Beta Oscillations Research Articles

Activating words without language: beta and theta oscillations reflect lexical access and control processes during verbal and non-verbal object recognition tasks.

The intention to name an object modulates neural responses during object recognition tasks. However, the nature of this modulation is still unclear. We established whether a core operation in language, i.e. lexical access, can be observed even when the task does not require language (size-judgment task), and whether response selection in verbal versus non-verbal semantic tasks relies on similar neuronal processes. We measured and compared neuronal oscillatory activities and behavioral responses to the same set of pictures of meaningful objects, while the type of task participants had to perform (picture-naming versus size-judgment) and the type of stimuli to measure lexical access (cognate versus non-cognate) were manipulated. Despite activation of words was facilitated when the task required explicit word-retrieval (picture-naming task), lexical access occurred even without the intention to name the object (non-verbal size-judgment task). Activation of words and response selection were accompanied by beta (25-35Hz) desynchronization and theta (3-7Hz) synchronization, respectively. These effects were observed in both picture-naming and size-judgment tasks, suggesting that words became activated via similar mechanisms, irrespective of whether the task involves language explicitly. This finding has important implications to understand the link between core linguistic operations and performance in verbal and non-verbal semantic tasks.

Efficient suppression of parkinsonian beta oscillations in a closed-loop model of deep brain stimulation with amplitude modulation.

Parkinson's disease (PD) is a movement disorder characterized by the pathological beta band (15-30 Hz) neural oscillations within the basal ganglia (BG). It is shown that the suppression of abnormal beta oscillations is correlated with the improvement of PD motor symptoms, which is a goal of standard therapies including deep brain stimulation (DBS). To overcome the stimulation-induced side effects and inefficiencies of conventional DBS (cDBS) and to reduce the administered stimulation current, closed-loop adaptive DBS (aDBS) techniques were developed. In this method, the frequency and/or amplitude of stimulation are modulated based on various disease biomarkers. Here, by computational modeling of a cortico-BG-thalamic network in normal and PD conditions, we show that closed-loop aDBS of the subthalamic nucleus (STN) with amplitude modulation leads to a more effective suppression of pathological beta oscillations within the parkinsonian BG. Our results show that beta band neural oscillations are restored to their normal range and the reliability of the response of the thalamic neurons to motor cortex commands is retained due to aDBS with amplitude modulation. Furthermore, notably less stimulation current is administered during aDBS compared with cDBS due to a closed-loop control of stimulation amplitude based on the STN local field potential (LFP) beta activity. Efficient models of closed-loop stimulation may contribute to the clinical development of optimized aDBS techniques designed to reduce potential stimulation-induced side effects of cDBS in PD patients while leading to a better therapeutic outcome.

“Neural dynamics supporting longitudinal plasticity of action naming across languages: MEG evidence from bilingual brain tumor patients”

Previous evidence suggests that distinct ventral and dorsal streams respectively underpin the semantic processing of object and action knowledge. Recently, we found that brain tumor patients with dorsal gliomas in frontoparietal hubs show a selective longitudinal compensation (post-vs. pre-surgery) during the retrieval of lexico-semantic information about actions (but not objects), indexed by power increases in beta rhythms (13–28 Hz). Here, we move one-step further and ask whether a similar organizational principle also stands across the different languages a bilingual speaks. To test this hypothesis, we combined a picture-naming task with MEG recordings and evaluated highly proficient Spanish-Basque bilinguals undergoing surgery for tumor resection in left frontoparietal regions. We assessed patients before and three months after surgery. At the behavioral level, we observed a similar performance across sessions irrespectively of the language at use, suggesting overall successful function preservation. At the oscillatory level, we found longitudinal selective power increases in beta for action naming in Spanish and Basque. Nevertheless, tumor resection triggered a differential reorganization of the L1 and the L2, with the latter one additionally recruiting the right hemisphere. Overall, our results provide evidence for (i) the specific involvement of frontoparietal regions in the semantic retrieval/representation of action knowledge across languages; (ii) a key role of beta oscillations as a signature of language compensation and (iii) the existence of divergent plasticity trajectories in L1 and L2 after surgery. By doing so, they provide new insights into the spectro-temporal dynamics supporting postoperative recovery in the bilingual brain.

