Hyperarousal and Brain Imaging Markers of Sleep Fragmentation
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Sleep fragmentation in insomnia is caused by hyperarousal, evidenced by increased brain activity and reduced inhibition in frontal, parietal and temporal regions. Quantitative EEG and MRI spectroscopy show higher frequency EEG waves and lower GABA levels during sleep and wakefulness. Positron emission tomography reveals less decrease in brain metabolism from wake to sleep in insomniacs, especially in areas involved in cognition, attention and self-awareness. Insomnia may result from failure of arousal systems to decline fully between sleep-wake cycles.
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Hyperarousal and Brain Imaging Markers of Sleep Fragmentation
- 1. Hyperarousal and Sleep Fragmentation Diego Garcia-Borreguero, MD, PhD Instituto del Sueño Madrid
- 2. Sleep fragmentation • Disruption of the normal sleep architecture by internal (typically disease) or external stimuli. • Usually in relation with daytime changes in mood, sleepiness, cognition, etc. • Caused by brief arousals that occur during a sleep period. • Restaurative effects of sleep depend on: • Frequency of the arousals • Type of arousals • Age • Effects depend mainly on the rate, and not on associated changes in the EEG.
- 4. Main PSG markers of sleep fragmentation – SL – WASO – N1% – Arousal index – PLMS -N3% -REM% -SE%
- 5. Hyperarousal • Sleep fragmentation result from increased physiological, cognitive and emotional arousal, a condition called hyperarousal. • Markers of hyperarousal: – Increased body temperature – Increased 24 hr metabolic rate – Increased heart rate and increased low frequency power in heart rate – Increased cortisol levels in the pre- and initial sleep periods
- 6. Main problems of the “hyperarousal theory” • Failure to fully replicate evidence of hyperarousal in patients with insomnia (?) • Symptom heterogeneity and insomnia subtypes in PI • i.e., short sleepers
- 8. Quantitative EEG in insomnia patients • Higher-frequency EEG power during – Wakefulness – Sleep onset period – NREM sleep – REM sleep
- 9. Higher EEG frequency during NREM sleep in insomnia as measured by qEEG (Krystal et al, 2002)
- 10. Limitations of qEEG Failure to provide information on: • Location of the activity? • Proximal or distal regulation? • Increased activation or decreased inhibition? • Effects on other brain regions?
- 12. Reduced GABAergic activity in occipital and anterior cingulate cortex Plante et al., 2012
- 13. Occipital Cortex GABA Levels in Primary Insomnia ( Morgan et al. 2012)
- 14. 1H Spectroscopy Neuroimaging GABA – Silencing and lesioning Gabaergic nuclei can induce insomnia – Allosteric modulators of GABA are effective short-term treatments of insomnia 1H MRS suggest that insomnia has lower levels in parieto-occipital cortex or anterior cingulate. Impaired inhibitory control in insomnia Glutamate - Dubious increased in parieto-occipital cortex Higher frequency EEG activity in Primary insomnia may be the result of reduced inhibition But 1H MRS possess a low spatial and temporal resolution…
- 15. HIGH DENSITY qEEG • High spacial resolution • Can identify regional variations of brain electrical activity and its source
- 16. Summary of findings- quantitative wake EEG Colombo et al, 2016
- 17. Low power in the high-upper alpha band during wake in insomnia (Colombo et al, 2016)
- 18. High density qEEG during NREM sleep Riedner et al, 2016
- 19. EEG power density by sleep stage Wake-like brain activity persist in insomnia even during deep sleep Riedner et al, 2016
- 20. Areas with higher alpha-power Riedner et al, 2016
- 21. Tc-99-HMPAO SPECT Hipoperfusion found in basal ganglia and in medial frontal, occipital and parietal regions during NREM sleep Smith et al, 2002
- 22. FDG-PET in insomnia No reduction in metabolic rate from wake to sleep in poor sleepers Lower metabolic rate during wake, compared to controls • 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. Nofzinger et al, 2004
- 24. Simultanous activation of both switches Sleep centers - Wake centers - INSOMNIA
- 25. Smaller sleep-wake differences in the left frontoparietal, occipital, lingual/fusiform, and precuneus/posterior cingulate cortex. Kay et al, 2016 Smaller sleep-wake difference in brain regions involved in cognition, self-referential processes, and affect. Group differences in relative glucose metabolism during wakefulness
- 26. Kay et al, 2016 Group differences in relative glucose metabolism during NREM sleep Lower relative rCMRglc in: • Anterior cingulate • Right medial temporal lobe • Right precuneus/post cingulate
- 27. Main affected brain areas• Fronto-parietal cortex • Temporo-medial cortex • Thalamus • Anterior cingulate • ARAS at the brainstem Insomnia is associated with an insufficient deactivation of brain areas involved in executive control, attention,and self- perception.
