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Objective: Repeated spaced sessions of repetitive transcranial magnetic stimulation (TMS) to the human primary motor cortex can lead to dose-dependent increases in motor cortical excitability. However, this has yet to be demonstrated in a defined cortical circuit. We aimed to examine the effects of repeated spaced cortical paired associative stimulation (cPAS) on excitability in the motor cortex., Methods: cPAS was delivered to the primary motor cortex (M1) and posterior parietal cortex (PPC) with two coils. In the multi-dose condition, three sessions of cPAS were delivered 50-min apart. The single-dose condition had one session of cPAS, followed by two sessions of a control cPAS protocol. Motor-evoked potentials were evaluated before and up to 40 min after each cPAS session as a measure of cortical excitability., Results: Compared to a single dose of cPAS, motor cortical excitability significantly increased after multi-dose cPAS. Increasing the number of cPAS sessions resulted in a cumulative, dose-dependent effect on excitability in the motor cortex, with each successive cPAS session leading to notable increases in potentiation., Conclusion: Repeated spaced cPAS sessions summate to increase motor cortical excitability induced by single cPAS., Significance: Repeated spaced cPAS could potentially restore abilities lost due to disorders like stroke., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Few studies have investigated tolerability, blinding, and double-blinding of High-Definition transcranial Direct Current Stimulation (HD-tDCS) at amplitudes above 2 milliamps (mA)., Objective: We examined a) tolerability of HD-tDCS during stimulation sessions and b) blinding and double blinding of participants and study team members., Methods: Data from a mixed neurologic sample of 292 older adults were pooled from 3046 HD-tDCS sessions (2329 active; 717 sham). Per electrode amplitudes ranged from 1 mA to 4 mA with total currents up to 10 mA. Participants completed a standardized sensation (tolerability) questionnaire after each session. Participants and study team members stated whether the participant received active or sham stimulation at the end of various sessions. Data were collapsed into the presence/absence of a symptom due to low rates of positive responding and were analyzed for both differences and bioequivalency., Results: There were no safety-related adverse events. HD-tDCS was well tolerated with mostly no ("none") or "mild" sensations reported across sessions, regardless of active or sham condition and in both stimulation naïve and experienced participants. There were no significant differences in side effects between active and sham, with some achieving bioequivalence. Tingling and itching were significantly more common after lower (<2 mA) than higher (≥3 mA) amplitude active sessions, while skin redness was significantly more common after higher amplitudes. Blinding was effective at the participant and study team levels., Conclusions: HD-tDCS was well tolerated with center electrode amplitudes up to 4 mA. The bimodal ramp-up/down format of the sham was effective for blinding. These results support higher scalp-based amplitudes that enable greater brain-based current intensities in older adults., Competing Interests: Declaration of competing interest The City University of New York holds patents on brain stimulation, with MB as an inventor. MB has equity in Soterix Medical Inc. MB consults, received grants, assigned inventions, and/or served on the SAB of SafeToddles, Boston Scientific, GlaxoSmithKline, Biovisics, Mecta, Lumenis, Halo Neuroscience, Google-X, i-Lumen, Humm, Allergan (Abbvie), Apple, Ybrain, Ceragem, Remz. There are no conflicts of interest for any other author., (Published by Elsevier Inc.)

