Widespread ripples synchronize human cortical activity during sleep, waking, and memory recall.

Declarative memory encoding, consolidation, and retrieval require the integration of elements encoded in widespread cortical locations. The mechanism whereby such "binding" of different components of mental events into unified representations occurs is unknown. The "binding-by-synchrony" theory proposes that distributed encoding areas are bound by synchronous oscillations enabling enhanced communication. However, evidence for such oscillations is sparse. Brief high-frequency oscillations ("ripples") occur in the hippocampus and cortex and help organize memory recall and consolidation. Here, using intracranial recordings in humans, we report that these ∼70-ms-duration, 90-Hz ripples often couple (within ±500 ms), co-occur (≥ 25-ms overlap), and, crucially, phase-lock (have consistent phase lags) between widely distributed focal cortical locations during both sleep and waking, even between hemispheres. Cortical ripple co-occurrence is facilitated through activation across multiple sites, and phase locking increases with more cortical sites corippling. Ripples in all cortical areas co-occur with hippocampal ripples but do not phase-lock with them, further suggesting that cortico-cortical synchrony is mediated by cortico-cortical connections. Ripple phase lags vary across sleep nights, consistent with participation in different networks. During waking, we show that hippocampo-cortical and cortico-cortical coripples increase preceding successful delayed memory recall, when binding between the cue and response is essential. Ripples increase and phase-modulate unit firing, and coripples increase high-frequency correlations between areas, suggesting synchronized unit spiking facilitating information exchange. co-occurrence, phase synchrony, and high-frequency correlation are maintained with little decrement over very long distances (25 cm). Hippocampo-cortico-cortical coripples appear to possess the essential properties necessary to support binding by synchrony during memory retrieval and perhaps generally in cognition.

Consolidation of emotional memory during waking rest depends on trait anxiety.

A short period of eyes-closed waking rest improves long-term memory for recently learned information, including declarative, spatial, and procedural memory. However, the effect of rest on emotional memory consolidation remains unknown. This preregistered study aimed to establish whether post-encoding rest affects emotional memory and how anxiety levels might modulate this effect. Participants completed a modified version of the dot-probe attention task that involved reacting to and encoding word stimuli appearing underneath emotionally negative or neutral photos. We tested the effect of waking rest on memory for these words and pictures by manipulating the state that participants entered just after this task (rest vs. active wake). Trait anxiety levels were measured using the State-Trait Anxiety Inventory and examined as a covariate. Waking rest improved emotional memory consolidation for individuals high in trait anxiety. These results suggest that the beneficial effect of waking rest on memory extends into the emotional memory domain but depends on individual characteristics such as anxiety.

Early sleep intervention for improving infant sleep quality: a randomized controlled trial, preliminary result.

BACKGROUND: Healthy sleep issues should provide to family within first 6 months of infant's life. This study aimed to evaluate the effect of early sleep intervention on nighttime sleep quality. METHODS: Eligible infants aged 4 months ± 2 weeks were randomized to receive early sleep intervention or usual care. Data on sleep variables were obtained via parental interview at baseline and 6 months of age. Using logistic regression to analyze the efficacy of early sleep intervention. RESULTS: At baseline, 335 eligible infants were enrolled and randomized. In total, 306 participants were final analyzed: early sleep intervention group (n = 148) and the usual care group (n = 158). The early sleep intervention group had a significantly longer nighttime sleep duration and a shorter night waking duration than the usual care group (585.20 ± 80.38 min vs. 496.14 ± 87.78 min, p < .001 and 61.01 ± 36.38 min vs. 89.72 ± 45.54 min, p < .001). At 6 months of age, the early sleep intervention group had a longer night sleep duration (≥ 4 h/time) than the usual care group (adjusted odds ratio: 2.39, 95% confidence interval: 1.34-4.28). CONCLUSIONS: Early sleep intervention should be recommended to infants at 4 months of age as a part of well childcare to improve infant sleep quality. TRIAL REGISTRATION: Thai Clinical Trials Registry (thaiclinicaltrial.org). Retrospective registered TCTR20230117001 (17/01/2023).

