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Traumatic brain injury (TBI) is a leading cause of disability. Sequelae can include functional impairments and psychiatric syndromes such as post-traumatic stress disorder (PTSD), depression and anxiety. Special Operations Forces (SOF) veterans (SOVs) may be at an elevated risk for these complications, leading some to seek underexplored treatment alternatives such as the oneirogen ibogaine, a plant-derived compound known to interact with multiple neurotransmitter systems that has been studied primarily as a treatment for substance use disorders. Ibogaine has been associated with instances of fatal cardiac arrhythmia, but coadministration of magnesium may mitigate this concern. In the present study, we report a prospective observational study of the Magnesium-Ibogaine: the Stanford Traumatic Injury to the CNS protocol (MISTIC), provided together with complementary treatment modalities, in 30 male SOVs with predominantly mild TBI. We assessed changes in the World Health Organization Disability Assessment Schedule from baseline to immediately (primary outcome) and 1 month (secondary outcome) after treatment. Additional secondary outcomes included changes in PTSD (Clinician-Administered PTSD Scale for DSM-5), depression (Montgomery-Åsberg Depression Rating Scale) and anxiety (Hamilton Anxiety Rating Scale). MISTIC resulted in significant improvements in functioning both immediately (P corrected  < 0.001, Cohen's d = 0.74) and 1 month (P corrected  < 0.001, d = 2.20) after treatment and in PTSD (P corrected  < 0.001, d = 2.54), depression (P corrected  < 0.001, d = 2.80) and anxiety (P corrected  < 0.001, d = 2.13) at 1 month after treatment. There were no unexpected or serious adverse events. Controlled clinical trials to assess safety and efficacy are needed to validate these initial open-label findings. ClinicalTrials.gov registration: NCT04313712 ., (© 2024. The Author(s).)

Treatment-resistant obsessive-compulsive disorder (OCD) occurs in approximately one-third of OCD patients. Obsessions may fluctuate over time but often occur or worsen in the presence of internal (emotional state and thoughts) and external (visual and tactile) triggering stimuli. Obsessive thoughts and related compulsive urges fluctuate (are episodic) and so may respond well to a time-locked brain stimulation strategy sensitive and responsive to these symptom fluctuations. Early evidence suggests that neural activity can be captured from ventral striatal regions implicated in OCD to guide such a closed-loop approach. Here, we report on a first-in-human application of responsive deep brain stimulation (rDBS) of the ventral striatum for a treatment-refractory OCD individual who also had comorbid epilepsy. Self-reported obsessive symptoms and provoked OCD-related distress correlated with ventral striatal electrophysiology. rDBS detected the time-domain area-based feature from invasive electroencephalography low-frequency oscillatory power fluctuations that triggered bursts of stimulation to ameliorate OCD symptoms in a closed-loop fashion. rDBS provided rapid, robust, and durable improvement in obsessions and compulsions. These results provide proof of concept for a personalized, physiologically guided DBS strategy for OCD., Competing Interests: Declaration of interests No funding from NeuroPace was received for this study nor were data analyses reported here conducted by NeuroPace employees. C.H.H., R.S.S., and C.E.R. have patents related to sensing and brain stimulation for the treatment of neuropsychiatric disorders. C.H.H. is a consultant for Boston Scientific and Insightec and receives honoraria for educational lectures., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Loss of control (LOC) eating, the subjective sense that one cannot control what or how much one eats, characterizes binge-eating behaviors pervasive in obesity and related eating disorders. Closed-loop deep-brain stimulation (DBS) for binge eating should predict LOC and trigger an appropriately timed intervention., Objective/hypothesis: This study aimed to identify a sensitive and specific biomarker to detect LOC onset for DBS. We hypothesized that changes in phase-locking value (PLV) predict the onset of LOC-associated cravings and distinguish them from potential confounding states., Methods: Using DBS data recorded from the nucleus accumbens (NAc) of two patients with binge eating disorder (BED) and severe obesity, we compared PLV between inter- and intra-hemispheric NAc subregions for three behavioral conditions: craving (associated with LOC eating), hunger (not associated with LOC), and sleep., Results: In both patients, PLV in the high gamma frequency band was significantly higher for craving compared to sleep and significantly higher for hunger compared to craving. Maximum likelihood classifiers achieved accuracies above 88% when differentiating between the three conditions., Conclusions: High-frequency inter- and intra-hemispheric PLV in the NAc is a promising biomarker for closed-loop DBS that differentiates LOC-associated cravings from physiologic states such as hunger and sleep. Future trials should assess PLV as a LOC biomarker across a larger cohort and a wider patient population transdiagnostically., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: (1) To delineate whether cognitive flexibility and inhibitory ability are neurocognitive markers of passive suicidal ideation (PSI), an early stage of suicide risk in depression and (2) to determine whether PSI is associated with volumetric differences in regions of the prefrontal cortex (PFC) in middle-aged and older adults with depression., Design: Cross-sectional study., Setting: University medical school., Participants: Forty community-dwelling middle-aged and older adults with depression from a larger study of depression and anxiety (NIMH R01 MH091342-05 PI: O'Hara)., Measurements: Psychiatric measures were assessed for the presence of a DSM-5 depressive disorder and PSI. A neurocognitive battery assessed cognitive flexibility, inhibitory ability, as well as other neurocognitive domains., Results: The PSI group ( n = 18) performed significantly worse on cognitive flexibility and inhibitory ability, but not on other neurocognitive tasks, compared to the group without PSI ( n = 22). The group with PSI had larger left mid-frontal gyri (MFG) than the no-PSI group. There was no association between cognitive flexibility/inhibitory ability and left MFG volume., Conclusions: Findings implicate a neurocognitive signature of PSI: poorer cognitive flexibility and poor inhibitory ability not better accounted for by other domains of cognitive dysfunction and not associated with volumetric differences in the left MFG. This suggests that there are two specific but independent risk factors of PSI in middle- and older-aged adults.

