EEG power during waking and NREM sleep in primary insomnia.

OBJECTIVE: Pathophysiological models of insomnia invoke the concept of 24-hour hyperarousal, which could lead to symptoms and physiological findings during waking and sleep. We hypothesized that this arousal could be seen in the waking electroencephalogram (EEG) of individuals with primary insomnia (PI), and that waking EEG power would correlate with non-REM (NREM) EEG. METHODS: Subjects included 50 PI and 32 good sleeper controls (GSC). Five minutes of eyes closed waking EEG were collected at subjects' usual bedtimes, followed by polysomnography (PSG) at habitual sleep times. An automated algorithm and visual editing were used to remove artifacts from waking and sleep EEGs, followed by power spectral analysis to estimate power from 0.5-32 Hz. RESULTS: We did not find significant differences in waking or NREM EEG spectral power of PI and GSC. Significant correlations between waking and NREM sleep power were observed across all frequency bands in the PI group and in most frequency bands in the GSC group. CONCLUSIONS: The absence of significant differences between groups in waking or NREM EEG power suggests that our sample was not characterized by a high degree of cortical arousal. The consistent correlations between waking and NREM EEG power suggest that, in samples with elevated NREM EEG beta activity, waking EEG power may show a similar pattern.

Multivariate prediction of emerging psychosis in adolescents at high risk for schizophrenia.

BACKGROUND: Accurate prediction of psychosis development in high-risk populations is an important but thus far elusive goal. Of the many diverse etiologic and risk factors identified thus far, few have been combined into prospective multivariate risk ascertainment models. We tested the predictive power of familial, neurobiological, socioenvironmental, cognitive and clinical risk factors through an integrative biopsychosocial model for emerging psychosis in young relatives at familial risk for schizophrenia. METHODS: 96 young first- and second- degree relatives of schizophrenia probands were followed for an average of 2.38 (SD=0.98) years to examine their trajectory towards psychosis. Iterative structural equation modelling utilizing multiple etiologic and risk factors was employed to estimate their joint contribution to prediction of psychosis development. RESULTS: The rate of conversion to psychosis over the study period was 12.5%. In the final model, clinical measures of schizotypy were directly predictive of conversion, with early (familial, biological, socioenvironmental) and cognitive risk factors indirectly predictive of psychosis through increased baseline clinical symptomatology. Our model provided an excellent fit to the observed data, with sensitivity of 0.17, specificity of 0.99, positive predictive value of 0.67 and negative predictive value of 0.89. CONCLUSIONS: Integrative modeling of multivariate data from familial, neurobiological, socioenvironmental, cognitive and clinical domains represents a powerful approach to prediction of psychosis development. The high specificity and low sensitivity found using a combination of such variables suggests that their utility may be in confirmatory testing among already selected high-risk individuals, rather than for initial screening. These findings also highlight the importance of data from a broad array of etiologic and risk factors, even within a familial high-risk population. With further refinement and validation, such methods could form key components of early detection, intervention and prevention programs.

Insomnia and objectively measured sleep disturbances predict treatment outcome in depressed patients treated with psychotherapy or psychotherapy-pharmacotherapy combinations.

