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Volume 14 No. 02
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Scientific Investigations

Increased EEG Theta Spectral Power in Sleep in Myotonic Dystrophy Type 1

Joseph Cheung, MD, MS1; Chad Ruoff, MD1; Hyatt Moore, PhD1; Katharine A. Hagerman, PhD2; Jennifer Perez2; Sarada Sakamuri, MD2; Simon C. Warby, PhD3; Emmanuel Mignot, MD, PhD1; John Day, MD, PhD2; Jacinda Sampson, MD, PhD2
1Stanford Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, California; 2Department of Neurology, Stanford University Hospitals and Clinics, Stanford, California; 3Department of Psychiatry, Université de Montréal, Montreal, QC, Canada

ABSTRACT

Study Objectives:

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder that involves the central nervous system (CNS). Individuals with DM1 commonly present with sleep dysregulation, including excessive daytime sleepiness and sleep-disordered breathing. We aim to characterize electroencephalogram (EEG) power spectra from nocturnal polysomnography (PSG) in patients with DM1 compared to matched controls to better understand the potential CNS sleep dysfunction in DM1.

Methods:

A retrospective, case-control (1:2) chart review of patients with DM1 (n = 18) and matched controls (n = 36) referred for clinical PSG at the Stanford Sleep Center was performed. Controls were matched based on age, sex, apnea-hypopnea index (AHI), body mass index (BMI), and Epworth Sleepiness Scale (ESS). Sleep stage and respiratory metrics for the two groups were compared. Power spectral analysis of the EEG C3-M2 signal was performed using the fast Fourier transformation.

Results:

Patients with DM1 had significantly increased theta percent power in stage N2 sleep compared to matched controls. Theta/beta and theta/alpha percent power spectral ratios were found to be significantly increased in stage N2, N3, all sleep stages combined, and all wake periods combined in patients with DM1 compared to controls. A significantly lower nadir O2 saturation was also found in patients with DM1 versus controls.

Conclusions:

Compared to matched controls, patients with DM1 had increased EEG theta spectral power. Increased theta/beta and theta/alpha power spectral ratios in nocturnal PSG may reflect DM1 pathology in the CNS.

Citation:

Cheung J, Ruoff C, Moore H, Hagerman KA, Perez J, Sakamuri S, Warby SC, Mignot E, Day J, Sampson J. Increased EEG theta spectral power in sleep in myotonic dystrophy type 1. J Clin Sleep Med. 2018;14(2):229–235.


BRIEF SUMMARY

Current Knowledge/Study Rationale: Individuals with myotonic dystrophy type 1 (DM1) commonly present with hypersomnolence and sleep-disordered breathing. To better understand sleep dysregulation in DM1, we retrospectively examined power spectra from nocturnal polysomnograms in individuals with DM1 and matched controls.

Study Impact: Differences in sleep electroencephalogram spectral characteristics, specifically theta power, may represent central nervous system changes due to DM1.

INTRODUCTION

Myotonic dystrophy type 1 (DM1) is the most common type of muscular dystrophy in adults.1,2 DM1 is a multi-systemic disorder, causing progressive muscle weakness and myotonia, along with cardiac, respiratory, ophthalmologic, endocrine, and cognitive involvement, as well as sleep disorders. The inheritance of DM1 is autosomal dominant. It is caused by a noncoding trinucleotide repeat expansion in the dystrophia myotonica protein kinase (DMPK) gene. The multisystemic involvement is believed to be caused by sequestration of spliceosomal proteins, such as muscleblind-like proteins (MBNL), causing aberrant splicing in a plethora of messenger RNAs. Affected individuals commonly report the central nervous system (CNS) symptoms of inattention, excessive daytime sleepiness (EDS), and fatigue among their most disabling symptoms, adversely affecting daily living, employability, and social function.36

DM1 is commonly associated with the occurrence of sleep-disordered breathing (SDB) with nocturnal hypoventilation and obstructive sleep apnea.716 In addition to SDB, EDS is the most common nonmuscular symptom,1721 reported in up to 70% to 90% of patients with DM1,22 and may present as an early symptom in the course of DM1. The degree of EDS experienced by patients with DM1 is out of proportion to the presence of SDB, as treatment of sleep apnea alone does not fully resolve EDS or fatigue.17 The pathophysiology of the underlying hypersomnia of DM1 is poorly understood.