Objective: The objective of the study was to investigate transcranial wave propagation through two low-intensity focused ultrasound (LIFU)-based brain stimulation techniques-transcranial focused ultrasound stimulation (tFUS) and transcranial pulse stimulation (TPS). Although tFUS involves delivering long trains of acoustic pulses, the newly introduced TPS delivers ultrashort (∼3 μs) pulses repeated at 4 Hz. Accordingly, only a single simulation study with limited geometry currently exists for TPS. We considered a high-resolution three-dimensional (3D) whole human head model in addition to water bath simulations. We anticipate that the results of this study will help researchers investigating LIFU have a better understanding of the effects of the two different techniques., Approach: With an objective to first reproduce previous computational results, we considered two spherical tFUS transducers that were previously modeled. We assumed identical parameters (geometry, position, and imaging data set) to demonstrate differences, purely because of the waveform considered. For simulations with a 3D head data set, we also considered a parabolic transducer that has been used for TPS delivery., Results: Our initial results successfully verified previous modeling workflow. The tFUS distribution was characterized by the typical elliptical profile, with its major axis perpendicular to the face of the transducer. The TPS distribution resembled two mirrored meniscus profiles, with its widest diameter oriented parallel to the face of the transducer. The observed intensity value differences were theoretical because the two waveforms differ in both intensity and time. The consideration of a realistic 3D human head model resulted in only a minor distortion of the two waveforms., Significance: This study simulated TPS administration using a 3D realistic image-derived data set. Although our comparison results are strictly limited to the model parameters and assumptions made, we were able to elucidate some clear differences between the two approaches. We hope this initial study will pave the way for systematic comparison between the two approaches in the future., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Acute Respiratory Distress Syndrome (ADRS) due to coronavirus disease 2019 (COVID-19) has been associated with muscle fatigue, corticospinal pathways dysfunction, and mortality. High-Definition transcranial Direct Current Stimulation (HD-tDCS) may be used to attenuate clinical impairment in these patients. The HD-RECOVERY randomized clinical trial was conducted to evaluate the efficacy and safety of HD-tDCS with respiratory rehabilitation in patients with moderate to severe ARDS due to COVID-19., Methods: Fifty-six critically ill patients were randomized 1:1 to active (n = 28) or sham (n = 28) HD-tDCS (twice a day, 30-min, 3-mA) plus respiratory rehabilitation for up to 10 days or until intensive care unit discharge. The primary outcome was ventilator-free days during the first 28 days, defined as the number of days free from mechanical ventilation. Furthermore, secondary outcomes such as delirium, organ failure, hospital length of stay and adverse effects were investigated., Results: Active HD-tDCS induced more ventilator-free days compared to sham HD-tDCS. Patients in the active group vs in the sham group experienced lower organ dysfunction, delirium, and length of stay rates over time. In addition, positive clinical response was higher in the active vs sham group. There was no significant difference in the prespecified secondary outcomes at 5 days. Adverse events were similar between groups., Conclusions: Among patients with COVID-19 and moderate to severe ARDS, use of active HD-tDCS compared with sham HD-tDCS plus respiratory rehabilitation resulted in a statistically significant increase in the number of ventilator-free days over 28 days. HD-tDCS combined with concurrent rehabilitation therapy is a safe, feasible, potentially add-on intervention, and further trials should examine HD-tDCS efficacy in a larger sample of patients with COVID-19 and severe hypoxemia., Competing Interests: Declaration of competing interest The City University of New York holds patents on brain stimulation with MB as inventor. MB has equity in Soterix Medical Inc. MB consults, received grants, assigned inventions, and/or serves on the SAB of SafeToddles, Boston Scientific, GlaxoSmithKline, Biophysics, Mecta, Lumenis, Halo Neuroscience, Google-X, i-Lumen, Humm, Allergan (Abbvie), Apple. AD is an employee and has equity in Soterix Medical Inc., (Copyright © 2022. Published by Elsevier Inc.)

