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Abstract Background Cognitive dysfunction is one of the common symptoms in patients with major depressive disorder (MDD). Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have been studied separately in the treatment of cognitive dysfunction in MDD patients. We aimed to investigate the effectiveness and safety of rTMS combined with tDCS as a new therapy to improve neurocognitive impairment in MDD patients. Methods In this brief 2-week, double-blind, randomized, and sham-controlled trial, a total of 550 patients were screened, and 240 MDD inpatients were randomized into four groups (active rTMS + active tDCS, active rTMS + sham tDCS, sham rTMS + active tDCS, sham rTMS + sham tDCS). Finally, 203 patients completed the study and received 10 treatment sessions over a 2-week period. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was performed to assess patients’ cognitive function at baseline and week 2. Also, we applied the 24-item Hamilton Depression Rating Scale (HDRS-24) to assess patients’ depressive symptoms at baseline and week 2. Results After 10 sessions of treatment, the rTMS combined with the tDCS group showed more significant improvements in the RBANS total score, immediate memory, and visuospatial/constructional index score (all p

Abstract The neuromodulation effect of low-intensity focused ultrasound (LIFU) is highly target-specific. Unintended off-target neuronal excitation can be elicited when the beam focusing accuracy and resolution are limited, whereas the resulted side effect has not been evaluated quantitatively. There is also a lack of methods addressing the minimization of such side effects. Therefore, this work introduces a computational model of unintended neuronal excitation during LIFU neuromodulation, which evaluates the off-target activation area (OTAA) by integrating an ultrasound field model with the neuronal spiking model. In addition, a phased array beam focusing scheme called constrained optimal resolution beamforming (CORB) is proposed to minimize the off-target neuronal excitation area while ensuring effective stimulation in the target brain region. A lower bound of the OTAA is analytically approximated in a simplified homogeneous medium, which could guide the selection of transducer parameters such as aperture size and operating frequency. Simulations in a human head model using three transducer setups show that CORB markedly reduces the OTAA compared with two benchmark beam focusing methods. The high neuromodulation resolution demonstrates the capability of LIFU to effectively limit the side effects during neuromodulation, allowing future clinical applications such as treatment of neuropsychiatric disorders.

Brain neuromodulation effectively treats neurological diseases and psychiatric disorders such as Depression. However, due to patient heterogeneity, neuromodulation treatment outcomes are often highly variable, requiring patient-specific stimulation protocols throughout the recovery stages to optimize treatment outcomes. Therefore, it is critical to personalize neuromodulation protocol to optimize the patient-specific stimulation targets and parameters by accommodating inherent interpatient variability and intersession alteration during treatments. The study aims to develop a personalized repetitive transcranial magnetic stimulation (rTMS) protocol and evaluate its feasibility in optimizing the treatment efficiency using an existing dataset from an antidepressant experimental imaging study in depression. The personalization of the rTMS treatment protocol was achieved by personalizing both stimulation targets and parameters via a novel approach integrating the functional brain network controllability analysis and optimal control analysis. First, the functional brain network controllability analysis was performed to identify the optimal rTMS stimulation target from the effective connectivity network constructed from patient-specific resting-state functional magnetic resonance imaging data. The optimal control algorithm was then applied to optimize the rTMS stimulation parameters based on the optimized target. The performance of the proposed personalized rTMS technique was evaluated using datasets collected from a longitudinal antidepressant experimental imaging study in depression (n = 20). Simulation models demonstrated that the proposed personalized rTMS protocol outperformed the standard rTMS treatment by efficiently steering a depressive resting brain state to a healthy resting brain state, indicated by the significantly less control energy needed and higher model fitting accuracy achieved. The node with the maximum average controllability of each patient was designated as the optimal target region for the personalized rTMS protocol. Our results also demonstrated the theoretical feasibility of achieving comparable neuromodulation efficacy by stimulating a single node compared to stimulating multiple driver nodes. The findings support the feasibility of developing personalized neuromodulation protocols to more efficiently treat depression and other neurological diseases.

