A new angle on transcranial magnetic stimulation coil orientation: A targeted narrative review.

Transcranial magnetic stimulation (TMS) is used to treat several neuropsychiatric disorders including depression, where it is effective in approximately half of patients for whom pharmacological approaches have failed. Treatment response is related to stimulation parameters such as the stimulation frequency, pattern, intensity, location, total number of pulses and sessions applied, as well as target brain network engagement. One critical but underexplored component of the stimulation procedure is the orientation or yaw angle of the commonly used figure-of-eight TMS coil, which is known to impact neuronal response to TMS. However, coil orientation has remained largely unchanged since TMS was first used to treat depression and continues to be based on motor cortex anatomy which may not be optimal for the dorsolateral prefrontal cortex treatment site. This targeted narrative review evaluates experimental, clinical, and computational evidence indicating that optimizing coil orientation may potentially improve TMS treatment outcomes. The properties of the electric field induced by TMS, the changes to this field caused by the differing conductivities of head tissues, and the interaction between coil orientation and the underlying cortical anatomy are summarized. We describe evidence that the magnitude and site of cortical activation, surrogate markers of TMS dosing and brain network targeting considered central in clinical response to TMS, are influenced by coil orientation. We suggest that coil orientation should be considered when applying therapeutic TMS and propose several approaches to optimizing this potentially important treatment parameter.

Controlling the Uptake and Release of Semiochemicals in Channel-Type Metal-Organic Frameworks Through Pore Expansion.

Semiochemicals can be used to manipulate insect behaviour for sustainable pest management strategies, but their high volatility is a major issue for their practical implementation. Inclusion of these molecules within porous materials is a potential solution to this issue, as it can allow for a slower and more controlled release. In this work, we demonstrate that a series of Zr(IV) and Al(III) metal-organic frameworks (MOFs) with channel-type pores enable controlled release of three semiochemicals over 100 days by pore size design, with the uptake and rate of release highly dependent on the pore size. Insight from grand canonical Monte Carlo simulations indicates that this is due to weaker MOF-guest interactions per guest molecule as the pore size increases. These MOFs are all stable post-release and can be reloaded to show near-identical re-release profiles. These results provide valuable insight on the diffusion behaviour of volatile guests in MOFs, and for the further development of porous materials for sustainable agriculture applications.

Single shot detection of alterations across multiple ionic currents from assimilation of cell membrane dynamics.

The dysfunction of ion channels is a causative factor in a variety of neurological diseases, thereby defining the implicated channels as key drug targets. The detection of functional changes in multiple specific ionic currents currently presents a challenge, particularly when the neurological causes are either a priori unknown, or are unexpected. Traditional patch clamp electrophysiology is a powerful tool in this regard but is low throughput. Here, we introduce a single-shot method for detecting alterations amongst a range of ion channel types from subtle changes in membrane voltage in response to a short chaotically driven current clamp protocol. We used data assimilation to estimate the parameters of individual ion channels and from these we reconstructed ionic currents which exhibit significantly lower error than the parameter estimates. Such reconstructed currents thereby become sensitive predictors of functional alterations in biological ion channels. The technique correctly predicted which ionic current was altered, and by approximately how much, following pharmacological blockade of BK, SK, A-type K+ and HCN channels in hippocampal CA1 neurons. We anticipate this assay technique could aid in the detection of functional changes in specific ionic currents during drug screening, as well as in research targeting ion channel dysfunction.

A back-translational study of descending interactions with the induction of hyperalgesia by high-frequency electrical stimulation in rat and human.