- 28. Summary • Greater high-frequency EEG activity across sleep-wake states, mostly regionalized to the frontal lobes or sensorimotor regions. • Reduced GABA concentrations in the medial parieto-occipital cortex and anterior cingulate. • Reduced brain activation, blood flow, and glucose metabolism across sleep and wake in major areas of executive control, salience or default mode networks. • Brain regions iden tified as having greater activity tend to be specific to insomnia and are related to conscious awareness.
Editor's Notes
- Frequency: No effects are seen when periodic arousals are >20 min PLMS cause daytime deficits only if followed by EEG changes Nonvisible arousals: caused by 4bpm BP without EEG change Older subjects are less sensitive to sleep depravation than younger ones
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- Interpretation of brain electrical activity requires careful consideration of its location, sources, and mechanisms. Critical questions to answer when interpreting EEG results include: Where does the activity occur in the brain? Is the source of the activity proximally regulated or influenced by distal brain regions or circuits? Are the mechanisms of the activity due to reduced inhibition or increased excitation? In addition, what is the influence of the activity on other brain regions? From the perspective of a hyperarousal model, one may predict that the source of higher-frequency EEG activity in PI originates from wake-promoting brain regions (ascending arousal systems) or from regional glutamatergic activity that promotes wakefulness. Answers to these questions, however, simply cannot be derived from standard PSG measures. Neuroimaging methods include a set of tools, complementary to PSG, that are beginning to more fully characterize the pathophysiology of PI.
- Winkelman et al. 2012
- Interventions: Participants kept sleep diaries and a regular time-in-bed schedule for 9 days, culminating in 2 consecutive nights of ambulatory polysomnography and a single proton MRS session. The main outcome measure was occipital GABA/creatine ratios; secondary measures in- cluded sleep measurements and relationship between polysomnographically measured time awake after sleep onset and occipital GABA content. Measurements and Results: The primary insomnia group was distinguished from persons with no sleep complaints on self-reported and polysom- nographically measured sleep. The two groups did not differ in age, sex, body mass index, habitual bed- and wake-times, napping, use of caffeine, or use of cigarettes. Mean occipital GABA level was 12% higher in persons with insomnia than in persons without sleep complaints (P < 0.05). In both groups, GABA levels correlated negatively with polysomnographically measured time awake after sleep onset (P < 0.05). Conclusions: Increased GABA levels in persons with insomnia may re ect an allostatic response to chronic hyperarousal. The preserved, nega- tive relationship between GABA and time awake after sleep onset supports this notion, indicating that the possible allostatic response is adaptive. 2—(A) GABA/Cr is negatively correlated to time awake after sleep onset in persons with primary insomnia (linear correlation, P < 0.05) and in controls (P < 0.05). There is no difference in R between groups (Rdiff = 0.021 ± 0.561 [90% confidence interval]). Mean GABA/Cr is higher in persons with insomnia (P < 0.05). (B) Relationship between GABA/Cr and PSQI in the insomnia and control groups. A trend toward a significant correlation was observed in the insomnia group (R = 0.19, P < 0.1). The projected y-intercepts are non-overlapping at confidence intervals of ~90% (0.163 ± 0.03 [90% CI] in the insomnia group and 0.123 ± 0.01 [90% CI] in the control group). (C) Shorter total sleep time is correlated with higher GABA/Cr in persons with primary insomnia (P < 0.05) but not in controls.