Prior work has revealed that mnemonic strategy training (MST) can enhance memory for specific content and engages regions in the frontoparietal cognitive control network. Evidence of transfer to novel content is less clear. Here, we provide secondary analysis of functional magnetic resonance imaging (fMRI) data acquired during a randomized controlled trial that compared MST to an active education control condition in patients with amnestic mild cognitive impairment (a-MCI). In the trial, thirty participants with a-MCI were randomized to the education program (EP) or MST, where they learned to apply the technique to face-name associations during four intervening hour long training sessions. Participants underwent pre- and post-training fMRI scans, during which they encoded both the trained (i.e., those used during the four training sessions) and untrained ('novel') face-name associations. The primary cognitive outcome measures revealed significantly improved memory for both trained and novel stimuli - effects supporting near transfer of MST. Relative to pre-training, there were significant and highly similar increases in activation for both trained and novel stimuli, especially in regions associated with the frontoparietal cognitive control network bilaterally, but also in temporal areas related to social cognition and emotional processing. Critically, this pattern of activation was notably different from the EP group. Thus, the changes in activation were consistent with the strategies trained and, combined with the cognitively-based near transfer effects, suggest that MST focused on face-name association enhances performance by engaging cognitive control and social/emotional processing. Finally, our data indicated that our MST is a relevant and efficient intervention to a-MCI., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Chronic Posttraumatic stress disorder (PTSD), characterized by symptoms of re-experiencing, hyperarousal, and avoidance, is challenging to treat as a significant proportion of patients remain symptomatic following even empirically supported interventions. The current case series investigated the effects of up to 10 sessions of high definition transcranial direct current stimulation (HD-tDCS) on symptoms of PTSD. Participants received HD-tDCS that targeted the right lateral temporal cortex (LTC; center cathode placed over T8), given this region's potential involvement in symptoms of re-experiencing and, possibly, hyperarousal. Five of the six enrolled patients completed at least 8 sessions. Of these five, four showed improvement in symptoms of re-experiencing after HD-tDCS. This improvement was accompanied by connectivity change in the right LTC as well as a larger extended fear network but not a control network that consisted of visual cortex regions; however, the nature of the change varied across participants as some showed increased connectivity whereas others showed decreased connectivity. These preliminary data suggest that HD-tDCS may be beneficial for treatment of specific PTSD symptoms, in at least some individuals, and warrants further investigation., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Published by Elsevier B.V.)

Learning and memory deficits characterize the diagnosis of amnestic mild cognitive impairment (aMCI), which is widely viewed as a clinical precursor to Alzheimer's type dementia. There is a growing interest in non-pharmacologic interventions, such as mnemonic strategies, for improving learning and memory in patients with aMCI as well as for maintaining functioning in healthy older adults. Using an ecologically relevant object-location association paradigm, we conducted a randomized, controlled, single-blind study in which healthy older adults and patients with aMCI were randomized to either mnemonic strategy training or a control group that was matched for stimulus exposure. We previously reported that mnemonic strategy training resulted in significantly greater learning and memory improvements compared to the matched exposure condition, in both aMCI patients and healthy controls. The current study examined changes in neocortical activation during encoding in a subset of participants who underwent functional magnetic resonance imaging (fMRI) scanning both before and after training. To minimize potential confounds in between-group comparisons, we employed non-linear cortex based alignment and included only correctly encoded stimuli in our analyses. When re-encoding stimuli learned during training (i.e., trained stimuli), we found a general enhancement of activation in right prefrontal and parietal regions, possibly reflecting practice-related improvement in coordinate spatial processing in all but the aMCI exposure group. Left hemisphere activation was typically only evident in the mnemonic strategy trained participants, regardless of diagnostic status, with the ventrolateral prefrontal cortex appearing especially important for strategy use. While encoding relatively novel stimuli, both mnemonic strategy groups (aMCI patients and healthy controls) demonstrated increased activation in a subset of regions showing change for the trained stimuli, indicating a mnemonic strategy-induced change in the processing of new information. These findings could not be explained by repeated exposure since there was little to no activation overlap in the respective exposure control groups. The current results reinforce the potential benefits of cognitive interventions in these growing populations and indicate that neuroplastic change in key rostral and lateral prefrontal regions mediate this behavioral change., Competing Interests: Conflicts of interest No author has any conflict of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Transcranial electrical stimulation (tES) aims to alter brain function