ABSTRACT: In humans and animals, high-frequency electrocutaneous stimulation (HFS) induces an "early long-term potentiation-like" sensitisation, where synaptic plasticity is underpinned by an ill-defined interaction between peripheral input and central modulatory processes. The relative contributions of these processes to the initial pain or nociceptive response likely differ from those that underpin development of the heightened response. To investigate the impact of HFS-induced hyperalgesia on pain and nociception in perception and neural terms, respectively, and to explore the impact of descending inhibitory pathway activation on the development of HFS-induced hyperalgesia, we performed parallel studies utilising identical stimuli to apply HFS concurrent to (1) a conditioned pain modulation paradigm during psychophysical testing in healthy humans or (2) a diffuse noxious inhibitory controls paradigm during in vivo electrophysiological recording of spinal neurones in healthy anaesthetised rats. High-frequency electrocutaneous stimulation alone induced enhanced perceptual responses to pinprick stimuli in cutaneous areas secondary to the area of electrical stimulation in humans and increased the excitability of spinal neurones which exhibited stimulus intensity-dependent coded responses to pinprick stimulation in a manner that tracked with human psychophysics, supporting their translational validity. Application of a distant noxious conditioning stimulus during HFS did not alter perceived primary or secondary hyperalgesia in humans or the development of primary or secondary neuronal hyperexcitability in rats compared with HFS alone, suggesting that, upon HFS-response initiation in a healthy nervous system, excitatory signalling escapes inhibitory control. Therefore, in this model, dampening facilitatory mechanisms rather than augmenting top-down inhibitions could prevent pain development.

Identification of potential Auxin Response Candidate genes for soybean rapid canopy coverage through comparative evolution and expression analysis.

Glycine max, soybean, is an abundantly cultivated crop worldwide. Efforts have been made over the past decades to improve soybean production in traditional and organic agriculture, driven by growing demand for soybean-based products. Rapid canopy cover development (RCC) increases soybean yields and suppresses early-season weeds. Genome-wide association studies have found natural variants associated with RCC, however causal mechanisms are unclear. Auxin modulates plant growth and development and has been implicated in RCC traits. Therefore, modulation of auxin regulatory genes may enhance RCC. Here, we focus on the use of genomic tools and existing datasets to identify auxin signaling pathway RCC candidate genes, using a comparative phylogenetics and expression analysis approach. We identified genes encoding 14 TIR1/AFB auxin receptors, 61 Aux/IAA auxin co-receptors and transcriptional co-repressors, and 55 ARF auxin response factors in the soybean genome. We used Bayesian phylogenetic inference to identify soybean orthologs of Arabidopsis thaliana genes, and defined an ortholog naming system for these genes. To further define potential auxin signaling candidate genes for RCC, we examined tissue-level expression of these genes in existing datasets and identified highly expressed auxin signaling genes in apical tissues early in development. We identified at least 4 TIR1/AFB, 8 Aux/IAA, and 8 ARF genes with highly specific expression in one or more RCC-associated tissues. We hypothesize that modulating the function of these genes through gene editing or traditional breeding will have the highest likelihood of affecting RCC while minimizing pleiotropic effects.

Determinants of perceived health in university employees.

Objective: Employee health plays an important role in overall campus health and wellbeing. Therefore, this research explored the physical, mental, and environmental determinants of perceived health in employees of higher education. Participants: 422 full-time employees from one university took the American College Health Association National Faculty and Staff Health Assessment (NFSHA) online in April 2021. Methods: A cross-sectional correlational design was used to explore which physical, mental, and environmental health factors influenced perceived health of employees. Results: Sleep, body mass index (BMI), flourishing, and the extent to which employees felt the university cared about their health and wellbeing were the four significant factors that increased the odds of employees reporting higher levels of perceived health. Conclusions: Using Bandura's reciprocal determinism as a theoretical lens, these results reinforce that behaviors, personal attributes, and the environment are interdependent and influence perceived health in this sample of university employees.

Quantitative LC-MS study of compounds found predictive of COVID-19 severity and outcome.