Resolving equivocal gain modulation of corticospinal excitability

The ratio between the input and output of neuronal populations, usually referred to as gain modulation, is rhythmically modulated along the oscillatory cycle. Previous research on spinal neurons, however, revealed contradictory findings: both uni- and bimodal patterns of increased responsiveness for synaptic input have been proposed for the oscillatory beta rhythm.In this study, we compared previous approaches of phase estimation directly on simulated data and empirically tested the corresponding predictions in healthy males and females. We applied single-pulse transcranial magnetic stimulation over the primary motor cortex at rest, and assessed the spinal output generated by this input. Specifically, the peak-to-peak amplitude of the motor evoked potential in the contralateral forearm was estimated as a function of the EMG phase at which the stimulus was applied. The findings indicated that human spinal neurons adhere to a unimodal pattern of increased responsiveness, and suggest that the rising phase of the upper beta band maximizes gain modulation. Importantly, a bimodal pattern of increased responsiveness was shown to result in an artifact during data analysis and filtering. This observation of invalid preprocessing could be generalized to other frequency bands (i.e., delta, theta, alpha, and gamma), different task conditions (i.e., voluntary muscle contraction), and EEG-based phase estimations. Appropriate analysis algorithms, such as broad-band filtering, enable us to accurately determine gain modulation of neuronal populations and to avoid erroneous phase estimations. This may facilitate novel phase-specific interventions for targeted neuromodulation.

Effect of music emotion on mu and beta oscillations

That music elicits motor signals has been suggested as the key to understanding how emotion may be experienced from it. While previous studies have demonstrated that music both induces movement and affects ongoing motor activities, little is known about the effect of its emotional content on neural-motor representation and how such an effect may be modified by concurrent movement. To fill this gap, we asked participants to tap their right index finger following flashes of a dot (movement) or just to count the flashes silently (no-movement) while listening to happy versus emotionally neutral music, when EEG was recorded. Results showed that happy music induced greater mu (8–13 Hz) suppression than neutral music in the no-movement but not the movement condition. For beta oscillations (16–24 Hz), happy music induced greater suppression than neutral music irrespective of concurrent movement. These findings suggest a close association between music emotion and motor representation at a neural level, supporting theories stipulating that emotion in music is experienced through motor representation, such as embodied music cognition and the Shared Affective Motion Experience model.

Detection of circadian rhythm disturbance of carbachol-induced beta wave dynamics in rat hippocampal slices using neural networks

Rats exhibit a circadian rhythm of locomotor activity. Recently, the relation between circadian rhythm and memory has been elucidated. Brain waves are related to memory processes and are modulated by circadian rhythm. Beta wave-like oscillations within 13–30 Hz can be induced by using carbachol, a cholinergic agonist, in rat hippocampal slices. In this study, we prepared hippocampal slices from rats maintained under light/dark (LD) or dark/dark (DD) conditions. We previously reported that carbachol-induced beta oscillations (CIBO) appeared at all times of the day, and oscillatory parameters, such as duration and inter-burst intervals, demonstrated significant diurnal changes. We also studied whether the time of day can be predicted using CIBO parameters and whether circadian disturbances can be detected with these parameters. Using CIBO parameters, a higher accuracy rate was obtained for time-of-day prediction than that when using the amount of locomotor activity during the day. The time of day was not correctly predicted when the parameters were applied under the DD condition, using the CIBO-parameter-trained neural network under LD conditions. Using the oscillatory parameters of the brain waves induced in the neuronal circuit will estimate the internal subjective time of the day and detect circadian disturbances such as DD condition. (199 words).

Association between Beta Oscillations from Subthalamic Nucleus and Quantitative Susceptibility Mapping in Deep Gray Matter Structures in Parkinson's Disease.

This study aimed to investigate the association between beta oscillations and brain iron deposition. Beta oscillations were filtered from the microelectrode recordings of local field potentials (LFP) in the subthalamic nucleus (STN), and the ratio of the power spectral density of beta oscillations (PSDXb) to that of the LFP signals was calculated. Iron deposition in the deep gray matter (DGM) structures was indirectly assessed using quantitative susceptibility mapping (QSM). The Unified Parkinson's Disease Rating Scale (UPDRS), part III, was used to assess the severity of symptoms. Spearman correlation coefficients were applied to assess the associations of PSDXb with QSM values in the DGM structures and the severity of symptoms. PSDXb showed a significant positive correlation with the average QSM values in DGM structures, including caudate and substantia nigra (SN) (p = 0.008 and 0.044). Similarly, the PSDXb showed significant negative correlations with the severity of symptoms, including axial symptoms and the gait in the medicine-off state (p = 0.006 for both). The abnormal iron metabolism in the SN and striatum pathways may be one of the underlying mechanisms for the occurrence of abnormal beta oscillations in the STN, and beta oscillations may serve as important pathophysiological biomarkers of PD.

