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While animal models of Alzheimer's disease (AD) have shown altered gamma oscillations (∼40 Hz) in local neural circuits, the low signal-to-noise ratio of gamma in the resting human brain precludes its quantification via conventional spectral estimates. Phase-amplitude coupling (PAC) indicating the dynamic integration between the gamma amplitude and the phase of low-frequency (4-12 Hz) oscillations is a useful alternative to capture local gamma activity. In addition, PAC is also an index of neuronal excitability as the phase of low-frequency oscillations that modulate gamma amplitude, effectively regulates the excitability of local neuronal firing. In this study, we sought to examine the local neuronal activity and excitability using gamma PAC, within brain regions vulnerable to early AD pathophysiology-entorhinal cortex and parahippocampus, in a clinical population of patients with AD and age-matched controls. Our clinical cohorts consisted of a well-characterized cohort of AD patients ( n = 50; age, 60 ± 8 years) with positive AD biomarkers, and age-matched, cognitively unimpaired controls ( n = 35; age, 63 ± 5.8 years). We identified the presence or the absence of epileptiform activity in AD patients (AD patients with epileptiform activity, AD-EPI+, n = 20; AD patients without epileptiform activity, AD-EPI-, n = 30) using long-term electroencephalography (LTM-EEG) and 1-hour long magnetoencephalography (MEG) with simultaneous EEG. Using the source reconstructed MEG data, we computed gamma PAC as the coupling between amplitude of the gamma frequency (30-40 Hz) with phase of the theta (4-8 Hz) and alpha (8-12 Hz) frequency oscillations, within entorhinal and parahippocampal cortices. We found that patients with AD have reduced gamma PAC in the left parahippocampal cortex, compared to age-matched controls. Furthermore, AD-EPI+ patients showed greater reductions in gamma PAC than AD-EPI- in bilateral parahippocampal cortices. In contrast, entorhinal cortices did not show gamma PAC abnormalities in patients with AD. Our findings demonstrate the spatial patterns of altered gamma oscillations indicating possible region-specific manifestations of network hyperexcitability within medial temporal lobe regions vulnerable to AD pathophysiology. Greater deficits in AD-EPI+ suggests that reduced gamma PAC is a sensitive index of network hyperexcitability in AD patients. Collectively, the current results emphasize the importance of investigating the role of neural circuit hyperexcitability in early AD pathophysiology and explore its potential as a modifiable contributor to AD pathobiology., Competing Interests: The authors of this manuscript do not have any conflicts of interest relevant to the content of this work., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β and misfolded tau proteins causing synaptic dysfunction, and progressive neurodegeneration and cognitive decline. Altered neural oscillations have been consistently demonstrated in AD. However, the trajectories of abnormal neural oscillations in AD progression and their relationship to neurodegeneration and cognitive decline are unknown. Here, we deployed robust event-based sequencing models (EBMs) to investigate the trajectories of long-range and local neural synchrony across AD stages, estimated from resting-state magnetoencephalography. The increases in neural synchrony in the delta-theta band and the decreases in the alpha and beta bands showed progressive changes throughout the stages of the EBM. Decreases in alpha and beta band synchrony preceded both neurodegeneration and cognitive decline, indicating that frequency-specific neuronal synchrony abnormalities are early manifestations of AD pathophysiology. The long-range synchrony effects were greater than the local synchrony, indicating a greater sensitivity of connectivity metrics involving multiple regions of the brain. These results demonstrate the evolution of functional neuronal deficits along the sequence of AD progression., Competing Interests: KK KK is a full-time employee of Ricoh Company, Ltd, KR, FS, KR, BM, JK, GR, KV, HK No competing interests declared, HM HM is a full-time employee of Ricoh Company, Ltd, KS KS is an employee of Signal Analysis Inc, SN SSN is a scientific consultant to MEGIN Inc. and a Medical Strategy Adviser to Hippoclinic Inc. He served on the scientific advisory board for Rune Labs Inc. from 2019-2022. He was the recipient of an industry contract from Ricoh MEG USA Inc, (© 2023, Kudo, Ranasinghe et al.)