INTRODUCTION: Since the beginning of the SARS-CoV-2 pandemic in December 2019 multiple metabolomics studies have proposed predictive biomarkers of infection severity and outcome. Whilst some trends have emerged, the findings remain intangible and uninformative when it comes to new patients. OBJECTIVES: In this study, we accurately quantitate a subset of compounds in patient serum that were found predictive of severity and outcome. METHODS: A targeted LC-MS method was used in 46 control and 95 acute COVID-19 patient samples to quantitate the selected metabolites. These compounds included tryptophan and its degradation products kynurenine and kynurenic acid (reflective of immune response), butyrylcarnitine and its isomer (reflective of energy metabolism) and finally 3',4'-didehydro-3'-deoxycytidine, a deoxycytidine analogue, (reflective of host viral defence response). We subsequently examine changes in those markers by disease severity and outcome relative to those of control patients' levels. RESULTS & CONCLUSION: Finally, we demonstrate the added value of the kynurenic acid/tryptophan ratio for severity and outcome prediction and highlight the viral detection potential of ddhC.

Heroin-Induced Transverse Myelitis in a Chronic Heroin User: A Case Report.

Transverse myelitis is a rare but documented sequela of heroin use. While the underlying etiology is not clearly elucidated, the prevailing pathophysiologic mechanism amongst existing literature suggests an immune-mediated hypersensitivity reaction due to heroin insufflation following a long period of abstinence. Outcomes vary among the limited reports, but prognosis tends to be poor due to an acute and rapidly progressive disease course. Here, we describe a case of extensive transverse myelitis in a chronic heroin user following heroin insufflation. This report hopes to provide greater insight into the underlying cause of this rare phenomenon due to our patient's discrepancy from the documented norm of heroin abstinence preceding disease onset.

The therapeutic use and efficacy of ketamine in alcohol use disorder and alcohol withdrawal syndrome: a scoping review.

Introduction: Alcohol use disorder (AUD) is the most prevalent substance use disorder (SUD) globally. In 2019, AUD affected 14.5 million Americans and contributed to 95,000 deaths, with an annual cost exceeding 250 billion dollars. Current treatment options for AUD have moderate therapeutic effects and high relapse rates. Recent investigations have demonstrated the potential efficacy of intravenous ketamine infusions to increase alcohol abstinence and may be a safe adjunct to the existing alcohol withdrawal syndrome (AWS) management strategies. Methods: We followed Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines to conduct a scoping review of two databases (PubMed and Google Scholar) for peer-reviewed manuscripts describing the use of ketamine in AUD and AWS. Studies that evaluated the use of ketamine in AUD and AWS in humans were included. We excluded studies that examined laboratory animals, described alternative uses of ketamine, or discussed other treatments of AUD and AWS. Results: We identified 204 research studies in our database search. Of these, 10 articles demonstrated the use of ketamine in AUD or AWS in humans. Seven studies investigated the use of ketamine in AUD and three studies described its use in AWS. Ketamine used in AUD was beneficial in reducing cravings, alcohol consumption and longer abstinence rates when compared to treatment as usual. In AWS, ketamine was used as an adjunct to standard benzodiazepine therapy during severe refractory AWS and at signs of delirium tremens. Adjunctive use of ketamine demonstrated earlier resolution of delirium tremens and AWS, reduced ICU stay, and lowered likelihood of intubation. Oversedation, headache, hypertension, and euphoria were the documented adverse effects after ketamine administration for AUD and AWS. Conclusion: The use of sub-dissociative doses of ketamine for the treatment of AUD and AWS is promising but more definitive evidence of its efficacy and safety is required before recommending it for broader clinical use.

The association between psychosocial factors and mental health symptoms in cervical spine pain with or without radiculopathy on health outcomes: a systematic review.

