Elevated Mortality Rate in Patients With Functional Seizures After Diagnosis and Referral.

Background and Objectives: To evaluate the standardized mortality ratio (SMR) of patients in the United States referred to a multidisciplinary clinic for treatment of functional seizures. Methods: We identified patients who had or had not died based on automated retrospective review of electronic health records from a registry of patients referred to a single-center multidisciplinary functional seizures treatment clinic. We calculated an SMR by comparing the number of observed deaths with the expected number of deaths in an age-matched, sex-matched, and race-matched population within the same state, and year records were available. Results: A total of 700 patients with functional seizures (mean age 37 years, 78% female) were followed up for 1,329 patient-years for a median of 15 months per patient (interquartile range 6-37 months). We observed 11 deaths, corresponding to a mortality rate of 8.2 per 1,000 patient-years and an SMR of 2.4 (95% confidence interval: 1.17-4.22). Five of 9 patients with identified circumstances around their death were in hospice care when they passed. None of the identified causes of death were related to seizures directly. Discussion: These data provide further evidence of elevated mortality in functional seizures soon after diagnosis and referral to treatment. These data from the decentralized health care system of the United States build on the findings from other countries with large-scale health registries.

Industry influence on mental health research: depression as a case example.

Emotional distress has been rising since before the COVID-19 pandemic and the public is told that depression is a major public health problem. For example, in 2017 depressive disorders were ranked as the third leading cause of "years lost to disability" and the World Health Organization now ranks depression as the single largest contributor to global disability. Although critical appraisals of the epidemiological data raise questions about the accuracy of population-based depression estimates, the dominance of the medical model and the marketing of psychotropics as "magic bullets," have contributed to a dramatic rise in the prescription of psychiatric drugs. Unfortunately, the pharmaceutical industry's influence on psychiatric research and practice has resulted in over-estimates of the effectiveness of psychotropic medications and an under-reporting of harms. This is because the principles that govern commercial entities are incongruent with the principles that guide public health research and interventions. In order to conduct mental health research and develop interventions that are in the public's best interest, we need non-reductionist epistemological and empirical approaches that incorporate a biopsychosocial perspective. Taking depression as a case example, we argue that the socio-political factors associated with emotional distress must be identified and addressed. We describe the harms of industry influence on mental health research and show how the emphasis on "scaling up" the diagnosis and treatment of depression is an insufficient response from a public health perspective. Solutions for reform are offered.

Concealment and fabrication by experienced research subjects.

BACKGROUND: Subjects who enroll in multiple studies have been found to use deception at times to overcome restrictive screening criteria. Deception undermines subject safety as well as study integrity. Little is known about the extent to which experienced research subjects use deception and what type of information is concealed, withheld, or distorted. PURPOSE: This study examined the prevalence of deception and types of deception used by subjects enrolling in multiple studies. METHODS: Self-report of deceptive behavior used to gain entry into clinical trials was measured among a sample of 100 subjects who had participated in at least two studies in the past year. RESULTS: Three quarters of subjects reported concealing some health information from researchers in their lifetime to avoid exclusion from enrollment in a study. Health problems were concealed by 32% of the sample, use of prescribed medications by 28%, and recreational drug use by 20% of the sample. One quarter of subjects reported exaggerating symptoms in order to qualify for a study and 14% reported pretending to have a health condition in order to qualify. LIMITATIONS: Although this study finds high rates of lifetime deceptive behavior, the frequency and context of this behavior is unknown. Understanding the context and frequency of deception will inform the extent to which it jeopardizes study integrity and safety. CONCLUSION: The use of deception threatens both participant safety and the integrity of research findings. Deception may be fueled in part by undue inducements, overly restrictive criteria for entry, and increased demand for healthy controls. Screening measures designed to detect deception among study subjects would aid in both protecting subjects and ensuring the quality of research findings.

Calcium/calmodulin kinase II in the pedunculopontine tegmental nucleus modulates the initiation and maintenance of wakefulness.

The pedunculopontine tegmentum nucleus (PPT) is critically involved in the regulation of wakefulness (W) and rapid eye movement (REM) sleep, but our understanding of the mechanisms of this regulation remains incomplete. The present study was designed to determine the role of PPT intracellular calcium/calmodulin kinase (CaMKII) signaling in the regulation of W and sleep. To achieve this aim, three different concentrations (0.5, 1.0, and 2.0 nmol) of the CaMKII activation inhibitor, KN-93, were microinjected bilaterally (100 nl/site) into the PPT of freely moving rats, and the effects on W, slow-wave sleep (SWS), REM sleep, and levels of phosphorylated CaMKII (pCaMKII) expression in the PPT were quantified. These effects, which were concentration-dependent and affected wake-sleep variables for 3 h, resulted in decreased W, due to reductions in the number and duration of W episodes; increased SWS and REM sleep, due to increases in episode duration; and decreased levels of pCaMKII expression in the PPT. Regression analyses revealed that PPT levels of pCaMKII were positively related with the total percentage of time spent in W (R(2) = 0.864; n = 28 rats; p < 0.001) and negatively related with the total percentage of time spent in sleep (R(2) = 0.863; p < 0.001). These data provide the first direct evidence that activation of intracellular CaMKII signaling in the PPT promotes W and suppresses sleep. These findings are relevant for designing a drug that could treat excessive sleepiness by promoting alertness.

Culture and the anxiety disorders: recommendations for DSM-V.

