Effects of oral temazepam on slow waves during non-rapid eye movement sleep in healthy young adults: A high-density EEG investigation.

Slow waves are characteristic waveforms that occur during non-rapid eye movement (NREM) sleep that play an integral role in sleep quality and brain plasticity. Benzodiazepines are commonly used medications that alter slow waves, however, their effects may depend on the time of night and measure used to characterize slow waves. Prior investigations have utilized minimal scalp derivations to evaluate the effects of benzodiazepines on slow waves, and thus the topography of changes to slow waves induced by benzodiazepines has yet to be fully elucidated. This study used high-density electroencephalography (hdEEG) to evaluate the effects of oral temazepam on slow wave activity, incidence, and morphology during NREM sleep in 18 healthy adults relative to placebo. Temazepam was associated with significant decreases in slow wave activity and incidence, which were most prominent in the latter portions of the sleep period. However, temazepam was also associated with a decrease in the magnitude of high-amplitude slow waves and their slopes in the first NREM sleep episode, which was most prominent in frontal derivations. These findings suggest that benzodiazepines produce changes in slow waves throughout the night that vary depending on cortical topography and measures used to characterize slow waves. Further research that explores the relationships between benzodiazepine-induced changes to slow waves and the functional effects of these waveforms is indicated.

Effects of oral temazepam on sleep spindles during non-rapid eye movement sleep: A high-density EEG investigation.

Benzodiazepines are commonly used medications that alter sleep spindles during non-rapid eye movement (NREM) sleep, however the topographic changes to these functionally significant waveforms have yet to be fully elucidated. This study utilized high-density electroencephalography (hdEEG) to investigate topographic changes in sleep spindles and spindle-range activity caused by temazepam during NREM sleep in 18 healthy adults. After an accommodation night, sleep for all participants was recorded on two separate nights after taking either placebo or oral temazepam 15 mg. Sleep was monitored using 256-channel hdEEG. Spectral analysis and spindle waveform detection of sleep EEG data were performed for each participant night. Global and topographic data were subsequently compared between temazepam and placebo conditions. Temazepam was associated with significant increases in spectral power from 10.33 to 13.83 Hz. Within this frequency band, temazepam broadly increased sleep spindle duration, and topographically increased spindle amplitude and density in frontal and central-posterior regions, respectively. Higher frequency sleep spindles demonstrated increased spindle amplitude and a paradoxical decrease in spindle density in frontal and centroparietal regions. Further analysis demonstrated temazepam both slowed the average frequency of spindle waveforms and increased the relative proportion of spindles at peak frequencies in frontal and centroparietal regions. These findings suggest that benzodiazepines have diverse effects on sleep spindles that vary by frequency and cortical topography. Further research that explores the relationships between topographic and frequency-dependent changes in pharmacologically-induced sleep spindles and the functional effects of these waveforms is indicated.

Altered overnight modulation of spontaneous waking EEG reflects altered sleep homeostasis in major depressive disorder: a high-density EEG investigation.

BACKGROUND: Prior investigations have suggested sleep homeostasis is altered in major depressive disorder (MDD). Low frequency activity (LFA) in the electroencephalogram during waking has been correlated with sleep slow wave activity (SWA), suggesting that waking LFA reflects sleep homeostasis in healthy individuals. This study investigated whether the overnight change in waking LFA and its relationship with sleep SWA are altered in MDD. METHODS: 256-channel high-density electroencephalography (hdEEG) recordings during waking (pre- and post-sleep) and during sleep were collected in 14 unmedicated, unipolar MDD subjects (9 women) and age- and sex-matched healthy controls (HC). RESULTS: Waking LFA (3.25-6.25 Hz) declined significantly overnight in the HC group, but not in the group of MDD subjects. Overnight decline of waking LFA correlated with sleep SWA in frontal brain regions in HC, but a comparable relationship was not found in MDD. LIMITATIONS: This study is not able to definitely segregate overnight changes in the waking EEG that may occur due to homeostatic and/or circadian factors. CONCLUSIONS: MDD involves altered overnight modulation of waking low frequency EEG activity that may reflect altered sleep homeostasis in the disorder. Future research is required to determine the functional significance and clinical implications of these findings.