BACKGROUND: Neck pain, with or without radiculopathy, can have significant negative effects on physical and mental wellbeing. Mental health symptoms are known to worsen prognosis across a range of musculoskeletal conditions. Understanding the association between mental health symptoms and health outcomes in this population has not been established. Our aim was to systematically review the association between psychosocial factors and/or mental health symptoms on health outcomes in adults with neck pain, with or without radiculopathy. METHODS: A systematic review of published and unpublished literature databases was completed. Studies reporting mental health symptoms and health outcomes in adults with neck pain with or without radiculopathy were included. Due to significant clinical heterogeneity, a narrative synthesis was completed. Each outcome was assessed using GRADE. RESULTS: Twenty-three studies were included (N = 21,968 participants). Sixteen studies assessed neck pain only (N = 17,604 participants); seven studies assessed neck pain with radiculopathy (N = 4,364 participants). Depressive symptoms were associated with poorer health outcomes in people with neck pain and neck pain with radiculopathy. These findings were from seven low-quality studies, and an additional six studies reported no association. Low-quality evidence reported that distress and anxiety symptoms were associated with poorer health outcomes in people with neck pain and radiculopathy and very low-quality evidence showed this in people with neck pain only. Stress and higher job strain were negatively associated with poorer health outcomes measured by the presence of pain in two studies of very low quality. CONCLUSIONS: Across a small number of highly heterogenous, low quality studies mental health symptoms are negatively associated with health outcomes in people with neck pain with radiculopathy and neck pain without radiculopathy. Clinicians should continue to utilise robust clinical reasoning when assessing the complex factors impacting a person's presentation with neck pain with or without radiculopathy. PROSPERO REGISTRATION NUMBER: CRD42020169497.

A transdiagnostic network for psychiatric illness derived from atrophy and lesions.

Psychiatric disorders share neurobiology and frequently co-occur. This neurobiological and clinical overlap highlights opportunities for transdiagnostic treatments. In this study, we used coordinate and lesion network mapping to test for a shared brain network across psychiatric disorders. In our meta-analysis of 193 studies, atrophy coordinates across six psychiatric disorders mapped to a common brain network defined by positive connectivity to anterior cingulate and insula, and by negative connectivity to posterior parietal and lateral occipital cortex. This network was robust to leave-one-diagnosis-out cross-validation and specific to atrophy coordinates from psychiatric versus neurodegenerative disorders (72 studies). In 194 patients with penetrating head trauma, lesion damage to this network correlated with the number of post-lesion psychiatric diagnoses. Neurosurgical ablation targets for psychiatric illness (four targets) also aligned with the network. This convergent brain network for psychiatric illness may partially explain high rates of psychiatric comorbidity and could highlight neuromodulation targets for patients with more than one psychiatric disorder.

Multisystem physiological perspective of human frailty and its modulation by physical activity.

"Frailty" is a term used to refer to a state characterized by enhanced vulnerability to, and impaired recovery from, stressors compared with a nonfrail state, which is increasingly viewed as a loss of resilience. With increasing life expectancy and the associated rise in years spent with physical frailty, there is a need to understand the clinical and physiological features of frailty and the factors driving it. We describe the clinical definitions of age-related frailty and their limitations in allowing us to understand the pathogenesis of this prevalent condition. Given that age-related frailty manifests in the form of functional declines such as poor balance, falls, and immobility, as an alternative we view frailty from a physiological viewpoint and describe what is known of the organ-based components of frailty, including adiposity, the brain, and neuromuscular, skeletal muscle, immune, and cardiovascular systems, as individual systems and as components in multisystem dysregulation. By doing so we aim to highlight current understanding of the physiological phenotype of frailty and reveal key knowledge gaps and potential mechanistic drivers of the trajectory to frailty. We also review the studies in humans that have intervened with exercise to reduce frailty. We conclude that more longitudinal and interventional clinical studies are required in older adults. Such observational studies should interrogate the progression from a nonfrail to a frail state, assessing individual elements of frailty to produce a deep physiological phenotype of the syndrome. The findings will identify mechanistic drivers of frailty and allow targeted interventions to diminish frailty progression.

PDL1 shapes the classical Hodgkin lymphoma microenvironment without inducing T-cell exhaustion.

