Functional connectivity (FC) during sleep has been shown to break down as non-rapid eye movement (NREM) sleep deepens before returning to a state closer to wakefulness during REM sleep. However, the specific spatial and temporal signatures of these fluctuations in connectivity patterns remain poorly understood. The goal of this study was to investigate how frequency-dependent network-level FC fluctuates during nocturnal sleep in healthy young adults using high-density electroencephalography (hdEEG). Specifically, we examined source-localized FC in resting-state networks during NREM2, NREM3, and REM sleep in the first three sleep cycles of 29 participants. Our results showed that FC within and between all resting-state networks decreased from NREM2 to NREM3 sleep in multiple frequency bands and in all sleep cycles. The data also highlighted a complex modulation of connectivity patterns during the transition to REM sleep whereby delta and sigma bands hosted a persistence of the connectivity breakdown in all networks, whereas a reconnection was observed in the default mode (DMN) and the attentional networks in frequency bands characterizing their organization during wake (i.e., alpha and beta bands, respectively). Finally, all network pairs (except the visual network) showed higher gamma-band FC during REM sleep in cycle three compared to earlier cycles during the night. Altogether, our results unravel the spatial and temporal characteristics of the well-known breakdown in connectivity observed as NREM sleep deepens. They also shed light on a complex pattern of connectivity during REM sleep that is consistent with both breakdown and reconnection processes that are network- and frequency-specific.
Auditory processing and the complexity of neural activity can both indicate residual conscious-ness levels and differentiate between states of arousal. However, how measures of neural signal diversity, or complexity, manifest in evoked activity, and, more generally, how the electrophys-iological characteristics of auditory responses change in states of reduced consciousness, re-main under-explored. Here, we tested the hypothesis that measures of neural complexity and the spectral slope would discriminate stages of sleep not only in spontaneous EEG, but also in auditory-evoked responses. High-density EEG was recorded in 21 participants to determine the spatial relationship between these measures, and between spontaneous and auditory-evoked signals. Results showed that the complexity and the spectral slope in the 2-20 Hz range dis-criminated between sleep stages and had a high correlation in sleep. In wakefulness, complexity was strongly correlated to the 20-40 Hz spectral slope. Auditory stimulation resulted in reduced complexity in sleep compared to spontaneous activity and modulated the spectral slope in wake-fulness. These findings demonstrate the persistence of electrophysiological markers of arousal during both spontaneous and evoked EEG activity and have direct applications to studies using auditory stimulation to probe neural functions in states of reduced consciousness.
Listening effort can be defined as a measure of cognitive resources used by listeners to perform a listening task. Several methods have been proposed to assess listening effort, but the reliability of these methods has not yet been thoroughly established, which is necessary before using them in research or clinical settings. This study included 32 participants who performed speech-in-noise tasks in two sessions (separated approx. 1 week apart) by listening to Sentences and Word lists presented at different signal-to-noise ratios (-9, -6, -3, and 0 dB). We assessed the test-retest reliability of the self-reported measure of listening effort and frontal midline theta (Fmθ) power, which has been proposed as a neural correlate of listening effort. The reliability of the percentage of correct words was also examined. Relative and absolute reliability was evaluated using intraclass correlation coefficients (ICC) and Bland-Altman analysis, respectively. The standard error of measurement (SEM) and the smallest detectable change (SDC) were also assessed. Overall, the reliability analysis revealed an acceptable between-session variability for the correct words and effort rating. However, Fmθ power showed high variability, which brings into question its use as a reliable correlate of listening effort.
A major challenge in neuroscience is to pinpoint neurobiological correlates of specific cognitive and neuropsychiatric traits. At the mesoscopic level, promising candidates for establishing such connections are brain oscillations that can be robustly recorded as local field potentials with varying frequencies in the hippocampus in vivo and in vitro. Inbred mouse strains show natural variation in hippocampal synaptic plasticity (e.g., long-term potentiation), a cellular correlate of learning and memory. However, their diversity in expression of different types of hippocampal network oscillations has not been fully explored. Here, we investigated hippocampal network oscillations in three widely used inbred mouse strains: C57BL/6J (B6J), C57BL/6NCrl (B6N) and 129S2/SvPasCrl (129) with the particular aim to identify common oscillatory characteristics in inbred mouse strains that show aberrant emotional/cognitive behaviour (B6N and 129) and compare them to “control” B6J strain. First, we detected higher gamma oscillation power in the hippocampal CA3 of both B6N and 129 strains. Second, an increased incidence of hippocampal sharp wave-ripple (SW-R) transients was evident in these strains. Third, we observed prominent differences in the densities of distinct interneuron types and CA3 associative network activity which are indispensable for sustainment of mesoscopic network oscillations. Together, these results supports the notion that in vitro hippocampal network oscillations, similar to classical plasticity read-outs measured in hippocampal slices, can be used as robust reductionist models to study electrophysiological correlates of emotional and cognitive phenotypes. Importantly, we add further evidence to profound physiological differences among inbred mouse strains commonly used in neuroscience research.
