Phase-amplitude Coupling Research Articles

Cross-Frequency Coupling as a Biomarker for Early Stroke Recovery

Background The application of neuroimaging-based biomarkers in stroke has enriched our understanding of post-stroke recovery mechanisms, including alterations in functional connectivity based on synchronous oscillatory activity across various cortical regions. Phase-amplitude coupling, a type of cross-frequency coupling, may provide additional mechanistic insight. Objective To determine how the phase of prefrontal cortex delta (1-3 Hz) oscillatory activity mediates the amplitude of motor cortex beta (13-20 Hz) oscillations in individual’s early post-stroke. Methods Participants admitted to an inpatient rehabilitation facility completed resting and task-based EEG recordings and motor assessments around the time of admission and discharge along with structural neuroimaging. Unimpaired controls completed EEG procedures during a single visit. Mixed-effects linear models were performed to assess within- and between-group differences in delta-beta prefrontomotor coupling. Associations between coupling and motor status and injury were also determined. Results Thirty individuals with stroke and 17 unimpaired controls participated. Coupling was greater during task versus rest conditions for all participants. Though coupling during affected extremity task performance decreased during hospitalization, coupling remained elevated at discharge compared to controls. Greater baseline coupling was associated with better motor status at admission and discharge and positively related to motor recovery. Coupling demonstrated both positive and negative associations with injury involving measures of lesion volume and overlap injury to anterior thalamic radiation, respectively. Conclusions This work highlights the utility of prefrontomotor cross-frequency coupling as a potential motor status and recovery biomarker in stroke. The frequency- and region-specific neurocircuitry featured in this work may also facilitate novel treatment strategies in stroke.

Cross-frequency modulation of postural fluctuations and scalp EEG in older adults: error amplification feedback for rapid balance adjustments.

Virtual error amplification (VEA) in visual feedback enhances attentive control over postural stability, although the neural mechanisms are still debated. This study investigated the distinct cortical control of unsteady stance in older adults using VEA through cross-frequency modulation of postural fluctuations and scalp EEG. Thirty-seven community-dwelling older adults (68.1 ± 3.6years) maintained an upright stance on a stabilometer while receiving either VEA or real error feedback. Along with postural fluctuation dynamics, phase-amplitude coupling (PAC) and amplitude-amplitude coupling (AAC) were analyzed for postural fluctuations under 2Hz and EEG sub-bands (theta, alpha, and beta). The results revealed a higher mean frequency of the postural fluctuation phase (p = .005) and a greater root mean square of the postural fluctuation amplitude (p = .003) with VEA compared to the control condition. VEA also reduced PAC between the postural fluctuation phase and beta-band EEG in the left frontal (p = .009), sensorimotor (p = .002), and occipital (p = .018) areas. Conversely, VEA increased the AAC of posture fluctuation amplitude and beta-band EEG in FP2 (p = .027). Neither theta nor alpha band PAC or AAC were affected by VEA. VEA optimizes postural strategies in older adults during stabilometer stance by enhancing visuospatial attentive control of postural responses and facilitating the transition of motor states against postural perturbations through a disinhibitory process. Incorporating VEA into virtual reality technology is advocated as a valuable strategy for optimizing therapeutic interventions in postural therapy, particularly to mitigate the risk of falls among older adults.

Differential phase-amplitude coupling in nucleus accumbens and orbitofrontal cortex reflects decision-making during a delay discounting task