Genuine beta bursts in human working memory: controlling for the influence of lower-frequency rhythms

Human working memory is associated with significant modulations in oscillatory brain activity. However, the functional role of brain rhythms at different frequencies is still debated. Modulations in the beta frequency range (15–40 Hz) are especially difficult to interpret because they could be artifactually produced by (more prominent) oscillations in lower frequencies that show non-sinusoidal properties. In this study, we investigate beta oscillations during working memory while controlling for the possible influence of lower frequency rhythms. We collected electroencephalography (EEG) data in 27 participants who performed a spatial working-memory task with two levels of cognitive load. In order to rule out the possibility that observed beta activity was affected by non-sinusoidalities of lower frequency rhythms, we developed an algorithm that detects transient beta oscillations that do not coincide with more prominent lower frequency rhythms in time and space. Using this algorithm, we show that the amplitude and duration of beta bursts decrease with memory load and during memory manipulation, while their peak frequency and rate increase. Together, our results show that human beta rhythms are functionally modulated during working memory and that these changes cannot be attributed to lower frequency rhythms with non-sinusoidal properties.

The mechanism of Parkinson oscillation in the cortex: Possible evidence in a feedback model projecting from the globus pallidus to the cortex.

The origin, location and cause of Parkinson's oscillation are not clear at present. In this paper, we establish a new cortex-basal ganglia model to study the origin mechanism of Parkinson beta oscillation. Unlike many previous models, this model includes two direct inhibitory projections from the globus pallidus external (GPe) segment to the cortex. We first obtain the critical calculation formula of Parkinson's oscillation by using the method of Quasilinear analysis. Different from previous studies, the formula obtained in this paper can include the self-feedback connection of GPe. Then, we use the bifurcation analysis method to systematically explain the influence of some key parameters on the oscillation. We find that the bifurcation principle of different cortical nuclei is different. In general, the increase of the discharge capacity of the nuclei will cause oscillation. In some special cases, the sharp reduction of the discharge rate of the nuclei will also cause oscillation. The direction of bifurcation simulation is consistent with the critical condition curve. Finally, we discuss the characteristics of oscillation amplitude. At the beginning of the oscillation, the amplitude is relatively small; with the evolution of oscillation, the amplitude will gradually strengthen. This is consistent with the experimental phenomenon. In most cases, the amplitude of cortical inhibitory nuclei (CIN) is greater than that of cortical excitatory nuclei (CEX), and the two direct inhibitory projections feedback from GPe can significantly reduce the amplitude gap between them. We calculate the main frequency of the oscillation generated in this model, which basically falls between 13 and 30 Hz, belonging to the typical beta frequency band oscillation. Some new results obtained in this paper can help to better understand the origin mechanism of Parkinson's disease and have guiding significance for the development of experiments.

The Decline of Cortical Beta Oscillation on the Function of Eye-hand Coordination in the Healthy Elderly.

There seems to be a correlation between changes in movement patterns with aging and brain activation. In the preparation and execution of movements, neural oscillations play an important role. In this study, cortical high frequency brain oscillations were analyzed in 15 healthy young adults and 15 elderly adults who participated in eye-hand coordination tasks. The brain activities of healthy young and older adults were recorded using electroencephalography (EEG). Elderly participants spent significantly more time completing the task than young participants. During eye-hand coordination in elderly groups, beta power decreased significantly in the central midline and parietal brain regions. The data suggest that healthy elderly subjects had intact cognitive performance, but relatively poor eye-hand coordination associated with loss of beta brain oscillation in the central midline and parietal cortex and reduced ability to attentional movement. Beta frequency in the parietal brain sites may contribute to attentional movement. This could be an important method for monitoring cognitive brain function changes as the brain ages.

GABAergic synaptic transmission and cortical oscillation patterns in the primary somatosensory area of a valproic acid rat model of autism spectrum disorder.

