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Background: Streptococcus pneumoniae (pneumococcus) is a leading cause of pneumonia in older adults. Successful control of pneumococci requires robust pulmonary neutrophil influx early in infection. However, aging is associated with aberrant neutrophil recruitment and the mechanisms behind that are not understood. Here we explored how neutrophil recruitment following pneumococcal infection changes with age and the host pathways regulating this., Results: Following pneumococcal infection there was a significant delay in early neutrophil recruitment to the lungs of aged mice. Neutrophils from aged mice showed defects in trans-endothelial migration in vitro compared to young controls. To understand the pathways involved, we examined immune modulatory extracellular adenosine (EAD) signaling, that is activated upon cellular damage. Signaling through the lower affinity A2A and A2B adenosine receptors had no effect on neutrophil recruitment to infected lungs. In contrast, inhibition of the high affinity A1 receptor in young mice blunted neutrophil recruitment to the lungs following infection. A1 receptor inhibition decreased expression of CXCR2 on circulating neutrophils, which is required for trans-endothelial migration. Indeed, A1 receptor signaling on neutrophils was required for their ability to migrate across endothelial cells in response to infection. Aging was not associated with defects in EAD production or receptor expression on neutrophils. However, agonism of A1 receptor in aged mice rescued the early defect in neutrophil migration to the lungs and improved control of bacterial burden., Conclusions: This study suggests age-driven defects in EAD damage signaling can be targeted to rescue the delay in pulmonary neutrophil migration in response to bacterial pneumonia., (© 2024. The Author(s).)

Background: Applying deep brain stimulation (DBS) to several brain regions has been investigated in attempts to treat highly treatment-resistant depression, with variable results. Our initial pilot data suggested that the bed nucleus of the stria terminalis (BNST) could be a promising therapeutic target., Objective: The aim of this study was to gather blinded data exploring the efficacy of applying DBS to the BNST in patients with highly refractory depression., Method: Eight patients with chronic severe treatment-resistant depression underwent DBS to the BNST. A randomised, double-blind crossover study design with fixed stimulation parameters was followed and followed by a period of open-label stimulation., Results: During the double-blind crossover phase, no consistent antidepressant effects were seen with any of the four stimulation parameters applied, and no patients achieved response or remission criteria during the blinded crossover phase or during a subsequent period of three months of blinded stimulation. Stimulation-related side effects, especially agitation, were reported by a number of patients and were reversible with adjustment of the stimulation parameters., Conclusions: The results of this study do not support the application of DBS to the BNST in patients with highly resistant depression or ongoing research utilising stimulation at this brain site. The blocked randomised study design utilising fixed stimulation parameters was poorly tolerated by the participants and does not appear suitable for assessing the efficacy of DBS at this location.

