Resting-state EEG signatures of Alzheimer's disease are driven by periodic but not aperiodic changes.

Electroencephalography (EEG) has shown potential for identifying early-stage biomarkers of neurocognitive dysfunction associated with dementia due to Alzheimer's disease (AD). A large body of evidence shows that, compared to healthy controls (HC), AD is associated with power increases in lower EEG frequencies (delta and theta) and decreases in higher frequencies (alpha and beta), together with slowing of the peak alpha frequency. However, the pathophysiological processes underlying these changes remain unclear. For instance, recent studies have shown that apparent shifts in EEG power from high to low frequencies can be driven either by frequency specific periodic power changes or rather by non-oscillatory (aperiodic) changes in the underlying 1/f slope of the power spectrum. Hence, to clarify the mechanism(s) underlying the EEG alterations associated with AD, it is necessary to account for both periodic and aperiodic characteristics of the EEG signal. Across two independent datasets, we examined whether resting-state EEG changes linked to AD reflect true oscillatory (periodic) changes, changes in the aperiodic (non-oscillatory) signal, or a combination of both. We found strong evidence that the alterations are purely periodic in nature, with decreases in oscillatory power at alpha and beta frequencies (AD < HC) leading to lower (alpha + beta) / (delta + theta) power ratios in AD. Aperiodic EEG features did not differ between AD and HC. By replicating the findings in two cohorts, we provide robust evidence for purely oscillatory pathophysiology in AD and against aperiodic EEG changes. We therefore clarify the alterations underlying the neural dynamics in AD and emphasize the robustness of oscillatory AD signatures, which may further be used as potential prognostic or interventional targets in future clinical investigations.

Determinants of exercise adherence in sedentary middle-aged and older adults.

Regular exercise positively impacts neurocognitive health, particularly in aging individuals. However, low adherence, particularly among older adults, hinders the adoption of exercise routines. While brain plasticity mechanisms largely support the cognitive benefits of exercise, the link between physiological and behavioral factors influencing exercise adherence remains unclear. This study aimed to explore this association in sedentary middle-aged and older adults. Thirty-one participants underwent an evaluation of cortico-motor plasticity using transcranial magnetic stimulation (TMS) to measure changes in motor-evoked potentials following intermittent theta-burst stimulation (iTBS). Health history, cardiorespiratory fitness, and exercise-related behavioral factors were also assessed. The participants engaged in a 2-month supervised aerobic exercise program, attending sessions three times a week for 60 min each, totaling 24 sessions at a moderate-to-vigorous intensity. They were divided into Completers (n = 19), who attended all sessions, and Dropouts (n = 12), who withdrew early. Completers exhibited lower smoking rates, exercise barriers, and resting heart rates compared to Dropouts. For Completers, TMS/iTBS cortico-motor plasticity was associated with better exercise adherence (r = -.53, corrected p = .019). Exploratory hypothesis-generating regression analysis suggested that post-iTBS changes (ß = -7.78, p = .013) and self-efficacy (ß = -.51, p = .019) may predict exercise adherence (adjusted-R2 = .44). In conclusion, this study highlights the significance of TMS/iTBS cortico-motor plasticity, self-efficacy, and cardiovascular health in exercise adherence. Given the well-established cognitive benefits of exercise, addressing sedentary behavior and enhancing self-efficacy are crucial for promoting adherence and optimizing brain health. Clinicians and researchers should prioritize assessing these variables to improve the effectiveness of exercise programs.

Light aerobic exercise modulates executive function and cortical excitability.

Single bouts of aerobic exercise can modulate cortical excitability and executive cognitive function, but less is known about the effect of light-intensity exercise, an intensity of exercise more achievable for certain clinical populations. Fourteen healthy adults (aged 22 to 30) completed the following study procedures twice (≥7 days apart) before and after 30 min of either light aerobic exercise (cycling) or seated rest: neurocognitive battery (multitasking performance, inhibitory control and spatial working memory), paired-pulse TMS measures of cortical excitability. Significant improvements in response times during multitasking performance and increases in intracortical facilitation (ICF) were seen following light aerobic exercise. Light aerobic exercise can modulate cortical excitability and some executive function tasks. Populations with deficits in multitasking ability may benefit from this intervention.