Autism spectrum disorder (ASD) is characterized by impaired social communication and interaction associated with repetitive or stereotyped behaviour. Prenatal valproic acid (VPA) exposure in rodents is a commonly used model of ASD. Resveratrol (RSV) has been shown to prevent interneuronal and behavioural impairments in the VPA model. We investigated the effects of prenatal VPA exposure and RSV on the GABAergic synaptic transmission, brain oscillations and on the genic expression of interneuron-associated transcription factor LHX6 in the primary somatosensory area (PSSA). Prenatal VPA exposure decreased the sIPSC and mIPSC frequencies and the sIPSC decay kinetics onto layers 4/5 pyramidal cells of PSSA. About 40% of VPA animals exhibited absence-like spike-wave discharge (SWD) events associated with behaviour arrest and increased power spectrum density of delta, beta and gamma cortical oscillations. VPA animals had reduced LHX6 expression in PSSA, but VPA animals treated with RSV had no changes on synaptic inhibition or LHX6 expression in the PSSA. SWD events associated with behaviour arrest and the abnormal increment of cortical oscillations were also absent in VPA animals treated with RSV. These findings provide new venues to investigate the role of both RSV and VPA in the pathophysiology of ASD and highlight the VPA animal model as an interesting tool to investigate pathways related to the aetiology and possible future therapies to this neuropsychiatric disorder.

Temporal profiles of cortical oscillations in novice performers for goal-directed aiming in a shooting task

Goal-directed aiming relies on the ability to control attention and visuomotor movements while preparing for motor execution. Research in precision sports has investigated cortical oscillations for supporting expert performance. However, the results may be influenced by adaptive and strategic behaviors after intensive training. Whether and at what time points distinctive oscillations support goal-directed aiming without such training remains elusive. In this electroencephalographic (EEG) study, we investigated how the theta, alpha and beta oscillations change to support accurate aiming before novices took an action. We first conducted a model-based analysis to examine the correlation of cortical oscillations with accurate shooting on a trial-by-trial basis in a within-individual manner. The results showed that alpha and beta oscillations at different time points during the aiming period were better predictors of aiming accuracy. We then compared the oscillatory power for good versus poor performance. The results showed decreases in the alpha and beta power across distributed cortical areas and an increase in the frontal theta power successively before shot release. Moreover, greater intertrial phase coherence was observed for good performance than for poor performance in posterior alpha activity and anterior beta activity during the aiming period. In conclusion, these results advance our understanding of the temporal dynamics of theta, alpha and beta oscillations in orchestrating goal setting, motor preparation and focused attention to monitoring both external and internal states for accurate aiming. Among the three, alpha and beta oscillations are critical for predicting aiming performance and theta oscillations reflect effortful cognitive control.

Role of adenosine A2A receptors in the loss of consciousness induced by propofol anesthesia.

The mechanism of propofol-anesthesia-induced loss of consciousness (LOC) remains largely unknown. We speculated that the adenosine A2A receptor serves as a vital molecular target in regulating LOC states under propofol anesthesia. c-Fos staining helped observe the changes in the neuronal activity in the nucleus accumbens (NAc). Initially, the adenosine signals in the NAc were measured under propofol anesthesia using fiber photometry recordings. Then, behavior tests and electrophysiological recordings were used to verify the effect of systemic A2A R agonist or antagonist treatment on propofol anesthesia. Next, the microinjection technique was used to clarify the role of the NAc A2A R under propofol anesthesia. Fiber photometry recordings were applied to assess the effect of A2A R agonist or antagonist systemic treatment on adenosine signal alterations in the NAc during propofol anesthesia. Then, as the GABAergic neurons are the main neurons in the NAc, we further measured the neuronal activity of GABAergic neurons. In our study, propofol anesthesia enhanced the neuronal activity in the NAc, and the adenosine signals were increased in the NAc. SCH58261 reduced the LOC time and sedative depth, while CGS21680 increased those via intraperitoneal injection. Additionally, CGS21680 increased the changes in delta, theta, alpha, beta, and low-gamma oscillations in the NAc. Moreover, microinjection of SCH58261 significantly shortened the LOC time, whereas microinjection of CGS21680 into the NAc significantly prolonged the LOC duration. The results illustrated that after A2A R agonist administration, the level of extracellular adenosine signals in the NAc was decreased and the neuronal activity of GABAergic neurons was enhanced, whereas after A2A R antagonist administration via intraperitoneal injection, the opposite occurred. This study reveals the vital role of the A2A R in propofol-induced LOC and that the A2A R could affect the maintenance of propofol anesthesia.

