharmacologic characterization of [1-(4-fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone (JNJ-42226314), a reversible and highly selective MAGL inhibitor. JNJ-42226314 inhibits MAGL in a competitive mode with respect to the 2-AG substrate. In rodent brain, the compound time- and dose-dependently bound to MAGL, indirectly led to CB1 occupancy by raising 2-AG levels, and raised norepinephrine levels in cortex. In vivo, the compound exhibited antinociceptive efficacy in both the rat complete Freund's adjuvant-induced radiant heat hypersensitivity and chronic constriction injury-induced cold hypersensitivity models of inflammatory and neuropathic pain, respectively. Though 30 mg/kg induced hippocampal synaptic depression, altered sleep onset, and decreased electroencephalogram gamma power, 3 mg/kg still provided approximately 80% enzyme occupancy, significantly increased 2-AG and norepinephrine levels, and produced neuropathic antinociception without synaptic depression or decreased gamma power. Thus, it is anticipated that the profile exhibited by this compound will allow for precise modulation of 2-AG levels in vivo, supporting potential therapeutic application in several central nervous system disorders. SIGNIFICANCE STATEMENT: Potentiation of endocannabinoid signaling activity via inhibition of the serine hydrolase monoacylglycerol lipase (MAGL) is an appealing strategy in the development of treatments for several disorders, including ones related to mood, pain, and inflammation. [1-(4-Fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone is presented in this report to be a novel, potent, selective, and reversible noncovalent MAGL inhibitor that demonstrates dose-dependent enhancement of the major endocannabinoid 2-arachidonoylglycerol as well as efficacy in models of neuropathic and inflammatory pain.

Electrocortical high frequency activity and respiratory entrainment in 6-hydroxydopamine model of Parkinson’s disease

Parkinson’s disease is characterized by motor symptoms (akinesia, rigidity, etc.), which are associated with the degeneration of the dopaminergic neurons of the midbrain. In addition, olfactory impairment that usually develops before the detection of motor deficits, is detected in 90% of Parkinsonian patients.Recent studies in mammals, have shown that slow cortical potentials phase-lock with nasal respiration. In several cortical areas, gamma synchronization of the electrographic activity is also coupled to respiration, suggesting than nasal respiratory entrainment could have a role in the processing of olfactory information.In the present study, we evaluate the role of midbrain dopaminergic neurons, in the modulation of the electrocorticogram activity and its respiratory entrainment during wakefulness and sleep. For this purpose, we performed a unilateral lesion of dopaminergic neurons of the substantia nigra pars compacta of the rat, with 6-hydroxydopamine.An increase in beta (20–35 Hz) together with a decrease in gamma power (60–95 Hz) in the motor cortex ipsilateral to the lesion was observed during wakefulness. These results correlated with the degree of motor alterations and dopamine measured at the striatum. Moreover, we found a decline in gamma coherence between the ipsilateral olfactory bulb and motor cortex. Also, at the olfactory bulb we noticed an increase in respiratory-gamma cross-frequency coupling after the lesion, while at the motor cortex, a decrease in respiratory potential entrainment of gamma activity was observed. Interestingly, we did not observe any significant modification either during Non-REM or REM sleep. These waking dysrhythmias may play a role both in the anosmia and motor deficits present in Parkinson disease.

Sleep dysfunction and EEG alterations in mice overexpressing alpha-synuclein.

Background:Sleep disruptions occur early and frequently in Parkinson’s disease (PD). PD patients also show a slowing of resting state activity. Alpha-synuclein is causally linked to PD and accumulates in sleep-related brain regions. While sleep problems occur in over 75% of PD patients and severely impact the quality of life of patients and caregivers, their study is limited by a paucity of adequate animal models.Objective:The objective of this study was to determine whether overexpression of wildtype alpha-synuclein could lead to alterations in sleep patterns reminiscent of those observed in PD by measuring sleep/wake activity with rigorous quantitative methods in a well-characterized genetic mouse model.Methods:At 10 months of age, mice expressing human wildtype alpha-synuclein under the Thy-1 promoter (Thy1-aSyn) and wildtype littermates underwent the subcutaneous implantation of a telemetry device (Data Sciences International) for the recording of electromyograms (EMG) and electroencephalograms (EEG) in freely moving animals. Surgeries and data collection were performed without knowledge of mouse genotype.Results:Thy1-aSyn mice showed increased non-rapid eye movement sleep during their quiescent phase, increased active wake during their active phase, and decreased rapid eye movement sleep over a 24-h period, as well as a shift in the density of their EEG power spectra toward lower frequencies with a significant decrease in gamma power during wakefulness.Conclusions:Alpha-synuclein overexpression in mice produces sleep disruptions and altered oscillatory EEG activity reminiscent of PD, and this model provides a novel platform to assess mechanisms and therapeutic strategies for sleep dysfunction in PD.

Dopamine acting at D1-like, D2-like and α1-adrenergic receptors differentially modulates theta and gamma oscillatory activity in primary motor cortex.