Interest in biology education research (BER) has been growing over the last two decades, yet few BER publications focus on community colleges, which serve a large percentage of the undergraduate student population and a majority of those students who identify with historically underserved groups. In this paper, we define community college biology education research (CC BER) as publications with a community college faculty member as an author, publications with a community college study context or a focus on community college biology teaching and learning, and publications that use community college students as a source of data. We conducted a literature review to quantify how CC BER has progressed since initial calls for broadening participation by recording the number of CC BER publications in seven prominent journals between 2016 and 2020. Our formal analysis of peer-reviewed BER literature indicates that there has been a statistically significant increase in CC BER publications from 3.2% to 5.9% of total BER publications since the last analysis in 2017. We conclude with a discussion of strategies for further broadening of participation in CC BER.

Cravings that precede loss of control (LOC) over food consumption present an opportunity for intervention in patients with the binge eating disorder (BED). In this pilot study, we used responsive deep brain stimulation (DBS) to record nucleus accumbens (NAc) electrophysiology during food cravings preceding LOC eating in two patients with BED and severe obesity (trial registration no. NCT03868670). Increased NAc low-frequency oscillations, prominent during food cravings, were used to guide DBS delivery. Over 6 months, we observed improved self-control of food intake and weight loss. These findings provide early support for restoring inhibitory control with electrophysiologically-guided NAc DBS. Further work with increased sample sizes is required to determine the scalability of this approach., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Preserving attention abilities is of great concern to older adults who are motivated to maintain their quality of life. Both cognitive and physical fitness interventions have been utilized in intervention studies to assess maintenance and enhancement of attention abilities in seniors, and a coupling of these approaches is a compelling strategy to buttress both cognitive and physical health in a time- and resource-effective manner. With this perspective, we created a closed-loop, motion-capture video game (Body-Brain Trainer: BBT) that adapts a player's cognitive and physical demands in an integrated approach, thus creating a personalized and cohesive experience across both domains. Older adults who engaged in two months of BBT improved on both physical fitness (measures of blood pressure and balance) and attention (behavioral and neural metrics of attention on a continuous performance task) outcome measures beyond that of an expectancy matched, active, placebo control group, with maintenance of improved attention performance evidenced 1 year later. Following training, the BBT group's improvement on the attention outcome measure exceeded performance levels attained by an untrained group of 20-year olds, and showed age-equilibration of a neural signature of attention shown to decline with age: midline frontal theta power. These findings highlight the potential benefits of an integrated, cognitive-physical, closed-loop training platform as a powerful tool for both cognitive and physical enhancement in older adults., (© 2022. The Author(s).)

Approach-Avoidance conflict (AAC) arises from decisions with embedded positive and negative outcomes, such that approaching leads to reward and punishment and avoiding to neither. Despite its importance, the field lacks a mechanistic understanding of which regions are driving avoidance behavior during conflict. In the current task, we utilized transcranial magnetic stimulation (TMS) and drift-diffusion modeling to investigate the role of one of the most prominent regions relevant to AAC-the dorsolateral prefrontal cortex (dlPFC). The first experiment uses in-task disruption to examine the right dlPFC's (r-dlPFC) causal role in avoidance behavior. The second uses single TMS pulses to probe the excitability of the r-dlPFC, and downstream cortical activations, during avoidance behavior. Disrupting r-dlPFC during conflict decision-making reduced reward sensitivity. Further, r-dlPFC was engaged with a network of regions within the lateral and medial prefrontal, cingulate, and temporal cortices that associate with behavior during conflict. Together, these studies use TMS to demonstrate a role for the dlPFC in reward sensitivity during conflict and elucidate the r-dlPFC's network of cortical regions associated with avoidance behavior. By identifying r-dlPFC's mechanistic role in AAC behavior, contextualized within its conflict-specific downstream neural connectivity, we advance dlPFC as a potential neural target for psychiatric therapeutics., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Electrophysiological resting state functional connectivity using high density electroencephalography (hdEEG) is gaining momentum. The increased resolution offered by hdEEG, usually either 128 or 256 channels, permits source localization of EEG signals on the cortical surface. However, the number of methodological options for the acquisition and analysis of resting state hdEEG is extremely large. These include acquisition duration, eyes open/closed, channel density, source localization methods, and functional connectivity metric., New Methods: We undertake an extensive examination of the test-retest reliability and methodological agreement of all these options for regional measures of functional connectivity., Results: Power envelope connectivity shows larger test-retest reliability than imaginary coherence across all bands. While channel density doesn't strongly impact reliability or agreement, source localization methods produce systematically different functional connectivity, highlighting an important obstacle for replicating results in the literature. Most importantly, reliability and agreement often plateaus at or after 6 minutes of acquisition, well beyond the typical duration of 3 minutes. Finally, our study demonstrates that resting EEG can be as or more reliable than resting fMRI acquired in the same individuals., Conclusions: The competitive reliability and agreement of power envelope connectivity greatly increases our confidence in measuring resting state connectivity using EEG and its capacity to find individual differences., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Motor impairment after stroke is due not only to direct tissue loss but also to disrupted connectivity within the motor network. Mixed results from studies attempting to enhance motor recovery with Transcranial Magnetic Stimulation (TMS) highlight the need for a better understanding of both connectivity after stroke and the impact of TMS on this connectivity. This study used TMS-EEG to map the causal information flow in the motor network of healthy adult subjects and define how stroke alters these circuits., Methods: Fourteen stroke patients and 12 controls received TMS to two sites (bilateral primary motor cortices) during two motor tasks (paretic/dominant hand movement vs. rest) while EEG measured the cortical response to TMS pulses. TMS-EEG based connectivity measurements were derived for each hemisphere and the change in connectivity (ΔC) between the two motor tasks was calculated. We analyzed if ΔC for each hemisphere differed between the stroke and control groups or across TMS sites, and whether ΔC correlated with arm function in stroke patients., Results: Right hand movement increased connectivity in the left compared to the right hemisphere in controls, while hand movement did not significantly change connectivity in either hemisphere in stroke. Stroke patients with the largest increase in healthy hemisphere connectivity during paretic hand movement had the best arm function., Conclusions: TMS-EEG measurements are sensitive to movement-induced changes in brain connectivity. These measurements may characterize clinically meaningful changes in circuit dynamics after stroke, thus providing specific targets for trials of TMS in post-stroke rehabilitation., (© 2021. The Author(s).)

