Ian M. Colrain

The effects of normal aging on sleep spindle and K-complex production

OBJECTIVES Despite a relatively large body of literature describing the characteristics of sleep spindles and K-complexes in young adults, relatively little research has been conducted in older individuals. The general consensus from the few studies that have addressed this issue is that there is a progressive decrease in the number of spindles and K-complexes with age, although there is large intra-individual variation. Whether or not these changes are an inevitable consequence of the aging process can be addressed by studying healthy older adults who provide an example of the effects of age independently from those of disease. METHODS Fourteen young adults (mean age=21.4+/-2.5 years) and 20 older adults (mean age=75.5+/-6.3 years) participated in the study. All subjects were neurologically and medically healthy and were not taking any medications with a known effect on the central nervous system or sleep. For each subject, a number of characteristics were determined including the number, density (SS/min), amplitude and frequency of all spindles as well as the number and density of K-complexes (KC/min). RESULTS Spindle number, density and duration as well as K-complex number and density were all significantly lower in the elderly compared to the young adults. The EEG frequency within the spindles was significantly higher in the elderly, although the absolute difference was less than 0.5 Hz. Multiple regression analysis indicated that spindle duration and K-complex density were able to predict over 90% of the variance in age. CONCLUSIONS The age-related decrease in sleep spindle and K-complex density is consistent with previous reports and may be interpreted as an age-related alteration of thalamocortical regulatory mechanisms.

Variation in longitudinal trajectories of regional brain volumes of healthy men and women (ages 10 to 85 years) measured with atlas-based parcellation of MRI

Numerous cross-sectional MRI studies have characterized age-related differences in regional brain volumes that differ with structure and tissue type. The extent to which cross-sectional assumptions about change are accurate depictions of actual longitudinal measurement remains controversial. Even longitudinal studies can be limited by the age range of participants, sex distribution of the samples, and scan intervals. To address these issues, we calculated trajectories of regional brain volume changes from T1-weighted (SPGR) MRI data, quantified with our automated, unsupervised SRI24 atlas-based registration and parcellation method. Longitudinal MRIs were acquired at 3T in 17 boys and 12 girls, age 10 to 14 years, and 41 men and 41 women, age 20 to 85 years at first scan. Application of a regression-based correction function permitted merging of data acquired at 3T field strength with data acquired at 1.5T from additional subjects, thereby expanding the sample to a total of 55 men and 67 women, age 20 to 85 years at first scan. Adjustment for individual supratentorial volume removed regional volume differences between men and women due to sex-related differences in head size. Individual trajectories were computed from data collected on 2 to 6 MRIs at a single field strength over a ~1 to 8 year interval. Using linear mixed-effects models, the pattern of trajectories over age indicated: rises in ventricular and Sylvian fissure volumes, with older individuals showing faster increases than younger ones; declines in selective cortical volumes with faster tissue shrinkage in older than younger individuals; little effect of aging on volume of the corpus callosum; more rapid expansion of CSF-filled spaces in men than women after age 60 years; and evidence for continued growth in central white matter through early adulthood with accelerated decline in senescence greater in men than women.

Event-related potential measures of the inhibition of information processing: II. The sleep onset period

The loss of consciousness during the sleep onset period is associated with dramatic changes in information processing. Human event-related potentials (ERPs) reflect these changes. Short- and mid-latency ERPs are only minimally affected by sleep onset. On the other hand, long-latency ERPs are very much affected. A negative wave, N1, peaking at approximately 100 ms gradually decreases in amplitude until it reaches baseline level during definitive stage 2 sleep. The changes in N1 are especially apparent when the subject no longer signals awareness of the external stimulus or when stage 1 is dominated by theta activity in the EEG. The positive peaks, P1 and P2, peaking at approximately 50 and 180 ms, respectively, may appear to increase in amplitude (i.e. also be less negative). A long-lasting processing negativity (PN) may overlap and summate with these peaks during the waking state. During sleep onset, the PN dissipates, thus explaining the apparent positive baseline shift in the ERP waveform. In an oddball task, when an alert and awake subject detects a rare, relevant stimulus, a large positive wave, P300, maximum over parietal areas of the scalp, is observed. This P300 is, however, widely dispersed and can be observed over frontal areas of the scalp. When the subject no longer signals detection of this target stimulus, P300 can no longer be recorded. During stage 1, the parietal P300 remains large, providing the subject overtly detects the target. The amplitude of the frontal aspect of P300 is much reduced as response times slow. This may reflect deactivation of the frontal lobes during the sleep onset period. The infrequent change of an otherwise rapidly presented homogenous train of stimuli is associated with another long-lasting negativity, the mismatch negativity (MMN). The MMN also decreases in amplitude during the sleep onset period, reaching baseline level during definitive sleep. The vertex sharp wave (VSW) becomes apparent during the sleep onset period. Associated with the VSW is a late negative ERP, sometimes called the sleep N2 or the N350, peaking between 300 and 350 ms. It is unique to the sleep onset and sleep periods, becoming very large during stage 1-theta or when the subject no longer shows signs of awareness of the external stimulus.

