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Rachel E Kaskie,1 Bianca Graziano,2 Fabio Ferrarelli1 1Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA; 2Department of Health Sciences, Università degli Studi di Milano, Milan, Italy Abstract: Schizophrenia is a major psychiatric disorder that has a massive, long-lasting negative impact on the patients as well as society. While positive symptoms (i.e., delusions and hallucinations), negative symptoms (i.e., anhedonia, social withdrawal), and cognitive impairments are traditionally considered the most prominent features of this disorder, the role of sleep and sleep disturbances has gained increasing prominence in clinical practice. Indeed, the vast majority of patients with schizophrenia report sleep abnormalities, which tend to precede illness onset and can predict an acute exacerbation of psychotic symptoms. Furthermore, schizophrenia patients often have a comorbid sleep disorder, including insomnia, obstructive sleep apnea, restless leg syndrome, or periodic limb movement disorder. Despite accumulating data, the links between sleep disorders and schizophrenia have not been thoroughly examined, in part because they are difficult to disentangle, as numerous factors contribute to their comorbidity, including medication status. Additionally, sleep disorders are often not the primary focus of clinicians treating this population, despite studies suggesting that comorbid sleep disorders carry their own unique risks, including worsening of psychotic symptoms and poorer quality of life. There is also limited information about effective management strategies for schizophrenia patients affected by significant sleep disturbances and/or sleep disorders. To begin addressing these issues, the present review will systematically examine the literature on sleep disorders and schizophrenia, focusing on studies related to 1) links between distinct sleep disorders and schizophrenia; 2) risks unique to patients with a comorbid sleep disorder; and 3) and management challenges and strategies. Keywords: psychosis, sleep disturbances, insomnia, obstructive sleep apnea

Simulated military operational stress (SMOS) provides a useful model to better understand resilience in humans as the stress associated with caloric restriction, sleep deficits, and fatiguing exertion degrades physical and cognitive performance. Habitual physical activity may confer resilience against these stressors by promoting favorable use-dependent neuroplasticity, but it is unclear how physical activity, resilience, and corticospinal excitability (CSE) relate during SMOS. To examine associations between corticospinal excitability, physical activity, and physical performance during SMOS. Fifty-three service members (age: 26 ± 5 yr, 13 women) completed a 5-day and -night intervention composed of familiarization, baseline, SMOS (2 nights/days), and recovery days. During SMOS, participants performed rigorous physical and cognitive activities while receiving half of normal sleep (two 2-h blocks) and caloric requirements. Lower and upper limb CSE were determined with transcranial magnetic stimulation (TMS) stimulus-response curves. Self-reported resilience, physical activity, military-specific physical performance (TMT), and endocrine factors were compared in individuals with high (HIGH) and low CSE based on a median split of lower limb CSE at baseline. HIGH had greater physical activity and better TMT performance throughout SMOS. Both groups maintained physical performance despite substantial psychophysiological stress. Physical activity, resilience, and TMT performance were directly associated with lower limb CSE. Individual differences in physical activity coincide with lower (but not upper) limb CSE. Such use-dependent corticospinal excitability directly relates to resilience and physical performance during SMOS. Future studies may use noninvasive neuromodulation to clarify the interplay among CSE, physical activity, and resilience and improve physical and cognitive performance. [ABSTRACT FROM AUTHOR]

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

Deficits in mediodorsal thalamus-dorsolateral prefrontal cortex (MDT-DLPFC) resting-state functional magnetic resonance imaging (rs-fMRI) connectivity and prefrontal sleep spindles have been reported in chronic and early course schizophrenia. However, the presence of these alterations in clinical high-risk for psychosis (CHR), alongside their relationships with underlying neurotransmission and cognitive function, remains to be established. Thirty-one CHR and thirty-two HC underwent: 1) 7 T rs-fMRI; 2) 7 T magnetic resonance spectroscopy imaging (MRSI); and 3) sleep electroencephalography (EEG). Rs-fMRI connectivity was analyzed by seeding the whole thalamus (WT) and seven thalamic subsections. Spindle duration was computed across all EEG channels. GABA/creatine (Cr) and glutamate/Cr were calculated in DLPFC and MDT. Relative to HC, CHR showed WT-DLPFC hypoconnectivity (p-FDR = 0.001), especially involving MDT-DLPFC (p-FDR < 0.001) and reduced prefrontal spindle duration (t-stat = -2.64, p = 0.010), while no differences were found for MRSI neuro-metabolites. We then performed clustering analysis using rs-fMRI connectivity and spindle duration to identify CHR and HC subgroups and predict their working memory (WM) performance. A cluster with intact rs-fMRI and spindle duration included mostly HC (83.33% purity), while a cluster with both measures altered involved almost entirely CHR (91.66% purity) and showed worse WM performances. We also examined MRSI metabolites' contribution