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Jessica R Lunsford-Avery,1 Jack D Edinger,1,2 Andrew D Krystal1,3 1Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, 27710, USA; 2Department of Medicine, National Jewish Health, Denver, CO, 80206, USA; 3Departments of Psychiatry and Neurology, University of California San Francisco School of Medicine, San Francisco, CA, 94143, USACorrespondence: Jessica R Lunsford-Avery, Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, 2608 Erwin Road Suite 300, Durham, NC, 27710, USA, Tel +1 919-681-0035, Fax +1 919-681-0016, Email jessica.r.avery@duke.eduPurpose: Sleep is vital to cognition, yet underlying mechanisms remain unclear. Although sleep duration and continuity are two well-established contributors, additional factors—including homeostatic sleep drive processes—may also underlie cognition-related sleep restoration. This study investigates the relative contributions of sleep EEG factors to psychomotor functioning in adults with insomnia and healthy controls (HC) to identify the most significant sleep factors supporting psychomotor functioning.Materials and Methods: Adults with insomnia (n = 37) and HC (n = 39) completed 3 nights of polysomnography and a complex psychomotor task (switching attention task; SAT). Univariate correlations identified the most significant predictors (traditional PSG, spectral EEG, initial delta peak, and overnight delta decline) of SAT performance, which were then entered into multivariable linear regressions examining whether predictors remained significant after accounting for shortened/fragmented sleep and whether relationships differed across groups.Results: In addition to greater wake after sleep onset (WASO; r = 0.33), a slower overnight delta decline (r = 0.50) and a lower initial delta peak (r = − 0.38) were the most significant predictors of poorer SAT performance. Both overnight delta decline (F(7, 68) = 12.52, p < 0.001) and initial delta peak (F(7, 68) = 7.85, p = 0.007) remained significant predictors after controlling for demographics, total sleep time, and WASO. Relationships were analogous across subject groups.Conclusion: Findings suggest that, in addition to sleep duration and continuity, processes related to recovery from and dissipation of homeostatic sleep drive may support psychomotor performance and broadly support daytime functioning in individuals with and without insomnia. Future research may examine overnight delta dynamics as transdiagnostic processes supporting cognition-related sleep restoration across a range of clinical populations.Keywords: insomnia, EEG, homeostatic sleep drive, delta power, cognition, reaction time

During hibernation, critical physiological processes are downregulated and thermogenically induced arousals are presumably needed periodically to fulfil those physiological demands. Among the processes incompatible with a hypome tabolic state is sleep. How

Chronic insomnia is a prevalent disorder associated with significant psychosocial, health, and economic impacts. Cognitive behavioral therapies (CBTs) and benzodiazepine receptor agonist (BzRA) medications are the most widely supported therapeutic approach

Sleep is essential to cognitive function and health in humans, yet the ultimate reasons for sleep-i.e. 'why' sleep evolved-remain mysterious. We integrate findings from human sleep studies, the ethnographic record, and the ecology and evolution of mammalia

STUDY OBJECTIVES: It has long been suspected that sleep is important for regulating body temperature and metabolic-rate. Hibernation, a state of acute hypothermia and reduced metabolic-rate, offers a promising system for investigating those relationships.

Objective: Cancer and its treatments disturb sleep-wake functioning; however, there is little information available on the characteristics and consequences of sleep problems associated with cancer. As part of an effort to improve measurement of sleep-wake functioning, we explored the scope of difficulties with sleep in a diverse group of patients diagnosed with cancer.Methods: We conducted 10 focus groups with patients recruited from the Duke University tumor registry and oncology/hematology clinics. Separate groups were held with patients scheduled to begin or currently undergoing treatment for breast, prostate, lung, colorectal, hematological, and other cancer types and with patients who were in posttreatment follow-up. The content of the focus group discussions was transcribed and analyzed for major themes by independent coders.Results: Participants not only reported causes of sleep disturbance common in other populations, such as pain and restless legs, but they also reported causes that may be unique to cancer populations, including abnormal dreams, anxiety about cancer diagnosis and recurrence, night sweats, and problems with sleep positioning. Many participants felt that sleep problems reduced their productivity, concentration, social interactions, and overall quality of life. Many also shared beliefs about the increased importance of sleep when fighting cancer.Conclusions: The findings underscore the need for interventions that minimize the negative impact of cancer and its treatments on sleep. This study will inform efforts now underway to develop a patient-reported measure of sleep-wake functioning that reflects the breadth of concepts considered important by patients with cancer. [ABSTRACT FROM AUTHOR]

Insomnia is a highly prevalent disorder that can lead to substantial impairments in quality of life and functional capacity. This condition occurs significantly more frequently in women than men. An important contributing factor is that insomnia can occur in association with hormonal changes that are unique to women, such as those of menopause or the late-luteal phase of the menstrual cycle. Another consideration is that women are more likely to suffer from major depression and anxiety disorders, which are also associated with insomnia. The reasons are unclear as are the reasons why women are at increased risk of primary insomnia. These conditions are frequently encountered in clinical practice and present a challenge to the practitioner because there is a striking lack of research data to serve as a guide. For example, there are no published studies to indicate how to safely and effectively manage insomnia that often occurs late in pregnancy. This article reviews the available literature related to these conditions with a focus on the epidemiologic data and diagnosis and treatment of insomnia and highlights the need for further research. [ABSTRACT FROM AUTHOR]