Background: Optimal design of clinical programs for patients with premature atherosclerotic cardiovascular disease (ASCVD) (men aged ≤ 50 years, women aged ≤ 55 years) requires an understanding of their priorities. We aimed to explore patient and family priorities for services in clinical programs. Methods: We co-designed this study with a Patient Partner Committee using a sequential exploratory mixed-methods design. In Phase I, we conducted semistructured interviews with participants from the Study to Avoid Cardiovascular Events in British Columbia (SAVE BC) (n = 15). In Phase II, we designed a questionnaire based on Phase I data and distributed it to all current SAVE BC participants. We collected close-ended responses (n = 116) and stratified data using participant category (index, family member), age, sex, and number of clinic visits. Results: We identified 4 major priorities for services in clinical programs: social support (weight: 62.6%), patient education (weight: 83.5%), mental health (weight: 50.7%), and lifestyle changes (85.1%). To address these priorities, participants wanted ASCVD clinical programs to enable recruitment of their family members, establish a comprehensive education component (with research updates in research programs), deliver mental health screening and support after myocardial infarction, and provide longitudinal sessions to support maintenance of lifestyle modifications. These services were identified in Phase I and verified in Phase II. Conclusion: We identified 4 priorities for services in clinical programs designed for patients with premature ASCVD and their families. Further research should be done to elucidate their outcomes and most effective methods to provide these services. Résumé: Introduction: La conception optimale des programmes cliniques des patients atteints d’une maladie cardiovasculaire athéroscléreuse (ASCVD pour atherosclerotic cardiovascular disease) prématurée (hommes âgés ≤ 50 ans, femmes âgées ≤ 55 ans) exige une compréhension de leurs priorités. Nous avions pour objectif d’examiner les priorités des patients et de leur famille en matière de services dans les programmes cliniques. Méthodes: Nous avons conçu la présente étude en collaboration avec le Patient Partner Commitee à l’aide d’un devis séquentiel exploratoire en méthodes mixtes. À la Phase 1, nous avons réalisé des entrevues auprès de participants de la Study to Avoid Cardiovascular Events in British Columbia (SAVE BC) (n = 15). À la Phase II, nous avons conçu un questionnaire en nous basant sur les données de la Phase I et l’avons distribué à tous les participants actuels de la SAVE BC. Nous avons recueilli les réponses fermées (n = 116) et stratifié les données en utilisant la catégorie (indice, membre de la famille), l’âge, le sexe et le nombre de consultations des participants. Résultats: Nous avons défini les 4 grandes priorités en matière de services dans les programmes cliniques : le soutien social (62,6 %), l’éducation des patients (83,5 %), la santé mentale (50,7 %) et les changements au mode de vie (85,1 %). Pour répondre à ces priorités, les participants voulaient des programmes cliniques sur la ASCVD pour favoriser le recrutement des membres de leur famille, établir un volet d’éducation complet (avec les dernières informations sur les travaux de recherche des programmes de recherche), offrir le dépistage de la santé mentale et le soutien après l’infarctus du myocarde, et offrir des séances longitudinales qui assureront le maintien des modifications au mode de vie. Ces services ont été définis à la Phase I et vérifiés à la Phase II. Conclusion: Nous avons défini les 4 priorités en matière de services dans les programmes cliniques conçus pour les patients atteints d’une ASCVD prématurée et leur famille. D’autres recherches devraient être réalisées pour élucider leurs résultats et les méthodes les plus efficaces pour offrir ces services.