Hopf bifurcation mechanism analysis in an improved cortex-basal ganglia network with distributed delays: An application to Parkinson’s disease

In this paper, we introduce general distributed delays (in pathways between different neurons) and self-feedback distributed delays (in self-feedback pathways) into an improved cortex-basal ganglia (BG) network to study possible Hopf bifurcation mechanisms for Parkinson’s oscillations. Hopf bifurcation critical conditions for discrete delays are obtained, which compare well to numerical simulations. General distributed delays inhibit oscillations in BG, but self-feedback distributed delays promote oscillations. The different effects of strong and weak kernels on Hopf bifurcations mainly depend on self-feedback distributed delays, strong kernels are more conducive to the generation of oscillations when self-feedback distributed delays exceed a certain value. The excitatory feedback and inhibitory feedback from cortex to BG have different effects on oscillation. We define four different states (absolutely stable, conditional stable, conditional oscillation and absolutely oscillation) in this model, which can explain different mechanisms of oscillation origin. An increase in distributed delays can induce the transition between supercritical (SPH) and subcritical (SBH) Hopf bifurcations, which in turn may cause the transition of oscillations in different frequency bands, such as beta oscillations and alpha oscillations. Near the SBH, frequencies increase with an increase in discrete delays; and the trend is opposite at the SPH. In general, the amplitude of oscillation increases with the increase of firing activation level. Discrete delays can improve the firing activation level of the BG and suppress oscillations in its adjacent circuits. With the increase of distributed delays, oscillatory regions evolve regularly and the roles of general distributed delays and self-feedback distributed delays are contrary. Different types of delay have different effects on oscillation frequency. Discrete delay and self-feedback distributed delay have similar effects on oscillation frequency, but are different from general distributed delay. Whether the frequency will change with an increase in delay depends on coupling weights.

Decreased Default Mode Network Connectivity Following 24 Hours of Capsaicin-induced Pain Persists During Immediate Pain Relief and Facilitation

Prolonged experimental pain models can help assess cortical mechanisms underlying the transition from acute to chronic pain such as resting-state functional connectivity (rsFC), especially in early stages. This crossover study determined the effects of 24-hour-capsaicin-induced pain on the default mode network rsFC, a major network in the dynamic pain connectome. Electroencephalographic rsFC measured by Granger causality was acquired from 24 healthy volunteers (12 women) at baseline, 1hour, and 24hours following the application of a control or capsaicin patch on the right forearm. The control patch was received maximum 1 week before the capsaicin patch. Following 24hours, the patch was cooled and later heated to assess rsFC changes in response to pain relief and facilitation, respectively. Compared to baseline, decreased rsFC at alpha oscillations (8-10Hz) was found following 1hour and 24hours of capsaicin application for connections projecting from medial prefrontal cortex (mPFC) and right angular gyrus (rAG) but not left angular gyrus (lAG) or posterior cingulate cortex (PCC): mPFC-PCC (1hour:P < .001, 24hours:P = .002), mPFC-rAG (1hour:P < .001, 24hours:P = .001), rAG-mPFC (1hour:P < .001, 24hours:P = .001), rAG-PCC (1hour:P < .001, 24hours:P = .004). Comparable decreased rsFC following 1hour and 24hours (P≤0.008) was found at beta oscillations, however, decreased projections from PCC were also found: PCC-rAG (P≤0.005) and PCC-lAG (P≤0.006). Pain NRS scores following 24hours (3.7±0.4) was reduced by cooling (0.3±0.1, P = .004) and increased by heating (4.8±0.6, P = .016). However, neither cooling nor heating altered rsFC. This study shows that 24hours of experimental pain induces a robust decrease in DMN connectivity that persists during pain relief or facilitation suggesting a possible shift to attentional and emotional processing in persistent pain. PerspectiveThis article shows decreased DMN connectivity that might reflect possible attentional and emotional changes during acute and prolonged pain. Understanding these changes could potentially help clinicians in developing therapeutic methods that can better target these attentional and emotional processes before developing into more persistent states.