Depression and insomnia are both significantly more prevalent in women than in men. Risks appear linked to fluctuations and transitions in gonadal hormones during various phases of women's lives, with the risk of depression greatest during the period from menarche to menopause. Increased risks of both insomnia and depression also coincide with the late luteal phase of the menstrual cycle, during and after pregnancy, and during the peri-/postmenopausal period. Gonadal hormones exert significant effects on the neurohumoral systems most intimately associated with depression and insomnia, with corresponding implications for treatment. Medications related to the serotonin system--the selective serotonin reuptake inhibitors, or SSRIs--appear to be uniquely effective in the treatment of insomnia and depression experienced by women. SSRIs and the nonbenzodiazepine receptor agonists are generally useful as first-line treatments in a number of circumstances; hormone replacement therapies can also be considered. Behavioral therapies for insomnia may be particularly relevant for postpartum patients because of safety concerns and to prevent the development of autonomous chronic insomnia, which may also increase the risk of depression. In light of the high risk of relapse and high likelihood of comorbidity, it is crucial to effectively treat both insomnia and depression in women. However, few data exist for many key areas related to the treatment of these disorders in women, and research is greatly needed. [ABSTRACT FROM AUTHOR]

Objective: Few studies have characterized the nature of sleep problems among adolescents with attention-deficit/hyperactivity disorder (ADHD) using polysomnography (PSG). Additionally, although adolescents with ADHD and adolescents with sleep disturbances display similar neurocognitive deficits, the role of sleep in contributing to neurocognitive impairment in adolescent ADHD is unknown. This study investigated differences in PSG-measured sleep among adolescents with ADHD compared with non-psychiatric controls and associations with neurocognition., Method: Medication-free adolescents aged 13 to 17 (N = 62, n = 31 with ADHD; mean age = 15.3 years; 50% female) completed a diagnostic evaluation, 3 nights of ambulatory PSG, the Cambridge Neuropsychological Test Automated Battery, and subjective reports of sleep and executive functioning. Linear regressions covarying for age, sex, and pubertal status examined group differences in sleep indices, and partial Pearson correlations assessed relations between sleep and neurocognition., Results: Although adolescents with ADHD did not exhibit differences in PSG-measured sleep duration, awakenings, or latency (ps > .05) compared with non-psychiatric controls, they displayed lower slow wave sleep percentage (β = -.40) and non-rapid eye movement (NREM) electroencephalogram (EEG) delta power (β = -.29). They also exhibited greater stage 2 percentage (β = .41), NREM EEG sigma power (β = .41), and elevated self-reported sleep disturbances (ps < .05). Lower NREM EEG delta power, increased high-frequency power, and slower decline in NREM EEG delta power overnight were associated with poorer neurocognition among adolescents with ADHD., Conclusion: Adolescents with ADHD reported more sleep disturbances than non-psychiatric controls and exhibited differences in sleep stage distribution and NREM sleep EEG frequency. Sleep-EEG spectral indices were associated with impaired neurocognition, suggesting that physiological sleep processes may underlie neurocognitive deficits in ADHD. Future studies may clarify whether sleep plays a causal role in neurocognitive impairments in adolescent ADHD and whether interventions normalizing sleep improve neurocognition., Plain Language Summary: This study investigated the sleep physiology in a sample of 62 adolescents, 31 with attention-deficit/hyperactivity disorder (ADHD) and 31 with no psychiatric diagnoses, aged 13 to 17. The authors found that medication-free adolescents with ADHD displayed reduced time in deep slow wave sleep, and increased time in lighter stage 2 sleep, than adolescents without a psychiatric diagnosis. Results indicate that disruptions in the amount and pattern of slow wave electroencephalogram (EEG) activity, as well as increased high frequency EEG power during sleep, were associated with lower cognitive performance among adolescents with ADHD. The study findings suggest that sleep physiology may contribute to cognitive deficits in ADHD and future research should assess whether interventions normalizing sleep improve cognitive performance in adolescents with ADHD., Clinical Trial Registration Information: Sleep Dysfunction and Neurocognitive Outcomes in Adolescent ADHD; https://clinicaltrials.gov/; NCT02897362., Diversity & Inclusion Statement: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list., (Copyright © 2024 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Despite tremendous advancements in neuroscience, there has been limited impact on patient care. Current psychiatric treatments are largely non-specific, and drug development is hindered by outdated, overinclusive diagnostic categories and a "one-size-fits-all" approach. Additionally, mechanisms underlying psychiatric illnesses and their treatments with conventional medications remain poorly understood. Precision psychiatry is a strategy that holds great promise for novel therapies targeting specific pathophysiologic mechanisms in selected patients, ultimately contributing to more effective, personalized treatments. Immunopsychiatry, which focuses on the immune system's role in psychiatric disorders, exemplifies the challenges and potential solutions for precision psychiatry. Despite understanding how inflammation contributes to psychiatric illness, results of clinical trials with anti-inflammatory drugs have been inconsistent and underwhelming. Shortcomings of these trials include a lack of focus on subgroups of patients with increased inflammation, the use of non-specific outcome variables (e.g., not specific to inflammation's impact on the brain and behavior), and failure to establish target engagement of the inflammatory response. To advance anti-inflammatory treatments, clinical trials should: 1) enrich for patients using predictive biomarkers; 2) use clinical outcome assessments that align with inflammation's effects on the brain; 3) consider novel diagnostic constructs linked to