Background Cognition is a vital sign and its deterioration is a major concern in clinical medicine. It is usually evaluated using neuropsychological assessments, which have innate limitations such as the practice effect. To compensate for these assessments, the oscillatory power of resting-state brain activity has recently become available. The power is obtained noninvasively using magnetoencephalography and is summarized by spectral parameters such as the median frequency (MF), individual alpha frequency (IAF), spectral edge frequency 95 (SEF95), and Shannon's spectral entropy (SSE). As these parameters are less sensitive to practice effects, they are suitable for longitudinal studies. However, their reliability remains unestablished, hindering their proactive use in clinical practice. Therefore, we aimed to quantify the within-participant reliability of these parameters using repeated measurements of healthy participants to facilitate their clinical use and to evaluate the observed changes/differences in these parameters reported in previous studies. Methodology Resting-state brain activity with eyes closed was recorded using magnetoencephalography for five minutes from 15 healthy individuals (29.3 ± 4.6 years old: ranging from 23 to 28 years old). The following four spectral parameters were calculated: MF, IAF, SEF95, and SSE. To quantify reliability, the minimal detectable change (MDC) and intraclass correlation coefficient (ICC) were computed for each parameter. In addition, we used MDCs to evaluate the changes and differences in the spectral parameters reported in previous longitudinal and cross-sectional studies. Results The MDC at 95% confidence interval (MDC95) of MF, IAF, SEF95, and SSE were 0.61 Hz, 0.44 Hz, 2.91 Hz, and 0.028, respectively. The ICCs of these parameters were 0.96, 0.92, 0.94, and 0.83, respectively. The MDC95 of these parameters was smaller than the mean difference in the parameters between cognitively healthy individuals and patients with dementia, as reported in previous studies. Conclusions The spectral parameter changes/differences observed in prior studies were not attributed to measurement errors but rather reflected genuine effects. Furthermore, all spectral parameters exhibited high ICCs (>0.8), underscoring their robust within-participant reliability. Our results support the clinical use of these parameters, especially in the longitudinal monitoring and evaluation of the outcomes of interventions., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2024, Okumura et al.)

Visuospatial perception is often impaired in people with Alzheimer's disease (AD). Because visuospatial information is thought to be processed in the visual dorsal stream, it is believed that brain activities in the dorsal stream will be altered in AD patients. In this study, we investigated whether regional brain activity related to visuospatial perception were associated with AD progression markers. An optic-flow task, which activates the dorsal stream associated with visuospatial perception, was performed, and the brain activities evoked by the task were evaluated using magnetoencephalography (MEG). First, we evaluated the responses to optic-flow stimuli in 21 cognitively unimpaired participants and determined the regions of interest (ROIs) where optic-flow activities were activated. Task-related activations were observed in 14 cortical regions including the dorsal stream: the right and left medial ventral occipital cortex (MVOcC), lateral occipital cortex (LOcC), precuneus (Pcun), inferior parietal lobule (IPL), superior parietal lobule (SPL), posterior superior temporal sulcus (pSTS), and fusiform gyri (FuG). Next, we performed correlation analyses between task-related activity in each ROI and two AD progression markers, global amyloid burden and parahippocampal gyrus (PHG) volume, for 25 participants who underwent amyloid positron emission tomography (PET) scans. We found that the global amyloid burden was negatively correlated with task-related activity in the left MVOcC and right SPL [r = -0.488 (p = 0.013) and r = -0.421 (p = 0.038), respectively]. Furthermore, significant positive correlations were observed between PHG volume and task-related activity in both the left and right SPL [r = 0.500 (p = 0.011) and r = 0.549 (p = 0.005), respectively]. Since the SPL is known to be responsible for visuospatial perception, these results suggest that MEG neuronal activity of patients performing the optic-flow activity can detect changes in brain activity