Man-Computer Problem Solving in Real-Time Naval Duels

The development of a new Man-Computer Problem Solving Methodology to be widely and effectively applied by the Navy has been the objective of this Research Project. The basic hypothesis that has been examined is as follows. If an interactive system would be available by which a human problem solver could put together, easily and quickly, a simulation of the problem and quickly perform tests of various solutions, perform an evaluation and then further improve the solution, then large scale economies and improved effectiveness would result. The research reported here may be considered to having taken the empirical approach. An experimental environment was selected, namely a Naval War. An interactive problem solving computer system was designed for this environment. To obtain an indication of the effectiveness of the system required the solution of problems in human engineering, computational methods and strategy in the areas of tracking and navigation, sonar applications and processing, and weapon application. New real-time interactive systems were incorporated to simplify the evolution of new problem solving methodologies

Pilot Testing of Peak Alpha Frequency Stability During Repetitive Transcranial Magnetic Stimulation

Over half of those diagnosed with post-traumatic stress disorder (PTSD) have comorbid major depressive disorder (MDD), and rates are even higher among military veterans. Transcranial magnetic stimulation (TMS) may be a safe and efficacious treatment for PTSD, both with and without comorbid MDD. Still, the mechanism of action of TMS is not fully understood, and it remains unclear which stimulation techniques (e.g., target regions, pulse strength/frequency, waveform) optimize treatment for these patients. Recent research indicated that a patient's unique individualized alpha frequency (IAF) may be used to guide brain stimulation treatment, and emerging data suggests that stimulation synchronized to the IAF may be efficacious for MDD. However, to our knowledge there are no studies to date that evaluate the stability of IAF over time in patients with comorbid PTSD and MDD. To this end, we used an eight-lead electroencephalography (EEG) system to record IAF before and after a course of TMS. Stimulation parameters were informed by prior studies of TMS for comorbid PTSD and MDD and included 5 Hz TMS to the left dorsolateral prefrontal cortex, at 120% of motor threshold, 3,000–4,000 pulses per session for up to 40 sessions. We tested whether IAF was changed with a course of TMS therapy and evaluated whether IAF predicted clinical outcomes. We observed no significant changes in IAF from baseline to post-treatment, and there was no relationship between IAF and clinical symptom change. These data demonstrate the stability of IAF with TMS and indicate its utility as a trait marker for future brain stimulation studies. This work does not support the use of IAF as predictor of clinical response to TMS as administered

A Man-Machine Competitive Game: A Naval Duel

The research reported here is the development of a man-machine game in which the competitors are the captain of a submarine and the commander of an opposing task force. This naval game has been implemented and tested in the Problem Solving Facility of the University of Pennsylvania under Contract NOnr 551(48) sponsored by the Methodology Division, Office of Naval Research. The broad objective of this research has been to experiment with and develop a man-machine framework in which an executive, scientist or engineer may employ strategies and tactics in an operational environment. A complete functional description of the game will be given in this report. This chapter provides an overview of the game and cites its salient characteristics. Chapter 2 presents the game through a play-by-play record of one competitor in an actual duel. Chapter 3 presents the various aspects of the Problem Solving methodology and developed tactics by means of three annotated duels. This also illustrates the versatility of the game and demonstrates the competitors\u27 capability to interact with the computer. Chapter 4 summarizes our research to date and lists planned refinements to the game. Additional documentation of the game structure is provided in the appendices

Neuroimaging Correlates of Suicidality in Decision-Making Circuits in Posttraumatic Stress Disorder

In depression, brain and behavioral correlates of decision-making differ between individuals with and without suicidal thoughts and behaviors. Though promising, it remains unknown if these potential biomarkers of suicidality will generalize to other high-risk clinical populations. To preliminarily assess whether brain structure or function tracked suicidality in individuals with posttraumatic stress disorder (PTSD), we measured resting-state functional connectivity and cortical thickness in two functional networks involved in decision-making, a ventral fronto-striatal reward network and a lateral frontal cognitive control network. Neuroimaging data and self-reported suicidality ratings, and suicide-related hospitalization data were obtained from 50 outpatients with PTSD and also from 15 healthy controls, and all were subjected to seed-based resting-state functional connectivity and cortical thickness analyses using a priori seeds from reward and cognitive control networks. First, general linear models (GLM) were used to evaluate whether ROI-to-ROI functional connectivity was predictive of self-reported suicidality after false discovery rate (FDR)-correction for multiple comparisons and covariance of age and depression symptoms. Next, regional cortical thickness statistics were included as predictors of ROI-to-ROI functional connectivity in follow-up GLMs evaluating structure-function relationships. Functional connectivity between reward regions was positively correlated with suicidality (p-FDR ≤ 0.05). Functional connectivity of the lateral pars orbitalis to anterior cingulate/paracingulate control regions also tracked suicidality (p-FDR ≤ 0.05). Furthermore, cortical thickness in anterior cingulate/paracingulate was associated with functional correlates of suicidality in the control network (p-FDR < 0.05). These results provide a preliminary demonstration that biomarkers of suicidality in decision-making networks observed in depression may generalize to PTSD and highlight the promise of these circuits as transdiagnostic biomarkers of suicidality