BackgroundPrevious work has identified a hierarchical organization of neural oscillations that supports performance of complex cognitive and perceptual tasks, and can be indexed with phase-amplitude coupling (PAC) between low- and high-frequency oscillations. Our aim was to employ enhanced source localization afforded by magnetoencephalography (MEG) to expand on earlier reports of intact auditory cortical PAC in schizophrenia and to investigate how PAC may evolve over the early and chronic phases of the illness.MethodsIndividuals with early schizophrenia (n=12) (≤5 years of illness duration), chronic schizophrenia (n=16) (>5 years of illness duration) and healthy comparators (n = 17) performed the auditory steady state response (ASSR) to 40, 30, and 20 Hz stimuli during MEG recordings. We estimated amplitude and PAC on the MEG ASSR source localized to the auditory cortices.ResultsGamma amplitude during 40-Hz ASSR exhibited a significant group by hemisphere interaction, with both patient groups showing reduced right hemisphere amplitude and no overall lateralization in contrast to the right hemisphere lateralization demonstrated in controls. We found significant PAC in the right auditory cortex during the 40-Hz entrainment condition relative to baseline, however, PAC did not differ significantly between groups.ConclusionsIn the current study, we demonstrated an apparent sparing of ASSR-related PAC across phases of the illness, in contrast with impaired cortical gamma oscillation amplitudes. The distinction between our PAC and evoked ASSR findings supports the notion of separate but interacting circuits for the generation and maintenance of sensory gamma oscillations. The apparent sparing of PAC in both early and chronic schizophrenia patients could imply that the neuropathology of schizophrenia differentially affects these mechanisms across different stages of the disease. Future studies should investigate the distinction between PAC during passive tasks and more cognitively demanding task such as working memory so that we can begin to understand the influence of schizophrenia neuropathology on the larger framework for modulating neurocomputational capacity.

A great deal of research has been performed with the promise of improving such critical cognitive functions as working memory (WM), with transcranial direct current stimulation (tDCS), a well-tolerated, inexpensive, easy-to-use intervention. Under the assumption that by delivering currents through electrodes placed in suitable locations on the scalp, it is possible to increase prefrontal cortex excitability and therefore improve WM. A growing number of studies have led to mixed results, leading to the realization that such oversimplified assumptions need revision. Models spanning currents to behavior have been advocated in order to reconcile and inform neurostimulation investigations. We articulate such multilevel exploration to tDCS/WM by briefly reviewing critical aspects at each level of analysis but focusing on the circuit level and how available biophysical WM models could inform tDCS. Indeed, such models should replace vague reference to cortical excitability changes with relevant tDCS net effects affecting neural computation and behavior in a more predictable manner. We will refer to emerging WM models and explore to what extent the general concept of excitation-inhibition (E/I) balance is a meaningful intermediate level of analysis, its relationship with gamma oscillatory activity, and the extent to which it can index tDCS effects. We will highlight some predictions that appear consistent with empirical evidence – such as non-linearities and trait dependency of effects and possibly a preferential effect on WM control functions – as well as limitations that appear related to the dynamical aspects of coding by persistent activity.

Abstract Background Dysregulation of the inositol cycle is implicated in a wide variety of human diseases, including developmental defects and neurological diseases. A homozygous frameshift mutation in IMPA1, coding for the enzyme inositol monophosphatase 1 (IMPase), has recently been associated with severe intellectual disability (ID) in a geographically isolated consanguineous family in Northeastern Brazil (Figueredo et al., 2016). However, the neurophysiologic mechanisms that mediate the IMPA1 mutation and associated ID phenotype have not been characterized. To this end, resting EEG (eyes-open and eyes-closed) was collected from the Figueredo et al. pedigree. Quantitative EEG measures, including mean power, dominant frequency and dominant frequency variability, were investigated for allelic associations using multivariate family-based association test using generalized estimating equations. Results We found that the IMPA1 mutation was associated with relative decreases in frontal theta band power as well as altered alpha-band variability with no regional specificity during the eyes-open condition. For the eyes-closed condition, there was altered dominant theta frequency variability in the central and parietal regions. Conclusions These findings represent the first human in vivo phenotypic assessment of brain function disturbances associated with a loss-of-function IMPA1 mutation, and thus an important first step towards an understanding the pathophysiologic mechanisms of intellectual disability associated with the mutation that affects this critical metabolic pathway.

