high-definition-transcranial-direct-current-stimulation-during-sleep

High-Definition Transcranial Direct Current Stimulation During Sleep

High-definition transcranial direct current stimulation (HD-tDCS) enables high spatial precision modulation of neural activity during sleep. This protocol ...

Beth Israel Deaconess Medical Center

Harvard Medical School

Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools for remote control of targeted cell populations using chemical actuators that bind to modified receptors. Despite the popularity of DREADDs in neuroscience and sleep research, potential effects of the DREADD actuator clozapine-N-oxide (CNO) on sleep have never been systematically tested. Here, we show that intraperitoneal injections of commonly used CNO doses (1, 5, and 10 mg/kg) alter sleep in wild-type male laboratory mice. Using electroencephalography (EEG) and electromyography (EMG) to analyse sleep, we found a dose-dependent suppression of rapid eye movement (REM) sleep, changes in EEG spectral power during non-REM (NREM) sleep, and altered sleep architecture in a pattern previously reported for clozapine. Effects of CNO on sleep could arise from back-metabolism to clozapine or binding to endogenous neurotransmitter receptors. Interestingly, we found that the novel DREADD actuator, compound 21 (C21, 3 mg/kg), similarly modulates sleep despite a lack of back-metabolism to clozapine. Our results demonstrate that both CNO and C21 can modulate sleep of mice not expressing DREADD receptors. This implies that back-metabolism to clozapine is not the sole mechanism underlying side effects of chemogenetic actuators. Therefore, any chemogenetic experiment should include a DREADD-free control group injected with the same CNO, C21, or newly developed actuator. We suggest that electrophysiological sleep assessment could serve as a sensitive tool to test the biological inertness of novel chemogenetic actuators.

Effects of clozapine-N-oxide and compound 21 on sleep in laboratory mice.

Major Depressive Disorder (MDD) presents considerable challenges to diagnosis and management due to symptom variability across time. Only recent work has highlighted the clinical implications for interrogating depression symptom variability. Thus, the present work investigates how sociodemographic, comorbidity, movement, and sleep data is associated with long-term depression symptom variability. Participant information included (N = 939) baseline sociodemographic and comorbidity data, longitudinal, passively collected wearable data, and Patient Health Questionnaire-9 (PHQ-9) scores collected over 12 months. An ensemble machine learning approach was used to detect long-term depression symptom variability via: (i) a domain-driven feature selection approach and (ii) an exhaustive feature-inclusion approach. SHapley Additive exPlanations (SHAP) were used to interrogate variable importance and directionality. The composite domain-driven and exhaustive inclusion models were both capable of moderately detecting long-term depression symptom variability (r = 0.33 and r = 0.39, respectively). Our results indicate the incremental predictive validity of sociodemographic, comorbidity, and passively collected wearable movement and sleep data in detecting long-term depression symptom variability.

Using digital phenotyping to capture depression symptom variability: detecting naturalistic variability in depression symptoms across one year using passively collected wearable movement and sleep data.

Despite its critical importance, the treatment of paraphilic disorders remains an often-overlooked domain both in clinical research and practice. Challenges have arisen in the morphing understanding of paraphilias and paraphilic disorders, now considered separate concepts, and efforts at developing a more nuanced understanding of these conditions is ongoing, resulting in a muddled history that can frustrate efforts at study and treatment. These populations are by nature more heterogeneous than may first be obvious-particularly among those with comorbid psychopathic traits-and may require a more nuanced and individualized approach based on risk, needs, and responsivity to treatment. Until recently, there were few guidelines to assist clinicians when confronted with these complicated clinical pictures and a sea of discrete studies investigating various biological and non-biological interventions. Treatments range from several variations of psychotherapy and behavioral therapies to SSRIs, anti-androgenic medications, to orchiectomy, all displaying varying degrees of effectiveness and evidence across decades of research. Fortunately, recent efforts to collate these studies supported by a task force of the World Federation of Societies of Biological Psychiatry (WFSBP) have helped form a better-focused and better-evidenced picture of effective treatments and the unique challenges faced by (and with) these populations.

Paraphilic disorders, psychopathy, and those who sexually offend: a narrative review of treatment modalities.

