Divergent Associations of Slow-Wave Sleep versus Rapid Eye Movement Sleep with Plasma Amyloid-Beta.

OBJECTIVE: Recent evidence shows that during slow-wave sleep (SWS), the brain is cleared from potentially toxic metabolites, such as the amyloid-beta protein. Poor sleep or elevated cortisol levels can worsen amyloid-beta clearance, potentially leading to the formation of amyloid plaques, a neuropathological hallmark of Alzheimer disease. Here, we explored how nocturnal neural and endocrine activity affects amyloid-beta fluctuations in the peripheral blood. METHODS: We acquired simultaneous polysomnography and all-night blood sampling in 60 healthy volunteers aged 20-68 years. Nocturnal plasma concentrations of amyloid-beta-40, amyloid-beta-42, cortisol, and growth hormone were assessed every 20 minutes. Amyloid-beta fluctuations were modeled with sleep stages, (non)oscillatory power, and hormones as predictors while controlling for age and participant-specific random effects. RESULTS: Amyloid-beta-40 and amyloid-beta-42 levels correlated positively with growth hormone concentrations, SWS proportion, and slow-wave (0.3-4Hz) oscillatory and high-band (30-48Hz) nonoscillatory power, but negatively with cortisol concentrations and rapid eye movement sleep (REM) proportion measured 40-100 minutes previously (all t values > |3|, p values < 0.003). Older participants showed higher amyloid-beta-40 levels. INTERPRETATION: Slow-wave oscillations are associated with higher plasma amyloid-beta levels, whereas REM sleep is related to decreased amyloid-beta plasma levels, possibly representing changes in central amyloid-beta production or clearance. Strong associations between cortisol, growth hormone, and amyloid-beta presumably reflect the sleep-regulating role of the corresponding releasing hormones. A positive association between age and amyloid-beta-40 may indicate that peripheral clearance becomes less efficient with age. ANN NEUROL 2024;96:46-60.

Fundamentals of sleep regulation: Model and benchmark values for fractal and oscillatory neurodynamics.

Homeostatic, circadian and ultradian mechanisms play crucial roles in the regulation of sleep. Evidence suggests that ratios of low-to-high frequency power in the electroencephalogram (EEG) spectrum indicate the instantaneous level of sleep pressure, influenced by factors such as individual sleep-wake history, current sleep stage, age-related differences and brain topography characteristics. These effects are well captured and reflected in the spectral exponent, a composite measure of the constant low-to-high frequency ratio in the periodogram, which is scale-free and exhibits lower interindividual variability compared to slow wave activity, potentially serving as a suitable standardization and reference measure. Here we propose an index of sleep homeostasis based on the spectral exponent, reflecting the level of membrane hyperpolarization and/or network bistability in the central nervous system in humans. In addition, we advance the idea that the U-shaped overnight deceleration of oscillatory slow and fast sleep spindle frequencies marks the biological night, providing somnologists with an EEG-index of circadian sleep regulation. Evidence supporting this assertion comes from studies based on sleep replacement, forced desynchrony protocols and high-resolution analyses of sleep spindles. Finally, ultradian sleep regulatory mechanisms are indicated by the recurrent, abrupt shifts in dominant oscillatory frequencies, with spindle ranges signifying non-rapid eye movement and non-spindle oscillations - rapid eye movement phases of the sleep cycles. Reconsidering the indicators of fundamental sleep regulatory processes in the framework of the new Fractal and Oscillatory Adjustment Model (FOAM) offers an appealing opportunity to bridge the gap between the two-process model of sleep regulation and clinical somnology.

Sustained polyphasic sleep restriction abolishes human growth hormone release.