Can Medication Free, Treatment-Resistant, Depressed Patients Who Initially Respond to TMS Be Maintained Off Medications? A Prospective, 12-Month Multisite Randomized Pilot Study

AbstractBackgroundRepetitive transcranial magnetic stimulation (TMS) is efficacious for acute treatment of resistant major depressive disorder (MDD), but there is little information on maintenance TMS after acute response.Objective/hypothesisThis pilot feasibility study investigated 12-month outcomes comparing two maintenance TMS approaches – a scheduled, single TMS session delivered monthly (SCH) vs. observation only (OBS).MethodsAntidepressant-free patients with unipolar, non-psychotic, treatment-resistant MDD participated in a randomized, open-label, multisite trial. Patients meeting protocol-defined criteria for improvement after six weeks of acute TMS were randomized to SCH or OBS regimens. TMS reintroduction was available for symptomatic worsening; all patients remained antidepressant-free during the trial.ResultsSixty-seven patients enrolled in the acute phase, and 49 (73%) met randomization criteria. Groups were matched, although more patients in the SCH group had failed ≥2 antidepressants (p = .035). There were no significant group differences on any outcome measure. SCH patients had nonsignificantly longer time to first TMS reintroduction, 91 ± 66 days, vs. OBS, 77 ± 52 days; OBS patients were nonsignificantly more likely to need reintroduction (odds ratio = 1.21, 95% CI .38–3.89). Reintroduction lasted 14.3 ± 17.8 days (SCH) and 16.9 ± 18.9 days (OBS); 14/18 (78%) SCH and 17/27 (63%) OBS responded to reintroduction. Sixteen patients (32.7%) completed all 53 weeks of the study.ConclusionsMaintaining treatment-resistant depressed patients off medications with periodic TMS appears feasible in some cases. There was no statistical advantage of SCH vs. OBS, although SCH was associated with a nonsignificantly longer time to relapse. Those who initially respond to TMS have a strong chance of re-responding if relapse occurs

A Prospective Study of the Impact of Transcranial Alternating Current Stimulation on EEG Correlates of Somatosensory Perception

The (8–12 Hz) neocortical alpha rhythm is associated with shifts in attention across sensory systems, and is thought to represent a sensory gating mechanism for the inhibitory control of cortical processing. The present preliminary study sought to explore whether alpha frequency transcranial alternating current stimulation (tACS) could modulate endogenous alpha power in the somatosensory system, and whether the hypothesized modulation would causally impact perception of tactile stimuli at perceptual threshold. We combined electroencephalography (EEG) with simultaneous brief and intermittent tACS applied over primary somatosensory cortex at individuals’ endogenous alpha frequency during a tactile detection task (n = 12 for EEG, n = 20 for behavior). EEG-measured pre-stimulus alpha power was higher on non-perceived than perceived trials, and analogous perceptual correlates emerged in early components of the tactile evoked response. Further, baseline normalized tactile detection performance was significantly lower during alpha than sham tACS, but the effect did not last into the post-tACS time period. Pre- to post-tACS changes in alpha power were linearly dependent upon baseline state, such that alpha power tended to increase when pre-tACS alpha power was low, and decrease when it was high. However, these observations were comparable in both groups, and not associated with evidence of tACS-induced alpha power modulation. Nevertheless, the tactile stimulus evoked response potential (ERP) revealed a potentially lasting impact of alpha tACS on circuit dynamics. The post-tACS ERP was marked by the emergence of a prominent peak ∼70 ms post-stimulus, which was not discernible post-sham, or in either pre-stimulation condition. Computational neural modeling designed to simulate macroscale EEG signals supported the hypothesis that the emergence of this peak could reflect synaptic plasticity mechanisms induced by tACS. The primary lesson learned in this study, which commanded a small sample size, was that while our experimental paradigm provided some evidence of an influence of tACS on behavior and circuit dynamics, it was not sufficient to induce observable causal effects of tACS on EEG-measured alpha oscillations. We discuss limitations and suggest improvements that may help further delineate a causal influence of tACS on cortical dynamics and perception in future studies

A single center phase II study of ixazomib in patients with relapsed or refractory cutaneous or peripheral T‐cell lymphomas

