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Transcranial magnetic stimulation (TMS) is a powerful tool to probe in vivo brain circuits, as it allows to assess several cortical properties such as excitability, plasticity and connectivity in humans. In the last 20 years, TMS has been applied to patients with dementia, enabling the identification of potential markers of the pathophysiology and predictors of cognitive decline; moreover, applied repetitively, TMS holds promise as a potential therapeutic intervention. The objective of this paper is to present a comprehensive review of studies that have employed TMS in dementia and to discuss potential clinical applications, from the diagnosis to the treatment. To provide a technical and theoretical framework, we first present an overview of the basic physiological mechanisms of the application of TMS to assess cortical excitability, excitation and inhibition balance, mechanisms of plasticity and cortico-cortical connectivity in the human brain. We then review the insights gained by TMS techniques into the pathophysiology and predictors of progression and response to treatment in dementias, including Alzheimer’s disease (AD)-related dementias and secondary dementias. We show that while a single TMS measure offers low specificity, the use of a panel of measures and/or neurophysiological index can support the clinical diagnosis and predict progression. In the last part of the article, we discuss the therapeutic uses of TMS. So far, only repetitive TMS (rTMS) over the left dorsolateral prefrontal cortex and multisite rTMS associated with cognitive training have been shown to be, respectively, possibly (Level C of evidence) and probably (Level B of evidence) effective to improve cognition, apathy, memory, and language in AD patients, especially at a mild/early stage of the disease. The clinical use of this type of treatment warrants the combination of brain imaging techniques and/or electrophysiological tools to elucidate neurobiological effects of neurostimulation and to optimally tailor rTMS treatment protocols in individual patients or specific patient subgroups with dementia or mild cognitive impairment.

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, β=−.70, p

The Discrete Event System Specification (DEVS) is a modular and hierarchical Modeling and Simulation (M&S) formalism based on systems theory that provides a general methodology for the construction of reusable models. Well-defined M&S structures have a positive impact when building simulation models because they can be applied systematically. However, even when DEVS can be used to model routing situations, the structures that emerge from this kind of problem are significant due to the handling of the flow of events. Often, the modeler ends with a lot of simulation models that refer to variants of the same component. The goal of this paper is to analyze the routing process domain from a conceptual modeling perspective through the use of a new DEVS extension called Routed DEVS (RDEVS). The RDEVS formalism is conceptually defined as a subclass of DEVS that manages a set of identified events inside a model network where each node combines a behavioral description with a routing policy. In particular, we study the modeling effort required to solve the M&S of routing problems scenarios employing a comparison between RDEVS modeling solutions and DEVS modeling strategies. Such a comparison is based on measures that promote the capture of the behavioral complexity of the final models. The results obtained highlight the modeling benefits of the RDEVS formalism as a constructor of routing processes. The proposed solution reduces the modeling effort involved in DEVS by specifying the event routing process directly in the RDEVS models using design patterns. The novel contribution is an advance in the understanding of how DEVS as a system modeling formalism supports best practices of software engineering in general and conceptual modeling in particular. The reusability and flexibility of the final simulation models, along with designs with low coupling and high cohesion, are the main benefits of the proposal that improve the M&S task applying a conceptual modeling perspective.

Purpose of the review The incidence of patellar instability in pediatric patients ranges is 50-100 in 100,000 patients per year. Risk of recurrent dislocations however has been cited from 8.6% to 88% depending on individual patient factors. This manuscript highlights the demographical, historical, and anatomic factors associated with recurrent patellar instability following a first-time patella dislocation in the pediatric population. Recent findings In recent years, various studies have focused on identifying risk factors for recurrent patellar instability following a primary patellar dislocation. A mix of patient factors, including age of first dislocation, patella alta, elevated tibial tubercle to trochlear groove and trochlear dysplasia have all been noted in the literature, which have helped to develop various scoring tools to predict recurrent dislocation following nonoperative treatment. Summary Risk of recurrent patellar instability in patients who have previously suffered a patellar dislocation can be due to many factors. These risk factors should be used and applied to a variety of risk scores in order to provide physicians and healthcare providers with a tool to counsel patients and families on their patellar redislocation risk and help guide further management.

Theta-burst stimulation (TBS) is a patterned form of repetitive transcranial magnetic stimulation (rTMS) that has been used to induce long-term modulation (plasticity) of corticospinal excitability in a drastically shorter duration protocol than conventional rTMS protocols. In this study we tested the reliability of the effects of two well defined TBS protocols, continuous TBS (cTBS) and intermittent TBS (iTBS), especially in relation to sham TBS, within and across the same 24 participants. All TBS protocols were repeated after approximately 1 month to assess the magnitude and reliability of the modulatory effects of each TBS protocol. Baseline and post-TBS changes in motor evoked potentials (MEP—measure of corticospinal excitability) amplitudes were compared across the cTBS, iTBS and sham TBS protocols and between the initial and retest visits. Overall, across participants, at the initial visit, iTBS facilitated MEPs as compared to baseline excitability, with sham eliciting the same effect. cTBS did not show a significant suppression of excitability compared to baseline MEPs at either visit, and even facilitated MEPs above baseline excitability at a single time point during the repeat visit. Otherwise, effects of TBS were generally diminished in the repeat visit, with iTBS and sham TBS replicating facilitation of MEPs above baseline excitability at similar time points. However, no protocol demonstrated consistent intra-individual modulation of corticospinal excitability upon retest. As the first study to test both iTBS and cTBS against sham TBS across repeat visits, our findings challenge the efficacy and reliability of TBS protocols and emphasize the importance of accounting for sham effects of TBS. Furthermore, given that therapeutic effects of TBS are hypothetically derived from consistent and repeated modulation of brain activity, the non-replicability of plasticity and sham effects call into question these basic mechanisms.

