Biology subjects

Manoach, D. S.

Publications and source records attributed to Manoach, D. S..

11 recordsLinked to original sources

bioRxiv2025

Changes in slow oscillations and sleep spindles by auditory stimulation positively correlate with memory consolidation in children with epilepsy and controls

BackgroundSleep-dependent memory consolidation is supported by sleep spindles during stages 2 and 3 non-rapid eye movement sleep. Sleep spindles and sleep-dependent memory consolidation are both decreased in Rolandic epilepsy (RE). Non-invasive auditory stimulation evokes SOs and SO-spindle complexes in healthy adults but the impact on memory consolidation has been inconsistent. ObjectiveWe investigated the effects of auditory stimulation during sleep on SOs, SO-spindle complexes, and sleep-dependent memory consolidation in children with RE and controls. MethodsA prospective cross-over study was conducted in children with RE and control. Children completed two nap visits with auditory or sham stimulation. SOs and SO-spindle complexes rates were measured offline using validated detectors. Sleep-dependent memory consolidation was assessed using the motor sequence typing task. ResultsAuditory stimulation evoked SOs and SO-spindle complexes broadly with maximal effect over frontal electrodes. Compared to sham, stimulation delivered during background activity evoked SOs (29.8% increase, p<0.001) and SO-spindle complexes (16.8% increase, p<0.001) and stimulations delivered near the peak of an ongoing SO upstate maximally evoked SOs (51.3% increase, p<0.001) and SO-spindle complexes (32.3% increase, p<0.001). Changes in frontal SO (1.9% improvement per increase in SO/min; p<0.001) and SO-spindle complexes (9.5% improvement per increase in SO-spindle/min) event rates due to auditory stimulation positively predicted changes in sleep-dependent memory consolidation. ConclusionAuditory stimulation reliably modulates sleep oscillations when delivered on background activity and during the upstate of SOs. As increased event rates improve memory consolidation, stimulation paradigms to increase SO and SO-spindle complex rates are required to enhance memory.

neuroscience↗

bioRxiv2024

Impaired sleep-dependent memory consolidation predicted by reduced sleep spindles in Rolandic epilepsy

Background and ObjectivesSleep spindles are prominent thalamocortical brain oscillations during sleep that have been mechanistically linked to sleep-dependent memory consolidation in animal models and healthy controls. Sleep spindles are decreased in Rolandic epilepsy and related sleep-activated epileptic encephalopathies. We investigate the relationship between sleep spindle deficits and deficient sleep dependent memory consolidation in children with Rolandic epilepsy. MethodsIn this prospective case-control study, children were trained and tested on a validated probe of memory consolidation, the motor sequence task (MST). Sleep spindles were measured from high-density EEG during a 90-minute nap opportunity between MST training and testing using a validated automated detector. ResultsTwenty-three children with Rolandic epilepsy (14 with resolved disease), and 19 age- and sex-matched controls were enrolled. Children with active Rolandic epilepsy had decreased memory consolidation compared to control children (p=0.001, mean percentage reduction: 25.7%, 95% CI [10.3, 41.2]%) and compared to children with resolved Rolandic epilepsy (p=0.007, mean percentage reduction: 21.9%, 95% CI [6.2, 37.6]%). Children with active Rolandic epilepsy had decreased sleep spindle rates in the centrotemporal region compared to controls (p=0.008, mean decrease 2.5 spindles/min, 95% CI [0.7, 4.4] spindles/min). Spindle rate positively predicted sleep-dependent memory consolidation (p=0.004, mean MST improvement of 3.9%, 95% CI [1.3, 6.4]%, for each unit increase in spindles per minute). DiscussionChildren with Rolandic epilepsy have a sleep spindle deficit during the active period of disease which predicts deficits in sleep dependent memory consolidation. This finding provides a mechanism and noninvasive biomarker to aid diagnosis and therapeutic discovery for cognitive dysfunction in Rolandic epilepsy and related sleep activated epilepsy syndromes.