Therapeutic noninvasive brain stimulation in Alzheimer's disease and related dementias.

PURPOSE OF REVIEW: Alzheimer's disease is a progressive neurodegenerative disease without effective pharmacological treatment. Noninvasive brain stimulation (NIBS) techniques, such as repetitive transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (tES), are increasingly being investigated for their potential to ameliorate the symptoms of Alzheimer's disease and related dementias (ADRD). RECENT FINDINGS: A comprehensive literature review for primary research reports that investigated the ability of TMS/tES to improve cognition in ADRD patients yielded a total of 20 reports since 2016. Eight studies used repetitive TMS and 12 used transcranial direct current stimulation, the most common form of tES. Eight of the studies combined NIBS with cognitive training. Promising results should encourage continued investigation, however there is currently insufficient evidence to support widespread adoption of NIBS-based clinical treatments for ADRD. SUMMARY: NIBS remains an active area of investigation for treatment of ADRD, though the predominance of small, heterogeneous, proof-of-principle studies precludes definitive conclusions. We propose the establishment of a consortium to achieve the benefits of large-scale, controlled studies using biomarker-based diagnostic characterization of participants, development of neurophysiological markers to verify target engagement, and standardization of parameters.

Direct current stimulation over the human sensorimotor cortex modulates the brain's hemodynamic response to tactile stimulation.

Tactile stimuli produce afferent signals that activate specific regions of the cerebral cortex. Noninvasive transcranial direct current stimulation (tDCS) effectively modulates cortical excitability. We therefore hypothesised that a single session of tDCS targeting the sensory cortices would alter the cortical response to tactile stimuli. This hypothesis was tested with a block-design functional magnetic resonance imaging protocol designed to quantify the blood oxygen level-dependent response to controlled sinusoidal pressure stimulation applied to the right foot sole, as compared with rest, in 16 healthy young adults. Following sham tDCS, right foot sole stimulation was associated with activation bilaterally within the precentral cortex, postcentral cortex, middle and superior frontal gyri, temporal lobe (subgyral) and cingulate gyrus. Activation was also observed in the left insula, middle temporal lobe, superior parietal lobule, supramarginal gyrus and thalamus, as well as the right inferior parietal lobule and claustrum (false discovery rate corrected, P < 0.05). To explore the regional effects of tDCS, brain regions related to somatosensory processing, and cortical areas underneath each tDCS electrode, were chosen as regions of interest. Real tDCS, as compared with sham tDCS, increased the percent signal change associated with foot stimulation relative to rest in the left posterior paracentral lobule. These results indicate that tDCS acutely modulated the cortical responsiveness to controlled foot pressure stimuli in healthy adults. Further study is warranted, in both healthy individuals and patients with sensory impairments, to link tDCS-induced modulation of the cortical response to tactile stimuli with changes in somatosensory perception.

Is neuroenhancement by noninvasive brain stimulation a net zero-sum proposition?

In the past several years, the number of studies investigating enhancement of cognitive functions through noninvasive brain stimulation (NBS) has increased considerably. NBS techniques, such as transcranial magnetic stimulation and transcranial current stimulation, seem capable of enhancing cognitive functions in patients and in healthy humans, particularly when combined with other interventions, including pharmacologic, behavioral and cognitive therapies. The "net zero-sum model", based on the assumption that brain resources are subjected to the physical principle of conservation of energy, is one of the theoretical frameworks proposed to account for such enhancement of function and its potential cost. We argue that to guide future neuroenhancement studies, the net-zero sum concept is helpful, but only if its limits are tightly defined.

Causal evidence supporting functional dissociation of verbal and spatial working memory in the human dorsolateral prefrontal cortex.