inflammation; and 4) verify target engagement. Moreover, greater attention should be paid to efforts to repurpose available anti-inflammatory drugs while awaiting development of novel treatments targeting more specific immune pathways. Taken together, a collaborative approach involving academia, industry, funding agencies, patients, payors, and policymakers is required to advance Immunopsychiatry and ultimately provide a roadmap for successful implementation of precision psychiatry., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Deep brain stimulation (DBS) of the anterior limb of the internal capsule (ALIC) is a circuit-based treatment for severe, refractory obsessive-compulsive disorder (OCD). The therapeutic effects of DBS are hypothesized to be mediated by direct modulation of a distributed cortico-striato-thalmo-cortical network underlying OCD symptoms. However, the exact underlying mechanism by which DBS exerts its therapeutic effects still remains unclear. In five participants receiving DBS for severe, refractory OCD (3 responders, 2 non-responders), we conducted a DBS On/Off cycling paradigm during the acquisition of functional MRI (23 fMRI runs) to determine the network effects of stimulation across a variety of bipolar configurations. We also performed tractography using diffusion-weighted imaging (DWI) to relate the functional impact of DBS to the underlying structural connectivity between active stimulation contacts and functional brain networks. We found that therapeutic DBS had a distributed effect, suppressing BOLD activity within regions such as the orbitofrontal cortex, dorsomedial prefrontal cortex, and subthalamic nuclei compared to non-therapeutic configurations. Many of the regions suppressed by therapeutic DBS were components of the default mode network (DMN). Moreover, the estimated stimulation field from the therapeutic configurations exhibited significant structural connectivity to core nodes of the DMN. Based upon these findings, we hypothesize that the suppression of the DMN by ALIC DBS is mediated by interruption of communication through structural white matter connections surrounding the DBS active contacts., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Objectives: Treatment-resistant depression is a leading cause of disability. Our center's trial for neurosurgical intervention for treatment-resistant depression involves a staged workup for implantation of a personalized, closed-loop neuromodulation device for refractory depression. The first stage ("stage 1") of workup involves implantation of 10 stereoelectroencephalography (SEEG) electrodes bilaterally into 5 anatomically defined brain regions and involves a specialized preoperative imaging and planning workup and a frame-based operating protocol., Methods: We rely on diffusion tractography when planning stereotactic targets for 3 of 5 anatomic areas. We outline the rationale and fiber tracts that we focus on for targeting amygdala, ventral striatum and ventral capsule, and subgenual cingulate. We also outline frame-based stereotactic considerations for implantation of SEEG electrodes., Expected Outcomes: Our method has allowed us to safely target all 5 brain areas in 3 of 3 trial participants in this ongoing study, with adequate fiber bundle contact in each of the 3 areas targeted using tractography. Furthermore, we ultimately used tractography data from our stage 1 workup to guide targeting near relevant fiber bundles for stage 2 (implantation of a responsive neuromodulation device). On completion of our data set, we will determine the overlap between volume of tissue activated for all electrodes and areas of interest defined by anatomy and tractography., Discussion: Our protocol outlined for SEEG electrode implantation incorporates tractography and frame-based stereotaxy., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Background: There are limited data regarding gamma-aminobutyric acid (GABA) allosteric modulator sleep-aid medications in persons with depression, insomnia, and suicidal ideation (SI)., Aims: This secondary analysis examined the relationship of age to insomnia and the impact of age on the treatment of insomnia with zolpidem extended-release (zolpidem-ER) in depressed suicidal patients. A prior report found that the addition of zolpidem-ER promoted significantly superior reductions in global severity of insomnia in depressed outpatients with insomnia and SI over 8 weeks, but here we report the differences among early, middle, and late insomnia., Methods: This secondary analysis examined the three early, middle, and late insomnia items of the Hamilton Rating Scale for Depression (HRSD) and their relationship to age and responsiveness to treatment with zolpidem-ER. One hundred and three patients with major depression, SI, and insomnia received open-label serotonin reuptake inhibitors and were randomly allocated 1:1 to receive zolpidem-ER or placebo at bedtime. Results: Older age at baseline was associated with worse middle and late insomnia, but not with early insomnia. Subsequent treatment with zolpidem-ER produced superior improvement in early and middle insomnia, but not late insomnia., Conclusions: These findings are consistent with the known age-related advancement of sleep timing in the general population and depressed outpatients and with the expected effects of a short half-life GABA allosteric modulator sleep aid. By implication, prescribers of pharmacologic treatment of insomnia in depressed patients should consider an alternative to zolpidem-ER when late insomnia is a concern.Trial registration number: ClinicalTrials.gov Identifier: NCT01689909., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. McCall reports royalties from Wolters Kluwer and payments from Carelon and Idorsia as a scientific advisor. Dr. Krystal reports consultancy to Axsome Therapeutics, Big Health, Eisai, Evecxia, Harmony Biosciences, Idorsia, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Millenium Pharmaceuticals, Merck, Neurocrine Biosciences, Neurawell, Pernix, Otsuka Pharmaceuticals, Sage, Takeda. Research support from Janssen Pharmaceuticals, Axsome Pharmaceutics, Attune, Harmony, Neurocrine Biosciences, Reveal Biosensors, The Ray and Dagmar Dolby Family Fund, and the National Institutes of Health. Stock options from Neurawell, Big-Health. Dr. Benca reports consultancy to Eisai, Idorsia, Genentech, Jazz, Merck, and Sage. Research support from Eisai.

