Eric A. Nofzinger

Forebrain activation in REM sleep: an FDG PET study

Rapid eye movement (REM) sleep is a behavioral state characterized by cerebral cortical activation with dreaming as an associated behavior. The brainstem mechanisms involved in the generation of REM sleep are well-known, but the forebrain mechanisms that might distinguish it from waking are not well understood. We report here a positron emission tomography (PET) study of regional cerebral glucose utilization in the human forebrain during REM sleep in comparison to waking in six healthy adult females using the 18F-deoxyglucose method. In REM sleep, there is relative activation, shown by increased glucose utilization, in phylogenetically old limbic and paralimbic regions which include the lateral hypothalamic area, amygdaloid complex, septal-ventral striatal areas, and infralimbic, prelimbic, orbitofrontal, cingulate, entorhinal and insular cortices. The largest area of activation is a bilateral, confluent paramedian zone which extends from the septal area into ventral striatum, infralimbic, prelimbic, orbitofrontal and anterior cingulate cortex. There are only small and scattered areas of apparent deactivation. These data suggest that an important function of REM sleep is the integration of neocortical function with basal forebrain-hypothalamic motivational and reward mechanisms. This is in accordance with views that alterations in REM sleep in psychiatric disorders, such as depression, may reflect dysregulation in limbic and paralimbic structures.

Symptoms of stress and depression as correlates of sleep in primary insomnia.

Objective: Previous studies have not evaluated the clinical correlates of the electroencephalographic spectral profile in patients with insomnia. In the preliminary study described here, we evaluated the extent to which symptoms of stress and depression are associated with subjective sleep complaints and quantitative measures of sleep in individuals with chronic insomnia. Methods: Subjects were 14 healthy adults who met criteria for primary insomnia as specified in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders. Measures of stress, depression, and subjective sleep quality were collected before subjects participated in a two-night laboratory sleep series. We hypothesized that elevated symptoms of stress and depression would be associated with subjective sleep complaints and electroencephalographic evidence of hyperarousal during sleep. Hyperarousal during sleep was defined as decreases in delta power and elevations in alpha and beta power throughout non–rapid eye movement sleep, and symptoms of stress were defined as the tendency to experience stress-related intrusive thoughts and the interaction between intrusion tendency and the number of recent stressful events (subjective stress burden). Results: A stronger tendency to experience stress-related intrusive thoughts was associated with greater sleep complaints and a trend toward higher beta power, whereas increases in subjective stress burden were associated with decreases in delta power. In addition, elevations in subclinical symptoms of depression were associated with greater sleep complaints and elevations in alpha power. Conclusions: Observed relationships among symptoms of stress, depression, subjective sleep complaints, and electroencephalographic power may be relevant to the discrepancy between subjective and objective measures of sleep in patients with insomnia and may be more broadly applicable to sleep complaints in association with stressful life events and major depression.

Placebo-controlled comparison of prazosin and cognitive-behavioral treatments for sleep disturbances in US Military Veterans.

OBJECTIVE Pharmacological and cognitive-behavioral treatments targeting insomnia and nightmares have been shown to be effective in the treatment of military veterans with sleep complaints comorbid with symptoms of stress-related disorders, including Post-Traumatic Stress Disorder (PTSD), but the two approaches have not been directly compared. This randomized controlled trial compared the effects of prazosin vs. a behavioral sleep intervention (BSI), targeting nightmares and insomnia against a placebo pill control condition on sleep and daytime symptoms. METHODS Fifty United States military veterans (mean age 40.9years, SD=13.2years) with chronic sleep disturbances were randomized to prazosin (n=18), BSI (n=17), or placebo (n=15). Each intervention lasted 8weeks. Participants completed self-report measures of insomnia severity, sleep quality, and sleep disturbances. All kept a sleep diary throughout the intervention period. Polysomnographic studies were conducted pre- and post-intervention. RESULTS Both active treatment groups showed greater reductions in insomnia severity and daytime PTSD symptom severity. Sleep improvements were found in 61.9% of those who completed the active treatments and 25% of those randomized to placebo. CONCLUSION BSI and prazosin were both associated with significant sleep improvements and reductions in daytime PTSD symptoms in this sample of military veterans. Sleep-focused treatments may enhance the benefits of first-line PTSD treatments.