to spindles and rs-fMRI connectivity with a within-group multivariable regression analysis. In HC, but not in CHR, MDT glutamate/Cr negatively predicted spindle duration and positively predicted MDT-DLPFC connectivity. Combined, these findings indicate that a multimodal neuroimaging approach can identify distinct thalamocortical dysfunctions in CHR individuals, thus informing future research aimed at developing personalized interventions in these individuals., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Abnormalities in dorsolateral prefrontal cortex (DLPFC) oscillations are neurophysiological signatures of schizophrenia thought to underlie its cognitive deficits. Transcranial magnetic stimulation with electroencephalography (TMS-EEG) provides a measure of cortical oscillations unaffected by sensory relay functionality and/or patients' level of engagement, which are important confounding factors in schizophrenia. Previous TMS-EEG work showed reduced fast, gamma-range oscillations and a slowing of the main DLPFC oscillatory frequency, or natural frequency, in chronic schizophrenia. However, it is unclear whether this DLPFC natural frequency slowing is present in early-course schizophrenia (EC-SCZ) and is associated with symptom severity and cognitive dysfunction., Methods: We applied TMS-EEG to the left DLPFC in 30 individuals with EC-SCZ and 28 healthy control participants. Goal-directed working memory performance was assessed using the AX-Continuous Performance Task. The EEG frequency with the highest cumulative power at the stimulation site, or natural frequency, was extracted. We also calculated the local relative spectral power as the average power in each frequency band divided by the broadband power., Results: Compared with the healthy control group, the EC-SCZ group had reduced DLPFC natural frequency (p = .0000002, Cohen's d = -2.32) and higher DLPFC beta-range relative spectral power (p = .0003, Cohen's d = 0.77). In the EC-SCZ group, the DLPFC natural frequency was inversely associated with negative symptoms. Across all participants, the beta band relative spectral power negatively correlated with AX-Continuous Performance Task performance., Conclusions: DLPFC oscillatory slowing is an early pathophysiological biomarker of schizophrenia that is associated with its symptom severity and cognitive impairments. Future work should assess whether noninvasive neurostimulation, including repetitive TMS, can ameliorate prefrontal oscillatory deficits and related clinical functions in patients with EC-SCZ., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Non-invasive brain stimulation (NIBS) techniques are designed to precisely and selectively target specific brain regions, thus enabling focused modulation of neural activity. Among NIBS technologies, low-intensity transcranial focused ultrasound (tFUS) has emerged as a promising new modality. The application of tFUS can safely and non-invasively stimulate deep brain structures with millimetric precision, offering distinct advantages in terms of accessibility to non-cortical regions over other NIBS methods. However, to date, several tFUS aspects still need to be characterized; furthermore, there are only a handful of studies that have utilized tFUS in psychiatric populations. This narrative review provides an up-to-date overview of key aspects of this NIBS technique, including the main components of a tFUS system, the neuronavigational tools used to precisely target deep brain regions, the simulations utilized to optimize the stimulation parameters and delivery of tFUS, and the experimental protocols employed to evaluate the efficacy of tFUS in psychiatric disorders. The main findings from studies in psychiatric populations are presented and discussed, and future directions are highlighted.

Purpose of Review: We review recent studies published from 2019 to 2024 examining slow waves and sleep spindles abnormalities across neurodevelopmental, mood, trauma-related, and psychotic disorders using polysomnography and Electroencephalogram (EEG)., Recent Findings: Individuals with attention-deficit/hyperactivity disorder (ADHD) showed higher slow-spindle activity, while findings on slow-wave activity were mixed. Individuals with autism spectrum disorder (ASD) showed inconsistent results with some evidence of lower spindle chirp and slow-wave amplitude. Individuals with depression displayed lower slow-wave and spindle parameters mostly in medicated patients. Individuals with post-traumatic stress disorder (PTSD) showed higher spindle frequency and activity, which were associated with their clinical symptoms. Psychotic disorders demonstrated the most consistent alterations, with lower spindle density, amplitude, and duration across illness stages that correlated with patients' symptom severity and cognitive deficits, whereas lower slow-wave measures were present in the early phases of the disorders. Sleep spindle and slow-wave abnormalities are present across psychiatric populations, with the most consistent alterations observed in psychotic disorders. Larger studies with standardized methodologies and longitudinal assessments are needed to establish the potential of these oscillations as neurophysiological biomarkers and/or treatment targets., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15-90. The effects of dementia, mild cognitive impairment, Parkinson's disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia ( p < 0.001), while neither depression nor ADHD showed consistent associations with VLM scores ( p > 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders.