How variability in the brain’s neurophysiologic signals evolves during development is important for a global, system-level understanding of brain maturation and its disturbance in neurodevelopmental disorders. In the current study, we use multiscale entropy (MSE), a measure that has been related to signal complexity, to investigate how this variability evolves during development across a broad range of temporal scales. We computed MSE, standard deviation (STD) and standard spectral analyses on resting EEG from 188 healthy individuals aged 8–22 years old. We found age-related increases in entropy at lower scales (

BackgroundSuboptimal medication adherence is a significant problem for patients with serious mental illness. Measuring medication adherence through subjective and objective measures can be challenging, time-consuming, and inaccurate. ObjectiveThe primary purpose of this feasibility and acceptability study was to evaluate the impact of a digital medicine system (DMS) among Veterans (patients) with serious mental illness as compared with treatment as usual (TAU) on medication adherence. MethodsThis open-label, 2-site, provider-randomized trial assessed aripiprazole refill adherence in Veterans with schizophrenia, schizoaffective disorder, bipolar disorder, or major depressive disorder. We randomized 26 providers such that their patients either received TAU or DMS for a period of 90 days. Semistructured interviews with patients and providers were used to examine the feasibility and acceptability of using the DMS. ResultsWe enrolled 46 patients across 2 Veterans Health Administration sites: 21 (46%) in DMS and 25 (54%) in TAU. There was no difference in the proportion of days covered by medication refill over 3 and 6 months (0.82, SD 0.24 and 0.75, SD 0.26 in DMS vs 0.86, SD 0.19 and 0.82, SD 0.21 in TAU, respectively). The DMS arm had 0.85 (SD 0.20) proportion of days covered during the period they were engaged with the DMS (mean 144, SD 100 days). Interviews with patients (n=14) and providers (n=5) elicited themes salient to using the DMS. Patient findings described the positive impact of the DMS on medication adherence, challenges with the DMS patch connectivity and skin irritation, and challenges with the DMS app that affected overall use. Providers described an overall interest in using a DMS as an objective measure to support medication adherence in their patients. However, providers described challenges with the DMS dashboard and integrating DMS data into their workflow, which decreased the usability of the DMS for providers. ConclusionsThere was no observed difference in refill rates. Among those who engaged in the DMS arm, the proportion of days covered by refills were relatively high (mean 0.85, SD 0.20). The qualitative analyses highlighted areas for further refinement of the DMS. Trial RegistrationClinicalTrials.gov NCT03881449; https://clinicaltrials.gov/ct2/show/NCT03881449

Retrograde BMP signaling and canonical pMad/Medea-mediated transcription regulate diverse target genes across subsets of Drosophila efferent neurons, to differentiate neuropeptidergic neurons and promote motor neuron terminal maturation. How a common BMP signal regulates diverse target genes across many neuronal subsets remains largely unresolved, although available evidence implicates subset-specific transcription factor codes rather than differences in BMP signaling. Here we examine the cis-regulatory mechanisms restricting BMP-induced FMRFa neuropeptide expression to Tv4-neurons. We find that pMad/Medea bind at an atypical, low affinity motif in the FMRFa enhancer. Converting this motif to high affinity caused ectopic enhancer activity and eliminated Tv4-neuron expression. In silico searches identified additional motif instances functional in other efferent neurons, implicating broader functions for this motif in BMP-dependent enhancer activity. Thus, differential interpretation of a common BMP signal, conferred by low affinity pMad/Medea binding motifs, can contribute to the specification of BMP target genes in efferent neuron subsets.