The human dorsolateral prefrontal cortex (dlPFC) is crucial for monitoring and manipulating information in working memory, but whether such contributions are domain-specific remains unsettled. Neuroimaging studies have shown bilateral dlPFC activity associated with working memory independent of the stimulus domain, but the causality of this relationship cannot be inferred. Repetitive transcranial magnetic stimulation (rTMS) has the potential to test whether the left and right dlPFC contribute equally to verbal and spatial domains; however, this is the first study to investigate the interaction of task domain and hemisphere using offline rTMS to temporarily modulate dlPFC activity. In separate sessions, 20 healthy right-handed adults received 1 Hz rTMS to the left dlPFC and right dlPFC, plus the vertex as a control site. The working memory performance was assessed pre-rTMS and post-rTMS using both verbal-'letter' and spatial-'location' versions of the 3-back task. The response times were faster post-rTMS, independent of the task domain or stimulation condition, indicating the influence of practice or other nonspecific effects. For accuracy, rTMS of the right dlPFC, but not the left dlPFC or vertex, led to a transient dissociation, reducing spatial, but increasing verbal accuracy. A post-hoc correlation analysis found no relationship between these changes, indicating that the substrates underlying the verbal and spatial domains are functionally independent. Collapsing across time, there was a trend towards a double dissociation, suggesting a potential laterality in the functional organisation of verbal and spatial working memory. At a minimum, these findings provide human evidence for domain-specific contributions of the dlPFC to working memory and reinforce the potential of rTMS to ameliorate cognition.

Phonetic categorization relies on motor simulation, but combinatorial phonological computations are abstract.

To identify a spoken word (e.g., dog), people must categorize the speech steam onto distinct units (e.g., contrast dog/fog,) and extract their combinatorial structure (e.g., distinguish dog/god). However, the mechanisms that support these two core functions are not fully understood. Here, we explore this question using transcranial magnetic stimulation (TMS). We show that speech categorization engages the motor system, as stimulating the lip motor area has opposite effects on labial (ba/pa)- and coronal (da/ta) sounds. In contrast, the combinatorial computation of syllable structure engages Broca's area, as its stimulation disrupts sensitivity to syllable structure (compared to motor stimulation). We conclude that the two ingredients of language-categorization and combination-are distinct functions in human brains.

Greater cognitive reserve is related to lower cortical excitability in healthy cognitive aging, but not in early clinical Alzheimer's disease.

Objective: To investigate the relationship between cortico-motor excitability and cognitive reserve (CR) in cognitively unimpaired older adults (CU) and in older adults with mild cognitive impairment or mild dementia due to Alzheimer's disease (AD). Methods: Data were collected and analyzed from 15 CU and 24 amyloid-positive AD participants aged 50-90 years. A cognitive reserve questionnaire score (CRQ) assessed education, occupation, leisure activities, physical activities, and social engagement. Cortical excitability was quantified as the average amplitude of motor evoked potentials (MEP amplitude) elicited with single-pulse transcranial magnetic stimulation delivered to primary motor cortex. A linear model compared MEP amplitudes between groups. A linear model tested for an effect of CRQ on MEP amplitude across all participants. Finally, separate linear models tested for an effect of CRQ on MEP amplitude within each group. Exploratory analyses tested for effect modification of demographics, cognitive scores, atrophy measures, and CSF measures within each group using nested regression analysis. Results: There was no between-group difference in MEP amplitude after accounting for covariates. The primary model showed a significant interaction term of group*CRQ (R2adj = 0.18, p = 0.013), but no main effect of CRQ. Within the CU group, higher CRQ was significantly associated with lower MEP amplitude (R2adj = 0.45, p = 0.004). There was no association in the AD group. Conclusion: Lower cortico-motor excitability is related to greater CRQ in CU, but not in AD. Lower MEP amplitudes may reflect greater neural efficiency in cognitively unimpaired older adults. The lack of association seen in AD participants may reflect disruption of the protective effects of CR. Future work is needed to better understand the neurophysiologic mechanisms leading to the protective effects of CR in older adults with and without neurodegenerative disorders.

Resting-state EEG signatures of Alzheimer's disease are driven by periodic but not aperiodic changes.