Sleep and respiratory stimulus specific dampening of cortical responsiveness in OSAS

The application of inspiratory occlusion stimuli produces cortical responses called respiratory-related evoked potentials (RREPs). During wakefulness the RREP waveform consists of early P1 and Nf components, an N1 and a P300. During non-REM sleep the predominant component is an N550, best seen in the averages of elicited K-complexes. Obstructive sleep apnea syndrome (OSAS) patients have been previously shown to have a normal wake RREP but to have a reduced amplitude N550 and a smaller proportion of elicited K-complexes than controls. The present study tested the hypothesis that this reflects a sleep-specific dampening peculiar to inspiratory effort-related stimuli, by assessing both respiratory and auditory evoked potentials (AEPs) during wakefulness and non-REM sleep in OSAS patients and controls. Auditory tones were presented in an oddball sequence during wakefulness and as a monotonous series during stage 2 sleep. Inspiratory occlusions, delivered for 500 msec via an nCPAP mask were also presented during wakefulness and stage 2 sleep, every three to five breaths. Data were collected from ten OSAS patients and ten controls. There were no significant differences in the amplitudes of the auditory N1 and P3 or the respiratory P1, Nf, N1 or P3 components during wakefulness. The amplitude of the auditory N550 and the proportion of elicited K-complexes did not differ between groups for auditory stimuli presented during stage 2 sleep. The respiratory N550 and K-complex elicitation rate were both significantly reduced in the OSAS group, despite there being no differences in the mask occlusion pressure response to the occlusion. The results confirm a blunted cortical response to inspiratory occlusions that is specific to sleep. The absence of significant group differences in the responses to auditory stimuli highlight that the sleep-related differences seen in OSAS patients are specific to the processing of inspiratory effort related stimuli.

The N550 component of the evoked K‐complex: A modality non‐specific response?

A large amplitude late negative deflection peaking between 500 and 650 ms is observable in the averaged K‐complex wave‐form. This peak is thus often labelled the N550. ‘N550’ appears during stage 2 and is maintained into slow wave sleep but is not apparent during REM. Most studies have employed auditory stimuli to elicit the K‐complex. Two experiments were run to examine the effects of stimulus modality on the topographical distribution of the N550. In the first experiment, the K‐complexes were elicited in an auditory oddball procedure. In the second experiment, K‐complexes were elicited by respiratory occlusions. Twenty‐nine channel recordings were used to increase spatial resolution. N550 was substantially larger in the average of trials containing K‐complexes than in trials in which a K‐complex could not be identified. N550 varied inversely in amplitude with the probability of accordance of the stimulus. The topographic distribution of the N550 was consistent between experiments. It was bilaterally symmetrical and was maximal over fronto‐central regions of the scalp. The results indicate that the N550 reflects the activity of a modality non‐specific, sleep dependent generator that responds to both interoceptive and external stimulation.

Source Dipole Analysis of the Early Components of the RREP

Occlusion of the inspiratory airway produces a series of early RREP components. The predominant early positive and negative peaks are seen over the parietal and frontal scalp respectively and have been hypothesised to represent parallel activation of somatosensory and motor cortices in a manner similar to electrically produced SEP components. An alternative hypothesis is that both components are produced by somatosensory cortex, with the frontally maximal negativity reflecting the activity of a tangential dipole source. Respiratory-related evoked potentials (RREPs) elicited by brief occlusion of the inspiratory airway, were recorded using 29 scalp electrodes from six subjects. Early latency components were analysed using the Electromagnetic Source Estimation (EMSE) program for modelling equivalent electrical dipoles, in order to suggest likely generator sources. Two hypotheses were tested: first, that radial dipoles generated by both pre- (motor cortex) and post-centrally (somatosensory cortex) produce the early components; and second, that generator sources are limited to the somatosensory cortex, with activity recorded as frontally maximal reflecting volume conduction from tangential dipoles. Results were highly consistent between subjects and suggested that Nf-P1 was best accounted for by two post-central and two pre-central radial dipoles supporting the first hypothesis. Locations of generator sources are discussed in relation to anatomical correlates.

The impact of smoking cessation on objective and subjective markers of sleep: review, synthesis, and recommendations.