Healthy aging is associated with a multitude of structural changes in the brain. These physical age-related changes are accompanied by increased variability in neural activity of all kinds, and this increased variability, collectively referred to as "neural noise," is argued to contribute to age-related cognitive decline. In this study, we examine the relationship between two particular types of neural noise in aging. We recorded scalp EEG from younger (20-30 years old) and older (60-70 years old) adults performing a spatial visual discrimination task. First, we used the 1/ f -like exponent of the EEG power spectrum, a putative marker of neural noise, to assess baseline shifts toward a noisier state in aging. Next, we examined age-related decreases in the trial-by-trial consistency of visual stimulus processing. Finally, we examined to what extent these two age-related noise markers are related, hypothesizing that greater baseline noise would increase the variability of stimulus-evoked responses. We found that visual cortical baseline noise was higher in older adults, and the consistency of older adults' oscillatory alpha (8-12 Hz) phase responses to visual targets was also lower than that of younger adults. Crucially, older adults with the highest levels of baseline noise also had the least consistent alpha phase responses, whereas younger adults with more consistent phase responses achieved better behavioral performance. These results establish a link between tonic neural noise and stimulus-associated neural variability in aging. Moreover, they suggest that tonic age-related increases in baseline noise might diminish sensory processing and, as a result, subsequent cognitive performance.

Importance: Despite the widespread awareness of functional magnetic resonance imaging findings suggesting a role for cortical connectivity networks in treatment selection for major depressive disorder, its clinical utility remains limited. Recent methodological advances have revealed functional magnetic resonance imaging-like connectivity networks using electroencephalography (EEG), a tool more easily implemented in clinical practice., Objective: To determine whether EEG connectivity could reveal neural moderators of antidepressant treatment., Design, Setting, and Participants: In this nonprespecified secondary analysis, data were analyzed from the Establishing Moderators and Biosignatures of Antidepressant Response in Clinic Care study, a placebo-controlled, double-blinded randomized clinical trial. Recruitment began July 29, 2011, and was completed December 15, 2015. A random sample of 221 outpatients with depression aged 18 to 65 years who were not taking medication for depression was recruited and assessed at 4 clinical sites. Analysis was performed on an intent-to-treat basis. Statistical analysis was performed from November 16, 2018, to May 23, 2019., Interventions: Patients received either the selective serotonin reuptake inhibitor sertraline hydrochloride or placebo for 8 weeks., Main Outcomes and Measures: Electroencephalographic orthogonalized power envelope connectivity analyses were applied to resting-state EEG data. Intent-to-treat prediction linear mixed models were used to determine which pretreatment connectivity patterns were associated with response to sertraline vs placebo. The primary clinical outcome was the total score on the 17-item Hamilton Rating Scale for Depression, administered at each study visit., Results: Of the participants recruited, 9 withdrew after first dose owing to reported adverse effects, and 221 participants (150 women; mean [SD] age, 37.8 [12.7] years) underwent EEG recordings and had high-quality pretreatment EEG data. After correction for multiple comparisons, connectome-wide analyses revealed moderation by connections within and between widespread cortical regions-most prominently parietal-for both the antidepressant and placebo groups. Greater alpha-band and lower gamma-band connectivity predicted better placebo outcomes and worse antidepressant outcomes. Lower connectivity levels in these moderating connections were associated with higher levels of anhedonia. Connectivity features that moderate treatment response differentially by treatment group were distinct from connectivity features that change from baseline to 1 week into treatment. The group mean (SD) score on the 17-item Hamilton Rating Scale for Depression was 18.35 (4.58) at baseline and 26.14 (30.37) across all time points., Conclusions and Relevance: These findings establish the utility of EEG-based network functional connectivity analyses for differentiating between responses to an antidepressant vs placebo. A role emerged for parietal cortical regions in predicting placebo outcome. From a treatment perspective, capitalizing on the therapeutic components leading to placebo response differentially from antidepressant response should provide an alternative direction toward establishing a placebo signature in clinical trials, thereby enhancing the signal detection in randomized clinical trials., Trial Registration: ClinicalTrials.gov identifier: NCT01407094.

Antidepressants are widely prescribed, but their efficacy relative to placebo is modest, in part because the clinical diagnosis of major depression encompasses biologically heterogeneous conditions. Here, we sought to identify a neurobiological signature of response to antidepressant treatment as compared to placebo. We designed a latent-space machine-learning algorithm tailored for resting-state electroencephalography (EEG) and applied it to data from the largest imaging-coupled, placebo-controlled antidepressant study (n = 309). Symptom improvement was robustly predicted in a manner both specific for the antidepressant sertraline (versus placebo) and generalizable across different study sites and EEG equipment. This sertraline-predictive EEG signature generalized to two depression samples, wherein it reflected general antidepressant medication responsivity and related differentially to a repetitive transcranial magnetic stimulation treatment outcome. Furthermore, we found that the sertraline resting-state EEG signature indexed prefrontal neural responsivity, as measured by concurrent transcranial magnetic stimulation and EEG. Our findings advance the neurobiological understanding of antidepressant treatment through an EEG-tailored computational model and provide a clinical avenue for personalized treatment of depression.