BackgroundThe impulsive choice is characterized by the preference for a small immediate reward over a bigger delayed one. The mechanisms underlying impulsive choices are linked to the activity in the Nucleus Accumbens (NAc), the orbitofrontal cortex (OFC), and the dorsolateral striatum (DLS). While the study of functional connectivity between brain areas has been key to understanding a variety of cognitive processes, it remains unclear whether functional connectivity differentiates impulsive-control decisions. MethodsTo study the functional connectivity both between and within NAc, OFC, and DLS during a delay discounting task, we concurrently recorded local field potential in NAc, OFC, and DLS in rats. We then quantified the degree of phase-amplitude coupling (PAC), coherence, and Granger Causality between oscillatory activities in animals exhibiting either a high (HI) or low (LI) tendency for impulsive choices. ResultsOur results showed a differential pattern of PAC during decision-making in OFC and NAc, but not in DLS. While theta-gamma PAC in OFC was associated with self-control decisions, a higher delta-gamma PAC in both OFC and NAc biased decisions toward impulsive choices in both HI and LI groups. Furthermore, during the reward event, Granger Causality analysis indicated a stronger NAc➔OFC gamma contribution in the HI group, while the LI group showed a higher OFC➔NAc gamma contribution. ConclusionsThe overactivity in NAc during reward in the HI group suggests that exacerbated contribution of NAcCore can lead to an overvaluation of reward that biases the behavior toward the impulsive choice.

Estrogen deficiency affects synchronized neural connectivity in the olfactory bulb-nucleus accumbens circuit: A local field potential study in ovariectomized mouse model

Estrogen plays a crucial role in regulating various brain functions, including cognitive, emotional, and social behaviors. Menopausal women face a decline in estrogen levels, which has been linked to several physical and mental health issues. However, the impact of estrogen on the olfactory bulb–nucleus accumbens (OB-NAc) circuit, which is essential for regulating emotions and cognitive behaviors, remains poorly understood. To test the hypothesis that estrogen deficiency affects signal processing, we recorded local field potentials (LFPs) using intracranial electrodes implanted in four-week-old ovariectomized (OVX) mice during an open-field test (OFT). The results showed a decrease in locomotor activity and increase in anxiety-like behaviors in OVX mice. Furthermore, we found a decrease in high-gamma power in the OB. We analyzed coherence and inter-region phase-amplitude coupling (ir-PAC) to explore the connectivity between the OB and NAc. We observed a decrease in low-gamma and high-gamma coherence in OVX mice. Additionally, we found that the direction of connectivity from the NAc to the OB was disrupted in OVX mice. In summary, our study provides evidence that estrogen deficiency is linked to synchronized neural connectivity changes in the OB–NAc circuit. These findings have implications for our understanding of the roles played by the OB–NAc neural circuit and estrogen in the regulation of general exploratory behavior and anxiety-like behavior.

The investigation of dysregulated visual perceptual organization in adults with autism spectrum disorders with phase-amplitude coupling and directed connectivity

The investigation of dysregulated visual perceptual organization in adults with autism spectrum disorders with phase-amplitude coupling and directed connectivity

An EEG Study on [Formula: see text] Phase-Amplitude Coupling-Based Functional Brain Network in Epilepsy Patients.

Epilepsy, a chronic neuropsychiatric brain disorder characterized with recurrent seizures, is closely associated with abnormal neural communications within the brain. Despite that the phase-amplitude coupling (PAC) has been suggested to offer a new way to observe neural interactions during epilepsy, however, few studies pay attention to alterations of the epileptic functional brain network based on PAC, especially on the [Formula: see text] PAC. Therefore, we use scalp electroencephalography (EEG) data of epileptic patients and the [Formula: see text] PAC modulation index (MI) to construct functional brain networks to examine variations of neural interactions during different epileptic phases. Statistically, the findings show that between-channel MI values in the post-ictal period significantly increase compared to that in the pre-ictal period, and the between-channel MI value has a close association with the information of phase and amplitude provided by the channels. Importantly, in both the phase-amplitude and amplitude-phase functional brain networks, the average node degree is remarkably higher in the post-ictal period than that in the pre-ictal period, whereas the characteristic path length in the ictal and post-ictal periods is significantly lower than that in the pre-ictal period. Besides, the average betweenness centrality in the post-ictal period is remarkably higher than that in the ictal period. Interestingly, the positive correlations between within-channel MI values and between-channel MI values can be observed during the pre-ictal, ictal and post-ictal periods. These findings suggest that the [Formula: see text] PAC-based functional brain network may provide a novel perspective to understanding alterations of neural interactions during the epileptic evolution, and may contribute to effectively controlling the spread of epileptic seizures.