Background Treatments of freezing of gait (FOG) in Parkinson's disease are suboptimal. Objective The aim of this study was to evaluate the effects of multiple sessions of transcranial direct current stimulation (tDCS) targeting the left dorsolateral prefrontal cortex and primary motor cortex (M1) on FOG. Methods Seventy-seven individuals with Parkinson's disease and FOG were enrolled in a double-blinded randomized trial. tDCS and sham interventions comprised 10 sessions over 2 weeks followed by five once-weekly sessions. FOG-provoking test performance (primary outcome), functional outcomes, and self-reported FOG severity were assessed. Results Primary analyses demonstrated no advantage for tDCS in the FOG-provoking test. In secondary analyses, tDCS, compared with sham, decreased self-reported FOG severity and increased daily living step counts. Among individuals with mild-to-moderate FOG severity, tDCS improved FOG-provoking test time and self-report of FOG. Conclusions Multisession tDCS targeting the left dorsolateral prefrontal cortex and M1 did not improve laboratory-based FOG-provoking test performance. Improvements observed in participants with mild-to-moderate FOG severity warrant further investigation. © 2021 International Parkinson and Movement Disorder Society.

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.

Objective: To assess whether exposure to non-invasive brain stimulation with transcranial alternating current stimulation at γ frequency (γ-tACS) applied over Pz (an area overlying the medial parietal cortex and the precuneus) can improve memory and modulate cholinergic transmission in mild cognitive impairment due to Alzheimer’s disease (MCI-AD). Methods: In this randomized, double-blind, sham controlled, crossover pilot study, participants were assigned to a single 60 min treatment with exposure to γ-tACS over Pz or sham tACS. Each subject underwent a clinical evaluation including assessment of episodic memory pre- and post-γ-tACS or sham stimulation. Indirect measures of cholinergic transmission evaluated using transcranial magnetic stimulation (TMS) pre- and post-γ-tACS or sham tACS were evaluated. Results: Twenty MCI-AD participants completed the study. No tACS-related side effects were observed, and the intervention was well tolerated in all participants. We observed a significant improvement at the Rey auditory verbal learning (RAVL) test total recall (5.7 [95% CI, 4.0 to 7.4], p

The dorsolateral prefrontal cortex (DLPFC) is a crucial brain region for inhibitory control, an executive function essential for behavioral self-regulation. Recently, inhibitory control has been shown to be important for endurance performance. Improvement in inhibitory control was found following transcranial direct current stimulation (tDCS) applied over the left DLPFC (L-DLPFC). This study examined the effect tDCS on both an inhibitory control and endurance performance in a group of healthy individuals. Twelve participants received either real tDCS (Real-tDCS) or placebo tDCS (Sham-tDCS) in randomized order. The anodal electrode was placed over the L-DLPFC while the cathodal electrode was placed above Fp2. Stimulation lasted 30 min with current intensity set at 2 mA. A Stroop test was administered to assess inhibitory control. Heart rate (HR), ratings of perceived exertion (RPE), and leg muscle pain (PAIN) were monitored during the cycling time to exhaustion (TTE) test, while blood lactate accumulation (∆B[La−]) was measured at exhaustion. Stroop task performance was improved after Real-tDCS as demonstrated by a lower number of errors for incongruent stimuli (p = 0.012). TTE was significantly longer following Real-tDCS compared to Sham-tDCS (p = 0.029, 17 ± 8 vs 15 ± 8 min), with significantly lower HR (p = 0.002) and RPE (p < 0.001), while no significant difference was found for PAIN (p > 0.224). ∆B[La−] was significantly higher at exhaustion in Real-tDCS (p = 0.040). Our findings provide preliminary evidence that tDCS with the anodal electrode over the L-DLPFC can improve both inhibitory control and endurance cycling performance in healthy individuals.

Interhemispheric inhibition (IHI) is a dual-site TMS protocol measuring inhibitory interactions between the primary motor cortices (M1). IHI is performed by applying an initial conditioning stimulus followed by a test stimulus to the contralateral M1. Conventionally, the response in the contralateral hand to the conditioning TMS pulse is either not measured, or discarded. The aim of this experiment was to investigate whether MEPs evoked from these conditioning stimuli can be utilised as non-conditioned, or ‘baseline’, responses, and therefore expedite IHI data collection. We evaluated short-latency (10 ms) and long-latency (40 ms) IHI bidirectionally in 14 healthy participants. There was no difference in MEP amplitudes evoked by conventional single TMS pulses randomly inserted into IHI blocks, and those evoked by the conditioning stimulus. Nor was there any significant difference in IHI magnitude when using single pulse MEPs or conditioning stimulus MEPs as baseline responses. The utilisation of conditioning stimuli dispenses with the need to insert dedicated single TMS pulses into IHI blocks, allowing for additional IHI data to be collected in the same amount of time.

Recent studies have revealed the possible role of choroid plexus (ChP) in Alzheimer’s disease (AD). T1-weighted MRI is the modality of choice for the segmentation of ChP in humans. Manual segmentation is considered the gold-standard technique, but given its time-consuming nature, large-scale neuroimaging studies of ChP would be impossible. In this study, we introduce a lightweight segmentation algorithm based on the Gaussian Mixture Model (GMM). We compared its performance against manual segmentation as well as automated segmentation by Freesurfer in three separate datasets: 1) patients with structural MRIs enhanced with contrast (n = 19), 2) young healthy subjects (n = 20), and 3) patients with AD (n = 20). GMM outperformed Freesurfer and showed high similarity with manual segmentation. To further assess the algorithm’s performance in large scale studies, we performed GMM segmentations in young healthy subjects from the Human Connectome Project (n = 1,067), as well as healthy controls, mild cognitive impairment (MCI), and AD patients from the Alzheimer’s Disease Neuroimaging Initiative (n = 509). In both datasets, GMM segmented ChP more accurately than Freesurfer. To show the clinical importance of accurate ChP segmentation, total AV1451 (tau) PET binding to ChP was measured in 108 MCI and 32 AD patients. GMM was able to reveal the higher AV1451 binding to ChP in AD compared with MCI. Our results provide evidence for the utility of the GMM in accurately segmenting ChP and show its clinical relevance in AD. Future structural and functional studies of ChP will benefit from GMM’s accurate segmentation.

Automated anesthesia systems that continuously monitor cortical excitability (CE) changes to govern drug infusion rates, are desirable. Paired‐pulse transcranial magnetic stimulation (ppTMS), with electromyography (EMG), provides noninvasive CE measures. We tested whether, and with what temporal resolution, ppTMS‐EMG detects dose‐dependent CE in rats anesthetized with continuous intravenous propofol. Motor‐evoked potentials (MEPs) were recorded every 20 seconds as either propofol bolus or change in infusion rate was applied. ppTMS‐derived measures varied in direct proportion to propofol dose with subminute temporal resolution. We conclude that ppTMS‐EMG enables real‐time markers of target engagement by anesthetics that may be incorporated into an automated device.