Purpose: Children with benign epilepsy with centrotemporal spikes have rare seizures emerging from the motor cortex, which they outgrow in adolescence, and additionally may have language deficits of unclear etiology. We piloted the use of transcranial magnetic stimulation paired with EMG and EEG (TMS-EMG, TMS-EEG) to test the hypotheses that net cortical excitability decreases with age and that use-dependent plasticity predicts learning., Methods: We assessed language and motor learning in 14 right-handed children with benign epilepsy with centrotemporal spikes. We quantified two TMS metrics of left motor cortex excitability: the resting motor threshold (measure of neuronal membrane excitability) and amplitude of the N100-evoked potential (an EEG measure of GABAergic tone). To test plasticity, we applied 1 Hz repetitive TMS to the motor cortex to induce long-term depression-like changes in EMG- and EEG-evoked potentials., Results: Children with benign epilepsy with centrotemporal spikes tolerate TMS; no seizures were provoked. Resting motor threshold decreases with age but is elevated above maximal stimulator output for half the group. N100 amplitude decreases with age after controlling for resting motor threshold. Motor cortex plasticity correlates significantly with language learning and at a trend level with motor learning., Conclusions: Transcranial magnetic stimulation is safe and feasible for children with benign epilepsy with centrotemporal spikes, and TMS-EEG provides more reliable outcome measures than TMS-EMG in this group because many children have unmeasurably high resting motor thresholds. Net cortical excitability decreases with age, and motor cortex plasticity predicts not only motor learning but also language learning, suggesting a mechanism by which motor cortex seizures may interact with language development.

Attention is a fundamental cognitive process that is critical for essentially all aspects of higher-order cognition and real-world activities. Younger generations have deeply embraced information technology and multitasking in their personal lives, school and the workplace, creating myriad challenges to their attention. While improving sustained attention in healthy young adults would be beneficial, enhancing this ability has proven notoriously difficult in this age group. Here we show that 6 weeks of engagement with a meditation-inspired, closed-loop software program (MediTrain) delivered on mobile devices led to gains in both sustained attention and working memory in healthy young adults. These improvements were associated with positive changes in key neural signatures of attentional control (frontal theta inter-trial coherence and parietal P3b latency), as measured by electroencephalography. Our findings suggest the utility of delivering aspects of the ancient practice of focused-attention meditation in a modern, technology-based approach and its benefits on enhancing sustained attention.

Concurrent single-pulse TMS-EEG (spTMS-EEG) is an emerging noninvasive tool for probing causal brain dynamics in humans. However, in addition to the common artifacts in standard EEG data, spTMS-EEG data suffer from enormous stimulation-induced artifacts, posing significant challenges to the extraction of neural information. Typically, neural signals are analyzed after a manual time-intensive and often subjective process of artifact rejection. Here we describe a fully automated algorithm for spTMS-EEG artifact rejection. A key step of this algorithm is to decompose the spTMS-EEG data into statistically independent components (ICs), and then train a pattern classifier to automatically identify artifact components based on knowledge of the spatio-temporal profile of both neural and artefactual activities. The autocleaned and hand-cleaned data yield qualitatively similar group evoked potential waveforms. The algorithm achieves a 95% IC classification accuracy referenced to expert artifact rejection performance, and does so across a large number of spTMS-EEG data sets (n = 90 stimulation sites), retains high accuracy across stimulation sites/subjects/populations/montages, and outperforms current automated algorithms. Moreover, the algorithm was superior to the artifact rejection performance of relatively novice individuals, who would be the likely users of spTMS-EEG as the technique becomes more broadly disseminated. In summary, our algorithm provides an automated, fast, objective, and accurate method for cleaning spTMS-EEG data, which can increase the utility of TMS-EEG in both clinical and basic neuroscience settings., (© 2018 Wiley Periodicals, Inc.)

Objective: Children with autism spectrum disorders (ASD) and sensory processing dysfunction (SPD) are reported to show difficulties involving cognitive and visuomotor control. We sought to determine whether performance on computerized, behavioral measures of cognitive control aimed at assessing selective attention, as well as visuomotor abilities differentiated children with ASD (n = 14), SPD (n = 14) and typically developing controls (TDC; n = 28)., Method: Cognitive control differences were measured by assessing selective attention-based abilities both with and without distracting stimuli, and visuomotor differences were measured by characterizing visuomotor tracking and tracing skills. Performance in cognitive control and visuomotor domains were investigated globally as composite scores, and specifically within each task., Results: Our results indicated that though the ASD group showed the most impaired selective attention performance, the SPD group had intermediate abilities-performing above the ASD group but below the TDC group. Furthermore, both the SPD and ASD groups demonstrated equally impaired visuomotor abilities relative to the TDC group. A correlational analysis between cognitive and visuomotor control suggest a relationship between these overlapping control networks., Conclusions: This study supports the importance of direct, phenotypic characterizations of control-based abilities in children with ASD and SPD to personalize characterization and treatment interventions for at-risk children. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Daily experiences demand both focused and broad allocation of attention for us to interact efficiently with our complex environments. Many types of attention have shown age-related decline, although there is also evidence that such deficits may be remediated with cognitive training. However, spatial attention abilities have shown inconsistent age-related differences, and the extent of potential enhancement of these abilities remains unknown. Here, we assessed spatial attention in both healthy younger and older adults and trained this ability in both age groups for 5 hr over the course of 2 weeks using a custom-made, computerized mobile training application. We compared training-related gains on a spatial attention assessment and spatial working memory task to age-matched controls who engaged in expectancy-matched, active placebo computerized training. Age-related declines in spatial attention abilities were observed regardless of task difficulty. Spatial attention training led to improved focused and distributed attention abilities as well as improved spatial working memory in both younger and older participants. No such improvements were observed in either of the age-matched control groups. Note that these findings were not a function of improvements in simple response time, as basic motoric function did not change after training. Furthermore, when using change in simple response time as a covariate, all findings remained significant. These results suggest that spatial attention training can lead to enhancements in spatial working memory regardless of age.