The rise of deepfakes and AI-generated images has raised concerns regarding their potential misuse in society. However, this commentary highlights the valuable opportunities these technologies offer for neuroscience research. Deepfakes provide accessible, realistic, and customisable dynamic face stimuli, while generative adversarial networks (GANs) can generate and modify diverse and high-quality static content. These advancements enhance the variability and ecological validity of research methods, and enable the creation of previously unattainable stimuli. When AI-generated images are informed by brain responses, they provide unique insights into the structure and function of visual systems. The authors encourage experimental psychologists and cognitive neuroscientists to stay informed about these emerging tools and embrace their potential to advance visual neuroscience.
The clinical assessment of patients with disorders of consciousness (DoC) relies on the observation of behavioral responses to standardized sensory stimulation. However, several medical comorbidities may directly impair the production of reproducible and appropriate responses, thus reducing the sensitivity of behavior-based diagnoses. One of these is Akinetic Mutism (AM), a rare neurological syndrome characterized by the inability to initiate volitional motor responses, sometimes associated with clinical presentations overlapping with those of DoC. Here we describe the case of a patient with large bilateral mesial frontal lesions showing a prolonged behavioral unresponsiveness and a severe disorganization of electroencephalographic (EEG) background, compatible with a vegetative state/unresponsive wakefulness syndrome (VS/UWS). By applying an unprecedented battery of multimodal longitudinal measurements encompassing spontaneous EEG, evoked potentials, event-related potentials, transcranial magnetic stimulation-evoked potentials, and structural and functional MRI, we provide (i) a demonstration of the preservation of consciousness despite unresponsiveness in the context of a complete AM, (ii) a plausible neurophysiological explanation of behavioral unresponsiveness and of its subsequent recovery during rehabilitation stay and (iii) novel insights into the relationships between DoC, AM and parkinsonism. The present case provides proof-of-principle evidence supporting the clinical utility of a multimodal hierarchical workflow combining conventional and advanced techniques to detect covert signs of consciousness in unresponsive patients.
Dopamine, a catecholamine neurotransmitter, has historically been associated with the encoding of reward, whereas its role in aversion has received less attention. Here, we systematically gathered the vast evidence of the role of dopamine in the simplest forms of aversive learning: classical fear conditioning and extinction. In the past, crude methods were used to augment or inhibit dopamine to study its relationship with fear conditioning and extinction. More advanced techniques such as conditional genetic, chemogenic, and optogenetic approaches now provide causal evidence for dopamine's role in these learning processes. Dopamine neurons encode conditioned stimuli during fear conditioning and extinction, and convey the signal via activation of D1-4 receptor sites particularly in the amygdala, prefrontal cortex, and striatum. The coordinated activation of dopamine receptors allows for the continuous formation, consolidation, retrieval, and updating of fear and extinction memory in a dynamic and reciprocal manner. Based on the reviewed literature, we conclude that dopamine is crucial for the encoding of classical fear conditioning and extinction and contributes in a way that is comparable to its role in encoding reward.
Environmental factors interact with biological and genetic factors influencing the development and well-being of an organism. The interest to better understand the role of environment on behavior and physiology led to the development of animal models of environmental manipulations. Environmental Enrichment (EE), an environmental condition that allows cognitive and sensory stimulation as well as social interaction, improves cognitive function, reduces anxiety and depressive-like behavior, and promotes neuroplasticity. In addition, it exerts protection against neurodegenerative disorders, cognitive aging and deficits aggravated by stressful experiences. Given the beneficial effects of EE on brain and behavior, preclinical studies focus on its protective role as an alternative, non-invasive manipulation, to help an organism to cope better with stress. A valid, reliable and effective animal model of chronic stress that enhances anxiety and depression-like behavior is the Chronic Unpredictable Mild Stress (CUMS). The variety of stressors and the unpredictability in the time and sequence of exposure to prevent habituation, render CUMS an ethologically relevant model. CUMS has been associated with dysregulation of the Hypothalamic-Pituitary-Adrenal axis, elevation in the basal levels of stress hormones, reduction in brain volume, dendritic atrophy and alterations in markers of synaptic plasticity. Although numerous studies have underlined the compensatory role of EE against the negative effects of various chronic stress regimens (e.g., restraint, social isolation), research concerning the interaction between EE and CUMS is sparse. The purpose of the current systematic review is to present up-to-date research findings regarding the protective role of EE against the negative effects of CUMS.