Sleep disturbance is commonly reported as a prominent subjective symptom by quitting smokers. However, little research on this issue has used objective measures of sleep quality. Previous research has relied mainly on retrospective report of sleep disturbance, with few studies investigating sleep during the initial period after quitting tobacco use. Studies that have used objective measurements suggest that sleep fragmentation is a common occurrence during the withdrawal period. In sleep medicine, sleep disturbance is viewed as a consequence of frequent arousals and is now considered to have particularly deleterious daytime consequences, including sleepiness and dysphoric mood. Recent work also indicates that such awakenings affect the cardiovascular system by providing repetitive bursts of sympathetic nervous system activation, possibly contributing to elevated levels of cardiovascular and cerebrovascular morbidity. Pharmacological treatments designed to facilitate smoking cessation are ineffective for sustained abstinence in many smokers, which may be related to sleep disturbance. Indeed, preliminary evidence suggests that the administration of nicotine replacement therapy (NRT) or bupropion can result in disrupted sleep, particularly in women. However, to better understand the role that nicotine withdrawal and bupropion or NRT treatment, independently and in combination, might play in sleep disturbance, it is necessary to develop a better understanding of the nature of the sleep disturbance than can be provided by self-report. This is particularly important for the development of treatment approaches targeted to ameliorate sleep disruption as part of an overall smoking cessation strategy. The present review seeks to report the current state of knowledge based on extant findings and argues for the need to conduct more detailed polysomnographic investigations of the potentially vicious cycle of smoking cessation leading to sleep disturbances that may prove iatrogenic to sustained cessation.

The respiratory‐related evoked potential: Effects of attention and occlusion duration

The present study assessed the effects of occlusion duration and attention on components of the respiratory-related evoked potential (RREP). Twenty-nine channel evoked potential recordings were obtained from 12 young adults exposed to a pseudorandom sequence of 100-, 200-, 400-, and 800-ms inspiratory occlusions, under attend and ignore conditions. Results demonstrated that the duration of an inspiratory occlusion does not affect RREP components systematically, highlighting the importance of the onset of the occlusion in producing the cortical responses. Attention resulted in augmentation of the N1, P2, and P3 components but did not affect the early latency Nf and P1 components. P1, N1, and P3 occurred with shorter latencies in the attend condition. One subject with poor duration estimation ability displayed substantially delayed P3 latency. This result highlights the relationship between P3 and perception of respiratory somatosensory information.

An examination of evoked K‐complex amplitude and frequency of occurrence in the elderly

The elderly consistently display lower levels of slow wave sleep (SWS), primarily because of the small amplitude of their delta activity. Given that delta electroencephalogram (EEG) and K‐complexes are thought to be generated by the same mechanisms, it was hypothesized that K‐complex amplitude and rate of production would be lower in the elderly. K‐complex amplitude was assessed by averaging K‐complex responses to auditory stimuli, and measuring the amplitude of the N550 component of the averaged evoked response. Ten young (five males and five females; mean age 23.10 ± 5.36 years) and 10 elderly adults (six males and four females; mean age=75.60 ± 4.48 years) who were neurologically healthy and free from medication spent two non‐consecutive nights in the sleep laboratory. EEG was recorded from six gold plate electrodes (Fz, Fcz, Cz, Cpz, Pz and O2) referenced to A1 + A2. Tone clicks (1000 Hz), of varying intensity from 70 to 100 decibels above measured awake detection threshold, were presented binaurally during stage 2 sleep. Responses were classified according to whether they produced: a K‐complex, a vertex sharp wave (VSW), both of these responses or neither response. They were then averaged separately for each response type. The elderly showed a substantially smaller N350 (averaged VSWs) and N550 amplitudes compared with the young subjects. The elderly also showed an augmented but delayed P2 component, followed by a long‐lasting positive EEG shift. The smaller amplitude of the averaged K‐complex N550 component is consistent with lower delta amplitudes previously reported in the elderly and with the hypothesis that K‐complexes and delta activity share the same generator mechanisms. The enhanced P2 component and the long‐lasting positive deflection in the EEG in the elderly indicate the existence of age differences other than smaller EEG amplitude.

Evoked potential components unique to non-REM sleep: relationship to evoked K-complexes and vertex sharp waves

Following the loss of wakeful consciousness, the averaging of responses to stimuli produce evoked potential waveforms with prominent components either unique to or greatly enhanced by non-REM sleep. In the sleep onset periods (stage 1) these are the P2 and N350. Following the establishment of stable sleep (stage 2 and SWS), the N550 and P900 are also prominent. Investigation of the EEG associated with individual responses indicates that a good proportion of stimuli elicit, K-complexes or vertex sharp waves (VSWs) and occasionally will elicit both. Recent work has indicated that the N550 in the averaged response is due to the presence of K-complexes and that the N350 is at least largely due to the presence of VSWs. The large size of these grapho-elements indicates that they are probably produced by a synchronized discharge of multiple neural units. Both are readily observed in the absence of external stimulation and occur as normal components of sleep, indeed the K-complex is used as one of the identifying features of the onset of stable non-REM sleep. The present review details the investigation of these features and their associated evoked potential components, in terms of stimulus features, brain states associated with their production, their scalp topography, and changes as a function of age.