The effect of experimentally-induced sleep fragmentation and estradiol suppression on neurobehavioral performance and subjective sleepiness in pre-menopausal women.

STUDY OBJECTIVES: Menopause is associated with nighttime sleep fragmentation, declining estradiol and impaired cognition. In a model of pharmacologically-induced estradiol suppression mimicking menopause, we examined the impact of menopause-pattern sleep fragmentation on daytime neurobehavioral performance and sleepiness in premenopausal women. METHODS: Twenty premenopausal women completed two 5-night inpatient studies in the mid-to-late follicular phase (estrogenized) and after pharmacological estradiol suppression (hypo-estrogenized). During each study, participants had an uninterrupted 8-hour sleep opportunity for two nights, followed by three nights where sleep was experimentally fragmented to mimic menopause-pattern sleep disturbance, and during which the sleep opportunity was extended to prevent shortening of the sleep duration. Neurobehavioral performance and subjective sleepiness were measured using the Psychomotor Vigilance Task and Karolinska Sleepiness Scale (KSS). RESULTS: Compared to unfragmented sleep, sleep fragmentation increased attentional lapses (+0.6 lapses, p<0.05), slowed reaction time (+9.4 milliseconds, p<0.01), and increased daytime sleepiness (+0.5 KSS score, p<0.001). Estradiol suppression increased attentional lapses (+0.8; p<0.001) and reaction time (+12.3, p<0.01) but did not significantly affect daytime sleepiness. The effect of sleep fragmentation on neurobehavioral performance differed by estradiol state, such that the adverse effects of sleep fragmentation on attentional lapses (+0.9, trend p=0.06) and reaction time (+15, p<0.05) were observed only when estrogenized. CONCLUSIONS: Menopause-pattern sleep fragmentation and estradiol suppression worsened neurobehavioral performance and daytime sleepiness, even while sleep duration was not reduced. The adverse effects of sleep fragmentation in the context of an adequate sleep duration highlight the importance of sleep continuity as a vital aspect of good sleep health.

Prevalence of autoimmune diseases in functional neurological disorder: influence of psychiatric comorbidities and biological sex.

BACKGROUND: Functional neurological disorder (FND) is a common and disabling neuropsychiatric condition, which disproportionally affects women compared with men. While the etiopathogenesis of this disorder remains elusive, immune dysregulation is emerging as one potential mechanism. To begin to understand the role of immune dysfunctions in FND, we assessed the prevalence of several common autoimmune diseases (ADs) in a large cohort of patients with FND and examined the influence of psychiatric comorbidities and biological sex. METHODS: Using a large biorepository database (Mass General Brigham Biobank), we obtained demographic and clinical data of a cohort of 643 patients diagnosed with FND between January 2015 and December 2021. The proportion of ADs was calculated overall, by sex and by the presence of psychiatric comorbidities. RESULTS: The overall prevalence of ADs in our sample was 41.9%, with connective tissue and autoimmune endocrine diseases being the most commonly observed ADs. Among patients with FND and ADs, 27.7% had ≥2 ADs and 8% met criteria for multiple autoimmune syndrome. Rates of ADs were significantly higher in subjects with comorbid major depressive disorder and post-traumatic stress disorder (p= 0.02). Women represented the largest proportion of patients with concurrent ADs, both in the overall sample and in the subgroups of interest (p's < 0.05). CONCLUSIONS: This study is unique in providing evidence of an association between FND and ADs. Future studies are needed to investigate the mechanisms underlying this association and to understand whether FND is characterised by distinct dysregulations in immune response.

Preexisting Depression and Daytime Sleepiness in Women and Men.

BACKGROUND: Sleep problems can persist following the treatment of depression and remission of symptoms. The extent to which having a previous history of depression may be associated with current daytime sleepiness is largely unknown. METHODS: Data were obtained from the spring 2017 American College Health Association-National College Health Assessment (ACHA-NCHA) survey (92 institutions) which assessed self-reported health in U.S. college students (n = 41,670). Among the sample, 93.5% were 18-24 year of age, and 69.6% women. Logistic regression estimated the association between reported prior lifetime diagnosis of depression and daytime sleepiness from the past 7 days, while adjusting for depressive symptoms and antidepressant use from the past year. Unadjusted and adjusted logistic regression models stratified by gender were performed. RESULTS: Among those who reported problems with sleepiness, 31.6% women and 19.4% men had a preexisting depression diagnosis. Individuals with preexisting depression were more likely than those without this diagnosis to report sleepiness problems (women: OR = 1.4, CI = 1.3-1.6, p < .001; men: OR = 1.2, CI = 1.0-1.4, p < .01). However, this association differed significantly by gender, with women with a preexisting depression diagnosis having a 13.0% greater likelihood of sleepiness compared to men. CONCLUSIONS: Those with a preexisting depression diagnosis, and specifically women, may be at risk for daytime sleepiness even in the absence of current depressive mood-related symptoms. Given that many individuals are at risk for daytime sleepiness, mental health initiatives, including those on college campuses, should incorporate sleep hygiene within their programming.