This article is based on a consensus conference, promoted and supported by the International Federation of Clinical Neurophysiology (IFCN), which took place in Siena (Italy) in October 2018. The meeting intended to update the ten-year-old safety guidelines for the application of transcranial magnetic stimulation (TMS) in research and clinical settings (Rossi et al., 2009). Therefore, only emerging and new issues are covered in detail, leaving still valid the 2009 recommendations regarding the description of conventional or patterned TMS protocols, the screening of subjects/patients, the need of neurophysiological monitoring for new protocols, the utilization of reference thresholds of stimulation, the managing of seizures and the list of minor side effects. New issues discussed in detail from the meeting up to April 2020 are safety issues of recently developed stimulation devices and pulse configurations; duties and responsibility of device makers; novel scenarios of TMS applications such as in the neuroimaging context or imaging-guided and robot-guided TMS; TMS interleaved with transcranial electrical stimulation; safety during paired associative stimulation interventions; and risks of using TMS to induce therapeutic seizures (magnetic seizure therapy). An update on the possible induction of seizures, theoretically the most serious risk of TMS, is provided. It has become apparent that such a risk is low, even in patients taking drugs acting on the central nervous system, at least with the use of traditional stimulation parameters and focal coils for which large data sets are available. Finally, new operational guidelines are provided for safety in planning future trials based on traditional and patterned TMS protocols, as well as a summary of the minimal training requirements for operators, and a note on ethics of neuroenhancement.

Combining non-invasive brain stimulation (NIBS) with resting-state functional magnetic resonance imaging (rs-fMRI) is a promising approach to characterize and potentially optimize the brain networks subtending cognition that changes as a function of age. However, whether multifocal NIBS approaches are able to modulate rs-fMRI brain dynamics in aged populations, and if these NIBS-induced changes are consistent with the simulated electric current distribution on the brain remains largely unknown. In the present investigation, thirty-one cognitively healthy older adults underwent two different multifocal real transcranial direct current stimulation (tDCS) conditions (C1 and C2) and a sham condition in a crossover design during a rs-fMRI acquisition. The real tDCS conditions were designed to electrically induce two distinct complex neural patterns, either targeting generalized frontoparietal cortical overactivity (C1) or a detachment between the frontal areas and the posteromedial cortex (C2). Data revealed that the two tDCS conditions modulated rs-fMRI differently. C1 increased the coactivation of multiple functional couplings as compared to sham, while a smaller number of connections increased in C1 as compared to C2. At the group level, C1-induced changes were topographically consistent with the calculated electric current density distribution. At the individual level, the extent of tDCS-induced rs-fMRI modulation in C1 was related with the magnitude of the simulated electric current density estimates. These results highlight that multifocal tDCS procedures can effectively change rs-fMRI neural functioning in advancing age, being the induced modulation consistent with the spatial distribution of the simulated electric current on the brain. Moreover, our data supports that individually tailoring NIBS-based interventions grounded on subject-specific structural data might be crucial to increase tDCS potential in future studies amongst older adults.

Altres ajuts: Fundació La Caixa (LCF/PR/PR16/11110004), Institut Guttmann i Fundació Abertis, ICREA Academia 2019 award research grants i INNOBRAIN (COMRDI15-1-0017) Age-related cognitive impairment (ARCI) has a profound impact on individuals, families, health care systems, and societies at large. Evidence suggests that ARCI is the consequence of underlying brain pathology. Therefore, efforts to minimize the impact of ARCI and thus closing the gap between health span and life span, which has widened in recent years, requires early detection and timely deployment of targeted, personalized interventions. Access to clinical experts is limited and technology screening and assessment methods are thus appealing. However, as traditionally implemented patients were deprived of the benefit of personalized connection with a clinician, which is particularly critical for the prescription and to ensure the adherence to and ultimate success of therapeutic interventions. We present the concept of Intelligent Technology Therapy Assistant (ITA) as a scalable solution that increases the reach of clinical experts while sustaining the personal connection between each patient and their clinician. We illustrate ITA with the "Guttman Neuro Personal Trainer" ®, a tele-rehabilitation platform that provides neuropsychological evaluation and care, and the Barcelona Brain Health Initiative (BBHI) multimodal intervention coaching app, a mobile-based platform that provides lifestyle coaching support in domains related to brain health. In addition, we discuss the translation of these models to a large-scale enterprise with Linus Health. To this end, we conclude with a discussion of challenges and opportunities to move the field forward.

Brain Health is defined as the development and preservation of optimal brain integrity and neural network functioning for a given age. Recent studies have related healthy habits with better maintenance of brain health across the lifespan. As a part of the Barcelona Brain Health Initiative (BBHI), a mHealth platform has been developed with the purpose of helping people to improve and monitor their healthy habits, facilitating the delivery of health coaching strategies. A decision support system (DSS), named Intelligent Coaching Assistant (ICA), has been developed to ease the work of professional brain health coaches, helping them design and monitor adherence to multidomain interventions in a more efficient manner. Personalized recommendations are based on users’ current healthy habits, individual preferences, and motivational aspects. Taking these inputs, an initial user profile is defined, and the ICA applies an algorithm for determining the most suitable personalized intervention plan. An initial validation has been done focusing on assessing the feasibility and usability of the solution, involving 20 participants for three weeks. We conclude that this kind of technology-based intervention is feasible and implementable in real-world settings. Importantly, the personalized intervention proposal generated by the DSS is feasible and its acceptability and usability are high.

We review the latest evidence from animal models, studies in humans using electrophysiology, experimental memory paradigms, and non-invasive brain stimulation (NIBS), in the form of transcranial alternating current stimulation (tACS), suggesting that the altered activity in networks that contribute to the autobiographical memory (ABM) deficits may be modifiable. ABM involves a specific brain network of interacting regions that store and retrieve life experiences. Deficits in ABM are early symptoms in patients with Alzheimer's disease (AD), and serve as relevant predictors of disease progression. The possibility to modify the neural substrates of ABM opens exciting avenues for the development of therapeutic approaches. Beyond a summary of the causal role of brain oscillations in ABM, we propose a new approach of modulating brain oscillations using personalized tACS with the possibility of reducing ABM deficits. We suggest that human experimental studies using cognitive tasks, EEG, and tACS can have future translational clinical implications.