Topographic and sex-related differences in sleep spindles in major depressive disorder: a high-density EEG investigation.

BACKGROUND: Sleep spindles are believed to mediate several sleep-related functions including maintaining disconnection from the external environment during sleep, cortical development, and sleep-dependent memory consolidation. Prior studies that have examined sleep spindles in major depressive disorder (MDD) have not demonstrated consistent differences relative to control subjects, which may be due to sex-related variation and limited spatial resolution of spindle detection. Thus, this study sought to characterize sleep spindles in MDD using high-density electroencephalography (hdEEG) to examine the topography of sleep spindles across the cortex in MDD, as well as sex-related variation in spindle topography in the disorder. METHODS: All-night hdEEG recordings were collected in 30 unipolar MDD participants (19 women) and 30 age and sex-matched controls. Topography of sleep spindle density, amplitude, duration, and integrated spindle activity (ISA) were assessed to determine group differences. Spindle parameters were compared between MDD and controls, including analysis stratified by sex. RESULTS: As a group, MDD subjects demonstrated significant increases in frontal and parietal spindle density and ISA compared to controls. When stratified by sex, MDD women demonstrated increases in frontal and parietal spindle density, amplitude, duration, and ISA; whereas MDD men demonstrated either no differences or decreases in spindle parameters. LIMITATIONS: Given the number of male subjects, this study may be underpowered to detect differences in spindle parameters in male MDD participants. CONCLUSIONS: This study demonstrates topographic and sex-related differences in sleep spindles in MDD. Further research is warranted to investigate the role of sleep spindles and sex in the pathophysiology of MDD.

Overnight changes in waking auditory evoked potential amplitude reflect altered sleep homeostasis in major depression.

OBJECTIVE: Sleep homeostasis is altered in major depressive disorder (MDD). Pre- to postsleep decline in waking auditory evoked potential (AEP) amplitude has been correlated with sleep slow wave activity (SWA), suggesting that overnight changes in waking AEP amplitude are homeostatically regulated in healthy individuals. This study investigated whether the overnight change in waking AEP amplitude and its relation to SWA is altered in MDD. METHOD: Using 256-channel high-density electroencephalography, all-night sleep polysomnography and single-tone waking AEPs pre- and postsleep were collected in 15 healthy controls (HC) and 15 non-medicated individuals with MDD. RESULTS: N1 and P2 amplitudes of the waking AEP declined after sleep in the HC group, but not in MDD. The reduction in N1 amplitude also correlated with fronto-central SWA in the HC group, but a comparable relationship was not found in MDD, despite equivalent SWA between groups. No pre- to postsleep differences were found for N1 or P2 latencies in either group. These findings were not confounded by varying levels of alertness or differences in sleep variables between groups. CONCLUSION: MDD involves altered sleep homeostasis as measured by the overnight change in waking AEP amplitude. Future research is required to determine the clinical implications of these findings.

Retinal projections to the subcortical visual system in congenic albino and pigmented rats.

The primary visual pathway in albino mammals is characterized by an increased decussation of retinal ganglion cell axons at the optic chiasm and an enhanced contralateral projection to the dorsal lateral geniculate nucleus. In contrast to the primary visual pathway, little is known about the organization of retinal input to most nuclei of the subcortical visual system in albino mammals. The subcortical visual system is a large group of retinorecipient nuclei in the diencephalon and mesencephalon. These areas mediate a range of behaviors that include both circadian and acute responses to light. We used a congenic strain of albino and pigmented rats with a mutation at the c locus for albinism (Fischer 344-c/+; LaVail MM, Lawson NR (1986) Development of a congenic strain of pigmented and albino rats for light damage studies. Exp Eye Res 43:867-869) to quantitatively assess the effects of albinism on retinal projections to a number of subcortical visual nuclei including the ventral lateral hypothalamus (VLH), ventral lateral preoptic area (VLPO), olivary pretectal nucleus (OPN), posterior limitans (PLi), commissural pretectal area (CPA), intergeniculate leaflet (IGL), ventral lateral geniculate nucleus (vLGN) and superior colliculus (SC). Following eye injections of the neuroanatomical tracer cholera toxin-beta, the distribution of anterogradely transported label was measured. The retinal projection to the contralateral VLH, PLi, CPA and IGL was enhanced in albino rats. No significant differences were found between albino and pigmented rats in retinal input to the VLPO, OPN and vLGN. These findings raise the possibility that enhanced retinofugal projections to subcortical visual nuclei in albinos may underlie some light-mediated behaviors that differ between albino and pigmented mammals.