Breastfeeding and Sleeping Patterns Among 6-12-Month-Old Infants in Norway.

BACKGROUND: Parental behavior and infant sleep patterns can vary widely both within and between cultures and settings. Breastfeeding during the second half-year of infancy has been associated with frequent night waking, which is perceived as sleep problem among the Western societies. An understanding of sleeping patterns among breastfed infants during the second half-year of infancy is important in supporting continued breastfeeding. OBJECTIVES: The study aimed to investigate the sleeping patterns among breastfed infants during second half-year of infancy. METHODS: This is a cross-sectional study. Three hundred and forty-two mothers of 6-12 months old breastfed infants completed the questionnaires on socio-demographic factors, breastfeeding practices, and infant sleeping patterns, which were assessed by using the Brief Infant Sleep Questionnaire (BISQ). The Cox regression model was used to assess the factors that were associated with night sleep duration whereas demographic factors and breastfeeding practices that were associated with night waking frequency were investigated using the Poisson regression model. RESULTS: On average, the breastfed infants slept for 11 h during the night and most infants were reported to have night waking (96.8%) and were breastfed at least once at night (93.5%). In the adjusted analyses, infants in the age group 9-12 months were less likely to sleep longer compared to infants in the 6-8 months age group [HR 1.52 95% CI (1.17, 1.98)]. A one-hour increase in daytime sleep and in night wakefulness increased the likelihood of waking up at night by 19% and 24%, respectively. Infants who had been vaccinated within the last 7 days and infants who were breastfed to sleep were more likely to have a shorter nighttime sleep duration. Nighttime breastfeeding frequency was significantly associated with a 17% increase in the likelihood of night waking [IRR 1.17 95% CI (1.13, 1.22)]. Infants who slept on their parents' bed were 1.28 times more likely to wake up at night compared to infants who slept in a separate room [IRR 1.28 95% CI (1.05, 1.59)]. Infants of parents who reported that their infants' sleep was not a problem were 34% less likely to wake up compared to infants of parents who reported that their infants' sleep was a problem [IRR 0.66 95% CI (0.49, 0.87)]. CONCLUSIONS FOR PRACTICE: Frequent night waking, bed sharing and night breastfeeding were common among 6-12 months old breastfed infants. Frequent night breastfeeding may lengthen an infant's nighttime sleep duration. The study findings indicate that adequate information and support should be given to breastfeeding mothers in relation to the sleeping pattern of breastfed infants in order to promote continued breastfeeding practices.

Cortical Ripples during NREM Sleep and Waking in Humans.

Hippocampal ripples index the reconstruction of spatiotemporal neuronal firing patterns essential for the consolidation of memories in the cortex during non-rapid eye movement sleep (NREM). Recently, cortical ripples in humans have been shown to enfold the replay of neuron firing patterns during cued recall. Here, using intracranial recordings from 18 patients (12 female), we show that cortical ripples also occur during NREM in humans, with similar density, oscillation frequency (∼90 Hz), duration, and amplitude to waking. Ripples occurred in all cortical regions with similar characteristics, unrelated to putative hippocampal connectivity, and were less dense and robust in higher association areas. Putative pyramidal and interneuron spiking phase-locked to cortical ripples during NREM, with phase delays consistent with ripple generation through pyramidal-interneuron feedback. Cortical ripples were smaller in amplitude than hippocampal ripples but were similar in density, frequency, and duration. Cortical ripples during NREM typically occurred just before the upstate peak, often during spindles. Upstates and spindles have previously been associated with memory consolidation, and we found that cortical ripples grouped cofiring between units within the window of spike timing-dependent plasticity. Thus, human NREM cortical ripples are as follows: ubiquitous and stereotyped with a tightly focused oscillation frequency; similar to hippocampal ripples; associated with upstates and spindles; and associated with unit cofiring. These properties are consistent with cortical ripples possibly contributing to memory consolidation and other functions during NREM in humans.SIGNIFICANCE STATEMENT In rodents, hippocampal ripples organize replay during sleep to promote memory consolidation in the cortex, where ripples also occur. However, evidence for cortical ripples in human sleep is limited, and their anatomic distribution and physiological properties are unexplored. Here, using human intracranial recordings, we demonstrate that ripples occur throughout the cortex during waking and sleep with highly stereotyped characteristics. During sleep, cortical ripples tend to occur during spindles on the down-to-upstate transition, and thus participate in a sequence of sleep waves that is important for consolidation. Furthermore, cortical ripples organize single-unit spiking with timing optimal to facilitate plasticity. Therefore, cortical ripples in humans possess essential physiological properties to support memory and other cognitive functions.