Patients who respond to an antidepressant are identified by retrospective analysis of their brain waves.

Rhythmic neural activity has been proposed to play a fundamental role in cognition. Both healthy and pathological aging are characterized by frequency-specific changes in oscillatory activity. However, the cognitive relevance of these changes across the spectrum from normal to pathological aging remains unknown. We examined electroencephalography (EEG) correlates of cognitive function in healthy aging and 2 of the most prominent and debilitating age-related disorders: type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD). Relative to healthy controls (HC), patients with AD were impaired on nearly every cognitive measure, whereas patients with T2DM performed worse mainly on learning and memory tests. A continuum of alterations in resting-state EEG was associated with pathological aging, generally characterized by reduced alpha (α) and beta (β) power (ADT2DMHC) and increased delta (δ) and theta (θ) power (ADT2DMHC), with some variations across different brain regions. There were also reductions in the frequency and power density of the posterior dominant rhythm in AD. The ratio of (α + β)/(δ + θ) was specifically associated with cognitive function in a domain- and diagnosis-specific manner. The results thus captured both similarities and differences in the pathophysiology of cerebral oscillations in T2DM and AD. Overall, pathological brain aging is marked by a shift in oscillatory power from higher to lower frequencies, which can be captured by a single cognitively relevant measure of the ratio of (α + β) over (δ + θ) power.

Objective Symptomatic head trauma associated with American-style football (ASF) has been linked to brain pathology, along with physical and mental distress in later life. However, the longer-term effects of such trauma on objective metrics of cognitive-motor function remain poorly understood. We hypothesized that ASF-related symptomatic head trauma would predict worse gait performance, particularly during dual task conditions (ie, walking while performing an additional cognitive task), in later life. Methods Sixty-six retired professional ASF players aged 29 to 75 years completed a health and wellness questionnaire. They also completed a validated smartphone-based assessment in their own homes, during which gait was monitored while they walked normally and while they performed a verbalized serial-subtraction cognitive task. Results Participants who reported more symptomatic head trauma, defined as the total number of impacts to the head or neck followed by concussion-related symptoms, exhibited greater dual task cost (ie, percentage increase) to stride time variability (ie, the coefficient of variation of mean stride time). Those who reported ≥1 hit followed by loss of consciousness, compared to those who did not, also exhibited greater dual task costs to this metric. Relationships between reported trauma and dual task costs were independent of age, body mass index, National Football League career duration, and history of musculoskeletal surgery. Symptomatic head trauma was not correlated with average stride times in either walking condition. Interpretation Remote, smartphone-based assessments of dual task walking may be utilized to capture meaningful data sensitive to the long-term impact of symptomatic head trauma in former professional ASF players and other contact sport athletes. ANN NEUROL 2020;87:75-83.

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-minutes 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.

The brain regions responsible for hallucinations remain unclear. We studied 89 brain lesions causing hallucinations using a recently validated technique termed lesion network mapping. We found that hallucinations occurred following lesions to a variety of different brain regions, but these lesion locations fell within a single functionally connected brain network. This network was defined by connectivity to the cerebellar vermis, inferior cerebellum (bilateral lobule X), and the right superior temporal sulcus. Within this single hallucination network, additional connections with the lesion location dictated the sensory modality of the hallucination: lesions causing visual hallucinations were connected to the lateral geniculate nucleus in the thalamus while lesions causing auditory hallucinations were connected to the dentate nucleus in the cerebellum. Our results suggest that lesions causing hallucinations localize to a single common brain network, but additional connections within this network dictate the sensory modality, lending insight into the causal neuroanatomical substrate of hallucinations.

To assess motor cortex neurophysiology, including the mechanisms of neuroplasticity, transcranial magnetic stimulation (TMS) is typically applied to the motor "hotspot"- the optimal site for inducing a twitch in a given target muscle. It is known that the effects of suprathreshold repetitive TMS (rTMS) spread along functional connections beyond the specific cortical stimulation target, and yet, it is unknown whether the aftereffects of subthreshold intermittent theta-burst stimulation (iTBS), an ultra-high frequency patterned rTMS protocol, extend beyond the targeted muscle. We investigated whether and to what extent iTBS induces changes in the cortical output to other intrinsic hand muscles with adjacent cortical representation to the target. Sixteen healthy adults underwent neuronavigated TMS-iTBS targeting the first dorsal interosseus (FDI) hotspot. Proportion of motor evoked potentials (MEPs) at the resting motor threshold (RMT), baseline MEP amplitude, and iTBS-induced changes in MEP amplitude were compared between FDI, abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles. MEP amplitudes recorded from the three muscles at RMT and suprathreshold intensities indicated the chosen hotspots were relatively selective for FDI. Nevertheless, iTBS induced significant facilitation of MEPs recorded from both FDI and APB, but not ADM. Surprisingly, the MEP modulation was greater in APB, even when controlling for the baseline MEP amplitude. These results indicate that iTBS modulation of cortico-spinal excitability extends beyond the representation of the targeted muscle. Results have implications both for how iTBS may be used in clinical treatment and for the safety guidelines for the application of iTBS.

Editor’s PerspectiveWhat We Already Know about This TopicWhat This Article Tells Us That Is NewBackgroundPostoperative delirium and postoperative cognitive dysfunction share risk factors and may co-occur, but their relationship is not well established. The primary goals of this study were to describe the prevalence of postoperative cognitive dysfunction and to investigate its association with in-hospital delirium. The authors hypothesized that delirium would be a significant risk factor for postoperative cognitive dysfunction during follow-up.MethodsThis study used data from an observational study of cognitive outcomes after major noncardiac surgery, the Successful Aging after Elective Surgery study. Postoperative delirium was evaluated each hospital day with confusion assessment method–based interviews supplemented by chart reviews. Postoperative cognitive dysfunction was determined using methods adapted from the International Study of Postoperative Cognitive Dysfunction. Associations between delirium and postoperative cognitive dysfunction were examined at 1, 2, and 6 months.ResultsOne hundred thirty-four of 560 participants (24%) developed delirium during hospitalization. Slightly fewer than half (47%, 256 of 548) met the International Study of Postoperative Cognitive Dysfunction-defined threshold for postoperative cognitive dysfunction at 1 month, but this proportion decreased at 2 months (23%, 123 of 536) and 6 months (16%, 85 of 528). At each follow-up, the level of agreement between delirium and postoperative cognitive dysfunction was poor (kappa less than .08) and correlations were small (r less than .16). The relative risk of postoperative cognitive dysfunction was significantly elevated for patients with a history of postoperative delirium at 1 month (relative risk = 1.34; 95% CI, 1.07–1.67), but not 2 months (relative risk = 1.08; 95% CI, 0.72–1.64), or 6 months (relative risk = 1.21; 95% CI, 0.71–2.09).ConclusionsDelirium significantly increased the risk of postoperative cognitive dysfunction in the first postoperative month; this relationship did not hold in longer-term follow-up. At each evaluation, postoperative cognitive dysfunction was more common among patients without delirium. Postoperative delirium and postoperative cognitive dysfunction may be distinct manifestations of perioperative neurocognitive deficits.