associated with visuospatial impairment related to AD., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ST, KK, HM, YM and TA are employees of Ricoh Company, Ltd. The authors declare that no other competing interests exist. The other authors have no competing financial conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Sleep is a highly stereotyped phenomenon, requiring robust spatiotemporal coordination of neural activity. Understanding how the brain coordinates neural activity with sleep onset can provide insights into the physiological functions subserved by sleep and the pathologic phenomena associated with sleep onset. We quantified whole-brain network changes in synchrony and information flow during the transition from wakefulness to light non-rapid eye movement (NREM) sleep, using MEG imaging in a convenient sample of 14 healthy human participants (11 female; mean 63.4 years [SD 11.8 years]). We furthermore performed computational modeling to infer excitatory and inhibitory properties of local neural activity. The transition from wakefulness to light NREM was identified to be encoded in spatially and temporally specific patterns of long-range synchrony. Within the delta band, there was a global increase in connectivity from wakefulness to light NREM, which was highest in frontoparietal regions. Within the theta band, there was an increase in connectivity in fronto-parieto-occipital regions and a decrease in temporal regions from wakefulness to Stage 1 sleep. Patterns of information flow revealed that mesial frontal regions receive hierarchically organized inputs from broad cortical regions upon sleep onset, including direct inflow from occipital regions and indirect inflow via parieto-temporal regions within the delta frequency band. Finally, biophysical neural mass modeling demonstrated changes in the anterior-to-posterior distribution of cortical excitation-to-inhibition with increased excitation-to-inhibition model parameters in anterior regions in light NREM compared with wakefulness. Together, these findings uncover whole-brain corticocortical structure and the orchestration of local and long-range, frequency-specific cortical interactions in the sleep-wake transition. SIGNIFICANCE STATEMENT Our work uncovers spatiotemporal cortical structure of neural synchrony and information flow upon the transition from wakefulness to light non-rapid eye movement sleep. Mesial frontal regions were identified to receive hierarchically organized inputs from broad cortical regions, including both direct inputs from occipital regions and indirect inputs via the parieto-temporal regions within the delta frequency range. Biophysical neural mass modeling revealed a spatially heterogeneous, anterior-posterior distribution of cortical excitation-to-inhibition. Our findings shed light on the orchestration of local and long-range cortical neural structure that is fundamental to sleep onset, and support an emerging view of cortically driven regulation of sleep homeostasis., (Copyright © 2023 the authors.)

Background/Introduction: Widespread network disruption has been hypothesized to be an important predictor of outcomes in patients with refractory temporal lobe epilepsy (TLE). Most studies examining functional network disruption in epilepsy have largely focused on the symmetric bidirectional metrics of the strength of network connections. However, a more complete description of network dysfunction impacts in epilepsy requires an investigation of the potentially more sensitive directional metrics of information flow. Methods: This study describes a whole-brain magnetoencephalography-imaging approach to examine resting-state directional information flow networks, quantified by phase-transfer entropy (PTE), in patients with TLE compared with healthy controls (HCs). Associations between PTE and clinical characteristics of epilepsy syndrome are also investigated. Results: Deficits of information flow were specific to alpha-band frequencies. In alpha band, while HCs exhibit a clear posterior-to-anterior directionality of information flow, in patients with TLE, this pattern of regional information outflow and inflow was significantly altered in the frontal and occipital regions. The changes in information flow within the alpha band in selected brain regions were correlated with interictal spike frequency and duration of epilepsy. Conclusions: Impaired information flow is an important dimension of network dysfunction associated with the pathophysiological mechanisms of TLE.