Practical measurements distinguishing physiological and pathological stereoelectroencephalography channels based on high-frequency oscillations in the human brain.

The present study aimed to identify various distinguishing features for use in the accurate classification of stereoelectroencephalography (SEEG) channels based on high-frequency oscillations (HFOs) inside and outside the epileptogenic zone (EZ). HFOs were detected in patients with focal epilepsy who underwent SEEG. Subsequently, HFOs within the seizure-onset and early spread zones were defined as pathological HFOs, whereas others were defined as physiological. Three features of HFOs were identified at the channel level, namely, morphological repetition, rhythmicity, and phase-amplitude coupling (PAC). A machine-learning (ML) classifier was then built to distinguish two HFO types at the channel level by application of the above-mentioned features, and the contributions were quantified. Further verification of the characteristics and classifier performance was performed in relation to various conscious states, imaging results, EZ location, and surgical outcomes. Thirty-five patients were included in this study, from whom 166 104 pathological HFOs in 255 channels and 53 374 physiological HFOs in 282 channels were entered into the analysis pipeline. The results revealed that the morphological repetitions of pathological HFOs were markedly higher than those of the physiological HFOs; this was also observed for rhythmicity and PAC. The classifier exhibited high accuracy in differentiating between the two forms of HFOs, as indicated by an area under the curve (AUC) of 0.89. Both PAC and rhythmicity contributed significantly to this distinction. The subgroup analyses supported these findings. The suggested HFO features can accurately distinguish between pathological and physiological channels substantially improving its usefulness in clinical localization. In this study, we computed three quantitative features associated with HFOs in each SEEG channel and then constructed a machine learning-based classifier for the classification of pathological and physiological channels. The classifier performed well in distinguishing the two channel types under different levels of consciousness as well as in terms of imaging results, EZ location, and patient surgical outcomes.

Altered cortical synaptic lipid signaling leads to intermediate phenotypes of mental disorders

Excitation/inhibition (E/I) balance plays important roles in mental disorders. Bioactive phospholipids like lysophosphatidic acid (LPA) are synthesized by the enzyme autotaxin (ATX) at cortical synapses and modulate glutamatergic transmission, and eventually alter E/I balance of cortical networks. Here, we analyzed functional consequences of altered E/I balance in 25 human subjects induced by genetic disruption of the synaptic lipid signaling modifier PRG-1, which were compared to 25 age and sex matched control subjects. Furthermore, we tested therapeutic options targeting ATX in a related mouse line. Using EEG combined with TMS in an instructed fear paradigm, neuropsychological analysis and an fMRI based episodic memory task, we found intermediate phenotypes of mental disorders in human carriers of a loss-of-function single nucleotide polymorphism of PRG-1 (PRG-1R345T/WT). Prg-1R346T/WT animals phenocopied human carriers showing increased anxiety, a depressive phenotype and lower stress resilience. Network analysis revealed that coherence and phase-amplitude coupling were altered by PRG-1 deficiency in memory related circuits in humans and mice alike. Brain oscillation phenotypes were restored by inhibtion of ATX in Prg-1 deficient mice indicating an interventional potential for mental disorders.

Fenobam modulates distinct electrophysiological mechanisms for regulating excessive gamma oscillations in the striatum of dyskinetic rats