neuroscience↗

bioRxiv2024

Hippocampal ripples mediate motor learning during brief rest breaks in humans

Critical aspects of motor learning and memory happen offline, during both wake and sleep. When healthy young people learn a motor sequence task, most of their performance improvement happens not while typing, but offline, during interleaved rest breaks. In contrast, the performance of patients with dense amnesia due to hippocampal damage actually gets worse over the rest breaks and improves while typing. These findings indicate that an intact hippocampus is necessary for offline motor learning during wake, but do not specify its mechanism. Here, we studied epilepsy patients (n=17) undergoing direct intracranial EEG monitoring of the hippocampus as they learned the same motor sequence task. Like healthy young people, they showed greater speed gains across rest breaks than while typing. They also showed higher hippocampal ripple rates during these rest breaks that predicted offline gains in speed. This suggests that motor learning during brief rest breaks during wake is mediated by hippocampal ripples. These results expand our understanding of the role of hippocampal ripples beyond declarative memory to include enhancing motor procedural memory. Significance StatementIn patients with epilepsy undergoing direct intracranial EEG monitoring of the hippocampus, we found a higher rate of ripples during the brief rest breaks of a motor sequence task than during task execution. These offline hippocampal ripples predicted the amount of performance improvement over the break. We conclude that the hippocampus contributes to motor learning during brief rest breaks, and propose that this offline learning is mediated by ripples.

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bioRxiv2023

A spectrum of altered non-rapid eye movement sleep in schizophrenia

BackgroundMultiple facets of sleep neurophysiology, including electroencephalography (EEG) metrics such as non-rapid eye movement (NREM) spindles and slow oscillations (SO), are altered in individuals with schizophrenia (SCZ). However, beyond group-level analyses which treat all patients as a unitary set, the extent to which NREM deficits vary among patients is unclear, as are their relationships to other sources of heterogeneity including clinical factors, illness duration and ageing, cognitive profiles and medication regimens. Using newly collected high density sleep EEG data on 103 individuals with SCZ and 68 controls, we first sought to replicate our previously reported (Kozhemiako et. al, 2022) group-level mean differences between patients and controls (original N=130). Then in the combined sample (N=301 including 175 patients), we characterized patient-to-patient variability in NREM neurophysiology. ResultsWe replicated all group-level mean differences and confirmed the high accuracy of our predictive model (Area Under the ROC Curve, AUC = 0.93 for diagnosis). Compared to controls, patients showed significantly increased between-individual variability across many (26%) sleep metrics, with patterns only partially recapitulating those for group-level mean differences. Although multiple clinical and cognitive factors were associated with NREM metrics including spindle density, collectively they did not account for much of the general increase in patient-to-patient variability. Medication regimen was a greater (albeit still partial) contributor to variability, although original group mean differences persisted after controlling for medications. Some sleep metrics including fast spindle density showed exaggerated age-related effects in SCZ, and patients exhibited older predicted biological ages based on an independent model of ageing and the sleep EEG. ConclusionWe demonstrated robust and replicable alterations in sleep neurophysiology in individuals with SCZ and highlighted distinct patterns of effects contrasting between-group means versus within-group variances. We further documented and controlled for a major effect of medication use, and pointed to greater age-related change in NREM sleep in patients. That increased NREM heterogeneity was not explained by standard clinical or cognitive patient assessments suggests the sleep EEG provides novel, nonredundant information to support the goals of personalized medicine. Collectively, our results point to a spectrum of NREM sleep deficits among SCZ patients that can be measured objectively and at scale, and that may offer a unique window on the etiological and genetic diversity that underlies SCZ risk, treatment response and prognosis.

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bioRxiv2023

NREM sleep oscillations and their relations with sleep-dependent memory consolidation in early course psychosis and first-degree relatives