Polymorphonuclear cells (PMNs) control Streptococcus pneumoniae (pneumococcus) infection through various antimicrobial activities. We previously found that reactive oxygen species (ROS) were required for optimal antibacterial function, however, the NADPH oxidase is known to be dispensable for the ability of PMNs to kill pneumococci. In this study, we explored the role of ROS produced by the mitochondria in PMN antimicrobial defense against pneumococci. We found that the mitochondria are an important source of overall intracellular ROS produced by murine PMNs in response to infection. We investigated the host and bacterial factors involved and found that mitochondrial ROS (MitROS) are produced independent of bacterial capsule or pneumolysin but presence of live bacteria that are in direct contact with PMNs enhanced the response. We further found that MyD88-/- PMNs produced less MitROS in response to pneumococcal infection suggesting that released bacterial products acting as TLR ligands are sufficient for inducing MitROS production in PMNs. To test the role of MitROS in PMN function, we used an opsonophagocytic killing assay and found that MitROS were required for the ability of PMNs to kill pneumococci. We then investigated the role of MitROS in host resistance and found that MitROS are produced by PMNs in response to pneumococcal infection. Importantly, treatment of mice with a MitROS scavenger prior to systemic challenge resulted in reduced survival of infected hosts. In exploring host pathways that control MitROS, we focused on extracellular adenosine, which is known to control PMN anti-pneumococcal activity, and found that signaling through the A2B adenosine receptor inhibits MitROS production by PMNs. A2BR-/- mice produced more MitROS and were significantly more resistant to infection. Finally, we verified the clinical relevance of our findings using human PMNs. In summary, we identified a novel pathway that controls MitROS production by PMNs, shaping host resistance against S. pneumoniae., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Herring et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Brain connectivity can be estimated through many analyses applied to electroencephalography (EEG) data. However, substantial heterogeneity in the implementation of connectivity methods exists. Heterogeneity in conceptualization of connectivity measures, data collection, or data preprocessing may be associated with variability in robustness of measurement. While it is difficult to compare the results of studies using different EEG connectivity measures, standardization of processing and reporting may facilitate the task. We discuss how factors such as referencing, epoch length and number, controls for volume conduction, artifact removal, and statistical control of multiple comparisons influence the EEG connectivity estimate for connectivity measures, and what can be done to control for potential confounds associated with these factors. Based on the results reported in previous literature, this article presents recommendations and a novel checklist developed for quality assessment of EEG connectivity studies. This checklist and its recommendations are made in an effort to draw attention to factors that may influence connectivity estimates and factors that need to be improved in future research. Standardization of procedures and reporting in EEG connectivity may lead to EEG connectivity studies being made more synthesizable and comparable despite variations in the methodology underlying connectivity estimates., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Background: Obsessive-compulsive disorder (OCD) is a chronic, disabling mental health condition with limited treatment options available to date. Numerous randomized controlled trials have explored the efficacy of repetitive transcranial magnetic stimulation (rTMS) in OCD. This meta-analysis synthesized data from selected randomized controlled trials and examined the impact of different treatment parameters to generate hypotheses that would direct future randomized controlled trials., Methods: A database search was performed to identify studies published in English up to October 2020. Randomized, sham-controlled studies that used rTMS to treat OCD were included. Effect sizes were calculated using Hedges' g for pre- to post-treatment Yale-Brown Obsessive Compulsive Scale scores. Subgroup analyses were conducted to assess the effects of variations in rTMS treatment parameters., Results: A total of 26 studies with 781 participants were included. Overall, rTMS demonstrated a modest effect on reduction of Yale-Brown Obsessive Compulsive Scale scores (Hedges' g = 0.64, 95% confidence interval = 0.39-0.89; p < .0001). The largest significant effect size was obtained by targeting the bilateral dorsolateral prefrontal cortex. High- and low-frequency rTMS showed comparable effects. Studies with follow-up data suggested that the effects of active rTMS remain significantly superior to those of sham 4 weeks after treatment., Conclusions: The therapeutic effects of rTMS are superior to those of sham in the treatment of OCD. Targeting the bilateral dorsolateral prefrontal cortex was the most favorable approach in administering rTMS. Further research is required to determine the optimal frequency, total pulses per session, and duration of treatment with rTMS for OCD., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Elderly individuals are at increased risk of life-threatening pulmonary infections. Neutrophils are a key determinant of the disease course of pathogen-induced pneumonia. Optimal host defense balances initial robust pulmonary neutrophil responses to control pathogen numbers, ultimately followed by the resolution of inflammation to prevent pulmonary damage. Recent evidence suggests that phenotypic and functional heterogeneity in neutrophils impacts host resistance to pulmonary pathogens. Apart from their apparent role in innate immunity, neutrophils also orchestrate subsequent adaptive immune responses during infection. Thus, the outcome of pulmonary infections can be shaped by neutrophils. This review summarizes the age-driven impairment of neutrophil responses and the contribution of these cells to the susceptibility of the elderly to pneumonia. We describe how aging is accompanied by changes in neutrophil recruitment, resolution, and function. We discuss how systemic and local changes alter the neutrophil phenotype in aged hosts. We highlight the gap in knowledge of whether these changes in neutrophils also contribute to the decline in adaptive immunity seen with age. We further detail the factors that drive dysregulated neutrophil responses in the elderly and the pathways that may be targeted to rebalance neutrophil activity and boost host resistance to pulmonary infections., (Copyright © 2021 American Society for Microbiology.)