Gamma oscillations have been frequently observed in levodopa-induced dyskinesia (LID), manifest as broadband (60-120 Hz) and narrowband (80-110 Hz) gamma activity in cortico-striatal projection. We investigated the electrophysiological mechanisms and correlation of gamma oscillations with dyskinesia severity, while assessing the administration of fenobam, a selective metabotropic glutamate receptor 5 (mGluR5) antagonist, in regulating dyskinesia-associated gamma activity. We conducted simultaneous electrophysiological recordings in Striatum (Str) and primary motor cortex (M1), together with Abnormal Involuntary Movement Scale scoring (AIMs). Phase-amplitude coupling (PAC), power, coherence, and Granger causality analyses were conducted for electrophysiological data. The findings demonstrated increased beta oscillations with directionality from M1 to Str in parkinsonian state. During on-state dyskinesia, elevated broadband gamma activity was modulated by the phase of theta activity in Str, while M1 → Str gamma causality mediated narrowband gamma oscillations in Str. Striatal gamma power (both periodic and aperiodic power), periodic power, peak frequency, and PAC at 80 min (corresponding to the peak dyskinesia) after repeated levodopa injections across recording days (day 30, 33, 36, 39, and 42) increased progressively, correlating with total AIMs. Additionally, a time-dependent parabolic trend of PAC, peak frequency and gamma power was observed after levodopa injection on day 42 from 20 to 120 min, which also correlated with corresponding AIMs. Fenobam effectively alleviates dyskinesia, suppresses enhanced gamma oscillations in the M1-Str directionality, and reduces PAC in Str. The temporal characteristics of gamma oscillations provide parameters for classifying LID severity. Antagonizing striatal mGluR5, a promising therapeutic target for dyskinesia, exerts its effects by modulating gamma activity.

Correlation Analysis of Multi-Scale Ictal EEG Signals in Juvenile Myoclonic Epilepsy.

To explore the time-frequency structure and cross-scale coupling of electroencephalography (EEG) signals during seizure in juvenile myoclonic epilepsy (JME), correlations between different leads, as well as dynamic evolution in epileptic discharge, progression and end of seizure were examined. EEG data were obtained for 10 subjects with JME and 10 normal controls and were decomposed using gauss continuous wavelet transform (CWT). The phase amplitude coupling (PAC) relationship between the 11th (4.57 Hz) and 17th (0.4 Hz) scale was investigated. Correlations were examined between the 11th and 17th scale EEG signals in different leads during seizure, using multi-scale cross correlation analysis. The time-frequency structure of JME subjects showed strong rhythmic activity in the 11th and 17th scales and a close PAC was identified. Correlation analysis revealed that the ictal JME correlation first increased in the anterior head early in seizure and gradually expanded to the posterior head. PAC was exhibited between the 11th and 17th scales during JME seizure. The results revealed that the correlation in the anterior leads was higher than the posterior leads. In the perictal period, the 17th scale EEG signal preceded the 11th scale signal and remained for some time after a seizure. This suggests that the 17th scale signal may play an important role in JME seizure.

Asymmetries of the subthalamic activity in Parkinson's disease: phase-amplitude coupling among local field potentials.

The role of brain asymmetries of dopaminergic neurons in motor symptoms of Parkinson's disease is still undefined. Local field recordings from the subthalamic nucleus revealed some neurophysiological biomarkers of the disease: increased beta activity, increased low-frequency activity and high-frequency oscillations. Phase-amplitude coupling coordinates the timing of neuronal activity and allows determining the mechanism for communication within distinct regions of the brain. In this study, we discuss the use of phase-amplitude coupling to assess the differences between the two hemispheres in a cohort of 24 patients with Parkinson's disease before and after levodopa administration. Subthalamic low- (12-20 Hz) and high-beta (20-30 Hz) oscillations were compared with low- (30-45 Hz), medium- (70-100 Hz) and high-frequency (260-360 Hz) bands. We found a significant beta-phase-amplitude coupling asymmetry between left and right and an opposite-side-dependent effect of the pharmacological treatment, which is associated with the reduction of motor symptoms. In particular, high coupling between high frequencies and high-beta oscillations was found during the OFF condition (P < 0.01) and a low coupling during the ON state (P < 0.0001) when the right subthalamus was assessed; exactly the opposite happened when the left subthalamus was considered in the analysis, showing a lower coupling between high frequencies and high-beta oscillations during the OFF condition (P < 0.01), followed by a higher one during the ON state (P < 0.01). Interestingly, these asymmetries are independent of the motor onset side, either left or right. These findings have important implications for neural signals that may be used to trigger adaptive deep brain stimulation in Parkinson's and could provide more exhaustive insights into subthalamic dynamics.

Age-dependent coupling characteristics of bilateral frontal EEG during desflurane anesthesia.