Central-positive complexes in ECT-induced seizures: Possible evidence for thalamocortical mechanisms

ObjectiveCentral-positive complexes (CPCs) are elicited during electroconvulsive therapy (ECT) as generalized high-amplitude waveforms with maximum positive voltage over the vertex. While these complexes have been qualitatively assessed in previous literature, quantitative analyses are lacking. This study aims to characterize CPCs across temporal, spatial, and spectral domains. MethodsHigh-density 64-electrode electroencephalogram (EEG) recordings during 50 seizures acquired from 11 patients undergoing right unilateral ECT allowed for evaluation of spatiotemporal characteristics of CPCs via source localization and spectral analysis. ResultsPeak-amplitude CPC scalp topology was consistent across seizures, showing maximal positive polarity over the midline fronto-central region and maximal negative polarity over the suborbital regions. The sources of these peak potentials were localized to the bilateral medial thalamus and cingulate cortical regions. Delta, beta, and gamma oscillations were correlated with the peak amplitude of CPCs during seizures induced during ketamine, whereas delta and gamma oscillations were associated with CPC peaks during etomidate anesthesia (excluding the dose-charge titration). ConclusionsOur findings demonstrate the consistency of CPC presence across participant, stimulus charge, time, and anesthetic agent, with peaks localized to bilateral medial thalamus and cingulate cortical regions and associated with delta, beta, and gamma band oscillations (depending on the anesthetic condition). SignificanceThe consistency and reproducibility of CPCs offers ECT as a new avenue for studying the dynamics of generalized seizure activity and thalamocortical networks.

Machine Learning Based on Event-Related EEG of Sustained Attention Differentiates Adults with Chronic High-Altitude Exposure from Healthy Controls.

(1) Objective: The aim of this study was to examine the effect of high altitude on inhibitory control processes that underlie sustained attention in the neural correlates of EEG data, and explore whether the EEG data reflecting inhibitory control contain valuable information to classify high-altitude chronic hypoxia and plain controls. (2) Methods: 35 chronic high-altitude hypoxic adults and 32 matched controls were recruited. They were required to perform the go/no-go sustained attention task (GSAT) using event-related potentials. Three machine learning algorithms, namely a support vector machine (SVM), logistic regression (LR), and a decision tree (DT), were trained based on the related ERP components and neural oscillations to build a dichotomous classification model. (3) Results: Behaviorally, we found that the high altitude (HA) group had lower omission error rates during all observation periods than the low altitude (LA) group. Meanwhile, the ERP results showed that the HA participants had significantly shorter latency than the LAs for sustained potential (SP), indicating vigilance to response-related conflict. Meanwhile, event-related spectral perturbation (ERSP) analysis suggested that lowlander immigrants exposed to high altitudes may have compensatory activated prefrontal cortexes (PFC), as reflected by slow alpha, beta, and theta frequency-band neural oscillations. Finally, the machine learning results showed that the SVM achieved the optimal classification F1 score in the later stage of sustained attention, with an F1 score of 0.93, accuracy of 92.54%, sensitivity of 91.43%, specificity of 93.75%, and area under ROC curve (AUC) of 0.97. The results proved that SVM classification algorithms could be applied to identify chronic high-altitude hypoxia. (4) Conclusions: Compared with other methods, the SVM leads to a good overall performance that increases with the time spent on task, illustrating that the ERPs and neural oscillations may provide neuroelectrophysiological markers for identifying chronic plateau hypoxia.

The Equations for Consciousness: A Reply to “Tracking the Travels,” a Review of Journey of the Mind

The Equations for Consciousness: A Reply to “Tracking the Travels,” a Review of <i>Journey of the Mind</i>