Several professional societies have provided recommendations for prescribing medications for insomnia. None has provided an integrative analysis that concurrently quantifies safety and efficacy (e.g., risk-benefit ratios). This represents an important gap for informing clinician decision-making. Accordingly, the aim of the present review is to provide such an analysis for five classes of sleep-promoting medications. Adverse event data values were extracted from the most recent FDA-approved package inserts and converted to an integer before being placebo-adjusted and standardized as a rate per 1000 (AEr). Efficacy data, pre-to-post self-reported data for active and placebo conditions were acquired from pivotal trials identified in "white papers" and systematic reviews/meta-analyses. Weighted effect sizes were calculated for subjective sleep latency, wake time after sleep onset and total sleep time, and then were averaged by medication class for each sleep continuity variable. Overall efficacy was represented by a single variable, SWT (sleep latency + wake time after sleep onset + total sleep time). Risk-benefit was represented using a simple ratio value. For safety, it was found that melatonin receptor agonists had the lowest adverse event rate (AEr = 43.1), and non-benzodiazepine benzodiazepine receptor agonists had the highest rate (AEr = 255.0). For efficacy, it was found that the pre-to-post placebo adjusted effect sizes were largest for benzodiazepines (effect size = 1.94) and smallest for melatonin receptor agonists (effect size = 0.109). For risk-benefit, histamine antagonist had the most favourable profile (risk-benefit = 69.5), while melatonin receptor agonist had the least favourable profile (risk-benefit = 395.7). Overall, the combined metric for risk-benefit suggests that treatment with a histamine antagonist is optimal and potentially represents the best first-line therapy for the medical management of insomnia., (© 2023 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Background and Objectives: Insomnia affects about one-third of patients with traumatic brain injury and is associated with worsened outcomes after injury. We hypothesized that higher levels of plasma neuroinflammation biomarkers at the time of TBI would be associated with worse 12-month insomnia trajectories., Methods: Participants were prospectively enrolled from 18 level-1 trauma centers participating in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury study from February 26, 2014, to August 8, 2018. Plasma glial fibrillary acidic protein (GFAP), high-sensitivity C-reactive protein (hsCRP), S100b, neuron-specific enolase (NSE), and ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1) were collected on days 1 (D1) and 14 (D14) after TBI. The insomnia severity index was collected at 2 weeks, 3, 6, and 12 months postinjury. Participants were classified into insomnia trajectory classes based on a latent class model. We assessed the association of biomarkers with insomnia trajectories, controlling for medical and psychological comorbidities and demographics., Results: Two thousand twenty-two individuals with TBI were studied. Elevations in D1 hsCRP were associated with persistent insomnia (severe, odds ratio [OR] = 1.33 [1.11, 1.59], p = 0.002; mild, OR = 1.10 [1.02, 1.19], p = 0.011). Similarly, D14 hsCRP elevations were associated with persistent insomnia (severe, OR = 1.27 [1.02, 1.59], p = 0.03). Of interest, D1 GFAP was lower in persistent severe insomnia (median [Q1, Q3]: 154 [19, 445] pg/mL) compared with resolving mild (491 [154, 1,423], p < 0.001) and persistent mild (344 [79, 1,287], p < 0.001). D14 GFAP was similarly lower in persistent (11.8 [6.4, 19.4], p = 0.001) and resolving (13.9 [10.3, 20.7], p = 0.011) severe insomnia compared with resolving mild (20.6 [12.4, 39.6]. Accordingly, increases in D1 GFAP were associated with reduced likelihood of having persistent severe (OR = 0.76 [95% CI 0.63-0.92], p = 0.004) and persistent mild (OR = 0.88 [0.81, 0.96], p = 0.003) compared with mild resolving insomnia. No differences were found with other biomarkers., Discussion: Elevated plasma hsCRP and, surprisingly, lower GFAP were associated with adverse insomnia trajectories after TBI. Results support future prospective studies to examine their utility in guiding insomnia care after TBI. Further work is needed to explore potential mechanistic connections between GFAP levels and the adverse insomnia trajectories.