Adaptation and Pilot Study of a Behavioral Intervention Targeting Morning Activation Deficits in Dementia Caregivers: Scheduling Activity and Monitoring Mornings (SAMM).

OBJECTIVES: Morning activation deficits (MADs) correlate with depression symptom persistence in older dementia caregivers. To clarify the potential of MADs as a target for depression interventions, we aimed to: 1) adapt an existing behavioral activation program, Engage therapy, to target mornings; and 2) evaluate effects on self-reported MADs and depression symptoms. METHODS: While trialing the 9-week Engage adaption (targeting mornings) in six older dementia caregivers, we incorporated feedback and finalized an adapted program called Scheduling Activity and Monitoring Mornings (SAMM). We delivered the SAMM protocol to 13 dementia caregivers (all female; mean age = 69, standard deviation = 7). We report modifications made/rationale, as well as changes in subjective MADs (relevant items from the Composite Scale of Morningness) and depression symptoms (Patient Health Questionnaire - 9). RESULTS: Using caregiver and expert input, we adapted the protocol to: include educational materials/content describing the potential relationship between morning inactivity and depression; target activity scheduling within 2 hours of awakening (preferably earlier); and focus only on the main components of morning activity scheduling, planning, and monitoring. This program was associated with decreases in subjective MADs averaging 29% at week 4, 52% at week 6, and 57% by week 9 (all p's <0.005). Initial depression symptoms were significantly reduced, by 62%, at week 9. CONCLUSIONS: These preliminary findings suggest that subjective MADs can be modified pragmatically, and that doing so may have antidepressant effects. A controlled trial with measures of the putative mechanism is needed to clarify whether, and if so how, targeting MAD with SAMM causally perturbs depression's mechanisms.

Habitual night waking associates with dynamics of waking cortical theta power in infancy.

The implications of the substantial individual differences in infant sleep for early brain development remain unclear. Here, we examined whether night sleep quality relates to daytime brain activity, operationalized through measures of EEG theta power and its dynamic modulation, which have been previously linked to later cognitive development. For this longitudinal study, 76 typically developing infants were studied (age: 4-14 months, 166 individual study visits) over the course of 6 months with one, two, three, or four lab visits. Habitual sleep was measured with a 7-day sleep diary and actigraphy, and the Brief Infant Sleep Questionnaire. Twenty-channel EEG was recorded while infants watched multiple rounds of videos of women singing nursery rhymes; oscillatory power in the theta band was extracted. Key metrics were average theta across stimuli and the slope of change in theta within the first novel movie. Both objective and subjective sleep assessment methods showed a relationship between more night waking and higher overall theta power and reduced dynamic modulation of theta over the course of the novel video stimuli. These results may indicate altered learning and consolidation in infants with more disrupted night sleep, which may have implications for cognitive development.

Effects of activity tracker-based counselling and live-web exercise on breast cancer survivors' sleep and waking time during Italy's COVID-19 lockdown.

The aim of the study was to compare the effects of weekly personal feedback, based on objectively measured physical activity, on daily sleep in breast cancer survivors (BCS) with those of an intervention that also included online supervised physical exercise sessions (OSPES). BCS benefiting from both personal feedback and OSPES (n = 24), from pre-lockdown (T0) to the first month (T1) of the national lockdown, experienced an increase in both total (p ≤ 0.001) and restorative (p ≤ 0.001) sleep time, inverting their trend from the first month of lockdown to its end (total sleeping time T1 vs. T2 0.01 ≤ p < .001, T1 vs. T3 p ≤ 0.001; restorative sleeping time T1 vs. T2 0.05 ≤ p < .01, T1 vs. T3 p ≤ 0.001). Supportive technology, together with the reception of weekly tailored advice and OSPES seems to improve both quality and quantity of sleep.