Multiple studies have observed rapid eye movement (REM) sleep dysregulation in DM1 with high REM sleep density and sleep onset REM periods on the Multiple Sleep Latency Test.21,2325 However, in contrast to narcolepsy, Ciafaloni et al.23 found that CSF hypocretin levels from patients with DM1 were within normal levels, suggesting that the cause of sleepiness differs from narcolepsy. Indeed, several lines of evidence suggest that the hypersomnia symptom in DM1 is likely due to underlying CNS abnormalities affecting sleep/wake regulation, rather than a product of muscle weakness or respiratory insufficiency alone.22,26,27 Furthermore, treatment with modafinil in individuals with DM1 caused variable responses, with some reporting subjective benefits.2832 Though in another study, treatment with modafinil in individuals with DM1 did not result in objective improvements as assessed by the Maintenance of Wakefulness Test.33

Increased electroencephalogram (EEG) theta spectral power and theta spectral power ratios have been reported in various neurocognitive disorders, including mild cognitive impairment34 and attention deficit/hyperactivity disorder.35 Identification of such EEG spectral changes may help correlate with CNS dysfunction in these disorders. Thus, the objective of the current retrospective study was to compare the polysomnography (PSG) EEG spectra of patients with DM1 and matched controls in order to identify electrophysiologic changes in EEG spectra signals that may reflect underlying CNS manifestations in DM1.

METHODS

A retrospective, case-control (1:2) chart review of DM1 (n = 18) and matched control patients (n = 36) referred for clinical PSG at the Stanford Sleep Center was performed. This study was approved by the Stanford University Institutional Review Board. Controls were selected from patients referred to the Stanford Sleep Clinic. Patients with DM1 received a diagnosis based on clinical presentation, electromyography, family history, genetic testing, or a combination of these. Patients with DM1 and controls were matched based on age, sex, apneahypopnea index (AHI), body mass index (BMI), and to avoid secondary effects due to sleepiness, Epworth Sleepiness Scale (ESS). It was important to match for AHI in the controls to avoid confounding as individuals with DM1 often have significant degrees of SDB.

Total sleep time (TST), periodic limb movement index, supine sleep time, nonsupine sleep time, sleep efficiency percentage, sleep onset latency, REM sleep latency, number of REM sleep periods, wake after sleep onset (WASO), minutes spent in sleep stages (stage N1, N2, N3, and R), percent of TST in sleep stages, respiratory metrics, AHI (supine, nonsupine, REM, and non-rapid eye movement), 3% O2 desaturation index (ODI), nadir O2 saturation, central apnea index, obstructive apnea index, percent of TST with O2 saturation (ranges 80 to 90, 70 to 80, and 60 to 70), for patients with DM1 and controls were compared using the two-tailed Student t test.

Power spectral analysis of the C3-M2 signal was performed through modified Welch averaging using a 6-second Hanning window and a 3-second overlap interval. The resulting windowed, fast Fourier transform-derived periodograms were then grouped according to sleep stage categories and averaged together to produce power spectrum in 1/6 Hz increments. Percent (relative) power spectra were then computed.

Sleep staging data included in the analysis were required to meet a minimum of 90 seconds in duration (3 epochs worth of data). In addition, a minimum of two continuous epochs had to be in the same sleep stage to be included in our analysis. Data from the first and last 15 seconds of these continuous segments were excluded from the analysis to minimize noise and uncertainty of sleep stage scoring that may be present in transitional epochs. All wake data were combined from periods of wake before sleep onset, WASO, and wake since last sleep epoch.

Artifact identification was performed to identify noisy windows for rejection. Five artifact detection methods were applied to the C3-M2 input signal: (1) high power: excessive power (> 1,000 μV2), lasting 5 seconds or longer, (2) electrode pop: any window containing excessive power (> 10,000 μV2), (3) flatline: any window containing almost no power (< 0.1 μV2) in all frequency bins, (4) Brunner method,36 and (5) high-frequency power: excessive power, lasting 3 seconds or longer, above 35 Hz.