Objectives.The purpose of this study is to investigate the age dependence of bilateral frontal electroencephalogram (EEG) coupling characteristics, and find potential age-independent depth of anesthesia monitoring indicators for the elderlies.Approach.We recorded bilateral forehead EEG data from 41 patients (ranged in 19-82 years old), and separated into three age groups: 18-40 years (n= 12); 40-65 years (n= 14), >65 years (n= 15). All these patients underwent desflurane maintained general anesthesia (GA). We analyzed the age-related EEG spectra, phase amplitude coupling (PAC), coherence and phase lag index (PLI) of EEG data in the states of awake, GA, and recovery.Main results.The frontal alpha power shows age dependence in the state of GA maintained by desflurane. Modulation index in slow oscillation-alpha and delta-alpha bands showed age dependence and state dependence in varying degrees, the PAC pattern also became less pronounced with increasing age. In the awake state, the coherence in delta, theta and alpha frequency bands were all significantly higher in the >65 years age group than in the 18-40 years age group (p< 0.05 for three frequency bands). The coherence in alpha-band was significantly enhanced in all age groups in GA (p< 0.01) and then decreased in recovery state. Notably, the PLI in the alpha band was able to significantly distinguish the three states of awake, GA and recovery (p< 0.01) and the results of PLI in delta and theta frequency bands had similar changes to those of coherence.Significance.We found the EEG coupling and synchronization between bilateral forehead are age-dependent. The PAC, coherence and PLI portray this age-dependence. The PLI and coherence based on bilateral frontal EEG functional connectivity measures and PAC based on frontal single-channel are closely associated with anesthesia-induced unconsciousness.

Single session cross-frequency bifocal tACS modulates visual motion network activity in young healthy population and stroke patients

BackgroundPhase synchronization over long distances underlies inter-areal communication and importantly, modulates the flow of information processing to adjust to cognitive demands. ObjectiveThis study investigates the impact of single-session, cross-frequency (Alpha-Gamma) bifocal transcranial alternating current stimulation (cf-tACS) to the cortical visual motion network on inter-areal coupling between the primary visual cortex (V1) and the medio-temporal area (MT) and on motion direction discrimination. MethodsBased on the well-established phase-amplitude coupling (PAC) mechanism driving information processing in the visual system, we designed a novel directionally tuned cf-tACS protocol. Directionality of information flow was inferred from the area receiving low-frequency tACS (e.g., V1) projecting onto the area receiving high-frequency tACS (e.g., MT), in this case, promoting bottom-up information flow (Forward-tACS). The control condition promoted the opposite top-down connection (from MT to V1, called Backward-tACS), both compared to a Sham-tACS condition. Task performance and EEG activity were recorded from 45 young healthy subjects. An additional cohort of 16 stroke patients with occipital lesions and impairing visual processing was measured to assess the influence of a V1 lesion on the modulation of V1-MT coupling. ResultsThe results indicate that Forward cf-tACS successfully modulated bottom-up PAC (V1 α-phase-MT ɣ-amplitude) in both cohorts, while producing opposite effects on the reverse MT-to-V1 connection. Backward-tACS did not change V1-MT PAC in either direction in healthy participants but induced a slight decrease in bottom-up PAC in stroke patients. However, these changes in inter-areal coupling did not translate into cf-tACS-specific behavioural improvements. ConclusionsSingle session cf-tACS can alter inter-areal coupling in intact and lesioned brains but is probably not enough to induce longer-lasting behavioural effects in these cohorts. This might suggest that a longer daily visual training protocol paired with tACS is needed to unveil the relationship between externally applied oscillatory activity and behaviourally relevant brain processing.