Discharge and Role of GABA Pontomesencephalic Neurons in Cortical Activity and Sleep-Wake States Examined by Optogenetics and Juxtacellular Recordings in Mice.

The cholinergic neurons in the pontomesencephalic tegmentum have been shown to discharge in association with and promote cortical activation during active or attentive waking and paradoxical or rapid eye movement sleep. However, GABA neurons lie intermingled with the cholinergic neurons and may contribute to or oppose this activity and role. Here we investigated in vitro and in vivo the properties, activities, and role of GABA neurons within the laterodorsal tegmental and sublaterodorsal tegmental nuclei (LDT/SubLDT) using male and female transgenic mice expressing channelrhodopsin-(ChR2)-EYFP in vesicular GABA transporter (VGAT)-expressing neurons. Presumed GABA (pGABA) neurons were identified by response to photostimulation and verified by immunohistochemical staining following juxtacellular labeling in vivo pGABA neurons were found to be fast-firing neurons with the capacity to burst when depolarized from a hyperpolarized membrane potential. When stimulated in vivo in urethane-anesthetized or unanesthetized mice, the pGABA neurons fired repetitively at relatively fast rates (∼40 Hz) during a continuous light pulse or phasically in bursts (>100 Hz) when driven by rhythmic light pulses at theta (4 or 8 Hz) frequencies. pNon-GABA, which likely included cholinergic, neurons were inhibited during each light pulse to discharge rhythmically in antiphase to the pGABA neurons. The reciprocal rhythmic bursting by the pGABA and pNon-GABA neurons drove rhythmic theta activity in the EEG. Such phasic bursting by GABA neurons also occurred in WT mice in association with theta activity during attentive waking and paradoxical sleep.SIGNIFICANCE STATEMENT Neurons in the pontomesencephalic tegmentum, particularly cholinergic neurons, play an important role in cortical activation, which occurs during active or attentive waking and paradoxical or rapid eye movement sleep. Yet the cholinergic neurons lie intermingled with GABA neurons, which could play a similar or opposing role. Optogenetic stimulation and recording of these GABA neurons in mice revealed that they can discharge in rhythmic bursts at theta frequencies and drive theta activity in limbic cortex. Such phasic burst firing also occurs during natural attentive waking and paradoxical sleep in association with theta activity and could serve to enhance sensory-motor processing and memory consolidation during these states.

No evidence of consolidation of evaluative conditioning during waking rest and sleep.

Research on evaluative conditioning (EC) shows that attitudes can emerge from co-occurrences of stimuli, and accumulating evidence suggests that EC usually depends on memory for these stimulus contingencies. Therefore, processes known to aid memory retention may be relevant for the development of stable attitudes. One such process may be memory consolidation, assumed to be promoted by waking rest and sleep. In two pre-registered experiments, we investigated whether waking rest (vs. cognitive activity, Experiment 1) and sleep (vs. wakefulness, Experiment 2) in between conditioning and measurement of EC, consolidate contingency memory and EC. Contrary to our predictions, waking rest (vs. cognitive activity) promoted neither contingency memory nor EC effects. Sleep (vs. wakefulness) decreased forgetting of contingency memory but crucially, it did not attenuate the impact of counterconditioning on contingency memory. Sleep also did not influence EC effects, nor the reduction of EC by counterconditioning. EC effects in both experiments were predicted by contingency memory. Yet, unexpectedly, EC effects occurred in the absence of contingency memory after waking rest, but neither after sleep nor in the active control conditions. Our findings emphasise a role of contingency memory in EC, but it remains unclear whether this role changes during waking rest.