Sleep spindles are believed to mediate sleep-dependent memory consolidation, particularly when coupled to neocortical slow oscillations. Schizophrenia is characterized by a deficit in sleep spindles that correlates with reduced overnight memory consolidation. Here, we examined sleep spindle activity, slow oscillation-spindle coupling, and both motor procedural and verbal declarative memory consolidation in early course, minimally medicated psychosis patients and non-psychotic first-degree relatives. Using a four-night experimental procedure, we observed significant deficits in spindle density and amplitude in patients relative to controls that were driven by individuals with schizophrenia. Schizophrenia patients also showed reduced sleep-dependent consolidation of motor procedural memory, which correlated with spindle density. Contrary to expectations, there were no group differences in the consolidation of declarative memory on a word pairs task. Nor did the relatives of patients differ in spindle activity or memory consolidation compared with controls, however increased consistency in the timing of SO-spindle coupling were seen in both patient and relatives. Our results extend prior work by demonstrating correlated deficits in sleep spindles and sleep-dependent motor procedural memory consolidation in early course, minimally medicated patients with schizophrenia, but not in first-degree relatives. This is consistent with other work in suggesting that impaired sleep-dependent memory consolidation has some specificity for schizophrenia and is a core feature rather than reflecting the effects of medication or chronicity. Statement of significanceWe investigated sleep neurophysiology and memory consolidation in minimally-medicated, early course psychosis patients and unaffected first-degree relatives of patients in a four-night study. Early-course schizophrenia patients had a sleep spindle deficit that correlated with reduced procedural memory consolidation. Although first-degree relatives did not show any deficit in spindles or memory consolidation, the spindles of both relatives and patients showed increased consistency of the temporal coupling of spindles with slow oscillations compared with controls. These results suggest that sleep spindle and memory consolidation deficits are a core feature of schizophrenia. Spindle deficits may be a biomarker of schizophrenia modifiable by treatment, and motivate the development of targeted novel interventions.

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bioRxiv2023

Human thalamic recordings reveal that epileptic spikes block sleep spindle production during non-rapid eye movement sleep

In severe epileptic encephalopathies, epileptic activity contributes to progressive cognitive dysfunction. Several epileptic encephalopathies share the trait of spike-wave activation during non-rapid eye movement sleep (EE-SWAS), a state dominated by sleep oscillations known to coordinate offline memory consolidation. How epileptic activity impacts these thalamocortical sleep oscillations has not been directly observed in humans. Using a unique dataset of simultaneous human thalamic and cortical recordings in subjects with and without EE-SWAS, we reconcile prior conflicting observations about how epileptic spikes coordinate with sleep oscillations and provide direct evidence for epileptic spike interference of sleep spindle production. We find that slow oscillations facilitate both epileptic spikes and sleep spindles during stage 2 sleep (N2) at different phases of the slow oscillation. We show that sleep activated cortical epileptic spikes propagate to the thalamus (thalamic spike rate is increased after a cortical spike, p[~]0). Thalamic spikes increase the spindle refractory period (p<1.5e-21). In patients with EE-SWAS, the abundance of thalamic spikes result in downregulation of spindles for 30 seconds after each thalamic spike (p=3.4e-11) and decreased overall spindle rate across N2 (p=2e-7). These direct human thalamocortical observations identify a novel mechanism through which epileptiform spikes could impact cognitive function, wherein sleep-activated epileptic spikes inhibit thalamic sleep spindles in epileptic encephalopathy.

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bioRxiv2022

Normative sleep spindle database and findings from 772 healthy children from birth through 18 years

Work in the last two decades has identified sleep spindles, discrete "sigma band" oscillations during stage 2 sleep, as a key oscillatory mechanism required for off-line memory consolidation. Although, sleep spindles are known to evolve concomitant with brain maturation and reflect cognitive function across the lifespan, the details of this developmental trajectory are unknown. To address this, we curated a database of sleep electroencephalograms from 772 developmentally normal children to characterize spindles from birth through 18 years. After validating an automated spindle detector against ~20,000 hand-marked spindles across ages, we demonstrate that sleep spindle features follow distinct age-specific patterns in distribution, rate, duration, frequency, estimated refractory period, and inter-hemispheric spindle lag. These data expand our current knowledge of normal physiological brain development and provide a large normative database to detect deviations in sleep spindles to aid discovery, biomarker development, and diagnosis in pediatric neurodevelopmental disorders.