Two Hz increments of percent power spectra data were averaged from PSGs from each of the patients with DM1 and controls. Welch t test was performed to compare patients with DM1 and controls. The frequency band for theta (4–8 Hz), beta (13–21 Hz), and alpha (8–12 Hz) ranges were also averaged. Finally, theta-to-beta and theta-to-alpha spectral percent power ratios were calculated and analyzed by linear regression.

RESULTS

Demographic data of patients with DM1 and controls are shown in Table 1, whereas clinical, respiratory, and sleep characteristics of patients with DM1 and controls are shown in Table 2 and Table S1 in the supplemental material. Using the muscle impairment rating scale,37 the average muscle weakness of patients with DM1 was 4 (mild to moderate proximal weakness). Spirometry results were available for 16 of the 18 patients with DM1, and averaged 72% predicted (range, 26% to 103%). Genetic testing results were available for 12 of the 18 patients with DM1, with average cytosine thymine guanine (CTG) repeat size of 600 (range 50 to 2,150). Stimulants were being used by three patients with DM1 and one control; antidepressant medications were used by three patients with DM1 and five controls.

Demographics of patients with DM1 and controls.

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Table 1

Demographics of patients with DM1 and controls.

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Respiratory and sleep characteristics of patients with DM1 and controls.

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Table 2

Respiratory and sleep characteristics of patients with DM1 and controls.

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Though not significantly different, patients with DM1 were found to have an average AHI of 25.3 events/h compared to controls with an AHI of 19.5 events/h. Patients with DM1 were found to have a significantly lower nadir O2 saturation compared to controls. We found that patients with DM1 had a higher 3% ODI, mixed apnea index, REM AHI, WASO time, and TST with oxygen saturation between 80% to 90% compared to controls. Although these characteristics were significant by t test (P < .05), upon controlling for nadir O2 saturation as a covariate by linear regression analysis, these differences among patients with DM1 and controls did not meet statistical significance. In terms of stage R sleep, we found that patients with DM1 had a mean of 83.7 minutes (standard deviation [SD] ± 39.6 minutes) of stage R sleep time and 21.0% ± 8.6% of stage R sleep per TST, compared to controls with a mean of 68.5 minutes ± 36.1 minutes of total stage R sleep time and 17.5% ± 8.1% of stage R sleep per TST, which was not statistically significant between groups.

Percent power spectra of PSG from patients with DM1 and controls are shown in Figure 1. A strong and general increase in theta power was seen in patients with DM1 versus controls across sleep stages, except for stage R. Two Hz increments of power spectra data were averaged, compared, and summarized in Table S2 and Table S3 in the supplemental material. After Bonferroni correction for multiple comparisons, a significant increase in power in 5 to 7 Hz within the theta range was found in stage N2 sleep in patients with DM1 in comparison with controls.

Percent power spectra from overnight polysomnography of DM1 cases and controls.

Mean and standard error of the mean for DM1 (blue) and controls (red). (A) All sleep stages combined [n(DM1) = 18, n(controls) = 36]. (B) Stage N1 sleep [n(DM1) = 16, n(controls) = 35]. (C) Stage N2 sleep [n(DM1) = 18, n(controls) = 36]. (D) Stage N3 sleep [n(DM1) = 15, n(controls) = 30]. (E) Stage R sleep [n(DM1) = 18, n(controls) = 34]. (F) All wake periods [n(DM1) = 18, n(controls) = 36]. DM1 = myotonic dystrophy type 1.

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Figure 1

Percent power spectra from overnight polysomnography of DM1 cases and controls.

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To further explore the unique PSG power spectra in DM1, theta/beta and theta/alpha power spectral ratios were computed for all patients with DM1 and controls. Boxplots of the ratios of theta/beta and theta/alpha power spectra in each sleep and wake stage from patients with DM1 and controls are shown in Figure 2 and Figure 3. Linear regression analysis was also carried out controlling nadir O2 saturation as a covariate (see Table S4 in the supplemental material). Theta/beta power spectral ratios were significantly higher in patients with DM1 versus controls in stage N2 sleep, stage N3 sleep, all sleep stages combined, and all wake periods combined. In addition, theta/ alpha power spectral ratios were significantly higher in patients with DM1 versus controls in stage N2 sleep, stage N3 sleep, all sleep stages combined, and all wake periods combined.