The loss of dopamine (DA) in Parkinson’s is accompanied by the emergence of exaggerated theta and beta frequency neuronal oscillatory activity in the primary motor cortex (M1) and basal ganglia. DA replacement therapy or deep brain stimulation reduces the power of these oscillations and this is coincident with an improvement in motor performance implying a causal relationship. Here we provide in vitro evidence for the differential modulation of theta and gamma activity in M1 by DA acting at receptors exhibiting conventional and non-conventional DA pharmacology. Recording local field potentials in deep layer V of rat M1, co-application of carbachol (CCh, 5 μM) and kainic acid (KA, 150 nM) elicited simultaneous oscillations at a frequency of 6.49 ± 0.18 Hz (theta, n = 84) and 34.97 ± 0.39 Hz (gamma, n = 84). Bath application of DA resulted in a decrease in gamma power with no change in theta power. However, application of either the D1-like receptor agonist SKF38393 or the D2-like agonist quinpirole increased the power of both theta and gamma suggesting that the DA-mediated inhibition of oscillatory power is by action at other sites other than classical DA receptors. Application of amphetamine, which promotes endogenous amine neurotransmitter release, or the adrenergic α1-selective agonist phenylephrine mimicked the action of DA and reduced gamma power, a result unaffected by prior co-application of D1 and D2 receptor antagonists SCH23390 and sulpiride. Finally, application of the α1-adrenergic receptor antagonist prazosin blocked the action of DA on gamma power suggestive of interaction between α1 and DA receptors. These results show that DA mediates complex actions acting at dopamine D1-like and D2-like receptors, α1 adrenergic receptors and possibly DA/α1 heteromultimeric receptors to differentially modulate theta and gamma activity in M1.

0014 TRACE AMINE-ASSOCIATED RECEPTOR 1 REGULATES WAKEFULNESS, BEHAVIORAL ACTIVATION AND EEG SPECTRAL COMPOSITION

Trace amines (TAs) are endogenous amino acid metabolites that are structurally similar to the biogenic amines. TAs are endogenous ligands for trace amine-associated receptor 1 (TAAR1), a GPCR that modulates dopaminergic, serotonergic, and glutamatergic activity. Selective TAAR1 agonists have been shown to have pro-cognitive, antipsychotic-like, anti-addiction, stress-reducing, weight-reducing, glucose-lowering and wake-promoting activities. We used Taar1 knockout (KO) and over-expressing (OE) mice and TAAR1 agonists to elucidate the role of TAAR1 in sleep/wake. EEG, EMG, body temperature (Tb) and locomotor activity (LMA) were recorded in Taar1 KO, OE and WT mice. Following a 24h recording to characterize baseline sleep/wake, mice were sleep-deprived (SD) for 6h. In separate experiments, mice were given three doses of the TAAR1 partial agonist RO5263397, caffeine, modafinil or vehicle p.o. Baseline wakefulness was modestly increased in OE compared to WT mice. Baseline theta (4.5-9Hz) and low gamma (30-60Hz) activity was elevated in KO compared to OE mice in NREM and REM sleep. Following SD, both KO and OE mice exhibited a homeostatic sleep rebound. In WT mice, RO5263397 increased waking and reduced NREM and REM sleep, decreased gamma power during wake and NREM, and decreased Tb without affecting LMA; these effects were absent in KO mice and potentiated in OE mice. By contrast, caffeine increased wake time, NREM gamma power, and LMA in all strains compared to vehicle; this effect was attenuated in KO and potentiated in OE mice. Subsequent studies confirmed that motor activation and gamma band activity increases induced by caffeine or modafinil are attenuated in KO mice compared to WT. TAAR1 overexpression increases wakefulness whereas TAAR1 partial agonism strongly increases wakefulness and reduces NREM and REM sleep. These results indicate a modulatory role for TAAR1 in sleep/wake and cortical activity and suggest TAAR1 as a novel target for wake-promoting therapeutics. NIH R01 NS082876.

Trace Amine-Associated Receptor 1 Regulates Wakefulness and EEG Spectral Composition.

Trace amine-associated receptor 1 (TAAR1) agonists have been shown to have procognitive, antipsychotic-like, anxiolytic, weight-reducing, glucose-lowering, and wake-promoting activities. We used Taar1 knockout (KO) and overexpressing (OE) mice and TAAR1 agonists to elucidate the role of TAAR1 in sleep/wake. EEG, EMG, body temperature (Tb), and locomotor activity (LMA) were recorded in Taar1 KO, OE, and WT mice. Following a 24 h recording to characterize basal sleep/wake parameters, mice were sleep deprived (SD) for 6 h. In another experiment, mice were given three doses of the TAAR1 partial agonist RO5263397, caffeine, or vehicle p.o. Baseline wakefulness was modestly increased in OE compared with WT mice. Baseline theta (4.5-9 Hz) and low gamma (30-60 Hz) activity was elevated in KO compared with OE mice in NREM and REM sleep. Following SD, both KO and OE mice exhibited a homeostatic sleep rebound. In WT mice, RO5263397 increased waking and reduced NREM and REM sleep, decreased gamma power during wake and NREM, and decreased Tb without affecting LMA; these effects were absent in KO mice and potentiated in OE mice. In contrast, caffeine increased wake time, NREM gamma power, and LMA in all strains compared with vehicle; this effect was attenuated in KO and potentiated in OE mice. TAAR1 overexpression modestly increases wakefulness, whereas TAAR1 partial agonism increases wakefulness and also reduces NREM and also REM sleep. These results indicate a modulatory role for TAAR1 in sleep/wake and cortical activity and suggest TAAR1 as a novel target for wake-promoting therapeutics.

