Berenson Allen Center for Noninvasive Brain Stimulation

BackgroundNeural hyper‐excitability and network dysfunction are neurophysiological hallmarks of Alzheimer's disease (AD) in animal studies, but their presence and clinical relevance in humans remain poorly understoodMethodWe introduce a novel perturbation‐based approach combining transcranial magnetic stimulation and electroencephalography (TMS‐EEG), alongside resting‐state EEG (rsEEG), to investigate neurophysiological basis of default mode network (DMN) dysfunction in early AD.ResultWhile rsEEG revealed global neural slowing and disrupted synchrony, these measures reflected widespread changes in brain neurophysiology without network‐specific insights. In contrast, TMS‐EEG identified network‐specific local hyper‐excitability in the parietal DMN and disrupted connectivity with frontal DMN regions, which uniquely predicted distinct cognitive impairments and mediated the link between structural brain integrity and cognition.ConclusionOur findings provide critical insights into how network‐specific neurophysiological disruptions contribute to AD‐related cognitive dysfunction. Perturbation‐based assessments hold promise as novel markers of early detection, disease progression, and target engagement for disease‐modifying therapies aiming to restore abnormal neurophysiology in AD

BackgroundAlzheimer’s disease (AD) is linked to abnormal cortical excitability. Recent studies have suggested that amyloid‐related cortical hyperexcitability may drive faster clinical decline and be related to spreading of tau. However, we lack non‐invasive methods to quickly and directly assay cortical excitability in AD patients. We generate an Input‐Output response curve (I/O Curve) using transcranial magnetic stimulation (TMS) with electromyography (EMG) to investigate mechanisms of cortical excitability in AD.MethodsParticipants included 52 biomarker‐positive early AD (CDR=0.5‐1, age 70±8, 37% female) and 51 cognitively normal older adults (CN; age 70±6.5, 53% female). Single‐pulse TMS was applied to left motor cortex to measure resting motor threshold (RMT). An I/O Curve was generated by delivering 10 pulses each at eight stimulation intensities (30‐100% maximum stimulator output (%MSO)). We recorded motor‐evoked potentials (MEP) from the right first dorsal interosseous muscle. RMTs were compared between AD and CN using a linear model controlling for scalp‐to‐cortex distance (SCD) and protocol (i.e., EEG cap). For the I/O curve, stimulation intensity was normalized to RMT (%MSO/RMT) and binned in 15% increments. MEP amplitudes along the I/O Curve were analyzed using a linear mixed effects model with effects of Group, %MSO/RMT, and Group*%MSO/RMT; covariates of age, sex, education, and APOE4 alleles; and participant‐level random effects. Contrasts were conducted comparing the groups at each point along the I/O curve.ResultsRMT was lower in AD than in CN (η² p =0.12, medium effect size, p = 0.004, Figure 1); SCD was a significant covariate (p = 0.006). The I/O Curve revealed an increased response in the AD group, with significant effects of Group (η² p =0.10, medium effect size; p = 0.007), %MSO/RMT (η² p =0.71, p <0.001), and Group*%MSO/RMT (η² p =0.05, small effect size, p = 0.013). Covariates were not significant. Increased excitability in AD was greatest at higher stimulation intensities (120‐135%MSO/RMT: Cohen’s d=0.286, small effect size, p = 0.015; 135‐150%MSO/RMT: Cohen’s d=0.495, medium effect size, p <0.001, Figure 2).ConclusionsTMS‐EMG confirms evidence of increased cortical excitability in AD. This was evident at lower intensities with the RMT model (implicating voltage‐gated Na+ channels) and higher intensities with the I/O Curve (implicating AMPA receptors). TMS may be useful to measure target engagement of novel therapies targeting cortical excitability in AD.

Objectives:Mindfulness-based interventions (MBIs) appear to improve emotion regulation (ER) in disorders involving emotional dysregulation like fibromyalgia (FM). Despite the therapeutic potential of transcranial direct current stimulation (tDCS) in FM, its concurrent application with mindfulness meditation (MM) has not yet been explored. Potential synergistic effects may arise from aligning neural mechanisms underlying both interventions. This study evaluated the impact of a 4-week MBI and a combined tDCS and MM intervention on ER, implementing a responder analysis approach for FM patients.Methods:Following the MBI, 40 participants with FM were randomly allocated to receive 10 days of 20 minutes MM combined with either anodal tDCS of the primary motor cortex (M1) or sham tDCS. ER was gauged using a composite score integrating 4 self-report questionnaires. We performed assessment at 6 time points (baseline, post-MBI, immediately postcombined intervention, 4 wk, 8 wk, and 12-wk follow-ups). Clinical responders were defined as patients exhibiting a clinically relevant reduction in FM symptom load.Results:Responders to the MBI showed better ER than nonresponders, lasting for 6 weeks. Interestingly, responders to the combined intervention in the sham group reported larger improvements in ER than nonresponders, which was not observed in the anodal tDCS group. No significant interaction between responder status and time was found for responders to either intervention.Discussion:Our findings evidence that mindfulness practice is able to improve ER in FM. However, the add-on combination of MM with M1-tDCS abolishes this mindfulness-induced effect. Therefore, based on our data, combining MM and M1-tDCS must be reconsidered as a therapeutic intervention targeting ER in FM.