Theta/beta ratio of EEG spectra by sleep stage.

Ratios of theta-to-beta power spectral ratios of DM1 (blue) and control (red) patients. Boxplots represent mean, upper and lower quartile; open circles are outliers (upper or lower quartile bounds ± interquartile distance). * = P < .05 linear regression analysis controlled for nadir O2 sat. DM1 = myotonic dystrophy type 1, EEG = electroencephalography.

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Figure 2

Theta/beta ratio of EEG spectra by sleep stage.

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Theta/alpha ratio of EEG spectra by sleep stage.

Ratios of theta-to-alpha power spectral ratios of DM1 (blue) and control (red) patients. Boxplots represent mean, upper and lower quartile; open circles are outliers (upper or lower quartile bounds ± interquartile distance). * = P < .05 linear regression analysis controlled for nadir O2 sat. DM1 = myotonic dystrophy type 1, EEG = electroencephalography.

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Figure 3

Theta/alpha ratio of EEG spectra by sleep stage.

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DISCUSSION

DM1 is a neuromuscular disorder affecting the CNS and presenting with EDS out of proportion to the degree of SDB. We studied the PSG and power spectra of patients with DM1 and matched controls. We sought to determine if changes in EEG power spectral characteristics occur in PSG as has been reported in other disorders, such as attention deficit/hyperactivity disorder.38 To our knowledge, power spectral analysis of EEG from overnight PSG in DM1 has not been reported.

Sleep disorders associated with DM1, most commonly hypersomnia and SDB, have been well described.6,22 We found that patients with DM1 had an average AHI of 25.3 events/h whereas the average BMI was relatively low at 22.3 kg/m2. Significant effort was made at the start of this retrospective study to identify control patients from our sleep clinic database in order to best match age, sex, AHI, BMI, and ESS. Of the respiratory and sleep characteristics we examined (Table 2), only nadir O2 saturation was found to be significantly lower in patients with DM1 (83.4%) compared to matched controls (89.4%). Of patients who had spirometry data available, 11 of the available 16 were abnormal. This is likely due to nocturnal hypoventilation attributed to neuromuscular weakness in patients with DM1.11

In contrast to previous studies, a significantly higher stage R sleep density in patients with DM1 compared to controls was not found. A possible reason for this discrepancy is that this retrospective study only included a relatively small sample size and thus limited our statistical power. Moreover, although other studies have used unmatched or age- and sex-matched controls in their respective studies,24,25 our controls were also matched for ESS and AHI. Hence, our controls could have a higher degree of sleepiness than controls used in other studies and may account for a slightly higher stage R sleep density, resulting in a lesser degree of a difference between our groups. Limitations of this retrospective study include a small sample size and the challenge to identify well-matched controls given the unique clinical characteristics presented in DM1. We had examined the correlation of number of triplet repeats in our individuals with DM1 with theta/alpha and theta/beta power spectral ratios, and no significant correlations were found. Triplet repeat size has also been shown to be highly variable between tissues, so triplet repeat size measurement from blood does not represent repeat size in brain39; triplet repeat size also varies between brain regions.40

Upon generation of our power spectral analysis (Figure 1), we observed an increase in theta power and a decrease in alpha power in patients with DM1 versus controls, most prominently seen in stage N2 sleep. As we separated the power spectra into 2-Hz frequency bins, a significant spectral power increase in the 5- to 7-Hz (theta) range and a significant decrease in the 9- to 11-Hz (alpha) range were found in patients with DM1 compared to controls.

The function of theta in the awake and sleeping human brain remains poorly understood. It was reported that sleep-deprived individuals showed an increased theta power during cognitive testing,41 and patients with narcolepsy showed a circadian increase in theta over the course of the day.42 Interestingly, theta is not increased during sleep in narcolepsy.43 In wakefulness, theta can also be increased in delirium.44 In patients with hepatic cirrhosis without overt encephalopathy, theta and delta power is increased in stage R sleep compared to controls; later when encephalopathy develops, theta and then later delta is increased in wakefulness.45 This response of theta to metabolic state may be relevant to patients with DM1 who are susceptible to anesthesia complications, not only from cardiopulmonary risks, but delirium and disproportionate response to benzodiazepines and opiates, suggesting an underlying organic susceptibility. Theta increases are also observed in neurodevelopmental disorders such as attention deficit/hyperactivity disorder.35,46,47