STUDY OBJECTIVES: Voluntary sleep restriction is a common phenomenon in industrialized societies aiming to increase time spent awake and thus productivity. We explored how restricting sleep to a radically polyphasic schedule affects neural, cognitive, and endocrine characteristics. METHODS: Ten young healthy participants were restricted to one 20-minute nap opportunity at the end of every 4 hours (i.e. six sleep episodes per 24 hours) without any extended core sleep window, which resulted in a cumulative sleep amount of just 2 hours per day (i.e. ~20 minutes per bout). RESULTS: All but one participant terminated this schedule during the first month. The remaining participant (a 25-year-old male) succeeded in adhering to a polyphasic schedule for five out of the eight planned weeks. Cognitive and psychiatric measures showed modest changes during polyphasic as compared to monophasic sleep, while in-blood cortisol or melatonin release patterns and amounts were apparently unaltered. In contrast, growth hormone release was almost entirely abolished (>95% decrease), with the residual release showing a considerably changed polyphasic secretional pattern. CONCLUSIONS: Even though the study was initiated by volunteers with exceptional intrinsic motivation and commitment, none of them could tolerate the intended 8 weeks of the polyphasic schedule. Considering the decreased vigilance, abolished growth hormone release, and neurophysiological sleep changes observed, it is doubtful that radically polyphasic sleep schedules can subserve the different functions of sleep to a sufficient degree.

Increased Aperiodic Neural Activity During Sleep in Major Depressive Disorder.

Background: In major depressive disorder (MDD), patients often express subjective sleep complaints, while polysomnographic studies report only subtle alterations of the electroencephalographic signal. We hypothesize that differentiating the signal into its oscillatory and aperiodic components may bring new insights into our understanding of sleep abnormalities in MDD. Specifically, we investigated aperiodic neural activity during sleep and its relationships with sleep architecture, depression severity, and responsivity to antidepressant treatment. Methods: Polysomnography was recorded in 38 patients with MDD (in unmedicated and 7-day-medicated states) and 38 age-matched healthy control subjects (N= 76). The aperiodic power component was calculated using irregularly resampled auto-spectral analysis. Depression severity was assessed with the Hamilton Depression Rating Scale. We replicated the analysis using 2 independently collected datasets of medicated patients and control subjects (N = 60 and N = 80, respectively). Results: Unmedicated patients showed flatter aperiodic slopes compared with control subjects during non-rapid eye movement (non-REM) stage 2 sleep (p = .009). Medicated patients showed flatter aperiodic slopes compared with their earlier unmedicated state (p values < .001) and control subjects during all sleep stages (p values < .03). In medicated patients, flatter aperiodic slopes during non-REM sleep were linked to the higher proportion of N1, lower proportion of REM, delayed onset of N3 and REM, and shorter total sleep time. Conclusions: Flatter slopes of aperiodic electroencephalographic power may reflect noisier neural activity due to increased excitation-to-inhibition balance, representing a new disease-relevant feature of sleep in MDD.

Decreased aperiodic neural activity in Parkinson's disease and dementia with Lewy bodies.

Neural oscillations and signal complexity have been widely studied in neurodegenerative diseases, whereas aperiodic activity has not been explored yet in those disorders. Here, we assessed whether the study of aperiodic activity brings new insights relating to disease as compared to the conventional spectral and complexity analyses. Eyes-closed resting-state electroencephalography (EEG) was recorded in 21 patients with dementia with Lewy bodies (DLB), 28 patients with Parkinson's disease (PD), 27 patients with mild cognitive impairment (MCI) and 22 age-matched healthy controls. Spectral power was differentiated into its oscillatory and aperiodic components using the Irregularly Resampled Auto-Spectral Analysis. Signal complexity was explored using the Lempel-Ziv algorithm (LZC). We found that DLB patients showed steeper slopes of the aperiodic power component with large effect sizes compared to the controls and MCI and with a moderate effect size compared to PD. PD patients showed steeper slopes with a moderate effect size compared to controls and MCI. Oscillatory power and LZC differentiated only between DLB and other study groups and were not sensitive enough to detect differences between PD, MCI, and controls. In conclusion, both DLB and PD are characterized by alterations in aperiodic dynamics, which are more sensitive in detecting disease-related neural changes than the traditional spectral and complexity analyses. Our findings suggest that steeper aperiodic slopes may serve as a marker of network dysfunction in DLB and PD features.