Classical Hodgkin lymphoma (CHL) is unusually sensitive to PD1 inhibition and PDL1 is highly expressed on CHL cells and in the tumor microenvironment. This could be interpreted as evidence of exhaustion, but paradoxically, PD1+ lymphocyte infiltration does not predict response to PD1 inhibitors and no increase in cytotoxic markers is seen after PD1 therapy as might be expected with reversal of exhaustion. In contrast to PD1, elevated PDL1 does predict response to PD1 inhibitors and recent data associate both retained CHL MHC-II expression and increased T helper (TH) T-cell receptor diversity with response, suggesting a connection to the TH compartment. We performed a phenotypic, spatial and functional assessment of T-cell exhaustion in CHL and found co-expression of an exhaustion marker and lower PD1 expression in CHL than in reactive nodes whereas the proliferative and cytokine production capacity were similar in CHL and the reactive nodes. We found no correlation between PDL1 expression and exhaustion signatures. Instead, we identified a strong association between PDL1 expression and CHL MHC-II expression, TH recruitment, and enrichment of TH1 regulatory cells. These data suggest that a dominant effect of PDL1 expression in CHL may be TH engagement and promotion of a regulatory microenvironment rather than maintenance of exhaustion.

Network Effects of Brain Lesions Causing Central Poststroke Pain.

OBJECTIVE: This study was undertaken to test whether lesions causing central poststroke pain (CPSP) are associated with a specific connectivity profile, whether these connections are associated with metabolic changes, and whether this network aligns with neuromodulation targets for pain. METHODS: Two independent lesion datasets were utilized: (1) subcortical lesions from published case reports and (2) thalamic lesions with metabolic imaging using 18F- fluorodeoxyglucose positron emission tomography-computed tomography. Functional connectivity between each lesion location and the rest of the brain was assessed using a normative connectome (n = 1,000), and connections specific to CPSP were identified. Metabolic changes specific to CPSP were also identified and related to differences in lesion connectivity. Therapeutic relevance of the network was explored by testing for alignment with existing brain stimulation data and by prospectively targeting the network with repetitive transcranial magnetic stimulation (rTMS) in 7 patients with CPSP. RESULTS: Lesion locations causing CPSP showed a specific pattern of brain connectivity that was consistent across two independent lesion datasets (spatial r = 0.82, p < 0.0001). Connectivity differences were correlated with postlesion metabolism (r = -0.48, p < 0.001). The topography of this lesion-based pain network aligned with variability in pain improvement across 12 prior neuromodulation targets and across 32 patients who received rTMS to primary motor cortex (p < 0.05). Prospectively targeting this network with rTMS improved CPSP in 6 of 7 patients. INTERPRETATION: Lesions causing pain are connected to a specific brain network that shows metabolic abnormalities and promise as a neuromodulation target. ANN NEUROL 2022;92:834-845.

Noise-activated barrier crossing in multiattractor dissipative neural networks.

Noise-activated transitions between coexisting attractors are investigated in a chaotic spiking network. At low noise level, attractor hopping consists of discrete bifurcation events that conserve the memory of initial conditions. When the escape probability becomes comparable to the intrabasin hopping probability, the lifetime of attractors is given by a detailed balance where the less coherent attractors act as a sink for the more coherent ones. In this regime, the escape probability follows an activation law allowing us to assign pseudoactivation energies to limit cycle attractors. These pseudoenergies introduce a useful metric for evaluating the resilience of biological rhythms to perturbations.

Discovery of a Partial Glucokinase Activator Clinical Candidate: Diethyl ((3-(3-((5-(Azetidine-1-carbonyl)pyrazin-2-yl)oxy)-5-isopropoxybenzamido)-1H-pyrazol-1-yl)methyl)phosphonate (BMS-820132).

Glucokinase (GK) is a key regulator of glucose homeostasis, and its small-molecule activators represent a promising opportunity for the treatment of type 2 diabetes. Several GK activators have been advanced into clinical trials and have demonstrated promising efficacy; however, hypoglycemia represents a key risk for this mechanism. In an effort to mitigate this hypoglycemia risk while maintaining the efficacy of the GK mechanism, we have investigated a series of amino heteroaryl phosphonate benzamides as ''partial" GK activators. The structure-activity relationship studies starting from a "full GK activator" 11, which culminated in the discovery of the "partial GK activator" 31 (BMS-820132), are discussed. The synthesis and in vitro and in vivo preclinical pharmacology profiles of 31 and its pharmacokinetics (PK) are described. Based on its promising in vivo efficacy and preclinical ADME and safety profiles, 31 was advanced into human clinical trials.