Our attentional focus is constantly shifting: In one moment, our attention may be intently concentrated on a specific spot, whereas in another moment we might spread our attention more broadly. Although much is known about the mechanisms by which we shift our visual attention from place to place, relatively little is known about how we shift the aperture of attention from more narrowly to more broadly focused. Here we introduce a novel attentional distribution task to examine the neural mechanisms underlying this process. In this task, participants are presented with an informative cue that indicates the location of an upcoming target. This cue can be perfectly predictive of the exact target location, or it can indicate-with varying degrees of certainty-approximately where the target might appear. This cue is followed by a preparatory period in which there is nothing on the screen except a central fixation cross. Using scalp EEG, we examined neural activity during this preparatory period. We find that, with decreasing certainty regarding the precise location of the impending target, participant RTs increased whereas target identification accuracy decreased. Additionally, the multivariate pattern of preparatory period visual cortical alpha (8-12 Hz) activity encoded attentional distribution. This alpha encoding was predictive of behavioral accuracy and RT nearly 1 sec later. These results offer insight into the neural mechanisms underlying how we use information to guide our attentional distribution and how that influences behavior.

Children with Sensory Processing Dysfunction (SPD) experience incoming information in atypical, distracting ways. Qualitative challenges with attention have been reported in these children, but such difficulties have not been quantified using either behavioral or functional neuroimaging methods. Furthermore, the efficacy of evidence-based cognitive control interventions aimed at enhancing attention in this group has not been tested. Here we present work aimed at characterizing and enhancing attentional abilities for children with SPD. A sample of 38 SPD and 25 typically developing children were tested on behavioral, neural, and parental measures of attention before and after a 4-week iPad-based at-home cognitive remediation program. At baseline, 54% of children with SPD met or exceeded criteria on a parent report measure for inattention/hyperactivity. Significant deficits involving sustained attention, selective attention and goal management were observed only in the subset of SPD children with parent-reported inattention. This subset of children also showed reduced midline frontal theta activity, an electroencephalographic measure of attention. Following the cognitive intervention, only the SPD children with inattention/hyperactivity showed both improvements in midline frontal theta activity and on a parental report of inattention. Notably, 33% of these individuals no longer met the clinical cut-off for inattention, with the parent-reported improvements persisting for 9 months. These findings support the benefit of a targeted attention intervention for a subset of children with SPD, while simultaneously highlighting the importance of having a multifaceted assessment for individuals with neurodevelopmental conditions to optimally personalize treatment.

MET is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and degraded by c-CBL E3-ubiquitin ligase. We investigated genetic variations of c-CBL in HNSCC and the relationship between c-CBL and MET expression. High MET, low c-CBL expression was detected in 10 cell lines and 73 tumor tissues. Two novel mutations (L254S, L281F), and the single nucleotide polymorphism (SNP) P782L were identified from archival tumor tissues. 27.3% of loss of heterozygosity was found at CBL locus. Ectopic expression of wild-type c-CBL in SCC-35 cells downregulated MET expression and decreased cell viability. These results suggest MET overexpression is related to altered c-CBL expression, which may influence tumorigenesis.

Assessing cognitive abilities in children is challenging for two primary reasons: lack of testing engagement can lead to low testing sensitivity and inherent performance variability. Here we sought to explore whether an engaging, adaptive digital cognitive platform built to look and feel like a video game would reliably measure attention-based abilities in children with and without neurodevelopmental disabilities related to a known genetic condition, 16p11.2 deletion. We assessed 20 children with 16p11.2 deletion, a genetic variation implicated in attention deficit/hyperactivity disorder and autism, as well as 16 siblings without the deletion and 75 neurotypical age-matched children. Deletion carriers showed significantly slower response times and greater response variability when compared with all non-carriers; by comparison, traditional non-adaptive selective attention assessments were unable to discriminate group differences. This phenotypic characterization highlights the potential power of administering tools that integrate adaptive psychophysical mechanics into video-game-style mechanics to achieve robust, reliable measurements., Competing Interests: JDB and WEM are employees of Akili Interactive Labs, which manufactures the Project: EVO device and supplied the device for use in this study. The remaining authors declare no conflict of interest.

Many studies have validated consumer-facing hardware platforms as efficient, cost-effective, and accessible data collection instruments. However, there are few reports that have assessed the reliability of these platforms as assessment tools compared with traditional data collection platforms. Here we evaluated performance on a spatial attention paradigm obtained by our standard in-lab data collection platform, the personal computer (PC), and compared performance with that of two widely adopted, consumer technology devices: the Apple (Cupertino, CA) iPad(®) 2 and Microsoft (Redmond, WA) Xbox(®) Kinect(®). The task assessed spatial attention, a fundamental ability that we use to navigate the complex sensory input we face daily in order to effectively engage in goal-directed activities. Participants were presented with a central spatial cue indicating where on the screen a stimulus would appear. We manipulated spatial cueing such that, on a given trial, the cue presented one of four levels of information indicating the upcoming target location. Based on previous research, we hypothesized that as information of the cued spatial area decreased (i.e., larger area of possible target location) there would be a parametric decrease in performance, as revealed by slower response times and lower accuracies. Identical paradigm parameters were used for each of the three platforms, and testing was performed in a single session with a counterbalanced design. We found that performance on the Kinect and iPad showed a stronger parametric effect across the cued-information levels than that on the PC. Our results suggest that not only can the Kinect and iPad be reliably used as assessment tools to yield research-quality behavioral data, but that these platforms exploit mechanics that could be useful in building more interactive, and therefore effective, cognitive assessment and training designs. We include a discussion on the possible contributing factors to the differential effects between platforms, as well as potential confounds of the study.