Changes in forebrain function from waking to REM sleep in depression: preliminary analyses [of 18F]FDG PET studies

Based on recent functional brain imaging studies of healthy human REM sleep, we hypothesized that alterations in REM sleep in mood disorder patients reflect a functional dysregulation within limbic and paralimbic forebrain structures during that sleep state. Six unipolar depressed subjects and eight healthy subjects underwent separate [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) PET scans during waking and during their first REM period of sleep. Statistical parametric mapping contrasts were performed to detect changes in relative regional cerebral glucose metabolism (rCMRglu) from waking to REM sleep in each group as well as interactions in patterns of change between groups. Clinical and EEG sleep comparisons from an undisturbed night of sleep were also performed. In contrast to healthy control subjects, depressed patients did not show increases in rCMRglu in anterior paralimbic structures in REM sleep compared to waking. Depressed subjects showed greater increases from waking to REM sleep in rCMRglu in the tectal area and a series of left hemispheric areas including sensorimotor cortex, inferior temporal cortex, uncal gyrus-amygdala, and subicular complex than did the control subjects. These observations indicate that changes in limbic and paralimbic function from waking to REM sleep differ significantly from normal in depressed patients.

Financial strain is a significant correlate of sleep continuity disturbances in late-life

Although psychological stress has been associated with disturbed sleep in younger populations, little is known about the stress-sleep relationship in late-life. In the present study, we evaluated relationships among a chronic stressor, ongoing financial strain, and sleep in a heterogenous sample (n=75) of community-dwelling elders (mean age=74.0 years). Self-report measures included ongoing financial strain, mental health, physical health and subjective sleep quality. Sleep duration, continuity, and architecture were measured by polysomnography (PSG). Analysis of variance and regression were used to test the hypothesis that ongoing financial strain is a significant correlate of disturbed sleep in the elderly. Covariates included age, sex, mental health and physical health. Analyses revealed that ongoing financial strain is a significant correlate of PSG-assessed sleep latency, wakefulness after sleep onset, and sleep efficiency. After adjusting for the effects of age, sex, mental health, and physical health on sleep, ongoing financial strain was associated with lower sleep efficiency (p<.01). Our results show that chronic stress, as measured by ongoing financial strain, is a significant correlate of sleep disturbances in the elderly, even after adjusting for factors known to impact sleep in late-life.

Affect Intensity and Phasic REM Sleep in Depressed Men before and after Treatment with Cognitive-Behavioral Therapy.

This article explored the relationship between daytime affect and REM sleep in 45 depressed men before and after treatment with cognitive-behavioral therapy and in a control group of 43 healthy subjects. The intensity of daytime affect (as measured by the sum of positive and negative affects) in depressed men correlated significantly and positively with phasic REM sleep measures at both pre- and posttreatment. This relationship was not found in healthy control subjects. In depressed men, both affect intensity and phasic REM sleep measures decreased over the course of treatment. The results suggest a relationship between phasic REM sleep and intensity of affect reported by depressed men. On the basis of this preliminary observation, it was hypothesized that abnormalities in phasic REM sleep in depressed patients are related, in part, to fundamental alterations in the intensity of their affective experience.

Electroencephalographic sleep in clinically stable schizophrenic patients: two-weeks versus six-weeks neuroleptic-free.

EEG sleep studies in schizophrenic patients are influenced by alterations in clinical state and medication status. The current study defines longitudinal alterations in electroencephalographic (EEG) sleep for 10 healthy men who were schizophrenic patients who remained relatively clinically stable during a double-blind neuroleptic withdrawal study. Clinical assessments and EEG sleep studies were performed at baseline on haloperidol, and then at 2-week and 6-week drug-free periods. Sleep continuity and rapid eye movement (REM) sleep measures declined not only between the haloperidol baseline and 2-week drug-free conditions, but continued to decline from 2-week to 6-weeks neuroleptic-free. Alterations in EEG sleep from the 2-week to 6-week haloperidol-free assessments did not correlate with changes in clinical symptoms suggesting effects related to drug-withdrawal or subclinical state changes. These results show that despite relative clinical stability over time, the EEG sleep of schizophrenic patients continues to change following withdrawal of a neuroleptic and is dependent on the duration of the drug-free interval.