non-invasively by applying current to electrodes on the scalp. Decades of research and technological advancement are associated with a growing diversity of tES methods and the associated nomenclature for describing these methods. Whether intended to produce a specific response so the brain can be studied or lead to a more enduring change in behavior (e.g. for treatment), the motivations for using tES have themselves influenced the evolution of nomenclature, leading to some scientific, clinical, and public confusion. This ambiguity arises from (i) the infinite parameter space available in designing tES methods of application and (ii) varied naming conventions based upon the intended effects and/or methods of application. Here, we compile a cohesive nomenclature for contemporary tES technologies that respects existing and historical norms, while incorporating insight and classifications based on state-of-the-art findings. We consolidate and clarify existing terminology conventions, but do not aim to create new nomenclature. The presented nomenclature aims to balance adopting broad definitions that encourage flexibility and innovation in research approaches, against classification specificity that minimizes ambiguity about protocols but can hinder progress. Constructive research around tES classification, such as transcranial direct current stimulation (tDCS), should allow some variations in protocol but also distinguish from approaches that bear so little resemblance that their safety and efficacy should not be compared directly. The proposed framework includes terms in contemporary use across peer-reviewed publications, including relatively new nomenclature introduced in the past decade, such as transcranial alternating current stimulation (tACS) and transcranial pulsed current stimulation (tPCS), as well as terms with long historical use such as electroconvulsive therapy (ECT). We also define commonly used terms-of-the-trade including electrode, lead, anode, and cathode, whose prior use, in varied contexts, can also be a source of confusion. This comprehensive clarification of nomenclature and associated preliminary proposals for standardized terminology can support the development of consensus on efficacy, safety, and regulatory standards., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Transcranial direct current stimulation (tDCS) is an in-demand form of neuromodulation generally regarded as safe and well tolerated. However, few studies have examined the safety, tolerability, or blinding of High Definition (HD-) tDCS, especially in older adults and at stimulation intensities of 2 milliamps (mA) or greater., Objective: We examined the rates of serious adverse events and common side effects to establish safety and tolerability, respectively, in HD-tDCS. Blinding was evaluated using participants' accuracy in correctly stating their condition (i.e., active or sham)., Methods: The sample included 101 older adults (M age  = 69.69, SD = 8.33; M educ  = 16.27, SD = 2.42) who participated in our double blind randomized controlled studies or in case studies that used HD-tDCS for 20-30 min at 2 mA (n = 66, 31 active) or 3 mA (n = 35, 20 active). Participants completed a standardized side effect questionnaire and were asked whether they received active or sham stimulation at the end of each session., Results: There were no serious adverse events and no participants withdrew, suggesting that HD-tDCS meets basic safety parameters. Tolerability was comparable between active and sham HD-tDCS regardless of intensity (2 mA and 3 mA) in first session (allp > .09). Tingling was the most commonly endorsed item (59% active; 56% sham) followed by burning sensation (51% active; 50% sham), the majority of which were mild in nature. "Severe" ratings were reported in fewer than 4% of sessions. Blinding appeared adequate since there were no significant group differences between individuals correctly stating their stimulation condition (χ2 = 0.689, p = .679). The above tolerability and blinding findings generally persisted when multiple session data (i.e., 186 total sessions) were considered., Conclusions: HD-tDCS appears well-tolerated and safe with effective sham-control in older adults, even at 3 mA. These data support the use of HD-tDCS in randomized controlled trials and clinical translation efforts., (Published by Elsevier Inc.)

Mild cognitive impairment (MCI) is widely regarded as an intermediate stage between typical aging and dementia, with nearly 50% of patients with amnestic MCI (aMCI) converting to Alzheimer's dementia (AD) within 30 months of follow-up (Fischer et al., 2007). The growing literature using resting-state functional magnetic resonance imaging reveals both increased and decreased connectivity in individuals with MCI and connectivity loss between the anterior and posterior components of the default mode network (DMN) throughout the course of the disease progression (Hillary et al., 2015; Sheline & Raichle, 2013; Tijms et al., 2013). In this paper, we use dynamic connectivity modeling and graph theory to identify unique brain "states," or temporal patterns of connectivity across distributed networks, to distinguish individuals with aMCI from healthy older adults (HOAs). We enrolled 44 individuals diagnosed with aMCI and 33 HOAs of comparable age and education. Our results indicated that individuals with aMCI spent significantly more time in one state in particular, whereas neural network analysis in the HOA sample revealed approximately equivalent representation across four distinct states. Among individuals with aMCI, spending a higher proportion of time in the dominant state relative to a state where participants exhibited high cost (a measure combining connectivity and distance), predicted better language performance and less perseveration. This is