Electroencephalography (EEG) has shown potential for identifying early-stage biomarkers of neurocognitive dysfunction associated with dementia due to Alzheimer's disease (AD). A large body of evidence shows that, compared to healthy controls (HC), AD is associated with power increases in lower EEG frequencies (delta and theta) and decreases in higher frequencies (alpha and beta), together with slowing of the peak alpha frequency. However, the pathophysiological processes underlying these changes remain unclear. For instance, recent studies have shown that apparent shifts in EEG power from high to low frequencies can be driven either by frequency specific periodic power changes or rather by non-oscillatory (aperiodic) changes in the underlying 1/f slope of the power spectrum. Hence, to clarify the mechanism(s) underlying the EEG alterations associated with AD, it is necessary to account for both periodic and aperiodic characteristics of the EEG signal. Across two independent datasets, we examined whether resting-state EEG changes linked to AD reflect true oscillatory (periodic) changes, changes in the aperiodic (non-oscillatory) signal, or a combination of both. We found strong evidence that the alterations are purely periodic in nature, with decreases in oscillatory power at alpha and beta frequencies (AD < HC) leading to lower (alpha + beta) / (delta + theta) power ratios in AD. Aperiodic EEG features did not differ between AD and HC. By replicating the findings in two cohorts, we provide robust evidence for purely oscillatory pathophysiology in AD and against aperiodic EEG changes. We therefore clarify the alterations underlying the neural dynamics in AD and emphasise the robustness of oscillatory AD signatures, which may further be used as potential prognostic or interventional targets in future clinical investigations.

Spectral power ratio as a measure of EEG changes in mild cognitive impairment due to Alzheimer's disease: a case-control study.

Adopting preventive strategies in individuals with subclinical Alzheimer's disease (AD) has the potential to delay dementia onset and reduce healthcare costs. Thus, it is extremely important to identify inexpensive, scalable, sensitive, and specific markers to track disease progression. The electroencephalography spectral power ratio (SPR: the fast to slow spectral power ratio), a measure of the shift in power distribution from higher to lower frequencies, holds potential for aiding clinical practice. The SPR is altered in patients with AD, correlates with cognitive functions, and can be easily implemented in clinical settings. However, whether the SPR is sensitive to pathophysiological changes in the prodromal stage of AD is unclear. We explored the SPR of individuals diagnosed with amyloid-positive amnestic mild cognitive impairment (Aß+aMCI) and its association with both cognitive function and amyloid load. The SPR was lower in Aß+aMCI than in the cognitively unimpaired individuals and correlated with executive function scores but not with amyloid load. Hypothesis-generating analyses suggested that aMCI participants with a lower SPR had an increased probability of a positive amyloid positron emission tomography. Future research may explore the potential of this measure to classify aMCI individuals according to their AD biomarker status.

Molecular hallmarks of long non-coding RNAs in aging and its significant effect on aging-associated diseases.

Aging is linked to the deterioration of many physical and cognitive abilities and is the leading risk factor for Alzheimer's disease. The growing aging population is a significant healthcare problem globally that researchers must investigate to better understand the underlying aging processes. Advances in microarrays and sequencing techniques have resulted in deeper analyses of diverse essential genomes (e.g., mouse, human, and rat) and their corresponding cell types, their organ-specific transcriptomes, and the tissue involved in aging. Traditional gene controllers such as DNA- and RNA-binding proteins significantly influence such programs, causing the need to sort out long non-coding RNAs, a new class of powerful gene regulatory elements. However, their functional significance in the aging process and senescence has yet to be investigated and identified. Several recent researchers have associated the initiation and development of senescence and aging in mammals with several well-reported and novel long non-coding RNAs. In this review article, we identified and analyzed the evolving functions of long non-coding RNAs in cellular processes, including cellular senescence, aging, and age-related pathogenesis, which are the major hallmarks of long non-coding RNAs in aging.

Reliability of resting-state EEG modulation by continuous and intermittent theta burst stimulation of the primary motor cortex: a sham-controlled study.

Theta burst stimulation (TBS) is a form of repetitive transcranial magnetic stimulation designed to induce changes of cortical excitability that outlast the period of TBS application. In this study, we explored the effects of continuous TBS (cTBS) and intermittent TBS (iTBS) versus sham TBS stimulation, applied to the left primary motor cortex, on modulation of resting state electroencephalography (rsEEG) power. We first conducted hypothesis-driven region-of-interest (ROI) analyses examining changes in alpha (8-12 Hz) and beta (13-21 Hz) bands over the left and right motor cortex. Additionally, we performed data-driven whole-brain analyses across a wide range of frequencies (1-50 Hz) and all electrodes. Finally, we assessed the reliability of TBS effects across two sessions approximately 1 month apart. None of the protocols produced significant group-level effects in the ROI. Whole-brain analysis revealed that cTBS significantly enhanced relative power between 19 and 43 Hz over multiple sites in both hemispheres. However, these results were not reliable across visits. There were no significant differences between EEG modulation by active and sham TBS protocols. Between-visit reliability of TBS-induced neuromodulatory effects was generally low-to-moderate. We discuss confounding factors and potential approaches for improving the reliability of TBS-induced rsEEG modulation.