The Deep Brain Stimulation (DBS) Think Tank XI was held on August 9-11, 2023 in Gainesville, Florida with the theme of "Pushing the Forefront of Neuromodulation". The keynote speaker was Dr. Nico Dosenbach from Washington University in St. Louis, Missouri. He presented his research recently published in Nature inn a collaboration with Dr. Evan Gordon to identify and characterize the somato-cognitive action network (SCAN), which has redefined the motor homunculus and has led to new hypotheses about the integrative networks underpinning therapeutic DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers, and researchers (from industry and academia) can freely discuss current and emerging DBS technologies, as well as logistical and ethical issues facing the field. The group estimated that globally more than 263,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year's meeting was focused on advances in the following areas: cutting-edge translational neuromodulation, cutting-edge physiology, advances in neuromodulation from Europe and Asia, neuroethical dilemmas, artificial intelligence and computational modeling, time scales in DBS for mood disorders, and advances in future neuromodulation devices., Competing Interests: ND has a financial interest in Turing Medical Inc. and may financially benefit if the company is successful in marketing FIRMM motion monitoring software products, may receive royalty income based on FIRMM technology developed at Washington University School of Medicine and Oregon Health and Sciences University and licensed to Turing Medical Inc, and is a co-founder of Turing Medical Inc. These potential conflicts of interest have been reviewed and are managed by Washington University School of Medicine. AH reports lecture fees for Boston Scientific and is a consultant for FxNeuromodulation and Abbott. RG is an employee of Rune Labs. JO'K is CEO and Founder of Machine Medicine Technologies. W-JN received honoraria for consulting from InBrain – Neuroelectronics that is a neurotechnology company and honoraria for talks from Medtronic that is a manufacturer of deep brain stimulation devices unrelated to this manuscript. SL has received speaking honoraria from Medtronic and is a consultant for Iota Biosciences. SS is a consultant for Zimmer Biomet, Neuropace, Koh Young, Boston Scientfic, Sensoria Therapeutics, Varian Medical; co-founder for Motif Neurotech. LM is an employee of Boston Scientific. AF has stock ownership in Inbrain Pharma and has received payments as consultant and/or speaker from Abbvie, Abbott, Boston Scientific, Ceregate, Dompé Farmaceutici, Inbrain Neuroelectronics, Ipsen, Medtronic, Iota, Syneos Health, Merz, Sunovion, Paladin Labs, UCB, Sunovion, and he has received research support from Abbvie, Boston Scientific, Medtronic, Praxis, ES and receives royalties from Springer. AH-B and RR are employees of Medtronic Inc. LM is an employee of Boston Scientific. YP is an employee of Abbott. DG is an employee of NeuroPace, owns NeuroPace stock, and has NeuroPace stock options. SM is a founder and shareholder of Newronika SpA. LK is the CEO of Newronika. MP-N has received speaker honoraria/travel costs from Medtronic, Boston Scientific, Abbott, Bial, and Abbvie and study reimbursements from Zambon, Licher, Boston Scientific, and Abbott. LC has received research support from National Institutes of Health and the National Network of Depression Centers and serves on the Board of Directors for the International Neuroethics Society (unpaid) as well as on the Advisory Council for the Institute of Neuroethics think and do thank (unpaid). CM is a paid consultant for Boston Scientific Neuromodulation, receives royalties from Hologram Consultants, Neuros Medical, Qr8 Health, and is a shareholder in the following companies: Hologram Consultants, Surgical Information Sciences, BrainDynamics, CereGate, Cardionomic, Enspire DBS. NH is a co-founder of Surgical Information Sciences (SIS), Inc. HM received consulting and IP licensing fees from Abbott Laboratories. AK has stock options in Neurawell and Big Health and is a consultant for Axsome Therapeutics, Big Health, Eisai, Evecxia, Harmony Biosciences, Idorsia, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Millenium Pharmaceuticals, Merck, Neurocrine Biosciences, Neurawell, Pernix, Otsuka Pharmaceuticals, Sage, and Takeda. NP is a consultant for Abbott and Sensoria Therapeutics. PS receives free research devices from Medtronic and fellowship support funding from Medtronic and BSCI and no personal income from anyone. KF reports receiving research support and fellowship support from Medtronic and Boston Scientific and research support from Functional Neuromodulation. MO serves as Medical Advisor the Parkinson's Foundation, and has received research grants from NIH, Parkinson's Foundation, the Michael J. Fox Foundation, the Parkinson Alliance, Smallwood Foundation, the Bachmann-Strauss Foundation, the Tourette Syndrome Association, and the UF Foundation. MO has received royalties for publications with Demos, Manson, Amazon, Smashwords, Books4Patients, Perseus, Robert Rose, Oxford and Cambridge (movement disorders books). MO is an associate editor for New England Journal of Medicine Journal, Watch Neurology, and JAMA Neurology. MO has participated in CME and educational activities (past 12-24 months) on movement disorders sponsored by WebMD/Medscape, RMEI Medical Education, American Academy of Neurology, Movement Disorders Society, Mediflix and by Vanderbilt University. The institution and not MO receives grants from industry. MO has participated as a site PI and/or co-I for several NIH, foundation, and industry sponsored trials over the years but has not received honoraria. Research projects at the University of Florida receive device and drug donations. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Johnson, Dosenbach, Gordon, Welle, Wilkins, Bronte-Stewart, Voon, Morishita, Sakai, Merner, Lázaro-Muñoz, Williamson, Horn, Gilron, O'Keeffe, Gittis, Neumann, Little, Provenza, Sheth, Fasano, Holt-Becker, Raike, Moore, Pathak, Greene, Marceglia, Krinke, Tan, Bergman, Pötter-Nerger, Sun, Cabrera, McIntyre, Harel, Mayberg, Krystal, Pouratian, Starr, Foote, Okun and Wong.)