- Magnetic resonance spectroscopy (MRS) uses magnetic resonance technology and specialized pulse sequences to quantify molecular concentrations in bodily tissue, including neuromolecules in the brain. High-field MRS provides a non-invasive means to study, at the regional level, alterations in several neurotransmitter systems potentially involved in insomnia, including glutamate and γ-aminobutyric acid (GABA). Offering superior signal-to-noise than non-proton MRS, 1H (proton) MRS is commonly performed to investigate the neuromolecular alterations associated with diseases. The resonant frequency of a nucleus in a magnetic field provides information about molecular groups that carry 1H, including the types of molecules present and their relative concentrations. The temporal resolution of MRS is relatively poor, and many MRS studies do not routinely monitor inter- or intra-individual differences in EEG states during scanning. The spatial resolution of MRS is also relatively poor, with large voxel sizes (1.5–3 cm3) that typically span multiple brain regions. These voxels are typically positioned deep in the neocortex to avoid the edges of the brain and ventricles while still capturing important gray matter regions, including the anterior cingulate, parieto-occipital, and temporal cortices. Glut is not increased in insomnia, but in insomnia in PTSD The primary inhibitory neurotransmitter in the CNS, GABA is critically involved in sleep-wake regulation, including circadian sleep processes, sleep initiation, sleep maintenance, generation of slow-wave sleep oscillations, and EEG power density [35,36,37,38,39]. The role of GABA in PI remains poorly understood. Silencing GABAergic neurons and lesioning GABAergic nuclei can induce an insomnia-like state in animals [35,40]. Conversely, positive allosteric modulators of the GABAA receptor (e.g., benzodiazepines, “z drugs”, and barbiturates) have sedating effects and are efficacious short-term treatments for insomnia [41,42]. With one exception that found that individuals with PI had higher GABA concentrations than GS in the occipital cortex [32], the majority of 1H MRS studies suggest insomnia is associated with lower GABA levels in the parieto-occipital cortex [30,31,33,34] or anterior cingulate [33]. Because MRS reflects presynaptic concentrations of GABA, these findings may suggest that insomnia involves impaired inhibitory control. Although both lower and higher GABA have been interpreted within the hyperarousal model of insomnia [43], the preponderance of the findings points toward lower GABA concentrations in PI that may be specific to the brain regions noted above. Such findings are consistent with the hypothesis that the higher-frequency EEG activity observed in patients with PI may be the result of reduced inhibition [44]. In other words, “hyperarousal”, as indexed by increased high-frequency EEG in PI, may be a result of impaired GABAergic inhibition rather than its cause.
- One high-density EEG study conducted during quiet wakefulness found that individuals with PI had higher beta activity than GS in large clusters spanning the prefrontal, frontal, central, right temporal, and bilateral posterior regions of the brain during an eyes-closed resting-state condition [45]. Source localization analysis suggested that spectral EEG differences likely originated from the sensorimotor cortices [45]. However, that study found no group differences in high-frequency EEG activity during an eyes-open resting-state condition. Another high-density EEG study suggests that greater high-frequency EEG power in PI is most prominent in the left frontal and frontal midline cortices during wakefulness and sleep onset. Source localization analysis found those differences likely originated from the frontal gyri and the anterior cingulate [46]. A recent high-density EEG pilot study found that individuals with PI had greater alpha and theta levels during N3 (delta) sleep than GS, suggesting that “wake-like” brain activity persists in insomnia even during the deepest stages of sleep [47]. Source localization suggested the heighted brain activity during NREM sleep originates from sensory and sensorimotor cortical areas [47]. As noted in the previous section, increased high-frequency EEG activity during wakefulness and “wake-like” EEG activity during NREM sleep may be due to reduced inhibition as well as increased excitation in particular brain regions. Ultimately, results from high-density EEG studies are mixed and the region- and state-specific differences found in these studies cast doubts on the assertion that insomnia involves 24-h, CNS-wide hyperarousal.