Responsive neurostimulation is a promising treatment for drug-resistant focal epilepsy; however, clinical outcomes are highly variable across individuals. The therapeutic mechanism of responsive neurostimulation likely involves modulatory effects on brain networks; however, with no known biomarkers that predict clinical response, patient selection remains empiric. This study aimed to determine whether functional brain connectivity measured non-invasively prior to device implantation predicts clinical response to responsive neurostimulation therapy. Resting-state magnetoencephalography was obtained in 31 participants with subsequent responsive neurostimulation device implantation between 15 August 2014 and 1 October 2020. Functional connectivity was computed across multiple spatial scales (global, hemispheric, and lobar) using pre-implantation magnetoencephalography and normalized to maps of healthy controls. Normalized functional connectivity was investigated as a predictor of clinical response, defined as percent change in self-reported seizure frequency in the most recent year of clinic visits relative to pre-responsive neurostimulation baseline. Area under the receiver operating characteristic curve quantified the performance of functional connectivity in predicting responders (≥50% reduction in seizure frequency) and non-responders (<50%). Leave-one-out cross-validation was furthermore performed to characterize model performance. The relationship between seizure frequency reduction and frequency-specific functional connectivity was further assessed as a continuous measure. Across participants, stimulation was enabled for a median duration of 52.2 (interquartile range, 27.0-62.3) months. Demographics, seizure characteristics, and responsive neurostimulation lead configurations were matched across 22 responders and 9 non-responders. Global functional connectivity in the alpha and beta bands were lower in non-responders as compared with responders (alpha, p fdr  < 0.001; beta, p fdr  < 0.001). The classification of responsive neurostimulation outcome was improved by combining feature inputs; the best model incorporated four features (i.e. mean and dispersion of alpha and beta bands) and yielded an area under the receiver operating characteristic curve of 0.970 (0.919-1.00). The leave-one-out cross-validation analysis of this four-feature model yielded a sensitivity of 86.3%, specificity of 77.8%, positive predictive value of 90.5%, and negative predictive value of 70%. Global functional connectivity in alpha band correlated with seizure frequency reduction (alpha, P  = 0.010). Global functional connectivity predicted responder status more strongly, as compared with hemispheric predictors. Lobar functional connectivity was not a predictor. These findings suggest that non-invasive functional connectivity may be a candidate personalized biomarker that has the potential to predict responsive neurostimulation effectiveness and to identify patients most likely to benefit from responsive neurostimulation therapy. Follow-up large-cohort, prospective studies are required to validate this biomarker. These findings furthermore support an emerging view that the therapeutic mechanism of responsive neurostimulation involves network-level effects in the brain., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Dorsal stream, which has a neuronal connection with dorsolateral prefrontal cortex (DLPFC), is known to be responsible for detection of motion including optic flow perception. Using magnetoencephalography (MEG), this study aimed to examine neural responses to optic flow stimuli with looming motion in the DLPFC in patients with mild cognitive impairment due to Alzheimer's disease (AD-MCI) compared with cognitively unimpaired participants (CU). We analyzed the neural responses by evaluating maximum source-localized power for the AD-MCI group (n = 11) and CU (n = 20), focusing on six regions of interest (ROIs) that form the DLPFC: right and left dorsal Brodmann area 9/46 (A9/46d), Brodmann area 46 (A46) and ventral Brodmann area 9/46 (A9/46v). We found significant differences in the maximum power between the groups in the left A46 and A9/46v. Moreover, in the left A9/46v, the maximum power significantly correlated with the Wechsler Memory Scale-Revised general memory score and delayed recall score. The maximum power in the left A9/46v also revealed high performance in AD-MCI versus CU classification with the area under the ROC curve of 0.90. This study demonstrated that MEG during the optic flow task can be useful in discriminating AD-MCI from CU., Competing Interests: M N-S, JK and CA have belonged to an endowment department, supported with an unrestricted grant from Ricoh Company, Ltd. since April 2019. This does not alter our adherence to PLOS ONE policies on sharing data and materials. MK, HM, KK and ST are employed by Ricoh Company, Ltd., this does not alter our adherence to PLOS ONE policies on sharing data and materials.

The effects of transcranial direct current stimulation (tDCS) likely depend on cortical N-methyl-D-aspartic acid (NMDA) neurotransmission; however, no previous studies have reported tDCS-mediated modulation of cortical NMDA neurotransmission in humans. The gamma-band auditory steady-state response (ASSR) to a 40 Hz stimulation likely reflects the integrity of cortical NMDA neurotransmission. The present study tested whether the effect of tDCS is reflected in gamma-band ASSRs during a 40 Hz stimulation. Using a double-blind, randomized, crossover study, we performed magnetoencephalography (MEG) and measured the ASSR in 24 healthy participants during 40 Hz of auditory stimulation after prefrontal tDCS (2 mA) or sham (i.e., placebo) treatment. Our results failed to reveal significant differences in any brain between the two conditions after the application of a frequency of approximately 40 Hz. Based on these results, the ASSR is an insufficient method to detect the effect of tDCS on cortical NMDA neurotransmission. Unexpectedly, the results revealed an enhanced beta-band event-related spectral perturbation (ERSP) in the left motor cortex after tDCS compared with that observed after the sham stimuli. Given that beta-band oscillations reflect many functions in motor cortices, the tDCS for the frontal areas had some effect on the left motor cortex while the participants were focusing on not pressing the button with their right index finger. An additional study with an adequate psychological task is necessary to draw a conclusion regarding this unexpected result.