Despite increasing prevalence and huge personal and societal burden, psychiatric diseases still lack treatments which can control symptoms for a large fraction of patients. Increasing insight into the neurobiology underlying these diseases has demonstrated wide-ranging aberrant activity and functioning in multiple brain circuits and networks. Together with varied presentation and symptoms, this makes one-size-fits-all treatment a challenge. There has been a resurgence of interest in the use of neurostimulation as a treatment for psychiatric diseases. Initial studies using continuous open-loop stimulation, in which clinicians adjusted stimulation parameters during patient visits, showed promise but also mixed results. Given the periodic nature and fluctuations of symptoms often observed in psychiatric illnesses, the use of device-driven closed-loop stimulation may provide more effective therapy. The use of a biomarker, which is correlated with specific symptoms, to deliver stimulation only during symptomatic periods allows for the personalized therapy needed for such heterogeneous disorders. Here, we provide the reader with background motivating the use of closed-loop neurostimulation for the treatment of psychiatric disorders. We review foundational studies of open- and closed-loop neurostimulation for neuropsychiatric indications, focusing on deep brain stimulation, and discuss key considerations when designing and implementing closed-loop neurostimulation., (© 2023. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Importance: Daytime functional impairments are the primary reasons for patients with insomnia to seek treatment, yet little is known about what the optimal treatment is for improving daytime functions and how best to proceed with treatment for patients whose insomnia has not remitted., Objectives: To compare the efficacy of behavioral therapy (BT) and zolpidem as initial therapies for improving daytime functions among patients with insomnia and evaluate the added value of a second treatment for patients whose insomnia has not remitted., Design, Setting, and Participants: In this sequential multiple-assignment randomized clinical trial conducted at institutions in Canada and the US, 211 adults with chronic insomnia disorder were enrolled between May 1, 2012, and December 31, 2015, and followed up for 12 months. Statistical analyses were performed on an intention-to-treat basis in April and October 2023., Interventions: Participants were randomly assigned to either BT or zolpidem as first-stage therapy, and those whose insomnia had not remitted received a second-stage psychological therapy (BT or cognitive therapy) or medication therapy (zolpidem or trazodone)., Main Outcomes and Measures: Study outcomes were daytime symptoms of insomnia, including mood disturbances, fatigue, functional impairments of insomnia, and scores on the 36-item Short-Form Health Survey (SF-36) physical and mental health components., Results: Among 211 adults with insomnia (132 women [63%]; mean [SD] age, 45.6 [14.9] years), 104 were allocated to BT and 107 to zolpidem at the first stage. First-stage treatment with BT or zolpidem yielded significant and equivalent benefits for most of the daytime outcomes, including depressive symptoms (Beck Depression Inventory-II mean score change, -3.5 [95% CI, -4.7 to -2.3] vs -4.3 [95% CI, -5.7 to -2.9]), fatigue (Multidimensional Fatigue Inventory mean score change, -4.7 [95% CI, -7.3 to -2.2] vs -5.2 [95% CI, -7.9 to -2.5]), functional impairments (Work and Social Adjustment Scale mean score change, -5.0 [95% CI, -6.7 to -3.3] vs -5.1 [95% CI, -7.2 to -2.9]), and mental health (SF-36 mental health subscale mean score change, 3.5 [95% CI, 1.9-5.1] vs 2.5 [95% CI, 0.4-4.5]), while BT produced larger improvements for anxiety symptoms relative to zolpidem (State-Trait Anxiety Inventory mean score change, -4.1 [95% CI, -5.8 to -2.4] vs -1.2 [95% CI, -3.0 to 0.5]; P = .02; Cohen d = 0.55). Second-stage therapy produced additional improvements for the 2 conditions starting with zolpidem at posttreatment in fatigue (Multidimensional Fatigue Inventory mean score change: zolpidem plus BT, -3.8 [95% CI, -7.1 to -0.4]; zolpidem plus trazodone, -3.7 [95% CI, -6.3 to -1.1]), functional impairments (Work and Social Adjustment Scale mean score change: zolpidem plus BT, -3.7 [95% CI, -6.4 to -1.0]; zolpidem plus trazodone, -3.3 [95% CI, -5.9 to -0.7]) and mental health (SF-36 mental health subscale mean score change: zolpidem plus BT, 5.3 [95% CI, 2.7-7.9]; zolpidem plus trazodone, 2.0 [95% CI, 0.1-4.0]). Treatment benefits achieved at posttreatment were well maintained throughout the 12-month follow-up, and additional improvements were noted for patients receiving the BT treatment sequences., Conclusions and Relevance: In this randomized clinical trial of adults with insomnia disorder, BT and zolpidem produced improvements for various daytime symptoms of insomnia that were no different between treatments. Adding a second treatment offered an added value with further improvements of daytime functions., Trial Registration: ClinicalTrials.gov Identifier: NCT01651442.

This article reviews the history of insomnia pharmacotherapy, documenting the evolution that has occurred over time in the increasing availability of medications with novel mechanisms of action that more specifically target the neural systems that modulate sleep/wake function. This evolution provides an increasing capacity to improve the effectiveness of insomnia pharmacotherapy by allowing the selection of medications that specifically target the particular type of sleep difficulty present in each patient. As a result, they can achieve a therapeutic effect with fewer effects on aspects of brain function other than those needed to achieve benefit, thereby minimising adverse effects. The accumulated evidence-base is such that it can serve as the basis for a personalised insomnia pharmacotherapy paradigm. Here we outline a set of best-practice recommendations for how to carry out optimised personalised insomnia pharmacotherapy based on that evidence base in the hope that it will improve the treatment delivered to the many individuals suffering from insomnia., (© 2023 European Sleep Research Society.)

The REST-IT study found the addition of zolpidem-controlled release (CR) provided a significant reduction in observer-rated measurement of suicidal ideation (the Columbia Suicide Severity Rating Scale) in 103 depressed outpatients with insomnia and suicidal ideation, but without significant change in a self-report measure of suicidal ideation (the Scale for Suicide Ideation). This secondary analysis of the REST-IT data examined the suicide item of another observer-rated scale, the Hamilton Rating Scale for Depression (HRSD), further clarifying the impact of insomnia-focused treatment on suicidal ideation. This analysis established a significant advantage for zolpidem-CR compared with placebo on the HRSD suicide item., Competing Interests: Declaration of Competing Interest Dr. McCall reports royalties from Wolters Kluwer and payments from Carelon and Idorsia as a scientific advisor. Dr Krystal reports Options: Neurawell, Big Health Research Grants: Janssen Pharmaceuticals, Axsome Pharmaceutics, Attune, Harmony, Neurocrine Biosciences, Reveal Biosensors, The Ray and Dagmar Dolby Family Fund, and the National Institutes of Health Consulting: Axsome Therapeutics, Big Health, Eisai, Evecxia, Harmony Biosciences, Idorsia, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Millenium Pharmaceuticals, Merck, Neurocrine Biosciences, Neurawell, Otsuka Pharmaceuticals, Sage, Takeda Dr Benca is a consultant to Eisai, Idorsia, Genentech, Merck, Jazz, Sage, and receives research support from Eisai No other authors have disclosures, (Copyright © 2023 Elsevier B.V. All rights reserved.)