- No differences with eyes opens. Figure 2—Less upper alpha and more broad beta relative power in insomnia, respectively, during the eyes open (EO) and eyes closed (EC) resting state. Compared to controls without sleep complaints (CTRL), individuals with insomnia disorder (ID) have less power in a narrow upper alpha frequency band over a bilateral frontal and left temporoparietal region during EO. During EC they show more power in a broad beta band over widespread regions. The left and right side of the figure show the results for the EO and EC resting state, respectively. The top row shows the log-transformed relative spectral power, averaged across scalp electrodes, of the two groups (red for ID, blue for CTRL). For each frequency bin and for each of the two groups separately, the median value (line) and its 95% bootstrap confidence interval (semi-transparent area) across participants is shown. The middle panels show the percentage of electrodes that are significantly different between groups at each frequency bin, when the P values (derived from the Threshold-Free Cluster- Enhancement procedure) are thresholded at 0.1 (gray) or 0.05 (black). The bottom panels show the topographical distribution of the within-group median log-transformed spectral power and the relative group difference statistic (Z), at the frequency bin where the largest number of significant electrodes was found, respectively 11.7 Hz in the EO and 19 Hz in the EC condition (indicated by the dashed line in the top panel). Electrodes where P is less than 0.05 are marked with a black dot Conclusion: The widespread high power in a broad beta band reported previously during sleep in insomnia is present as well during eyes closed wakefulness, suggestive of a round-the-clock hyperarousal. Low power in the upper alpha band during eyes open is consistent with low cortical inhibition and attentional filtering. The fine-grained HD-EEG findings suggest that, while more feasible than PSG, wake EEG of short duration with a few well-chosen electrodes and frequency bands, can provide valuable features of insomnia.
- In this study, we examined the sleep hdEEG of subjects in whom insomnia was diagnosed compared to good sleeping controls. We found that insomnia subjects had a global increase in high-frequency EEG activity (> 16 Hz) combined with a more circumscribed difference in theta (4–8 Hz) and alpha (8–12 Hz) power bands compared to good sleeping controls.
- When deep NREM sleep (N3) was examined, the high-frequency difference between groups diminished, whereas the higher regional alpha activity in insomnia subjects persisted. Furthermore, source imaging analysis demonstrated that sensory and sensorimotor cortical areas consistently exhibited elevated levels of alpha activity during deep NREM sleep in insomnia subjects relative to good sleeping controls. As NREM sleep deepened, however, the influence of global high-frequency EEG power seemed to diminish in our sample. Indeed, the most intriguing and novel finding reported here is the regionally specific elevation in alpha EEG activity that occurred prominently during the deepest NREM sleep in insomnia subjects compared to controls. The disappearance of alpha activity is well known as the quintessential marker of the transition into sleep (stage N1). However, although first described over 40 y ago, the reappearance of alpha during slow wave sleep, so-called alpha-delta sleep, is still poorly understood. Alpha-delta sleep has been associated with chronic pain (i.e., fibromyalgia), chronic fatigue, and more generally with conditions involving nonrestorative sleep, including insomnia,23,63,64 and was recently reported to be a harbinger of future arousal.65 However, it has also been argued that the presence of alpha activity is not sufficient to produce nonrestorative sleep.66,67 Here, we describe higher alpha activity in a group of insomnia subjects that were neither included nor excluded from the study for the presence of alpha activity occurring during sleep. When this group was compared to age- and sex-matched good sleeping controls for average spectral density during N3 sleep, they nonetheless exhibited significantly more alpha activity. Although strong enough to show up in the global average, it was apparent that the between-group difference observed in alpha power had a specific scalp topography, suggesting that not all cortical areas were equally affected.
- Intriguingly, many of the areas with the most reliably higher alpha in insomnia subjects were sensory areas (including parts of the visual, auditory, and somatosensory cortices) as well as premotor and primary motor areas (Table 2). Locally increased alpha in sensory and motor areas for insomnia compared to good sleeping control subjects during deep nonrapid eye movement (NREM) sleep. Inflated cortical map showing the T-values of the areas that were significantly different (P < 0.05) between insomnia and good sleeping control subjects using a statistical nonparametric mapping cluster test. Functional areas that are most significantly different include visual (Brodmann areas 18, 19), somatosensory (2, 3, 7, and 40) areas, motor (4) and premotor (6) areas. Auditory and language areas (22, 40) also show increases.