The transcription factor GATA‐3, highly expressed in many cutaneous T‐cell lymphoma (CTCL) and peripheral T‐cell lymphomas (PTCL), confers resistance to chemotherapy in a cell‐autonomous manner. As GATA‐3 is transcriptionally regulated by NF‐κB, we sought to determine the extent to which proteasomal inhibition impairs NF‐κB activation and GATA‐3 expression and cell viability in malignant T cells. Proteasome inhibition, NF‐κB activity, GATA‐3 expression, and cell viability were examined in patient‐derived cell lines and primary T‐cell lymphoma specimens ex vivo treated with the oral proteasome inhibitor ixazomib. Significant reductions in cell viability, NF‐κB activation, and GATA‐3 expression were observed preclinically in ixazomib‐treated cells. Therefore, an investigator‐initiated, single‐center, phase II study with this agent in patients with relapsed/refractory CTCL/PTCL was conducted. Concordant with our preclinical observations, a significant reduction in NF‐κB activation and GATA‐3 expression was observed in an exceptional responder following one month of treatment with ixazomib. While ixazomib had limited activity in this small and heterogeneous cohort of patients, inhibition of the NF‐κB/GATA‐3 axis in a single exceptional responder suggests that ixazomib may have utility in appropriately selected patients or in combination with other agents.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139920/1/ajh24895.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139920/2/ajh24895_am.pd

Examining the neural mechanisms of rTMS: a naturalistic pilot study of acute and serial effects in pharmacoresistant depression

IntroductionPrevious studies have demonstrated the effectiveness of therapeutic repetitive transcranial magnetic stimulation (rTMS) to treat pharmacoresistant depression. Nevertheless, these trials have primarily focused on the therapeutic and neurophysiological effects of rTMS following a long-term treatment course. Identifying brain-based biomarkers of early rTMS therapeutic response remains an important unanswered question. In this pilot study, we examined the effects of rTMS on individuals with pharmacoresistant depression using a graph-based method, called Functional Cortical Networks (FCN), and serial electroencephalography (EEG). We hypothesized that changes in brain activity would occur early in treatment course.MethodsA total of 15 patients with pharmacoresistant depression underwent five rTMS sessions (5Hz over the left dorsolateral prefrontal cortex, 120%MT, up to 4,000 pulses/session). Five participants received additional rTMS treatment, up to 40 sessions. Resting EEG activity was measured at baseline and following every five sessions, using 64-channel EEG, for 10 minutes with eyes closed. An FCN model was constructed using time-varying graphs and motif synchronization. The primary outcome was acute changes in weighted-node degree. Secondary outcomes included serial FFT-based power spectral analysis and changes in depressive symptoms measured by the 9-Item Patient Health Questionnaire (PHQ-9) and the 30-item Inventory of Depressive Symptoms-Self Report (IDS-SR).ResultsWe found a significant acute effect over the left posterior area after five sessions, as evidenced by an increase in weighted-node degree of 37,824.59 (95% CI, 468.20 to 75,180.98) and a marginal enhancement in the left frontal region (t (14) = 2.0820, p = 0.056). One-way repeated measures ANOVA indicated a significant decrease in absolute beta power over the left prefrontal cortex (F (7, 28) = 2.37, p = 0.048) following ten rTMS sessions. Furthermore, a significant clinical improvement was observed following five rTMS sessions on both PHQ-9 (t (14) = 2.7093, p = 0.017) and IDS-SR (t (14) = 2.5278, p = 0.024) and progressed along the treatment course.DiscussionOur findings suggest that FCN models and serial EEG may contribute to a deeper understanding of mechanisms underlying rTMS treatment. Additional research is required to investigate the acute and serial effects of rTMS in pharmacoresistant depression and assess whether early EEG changes could serve as predictors of therapeutic rTMS response

Vaccination with SARS-CoV-2 variants of concern protects mice from challenge with wild-type virus.

Funder: open philanthropy projectFunder: jpb foundationVaccines against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) have been highly efficient in protecting against Coronavirus Disease 2019 (COVID-19). However, the emergence of viral variants that are more transmissible and, in some cases, escape from neutralizing antibody responses has raised concerns. Here, we evaluated recombinant protein spike antigens derived from wild-type SARS-CoV-2 and from variants B.1.1.7, B.1.351, and P.1 for their immunogenicity and protective effect in vivo against challenge with wild-type SARS-CoV-2 in the mouse model. All proteins induced high neutralizing antibodies against the respective viruses but also induced high cross-neutralizing antibody responses. The decline in neutralizing titers between variants was moderate, with B.1.1.7-vaccinated animals having a maximum fold reduction of 4.8 against B.1.351 virus. P.1 induced the most cross-reactive antibody responses but was also the least immunogenic in terms of homologous neutralization titers. However, all antigens protected from challenge with wild-type SARS-CoV-2 in a mouse model