Sleep is a highly stereotyped phenomenon, requiring robust spatiotemporal coordination of neural activity. Understanding how the brain coordinates neural activity with sleep onset can provide insights into the physiological functions subserved by sleep and the pathologic phenomena associated with sleep onset. We quantified whole-brain network changes in synchrony and information flow during the transition from wakefulness to light non-rapid eye movement (NREM) sleep, using MEG imaging in a convenient sample of 14 healthy human participants (11 female; mean 63.4 years [SD 11.8 years]). We furthermore performed computational modeling to infer excitatory and inhibitory properties of local neural activity. The transition from wakefulness to light NREM was identified to be encoded in spatially and temporally specific patterns of long-range synchrony. Within the delta band, there was a global increase in connectivity from wakefulness to light NREM, which was highest in frontoparietal regions. Within the theta band, there was an increase in connectivity in fronto-parieto-occipital regions and a decrease in temporal regions from wakefulness to Stage 1 sleep. Patterns of information flow revealed that mesial frontal regions receive hierarchically organized inputs from broad cortical regions upon sleep onset, including direct inflow from occipital regions and indirect inflow via parieto-temporal regions within the delta frequency band. Finally, biophysical neural mass modeling demonstrated changes in the anterior-to-posterior distribution of cortical excitation-to-inhibition with increased excitation-to-inhibition model parameters in anterior regions in light NREM compared with wakefulness. Together, these findings uncover whole-brain corticocortical structure and the orchestration of local and long-range, frequency-specific cortical interactions in the sleep-wake transition. SIGNIFICANCE STATEMENT Our work uncovers spatiotemporal cortical structure of neural synchrony and information flow upon the transition from wakefulness to light non-rapid eye movement sleep. Mesial frontal regions were identified to receive hierarchically organized inputs from broad cortical regions, including both direct inputs from occipital regions and indirect inputs via the parieto-temporal regions within the delta frequency range. Biophysical neural mass modeling revealed a spatially heterogeneous, anterior-posterior distribution of cortical excitation-to-inhibition. Our findings shed light on the orchestration of local and long-range cortical neural structure that is fundamental to sleep onset, and support an emerging view of cortically driven regulation of sleep homeostasis., (Copyright © 2023 the authors.)