126. Challenges Identifying Peak Frequencies of Cross-Frequency Phase-Amplitude Coupling: Implications for Frequency Personalization of tACS in Clinical Trials

126. Challenges Identifying Peak Frequencies of Cross-Frequency Phase-Amplitude Coupling: Implications for Frequency Personalization of tACS in Clinical Trials

Human local field potentials in motor and non-motor brain areas encode upcoming movement direction

Limb movement direction can be inferred from local field potentials in motor cortex during movement execution. Yet, it remains unclear to what extent intended hand movements can be predicted from brain activity recorded during movement planning. Here, we set out to probe the directional-tuning of oscillatory features during motor planning and execution, using a machine learning framework on multi-site local field potentials (LFPs) in humans. We recorded intracranial EEG data from implanted epilepsy patients as they performed a four-direction delayed center-out motor task. Fronto-parietal LFP low-frequency power predicted hand-movement direction during planning while execution was largely mediated by higher frequency power and low-frequency phase in motor areas. By contrast, Phase-Amplitude Coupling showed uniform modulations across directions. Finally, multivariate classification led to an increase in overall decoding accuracy (>80%). The novel insights revealed here extend our understanding of the role of neural oscillations in encoding motor plans.

Control of working memory by phase–amplitude coupling of human hippocampal neurons

Retaining information in working memory is a demanding process that relies on cognitive control to protect memoranda-specific persistent activity from interference1,2. However, how cognitive control regulates working memory storage is unclear. Here we show that interactions of frontal control and hippocampal persistent activity are coordinated by theta–gamma phase–amplitude coupling (TG-PAC). We recorded single neurons in the human medial temporal and frontal lobe while patients maintained multiple items in their working memory. In the hippocampus, TG-PAC was indicative of working memory load and quality. We identified cells that selectively spiked during nonlinear interactions of theta phase and gamma amplitude. The spike timing of these PAC neurons was coordinated with frontal theta activity when cognitive control demand was high. By introducing noise correlations with persistently active neurons in the hippocampus, PAC neurons shaped the geometry of the population code. This led to higher-fidelity representations of working memory content that were associated with improved behaviour. Our results support a multicomponent architecture of working memory1,2, with frontal control managing maintenance of working memory content in storage-related areas3–5. Within this framework, hippocampal TG-PAC integrates cognitive control and working memory storage across brain areas, thereby suggesting a potential mechanism for top-down control over sensory-driven processes.

Meditation-type specific reduction in infra-slow activity of electroencephalogram.

Meditation is renowned for its positive effects on cognitive abilities and stress reduction. It has been reported that the amplitude of electroencephalographic (EEG) infra-slow activity (ISA, < 0.1Hz) is reduced as the stress level decreases. Consequently, we aimed to determine if EEG ISA amplitude decreases as a result of meditation practice across various traditions. To this end, we analyzed an open dataset comprising EEG data acquired during meditation sessions from experienced practitioners in the Vipassana tradition-which integrates elements of focused attention and open monitoring, akin to mindfulness meditation-and in the Himalayan Yoga and Isha Shoonya traditions, which emphasize focused attention and open monitoring, respectively. A general trend was observed where EEG ISA amplitude tended to decrease in experienced meditators from these traditions compared to novices, particularly significant in the 0.03-0.08Hz band for Vipassana meditators. Therefore, our analysis focused on this ISA frequency band. Specifically, a notable decrease in EEG ISA amplitude was observed in Vipassana meditators, predominantly in the left-frontal region. This reduction in EEG ISA amplitude was also accompanied by a decrease in phase-amplitude coupling (PAC) between the ISA phase and alpha band (8-12Hz) amplitude, which implied decreased neural excitability fluctuations. Our findings suggest that not only does EEG ISA amplitude decrease in experienced meditators from traditions that incorporate both focused attention and open monitoring, but this decrease may also signify a diminished influence of neural excitability fluctuations attributed to ISA.