Overexpression of Dyrk1A, a Down Syndrome Candidate, Decreases Excitability and Impairs Gamma Oscillations in the Prefrontal Cortex.

DYRK1Ais a major candidate gene in Down syndrome. Its overexpression results into altered cognitive abilities, explained by defective cortical microarchitecture and excitation/inhibition imbalance. An open question is how these deficits impact the functionality of the prefrontal cortex network. Combining functional, anatomical, and computational approaches, we identified decreased neuronal firing rate and deficits in gamma frequency in the prefrontal cortices of transgenic mice overexpressingDyrk1A We also identified a reduction of vesicular GABA transporter punctae specifically on parvalbumin positive interneurons. Using a conductance-based computational model, we demonstrate that this decreased inhibition on interneurons recapitulates the observed functional deficits, including decreased gamma power and firing rate. Our results suggest that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of Down syndrome.

Distribution, Amplitude, Incidence, Co-Occurrence, and Propagation of Human K-Complexes in Focal Transcortical Recordings

K-complexes (KCs) are thought to play a key role in sleep homeostasis and memory consolidation; however, their generation and propagation remain unclear. The commonly held view from scalp EEG findings is that KCs are primarily generated in medial frontal cortex and propagate parietally, whereas an electrocorticography (ECOG) study suggested dorsolateral prefrontal generators and an absence of KCs in many areas. In order to resolve these differing views, we used unambiguously focal bipolar depth electrode recordings in patients with intractable epilepsy to investigate spatiotemporal relationships of human KCs. KCs were marked manually on each channel, and local generation was confirmed with decreased gamma power. In most cases (76%), KCs occurred in a single location, and rarely (1%) in all locations. However, if automatically detected KC-like phenomena were included, only 15% occurred in a single location, and 27% occurred in all recorded locations. Locally generated KCs were found in all sampled areas, including cingulate, ventral temporal, and occipital cortices. Surprisingly, KCs were smallest and occurred least frequently in anterior prefrontal channels. When KCs occur on two channels, their peak order is consistent in only 13% of cases, usually from prefrontal to lateral temporal. Overall, the anterior–posterior separation of electrode pairs explained only 2% of the variance in their latencies. KCs in stages 2 and 3 had similar characteristics. These results open a novel view where KCs overall are universal cortical phenomena, but each KC may variably involve small or large cortical regions and spread in variable directions, allowing flexible and heterogeneous contributions to sleep homeostasis and memory consolidation.

Epileptic Discharges Affect the Default Mode Network – fMRI and Intracerebral EEG Evidence

Functional neuroimaging studies of epilepsy patients often show, at the time of epileptic activity, deactivation in default mode network (DMN) regions, which is hypothesized to reflect altered consciousness. We aimed to study the metabolic and electrophysiological correlates of these changes in the DMN regions. We studied six epilepsy patients that underwent scalp EEG-fMRI and later stereotaxic intracerebral EEG (SEEG) sampling regions of DMN (posterior cingulate cortex, Pre-cuneus, inferior parietal lobule, medial prefrontal cortex and dorsolateral frontal cortex) as well as non-DMN regions. SEEG recordings were subject to frequency analyses comparing sections with interictal epileptic discharges (IED) to IED-free baselines in the IED-generating region, DMN and non-DMN regions. EEG-fMRI and SEEG were obtained at rest. During IEDs, EEG-fMRI demonstrated deactivation in various DMN nodes in 5 of 6 patients, most frequently the pre-cuneus and inferior parietal lobule, and less frequently the other DMN nodes. SEEG analyses demonstrated decrease in gamma power (50–150 Hz), and increase in the power of lower frequencies (<30 Hz) at times of IEDs, in at least one DMN node in all patients. These changes were not apparent in the non-DMN regions. We demonstrate that, at the time of IEDs, DMN regions decrease their metabolic demand and undergo an EEG change consisting of decreased gamma and increased lower frequencies. These findings, specific to DMN regions, confirm in a pathological condition a direct relationship between DMN BOLD activity and EEG activity. They indicate that epileptic activity affects the DMN, and therefore may momentarily reduce the consciousness level and cognitive reserve.