- A reasonable assumption of a hyperarousal model of insomnia is that blood flow would be positively associated with “arousal”, at least in brain regions associated with arousal. Such an assumption is difficult to prove, and some have argued that lower blood flow may be consistent with a hyperarousal model of insomnia [50]. Although it is unlikely that gross blood flow is a sensitive correlate of arousal, lower blood flow during wake and NREM sleep seems counterintuitive from the perspective of a general hyperarousal model of insomnia.
- First, patients with PI had smaller sleep-wake differences in relative regional cerebral metabolic rate for glucose (rCMRglc) than GS in the medial prefrontal, anterior cingulate, insula, thalamus, hippocampus, amygdala, hypothalamus, and brainstem. Second, during the wake state, individuals with PI had lower relative rCMRglc than GS in a broad region of the frontal cortex bilaterally, left superior temporal gyrus, left occipital cortex, left parietal cortex, thalamus, hypothalamus, and brainstem reticular formation. Third, individuals with PI had greater whole-brain glucose metabolism than GS across sleep-wake states [51]. The results of that study have been widely cited as support for the hyperarousal model of insomnia. disturbances and daytime fatigue reported by patients with insomnia. The pattern of whole brain hypermetabolism across waking and sleep states and the failure of wakepromoting structures to decline in metabolism from waking to sleep states suggest that the higher cerebral metabolism in non-REM sleep in patients with insomnia may be due to a lack of a reduction in activity in these subcortical structures in the transition from waking to sleep. The reduced relative waking metabolism in the prefrontal cortex in patients with insomnia suggests that these patients are chronically sleep deprived, perhaps from inefficient sleep
- First, individuals with PI had a smaller sleep-wake difference than GS in relative rCMRglc in brain regions involved in cognition, self-referential processes, and affect. These regions include the left frontoparietal, occipital, lingual/fusiform, and precuneus/posterior cingulate cortices. Second, during quiet wakefulness, individuals with PI had lower relative rCMRglc than GS in widespread regions of the brain spanning the neocortex to the brainstem (Figure 1). Patients with PI had higher relative rCMRglc than GS only in the cerebellum during the waking state.
- sleep. We assessed relative regional cerebral metabolic rate for glucose (rCMRglc) in a sample of 44 patients with primary insomnia (PI) and 40 good sleeper controls (GS) during NREM sleep. Patients with PI had lower relative rCMRglc in three clusters centered on the anterior cingulate, right medial temporal lobe, and right precuneus/posterior cingulate; p3DC_corrected <0.05 for all clusters. A full list of brain regions involving these clusters is presented in Table 1. The color bar represents t values; blue indicates regions where PI had lower relative rCMRglc than GS during NREM sleep. This figure was originally published in the journal Sleep in 2016 [52]. Used with permission. Note: L indicates the left side of the brain, R indicates the right side of the brain, and 3DC_corrected indicates that familywise error (FWE) correction and clusterwise extent thresholds were determined using 3dClustSim [53]. Figure 1. Group differences in relative glucose metabolism wakefulness. We assessed relative regional cerebral metabolic rate for glucose (rCMRglc) in a sample of 44 patients with primary insomnia (PI) and 40 good sleeper controls (GS) during morning wakefulness. Patients with PI had lower relative rCMRglc in four clusters spanning the neocortex and brainstem. Patients with PI also had higher relative rCMRglc than GS in the right cerebellum. All clusters were significant at p3DC_corrected < 0.05. A full list of brain regions involving these clusters is presented in Table 1. The color bar represents t values; blue indicates regions where patients with PI had lower relative rCMRglc than GS and orange indicates regions where patients with PI had higher relative rCMRglc than GS during wakefulness. This figure was originally published in the journal Sleep [52]. Used with permission. Note: L indicates the left side of the brain, R indicates the right side of the brain, and 3DC_corrected indicates that familywise error (FWE) correction and clusterwise extent thresholds