Small cell lung cancer (SCLC) is a devastating disease, and current therapies have not greatly improved the 5-year survival rates. Topoisomerase (Top) inhibition is a treatment modality for SCLC; however, the response is short lived. Consequently, our research has focused on improving SCLC therapeutics through the identification of novel targets. Previously, we identified MNNG HOS transforming gene (MET) to be overexpressed and functional in SCLC. Herein, we investigated the therapeutic potential of combinatorial targeting of MET using SU11274 and Top1 using 7-ethyl-10-hydroxycamptothecin (SN-38). MET and TOP1 gene copy numbers and protein expression were determined in 29 patients with limited (n = 11) and extensive (n = 18) disease. MET gene copy number was significantly increased (>6 copies) in extensive disease compared with limited disease (P = 0.015). Similar TOP1 gene copy numbers were detected in limited and extensive disease. Immunohistochemical staining revealed a significantly higher Top1 nuclear expression in extensive (0.93) versus limited (0.15) disease (P = 0.04). Interestingly, a significant positive correlation was detected between MET gene copy number and Top1 nuclear expression (r = 0.5). In vitro stimulation of H82 cells revealed hepatocyte growth factor (HGF)-induced nuclear colocalization of p-MET and Top1. Furthermore, activation of the HGF/MET axis enhanced Top1 activity, which was abrogated by SU11274. Combination of SN-38 with SU11274 dramatically decreased SCLC growth as compared with either drug alone. Collectively, these findings suggest that the combinatorial inhibition of MET and Top1 is a potentially efficacious treatment strategy for SCLC., (©2013 AACR.)

Many skin infections are caused by Staphylococcus aureus, a bacterial pathogen that produces virulence factors associated with these conditions such as exfoliative toxins A and B (ETA, ETB) and the leukotoxin Panton-Valentine leukocidin (PVL). Herein, we examine the potential of skin-infecting S. aureus to produce virulence factors and their impact on the local immune response. Toxin gene profiles were generated from 188 S. aureus isolated as single infecting organisms from skin lesions and demonstrated a higher potential to express ETA, ETB, and PVL than community isolates (p < 0.001). Within the study isolate group, the prevalence of genes encoding PVL was higher among methicillin-resistant S. aureus (MRSA; n = 49), while genes encoding ETs were more prevalent in methicillin-susceptible S. aureus (MSSA; n = 139). When lesion-associated white blood cell (WBC) counts were dichotomized into high- or low-WBC-count-associated bacteria, the gene for ETA was found to be associated with a low WBC count among MSSA (p = 0.001). The ETA-induced mouse model of staphylococcal scalded skin syndrome was used to investigate the link between ETA and cytokine production. Elevated IL-6 levels in the serum and increased expression of IL-6 mRNA in the skin were detected in response to ETA exposure. These findings were recapitulated in vitro using primary human keratinocytes. Thus, S. aureus may influence the local immune response via ETA cleavage of desmoglein 1 and the induction of cutaneous IL-6 expression.

Despite progress in locoregional and systemic therapies, patient survival from lung cancer remains a challenge. Receptor tyrosine kinases are frequently implicated in lung cancer pathogenesis, and some tyrosine kinase inhibition strategies have been effective clinically. The EphB4 receptor tyrosine kinase has recently emerged as a potential target in several other cancers. We sought to systematically study the role of EphB4 in lung cancer. Here, we demonstrate that EphB4 is overexpressed 3-fold in lung tumors compared to paired normal tissues and frequently exhibits gene copy number increases in lung cancer. We also show that overexpression of EphB4 promotes cellular proliferation, colony formation, and motility, while EphB4 inhibition reduces cellular viability in vitro, halts the growth of established tumors in mouse xenograft models when used as a single-target strategy, and causes near-complete regression of established tumors when used in combination with paclitaxel. Taken together, these data suggest an important role for EphB4 as a potential novel therapeutic target in lung cancer. Clinical trials investigating the efficacy of anti-EphB4 therapies as well as combination therapy involving EphB4 inhibition may be warranted.

Introduction: Altered expression of MUC4 plays an oncogenic role in various cancers, including pancreatic, ovarian, and breast. This study evaluates the expression and role of MUC4 in non-small-cell lung cancer (NSCLC)., Methods: We used a paired system of MUC4-expressing (H292) and MUC4-nonexpressing (A549) NSCLC cell lines to analyze MUC4-dependent changes in growth rate, migration, and invasion using these sublines. We also evaluated the alterations of several tumor suppressor, proliferation, and metastasis markers with altered MUC4 expression. Furthermore, the association of MUC4 expression (by immunohistochemistry) in lung cancer samples with patient survival was evaluated., Results: MUC4-expressing lung cancer cells demonstrated a less proliferative and metastatic phenotype. Up-regulation of p53 in MUC4-expressing lung cancer cells led to the accumulation of cells at the G2/M phase of cell cycle progression. MUC4 expression attenuated Akt activation and decreased the expression of Cyclins D1 and E, but increased the expression of p21 and p27. MUC4 expression abrogated cancer cell migration and invasion by altering N- & E-cadherin expression and FAK phosphorylation. A decrease in MUC4 expression was observed with increasing tumor stage (mean composite score: stage I, 2.4; stage II, 1.8; stage III, 1.4; and metastatic, 1.2; p = 0.0093). Maximal MUC4 expression was associated with a better overall survival (p = 0.042)., Conclusion: MUC4 plays a tumor-suppressor role in NSCLC by altering p53 expression in NSCLC. Decrease in MUC4 expression in advanced tumor stages also seems to confirm the novel protective function of MUC4 in NSCLC.