Background: Growing evidence indicates that anhedonia is a multifaceted construct. This study examined the possibility of identifying subgroups of people with anhedonia using multiple reward-related measures to provide greater understanding the Research Domain Criteria's Positive Valence Systems Domain and pathways for developing treatments., Methods: Latent profile analysis of baseline data from a study that examined the effects of a novel kappa opioid receptor (KOR) antagonist drug on measures and biomarkers associated with anhedonia was used to identify subgroups. Measures included ventral striatal activation during the Monetary Incentive Delay task, response bias in the Probabilistic Reward Task, reward valuation scores from the Effort-Expenditure for Rewards Task, and scores from reward-related self-report measures., Results: Two subgroups were identified, which differed on self-report measures of reward. Participants in the subgroup reporting more anhedonia also reported more depression and had greater illness severity and functional impairments. Graphs of change with treatment showed a trend for the less severe subgroup to demonstrate higher response to KOR antagonist treatment on the neuroimaging measure, probabilistic reward task, and ratings of functioning; the subgroup with greater severity showed a trend for higher treatment response on reward-related self-report measures., Limitations: The main limitations include the small sample size and exploratory nature of analyses., Conclusions: Evidence of possible dissociation between self-reported measures of anhedonia and other measures with respect to treatment response emerged. These results highlight the importance for future research to consider severity of self-reported reward-related deficits and how the relationship across measurement methods may vary with severity., Competing Interests: Declaration of competing interest Darrow: reports no financial relationship with commercial interests. Pizzagalli: Over the past 3 years, Dr. Pizzagalli has received consulting fees from Albright Stonebridge Group, Boehringer Ingelheim, Compass Pathways, Engrail Therapeutics, Neumora Therapeutics (formerly BlackThorn Therapeutics), Neurocrine Biosciences, Neuroscience Software, Otsuka, Sunovion, and Takeda; he has received honoraria from the Psychonomic Society and American Psychological Association (for editorial work) and from Alkermes; he has received research funding from the Brain and Behavior Research Foundation, Dana Foundation, Wellcome Leap, Millennium Pharmaceuticals, and NIMH; he has received stock options from Compass Pathways, Engrail Therapeutics, Neumora Therapeutics, and Neuroscience Software; he has a financial interest in Neumora Therapeutics, which has licensed the copyright to the human version of the probabilistic reward task through Harvard University. No funding from these entities was used to support the current work, and all views expressed are solely those of the authors. Smoski: reports no financial relationships with commercial interests. Mathew: Dr. Mathew has been a consultant for Allergan, Alkermes, Axsome Therapeutics, BioXcel Therapeutics, Clexio Biosciences, Eleusis, EMA Wellness, Engrail Therapeutics, Intra-Cellular Therapies, Greenwich Biosciences, Janssen, Levo Therapeutics, Neurocrine, Perception Neuroscience, Praxis Precision Medicines, Relmada Therapeutics, Sage Therapeutics, Signant Health and Seelos Therapeutics, and received research support from Biohaven, Janssen, Merck, NIH, NeuroRx, PCORI, Sage Therapeutics, VA, and VistaGen Therapeutics, drug from Biohaven for NIMH-funded study, and support from the Michael E. Debakey VA Medical Center (Houston, TX) for use of resources and facilities and The Menninger Clinic, Houston, Texas. Nurnberger: J.N. has received research funding from Janssen and Assurex. Lisanby: S.H.L. is a co-inventor on a patent for TMS Technology, unrelated to this manuscript. S.H.L. contributed to this article while at Duke University, before joining the National Institute of Mental Health. The views expressed are her own and do not necessarily represent the views of the National Institutes of Health, the Department of Health, or the US government. Iosifescu: In the past 5 years, Dr. Iosifescu has received consulting fees from Alkermes, Axsome, Allergan, Biogen, the Centers for Psychiatric Excellence, Global Medical Education, MyndAnalytics (CNS Response), Jazz, Lundbeck, Otsuka, Precision Neuroscience, Sage, Sunovion; and he has received research grant support (through his academic institutions) from Alkermes, AstraZeneca, Brainsway, LiteCure, NeoSync, Roche, and Shire. Murrough: In the past 5 years, Dr. Murrough has served as a consultant to Allergan, Boehreinger Ingelheim, Clexio Biosciences, Global Medical Education (GME), Otsuka, Sage Therapeutics, and Engrail Therapeutics. Dr. Murrough is named on a patent pending for neuropeptide Y as a treatment for mood and anxiety disorders and on a patent pending for the use of KCNQ channel openers to treat depression and related conditions. The Icahn School of Medicine (employer of Dr. Murrough) is named on a patent and has entered into a licensing agreement and will receive payments related to the use of ketamine or esketamine for the treatment of depression. The Icahn School of Medicine is also named on a patent related to the use of ketamine for the treatment of PTSD. Dr. Murrough is not named on these patents and will not receive any payments. Yang: reports no financial relationship with commercial interests. Weiner: reports no financial relationship with commercial interests. Sanacora: has consulted for Allergan, Alkermes, AstraZeneca, Avanier Pharmaceuticals, Axsome Therapeutics, Biogen, Biohaven Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Clexio Biosciences, Denovo Biopharma, EMA- Wellness, Engrail, Freedom, Gilgamesh, Hoffman La-Roche, Intra-Cellular Therapies, Janssen, Levo, Lundbeck, Merck, Naurex, Navitor Pharmaceuticals, Neurocrine Biosciences, Novartis, Noven Pharmaceuticals, Otsuka, Praxis Therapeutics, Perception Neuroscience, Praxis Therapeutics, Sage Pharmaceuticals, Seelos Pharmaceuticals, Taisho Pharmaceuticals, Teva, Valeant, Vistagen Therapeutics, and XW Labs. GS also received research funding from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Hoffman La-Roche, Merck, Naurex, Servier and Usona Institute. G.S. holds equity in BioHaven Pharmaceuticals and is a co-inventor on a US patent (#8,778,979) held by Yale University and a co-inventor on US Provisional Patent Application No. 047162-7177P1 (00754) filed on August 20, 2018, by Yale University Office of Cooperative Research. Yale University (Employer of Dr. Sanacora) has a financial relationship with Janssen Pharmaceuticals and may in the future receive financial benefits from this relationship. Keefe: During the period that work was conducted on this study, R.S.E.K. was the owner of VeraSci, a for-profit company that provides clinical trial support and other services for over 100 pharmaceutical companies and other institutions. Song: has received research support from the NIH and GE Healthcare. Goodman: W.G. has consulted for Biohaven Pharmaceuticals, received research funding from the NIH, the McNair Foundation, and Biohaven Pharmaceuticals, and received donated devices from Medtronic. Whitton: Dr. Whitton was partially supported by a grant from the National Health and Medical Research Council of Australia (GNT: 1110773). Potter: Is on a DSMB for Agene-Bio and Regenacy, has stock ownership in Merck, and has received consulting fees from Karuna, Eliem, Neurocrine, Emerald Lake Safety, Boston Pharmaceuticals, and Otsuka and receives research funding from the NIH as a co-PI on a small business grant to praxis Bioresearch. Krystal: Dr. Krystal has received research grants from Janssen Pharmaceuticals, Axsome Pharmaceutics, Reveal Biosensors, The Ray and Dagmar Dolby Family Fund, and the National Institutes of Health. He has received consulting fees from Adare, Axsome Therapeutics, Big Health, Eisai, Evecxia, Ferring Pharmaceuticals, Galderma, Harmony Biosciences, Idorsia, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Millenium Pharmaceuticals, Merck, Neurocrine Biosciences, Neurawell, Pernix, Otsuka Pharmaceuticals, Sage, Takeda, and Angelini. He owns options of Big Health., (Copyright © 2023 Elsevier B.V. All rights reserved.)

We previously described five trajectories of insomnia (each defined by a distinct pattern of insomnia severity over 12 months following traumatic brain injury [TBI]). Our objective in the present study was to estimate the association between insomnia trajectory status and trajectories of mental health and neurocognitive outcomes during the 12 months after TBI. In this study, participants included N  = 2022 adults from the Federal Inter-agency Traumatic Brain Injury Repository database and Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. The following outcome measures were assessed serially at 2 weeks, and 3, 6, and 12 months post-injury: Insomnia Severity Index, Patient Health Questionnaire, Post-Traumatic Stress Disorder (PTSD) Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), Patient Reported Outcomes Measurement Information System-Pain, and Quality of Life After Brain Injury-Overall Scale. Neurocognitive performance was assessed at 2 weeks, and 6 and 12 months using the Wechsler Adult Intelligence Scales Processing Speed Index and the Trails Making Test Parts A and B. Results indicated that g reater insomnia severity was associated with greater abnormality in mental health, quality of life, and neuropsychological testing outcomes. The pattern of insomnia over time tracked the temporal pattern of all these outcomes for all but a very small number of participants. Notably, severe insomnia at 3 or 6 months post-TBI was a risk factor for poor recovery at 12 months post-injury. In conclusion, in this well-characterized sample of individuals with TBI, insomnia severity generally tracked severity of depression, pain, PTSD, quality of life, and neurocognitive outcomes over 12 months post-injury. More intensive sleep assessment is needed to elucidate the nature of these relationships and to help inform best strategies for intervention.