Parkinson’s Disease (PD) and vitamin D share a unique link as Vitamin D deficiency (VDD) prevails in PD. Thus, an in-depth understanding of Vitamin D biology in PD might be crucial for therapeutic strategies emphasizing Vitamin D. Specifically, explicating the effect of VDD and genetic polymorphisms of vitamin D-associated genes in PD, like VDR (Vitamin D Receptor) or GC (Vitamin D Binding Protein), may aid the process along with polymorphisms of Vitamin D metabolizing genes (e.g., CYP2R1, CYP27A1) in PD. Literature review of single nucleotide polymorphisms (SNPs) related to Vitamin D levels [GC (GC1-rs7041, GC2-rs4588), CYP2R1, CYP24A1, CYP27B1] and Vitamin D function [VDR (FokI - rs2228570, ApaI - rs7976091, BsmI-rs1544410, TaqI-rs731236)] was conducted to explore their relationship with PD severity globally. Furthermore, the DisGeNET database was utilized to explore the gene-disease associations in PD, and STRING alongside Cytoscape was utilized to identify critical genes associated with PD. VDR-FokI polymorphism was reported to be significantly associated with PD in Hungarian, Chinese, and Japanese populations, whereas VDR-ApaI polymorphism was found to affect PD in the Iranian population. However, VDR-TaqI and BsmI polymorphisms had no significant association with PD severity. Conversely, GC1 polymorphisms reportedly affected Vitamin D levels without influencing the disease severity. CYP2R1 (excluding rs1993116) was also reportedly linked to clinical manifestations of PD. Genetic polymorphisms might cause VDD despite enough sunlight exposure and vitamin D-rich food intake, enhancing inflammation, and thereby influencing PD pathophysiology. Knowledge of the polymorphisms associated with vitamin D appears promising for developing new therapeutic strategies against PD.
Alzheimer’s Disease (AD) is a familial or sporadic severe neurodegenerative disorder that leads to short-term memory impairment followed by progressive cognitive deterioration of executive functions. AD frequency is increasing with a consequent socio-economic burden and there is an urgent need to understand its aetiological complexity, find reliable animal models and identify effective therapeutic treatments. AD diagnosis relies on a series of neuropsychiatric criteria and the detection of two pathognomonic protein aggregates in the brain parenchyma: amyloid plaques and neurofibrillary tangles. The concurrence of these aggregates seems to be mostly present in humans. In this issue, Vacher and colleagues demonstrate the notable coexistence of AP deposition and hyperphosphorylated tau in the brains of dolphins. Here we discuss the relevance of this finding and how they could help understanding AD
Non-invasive sensory stimulation in the range of the brain’s gamma rhythm (30-100 Hz) is emerging as a new potential therapeutic strategy for the treatment of Alzheimer’s disease (AD). Here we investigated the effect of repeated combined exposure to 40 Hz synchronized sound and light stimuli on hippocampal long-term potentiation (LTP) in vivo in three rat models of early AD. We employed a very complete model of AD amyloidosis, amyloid precursor protein (APP)-overexpressing transgenic McGill-R-Thy1-APP rats at an early pre-plaque stage, systemic treatment of transgenic APP rats with corticosterone modelling certain environmental AD risk factors and, importantly, intracerebral injection of highly disease-relevant AD patient-derived synaptotoxic beta-amyloid and tau in wild-type animals. We found that daily sessions of 40 Hz sensory stimulation fully abrogated the inhibition of LTP in all three models. Moreover, there was a negative correlation between the magnitude of LTP and the level of active caspase-1 in the hippocampus of transgenic APP animals which suggests that the beneficial effect of 40 Hz stimulation was dependent on modulation of pro-inflammatory mechanisms. Our findings support ongoing clinical trials of gamma-patterned sensory stimulation in early AD.