OBJECTIVE: Insomnia and objectively measured sleep disturbances predict poor treatment outcomes in patients with major depressive disorder (MDD). However, prior research has utilized individual clinical trials with relatively small sample sizes and has focused on insomnia symptoms or objective measures, but not both. The present study is a secondary analysis that examines the degree to which insomnia, objective sleep disturbances, or their combination predicts depression remission following pharmacotherapy and/or psychotherapy treatment. METHOD: Participants were 711 depressed (DSM criteria) patients drawn from 6 clinical trials. Remission status, defined as a score of ≤ 7 on the Hamilton Depression Rating Scale (HDRS) over 2 consecutive months, served as the primary outcome. Insomnia was assessed via the 3 sleep items on the HDRS. Objectively measured short sleep duration (total sleep time ≤ 6 hours) and prolonged sleep latency (> 30 minutes) or wakefulness after sleep onset (> 30 minutes) were derived from in-laboratory polysomnographic sleep studies. Logistic regression predicted the odds of nonremission according to insomnia, each of the objective sleep disturbances, or their combination, after adjusting for age, sex, treatment modality, and baseline depressive symptoms. RESULTS: Prolonged sleep latency alone (OR = 3.53; 95% CI, 1.28-9.73) or in combination with insomnia (OR = 2.11; 95% CI, 1.13-3.95) predicted increased risk of nonremission. In addition, insomnia and sleep duration individually and in combination were each associated with a significantly increased risk of nonremission (P values < .05). CONCLUSIONS: Findings suggest that objectively measured prolonged sleep latency and short sleep duration independently or in conjunction with insomnia are risk factors for poor depression treatment outcome.

Sleep correlates of cognition in early course psychotic disorders.

BACKGROUND: Slow waves and sleep spindles, the main oscillations during non-rapid eye movement sleep, have been thought to be related to cognitive processes, and are impaired in psychotic disorders. Cognitive impairments, seen early in the course of psychotic disorders, may be related to alterations in these oscillations, but few studies have examined this relationship. METHOD: Twenty seven untreated patients with a recently diagnosed psychotic disorder had polysomnographic sleep studies and neuro-cognitive testing. RESULTS: Reduced power in the sigma range, which reflects spindle density, was associated with impaired attention, and reasoning, but not intelligence quotient (IQ). Slow wave sleep measures were not significantly associated with any cognitive measures. CONCLUSIONS: Impairments in sleep spindles may be associated with cognitive deficits in the early course of psychotic disorders. These observations may help clarify neuro-biologic mechanisms of cognitive deficits in psychotic disorders such as schizophrenia.

Gray matter loss in young relatives at risk for schizophrenia: relation with prodromal psychopathology.

The maturation of neocortical regions mediating social cognition during adolescence and young adulthood in relatives of schizophrenia patients may be vulnerable to heritable alterations of neurodevelopment. Prodromal psychotic symptoms, commonly emerging during this period in relatives, have been hypothesized to result from alterations in brain regions mediating social cognition. We hypothesized these regions to show longitudinal alterations and these alterations to predict prodromal symptoms in adolescent and young adult relatives of schizophrenia patients. 27 Healthy controls and 23 relatives were assessed at baseline and one-year follow-up using scale of prodromal symptoms and gray matter volumes of hypothesized regions from T1-MRI images. Regional volumes showing deficits on ANCOVA and repeated-measures ANCOVAs (controlling intra cranial volume, age and gender) were correlated with prodromal symptoms. At baseline, bilateral amygdalae, bilateral pars triangulares, left lateral orbitofrontal, right frontal pole, angular and supramarginal gyrii were smaller in relatives compared to controls. Relatives declined but controls increased or remained stable on bilateral lateral orbitofrontal, left rostral anterior cingulate, left medial prefrontal, right inferior frontal gyrus and left temporal pole volumes at follow-up relative to baseline. Smaller volumes predicted greater severity of prodromal symptoms at both cross-sectional assessments. Longitudinally, smaller baseline volumes predicted greater prodromal symptoms at follow-up; greater longitudinal decreases in volumes predicted worsening (increase) of prodromal symptoms over time. These preliminary findings suggest that abnormal longitudinal gray matter loss may occur in regions mediating social cognition and may convey risk for prodromal symptoms during adolescence and early adulthood in individuals with a familial diathesis for schizophrenia.

Longitudinal treatment outcome of African American and Caucasian patients with first episode psychosis.