Soil nematodes play crucial roles in the soil food web and are a suitable indicator for assessing soil environments and ecosystems. Previous nematode community analyses based on nematode morphology classification have been shown to be useful for assessing various soil environments. Here we have conducted DNA barcode analysis for soil nematode community analyses in Japanese soils. We isolated nematodes from two different environmental soils of an unmanaged flowerbed and an agricultural field using the improved flotation-sieving method. Small subunit (SSU) rDNA fragments were directly amplified from each of 68 (flowerbed samples) and 48 (field samples) isolated nematodes to determine the nucleotide sequence. Sixteen and thirteen operational taxonomic units (OTUs) were obtained by multiple sequence alignment from the flowerbed and agricultural field nematodes, respectively. All 29 SSU rDNA-derived OTUs (rOTUs) were further mapped onto a phylogenetic tree with 107 known nematode species. Interestingly, the two nematode communities examined were clearly distinct from each other in terms of trophic groups: Animal predators and plant feeders were markedly abundant in the flowerbed soils, in contrast, bacterial feeders were dominantly observed in the agricultural field soils. The data from the flowerbed nematodes suggests a possible food web among two different trophic nematode groups and plants (weeds) in the closed soil environment. Finally, DNA sequences derived from the mitochondrial cytochrome oxidase c subunit 1 (COI) gene were determined as a DNA barcode from 43 agricultural field soil nematodes. These nematodes were assigned to 13 rDNA-derived OTUs, but in the COI gene analysis were assigned to 23 COI gene-derived OTUs (cOTUs), indicating that COI gene-based barcoding may provide higher taxonomic resolution than conventional SSU rDNA-barcoding in soil nematode community analysis.

Human myelogenous leukaemic cells can be induced to differentiate into the monocyte/macrophage pathway by protein inducers called differentiation inducing factors (DIF) in conditioned media of mitogen-stimulated human peripheral blood leukocytes. However, human DIF has not yet been well characterized. DIF is known to be a T-cell lymphokine, as it can be obtained from the T-cell line HUT-102 and can be partially purified from medium conditioned by phytohaemagglutinin (PHA)-stimulated lymphocytes. We found that monocytes also produce factor(s) that induce differentiation of human myelogenous leukaemia cell lines to cells with macrophage-like characteristics. This factor(s) has activity different from that of colony-stimulating factor(s) or interferons. We have now purified a DIF to homogeneity from medium conditioned by PHA-stimulated leukocytes using a human myeloblastic leukemia cell line, ML-1, as target cells. The purified DIF has a relative molecular mass (Mr) of approximately 17,000, with an NH2-terminal sequence the same as that of human tumour necrosis factor (TNF). Recombinant human TNF (rHuTNF) induces differentiation of ML-1 cells and an anti-pDIF monoclonal antibody can neutralize both differentiation inducing activity and cytotoxic activity of DIF and rHuTNF. The findings indicate that one of the DIF(s) produced by leukocytes is probably TNF.

Tubuloreticular inclusions (TRI) were induced in normal blood lymphocytes after incubation with Staphylococcus aureus Cowan 1 (STA), but they were not induced by pokeweed mitogen (PWM), as we reported previously. TRI were also induced in Raji cells when grown in the medium of STA culture. Alpha-interferon (alpha IFN) was detected only in the medium of STA culture and not in PWM culture. The cells of PWM cultures formed TRI when exposed to various concentrations of human leukocyte alpha IFN. The incidences of TRI-positive cells in the presence of 50-500 IU/ml of alpha IFN were 3-5% on day 2 and increased to 10% on day 7. On days 5-7 of the PWM cultures, plasmacytoid cells containing TRI were seen not infrequently. In the presence of a high concentration of alpha IFN (10,000 IU/ml), which was sufficient to inhibit cell growth and differentiation, the growth of the TRI region was not altered and the incidence of TRI-positive cells was 9% on day 2 and increased to 15% on day 7. Our observations suggest that the TRI formation in STA culture is attributable to the alpha IFN produced endogenously by STA-stimulated cells and that some relationship might exist between the incidences of TRI-positive cells in these mitogen-stimulated cultures and the biologic functions of IFN.