BACKGROUND: The anxiety disorders specified in the fourth edition, text revision, of The Diagnostic and Statistical Manual (DSM-IV-TR) are identified universally in human societies, and also show substantial cultural particularities in prevalence and symptomatology. Possible explanations for the observed epidemiological variability include lack of measurement equivalence, true differences in prevalence, and limited validity or precision of diagnostic criteria. One central question is whether, through inadvertent "over-specification" of disorders, the post-DSM-III nosology has missed related but somewhat different presentations of the same disorder because they do not exactly fit specified criteria sets. This review canvases the mental health literature for evidence of cross-cultural limitations in DSM-IV-TR anxiety disorder criteria. METHODS: Searches were conducted of the mental health literature, particularly since 1994, regarding cultural or race/ethnicity-related factors that might limit the universal applicability of the diagnostic criteria for six anxiety disorders. RESULTS: Possible mismatches between the DSM criteria and the local phenomenology of the disorder in specific cultural contexts were found for three anxiety disorders in particular. These involve the unexpectedness and 10-minute crescendo criteria in Panic Disorder; the definition of social anxiety and social reference group in Social Anxiety Disorder; and the priority given to psychological symptoms of worry in Generalized Anxiety Disorder. Limited evidence was found throughout, particularly in terms of neurobiological markers, genetic risk factors, treatment response, and other DSM-V validators that could help clarify the cross-cultural applicability of criteria. CONCLUSIONS: On the basis of the available data, options and preliminary recommendations for DSM-V are put forth that should be further evaluated and tested.

Activation of phasic pontine-wave generator prevents rapid eye movement sleep deprivation-induced learning impairment in the rat: a mechanism for sleep-dependent plasticity.

Animal and human studies of sleep and learning have demonstrated that training on various tasks increases subsequent rapid eye movement (REM) sleep and phasic pontine-wave (P-wave) activity, followed by improvement in performance on the learned task. It is well documented that REM sleep deprivation after learning trials blocks the expected improvement in performance on subsequent retesting. Our aim was to test whether experimentally induced P-wave generator activation could eliminate the learning impairment produced by post-training REM sleep deprivation. Rats were trained on a two-way active avoidance-learning task. Immediately thereafter, two groups of those rats received a control vehicle (100 nl saline) microinjection and one group received a carbachol (50 ng in 100 nl saline) microinjection into the P-wave generator. The carbachol-injected group and one of the two control saline microinjected groups were selectively deprived of REM sleep during a 6 hr polygraphic recording session. All rats were then tested on the avoidance-learning task. The rats that received both the control saline injection and REM sleep deprivation showed learning deficits compared with the control saline-injected rats that were allowed to sleep normally. In contrast, the rats that received the carbachol microinjection and REM sleep deprivation demonstrated normal learning. These results demonstrate, for the first time, that carbachol-induced activation of the P-wave generator prevents the memory-impairing effects of post-training REM sleep deprivation. This evidence supports our hypothesis that the activation of the P-wave generator during REM sleep deprivation enhances a physiological process of memory, which occurs naturally during post-training REM sleep.

Regulation of rapid eye movement sleep in the freely moving rat: local microinjection of serotonin, norepinephrine, and adenosine into the brainstem.

STUDY OBJECTIVES: Considerable evidence suggests that rapid eye movement (REM) sleep is induced by glutamatergic activation of cholinergic cells within the pedunculopontine tegmentum (PPT). The aim of this study is to test a popular hypothesis that serotonin, norepinephrine, and adenosine act on PPT cells to regulate REM sleep. This study also tests an alternate hypothesis that serotonin may inhibit REM sleep signs by direct action on the individual REM sleep sign generators. DESIGN: Serotonin, norepinephrine, and adenosine were locally microinjected into the PPT and serotonin was microinjected into the pontine-wave (P-wave) generator (dorsal part of the locus subcoeruleus nucleus) while quantifying the effects on REM sleep and P-wave activity in freely moving rats. SETTING: N/A. PARTICIPANTS: N/A. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Local microinjections of serotonin, norepinephrine, and adenosine into the PPT did not change REM sleep. Microinjection of serotonin into the P-wave generator suppressed P-wave activity but not REM sleep. CONCLUSIONS: The present findings provide direct evidence that serotonin, norepinephrine, and adenosine-induced REM sleep suppression in the behaving rat are not mediated by the PPT. The results also provide direct evidence, for the first time, that serotonin suppresses P-wave activity by acting directly on the P-wave generator. These results suggest that the serotonin-induced inhibition of REM sleep in the freely moving rat is probably not mediated through the mesopontine cholinergic cell compartment but, rather, through individual REM sleep sign generators.

Effects of passive-avoidance training on sleep-wake state-specific activity in the basolateral and central nuclei of the amygdala.

This study examined the effects of intense emotional learning on the sleep-wake state-specific electroencephalographic (EEG) activities of the basolateral (BLA) and central (CeA) nuclei of the amygdala. Rats were trained on a passive-avoidance learning (PAL) protocol that was followed by 6 hr of undisturbed polygraphic recording and a PAL test. After PAL training, the total amount of REM sleep decreased: high-frequency EEG power decreased in the CeA during REM sleep and increased in the BLA during all sleep-wake stages. These results suggest that there is no homeostatic demand for REM sleep after intense emotional learning. However, the PAL-specific changes in the local EEG suggest that some form of memory processing may occur within the amygdala during REM sleep.