The purpose of our analyses to examine the outcome differences between African American and Caucasian first-episode psychotic patients over the course of one year, to explore the interactive effects of gender, diagnosis, and race on treatment outcome. A consecutive series of patients (N=199) were recruited into our study from the inpatient and outpatient services at a psychiatric clinic. Global functioning, positive, negative, affective, and depression symptoms and treatment adherence were assessed at baseline prior to treatment and during follow-up up to one year. African American patients (N=62) were found to experience significantly less improvement in symptoms, bizarre behavior, avolition, anhedonia, and functional performance, and affective symptoms than their Caucasian counterparts (N=137). In addition, African American female patients experienced less improvement in affective flattening. While both groups of patients have experienced significant improvement during the one-year treatment, that of the African American patients was less optimal.

Examining initial sleep onset in primary insomnia: a case-control study using 4-second epochs.

STUDY OBJECTIVES: To explore the sleep onset process in primary insomnia patients, new rules for scoring 4-second epochs were implemented to score sleep and artifacts during initial sleep onset. Conventional scorings in 20-second and 60-second epochs were also obtained. METHODS: The start of the initial 60-second epoch of stage 1 was used to define "time zero" (t0). Sleep onset periods from 11 patients and 11 individually age- and sex-matched controls spanned from 5 minutes before t0 through 29 minutes after t0. Using the new rules, the periods were scored blind to group assignment. This t0 time-referenced the data analysis to one plausible midpoint in the sleep onset process. In parallel, latencies were time-referenced from good night time. RESULTS: Reliability in scoring sleep and artifacts was adequate (kappa = 0.68 & 0.63, respectively, p <0.001). Group differences in sleep latencies were marginal in 60-second and 20-second scoring but significant with a definition of 4-second sleep latency. Patients had more 4-second epochs scored as awake (Mantel-Haenszel chi2 = 271, d.f. = 1, p <0.001) and containing artifact (M-H chi2 = 143, p <0.001). Patients took longer to achieve 30 continuous 4-second epochs of NREM sleep (Breslow chi2 = 4.03, d.f. = 1, p = 0.045) after t0. Patients accumulated sleep more slowly with all 3 scoring rules after t0. A slower rate of accumulating sleep after t0 was detected only with the 4-second scoring (p = 0.047). CONCLUSIONS: Evidence was present for momentary state-switching instabilities in the patients during the initial sleep onset process. Using rules for scoring small epochs may reveal such instabilities more readily than traditional scoring methods.

Effects of a brief behavioral treatment for late-life insomnia: preliminary findings.

STUDY OBJECTIVES: Insomnia is a chronic and prevalent sleep disorder in adults older than 65 years. Hypnotics raise safety concerns in this group, and standard behavioral treatments are time consuming. This preliminary report addresses the effects of a brief behavioral treatment for insomnia in older adults who present with the typical psychiatric and medical comorbidities of aging. METHODS: Thirty-five older adults (10 men, 25 women, mean age = 70.2 +/- 6.4 years old) were randomly assigned to a brief behavioral treatment for insomnia (BBTI; n=17) or to an information-only control (IC; n=18) condition. All subjects completed clinician-administered and self-report measures of sleep quality, as well as a sleep diary, at baseline. Interventions were delivered in a single individual session with a booster session administered 2 weeks later. Postintervention assessments were completed after 4 weeks. RESULTS: Significant improvements in self-report and sleep diary measures and mild-to-moderate improvement in anxiety and depression were observed after treatment in participants randomly assigned to BBTI, as compared with participants randomly assigned to IC. At post-treatment assessment, 12 BBTI participants (71%) and 7 IC participants (39%) met criteria for response. Nine BBTI participants (53%) met criteria for remission, whereas, in the IC group, 3 participants (17%) met the criteria. CONCLUSION: BBTI was associated with significant improvements in sleep measures and in daytime symptoms of anxiety and depression. BBTI appears to be a promising intervention for older adults with insomnia.

Regional cerebral metabolic correlates of WASO during NREM sleep in insomnia.