Neuromodulatory effects and reproducibility of the most widely used repetitive transcranial magnetic stimulation protocols.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is widely used in both research and clinical settings to modulate human brain function and behavior through the engagement of the mechanisms of plasticity. Based upon experiments using single-pulse TMS as a probe, the physiologic mechanism of these effects is often assumed to be via changes in cortical excitability, with 10 Hz rTMS increasing and 1 Hz rTMS decreasing the excitability of the stimulated region. However, the reliability and reproducibility of these rTMS protocols on cortical excitability across and within individual subjects, particularly in comparison to robust sham stimulation, have not been systematically examined. OBJECTIVES: In a cohort of 28 subjects (39 ± 16 years), we report the first comprehensive study to (1) assess the neuromodulatory effects of traditional 1 Hz and 10 Hz rTMS on corticospinal excitability against both a robust sham control, and two other widely used patterned rTMS protocols (intermittent theta burst stimulation, iTBS; and continuous theta burst stimulation, cTBS), and (2) determine the reproducibility of all rTMS protocols across identical repeat sessions. RESULTS: At the group level, neither 1 Hz nor 10 Hz rTMS significantly modulated corticospinal excitability. 1 Hz and 10 Hz rTMS were also not significantly different from sham and both TBS protocols. Reproducibility was poor for all rTMS protocols except for sham. Importantly, none of the real rTMS and TBS protocols demonstrated greater neuromodulatory effects or reproducibility after controlling for potential experimental factors including baseline corticospinal excitability, TMS coil deviation and the number of individual MEP trials. CONCLUSIONS: These results call into question the effectiveness and reproducibility of widely used rTMS techniques for modulating corticospinal excitability, and suggest the need for a fundamental rethinking regarding the potential mechanisms by which rTMS affects brain function and behavior in humans.

Reliability of resting-state EEG modulation by continuous and intermittent theta burst stimulation of the primary motor cortex: A sham-controlled study.

Theta burst stimulation (TBS) is a form of repetitive transcranial magnetic stimulation designed to induce changes of cortical excitability that outlast the period of TBS application. In this study, we explored the effects of continuous TBS (cTBS) and intermittent TBS (iTBS) versus sham TBS stimulation, applied to the primary motor cortex, on modulation of resting state electroencephalography (rsEEG) power. We first conducted hypothesis-driven region-of-interest (ROI) analyses examining changes in alpha (8-12 Hz) and beta (13-21 Hz) bands over the left and right motor cortex. Additionally, we performed data-driven whole-brain analyses across a wide range of frequencies (1-50 Hz) and all electrodes. Finally, we assessed the reliability of TBS effects across two sessions approximately 1 month apart. None of the protocols produced significant group-level effects in the ROI. Whole-brain analysis revealed that cTBS significantly enhanced relative power between 19-43 Hz over multiple sites in both hemispheres. However, these results were not reliable across visits. There were no significant differences between EEG modulation by active and sham TBS protocols. Between-visit reliability of TBS-induced neuromodulatory effects was generally low-to-moderate. We discuss confounding factors and potential approaches for improving the reliability of TBS-induced rsEEG modulation.

Corticomotor plasticity as a predictor of response to high frequency transcranial magnetic stimulation treatment for major depressive disorder.