Alzheimer's disease (AD) is characterized by impaired inhibitory circuitry and GABAergic dysfunction, which is associated with reduced fast brain oscillations in the gamma band (γ, 30-90Hz) in several animal models. Investigating such activity in human patients could lead to the identification of novel biomarkers of diagnostic and prognostic value. The current study aimed to test a multimodal "Perturbation-based" transcranial Alternating Current Stimulation-Electroencephalography (tACS)-EEG protocol to detect how responses to tACS in AD patients correlate with patients' clinical phenotype. Fourteen participants with mild to moderate dementia due to AD underwent a baseline assessment including cognitive status, peripheral neuroinflammation, and resting-state (rs)EEG. The tACS-EEG recordings included brief (6') tACS blocks of gamma (i.e., 40Hz) stimulation administered through 4 different montages, with Pre/Post 32-Channels EEG for each block. Changes in tACS-EEG and rsEEG γ band power with respect to baseline were adopted as a metric of induction and compared with cognitive scores and neuroinflammatory biomarkers. We found positive correlations between 40Hz-induced γ activity in fronto-central-parietal areas and patient cognitive status and negative ones with neuroinflammatory markers. Participants with greater cognitive impairment exhibited less γ induction and higher peripheral neuroinflammation. The same analysis performed with spectral power from baseline rsEEG resulted in no significant correlations, promoting the value of tACS-based perturbation for capturing individual differences in pathology-related brain features. Our work suggests a link between tACS-induced γ band spectral power and clinical severity, with weaker γ induction corresponding to more severe clinical/cognitive impairment. This study provides preliminary support for the development of novel physiological biomarkers and therapeutic targets based on disease severity.

The use of dietary supplements by patients with chronic liver disease is prevalent and rising. Despite the known risks of dietary supplements, including hepatotoxicity, adulteration, and contamination, patients with chronic liver disease often turn to dietary supplements to support their liver and/or overall health but are not necessarily empowered with the information or guidance from their liver practitioner to do so. This article provides practitioners with a framework for balancing the risks and benefits of dietary supplements in patients with chronic liver disease, offering examples of independent resources and certifications to use this framework in clinical practice. We offer 3 common clinical scenarios to highlight how the use of this framework can improve communication and decision-making in clinical practice. By adapting principles from Integrative Medicine, this article advocates for a patient-centered approach to dietary supplements in patients with chronic liver disease, encouraging open dialogue between clinicians and their patients to facilitate informed decision-making and personalized care.

Brain imaging studies have recently provided some evidence in favour of covert cognitive processes ongoing in patients with disorders of consciousness (DoC) (e.g., minimally consciousness states, vegetative state/unresponsive wakefulness syndrome) engaged in passive sensory stimulation or active tasks such as motor imagery. In this exploratory study, we used transcranial magnetic stimulation (TMS) of the motor cortex to assess modulations of corticospinal excitability induced by action observation in eleven patients with DoC. Action observation is known to facilitate corticospinal excitability in healthy subjects, unveiling how the observer&amp;rsquo;s motor system maps others&amp;rsquo; actions onto her/his motor repertoire. Additional stimuli were non-biological motion and acoustic startle stimuli, provided that sudden and loud acoustic stimulation is known to lower corticospinal excitability in healthy subjects. Results indicate that some form of motor resonance is spared in a subset of patients with DoC with some significant difference between biological and non-biological motion stimuli. However, there was no covariation between corticospinal excitability and the type of DoC diagnosis (i.e., whether VS/UWS or MCS). Similarly, no covariation was detected with clinical changes between admission and discharge in clinical outcome measures. Both motor resonance and biological/non-biological motion discrimination correlated with the amplitude of the N20 somatosensory evoked potentials following the stimulation of the median nerve at the wrist (i.e., the temporal marker signalling the activation of the contralateral primary somatosensory cortex). Moreover, the startle-evoking stimulus produced an anomalous increase in corticospinal excitability, suggesting a functional dissociation between cortical and subcortical circuits in patients with DoC. Further work is needed to better comprehend the conditions in which corticospinal facilitation occurs and whether and how they may relate to individual clinical parameters.