Putative contributors to the secular increase in obesity: exploring the roads less traveled.

OBJECTIVE: To investigate plausible contributors to the obesity epidemic beyond the two most commonly suggested factors, reduced physical activity and food marketing practices. DESIGN: A narrative review of data and published materials that provide evidence of the role of additional putative factors in contributing to the increasing prevalence of obesity. DATA: Information was drawn from ecological and epidemiological studies of humans, animal studies and studies addressing physiological mechanisms, when available. RESULTS: For at least 10 putative additional explanations for the increased prevalence of obesity over the recent decades, we found supportive (although not conclusive) evidence that in many cases is as compelling as the evidence for more commonly discussed putative explanations. CONCLUSION: Undue attention has been devoted to reduced physical activity and food marketing practices as postulated causes for increases in the prevalence of obesity, leading to neglect of other plausible mechanisms and well-intentioned, but potentially ill-founded proposals for reducing obesity rates.

Effects of sleep deprivation on wound healing.

Sleep deprivation is widely regarded as a stressor and has been shown to have significant effects on host defences. Severely sleep-deprived rats develop lesions on their paws and tails, suggesting possible deficits in the healing process. The purpose of this study was to assess the impact of rapid eye-movement (REM) sleep deprivation (RSD) on wound healing in a rat model. Male dark-hooded Long-Evans rats, 2-4 months old, were subjected to dorsal application of two sterile punch biopsies, each 3.5 mm in size. Biopsies were performed either immediately before or immediately after 5 days of sleep deprivation. Wound healing in REM sleep-deprived animals was compared with home cage control and yoked control animals. RSD did not produce differences in the rate of healing, regardless of the timing of the biopsy punch. RSD does not appear to have significant effects on wound healing and thus appears to act differently from other types of stressors on wound healing.

Functional but not structural subgenual prefrontal cortex abnormalities in melancholia.

Major depression is a heterogeneous condition, and the search for neural correlates specific to clinically defined subtypes has been inconclusive. Theoretical considerations implicate frontostriatal, particularly subgenual prefrontal cortex (PFC), dysfunction in the pathophysiology of melancholia--a subtype of depression characterized by anhedonia--but no empirical evidence has been found yet for such a link. To test the hypothesis that melancholic, but not nonmelancholic depression, is associated with the subgenual PFC impairment, concurrent measurement of brain electrical (electroencephalogram, EEG) and metabolic (positron emission tomography, PET) activity were obtained in 38 unmedicated subjects with DSM-IV major depressive disorder (20 melancholic, 18 nonmelancholic subjects), and 18 comparison subjects. EEG data were analyzed with a tomographic source localization method that computed the cortical three-dimensional distribution of current density for standard frequency bands, allowing voxelwise correlations between the EEG and PET data. Voxel-based morphometry analyses of structural magnetic resonance imaging (MRI) data were performed to assess potential structural abnormalities in melancholia. Melancholia was associated with reduced activity in the subgenual PFC (Brodmann area 25), manifested by increased inhibitory delta activity (1.5-6.0 Hz) and decreased glucose metabolism, which themselves were inversely correlated. Following antidepressant treatment, depressed subjects with the largest reductions in depression severity showed the lowest post-treatment subgenual PFC delta activity. Analyses of structural MRI revealed no group differences in the subgenual PFC, but in melancholic subjects, a negative correlation between gray matter density and age emerged. Based on preclinical evidence, we suggest that subgenual PFC dysfunction in melancholia may be associated with blunted hedonic response and exaggerated stress responsiveness.