A method for the assessment of the functional neuroanatomy of human sleep using FDG PET

Although sleep is characterized by relative behavioral inactivity, cortical activity is known to cycle in well-defined periods across this state. Cognitive function during sleep has been difficult to define, although disturbances in sleep are known to result from, and to cause, various human pathologies, including neuropsychiatric disorders. Assessment of brain function in humans (related to cognitive operations) during sleep has been limited, until recently, to surface electrophysiologic recordings that limit analysis of regional function, particularly in deep structures. The current report describes one method of assessing human forebrain activation during sleep using the [18F]2-fluoro-2-deoxy-d-glucose ([18F]FDG) method and positron emission tomography (PET) measures of regional cerebral glucose utilization. In comparison with other functional brain imaging techniques (e.g., assessment of blood flow or functional magnetic resonance imaging), this method offers the advantage of a more naturalistic study of sleep since subjects do not have to sleep in a scanning device. This leads to a higher rate of successful completion of studies. The primary disadvantage of this method is the decreased temporal resolution necessitating assessments of global sleep states (e.g., REM or NREM) as opposed to assessing events within a sleep state (e.g., sleep spindles or rapid eye movements).

Chronotype and Diurnal Patterns of Positive Affect and Affective Neural Circuitry in Primary Insomnia

While insomnia is a well‐established risk factor for the initial onset, recurrence or relapse of affective disorders, the specific characteristics of insomnia that confer risk remain unclear. Patients with insomnia with an evening chronotype may be one particularly high‐risk group, perhaps due to alterations in positive affect and its related affective circuitry. We explored this possibility by comparing diurnal patterns of positive affect and the activity of positive affect‐related brain regions in morning‐ and evening‐types with insomnia. We assessed diurnal variation in brain activity via the relative regional cerebral metabolic rate of glucose uptake by using [18F]fluorodeoxyglucose‐positron emission tomography during morning and evening wakefulness. We focused on regions in the medial prefrontal cortex and striatum, which have been consistently linked with positive affect and reward processing. As predicted, chronotypes differed in their daily patterns in both self‐reported positive affect and associated brain regions. Evening‐types displayed diurnal patterns of positive affect characterized by phase delay and smaller amplitude compared with those of morning‐types with insomnia. In parallel, evening‐types showed a reduced degree of diurnal variation in the metabolism of both the medial prefrontal cortex and the striatum, as well as lower overall metabolism in these regions across both morning and evening wakefulness. Taken together, these preliminary findings suggest that alterations in the diurnal activity of positive affect‐related neural structures may underlie differences in the phase and amplitude of self‐reported positive affect between morning and evening chronotypes, and may constitute one mechanism for increased risk of mood disorders among evening‐type insomniacs.

Diurnal Variation in Regional Brain Glucose Metabolism in Depression

BACKGROUND This study compared diurnal variation in mood and regional cerebral metabolic rate of glucose (rCMRglc) in depressed and healthy subjects. METHODS Depressed and healthy subjects were investigated using [18F]-fluoro-deoxyglucose positron emission tomography scans during morning and evening wakefulness. All subjects completed subjective mood ratings at both times of day. Statistical parametric mapping was used to compare rCMRglc between the two groups across time of day. RESULTS Depressed patients showed evening mood improvements compared with healthy subjects. Compared with healthy subjects, depressed patients showed smaller increases in rCMRglc during evening relative to morning wakefulness in lingual and fusiform cortices, midbrain reticular formation, and locus coeruleus and greater increases in rCMRglc in parietal and temporal cortices. Depressed patients had hypermetabolism in limbic-paralimbic regions and hypometabolism in frontal and parietal cortex at both times of day compared with healthy subjects. CONCLUSIONS Variation in rCMRglc differs across times of day in depressed and healthy subjects. In depressed patients, evening mood improvements were associated with increased metabolic activity in ventral limbic-paralimbic, parietal, temporal, and frontal regions and in the cerebellum. This increased metabolic pattern during evening wakefulness may reflect partial normalization of primary and compensatory neural systems involved in affect production and regulation.