BACKGROUND: Many patients with treatment-resistant depression (TRD) respond to repetitive transcranial magnetic stimulation (rTMS) treatment. This study aimed to investigate whether modulation of corticomotor excitability by rTMS predicts response to rTMS treatment for TRD in 10 Hz and intermittent theta-burst stimulation (iTBS) protocols. METHODS: Thirteen TRD patients underwent two evaluations of corticomotor plasticity-assessed as the post-rTMS (10 Hz, iTBS) percent change (%∆) in motor evoked potential (MEP) amplitude elicited by single-pulse TMS. Following corticomotor plasticity evaluations, patients subsequently underwent a standard 6-week course of 10 Hz rTMS (4 s train, 26 s inter-train interval, 3000 total pulses, 120% of motor threshold) to the left dorsolateral prefrontal cortex. Treatment efficacy was assessed by the Beck Depression Inventory II (BDI-II) and Hamilton Depression Rating Scale (HAM-D). The change in MEPs was compared between 10 Hz and iTBS conditions and related to the change in BDI-II and HAM-D scores. RESULTS: Analyses of variance revealed that across all time-points, higher post-10 Hz MEP change was a significant predictor of greater improvement on the BDI-II (p < 0.001) and HAM-D (p = 0.022). This relationship was not observed with iTBS (p-values≥0.100). Post-hoc tests revealed the MEP change 20 min post-10 Hz was the strongest predictor of BDI-II improvement. LIMITATIONS: Cortical excitability was measured from the motor cortex, rather than the dorsolateral prefrontal cortex, where treatment is applied. The 10 Hz and iTBS protocols were performed at different intensities consistent with common practice. CONCLUSIONS: Modulation of corticomotor excitability by 10 Hz can predict response to rTMS treatment with 10 Hz rTMS.

Phase matters when there is power: Phasic modulation of corticospinal excitability occurs at high amplitude sensorimotor mu-oscillations.

Prior studies have suggested that oscillatory activity in cortical networks can modulate stimulus-evoked responses through time-varying fluctuations in neural excitation-inhibition dynamics. Studies combining transcranial magnetic stimulation (TMS) with electromyography (EMG) and electroencephalography (EEG) can provide direct measurements to examine how instantaneous fluctuations in cortical oscillations contribute to variability in TMS-induced corticospinal responses. However, the results of these studies have been conflicting, as some reports showed consistent phase effects of sensorimotor mu-rhythms with increased excitability at the negative mu peaks, while others failed to replicate these findings or reported unspecific mu-phase effects across subjects. Given the lack of consistent results, we systematically examined the modulatory effects of instantaneous and pre-stimulus sensorimotor mu-rhythms on corticospinal responses with offline EEG-based motor evoked potential (MEP) classification analyses across five identical visits. Instantaneous sensorimotor mu-phase or pre-stimulus mu-power alone did not significantly modulate MEP responses. Instantaneous mu-power analyses showed weak effects with larger MEPs during high-power trials at the overall group level analyses, but this trend was not reproducible across visits. However, TMS delivered at the negative peak of high magnitude mu-oscillations generated the largest MEPs across all visits, with significant differences compared to other peak-phase combinations. High power effects on MEPs were only observed at the trough phase of ongoing mu oscillations originating from the stimulated region, indicating site and phase specificity, respectively. More importantly, such phase-dependent power effects on corticospinal excitability were reproducible across multiple visits. We provide further evidence that fluctuations in corticospinal excitability indexed by MEP amplitudes are partially driven by dynamic interactions between the magnitude and the phase of ongoing sensorimotor mu oscillations at the time of TMS, and suggest promising insights for (re)designing neuromodulatory TMS protocols targeted to specific cortical oscillatory states.

A structured ICA-based process for removing auditory evoked potentials.