Fos immunoreactivity in rat subcortical visual shell in response to illuminance changes.

Immediate early gene expression has been used frequently as a marker of activity in the circadian visual system. Recent evidence suggests that the pretectum participates in orchestrating sleep and circadian responses to light. Lesions of the pretectum eliminate dark shift-induced rapid eye movement sleep triggering in albino rats, and compromise circadian phase shifts in hamsters. We hypothesized that regions of the pretectum respond to light with robust and region-specific Fos activation, similar to the suprachiasmatic nucleus and intergeniculate leaflet. We used Fos expression, the protein product of the immediate early gene c-fos, as a functional marker to measure the responses of neurons following acute lighting changes. Rats maintained on a 12:12 light-dark cycle were subjected to a shift from light-to-dark or from dark-to-light at midday (Zeitgeber time 6) or midnight (Zeitgeber time 18). Fos expression was visualized with immunocytochemistry and quantified with an automated scoring system. We found three regions in the pretectum (the olivary pretectal nucleus, posterior limitans, and a region homologous to the hamster commissural pretectal nucleus), and two regions in the lateral geniculate complex (the intergeniculate leaflet and ventral lateral geniculate nucleus) that demonstrated significant Fos activation in response to light. Furthermore, the olivary pretectal nucleus, the posterior limitans, and the ventral lateral geniculate nucleus showed preferential Fos activation after acute light onset rather than following chronic exposure to light at midday, whereas at midnight these nuclei showed Fos activation following both chronic light exposure and acute light onset. Given the extensive anatomical connections between pretectal nuclei and other nuclei in the subcortical visual shell, as well as with centers for sleep and arousal, it is highly plausible that these pretectal nuclei integrate information about changes in illuminance, and aid in the coordination of acute behavioral responses to light.

Age-associated changes in the serotonergic system in rat superior colliculus and pretectum.

The purpose of this study was to investigate whether aging alters serotonergic innervation of the superior colliculus and pretectum in rats. The superior colliculus has one of the highest concentrations of serotonin in the rat central nervous system. Young and old male F344 rats (<6 months, and >18 months, albino and pigmented) were used in all experiments. Coronal sections through the superior colliculus and pretectum were incubated with antibodies to serotonin, the serotonin 2A receptor, and the serotonin transporter. Immunocytochemical staining was analyzed semi-quantitatively. The results indicate that with age there is an increase in serotonin immunoreactivity throughout the entire superior colliculus and pretectum, a decrease in levels of serotonin 2A receptor staining in select layers of superior colliculus, and no change in serotonin transporter immunoreactivity. Albino rats differ from pigmented rats in that they have enhanced serotonergic immunoreactivity in the superficial layers of superior colliculus, a region that receives direct retinal input. These data suggest that the age-related changes in the serotonergic system in the superior colliculus and pretectum may account for some of the alterations in light-mediated behaviors with aging.

Consequences of insomnia and its therapies.

Insomnia has a number of clinically significant associations. In particular, patients with chronic insomnia have higher rates of psychiatric and medical illnesses, and insomnia is an important risk factor in the development of depression. Insomniacs also have higher rates of health care utilization and reduced quality of life. This article reviews important clinical correlates of insomnia and evidence for possible causal relationships between sleep and health.

Anterior cingulate activity as a predictor of degree of treatment response in major depression: evidence from brain electrical tomography analysis.