were determined using 3dClustSim [53]. Brain Sci. 2017, 7, 23 5 of 19 Figure 1. Group differences in relative glucose metabolism during wakefulness. We assessed relative regional cerebral metabolic rate for glucose (rCMRglc) in a sample of 44 patients with primary insomnia (PI) and 40 good sleeper controls (GS) during morning wakefulness. Patients with PI had lower relative rCMRglc in four clusters spanning the neocortex and brainstem. Patients with PI also had higher relative rCMRglc than GS in the right cerebellum. All clusters were significant at p3DC_corrected <0.05. A full list of brain regions involving these clusters is presented in Table 1. The color bar represents t values; blue indicates regions where patients with PI had lower relative rCMRglc than GS and orange indicates regions where patients with PI had higher relative rCMRglc than GS during wakefulness. This figure was originally published in the journal Sleep [52]. Used with permission. Note: L indicates the left side of the brain, R indicates the right side of the brain, and 3DC_corrected indicates that familywise error (FWE) correction and clusterwise extent thresholds were determined using 3dClustSim [53]. Figure 2. Group differences in relative glucose metabolism during non-rapid eye movement (NREM) sleep. We assessed relative regional cerebral metabolic rate for glucose (rCMRglc) in a sample of 44 patients with primary insomnia (PI) and 40 good sleeper controls (GS) during NREM sleep. Patients with PI had lower relative rCMRglc in three clusters centered on the anterior cingulate, right medial temporal lobe, and right precuneus/posterior cingulate; p3DC_corrected <0.05 for all clusters. A full list of brain regions involving these clusters is presented in Table 1. The color bar represents t values; blue indicates regions where PI had lower relative rCMRglc than GS during NREM sleep. This figure was originally published in the journal Sleep in 2016 [52]. Used with permission. Note: L indicates the left side of the brain, R indicates the right side of the brain, and 3DC_corrected indicates that familywise error (FWE) correction and clusterwise extent thresholds were determined using 3dClustSim [53]. Figure 2. Group differences in relative glucose metabolism during non-rapid eye movement (NREM) sleep. We assessed relative regional cerebral metabolic rate for glucose (rCMRglc) in a sample of 44 patients with primary insomnia (PI) and 40 good sleeper controls (GS) during NREM sleep. Patients with PI had lower relative rCMRglc in three clusters centered on the anterior cingulate, right medial temporal lobe, and right precuneus/posterior cingulate; p3DC_corrected < 0.05 for all clusters. A full list of brain regions involving these clusters is presented in Table 1. The color bar represents t values; blue indicates regions where PI had lower relative rCMRglc than GS during NREM sleep. This figure was originally published in the journal Sleep in 2016 [52]. Used with permission. Note: L indicates the left side of the brain, R indicates the right side of the brain, and 3DC_corrected indicates that familywise error (FWE) correction and clusterwise extent thresholds were determined using 3dClustSim [53]. Patients with PI had higher relative rCMRglc than GS only in the cerebellum during the waking state. During NREM sleep, individuals with PI had lower relative rCMRglc than GS in clusters limited to limbic brain regions, many of of which are involved in the salience and default mode networks, including the anterior cingulate, medial frontal gyrus, orbitofrontal cortex, inferior frontal gyrus, right posterior cingulate, and bilateral precuneus (Figure 2). See Table 1 for a complete list of brain regions showing group differences in relative rCMRglc during wake and NREM sleep in PI compared to GS. Third, no group differences were identified in semi-quantitative whole-brain glucose metabolism [52]. Although smaller sleep-wake differences can be explained within a hyperarousal framework, lower relative rCMRglc in patients with PI compared with GS during NREM sleep in limbic brain regions is more difficult to explain within this framework. Collectively, these results highlight the complex regional pathophysiology of insomnia across sleep-wake states, a complexity that is not easily explained by a global hyperarousal mechanism.
- Corteza frontoparietal Corteza temporo-medial Tálamo Area cingulada anterior SRA del Tronco del Encéfalo