Transcranial magnetic stimulation (TMS)-evoked potentials (TEPs), recorded using electroencephalography (EEG), reflect a combination of TMS-induced cortical activity and multi-sensory responses to TMS. The auditory evoked potential (AEP) is a high-amplitude sensory potential-evoked by the "click" sound produced by every TMS pulse-that can dominate the TEP and obscure observation of other neural components. The AEP is peripherally evoked and therefore should not be stimulation site specific. We address the problem of disentangling the peripherally evoked AEP of the TEP from components evoked by cortical stimulation and ask whether removal of AEP enables more accurate isolation of TEP. We hypothesized that isolation of the AEP using Independent Components Analysis (ICA) would reveal features that are stimulation site specific and unique individual features. In order to improve the effectiveness of ICA for removal of AEP from the TEP, and thus more clearly separate the transcranial-evoked and non-specific TMS-modulated potentials, we merged sham and active TMS datasets representing multiple stimulation conditions, removed the resulting AEP component, and evaluated performance across different sham protocols and clinical populations using reduction in Global and Local Mean Field Power (GMFP/LMFP) and cosine similarity analysis. We show that removing AEPs significantly reduced GMFP and LMFP in the post-stimulation TEP (14 to 400 ms), driven by time windows consistent with the N100 and P200 temporal characteristics of AEPs. Cosine similarity analysis supports that removing AEPs reduces TEP similarity between subjects and reduces TEP similarity between stimulation conditions. Similarity is reduced most in a mid-latency window consistent with the N100 time-course, but nevertheless remains high in this time window. Residual TEP in this window has a time-course and topography unique from AEPs, which follow-up exploratory analyses suggest could be a modulation in the alpha band that is not stimulation site specific but is unique to individual subject. We show, using two datasets and two implementations of sham, evidence in cortical topography, TEP time-course, GMFP/LMFP and cosine similarity analyses that this procedure is effective and conservative in removing the AEP from TEP, and may thus better isolate TMS-evoked activity. We show TEP remaining in early, mid and late latencies. The early response is site and subject specific. Later response may be consistent with TMS-modulated alpha activity that is not site specific but is unique to the individual. TEP remaining after removal of AEP is unique and can provide insight into TMS-evoked potentials and other modulated oscillatory dynamics.

Reproducibility of cortical response modulation induced by intermittent and continuous theta-burst stimulation of the human motor cortex.

BACKGROUND: Over the past decade, the number of experimental and clinical studies using theta-burst-stimulation (TBS) protocols of transcranial magnetic stimulation (TMS) to modulate brain activity has risen substantially. The use of TBS is motivated by the assumption that these protocols can reliably and lastingly modulate cortical excitability despite their short duration and low number of stimuli. However, this assumption, and thus the experimental validity of studies using TBS, is challenged by recent work showing large inter- and intra-subject variability in response to TBS protocols. OBJECTIVES: To date, the reproducibility of TBS effects in humans has been exclusively assessed with motor evoked potentials (MEPs), which provide an indirect and limited measure of cortical excitability. Here we combined TMS with electroencephalography (TMS-EEG) and report the first comprehensive investigation of (1) direct TMS-evoked cortical responses to intermittent (iTBS) and continuous TBS (cTBS) of the human motor cortex, and (2) reproducibility of both iTBS- and cTBS-induced cortical response modulation against a robust sham control across repeat visits with commonly used cortical responsivity metrics. RESULTS: We show that although single pulse TMS generates stable and reproducible cortical responses across visits, the modulatory effects of TBS vary substantially both between and within individuals. Overall, at the group level, most measures of the iTBS and cTBS-induced effects were not significantly different from sham-TBS. Most importantly, none of the significant TBS-induced effects observed in visit-1 were reproduced in visit-2. CONCLUSIONS: Our findings suggest that the generally accepted mechanisms of TBS-induced neuromodulation, i.e. through changes in cortical excitability, may not be accurate. Future research is needed to determine the mechanisms underlying the established therapeutic effects of TBS in neuropsychiatry and examine reproducibility of TBS-induced neuromodulation through oscillatory response dynamics.

Higher motor cortical excitability linked to greater cognitive dysfunction in Alzheimer's disease: results from two independent cohorts.

Prior studies have reported increased cortical excitability in people with Alzheimer's disease (AD), but findings have been inconsistent, and how excitability relates to dementia severity remains incompletely understood. The objective of this study was to investigate the association between a transcranial magnetic stimulation (TMS) measure of motor cortical excitability and measures of cognition in AD. A retrospective cross-sectional analysis tested the relationship between resting motor threshold (RMT) and the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) across two independent samples of AD participants (a discovery cohort, n=22 and a larger validation cohort, n=129) and a control cohort of cognitively normal adults (n=26). RMT was correlated with ADAS-Cog in the discovery-AD cohort (n=22, ß=-.70, p<0.001) but not in the control cohort (n=26, ß=-0.13, p=0.513). This relationship was confirmed in the validation-AD cohort (n=129, ß=-.35, p<0.001). RMT can be a useful neurophysiological marker of progressive global cognitive dysfunction in AD. Future translational research should focus on the potential of RMT to predict and track individual pathophysiological trajectories of aging.