Decreased delta-band event-related power in dementia with Lewy bodies with a mutation in the glucocerebrosidase gene.

OBJECTIVE: To compare event-related oscillations in patients with dementia with Lewy bodies (DLB) who are carriers and non-carriers of glucocerebrosidase (GBA) mutations. METHODS: EEG was recorded during a visual oddball task in eight Ashkenazi Jewish DLB patients with the N370S mutation in theGBAgene (GBA-DLB) and eleven DLB non-carriers. The time-frequency power and inter-trial phase clustering were calculated from the Morlet wavelet convolution for the midline electrodes. RESULTS: Task performance and cognitive assessments were comparable between groups. While the within-non-GBA-DLB group analysis revealed delta-band power synchronization relative to the baseline (p = 0.01, Cohen's d = 1.0), the within-GBA-DLB-group analysis detected no event-related changes in power. Both groups showed an increase relative to the baseline in the delta and theta bands inter-trial phase clustering (all p < 0.03, d > 1.3). The between-group analysis revealed that event-related power - but not clustering - was lower in GBA-DLB compared to non-carriers in the delta band at Fz and Cz (p = 0.04, d = -0.9). CONCLUSIONS: GBA-DLB patients showed decreased delta-band power compared to non-carriers despite the similar cognitive performance, whereas inter-trial phase clustering was comparable in both groups. SIGNIFICANCE: Preserved inter-trial phase clustering possibly compensates for the impaired power by eliciting the appropriate functional configuration needed for stimulus processing and task performance.

Event-related oscillations differentiate between cognitive, motor and visual impairments.

BACKGROUND: Parkinson's disease (PD) and dementia with Lewy bodies (DLB) share pathological and clinical similarities while differing in the timing and severity of motor cognitive and visual impairment. Previous EEG studies found abnormal neural oscillations in PD, mild cognitive impairment (MCI) and Alzheimer's disease, however, the electrophysiological signature of clinical symptoms is still unclear. We assessed the specificity of event-related oscillations in distinguishing between cognitive, motor and visual involvement in patients with neurodegenerative conditions. METHODS: EEG was recorded during a visual oddball task in 30 PD, 28 DLB, 30 MCI patients and 32 age-matched healthy controls. Target and non-target event-related power were examined in the time-frequency domain using complex Morlet wavelet convolution and compared within and between the study groups. RESULTS: MCI (z = - 1.8, p = 0.04, Cohen's d = - 0.5) and DLB (z = - 3.1, p < 0.001, d = - 1.0) patients showed decreased delta-band target event-related synchronization compared to participants with normal cognition. PD (z = 1.6, p = 0.05, d = 0.5) and DLB (z = 2.7, p < 0.01, d = 0.9) patients showed decreased beta suppression compared to MCI patients and controls. DLB patients with visual hallucinations (VH) showed decreased early-alpha suppression (z = 2.08, p = 0.019, d = 3.19, AUC = 1.0 ± 0.0) compared to DLB-VH-. CONCLUSIONS: Decreased event-related delta-band synchronization, reflecting a decline in information processing ability, was characteristic of cognitive impairment due to any cause. Decreased event-related beta suppression, reflecting impaired execution of motor action, was specific to PD and DLB. Decreased event-related early-alpha suppression was characteristic of the presence of VH in DLB. These findings show that specific oscillations may reflect specific clinical symptoms, being a marker of network dysfunction.

Can brain stimulation boost memory performance?

Memory performance is crucial across the human life, from early education to age-related decline. A new study in PLOS Biology found that verbal learning can be enhanced by applying repetitive transcranial magnetic stimulation (rTMS) over the left prefrontal cortex.

Associations between visual hallucinations and impaired visuo-spatial abilities in dementia with Lewy bodies.

