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Key points Synchronized TMS pulses with pre-defined brain oscillatory phases allows to evaluate the impact of brain states on TMS effects. TMS pulses over M1 at the negative peak of μ-frequency band induces higher phase-lock synchronization with interconnected contralateral homologous regions. Cortico-cortical synchronization changes are linearly predicted by the fiber density and cross-section of the white matter tract that connect the two brain regions. Phase-dependent TMS delivery might be crucial not only to amplify local effects but also to increase magnitude and reliability of within-network synchronization. Abstract Recent studies have synchronized transcranial magnetic stimulation (TMS) application with pre-defined brain oscillatory phases showing how the effect of a perturbation depends on the brain state. However, none have investigated if phase-dependent TMS can possibly modulate connectivity with homologous distant brain regions belonging to the same network. In the framework of network-targeted TMS, we investigated whether stimulation delivered at a specific phase of ongoing brain oscillations might favor stronger cortico-cortical (c-c) synchronization of distant network nodes connected to the stimulation target. Neuronavigated TMS pulses were delivered over the primary motor cortex (M1) during ongoing electroencephalography recording in twenty-four healthy individuals over two repeated sessions 1-month apart. Stimulation effects were analyzed considering whether the TMS pulse was delivered at the time of a positive (peak) or negative (trough) phase of μ-frequency oscillation, which determines c-c synchrony within homologous areas of the sensorimotor network. Diffusion Weighted Imaging was used to study c-c connectivity within the sensorimotor network and identify contralateral regions connected with the stimulation spot. Depending on when during the μ-activity the TMS-pulse was applied (peak or trough), its impact on inter-hemispheric network synchrony varied significantly. Higher M1-M1 phase-lock synchronization with after the TMS-pulse (0-200ms) in the μ-frequency band was found for trough compared to peak stimulation trials in both study visits. Phase-dependent TMS delivery might be crucial not only to amplify local effects but also to increase magnitude and the reliability of the response to the external perturbation, with implications for interventions aimed at engaging more distributed functional brain networks. This article is protected by copyright. All rights reserved.

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.

Objective The purpose of this study was to determine the extent to which therapeutic processes - working alliance and depth of experiencing - contributed to outcome. Method Individual differences in these processes were examined at the early and working phases to determine their impact on symptom reduction. An archival data set of N = 42 individuals who underwent emotion-focused therapy for trauma for childhood maltreatment was used to examine the differential quality of client processes throughout treatment. Results For those who had difficulty forming an alliance early in therapy, alliance scores during the working phase were the best predictor of outcome (β = -.42). This was complemented by a process change of improvement in alliance from the early to working phases (d = 1.0). In contrast, for those who had difficulty engaging in deepened experiencing early in therapy, depth of experiencing in the working phase was the best predictor of outcome (β = -.36). This was complemented by an improvement in depth of experiencing from the early to working phases (d = .69). Conclusions The findings of this study suggest that focusing on the process that clients have trouble with early in therapy contributes to the best treatment outcome. Practitioner points Sometimes early treatment sessions reveal an abundance of one kind of processing but limitations to another, which poses a puzzle for treatment planning. Our findings suggest that within the first four sessions, therapists could develop tailored treatments based on the relative presence or absence of critical therapeutic changes processes. When it becomes evident that therapy is progressing with a weaker alliance between client and therapist, therapists should redouble their efforts in alliance-building. However, when therapy is developing in a fashion that lacks deep emotional experiencing on the part of the client, treatment efforts should aim to facilitate a richer exploration of moment-by-moment experience. As such, our findings suggest relying on the existing processing strengths within a dyad (e.g., emphasis on an already strong relationships, or augmenting an existing aptitude for deeper experiencing) while shortcomings exist in another kind of process is not optimal responding. Therapists should focus their work on the process that clients have trouble with early in therapy to facilitate the best treatment outcome.

Objective Cathodal direct current stimulation (cDCS) induces long-term depression (LTD)-like reduction of cortical excitability (DCS-LTD), which has been tested in the treatment of epilepsy with modest effects. In part, this may be due to variable cortical neuron orientation relative to the electric field. We tested, in vivo and in vitro, whether DCS-LTD occurs throughout the cortical thickness, and if not, then whether drug-DCS pairing can enhance the uniformity of the cortical response and the cDCS antiepileptic effect. Methods cDCS-mediated changes in cortical excitability were measured in vitro in mouse motor cortex (M1) and in human postoperative neocortex, in vivo in mouse somatosensory cortex (S1), and in a mouse kainic acid (KA)-seizure model. Contributions of N-methyl-D-aspartate-type glutamate receptors (NMDARs) to cDCS-mediated plasticity were tested with application of NMDAR blockers (memantine/D-AP5). Results cDCS reliably induced DCS-LTD in superficial cortical layers, and a long-term potentiation (LTP)-like enhancement (DCS-LTP) was recorded in deep cortical layers. Immunostaining confirmed layer-specific increase of phospho-S6 ribosomal protein in mouse M1. Similar nonuniform cDCS aftereffects on cortical excitability were also found in human neocortex in vitro and in S1 of alert mice in vivo. Application of memantine/D-AP5 either produced a more uniform DCS-LTD throughout the cortical thickness or at least abolished DCS-LTP. Moreover, a combination of memantine and cDCS suppressed KA-induced seizures. Interpretation cDCS aftereffects are not uniform throughout cortical layers, which may explain the incomplete cDCS clinical efficacy. NMDAR antagonists may augment cDCS efficacy in epilepsy and other disorders where regional depression of cortical excitability is desirable. ANN NEUROL 2020;88:489-502.

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.

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.

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.

Having the means to share research data openly is essential to modern science. For human research, a key aspect in this endeavor is obtaining consent from participants, not just to take part in a study, which is a basic ethical principle, but also to share their data with the scientific community. To ensure that the participants' privacy is respected, national and/or supranational regulations and laws are in place. It is, however, not always clear to researchers what the implications of those are, nor how to comply with them. The Open Brain Consent (https://open-brain-consent.readthedocs.io) is an international initiative that aims to provide researchers in the brain imaging community with information about data sharing options and tools. We present here a short history of this project and its latest developments, and share pointers to consent forms, including a template consent form that is compliant with the EU general data protection regulation. We also share pointers to an associated data user agreement that is not only useful in the EU context, but also for any researchers dealing with personal (clinical) data elsewhere. Non