Sustained improvement with mindfulness-based therapy for psychogenic nonepileptic seizures.

BACKGROUND: We previously reported on the efficacy of a manualized 12-session mindfulness-based therapy (MBT) for psychogenic nonepileptic seizures (PNES). Completion of MBT provided improvements in weekly PNES frequency and self-rated intensity. OBJECTIVES: In this study, we aimed to determine sustainability of improvement of seizure-related measures at 3- to 6-month follow-up after treatment completion. We also examined changes at treatment end and at follow-up on therapeutic targets of the MBT program. METHODS: Patients with documented PNES were recruited from 2014 to 2018. Baseline measures were collected at time of diagnosis (T0) and at first follow-up post-diagnosis (T1). Outcomes are reported at MBT treatment completion (T3) and 3- to 6-month follow-up (T4). The Wilcoxon signed-rank test was used for pair-wise comparisons of PNES frequency; linear mixed models were used for other outcomes. RESULTS: Fourteen of the 26 MBT completers (54%) attended follow-up (median 147.5 days between T3 and T4). PNES frequency, intensity, and number of days/week with PNES remained reduced at T4 (p < 0.01 for all; median frequency reduction 1.3/week from T1). Illness perception and feeling understood remained improved at T4 (p < 0.001 for both) as did worry about PNES (p < 0.05). Illness attribution (physical, mental or both) changed from T0 to T3 (p < 0.01), but not to T4. Psychological flexibility did not change over time. CONCLUSION: Previously reported improvements in seizure-related measures with MBT at treatment conclusion were maintained at 3- to 6-month follow-up. There were sustained improvements in some underlying processes (illness perception, feeling understood, and symptom worry) over the course of treatment and at follow-up. Long-term benefits of MBT need to be established with randomized controlled trials.

Neurostimulation for the treatment of functional neurological disorder: A systematic review.

Functional Neurological Disorder (FND), also known as conversion disorder, is characterized by neurological symptoms that are incompatible with any known structural disorder and best explained by a biopsychosocial model. Evidence-based treatments for FND are limited, with cognitive behavioral therapy (CBT) and physiotherapy being the most effective interventions [1]. In recent years, functional neuroimaging studies have provided robust evidence of alterations in activity and connectivity in multiple brain networks in FND. This body of evidence suggests that neurocircuitry-based interventions, such as non-invasive brain stimulation techniques (NIBS), may also represent an effective therapeutic option for patients with FND. In this systematic review, we outline the current state of knowledge of NIBS in FND, and discuss limitations and future directions that may help establish the efficacy of NIBS as a therapeutic option for FND.

Cerebellar-Prefrontal Network Connectivity and Negative Symptoms in Schizophrenia.

OBJECTIVE: The interpretability of results in psychiatric neuroimaging is significantly limited by an overreliance on correlational relationships. Purely correlational studies cannot alone determine whether behavior-imaging relationships are causal to illness, functionally compensatory processes, or purely epiphenomena. Negative symptoms (e.g., anhedonia, amotivation, and expressive deficits) are refractory to current medications and are among the foremost causes of disability in schizophrenia. The authors used a two-step approach in identifying and then empirically testing a brain network model of schizophrenia symptoms. METHODS: In the first cohort (N=44), a data-driven resting-state functional connectivity analysis was used to identify a network with connectivity that corresponds to negative symptom severity. In the second cohort (N=11), this network connectivity was modulated with 5 days of twice-daily transcranial magnetic stimulation (TMS) to the cerebellar midline. RESULTS: A breakdown of connectivity in a specific dorsolateral prefrontal cortex-to-cerebellum network directly corresponded to negative symptom severity. Restoration of network connectivity with TMS corresponded to amelioration of negative symptoms, showing a statistically significant strong relationship of negative symptom change in response to functional connectivity change. CONCLUSIONS: These results demonstrate that a connectivity breakdown between the cerebellum and the right dorsolateral prefrontal cortex is associated with negative symptom severity and that correction of this breakdown ameliorates negative symptom severity, supporting a novel network hypothesis for medication-refractory negative symptoms and suggesting that network manipulation may establish causal relationships between network markers and clinical phenomena.

Therapeutic Noninvasive Brain Stimulation in Alzheimer's Disease.

Alzheimer's disease (AD) is a looming public health crisis that currently lacks an effective treatment. Noninvasive Brain Stimulation (NBS), particularly transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), offers a promising alternative approach to pharmacological interventions for an increasing number of neurological and psychiatric conditions. The aim of this review is summarize data from therapeutic trials of NBS in AD and other dementing illnesses. Despite the potential of NBS, there is limited theoretical framework and a lack of guidelines for its applications to AD. Several published clinical trials failed to report key parameters of the interventions thus limiting the utility of the study to assess efficacy and safety. Our review concludes with some suggestions for future studies aimed to advance research into NBS as a potential treatment for the symptoms and disabilities caused by AD and to enable comparison of results across trials. Ultimately, appropriately powered, and controlled, multi-site randomized clinical trials will be needed to evaluate the therapeutic potential of NBS in AD.