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bioRxiv2021

Non-rapid eye movement sleep and wake neurophysiology in schizophrenia

Motivated by the potential of objective neurophysiological markers to index thalamocortical function in patients with severe psychiatric illnesses, we comprehensively characterized key NREM sleep parameters across multiple domains, their interdependencies, and their relationship to waking event-related potentials and symptom severity. In 130 schizophrenia (SCZ) patients and controls, we confirmed a marked reduction in sleep spindle density in SCZ and extended these findings to show that only slow spindles predicted symptom severity, and that fast and slow spindle properties were largely uncorrelated. We also describe a novel measure of slow oscillation and spindle interaction that was attenuated in SCZ. The main sleep findings were replicated in a demographically distinct sample, and a joint model, based on multiple NREM components, predicted disease status in the replication cohort. Although also altered in patients, auditory event-related potentials elicited during wake were unrelated to NREM metrics. Consistent with a growing literature implicating thalamocortical dysfunction in SCZ, our characterization identifies independent NREM and wake EEG biomarkers that may index distinct aspects of SCZ pathophysiology and point to multiple neural mechanisms underlying disease heterogeneity. This study lays the groundwork for evaluating these neurophysiological markers, individually or in combination, to guide efforts at treatment and prevention as well as identifying individuals most likely to benefit from specific interventions.

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bioRxiv2018

The hippocampus is necessary for the sleep-dependent consolidation of a task that does not require the hippocampus for initial learning

During sleep, the hippocampus plays an active role in consolidating memories that depend on it for initial encoding. There are hints in the literature that the hippocampus may have a broader influence, contributing to the consolidation of memories that may not initially require the area. We tested this possibility by evaluating learning and consolidation of the motor sequence task (MST) in hippocampal amnesics and demographically matched control participants. While the groups showed similar initial learning, only controls exhibited evidence of sleep-dependent consolidation. These results demonstrate that the hippocampus can be required for normal consolidation of a task without being required for its acquisition, suggesting that the area plays a broader role in coordinating sleep-dependent memory consolidation than has previously been assumed.

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bioRxiv2018

Large-Scale Structure and Individual Fingerprints of Locally Coupled Sleep Oscillations

The temporal coordination of slow oscillations and sleep spindles is believed to underlie processes of sleep-dependent memory consolidation and reorganization. Accumulating evidence of the predominantly local expression of these individual oscillatory rhythms suggests that their interaction may have a similar local component. However, it is unclear whether local coupling holds uniformly across the cortex, and whether and how these dynamics differ between fast and slow spindles, and sleep stages. Moreover, substantial individual variability in the expression of both spindles and slow oscillations raise the possibility that their cross-frequency interactions show similar individual differences. Using two nights of multi-channel electroencephalography recordings from 24 healthy individuals, we characterized the topography of slow oscillation-spindle coupling. We found that locally coupled oscillations occur over widespread cortical areas, but that their dynamics vary with spindle class, sleep stage, and location. Moreover, the phase of the slow oscillation cycle at which spindles were expressed differed markedly across individuals but was stable across nights. However, individual variability of coupling phase was not correlated with overnight memory change. These findings both add an important spatial aspect to our understanding of the temporal coupling of sleep oscillations and demonstrate the heterogeneity of coupling dynamics, which must be taken into account when formulating mechanistic accounts of sleep-related memory processing.

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bioRxiv2017

Individual differences in frequency and topography of slow and fast sleep spindles

Sleep spindles are transient oscillatory waveforms occurring during non-rapid eye movement (NREM) sleep and are implicated in plasticity and memory processes. In humans, spindles can be classified as either slow or fast, but large individual differences in spindle frequency as well as methodological difficulties have hindered progress towards understanding their function. Using two nights of high-density electroencephalography recordings from healthy individuals, we first characterize the individual variability of NREM spectra and demonstrate the difficulty of determining subject-specific spindle frequencies. We then introduce a novel spatial filtering approach that can reliably separate subject-specific spindle activity into slow and fast components that are stable across nights and across N2 and N3 sleep. We then proceed to provide detailed analyses of the topographical expression of individualized slow and fast spindle activity. Group-level analyses conform to known spatial properties of spindles, but also uncover novel differences between sleep stages and spindle classes. Moreover, subject-specific examinations reveal that individual topographies show considerable variability that is stable across nights. Finally, we demonstrate that topographical maps depend nontrivially on the spindle metric employed. In sum, our findings indicate that group-level approaches mask substantial individual variability of spindle dynamics, in both the spectral and spatial domains. We suggest that leveraging, rather than ignoring, such differences may prove useful to further our understanding of the physiology and functional role of sleep spindles.

neuroscience↗