Background: Former American football players have a higher prevalence of cognitive impairment than that of the US general population. It remains unknown what aspects of playing football are associated with neuropsychiatric outcomes. Hypothesis: It was hypothesized that seasons of professional football, playing position, and experience of concussions were associated with cognition-related quality of life (QOL) and indicators of depression and anxiety. Study Design: Descriptive epidemiology study. Methods: The authors examined whether seasons of professional football, playing position, and experience of concussions, as measured by self-report of 10 symptoms, were associated with cognition-related QOL and indicators of depression and anxiety in a cross-sectional survey conducted 2015 to 2017. Cognition-related QOL was measured by the short form of the Quality of Life in Neurological Disorders: Applied Cognition–General Concerns. The Patient Health Questionnaire–4 measured depression and anxiety symptoms. Of 13,720 eligible men with apparently valid contact information, 3506 players returned a questionnaire at the time of this analysis (response rate = 25.6%). Results: Seasons of professional play (risk ratio [RR] per 5 seasons = 1.19, 95% CI = 1.06-1.34) and playing position were associated with cognition-related QOL. Each 5 seasons of play was associated with 9% increased risk of indicators of depression at borderline statistical significance ( P = .05). When compared with former kickers, punters, and quarterbacks, men who played any other position had a higher risk of poor cognition-related QOL, depression, and anxiety. Concussion symptoms were strongly associated with poor cognition-related QOL (highest concussion quartile, RR = 22.3, P < .001), depression (highest quartile, RR = 6.0, P < .0001), and anxiety (highest quartile, RR = 6.4, P < .0001), even 20 years after last professional play. Conclusion: The data suggest that seasons of play and playing position in the NFL are associated with lasting neuropsychiatric health deficits. Additionally, poor cognition-related QOL, depression, and anxiety appear to be associated with concussion in the long term.

Background The long-term health consequences of participation in American style football (ASF) are not well understood. Methods We conducted a retrospective cohort study of men who had played in the NFL after 1960. Participants were studied using a standardized self-administered questionnaire designed to determine both the exposure history to ASF and the prevalence of chronic pain, sleep apnea, cardiometabolic disease, and neurocognitive impairment. Logistic regression and negative binomial regression models were used to assess associations between age, ethnicity, body-mass index during professional football career, field position, and football career duration with individual and multiple afflictions. Results In this cohort of former NFL players (n = 3745), approximately one quarter of the eligible former players (27%) reported two or more medical afflictions (chronic pain, cardiometabolic disease, sleep apnea, or neurocognitive impairment). Career duration was significantly associated with an increase in the number of comorbidities. Age, race, and body-mass index were associated with all affliction categories, other than neurocognitive impairment, which was similarly prevalent in middle-aged players and older players. Earlier age when first playing the sport was protective against cardiometabolic affliction. Conclusions Former NFL players report significant combinations of cross-system afflictions. Future work will be required to determine mechanistic underpinnings. However, attention to the whole player, rather than specific organ systems seems critical to improve long-term health outcomes in former ASF professional athletes.

Concurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG) has emerged as a powerful tool to non-invasively probe brain circuits in humans, allowing for the assessment of several cortical properties such as excitability and connectivity. Over the past decade, this technique has been applied to various clinical populations, enabling the characterization and development of potential TMS-EEG predictors and markers of treatments and of the pathophysiology of brain disorders. The objective of this article is to present a comprehensive review of studies that have used TMS-EEG in clinical populations and to discuss potential clinical applications. To provide a technical and theoretical framework, we first give an overview of TMS-EEG methodology and discuss the current state of knowledge regarding the use of TMS-EEG to assess excitability, inhibition, plasticity and connectivity following neuromodulatory techniques in the healthy brain. We then review the insights afforded by TMS-EEG into the pathophysiology and predictors of treatment response in psychiatric and neurological conditions, before presenting recommendations for how to address some of the salient challenges faced in clinical TMS-EEG research. Finally, we conclude by presenting future directions in line with the tremendous potential of TMS-EEG as a clinical tool.

Background Several lines of investigations converge upon aberrant synaptic plasticity as a potential pathophysiological characteristic of schizophrenia. In vivo experiments using neuromodulatory perturbation techniques like Transcranial Magnetic and Direct Current Stimulation (TMS & tDCS) have been increasingly used to measure ‘motor cortical plasticity’ in schizophrenia. A systematic quantification of cortical plasticity and its moderators in schizophrenia is however lacking. Method The PubMed/MEDLINE database was searched for studies up to December 31st, 2017 that examined case-control experiments comparing neuromodulation following single-session of TMS or tDCS. The primary outcome was the standardized mean difference for differential changes in motor evoked potential (MEP) amplitudes measured with single-pulse TMS (MEP Δ) between patients and healthy subjects following TMS or tDCS. After examining heterogeneity, meta-analyses were performed using fixed effects models. Results A total of 16 datasets comparing cortical plasticity (MEP Δ) between 189 schizophrenia patients and 187 healthy controls were included in the meta-analysis. Patients demonstrated diminished MEP Δ with effect sizes (Cohen's d) ranging from 0.66 (LTP-like plasticity) to 0.68 (LTD-like plasticity). Heterosynaptic plasticity studies demonstrated a greater effect size (0.79) compared to homosynaptic plasticity studies (0.62), though not significant (P = 0.43). Clinical, perturbation protocol- and measurement-related factors, and study quality did not significantly moderate the aberrant plasticity demonstrated in schizophrenia. Conclusions Schizophrenia patients demonstrate diminished LTP- and LTD-like motor cortical plasticity, which is not influenced by the various clinical and experimental protocol related confounders. These consistent findings should encourage the use of perturbation-based biomarkers to characterize illness trajectories and treatment response.