OBJECTIVE: The anterior cingulate cortex has been implicated in depression. Results are best interpreted by considering anatomic and cytoarchitectonic subdivisions. Evidence suggests depression is characterized by hypoactivity in the dorsal anterior cingulate, whereas hyperactivity in the rostral anterior cingulate is associated with good response to treatment. The authors tested the hypothesis that activity in the rostral anterior cingulate during the depressed state has prognostic value for the degree of eventual response to treatment. Whereas prior studies used hemodynamic imaging, this investigation used EEG. METHOD: The authors recorded 28-channel EEG data for 18 unmedicated patients with major depression and 18 matched comparison subjects. Clinical outcome was assessed after nortriptyline treatment. Of the 18 depressed patients, 16 were considered responders 4-6 months after initial assessment. A median split was used to classify response, and the pretreatment EEG data of patients showing better (N=9) and worse (N=9) responses were analyzed with low-resolution electromagnetic tomography, a new method to compute three-dimensional cortical current density for given EEG frequency bands according to a Talairach brain atlas. RESULTS: The patients with better responses showed hyperactivity (higher theta activity) in the rostral anterior cingulate (Brodmann's area 24/32). Follow-up analyses demonstrated the specificity of this finding, which was not confounded by age or pretreatment depression severity. CONCLUSIONS: These results, based on electrophysiological imaging, not only support hemodynamic findings implicating activation of the anterior cingulate as a predictor of response in depression, but they also suggest that differential activity in the rostral anterior cingulate is associated with gradations of response.

Effects of amygdala lesions on sleep in rhesus monkeys.

The amygdala is important in processing emotion and in the acquisition and expression of fear and anxiety. It also appears to be involved in the regulation of sleep and wakefulness. The purpose of this study was to assess the effects of, fiber-sparing lesions of the amygdala on sleep in rhesus monkeys (Macaca mulatta). We recorded sleep from 18 age-matched male rhesus monkeys, 11 of which had previously received ibotenic acid lesions of the amygdala and seven of which were normal controls. Surface electrodes for sleep recording were attached and the subjects were seated in a restraint chair (to which they had been adapted) for the nocturnal sleep period. Despite adaptation, control animals had sleep patterns characterized by frequent arousals. Sleep was least disrupted in animals with large bilateral lesions of the amygdala. They had more sleep and a higher proportion of rapid-eye-movement (REM) sleep than did either animals with smaller lesions or control animals. Based on these results, it seems likely that, in the primate, the amygdala plays a role in sleep regulation and may be important in mediating the effects of emotions/stress on sleep. These findings may also be relevant to understanding sleep disturbances associated with psychopathology.

The pretectum mediates rapid eye movement sleep regulation by light.

A variety of sensory stimuli (e.g., visual, auditory, and thermal) are known to induce rapid eye movement (REM) sleep in mammals. Studies have examined the induction of REM sleep in albino rats by light-to-dark transitions, a phenomenon referred to as REM sleep triggering. Recent research has demonstrated that aspiration lesions of the superior colliculus (SC) and pretectal area attenuated REM sleep triggering. To define more specifically the area or areas involved in mediating REM sleep responses to changes in illumination, fiber-sparing neurotoxic lesions were made to the pretectum (PT) or the SC. Lesions of the PT attenuated REM sleep triggering, whereas lesions of the SC did not. Thus, the role of the PT may be expanded to include the regulation of REM sleep in response to photic stimulation in albino rats. These findings provide a paradigm in which to study mechanisms of REM sleep generation and the effects of light on behavioral state.

EEG alpha power and alpha power asymmetry in sleep and wakefulness.

Asymmetry of waking electroencephalography (EEG) alpha power in frontal regions has been correlated with waking emotional reactivity and the emotional content of dream reports. Little is known regarding alpha asymmetry during sleep. The present study was performed to compare alpha power and alpha power asymmetry in various brain regions across states of sleep and wakefulness. Waking and sleep EEG were recorded in a group of patients undergoing polysomnographic evaluation for possible sleep disorders. Alpha EEG asymmetry in frontal and temporal regions was significantly correlated in waking versus sleep, particularly during rapid eye movement (REM) sleep. These results suggest that patterns of frontal alpha asymmetry are stable across sleep and waking and may be related to emotional reactivity during dreaming. During sleep, alpha power was highest during slow-wave sleep and lowest during REM sleep. Implications of these data for understanding the functional significance of alpha power during waking and sleeping are considered.