Sleep is a vital restorative process that has occupied our curiosity for millennia. Despite our longstanding research efforts, the biology of sleep and its connection to mental states remains enigmatic. Unsurprisingly, sleep and wakefulness, the fundamental processes between which our mental states oscillate, are inseparable from our physical and mental health. Thus, clinical consideration of sleep impairments warrants a transdiagnostic approach whilst appropriately acknowledging that certain individual disorders (e.g. depression, schizophrenia) may have somewhat distinct sleep disturbances. Moreover, our knowledge of the anatomy and physiology of sleep regulation-albeit limited-forms the foundation for current treatments for sleep difficulties. This pictorial article overviews the core concepts and future of sleep neuroscience and mental state biology for trainees and practitioners in psychiatry and related professions.

Neuroscience in pictures: 2. Sleep, wakefulness, and mental state biology.

Despite the frequent diagnostic delays of rare neurologic diseases (RND), it remains difficult to study RNDs and their comorbidities due to their rarity and hence the statistical underpowering. Affecting one to two in a million annually, stiff person syndrome (SPS) is an RND characterized by painful muscle spasms and rigidity. Leveraging underutilized electronic health records (EHR), this study showcased a machine-learning-based framework to identify clinical features that optimally characterize the diagnosis of SPS.

Machine learning characterization of a rare neurologic disease via electronic health records: a proof-of-principle study on stiff person syndrome.

Atypical presentation of schizophrenia with ablution avoidance: A case report.

Schizophrenia is a complex, heritable brain disorder characterized by psychotic, negative, cognitive, mood, and motor symptoms. This pictorial review explores the multifaceted nature of schizophrenia, from its etiology to prevention strategies. We discuss the interplay of genetic and environmental risk factors, neurobiological underpinnings, and stepwise progression. Recent advances in understanding circuit-level pathophysiology and neurotransmitter systems beyond dopamine are highlighted along with neuropathological findings, particularly the exaggerated synaptic pruning hypothesis. Based on these developments, we present an updated perspective on pharmacological interventions. Finally, we outline preventative strategies across different stages, emphasizing early intervention. This overview, designed as a teaching resource, aims to provide trainees, clinicians and researchers with a current understanding of schizophrenia's neurobiological underpinnings and the implications of such understanding to the evolving landscape of its diagnosis and management.

Neuroscience in Pictures: 3. Schizophrenia.

Major depressive disorder represents a complex heterogeneous syndrome with significant public health impact. This pictorial review explores the multifaceted pathophysiology of depression through the case of an individual suffering from depression. Genetic vulnerability and environmental etiological factors, including early life adversity, and their interactions create a biological diathesis through alterations in stress response systems and neural circuitry. We review current evidence for several interconnected pathophysiological mechanisms underlying depression, including monoamine neurotransmission, hypothalamic-pituitary-adrenal axis dysfunction, chronic inflammation, and reduced neuroplasticity. Using the Research Domain Criteria framework, we connect these mechanisms across multiple levels of analysis-from genes, circuits to behavior. Neuroimaging findings highlight disruptions in key networks including the default mode, salience, and executive control circuits. The effectiveness of pharmacological, psychotherapeutic and other non-pharmacological interventions in depression underscores the importance of targeting multiple biological systems. This review emphasizes depression's complex etiology involving dynamic interactions between genetic predisposition, environmental stressors, and neurobiological alterations, suggesting the need for personalized, multimodal therapeutic approaches.

Neuroscience in Pictures: 4. Depression.