Individuals diagnosed with schizophrenia spectrum disorders (SSD) exhibit a constellation of sensory and perceptual impairments, including hyporeactivity to external input. However, individuals with SSD also report subjective experiences of sensory flooding, suggesting sensory hyperexcitability. To identify the extent to which behavioral indices of hyperexcitability are related to non-psychotic symptoms of schizophrenia, we tested a non-clinical population measured for schizophrenia-like traits (schizotypy), and a behavioral measure of sensory hyperexcitability, specifically the number of illusions seen in the Pattern Glare Test. Two samples totaling 913 individuals completed an online version of the Schizotypal Personality Questionnaire – Brief Revised (SPQ-BR) and the Pattern Glare Test. Individuals with higher schizotypy traits reported more illusions in the Pattern Glare Test. Additionally, one of the three SPQ-BR factors, the disorganized factor, significantly predicted the number of illusions reported. These data illustrate the potential for research in non-clinical samples to inform clinically relevant research.
Post-stroke depression (PSD), a common complication after stroke, severely affects the recovery and quality of life of patients with stroke. Owing to its complex mechanisms, PSD treatment remains highly challenging. Hippocampal synaptic plasticity is one of the key factors leading to PSD; however, the precise molecular mechanisms remain unclear. Numerous studies have found that neurotrophic factors, protein kinases, and neurotransmitters influence depressive behavior by modulating hippocampal synaptic plasticity. This review further elaborates on the role of hippocampal synaptic plasticity in PSD by summarizing recent research and analyzing possible molecular mechanisms. Evidence for the correlation between hippocampal mechanisms and PSD helps to better understand the pathological process of PSD and improve its treatment.
Obesity is rising globally and is associated with neurodevelopmental and psychiatric disorders among children, adolescents, and young adults. Whether obesity is the cause or the consequence of these disorders remains unclear. To examine the behavioural effects of obesity systematically, locomotion, anxiety, and social behaviour were assessed in male and female C57Bl/6J mice using the open field (OF), elevated plus maze (EPM) and social preference (SP) task. First, the effects of age, sex and prior exposure to the tasks were examined in control mice, before investigating post-weaning consumption of a high fat, high sugar (HFHS) diet commonly consumed in human populations with high rates of obesity. In the OF and EPM, locomotor activity and anxiety-related behaviours were reduced by age in both sexes, but with different sex-specific profiles. Prior exposure to the tasks reduced locomotion in the OF in a sex-specific manner but had little effect on behaviour in the EPM in either sex. The HFHS diet reduced food and calorie intake and increased body mass and fat deposition in both sexes. In the OF, both male and female HFHS mice showed reduced locomotion, whereas, in the EPM, only HFHS female mice displayed reduced anxiety-related behaviours. Both male and female HFHS mice had a significantly higher SP index than controls. Collectively, the findings demonstrate that the behavioural effects of age, prior exposure and of diet-induced obesity all depend on the sex of the mouse. This emphasises the importance of including both sexes when assessing behavioural phenotypes arising from dietary manipulations.
Limited axon regeneration following peripheral nerve injury may be related to activation of the lysosomal protease, asparaginyl endopeptidase (AEP, δ-secretase), and its degradation of the microtubule associated protein, Tau. Activity of AEP was increased at the site of sciatic nerve transection and repair but blocked in mice treated systemically with a specific AEP inhibitor, compound 11 (CP11). Treatments with CP11 enhanced axon regeneration in vivo. Amplitudes of compound muscle action potentials recorded four weeks after nerve transection and repair and two weeks after daily treatments with CP11 were double those of vehicle-treated mice. At that time after injury, axons of significantly more motor and sensory neurons had regenerated successfully and reinnervated the tibialis anterior and gastrocnemius muscles in CP11-treated mice than vehicle-treated controls. In cultured adult dorsal root ganglion neurons derived from wild type mice that were treated in vitro for 24 hours with CP11, neurites were nearly 50% longer than in vehicle-treated controls, and similar to neurite lengths in cultures treated with the TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF). Combined treatment with CP11 and 7,8-DHF did not enhance outgrowth more than treatments with either one alone. Enhanced neurite outgrowth produced by CP11 was found also in the presence of the TrkB inhibitor, ANA-12, indicating that the enhancement was independent of TrkB signaling. Longer neurites were found after CP11 treatment in both TrkB+ and TrkB- neurons. Delta secretase inhibition by CP11 is a treatment for peripheral nerve injury with great potential.