the first report to examine neural network dynamics in individuals with aMCI., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Transcranial direct current stimulation (tDCS) is investigated to modulate neuronal function by applying a fixed low-intensity direct current to scalp., Objectives: We critically discuss evidence for a monotonic response in effect size with increasing current intensity, with a specific focus on a question if increasing applied current enhance the efficacy of tDCS., Methods: We analyzed tDCS intensity does-response from different perspectives including biophysical modeling, animal modeling, human neurophysiology, neuroimaging and behavioral/clinical measures. Further, we discuss approaches to design dose-response trials., Results: Physical models predict electric field in the brain increases with applied tDCS intensity. Data from animal studies are lacking since a range of relevant low-intensities is rarely tested. Results from imaging studies are ambiguous while human neurophysiology, including using transcranial magnetic stimulation (TMS) as a probe, suggests a complex state-dependent non-monotonic dose response. The diffusivity of brain current flow produced by conventional tDCS montages complicates this analysis, with relatively few studies on focal High Definition (HD)-tDCS. In behavioral and clinical trials, only a limited range of intensities (1-2 mA), and typically just one intensity, are conventionally tested; moreover, outcomes are subject brain-state dependent. Measurements and models of current flow show that for the same applied current, substantial differences in brain current occur across individuals. Trials are thus subject to inter-individual differences that complicate consideration of population-level dose response., Conclusion: The presence or absence of simple dose response does not impact how efficacious a given tDCS dose is for a given indication. Understanding dose-response in human applications of tDCS is needed for protocol optimization including individualized dose to reduce outcome variability, which requires intelligent design of dose-response studies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This review updates and consolidates evidence on the safety of transcranial Direct Current Stimulation (tDCS). Safety is here operationally defined by, and limited to, the absence of evidence for a Serious Adverse Effect, the criteria for which are rigorously defined. This review adopts an evidence-based approach, based on an aggregation of experience from human trials, taking care not to confuse speculation on potential hazards or lack of data to refute such speculation with evidence for risk. Safety data from animal tests for tissue damage are reviewed with systematic consideration of translation to humans. Arbitrary safety considerations are avoided. Computational models are used to relate dose to brain exposure in humans and animals. We review relevant dose-response curves and dose metrics (e.g. current, duration, current density, charge, charge density) for meaningful safety standards. Special consideration is given to theoretically vulnerable populations including children and the elderly, subjects with mood disorders, epilepsy, stroke, implants, and home users. Evidence from relevant animal models indicates that brain injury by Direct Current Stimulation (DCS) occurs at predicted brain current densities (6.3-13 A/m(2)) that are over an order of magnitude above those produced by conventional tDCS. To date, the use of conventional tDCS protocols in human trials (≤40 min, ≤4 milliamperes, ≤7.2 Coulombs) has not produced any reports of a Serious Adverse Effect or irreversible injury across over 33,200 sessions and 1000 subjects with repeated sessions. This includes a wide variety of subjects, including persons from potentially vulnerable populations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Allocentric navigation declines with age and neurologic disease whereas egocentric navigation does not; differences that likely arise from maladaptive changes in brain regions mediating spatial (parietal cortex; hippocampus) but not procedural processing (caudate nucleus). Transcranial direct current stimulation (tDCS) holds promise for treating such decline given its ability to modulate neuronal excitability, but its effects have yet to be examined on spatial navigation., Objectives/hypotheses: Using healthy young adults as a model, Study 1 intended to validate a novel spatial navigation paradigm using functional magnetic resonance imaging (fMRI). Using these data to determine targets for tDCS, Study 2 aimed to determine if 1) stimulation modulates activation in a polarity-specific manner; 2) stimulation results in global and/or task-specific activation changes; 3) activation changes are accompanied by changes in effective connectivity., Methods: All participants underwent fMRI while learning allocentric and egocentric environments. Twelve participants completed Study 1. In Study 2, 16 participants were randomized to 20 min of tDCS (2 mA) using a montage with the anode over PZ and cathode over AF4 (P+F-) or the reverse montage (P-F+)., Results: Study 1 revealed that distinct networks preferentially mediate allocentric and egocentric navigation. Study 2 revealed polarity-dependent changes in activation and connectivity. The P+F- montage increased these measures in spatial regions, especially during allocentric navigation, and the caudate nucleus. Conversely, the P-F+ montage increased activation and connectivity in lateral prefrontal cortices and posterior hippocampus., Conclusions: These findings support the neuromodulatory effects of tDCS in non-motor areas and demonstrate proof-of-principle for ameliorating age- and disease-related decline in navigational abilities., (Published by Elsevier Inc.)