Objective: An area of need in cancer informatics is the ability to store images in a comprehensive database as part of translational cancer research. To meet this need, we have implemented a novel tandem database infrastructure that facilitates image storage and utilisation., Background: We had previously implemented the Thoracic Oncology Program Database Project (TOPDP) database for our translational cancer research needs. While useful for many research endeavours, it is unable to store images, hence our need to implement an imaging database which could communicate easily with the TOPDP database., Methods: The Thoracic Oncology Research Program (TORP) imaging database was designed using the Research Electronic Data Capture (REDCap) platform, which was developed by Vanderbilt University. To demonstrate proof of principle and evaluate utility, we performed a retrospective investigation into tumour response for malignant pleural mesothelioma (MPM) patients treated at the University of Chicago Medical Center with either of two analogous chemotherapy regimens and consented to at least one of two UCMC IRB protocols, 9571 and 13473A., Results: A cohort of 22 MPM patients was identified using clinical data in the TOPDP database. After measurements were acquired, two representative CT images and 0-35 histological images per patient were successfully stored in the TORP database, along with clinical and demographic data., Discussion: We implemented the TORP imaging database to be used in conjunction with our comprehensive TOPDP database. While it requires an additional effort to use two databases, our database infrastructure facilitates more comprehensive translational research., Conclusions: The investigation described herein demonstrates the successful implementation of this novel tandem imaging database infrastructure, as well as the potential utility of investigations enabled by it. The data model presented here can be utilised as the basis for further development of other larger, more streamlined databases in the future.

A major contributing factor to glioma development and progression is its ability to evade the immune system. This chapter will explore the mechanisms utilized by glioma to mediate immunosuppression and immune evasion. These include intrinsic mechanisms linked to its location within the brain and interactions between glioma cells and immune cells. Lack of recruitment of naïve effector immune cells perhaps accounts for most of the immune suppression mediated by these tumor cells. This is enhanced by increased recruitment of microglia which resemble immature antigen presenting cells that are unable to support T-cell mediated immunity. Furthermore, secreted factors like TGF-β, COX-2 and IL-10, altered costimulatory molecules and inhibition of STAT-3 all contribute to the recruitment and expansion of regulatory T cells, which further modulate the immunosuppressive environment of glioma. In light of these findings, multiple immunotherapeutic treatment modalities are currently being explored.

Background: In recent years, there has been tremendous growth and interest in translational research, particularly in cancer biology. This area of study clearly establishes the connection between laboratory experimentation and practical human application. Though it is common for laboratory and clinical data regarding patient specimens to be maintained separately, the storage of such heterogeneous data in one database offers many benefits as it may facilitate more rapid accession of data and provide researchers access to greater numbers of tissue samples., Description: The Thoracic Oncology Program Database Project was developed to serve as a repository for well-annotated cancer specimen, clinical, genomic, and proteomic data obtained from tumor tissue studies. The TOPDP is not merely a library-it is a dynamic tool that may be used for data mining and exploratory analysis. Using the example of non-small cell lung cancer cases within the database, this study will demonstrate how clinical data may be combined with proteomic analyses of patient tissue samples in determining the functional relevance of protein over and under expression in this disease. Clinical data for 1323 patients with non-small cell lung cancer has been captured to date. Proteomic studies have been performed on tissue samples from 105 of these patients. These tissues have been analyzed for the expression of 33 different protein biomarkers using tissue microarrays. The expression of 15 potential biomarkers was found to be significantly higher in tumor versus matched normal tissue. Proteins belonging to the receptor tyrosine kinase family were particularly likely to be over expressed in tumor tissues. There was no difference in protein expression across various histologies or stages of non-small cell lung cancer. Though not differentially expressed between tumor and non-tumor tissues, the over expression of the glucocorticoid receptor (GR) was associated improved overall survival. However, this finding is preliminary and warrants further investigation., Conclusion: Though the database project is still under development, the application of such a database has the potential to enhance our understanding of cancer biology and will help researchers to identify targets to modify the course of thoracic malignancies.

Oncolytic adenoviral virotherapy is an attractive treatment modality for cancer. However, following intratumoral injections, oncolytic viruses fail to efficiently migrate away from the injection site and are rapidly cleared by the immune system. We have previously demonstrated enhanced viral delivery and replicative persistence in vivo using human bone marrow-derived mesenchymal stem cells (MSCs) as delivery vehicles. In this study, we evaluated the immune response to adenovirus (Ad)-loaded MSCs using the semipermissive cotton rat (CR) model. First, we isolated MSCs from CR bone marrow aspirates. Real-time quantitative PCR analysis revealed that CR MSCs supported the replication of Ads in vitro. Moreover, we observed similar levels of suppression of T-cell proliferation in response to mitogenic stimulation, by MSCs alone and virus-loaded MSCs. Additionally, we found that MSCs suppressed the production of interferon-γ (IFN-γ) by activated T cells. In our in vivo model, CR MSCs enhanced the dissemination and persistence of Ad, compared to virus injection alone. Collectively, our data suggest that the use of MSCs as a delivery strategy for oncolytic Ad potentially offers a myriad of benefits, including improved delivery, enhanced dissemination, and increased persistence of viruses via suppression of the antiviral immune response.

Glioblastoma multiforme (GBM) is the most common and lethal primary malignant brain tumor. The traditional treatments for GBM, including surgery, radiation, and chemotherapy, only modestly improve patient survival. Therefore, immunotherapy has emerged as a novel therapeutic modality. Immunotherapeutic strategies exploit the immune system's ability to recognize and mount a specific response against tumor cells, but not normal cells. Current immunotherapeutic approaches for glioma can be divided into 3 categories: immune priming (active immunotherapy), immunomodulation (passive immunotherapy), and adoptive immunotherapy. Immune priming sensitizes the patient's immune cells to tumor antigens using various vaccination protocols. In the case of immunomodulation, strategies are aimed at reducing suppressive cytokines in the tumor microenvironment or using immune molecules to specifically target tumor cells. Adoptive immunotherapy involves harvesting the patient's immune cells, followed by ex vivo activation and expansion before reinfusion. This article provides an overview of the interactions between the central nervous system and the immune system, and discusses the challenges facing current immunotherapeutic strategies.