BACKGROUND Intensive robot-assisted arm training in the chronic phase of stroke recovery can lead to clinical improvement. Combinatorial therapeutic approaches are sought to further optimize stroke recovery. Transcranial direct current stimulation (tDCS) is one candidate to combine with robotic training, as transient increases in excitability and improvements in motor behavior have separately been reported. OBJECTIVE To determine whether tDCS, delivered prior to robotic training, could augment clinical improvement. METHODS We conducted a dual-site, randomized controlled trial in 82 chronic ischemic stroke patients (inclusion > 6 m post-injury, dominant hemisphere, first stroke; residual hemiparesis) who were split into two groups to receive tDCS (M1-SO montage, anode ipsilesional, 5×7 cm electrodes, 2 mA, 20 mins) or sham tDCS, prior to robotic upper-limb training (12 weeks; 36 sessions; shoulder-elbow robot or wrist robot on alternating sessions). The primary end-point was taken after 12 weeks of training, and assessed with the Upper Extremity Fugl-Meyer impairment scale (FM). Corticomotor conduction was assessed with transcranial magnetic stimulation (TMS). RESULTS For the combined group (n = 82; post-training) robotic training increased the FM by 7.36 points compared to baseline (p

PURPOSE OF REVIEW: Alzheimer’s disease (AD) is a progressive neurodegenerative disease without effective pharmacological treatment. Noninvasive brain stimulation (NIBS) techniques, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial electrical stimulation (tES), are increasingly being investigated for their potential to ameliorate the symptoms of AD 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 rTMS and twelve used transcranial direct current stimulation (tDCS), the most common form of tES. Eight of the studies combined NIBS with cognitive training. Promising results should encourage continued investigation, however there is presently 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.

The default-mode network (DMN) is affected by advancing age, where particularly long-range connectivity has been consistently reported to be reduced as compared to young individuals. We examined whether there were any differences in the effects of intermittent theta-burst stimulation (iTBS) in DMN connectivity between younger and older adults, its associations with cognition and brain integrity, as well as with long-term cognitive status. Twenty-four younger and 27 cognitively normal older adults were randomly assigned to receive real or sham iTBS over the left inferior parietal lobule between two resting-state functional magnetic resonance imaging (rs-fMRI) acquisitions. Three years later, those older adults who had received real iTBS underwent a cognitive follow-up assessment. Among the younger adults, functional connectivity increased following iTBS in distal DMN areas from the stimulation site. In contrast, older adults exhibited increases in connectivity following iTBS in proximal DMN regions. Moreover, older adults with functional responses to iTBS resembling those of the younger participants exhibited greater brain integrity and higher cognitive performance at baseline and at the 3-year follow-up, along with less cognitive decline. Finally, we observed that ‘young-like’ functional responses to iTBS were also related to the educational background attained amongst older adults. The present study reveals that functional responses of the DMN to iTBS are modulated by age. Furthermore, combining iTBS and rs-fMRI in older adults may allow characterizing distinctive cognitive profiles in aging and its progression, probably reflecting network plasticity systems that may entail a neurobiological substrate of cognitive reserve.

Malignant brain tumours are among the most aggressive human cancers, and despite intensive efforts made over the last decades, patients' survival has scarcely improved. Recently, high-grade gliomas (HGG) have been found to be electrically integrated with healthy brain tissue, a communication that facilitates tumour mitosis and invasion. This link to neuronal activity has provided new insights into HGG pathophysiology and opened prospects for therapeutic interventions based on electrical modulation of neural and synaptic activity in the proximity of tumour cells, which could potentially slow tumour growth. Noninvasive brain stimulation (NiBS), a group of techniques used in research and clinical settings to safely modulate brain activity and plasticity via electromagnetic or electrical stimulation, represents an appealing class of interventions to characterise and target the electrical properties of tumour-neuron interactions. Beyond neuronal activity, NiBS may also modulate function of a range of substrates and dynamics that locally interacts with HGG (e.g., vascular architecture, perfusion and blood-brain barrier permeability). Here we discuss emerging applications of NiBS in patients with brain tumours, covering potential mechanisms of action at both cellular, regional, network and whole-brain levels, also offering a conceptual roadmap for future research to prolong survival or promote wellbeing via personalised NiBS interventions.

OBJECTIVE Among older adults, the ability to stand or walk while performing cognitive tasks (ie, dual-tasking) requires coordinated activation of several brain networks. In this multicenter, double-blinded, randomized, and sham-controlled study, we examined the effects of modulating the excitability of the left dorsolateral prefrontal cortex (L-DLPFC) and the primary sensorimotor cortex (SM1) on dual-task performance "costs" to standing and walking. METHODS Fifty-seven older adults without overt illness or disease completed 4 separate study visits during which they received 20 minutes of transcranial direct current stimulation (tDCS) optimized to facilitate the excitability of the L-DLPFC and SM1 simultaneously, or each region separately, or neither region (sham). Before and immediately after stimulation, participants completed a dual-task paradigm in which they were asked to stand and walk with and without concurrent performance of a serial-subtraction task. RESULTS tDCS simultaneously targeting the L-DLPFC and SM1, as well as tDCS targeting the L-DLPFC alone, mitigated dual-task costs to standing and walking to a greater extent than tDCS targeting SM1 alone or sham (p

Background: 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 specificObjectives/Methods: 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 Potentials (GMFA/LMFA) and cosine similarity analysis.Results: We show that removing AEPs significantly reduced GMFA and LMFA 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 analyses suggest could be a modulation in the alpha band that is not stimulation site specific but is unique to individual subject.Conclusion(s): We show, using two datasets and two implementations of sham, evidence in cortical topography, TEP time-course, GMFA/LMFA and cosine similarity analyses that this procedure is effective and conservative in removing the AEP from TEP, and thereby reveals better defined TMS-evoked activity. We show TEP remaining in early, mid and late latencies. The early response is site and subject specific. Later responses are 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.