STUDY OBJECTIVE: To investigate the non-rapid eye movement (NREM) sleep-related regional cerebral metabolic correlates of wakefulness after sleep onset (WASO) in patients with primary insomnia. METHODS: Fifteen patients who met DSM-IV criteria for primary insomnia completed 1-week sleep diary (subjective) and polysomnographic (objective) assessments of WASO and regional cerebral glucose metabolic assessments during NREM sleep using [18F] fluoro-2-deoxy-D-glucose positron emission tomography. Whole-brain voxel-by-voxel correlations, as well as region of interest analyses, were performed between subjective and objective WASO and relative regional cerebral metabolism using the statistical software SPM2. RESULTS: Subjective WASO was significantly greater than objective WASO, but the 2 measures were positively correlated. Objective WASO correlated positively with the percentage of stage 2 sleep and negatively with the percentage of stages 3 and 4 sleep. Both subjective and objective WASO positively correlated with NREM sleep-related cerebral glucose metabolism in the pontine tegmentum and in thalamocortical networks in a frontal, anterior temporal, and anterior cingulate distribution. CONCLUSIONS: Increased relative metabolism in these brain regions during NREM sleep in patients with insomnia is associated with increased WASO measured either subjectively or objectively. These effects are related to the lighter sleep stages of patients with more WASO and may result from increased activity in arousal systems during sleep and or to activity in higher-order cognitive processes related to goal-directed behavior, conflict monitoring, emotional awareness, anxiety, and fear. Such changes may decrease arousal thresholds and/or increase perceptions of wakefulness in insomnia.

Alterations in regional cerebral glucose metabolism across waking and non-rapid eye movement sleep in depression.

BACKGROUND: Depression is associated with sleep disturbances, including alterations in non-rapid eye movement (NREM) sleep. Non-rapid eye movement sleep is associated with decreases in frontal, parietal, and temporal cortex metabolic activity compared with wakefulness. OBJECTIVE: To show that depressed patients would have less of a decrease than controls in frontal metabolism between waking and NREM sleep and to show that during NREM sleep, they would have increased activity in structures that promote arousal. DESIGN: Subjects completed electroencephalographic sleep and regional cerebral glucose metabolism assessments during both waking and NREM sleep using [(18)F]fluoro-2-deoxy-D-glucose positron emission tomography. SETTING: General clinical research center. PATIENTS: The study included 29 unmedicated patients who met the Structured Clinical Interview for DSM-IV criteria for current major depression and who had a score of 15 or greater on a 17-item Hamilton Rating Scale for Depression and 28 medically healthy subjects of comparable age and sex who were free of mental disorders. MAIN OUTCOME MEASURES: Electroencephalographic sleep and regional cerebral metabolism during waking and NREM sleep. RESULTS: Depressed patients showed smaller decreases than healthy subjects in relative metabolism in broad regions of the frontal, parietal, and temporal cortex from waking to NREM sleep. Depressed patients showed larger decreases than healthy subjects in relative metabolism in the left amygdala, anterior cingulate cortex, cerebellum, parahippocampal cortex, fusiform gyrus, and occipital cortex. However, in post hoc analyses, depressed patients showed hypermetabolism in these areas during both waking and NREM sleep. CONCLUSIONS: The smaller decrease in frontal metabolism from waking to NREM sleep in depressed patients is further evidence for a dynamic sleep-wake alteration in prefrontal cortex function in depression. Hypermetabolism in a ventral emotional neural system during waking in depressed patients persists into NREM sleep.

Functional neuroimaging evidence for hyperarousal in insomnia.

OBJECTIVE: The authors investigated the neurobiological basis of poor sleep and daytime fatigue in insomnia. METHOD: [(18)F]Fluorodeoxyglucose positron emission tomography was used to assess regional cerebral glucose metabolism of seven patients with insomnia and 20 healthy subjects. RESULTS: Compared with healthy subjects, patients with insomnia showed greater global cerebral glucose metabolism during sleep and while awake, a smaller decline in relative metabolism from waking to sleep states in wake-promoting regions, and reduced relative metabolism in the prefrontal cortex while awake. CONCLUSIONS: Subjectively disturbed sleep in patients with insomnia is associated with greater brain metabolism. The inability to fall asleep may be related to a failure of arousal mechanisms to decline in activity from waking to sleep states. Further, daytime fatigue may reflect decreased activity in the prefrontal cortex resulting from inefficient sleep.