Thalamic metabolic rate predicts EEG alpha power in healthy control subjects but not in depressed patients.

BACKGROUND: EEG alpha power has been demonstrated to be inversely related to mental activity and has subsequently been used as an indirect measure of brain activation. The hypothesis that the thalamus serves as a neuronal oscillator of alpha rhythms has been supported by studies in animals, but only minimally by studies in humans. METHODS: In the current study, PET-derived measures of regional glucose metabolism, EEG, and structural MRI were obtained from each participant to assess the relation between thalamic metabolic activity and alpha power in depressed patients and healthy controls. The thalamus was identified and drawn on each subject's MRI. The MRI was then co-registered to the corresponding PET scan and metabolic activity from the thalamus extracted. Thalamic activity was then correlated with a 30-min aggregated average of alpha EEG power. RESULTS: Robust inverse correlations were observed in the control data, indicating that greater thalamic metabolism is correlated with decreased alpha power. No relation was found in the depressed patient data. CONCLUSIONS: The results are discussed in the context of a possible abnormality in thalamocortical circuitry associated with depression.

REM sleep in response to light and dark in congenic albino and pigmented F344 rats.

Sleep was recorded in congenic F344 albino (c/c) and pigmented (c/+) rats while they were exposed to various light-dark schedules at 10, 50 and 100 lux. In short LD schedules (1:1 and 3:3), both c/c and c/+ rats had similar patterns of NREM and waking in the light and dark. NREM was higher in the light and there was more wakefulness in the dark. These differences were accentuated with increased light intensity. In contrast, substantial effects on REM sleep were seen only in the c/c rats and increased light levels also enhanced these effects. REM sleep in pigmented c/+ rats was virtually unaffected by lighting changes. These results indicate that different systems are involved in regulating sleep-waking and REM sleep responses to light and further that these systems are differentially affected by alleles at (or near) the c locus and/or albinism.

Metabolic rate in the right amygdala predicts negative affect in depressed patients.

The role of the amygdala in major depression was investigated. Resting regional cerebral metabolic rate (rCMRglu) was measured with [18F]fluorodeoxyglucose positron emission tomography (PET) in two samples of subjects using two different PET cameras. The samples consisted of 10 and 17 medication-free depressives and 11 and 13 controls, respectively. Using coregistration of PET and magnetic resonance images, regions were individually delineated for the amygdala and thalamus, the latter of which was used as a control region. Within the depressed groups, right amygdalar rCMRglu was positively correlated with negative affect. Thalamic rCMRglu was not related to negative affect, and amygdalar rCMRglu accounted for a significant portion of variance in depressives' negative affect scores over and above the contribution of thalamic rCMRglu.

Effects of lighting conditions on sleep and wakefulness in albino Lewis and pigmented Brown Norway rats.

STUDY OBJECTIVES: Previous studies have demonstrated that albino but not pigmented rats show acute increases in REM sleep following light-to-dark transitions. Light and dark have also been shown to have direct effects on NREM sleep and wakefulness in albino rats. Little is known, however, about the direct light-dark effects on sleep patterns in pigmented animals. The purpose of the present study was to compare the direct effects of light and dark on REM sleep, NREM sleep, and waking in albino Lewis and pigmented Brown Norway (BN) rats. DESIGN: Groups of albino Lewis and pigmented Brown Norway (BN) rats were exposed to various light-dark (LD) schedules. In the first experiment, the lighting schedules were LD 12:12 and LD 3:3. The second experiment compared LD 12:12 with an irregular schedule consisting of short light and dark periods of unequal length. MEASUREMENTS AND RESULTS: Both Lewis and BN rats slept more during the light and were awake more during the dark on all schedules. REM sleep patterns in light and dark periods were opposite, however. Lewis rats spent more of their sleep in REM sleep during dark than the light, whereas BN rats had a higher proportion of REM sleep in the light. CONCLUSIONS: The results suggest that there are substantial direct effects of light and dark on sleep in pigmented as well as in albino rats, although these effects are not always the same in magnitude or even in direction.