Study Objectives: Microstates are semi-stable voltage topographies that account for most of electroencephalogram (EEG) variance. However, the impact of time of the day and sleep on microstates has not been examined. To address this gap, we assessed whether microstates differed between the evening and morning and whether sleep slow waves correlated with microstate changes in healthy participants., Methods: Forty-five healthy participants were recruited. Each participant underwent 6 minutes of resting state EEG recordings in the evening and morning, interleaved by sleep EEGs. Evening-to-morning changes in microstate duration, coverage, and occurrence were assessed. Furthermore, correlation between microstate changes and sleep slow-wave activity (SWA) and slow-wave density (SWD) were performed., Results: Two-way ANOVAs with microstate class (A, B, C, and D) and time (evening and morning) revealed significant microstate class × time interaction for duration (F(44) = 5.571, p = 0.002), coverage (F(44) = 6.833, p = 0.001), and occurrence (F(44) = 5.715, p = 0.002). Post hoc comparisons showed significant effects for microstate C duration (padj = 0.048, Cohen's d = -0.389), coverage (padj = 0.002, Cohen's d = -0.580), and occurrence (padj = 0.002, Cohen's d = -0.606). Topographic analyses revealed inverse correlations between SWD, but not SWA, and evening-to-morning changes in microstate C duration (r = -0.51, padj = 0.002), coverage (r = -0.45, padj = 0.006), and occurrence (r = -0.38, padj = 0.033)., Conclusions: Microstate characteristics showed significant evening-to-morning changes associated with, and possibly regulated by, sleep slow waves. These findings suggest that future microstate studies should control for time of day and sleep effects., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Schizophrenia (SCZ) is a complex psychiatric disorder characterized by a wide range of clinical symptoms, including disrupted sleep. In recent years, there has been growing interest in assessing alterations in sleep parameters in patients with SCZ. Sleep spindles are brief (0.5-2 s) bursts of 12- to 16-Hz rhythmic electroencephalogram (EEG) oscillatory activity occurring during non-rapid eye movement (NREM) sleep. Spindles have been implicated in several critical brain functions, including learning, memory and plasticity, and are thought to reflect the integrity of underlying thalamocortical circuits. This review aims to provide an overview of the current research investigating sleep spindles in SCZ. After briefly describing the neurophysiological features of sleep spindles, I will discuss alterations in spindle characteristics observed in SCZ, their associations with the clinical symptomatology of these patients and their putative underlying neuronal and molecular mechanisms. I will then discuss the utility of sleep spindle measures as predictors of treatment response and disease progression. Finally, I will highlight future directions for research in this emerging field, including the prospect of utilizing sleep spindles as neurophysiological biomarkers of SCZ., (© 2023 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Individuals at clinical high risk for psychosis (CHR) present subsyndromal psychotic symptoms that can escalate and lead to the transition to a diagnosable psychotic disorder. Identifying biological parameters that are sensitive to these symptoms can therefore help objectively assess their severity and guide early interventions in CHR. Reduced slow wave oscillations (∼1 Hz) during non-rapid eye movement sleep were recently observed in first-episode psychosis patients and were linked to the intensity of their positive symptoms. Here, we collected overnight high-density EEG recordings from 37 CHR and 32 healthy control (HC) subjects and compared slow wave (SW) activity and other SW parameters (i.e., density and negative peak amplitude) between groups. We also assessed the relationships between clinical symptoms and SW parameters in CHR. While comparisons between HC and the entire CHR group showed no SW differences, CHR individuals with higher positive symptom severity (N = 18) demonstrated a reduction in SW density in an EEG cluster involving bilateral prefrontal, parietal, and right occipital regions compared to matched HC individuals. Furthermore, we observed a negative correlation between SW density and positive symptoms across CHR individuals, suggesting a potential target for early treatment interventions., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Depression is associated with diminished positive affect (PA), postulated to reflect frontostriatal reward circuitry disruptions. Depression has consistently been associated with higher dorsomedial prefrontal cortex (dmPFC) activation, a region that regulates PA through ventral striatum (VS) connections. Low PA in depression may reflect dmPFC's aberrant functional connectivity (FC) with the VS. To test this, we applied theta burst stimulation (TBS) to dmPFC in 29 adults with depression (79% female, M age  = 21.4, SD = 2.04). Using a randomized, counterbalanced