Pharmacodynamics Assessment of Aducanumab in 5XFAD mice: A MODEL‐AD PTC Study

AbstractBackgroundThe Preclinical Testing Core (PTC) of the Model Organism Development for Evaluation of Late Onset Alzheimer’s Disease (MODEL‐AD) consortium established a rigorous preclinical drug testing strategy with go/no‐go decision points that permits unbiased assessments of therapeutic agents. As part of the pipeline validation, the chimeric murinized therapeutic antibody aducanumab (chAducanumab), was selected for evaluation in 5XFAD mice.MethodsInitial PK modeling and simulation was guided by literature and Aβ reductions from a pilot cohort of 9 month aged 5XFAD mice following 1x/week treatment of 30 mg/kg chAducanumab for 4 weeks. These pilot data were used to inform the chronic dosing regimen for the PD study which started at an age in 5XFAD mice where significant amyloid plaque accumulation was present (9 mos). PD endpoints (n=10‐12/sex/genotype/treatment) were assessed at the conclusion of chronic treatment, and included: 18‐FDG and 18F‐AV45 PET/CT, autoradiography, immunohistochemistry, AB40 and AB42 in plasma and brain fractions, and a behavioral battery. An additional cohort was enrolled for comprehensive cognitive testing using touchscreen learning and pattern separation tasks and evaluated for electroencephalography (EEG) activity using wireless telemetry.ResultsPK/PD modeling revealed slow clearance of chAducanumab following IP dosing with a T1/2 of ∼2.5 days. Therefore, the dose regimen for chronic PD studies included 0.1, 1.56, and 30 mg/kg administered 1x weekly for 12 weeks. Treatment with chAducanumab resulted in dose‐ and sex‐dependent reduction in amyloid deposition via 18F‐AV45 PET. Glucose uptake via 18F‐FDG PET similarly showed a dose dependent reversal of glycolytic loss in key brain regions. Cognitive assessments indicated no effect on learning however an improvement in pattern separation was observed with chAducanumab in females but not males. EEG analysis revealed improvements in delta, alpha, and beta oscillations with chAducanumab treatment. Multi‐omics analysis are in progress.ConclusionschAducanumab treatment in 5XFAD mice resulted in the expected reductions in brain amyloid consistent with clinical findings. Moreover, chAducanumab showed a unique glycolytic restoration profile in 5XFAD mice and improvements in some aspects of cognitive function. Together these data positively support pipeline validation of the MODEL‐AD PTC for evaluating therapeutic antibodies.

Spectral signatures associated with cognitive aging, APOE4, amyloid‐β and measures of axonal integrity in cognitively unimpaired adults

AbstractBackgroundOscillatory brain rhythms are a defining feature of neuronal activity that support cognition in humans. Previous studies that showed associations of spectral changes in individuals who harbor high risk for Alzheimer’s disease (AD) were limited to identify abnormalities within select brain regions defined apriori. Comprehensive whole‐brain spatiotemporal patterns of oscillatory changes associated with cognitive‐aging and with AD risk are only partly known. Our main goals were to understand how frequency specific spectral changes relate to cognitive abilities in normal aging and to identify oscillatory signatures that indicate pre‐symptomatic AD pathophysiological processes in cognitively unimpaired elderly.MethodsWe used magnetoencephalography (MEG) to study the spectral signatures within delta‐theta (2‐7Hz), alpha (8‐12Hz) and beta (13‐35Hz) oscillations, in cognitively unimpaired adults (n=70). Using a partial‐least‐square regression, we correlated spectral patterns to executive, memory, and processing‐speed abilities (n=40). Next, we compared the spectral signatures between amyloid‐β (Aβ)+ vs. Aβ‐ and between APOE‐Ɛ4+ vs. APOE‐Ɛ4‐, in sub‐cohorts evaluated with Aβ‐PET (n=46) and APOE4 (n=65), respectively. In a subset of participants (n=19), we also examined associations between spectral signatures and cerebrospinal fluid (CSF) markers indicating damage to: presynaptic (growth‐associated protein‐43, GAP43); postsynaptic (neurogranin, NG); axonal (neurofilament light chain, NFL), levels.ResultsAn age dependent, low‐grade, increase in alpha power and decrease in delta‐theta power were associated with better cognitive performance in memory, executive and processing speed (Figure‐1). APOE4+ individuals showed reduced alpha power within bilateral medial temporal and right precuneus, compared to APOE4‐. Aβ+ individuals showed a dual pattern of alpha change with increased frontal and reduced medial and lateral temporal cortex pattern and a frontally distributed increased delta‐theta power (Figure‐2). Higher CSF‐NFL was correlated with lower alpha power.ConclusionsOur findings demonstrate that higher alpha power indicates a positive spectral change towards better cognitive health in aging. Importantly, a reduced alpha power signature indicated early neurodegenerative changes, as demonstrated by: (1)Aβ+ individuals and APOE‐Ɛ4+ individuals showing reduced alpha power within the regions known for earliest tau accumulations; (2) lower alpha correlating with higher NFL, which reflects Aβ‐independent neurodegeneration. Collectively alpha signatures may indicate tau related neuropathology with aging and in early AD.