Increased activation of anterior paralimbic and executive cortex from waking to rapid eye movement sleep in depression.

BACKGROUND: Depression is associated with sleep disturbances, including alterations in rapid eye movement (REM) sleep, that may relate to the neurobiology of the disorder. Given that REM sleep activates limbic and anterior paralimbic cortex and that depressed patients demonstrate increases in electroencephalographic sleep measures of REM, we hypothesized greater activation of these structures during waking to REM sleep in depressed patients. DESIGN: Subjects completed electroencephalographic sleep and regional cerebral glucose metabolism assessments during both waking and REM sleep using [(18)F]fluoro-2-deoxy-D-glucose positron emission tomography. SETTING: Patients and healthy subjects recruited from the general community to participate in a research study of depression at an academic medical center. Patients Twenty-four unmedicated patients who met the Structured Clinical Interview for DSM-IV criteria for current major depression and who had a score of 15 or higher on a 17-item Hamilton Rating Scale for Depression; 14 medically healthy subjects of comparable age and sex who were free of mental disorders. MAIN OUTCOME MEASURES: Electroencephalographic sleep, semiquantitative and relative regional cerebral metabolism during waking and REM sleep. RESULTS: Depressed patients showed greater REM sleep percentages. While both healthy and depressed patients activated anterior paralimbic structures from waking to REM sleep, the spatial extent of this activation was greater in the depressed patients. Additionally, depressed patients showed greater activation in bilateral dorsolateral prefrontal, left premotor, primary sensorimotor, and left parietal cortices, as well as in the midbrain reticular formation. CONCLUSIONS: Increased anterior paralimbic activation from waking to REM sleep may be related to affective dysregulation in depressed patients. Increased activation of executive cortex may be related to a cognitive dysregulation. These results suggest that altered function of limbic/anterior paralimbic and prefrontal circuits in depression is accentuated during the REM sleep state. The characteristic sleep disturbances of depression may reflect this dysregulation.

Measuring sleep habits without using a diary: the sleep timing questionnaire.

STUDY OBJECTIVES: To develop a single-administration instrument yielding equivalent measures of sleep to those obtained from a formal (2-week) sleep diary. DESIGN & SETTING: A single-administration Sleep riming Questionnaire (STQ) is described (and reproduced in the Appendix). Test-retest reliability was examined in 40 subjects who were given the STQ on two occasions separated by less than 1 year. Convergent validity was measured both by comparing STO-derived measures with objective measures derived from wrist actigraphy (n=23) and by comparing STQ-derived measures with other subjective measures derived from a detailed 2-week sleep diary in two nonoverlapping samples (n=101, 93). Correlations of STQ measures with age and momingness-eveningness (chronotype) were also examined. SUBJECTS: The analyses used sample sizes of 40, 23, 101, and 93 (both genders, overall age range 20y-89y). Most subjects were healthy volunteers; some Study 4 subjects were patients (enrolled in research protocols). RESULTS: Test-retest reliability for the STQ was demonstrated for estimates of bedtime (r = 0.705, p < 0.001) and waketime (r = 0.826, p < 0.001). Convergent validity using wrist actigraphy was demonstrated by correlations of 0.592 (p < 0.005) for bedtime, and of 0.769 (p < 0.001) for waketime. Diary studies indicated STQ bedtime and waketime data to be highly correlated (at about 0.8) with those obtained from a formal 2-week sleep diary. The STQ also provided data on estimated sleep latency and wake after sleep onset (WASO), which correlated reliably (at about 0.7) with average nightly ratings of these variables from a 2-week sleep diary. Mean estimated values of sleep latency and WASO from the two instruments were within 1 minute of each other. ST-derived bedtimes and waketimes correlated with both age and chronotype in the expected direction (older subjects earlier, morning types earlier). CONCLUSION: The STQ may be a reliable valid measure of sleep timing that could provide a time-efficient alternative to traditional sleep diaries.