Objectives: In dementia with Lewy bodies (DLB) recurrent visual hallucinations (VH) often coexist or occur consecutively to impaired visual perception. Since in-depth neuropsychological testing is time-consuming, and therefore, not routinely performed in clinical settings, we aimed to explore whether standard cognitive screening tests may be helpful to alert a clinician to the presence of VH in DLB by exploring association between visuo-spatial dysfunction and VH. Method: The clock drawing, cube, and pentagons copying items from Montreal Cognitive Assessment and Mini-Mental State Exam and nonmotor Hooper visual organization test (HVOT) have been scored in DLB patients with and without VH using traditional and extended scoring methods. Results: Forty-five of 69 (65%) DLB patients were VH-positive (VH+). VH+ patients performed worse on the clock drawing (8.8/16 vs. 11.9/16, p = .016) with a higher rate of misrepresentation of time (69% vs. 29%, p = .002) and numbers (53% vs. 25%, p = .024). Likewise, VH+ patients performed worse on the HVOT (13.3/30 vs. 15.7/30, p = .009) having more isolated (6.2/30 vs. 4.4/30, p = .012) types of responses compared to VH- patients. Both groups had similar copying ability (p > .05). The VH discriminative accuracy of the clock drawing was comparable to that of the more elaborate test of visual perception, the HVOT. Conclusions: In DLB impaired drawing and visual organization, but not copying ability is associated with the presence of VH. The simple clock drawing test can be helpful to alert a clinician to the possibility of VH in DLB. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The Effect of GBA Mutations and APOE Polymorphisms on Dementia with Lewy Bodies in Ashkenazi Jews.

BACKGROUND: Glucocerebrosidase (GBA) gene mutations and APOE polymorphisms are common in dementia with Lewy bodies (DLB), however their clinical impact is only partially elucidated. OBJECTIVE: To explore the clinical impact of mutations in the GBA gene and APOE polymorphisms separately and in combination, in a cohort of Ashkenazi Jewish (AJ) patients with DLB. METHODS: One hundred consecutively recruited AJ patients with clinically diagnosed DLB underwent genotyping for GBA mutations and APOE polymorphisms, and performed cognitive and motor clinical assessments. RESULTS: Thirty-two (32%) patients with DLB were carriers of GBA mutations and 33 (33%) carried an APOE ɛ4 allele. GBA mutation carriers had a younger age of onset (mean [SD] age, 67.2 years [8.9] versus 71.97 [5.91]; p = 0.03), poorer cognition as assessed by the Mini-Mental State Examination (21.41 [6.9] versus 23.97 [5.18]; p < 0.005), and more severe parkinsonism as assessed with the Unified Parkinson's Disease Rating Scale motor part III (34.41 [13.49] versus 28.38 [11.21]; p = 0.01) compared to non-carriers. There were statistically significant interactions between the two genetic factors, so that patients who carried both a mild GBA mutation and the APOE ɛ4 allele (n = 9) had more severe cognitive (p = 0.048) and motor dysfunction (p = 0.037). CONCLUSION: We found a high frequency of both GBA mutations and the APOE ɛ4 allele among AJ patients with DLB, both of which have distinct effects on the clinical disease phenotype, separately and in combination.

Differential changes in visual and auditory event-related oscillations in dementia with Lewy bodies.

OBJECTIVE: Aside from the cognitive impairment, patients with dementia with Lewy bodies (DLB) have a high frequency of visual hallucinations and a number of other vision-related symptoms, whereas auditory hallucinations are less frequent. To better understand the differential dysfunction of the visual network in DLB, we compared auditory and visual event-related potentials and oscillations in patients with DLB. METHODS: Event-related potentials elicited by visual and auditory oddball tasks were recorded in 23 patients with DLB and 22 healthy controls and analyzed in time and time-frequency domain. RESULTS: DLB patients had decreased theta band activity related to both early sensory and later cognitive processing in the visual, but not in the auditory task. Patients had lower delta and higher alpha and beta bands power related to later cognitive processing in both auditory and visual tasks. CONCLUSIONS: In DLB visual event-related oscillations are characterized by a decrease in theta and lack of inhibition in alpha bands. SIGNIFICANCE: Decreased theta and a lack of inhibition in alpha band power might be an oscillatory underpinning of some classical DLB symptoms such as fluctuations in attention and high-level visual disturbances and a potential marker of dysfunction of the visual system in DLB.