Phase-amplitude coupling detection and analysis of human 2-dimensional neural cultures in multi-well microelectrode array in vitro

BackgroundHuman induced pluripotent stem cell (hiPSC)- derived neurons offer the possibility of studying human-specific neuronal behaviors in physiologic and pathologic states in vitro. It is unclear whether cultured neurons can achieve the fundamental network behaviors required to process information in the brain. Investigating neuronal oscillations and their interactions, as occurs in cross-frequency coupling (CFC), addresses this question. New methodsWe examined whether networks of two-dimensional (2D) cultured hiPSC-derived cortical neurons grown with hiPSC-derived astrocytes on microelectrode array plates recapitulate the CFC that is present in vivo. We employed the modulation index method for detecting phase-amplitude coupling (PAC) and used offline spike sorting to analyze the contribution of single neuron spiking to network behavior. ResultsWe found that PAC is present, the degree of PAC is specific to network structure, and it is modulated by external stimulation with bicuculline administration. Modulation of PAC is not driven by single neurons, but by network-level interactions. Comparison with existing methodsPAC has been demonstrated in multiple regions of the human cortex as well as in organoids. This is the first report of analysis demonstrating the presence of coupling in 2D cultures. ConclusionCFC in the form of PAC analysis explores communication and integration between groups of neurons and dynamical changes across networks. In vitro PAC analysis has the potential to elucidate the underlying mechanisms as well as capture the effects of chemical, electrical, or ultrasound stimulation; providing insight into modulation of neural networks to treat nervous system disorders in vivo.

Brain oscillatory processes related to sequence memory in healthy older adults

Sequence memory is subject to age-related decline, but the underlying processes are not yet fully understood. We analyzed electroencephalography (EEG) in 21 healthy older (60–80 years) and 26 young participants (20–30 years) and compared time-frequency spectra and theta-gamma phase-amplitude-coupling (PAC) during encoding of the order of visually presented items. In older adults, desynchronization in theta (4–8 Hz) and synchronization in gamma (30–45 Hz) power did not distinguish between subsequently correctly and incorrectly remembered trials, while there was a subsequent memory effect for young adults. Theta-gamma PAC was modulated by item position within a sequence for older but not young adults. Specifically, position within a sequence was coded by higher gamma amplitude for successive theta phases for later correctly remembered trials. Thus, deficient differentiation in theta desynchronization and gamma oscillations during sequence encoding in older adults may reflect neurophysiological correlates of age-related memory decline. Furthermore, our results indicate that sequences are coded by theta-gamma PAC in older adults, but that this mechanism might lose precision in aging.

Modulation index predicts the effect of ethosuximide on developmental and epileptic encephalopathy with spike-and-wave activation in sleep

PurposeIn developmental and epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS), the thalamocortical network is suggested to play an important role in the pathophysiology of the progression from focal epilepsy to DEE-SWAS. Ethosuximide (ESM) exerts effects by blocking T-type calcium channels in thalamic neurons. With the thalamocortical network in mind, we studied the prediction of ESM effectiveness in DEE-SWAS treatment using phase-amplitude coupling (PAC) analysis. MethodsWe retrospectively enrolled children with DEE-SWAS who had an electroencephalogram (EEG) recorded between January 2009 and September 2022 and were prescribed ESM at Okayama University Hospital. Only patients whose EEG showed continuous spike-and-wave during sleep were included. We extracted 5-min non-rapid eye movement sleep stage N2 segments from EEG recorded before starting ESM. We calculated the modulation index (MI) as the measure of PAC in pair combination comprising one of two fast oscillation types (gamma, 40–80 Hz; ripples, 80–150 Hz) and one of five slow-wave bands (delta, 0.5–1, 1–2, 2–3, and 3–4 Hz; theta, 4–8 Hz), and compared it between ESM responders and non-responders. ResultsWe identified 20 children with a diagnosis of DEE-SWAS who took ESM. Fifteen were ESM responders. Regarding gamma oscillations, significant differences were seen only in MI with 0.5–1 Hz slow waves in the frontal pole and occipital regions. Regarding ripples, ESM responders had significantly higher MI in coupling with all slow waves in the frontal pole region, 0.5–1, 3–4, and 4–8 Hz slow waves in the frontal region, 3–4 Hz slow waves in the parietal region, 0.5–1, 2–3, 3–4, and 4–8 Hz slow waves in the occipital region, and 3–4 Hz slow waves in the anterior-temporal region. SignificanceHigh MI in a wider area of the brain may represent the epileptic network mediated by the thalamus in DEE-SWAS and may be a predictor of ESM effectiveness.