Gamma oscillations in the pedunculopontine nucleus are regulated by F-actin: neuroepigenetic implications.

The pedunculopontine nucleus (PPN) is part of the reticular activating system (RAS) in charge of arousal and rapid eye movement sleep. The presence of high-frequency membrane oscillations in the gamma-band range in the PPN has been extensively demonstrated both in vivo and in vitro. Our group previously described histone deacetylation (HDAC) inhibition in vitro induced protein changes in F-actin cytoskeleton and intracellular Ca2+ concentration regulation proteins in the PPN. Here, we present evidence that supports the presence of a fine balance between HDAC function and calcium calmodulin kinase II-F-actin interactions in the PPN. We modified F-actin polymerization in vitro by using jasplakinolide (1 µM, a promoter of F-actin stabilization), or latrunculin-B (1 µM, an inhibitor of actin polymerization). Our results showed that shifting the balance in either direction significantly reduced PPN gamma oscillation as well as voltage-dependent calcium currents.

No evidence for spontaneous cross-frequency phase-phase coupling in the human hippocampus.

Cross-frequency phase-phase coupling (PPC) has been suggested to play a role in cognitive processing and, in particular, in memory consolidation during sleep. Controversial results have been reported regarding the existence of spontaneous phase-phase coupling in the hippocampus. Here, we investigated this phenomenon in intracranial EEG recordings from the human hippocampus acquired during waking state and different sleep stages. We estimated the strength of interactions between different pairs of frequency bands and evaluated the statistical significance of findings using surrogates that build on different null hypotheses. Indications for spontaneous phase-phase coupling were only observed when testing with less rigorous surrogates. When requiring that all four surrogate tests be passed, however, there were no significant indications for phase-phase coupling. In conclusion, we did not detect evidence for spontaneous cross-frequency phase-phase coupling in the human hippocampus.

Hypocretin (orexin) is critical in sustaining theta/gamma-rich waking behaviors that drive sleep need.

Hcrt gene inactivation in mice leads to behavioral state instability, abnormal transitions to paradoxical sleep, and cataplexy, hallmarks of narcolepsy. Sleep homeostasis is, however, considered unimpaired in patients and narcoleptic mice. We find that whereas Hcrtko/ko mice respond to 6-h sleep deprivation (SD) with a slow-wave sleep (SWS) EEG δ (1.0 to 4.0 Hz) power rebound like WT littermates, spontaneous waking fails to induce a δ power reflecting prior waking duration. This correlates with impaired θ (6.0 to 9.5 Hz) and fast-γ (55 to 80 Hz) activity in prior waking. We algorithmically identify a theta-dominated wakefulness (TDW) substate underlying motivated behaviors and typically preceding cataplexy in Hcrtko/ko mice. Hcrtko/ko mice fully implement TDW when waking is enforced, but spontaneous TDW episode duration is greatly reduced. A reformulation of the classic sleep homeostasis model, where homeostatic pressure rises exclusively in TDW rather than all waking, predicts δ power dynamics both in Hcrtko/ko and WT mouse baseline and recovery SWS. The low homeostatic impact of Hcrtko/ko mouse spontaneous waking correlates with decreased cortical expression of neuronal activity-related genes (notably Bdnf, Egr1/Zif268, and Per2). Thus, spontaneous TDW stability relies on Hcrt to sustain θ/fast-γ network activity and associated plasticity, whereas other arousal circuits sustain TDW during SD. We propose that TDW identifies a discrete global brain activity mode that is regulated by context-dependent neuromodulators and acts as a major driver of sleep homeostasis. Hcrt loss in Hcrtko/ko mice causes impaired TDW maintenance in baseline wake and blunted δ power in SWS, reproducing, respectively, narcolepsy excessive daytime sleepiness and poor sleep quality.

Parental and preimaginal exposure to methylmercury disrupts locomotor activity and circadian rhythm of adult Drosophila melanogaster.