Background: Malignant gliomas remain refractory to treatment despite advances in chemotherapy and surgical techniques. Viral vectors developed to treat gliomas have had low transduction capabilities, limiting their use. Gliomas over-express CD46, CD80, and CD86, all of which bind adenovirus serotype 3., Methods: To increase the infectivity and replication of oncolytic vectors in malignant brain tumors, we created a conditionally replicating adenovirus, CRAd-Survivin-5/3, which contains a survivin promoter-driving E1A and a chimeric fiber consisting of adenovirus serotype 3 knob., Results: In vitro, this modified CRAd showed ten- to 100-fold increased cytotoxicity against glioma cells. Ex vivo analysis of primary glioblastoma multiforme samples infected with CRAd-Survivin-5/3 showed an increase in cytotoxicity of 20-30% compared to adenovirus wild-type (AdWT). In normal human astrocytes and normal brain tissues, CRAd-Survivin-5/3 exhibited 30-40% and 10-15% lower cytotoxicity than AdWT, respectively. In an intracranial xenograft model of glioma, this oncolytic virus increased tumor-free survival and overall lifespan by 50% compared to controls (p < 0.05)., Conclusions: CRAd-Survivin-5/3 represents an attractive alternative to existing vectors and should be tested further in the pre-clinical setting.

Regulatory T cells (CD4+CD25+FoxP3+, Treg) have been shown to play a major role in suppression of the immune response to malignant gliomas. In this study, we investigated the kinetics of Treg infiltration in metastatic brain tumor models, including melanoma, breast and colon cancers. Our data indicate that both CD4+ and Treg infiltration are significantly increased throughout the time of metastatic tumor progression. These findings were recapitulated in human CNS tumor samples of metastatic melanoma and non-small cell lung carcinoma. Collectively, these data support investigating immunotherapeutic strategies targeting Treg in metastatic CNS tumors.

Conditionally replicative adenoviruses (CRAds) are often evaluated in mice; however, normal and cancerous mouse tissues are poorly permissive for human CRAds. As the cotton rat (CR) is a semipermissive animal and the Syrian hamster (SH) is a fully permissive model for adenoviral replication, we compared them in a single study following intracranial (i.c.) injection of a novel glioma-targeting CRAd. Viral genomic copies were quantified by real-time PCR in brain, blood, liver and lung. The studies were corroborated by immunohistochemical, serological and immunological assays. CR had a multiple log higher susceptibility for adenoviral infection than SH. A similar amount of genomic copies of CRAd-Survivin-pk7 and human adenovirus serotype 5 (AdWT) was found in the brain of CR and in all organs from SH. In blood and lung of CR, AdWT had more genomic copies than CRAd-Survivin-pk7 in some of the time points studied. Viral antigens were confirmed in brain slices, an elevation of serum transaminases was observed in both models, and an increase in anti-adenoviral antibodies was detected in SH sera. In conclusion, CR represents a sensitive model for studying biodistribution of CRAds after i.c. delivery, allowing for the detection of differences in the replication of CRAd-Survivin-pk7 and AdWT that were not evident in SH.

Adoptive T-cell therapy with CD8(+) CTLs is often characterized by poor persistence of the transferred T cells and limited effector responses. Improved persistence and therapeutic efficacy have been noted when antigen-activated CD8(+) T cells express properties of memory cells. The current study was undertaken to more precisely characterize the development of memory-like CD8(+) T cells from short-term CTLs in vitro and upon transfer in vivo, including their antitumor activity. Ovalbumin (OVA)-specific OT-I CTLs acquired phenotypic and functional properties of memory cells 2 to 3 days later either by lowering the concentration of antigen to a level that does not support primary responses and providing a survival signal through transgenic Bcl-2 in vitro or simply by transferring early day 3 CTLs to antigen-free lymphoid-replete mice. In lymphoid-replete mice, established OVA-expressing E.G7 tumor was rejected by short-term CTLs that simultaneously acquired memory-like properties in secondary lymphoid tissues, where tumor antigen level remained low. Collectively, these data indicate that CTLs readily converted to memory-like cells upon lowering antigen to a concentration that selectively supports memory responses and suggest that such conversion predicts successful adoptive immunotherapy.

The aggressive nature of gliomas is closely related to their capacity to evade the anti-tumoral immune response. The mechanisms implicated in this phenomenon are only partially understood. A subset of T cells, termed CD4+ CD25+ regulatory T cells (Treg), have been shown to inhibit the actions of effector lymphocytes. These Tregs are increased in the blood and tumors of glioma patients and animals with experimental brain tumors. Moreover, tumor infiltration by Tregs correlates with tumor grade and in animal models, depletion of Tregs is associated with prolonged survival. This review focuses on the role of Tregs in the immune suppression exhibited by malignant gliomas. The biology of these cells is briefly described in this context and finally, potential therapeutic strategies related to Treg ablation are explored.

IL-7 and IL-15 are important cytokines for CD8 memory T cells. However, the extent that IL-7 is essential for CD8 T cell memory remains unclear because blocking IL-7 in vivo results in near complete inhibition of T cell development with the few mature T cells exhibiting functional abnormalities. To bypass this complication, CD8 memory development was examined utilizing a mouse model where transgenic IL-7Ralpha was selectively expressed in the thymus of IL-7Ralpha(-/-) mice. T cell development was corrected but the resulting peripheral T cells were essentially IL-7 non-responsive. Activation of IL-7R-defective OT-I CD8(+) T cells with OVA(257-264) and IL-2 readily yielded CTL. Upon further culture with IL-15, these CTL expressed phenotypic and functional properties of central memory-like cells. Thus, IL-7R-defective CD8(+) T cells do not exhibit intrinsic defects in effector or memory development. When IL-7R-defective OT-I CTL were adoptively transferred into normal or IL-15(-/-) recipient mice in a non-inflammatory setting, they converted into memory-like cells, but did not persist, which was even more striking in IL-15(-/-) recipients. This poor persistence was rescued after expression of transgenic Bcl-2 in IL-7R-defective OT-I T cells. Collectively, these data indicate that IL-7 is non-redundantly required for the survival of CD8 memory T cells.