Context processing involves a flexible and continually updated representation of task relevant information and is a core aspect of cognitive control. The expectancy AX Continuous Performance Test (AXCPT) was designed to specifically measure context processing and has been widely applied to elucidate mechanisms of cognitive control and their impairments in conditions such as aging and schizophrenia. Here we present a large-sample, cross-sectional study of context processing aimed at characterizing its normal development from childhood to early adulthood (8 to 22 years old). We track the age-related changes in the standard AXCPT performance measures and also investigate their validity using detailed data-driven method. We show how critical maturational changes in context processing can be validly tracked from mid-adolescence onward with increasing reliance on preparatory, proactive strategies well into early adulthood. However, the early maturation from childhood into adolescence showed a sharp, two-fold discontinuity: while standard measures provide partially conflicting results suggesting an early worsening of proactive strategies, further analyses do not support their validity during this period. Our findings advocate the existence of multiple preparatory strategies that cannot be captured by indices that assume a simple dichotomy of proactive vs. reactive strategies. When evaluating context processing differences over development or in clinical populations, we advocate the explicit testing of the assumptions underlying standard AXCPT indices through complementary data-driven methods.

There has been accumulating evidence that cognitive control can be adaptively regulated by monitoring for processing conflict as an index of online control demands. However, it is not yet known whether top-down control mechanisms respond to processing conflict in a manner specific to the operative task context or confer a more generalized benefit. While previous studies have examined the taskset-specificity of conflict adaptation effects, yielding inconsistent results, control-related performance adjustments following errors have been largely overlooked. This gap in the literature underscores recent debate as to whether post-error performance represents a strategic, control-mediated mechanism or a nonstrategic consequence of attentional orienting. In the present study, evidence of generalized control following both high conflict correct trials and errors was explored in a task-switching paradigm. Conflict adaptation effects were not found to generalize across tasksets, despite a shared response set. In contrast, post-error slowing effects were found to extend to the inactive taskset and were predictive of enhanced post-error accuracy. In addition, post-error performance adjustments were found to persist for several trials and across multiple task switches, a finding inconsistent with attentional orienting accounts of post-error slowing. These findings indicate that error-related control adjustments confer a generalized performance benefit and suggest dissociable mechanisms of post-conflict and post-error control.

Evidence indicates that synchronization of cortical activity at gamma-band frequencies, mediated through GABA-A receptors, is important for perceptual/cognitive processes. To study GABA signaling in vivo, we recently used a novel positron emission tomography (PET) paradigm measuring the change in binding of the benzodiazepine (BDZ) site radiotracer [(11)C]flumazenil associated with increases in extracellular GABA induced via GABA membrane transporter (GAT1) blockade with tiagabine. GAT1 blockade resulted in significant increases in [(11)C]flumazenil binding potential (BPND) over baseline in the major functional domains of the cortex, consistent with preclinical studies showing that increased GABA levels enhance the affinity of GABA-A receptors for BDZ ligands. In the current study we sought to replicate our previous results and to further validate this approach by demonstrating that the magnitude of increase in [(11)C]flumazenil binding observed with PET is directly correlated with tiagabine dose. [(11)C]flumazenil distribution volume (VT) was measured in 18 healthy volunteers before and after GAT1 blockade with tiagabine. Two dose groups were studied (n = 9 per group; Group I: tiagabine 0.15 mg/kg; Group II: tiagabine 0.25 mg/kg). GAT1 blockade resulted in increases in mean (± SD) [(11)C]flumazenil VT in Group II in association cortices (6.8 ± 0.8 mL g-1 vs. 7.3 ± 0.4 mL g-1;p = 0.03), sensory cortices (6.7 ± 0.8 mL g-1 vs. 7.3 ± 0.5 mL g-1;p = 0.02) and limbic regions (5.2 ± 0.6 mL g-1 vs. 5.7 ± 0.3 mL g-1;p = 0.03). No change was observed at the low dose (Group I). Increased orbital frontal cortex binding of [(11)C]flumazenil in Group II correlated with the ability to entrain cortical networks (r = 0.67, p = 0.05) measured via EEG during a cognitive control task. These data provide a replication of our previous study demonstrating the ability to measure in vivo, with PET, acute shifts in extracellular GABA.