Previous evidence suggests that transcranial direct current stimulation (tDCS) to the left dorsolateral prefrontal cortex (l-DLPFC) can enhance episodic memory in subjects with subjective cognitive decline (SCD), known to be at risk of dementia. Our main goal was to replicate such findings in an independent sample and elucidate if baseline magnetic resonance imaging (MRI) characteristics predicted putative memory improvement. Thirty-eight participants with SCD (aged: 60–65 years) were randomly assigned to receive active (N = 19) or sham (N = 19) tDCS in a double-blind design. They underwent a verbal learning task with 15 words (DAY-1), and 24 h later (DAY-2) stimulation was applied for 15 min at 1.5 mA targeting the l-DLPFC after offering a contextual reminder. Delayed recall and recognition were measured 1 day after the stimulation session (DAY-3), and at 1-month follow-up (DAY-30). Before the experimental session, structural and functional MRI were acquired. We identified a group∗time interaction in recognition memory, being the active tDCS group able to maintain stable memory performance between DAY-3 and DAY-30. MRI results revealed that individuals with superior tDCS-induced effects on memory reconsolidation exhibited higher left temporal lobe thickness and greater intrinsic FC within the default-mode network. Present findings confirm that tDCS, through the modulation of memory reconsolidation, is capable of enhancing performance in people with self-perceived cognitive complaints. Results suggest that SCD subjects with more preserved structural and functional integrity might benefit from these interventions, promoting maintenance of cognitive function in a population at risk to develop dementia.

Background: Previous studies have compared the use of continuous nerve catheter versus single-shot nerve block approaches to regional anesthesia in ACL Reconstruction (ACLR), but they have primarily focused on adult populations. A paucity of data exists comparing these regional anesthesia techniques in children. Hypothesis/Purpose: To compare postoperative pain, strength, and functional outcomes between pediatric ACLR patients undergoing femoral nerve catheter (FNC) placement with single-shot sciatic block and those receiving femoral and sciatic single-shot nerve blocks (SSNB). Methods: Pediatric patients (≤18 years) undergoing primary ACLR between 1/2018-8/2019 at an urban tertiary care children’s hospital were identified. Patients were grouped based on regional anesthetic technique (FNC vs. SSNB). Emergency department (ED) visits, clinic visits, and calls for uncontrolled pain and narcotic refills were compared between these two groups. Outcomes including PROMIS scores, strength testing, and active range of motion (AROM) were also compared. Multiple imputation analysis was used to reduce bias as a result of missed follow-up. Results: 78 patients met inclusion criteria (FNC-36 patients, SSNB-42 patients). There were no differences in age, sex, BMI, or surgical technique between cohorts (Table I). Block preparation time (pConclusion: SSNB was associated with shorter operative times and better PROMIS physical function – mobility scores at 1 week compared to FNC. No other differences were observed in post-operative pain management, and cohorts were without differences in AROM and isokinetic strength by 6 months. Tables/Figures: [Table: see text][Table: see text]

TAK-653 is a novel α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-positive allosteric modulator being developed as a potential therapeutic for major depressive disorder (MDD). Currently, there are no translational biomarkers that evaluate physiological responses to the activation of glutamatergic brain circuits available. Here, we tested whether noninvasive neurostimulation, specifically single-pulse or paired-pulse motor cortex transcranial magnetic stimulation (spTMS and ppTMS, respectively), coupled with measures of evoked motor response captures the pharmacodynamic effects of TAK-653 in rats and healthy humans. In the rat study, five escalating TAK-653 doses (0.1–50 mg/kg) or vehicle were administered to 31 adult male rats, while measures of cortical excitability were obtained by spTMS coupled with mechanomyography. Twenty additional rats were used to measure brain and plasma TAK-653 concentrations. The human study was conducted in 24 healthy volunteers (23 males, 1 female) to assess the impact on cortical excitability of 0.5 and 6 mg TAK-653 compared with placebo, measured by spTMS and ppTMS coupled with electromyography in a double-blind crossover design. Plasma TAK-653 levels were also measured. TAK-653 increased both the mechanomyographic response to spTMS in rats and the amplitude of motor-evoked potentials in humans at doses yielding similar plasma concentrations. TAK-653 did not affect resting motor threshold or paired-pulse responses in humans. This is the first report of a translational functional biomarker for AMPA receptor potentiation and indicates that TMS may be a useful translational platform to assess the pharmacodynamic profile of glutamate receptor modulators.

Alzheimer's disease (AD) is an irreversible, progressive brain disorder that can cause dementia (Alzheimer's disease-related dementia, ADRD) with growing cognitive disability and vast physical, emotional, and financial pressures not only on the patients but also on caregivers and families. Loss of memory is an early and very debilitating symptom in AD patients and a relevant predictor of disease progression. Data from rodents, as well as human studies, suggest that dysregulation of specific brain oscillations, particularly in the hippocampus, is linked to memory deficits. Animal and human studies demonstrate that non-invasive brain stimulation (NIBS) in the form of transcranial alternating current stimulation (tACS) allows to reliably and safely interact with ongoing oscillatory patterns in the brain in specific frequencies. We developed a protocol for patient-tailored home-based tACS with an instruction program to train a caregiver to deliver daily sessions of tACS that can be remotely monitored by the study team. We provide a discussion of the neurobiological rationale to modulate oscillations and a description of the study protocol. Data of two patients with ADRD who have completed this protocol illustrate the feasibility of the approach and provide pilot evidence on the safety of the remotely-monitored, caregiver-administered, home-based tACS intervention. These findings encourage the pursuit of a large, adequately powered, randomized controlled trial of home-based tACS for memory dysfunction in ADRD.