Symptom reports in severe chronic insomnia.

STUDY OBJECTIVES: To describe patterns and severities of the daytime and nighttime symptoms of chronic insomnia patients. DESIGN: Exploratory chart review from clinicians' evaluation summaries, a self-report screening instrument, the Pittsburgh Sleep Quality Index, the Beck Depression Inventory, the Epworth Sleepiness Scale, and the Hopkins Symptom Checklist-90 (HSCL90). SETTING: A regional sleep disorders referral clinic. PATIENTS OR PARTICIPANTS: 94 patients with chronic insomnia (DSM-IV code 307.42), classified into the subgroups "Primary Insomnia," "Depression-Related," "Anxiety-Related," and "Other". INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Frequent symptoms occurred not only in nocturnal domains (e.g., sleep disturbances, environmental sensitivity), but also in daytime domains (e.g., cognitive difficulties, sleepiness). Compared to primary insomnia patients, those with depression-related insomnia endorsed more severe symptoms. All subgroups endorsed a generally similar symptom profile when single symptoms were considered in isolation. When considered conjointly, severe symptoms typical of depression and generalized social alienation had a high negative predictive value for primary insomnia. The number of severe symptoms on the HSCL90 was related to fewer sleep hours in the nonprimary insomnia subgroup but not in the primary insomnia subgroup. CONCLUSIONS: Patients with chronic insomnia report significant daytime as well as nighttime symptoms. Depression-related and primary insomnias were separable only by some highly characteristic symptoms of depression. Diagnostic subgroups of insomnia patients may vary in how their overall distress relates to diminished self-reported sleep. Nighttime and daytime symptoms need to be assessed together when measuring insomnia severity.

Human regional cerebral glucose metabolism during non-rapid eye movement sleep in relation to waking.

Sleep is an essential human function. Although the function of sleep has generally been regarded to be restorative, recent data indicate that it also plays an important role in cognition. The neurobiology of human sleep is most effectively analysed with functional imaging, and PET studies have contributed substantially to our understanding of both rapid eye movement (REM) and non-rapid eye movement (NREM) sleep. In this study, PET was used to determine patterns of regional glucose metabolism in NREM sleep compared with waking. We hypothesized that brain structures related to waking cognitive function would show a persistence of function into the NREM sleep state. Fourteen healthy subjects (age range 21-49 years; 10 women, 4 men) underwent concurrent EEG sleep studies and [(18)F]fluoro-2-deoxy-D-glucose PET scans during waking and NREM sleep. Whole-brain glucose metabolism declined significantly from waking to NREM sleep. Relative decreases in regional metabolism from waking to NREM sleep occurred in wide areas of frontal, parietal, temporal and occipital association cortex, primary visual cortex, and in anterior/dorsomedial thalamus. After controlling for the whole-brain declines in absolute metabolism, relative increases in regional metabolism from waking to NREM were found bilaterally in the dorsal pontine tegmentum, hypothalamus, basal forebrain, ventral striatum, anterior cingulate cortex and extensive regions of the mesial temporal lobe, including the amygdala and hippocampus, and in the right dorsal parietal association cortex and primary somatosensory and motor cortices. The reductions in relative metabolism in NREM sleep compared with waking are consistent with prior findings from blood flow studies. The relative increases in glucose utilization in the basal forebrain, hypothalamus, ventral striatum, amygdala, hippocampus and pontine reticular formation are new observations that are in accordance with the view that NREM sleep is important to brain plasticity in homeostatic regulation and mnemonic processing.