Methylmercury (MeHg) is a well-known toxic pollutant. However, little is known about the effects of this toxic agent in an adult as a consequence of a parental or preimaginal exposure. This study used Drosophila melanogaster to investigate whether a parental or a preimaginal (eggs-larvae-pupae stages) exposure could impact parameters as viability, locomotor activity, and sleep patterns of fruit flies. Thus, we performed two exposure protocols. One where just parents were exposed to MeHg (0-12 µM) during 24 h, then flies were transferred to lay eggs in a healthy medium (without MeHg). In the other, flies were set to lay eggs in a MeHg medium, same concentrations, and discarded after this (preimaginal exposure). Viability was evaluated from egg to adult flies. F1 progeny was collected within 24 h and transferred to a fresh healthy medium. Sleep behavior analysis was performed using Drosophila Active Monitoring System (DAMS), and the locomotor activity was evaluated by climbing assay. Results have shown that the parental exposure had a significant impact on F1 progeny reducing viability and locomotor activity performance, but no significant circadian rhythm alterations. Whereas the preimaginal exposure had a stronger effect decreasing viability and locomotor activity, it also disrupted sleep patterns. MeHg preimaginal exposure showed a longer sleep duration and lower daily activity. Results corroborate the hypothesis that low MeHg exposure could trigger subclinical symptoms related to a 'neurotoxicological development effect'. Complementary investigations could clarify the underlying mechanisms of MeHg effects in neural functions due to parental and early development exposure to this toxicant.

Factors modulating the effects of waking rest on memory.

Study results indicate that moments of unoccupied rest immediately after learning serve an essential cognitive function: memory consolidation. However, there also are findings suggesting that waking rest after learning has similar effects on delayed memory performance as an active wake condition, where participants work on a cognitive distractor task. Based on these studies, we highlight several potentially modulating factors of the so-called resting effect.

Neuroepigenetics of arousal: Gamma oscillations in the pedunculopontine nucleus.

Four major discoveries on the function of the pedunculopontine nucleus (PPN) have significantly advanced our understanding of the role of arousal in neurodegenerative disorders. The first was the finding that stimulation of the PPN-induced controlled locomotion on a treadmill in decerebrate animals, the second was the revelation of electrical coupling in the PPN and other arousal and sleep-wake control regions, the third was the determination of intrinsic gamma band oscillations in PPN neurons, and the last was the discovery of gene transcription resulting from the manifestation of gamma activity in the PPN. These discoveries have led to novel therapies such as PPN deep brain stimulation (DBS) for Parkinson's disease (PD), identified the mechanism of action of the stimulant modafinil, determined the presence of separate mechanisms underlying gamma activity during waking versus REM sleep, and revealed the presence of gene transcription during the manifestation of gamma band oscillations. These discoveries set the stage for additional major advances in the treatment of a number of disorders.

Bottom-up gamma and bipolar disorder, clinical and neuroepigenetic implications.

OBJECTIVES: This limited review examines the role of the reticular activating system (RAS), especially the pedunculopontine nucleus (PPN), one site of origin of bottom-up gamma, in the symptoms of bipolar disorder (BD). METHODS: The expression of neuronal calcium sensor protein 1 (NCS-1) in the brains of BD patients is increased. It has recently been found that all PPN neurons manifest intrinsic membrane beta/gamma frequency oscillations mediated by high threshold calcium channels, suggesting that it is one source of bottom-up gamma. This review specifically addresses the involvement of these channels in the manifestation of BD. RESULTS: Excess NCS-1 was found to dampen gamma band oscillations in PPN neurons. Lithium, a first line treatment for BD, was found to decrease the effects of NCS-1 on gamma band oscillations in PPN neurons. Moreover, gamma band oscillations appear to epigenetically modulate gene transcription in PPN neurons, providing a new direction for research in BD. CONCLUSIONS: This is an area needing much additional research, especially since the dysregulation of calcium channels may help explain many of the disorders of arousal in, elicit unwanted neuroepigenetic modulation in, and point to novel therapeutic avenues for, BD.

Effect of mobile phone radiofrequency signal on the alpha rhythm of human waking EEG: A review.