Purpose Animal and proof-of-principle human studies suggest that cathodal transcranial direct current stimulation may suppress seizures in drug-resistant focal epilepsy. The present study tests the safety, tolerability, and effect size of repeated daily cathodal transcranial direct current stimulation in epilepsy have not been established, limiting development of clinically meaningful interventions. Methods We conducted a 2-center, open-label study on 20 participants with medically refractory, focal epilepsy, aged 9 to 56 years (11 women and 9 children younger than18 years). Each participant underwent 10 sessions of 20 minutes of cathodal transcranial direct current stimulation over 2 weeks. Multielectrode montages were designed using a realistic head model-driven approach to conduct an inhibitory electric field to the target cortical seizure foci and surrounding cortex to suppress excitability and reduce seizure rates. Patients recorded daily seizures using a seizure diary 8 weeks prior, 2 weeks during, and 8 to 12 weeks after the stimulation period. Results The median seizure reduction was 44% relative to baseline and did not differ between adult and pediatric patients. Three patients experienced an increase in seizure frequency of >50% during the stimulation period; in one, a 36% increase in seizure frequency persisted through 12 weeks of follow-up. Otherwise, participants experienced only minor adverse events-the most common being scalp discomfort during transcranial direct current stimulation. Conclusions This pilot study supports the safety and efficacy of multifocal, personalized, multichannel, cathodal transcranial direct current stimulation for adult and pediatric patients with medication-refractory focal epilepsy, although identifies a possibility of seizure exacerbation in some. The data also provide insight into the effect size to inform the design of a randomized, sham-stimulation controlled trial.

OBJECTIVE. To test whether change in motor evoked potential (ΔMEP) induced by continuous theta-burst stimulation (cTBS) of motor cortex (M1) distinguishes adults with autism spectrum disorder (ASD) from neurotypicals, and to explore the contribution of two common polymorphisms related to neuroplasticity. METHODS. 44 adult neurotypical (NT) participants (age 21–65, 34 males) and 19 adults with ASD (age 21–58, 17 males) prospectively underwent M1 cTBS. Their data were combined with previously obtained results from 35 NT and 35 ASD adults. RESULTS. ΔMEP at 15 minutes post-cTBS (T15) was a significant predictor of diagnosis (p=0.04) in the present sample (n=63). T15 remained a significant predictor in a larger sample (n=91) and when partially imputed based on T10–T20 from a yet-greater sample (N=133). T15 also remained a significant predictor of diagnosis among brain-derived neurotrophic factor (BDNF) Met+ and apolipoprotein E (APOE) ε4− subjects (p’s0.19). CONCLUSIONS. ΔMEP at T15 post-cTBS is a significant biomarker for adults with ASD, and its utility is modulated by BDNF and APOE polymorphisms. SIGNIFICANCE. M1 cTBS response is a physiologic biomarker for adults with ASD in large samples, and controlling for BDNF and APOE polymorphisms can improve its diagnostic utility.

Background While morbid obesity is associated with increased infection after total hip arthroplasty, little is known on the outcomes after 2-stage reimplantation for prosthetic joint infection (PJI) in this population. The purpose of this study is to evaluate the impact of morbid obesity (body mass index>40 kg/m2) on reinfection, postoperative complications, readmissions, and reoperations. Methods We conducted a retrospective review of 107 patients undergoing first time 2-stage reimplantation for PJI from 2013 to 2019. 18 patients (50% women) with body mass index>40 kg/m2 were identified. To minimize confounders, three propensity score matched cohorts were created, yielding 16 nonobese ( 40 kg/m2) patients. Outcomes were compared using chi-square or Fisher’s exact tests. All patients had minimum 12-month follow-up, with mean follow-up of 36.3, 30.1, and 40.0 months in the nonobese, obese, and morbidly obese cohorts, respectively. Results Compared with nonobese patients, morbidly obese patients had a higher rate of reinfection (0% vs 33%, P = .020 and higher likelihood of length of stay>4 days (19% vs 61%, P = .012). In addition, compared with nonobese and obese patients, morbidly obese patients had higher rate of return to the operating room for any reason (13% vs 19% vs 50%, respectively, P = .020). No differences between cohorts were found regarding complications, death, or revision surgery. Conclusion Morbidly obese patients have significantly increased risk of reinfection and reoperation after 2-stage reimplantation for PJI when compared with obese and nonobese patients. These data can be used to counsel morbidly obese patients contemplating total hip arthroplasty and supports the notion of deferring arthroplasty in this population pending optimization.

ObjectiveInterindividual variability of single and paired-pulse TMS data has limited the clinical and experimental applicability of these methods. This study brought together over 60 TMS researchers to create the largest known sample of individual participant single and paired-pulse TMS data to date, enabling a more comprehensive evaluation of factors driving response variability.Methods118 corresponding authors provided deidentified individual TMS data. Mixed-effects regression investigated a range of individual and study level variables for their contribution to variability in response to single and pp TMS data.Results687 healthy participant’s TMS data was pooled across 35 studies. Target muscle, pulse waveform, neuronavigation use, and TMS machine significantly predicted an individual’s single pulse TMS amplitude. Baseline MEP amplitude, M1 hemisphere, and biphasic AMT significantly predicted SICI response. Baseline MEP amplitude, test stimulus intensity, interstimulus interval, monophasic RMT, monophasic AMT, and biphasic RMT significantly predicted ICF response. Age, M1 hemisphere, and TMS machine significantly predicted motor threshold.ConclusionsThis large-scale analysis has identified a number of factors influencing participants’ responses to single and paired pulse TMS. We provide specific recommendations to increase the standardisation of TMS methods within and across laboratories, thereby minimising interindividual variability in single and pp TMS data.Highlights687 healthy participant’s TMS data was pooled across 35 studiesSignificant relationships between age and resting motor thresholdSignificant relationships between baseline MEP amplitude and SICI/ICF

BACKGROUND Former American style football players (ASF players) have recognized health concerns associated with prior sport participation. It remains unknown whether categorizations of current health conditions, referred to in this report as afflictions (conceptually framed as neurocognitive, cardiovascular, cardiometabolic, sleep apnea, and chronic pain) are associated with physical and mental function. OBJECTIVE To evaluate the association of afflictions to physical and mental function. It was hypothesized that former National Football League players with any affliction would have worse function compared to unafflicted participants. It was anticipated that multiple afflictions would result in cumulative loss of function. DESIGN Cross-sectional retrospective design. SETTING Academic medical multisite hospital system. PARTICIPANTS A total of 3913 of 15,611 former ASF players who played professionally from 1960 to 2019 (response rate 25%). Assessment of Risk Factors Self-report survey. MAIN OUTCOME MEASURES Each participant completed the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale and Physical Function questionnaires. Responses were used to generate two physical function and one mental function subscale scores. Raw scores were converted to T-scores categorized as impaired (T-score