design, we administered 3 types of TBS at different sessions: intermittent (iTBS; potentiating), continuous (cTBS; depotentiating), and sham TBS (control). We used neuronavigation to target personalized dmPFC targets based on VS-dmPFC FC. PA and negative affect (NA), and resting-state fMRI were collected pre- and post-TBS. We found no changes in PA or NA with time (pre/post), condition (iTBS, cTBS, sham), or their interaction. Functional connectivity (FC) between the nucleus accumbens and dmPFC showed a significant condition (cTBS, iTBS, and sham) by time (pre-vs. post-TBS) interaction, and post-hoc testing showed decreased pre-to post-TBS for cTBS but not iTBS or sham. For cTBS only, reduced FC pre/post stimulation was associated with increased PA (but not NA). Our findings lend support to the proposed mechanistic model of aberrant FC between the dmPFC and VS in depression and suggest a way forward for treating depression in young adults. Future studies need to evaluate multi-session TBS to test clinical effects., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Sleep spindles and slow waves are the two main oscillatory activities occurring during nonrapid eye movement (NREM) sleep. Here, we will first describe the electrophysiological characteristics of these sleep oscillations along with the neurophysiological and molecular mechanisms underlying their generation and synchronization in the healthy brain. We will then review the extant evidence of deficits in sleep spindles and, to a lesser extent, slow waves, including in slow wave-spindle coupling, in patients with Schizophrenia (SCZ) across the course of the disorder, from at-risk to chronic stages. Next, we will discuss how these sleep oscillatory deficits point to defects in neuronal circuits within the thalamocortical network as well as to alterations in molecular neurotransmission implicating the GABAergic and glutamatergic systems in SCZ. Finally, after explaining how spindle and slow waves may represent neurophysiological biomarkers with predictive, diagnostic, and prognostic potential, we will present novel pharmacological and neuromodulatory interventions aimed at restoring sleep oscillatory deficits in SCZ, which in turn may serve as target engagement biomarkers to ameliorate the clinical symptoms and the quality of life of individuals affected by this devastating brain disorder., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Disruptions in circadian rhythms can occur in healthy aging; however, these changes are more severe and pervasive in individuals with age-related and neurodegenerative diseases, such as dementia. Circadian rhythm alterations are also present in preclinical stages of dementia, for example, in patients with mild cognitive impairments (MCI); thus, providing a unique window of opportunity for early intervention in neurodegenerative disorders. Nonetheless, there is a lack of studies examining the association between relevant changes in circadian rhythms and their relationship with cognitive dysfunctions in MCI individuals. In this review, circadian system alterations occurring in MCI patients are examined compared to healthy aging individuals while also considering their association with MCI neurocognitive alterations. The main findings are that abnormal circadian changes in rest-activity, core body temperature, melatonin, and cortisol rhythms appear in the MCI stage and that these circadian rhythm disruptions are associated with some of the neurocognitive deficits observed in MCI patients. In addition, preliminary evidence indicates that interventions aimed at restoring regular circadian rhythms may prevent or halt the progress of neurodegenerative diseases and mitigate their related cognitive impairments. Future longitudinal studies with repeated follow-up assessments are needed to establish the translational potential of these findings in clinical practice., (© 2022 Wiley-VCH GmbH.)

Sleep disturbance is commonly reported in patients with schizophrenia spectrum disorder (SSD) in the clinical setting. Sleep features can be assessed subjectively, with self-report sleep questionnaires, and objectively with actigraphy and electroencephalogram recordings. Traditionally, electroencephalogram studies have focused on sleep architecture. More recently, numerous studies have investigated alterations in sleep-specific rhythms, including electroencephalogram oscillations, such as sleep spindles and slow waves, in patients with SSD compared with control subjects. Here, I briefly discuss how sleep disturbance is highly prevalent in patients with SSD and I present findings from studies demonstrating abnormalities in sleep architecture and sleep-oscillatory rhythms, with an emphasis on sleep spindles and slow-wave deficits, in these patients. This increasing body of evidence highlights the importance of sleep disturbance in SSD and points to several future research directions with related clinical implications, thus showing that sleep disturbance is more than just a symptom in these patients., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)