In response to the exponential increase in mobile phone use and the resulting increase in exposure to radiofrequency electromagnetic fields (RF-EMF), there have been several studies to investigate via electroencephalography (EEG) whether RF-EMF exposure affects brain activity. Data in the literature have shown that exposure to radiofrequency signals modifies the waking EEG with the main effect on the alpha band frequency (8-13 Hz). However, some studies have reported an increase in alpha band power, while others have shown a decrease, and other studies showed no effect on EEG power. Given that changes in the alpha amplitude are associated with attention and some cognitive aspects of human behavior, researchers deemed necessary to look whether alpha rhythm was modulated under RF-EMF exposure. The present review aims at comparing and discussing the main findings obtained so far regarding RF-EMF effects on alpha rhythm of human waking spontaneous EEG, focusing on differences in protocols between studies, which might explain the observed discrepancies and inconclusive results.

Accuracy of MDS-UPDRS section IV for detecting motor fluctuations in Parkinson's disease.

BACKGROUND: In a precedent paper, we validated part IV of the Unified Parkinson's Disease Rating Scale (UPDRS) for detecting motor fluctuations in Parkinson's Disease (PD) patients using a 12-h Waking-Day Motor Assessment (WDMA) as gold standard, showing a high sensitivity (> 80%) and a lower specificity (< 45%). The aim of this study was to validate the Movement Disorder Society-UPDRS (MDS-UPDRS) part IV, especially items 4.3 and 4.5, using the same methodology. METHODS: PD patients attending the Movement Disorders Clinic at the University Hospital in Catania were consecutively enrolled in the study. A diurnal WDMA was performed to detect motor fluctuations. At each time interval, the motor impairment was evaluated using the motor section of the MDS-UPDRS. Presence or absence of motor fluctuations and the type of motor fluctuation were assessed by four blinded expert raters in movement disorders, by evaluating the graphical representations of the WDMA. We evaluated sensitivity and specificity together with 95% Confidence Interval (CI) of items 4.3 and 4.5, using WDMA as gold standard. RESULTS: We estimated for item 4.3 of the MDS-UPDRS a sensitivity of 74.3% (95% CI 56.7-87.5) and a specificity of 70.6% (95% CI 44-89.7), while for item 4.5, a sensitivity of 67.9% (95% CI 47.6-84.1) and a specificity of 66.7% (95% CI 44.7-84.4). CONCLUSIONS: The present showed a higher specificity level for MDS-UPDRS with respect to the UPDRS, while a slightly lower sensitivity mainly for predictable OFF.

Global variation in diurnal cortisol rhythms: evidence from Garisakang forager-horticulturalists of lowland Papua New Guinea.

The hypothalamic-pituitary-adrenal (HPA) axis represents an important and evolutionarily ancient biological pathway linking physical and psychological stressors with human health. Despite considerable research exploring the physiological stress response among developed populations, few studies have examined HPA activity in non-industrialized contexts, restricting understanding of variation in human stress reactivity across global socio-ecological diversity. The present study addresses this shortcoming by investigating diurnal cortisol rhythms among Garisakang forager-horticulturalists of remote, lowland Papua New Guinea. Using a large sample of repeated salivary cortisol measurements from 169 participants (age 4-70 years), multilevel growth curve models were constructed to assess Garisakang waking cortisol concentrations and diurnal cortisol slopes. As predicted, results demonstrate identifiable but substantially diminished diurnal cortisol rhythms relative to those of industrialized populations. Sample-wide, Garisakang cortisol concentrations are highest upon waking (mean = 4.86 nmol/L) and decrease throughout the day at a mean rate of only -0.18 nmol/L/h or -6.20%/h. Age and sex significantly predict evaluated cortisol parameters in ways not consistently reported among industrialized populations, suggesting that Garisakang diurnal cortisol rhythms are defined by distinct ontogenetic trajectories across the lifespan. These findings highlight cross-cultural diversity in HPA activity and have important implications for understanding basic mechanisms of the physiological stress response in contexts of chronic physical stressors such as limited nutrition, heavy burden of infectious disease, and high levels of physical activity.