Moreover, at this time the molecular basis of EDS in DM1 remains unknown. Given our findings, we speculate that the molecular pathogenicity of DM1 changes the sleep regulatory circuits in the CNS, as seen from changes in the EEG spectra. Indeed, this was supported by a recent study showing that in Mbnl2 knockout mice (a model of DM1), DM1-associated RNA splicing alternations parallel those seen in DM1 and these mice showed increased EEG theta power.48 In a study of autopsy transcriptome, DM1 brain showed splicing changes in 2,781 genes, and gene ontology analysis implicated pathways of synaptic transmission, neuronal projection and differentiation, and intracellular, axonal, and microtubule transport.49

Furthermore, in this DM1 study, we found that the theta/ beta and theta/alpha power spectral ratios were significantly increased in PSG of patients with DM1 compared to matched controls (see Figure 2, Figure 3, and Table S4). In particular, the observed increase in theta/beta and theta/alpha ratios was found in stage N2 sleep, stage N3 sleep, all sleep stages combined, and in all wake periods combined. We did not see any significant difference in stage R sleep alone, nor in stage N1 sleep alone, though the latter could be due to the brief time spent in stage N1 sleep. At this time, we do not know the origin of this characteristic PSG power spectra finding in DM1.

Increased theta/beta ratio in the awake brain can be seen in attention deficit disorder50 and this increase can respond to pharmacologic treatment. In awake children ages 7 to 12 years with Asperger syndrome, there is an increase in delta and theta and decrease in alpha compared to controls.51 Interestingly, studies of power spectra in sleep of children (mean age 11 years) with borderline intellectual functioning show a decrease in gamma and increase in delta in all sleep stages, but no significant change in theta.52 In this retrospective study of adults with DM1 and sleep study-referred normal patients, we unfortunately do not have neurocognitive testing scores. In awake patients without Alzheimer disease and with dementia, an increase in theta was seen that was not observed in patients with Alzheimer disease or in controls.53 In awake patients with REM behavior disorder (52% of whom developed Parkinson disease, multiple system atrophy, or Lewy body dementia over the 3.2-year follow-up) increased delta and theta was seen compared to controls.54 Therefore, altered EEG has been documented in many neurological conditions, though the particular pattern seen here may be specific to DM1.

Increased theta power in DM1 PSGs was most strongly observed in stage N2 sleep, but also was seen in wakefulness and stage N3 sleep. We conclude increased theta is not simply a feature of sleepiness or sleep disorder, because controls matched for ESS did not show similar features. Theta can reflect differences in state (sleepiness, circadian periodicity, encephalopathy) or structure (development or degeneration). We are conducting ongoing studies of sleep and cognitive function in children and adults with DM1 to further investigate changes in EEG spectral power associated with sleep dysregulation.

In conclusion, we found that patients with DM1 had significantly increased theta power in stage N2 sleep. When expressed as theta/beta and theta/alpha power spectral ratios, we found significant increases in stage N2 sleep, stage N3 sleep, and wake in DM1 compared to controls. Further studies with daytime EEG are warranted to corroborate the current findings.

DISCLOSURE STATEMENT

Work for this study was performed at Stanford University and Stanford Health Care. All authors have read and approved the manuscript. Funding for this study was provided by NIH P01, DMCRN, Muscular Dystrophy Association, and Myotonic Dystrophy Foundation. Dr. Joseph Cheung is supported by a NHLBI T32 training grant HL110952. The authors report no conflicts of interest.

ABBREVIATIONS

AHI

apnea-hypopnea index

BMI

body mass index

CNS

central nervous system

DM1

myotonic dystrophy type 1

EEG

electroencephalography

ESS

Epworth Sleepiness Scale

EDS

excessive daytime sleepiness

SDB

sleep-disordered breathing

ODI

oxygen desaturation index

PSG

polysomnography

REM

rapid eye movement

TST

total sleep time

WASO

wake after sleep onset

ACKNOWLEDGMENTS

The authors thank Oscar Carillo for assisting with sleep data collection. We also thank patients and families who participated in this research.

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