Non-invasive brain stimulation (NIBS) methods carry particular appeal as non-pharmacological approaches to inducing or improving sleep. However, intense research efforts to use transcranial magnetic stimulation (TMS) and electrical stimulation (tES) for sleep modulation have not yet delivered evidence-based NIBS treatments in sleep medicine. The main obstacles lie in insufficiently robust stimulation protocols that affect neurophysiological and self-reported sleep parameters, inadequately controlled-and explained-placebo effects, and heterogeneity in patient populations and outcome parameters. Recent technological advances, e.g., transcranial ultrasound stimulation (TUS) and temporal interference stimulation (TIS), make deep brain structures feasible targets. Real-time approaches, e.g., closed-loop auditory stimulation (CLAS), demonstrate efficacious modulation of different sleep oscillations by tuning stimulation to ongoing brain activity. The identification of sleep-regulatory regions and cell types in the cerebral cortex and thalamus provides new specific targets. To turn this neuroscientific progress into therapeutic advancement, conceptual reframing is warranted. Chronic insomnia may not be optimally suited to demonstrate NIBS efficacy due to the mismatch between self-reported symptoms and polysomnographic sleep parameters. More feasible initial approaches could be to (1) modulate specific sleep oscillations to promote specific sleep functions, (2) modify nightmares and traumatic memories with targeted memory reactivation, (3) increase 'wake intensity' in patients with depression to improve daytime fatigue and elevate sleep pressure and (4) disrupt pathological activity in sleep-dependent epilepsies. Effective treatments in these areas of sleep medicine seem in reach but require rigorously designed clinical trials to identify which NIBS strategies bring real benefit in sleep medicine.

The Future of Non-Invasive Brain Stimulation in Sleep Medicine.

Human memory tends to bias negative over neutral information. Recent evidence suggests that this bias may be due to a categorical effect of emotionally salient information, which diminishes when negative information is less frequent. Moreover, sleep loss has been shown to impair memory. Here, we aimed to replicate this categorical-over valence-bias for emotional information and determine the influence of total sleep deprivation (TSD) on this effect.

The categorical effect of negative emotion on memory before and after sleep deprivation.

Feigning and fabrication by a patient can evoke anger and distress in staff and generate diagnosis and management challenges. When faced with difficulties that can lead to moral injury among health care providers, and even risk compromised patient care, clinical teams must balance empathy with appropriate boundaries. This case report examines an individual with a history of polysubstance use and acute-on-chronic pain whose persistent patterns of fabrication-spanning exaggerated military service, terminal illness, family trauma, and academic accomplishments-posed substantial risk-assessment and treatment-planning challenges across multiple clinical presentations. Insights from three expert discussants with distinct specializations in psychodynamic formulation, distress management, and forensic psychiatry are provided. Through their analyses, the complex interplay among chronic pain, inadequate distress tolerance, personality pathology, and health care utilization are evaluated in conjunction with evidence-based approaches to differential diagnosis and management. This article presents practical recommendations for preserving therapeutic engagement while protecting appropriate boundaries and, ultimately, working toward optimized care delivery for such challenging, vulnerable patients.

Article	Year
Effects of clozapine-N-oxide and compound 21 on sleep in laboratory mice. eLife\| PubMed ID: 36892930	2023
Using digital phenotyping to capture depression symptom variability: detecting naturalistic variability in depression symptoms across one year using passively collected wearable movement and... Translational psychiatry\| PubMed ID: 38071317	2023
Paraphilic disorders, psychopathy, and those who sexually offend: a narrative review of treatment modalities. International journal of impotence research\| PubMed ID: 38160223	2025
Neuroscience in pictures: 2. Sleep, wakefulness, and mental state biology. Asian journal of psychiatry\| PubMed ID: 38838457	2024
Machine learning characterization of a rare neurologic disease via electronic health records: a proof-of-principle study on stiff person syndrome. BMC neurology\| PubMed ID: 39097681	2024
Atypical presentation of schizophrenia with ablution avoidance: A case report. Schizophrenia research\| PubMed ID: 39208770	2024
Neuroscience in Pictures: 3. Schizophrenia. Asian journal of psychiatry\| PubMed ID: 39427364	2024
Neuroscience in Pictures: 4. Depression. Asian journal of psychiatry\| PubMed ID: 40139021	2025
The Future of Non-Invasive Brain Stimulation in Sleep Medicine. Journal of sleep research\| PubMed ID: 40370279	2025
The categorical effect of negative emotion on memory before and after sleep deprivation. Neuropsychologia\| PubMed ID: 40543569	2025
Badge of Courage: Pain and Suffering After Military Service in a Nonveteran. Harvard review of psychiatry\| PubMed ID: 40643589	2025

Seo Ho Song

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