The elderly are susceptible to serious infections by Streptococcus pneumoniae (pneumococcus), which calls for a better understanding of the pathways driving the decline in host defense in aging. We previously found that extracellular adenosine (EAD) shaped polymorphonuclear cell (PMN) responses, which are crucial for controlling infection. EAD is produced by CD39 and CD73, and signals via A1, A2A, A2B, and A3 receptors. The objective of this study was to explore the age-driven changes in the EAD pathway and its impact on PMN function. We found in comparison to young mice, PMNs from old mice expressed significantly less CD73, but similar levels of CD39 and adenosine receptors. PMNs from old mice failed to efficiently kill pneumococci ex vivo; however, supplementation with adenosine rescued this defect. Importantly, transfer of PMNs expressing CD73 from young mice reversed the susceptibility of old mice to pneumococcal infection. To identify which adenosine receptor(s) is involved, we used specific agonists and inhibitors. We found that A1 receptor signaling was crucial for PMN function as inhibition or genetic ablation of A1 impaired the ability of PMNs from young mice to kill pneumococci. Importantly, activation of A1 receptors rescued the age-associated defect in PMN function. In exploring mechanisms, we found that PMNs from old mice failed to efficiently kill engulfed pneumococci and that A1 receptor controlled intracellular killing. In summary, targeting the EAD pathway reverses the age-driven decline in PMN antimicrobial function, which has serious implications in combating infections., (© 2020 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Extracellular adenosine production is crucial for host resistance against Streptococcus pneumoniae (pneumococcus) and is thought to affect antibacterial immune responses by neutrophils. However, whether extracellular adenosine alters direct host-pathogen interaction remains unexplored. An important determinant for lung infection by S. pneumoniae is its ability to adhere to the pulmonary epithelium. Here we explored whether extracellular adenosine can directly impact bacterial adherence to lung epithelial cells. We found that signaling via A1 adenosine receptor significantly reduced the ability of pneumococci to bind human pulmonary epithelial cells. A1 receptor signaling blocked bacterial binding by reducing the expression of platelet-activating factor receptor, a host protein used by S. pneumoniae to adhere to host cells. In vivo, A1 was required for control of pneumococcal pneumonia as inhibiting it resulted in increased host susceptibility. As S. pneumoniae remain a leading cause of community-acquired pneumonia in the elderly, we explored the role of A1 in the age-driven susceptibility to infection. We found no difference in A1 pulmonary expression in young versus old mice. Strikingly, triggering A1 signaling boosted host resistance of old mice to S. pneumoniae pulmonary infection. This study demonstrates a novel mechanism by which extracellular adenosine modulates resistance to lung infection by targeting bacterial-host interactions., (© 2019 John Wiley & Sons Ltd.)

Background: Repetitive Transcranial Magnetic Stimulation (rTMS) is widely approved treatment for major depressive disorder (MDD). However, around 50% of individuals who recover from depression following rTMS interventions experience a relapse of depressive symptomatology by 12 months. The short-term durability of the rTMS treatment effect has been systematically investigated. However, variables relating to the long-term durability of the antidepressant effect produced by rTMS are less understood. Therefore, the current review systematically assessed the research on variables relating to relapse following rTMS., Method: This systematic review was performed according to PRISMA guidelines. A comprehensive electronic literature search for terms related to relapse following rTMS treatment for MDD was performed on studies published before the end of October 2018., Results: A total of 18 studies assessing relapse related variables were identified. While there is some indication that comorbid anxiety, acute response, and residual symptomatology may hold predictive potential for depressive relapse following rTMS treatment, findings were not sufficient to draw reliable conclusions., Discussion: Identified studies assessed three main categories of variables including demographic information, clinical characteristics and rating scale scores, and rTMS treatment specific factors. Only a small number of studies were available, and considerable inconsistency exists between studies, only limited conclusions were able to be drawn., Conclusion: More studies assessing a wider range of predictor variables such as cognitive or neuroimaging markers are needed., (Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.)

Depression following a traumatic brain injury (TBI) is common and difficult to treat using standard approaches. The current study investigated, for the first time, transcranial magnetic stimulation (TMS) for the treatment of post TBI depression. We specifically assessed the safety, tolerability, and efficacy of TMS in this patient population. We also explored cognitive outcomes. Twenty-one patients with a current episode of major depression subsequent to a TBI participated in a randomized double-blind placebo-controlled trial of repetitive TMS (rTMS). Sequential bilateral rTMS (to the left and right dorsolateral prefrontal cortex) was provided in 20 treatments over a period of 4 weeks. Patients were randomly allocated to receive either active or sham stimulation. There were no adverse effects and treatment was well tolerated. There was no significant effect of rTMS on post-TBI depression, with all patients showing a significant improvement in depressive symptoms irrespective of their treatment group ( p  = 0.002). There were significant improvements in cognition following active rTMS in the areas of working memory ( p  = 0.021) and executive function ( p  = 0.029). rTMS was shown to be safe and well tolerated in patients who had developed depression after a TBI. We did not find a therapeutic effect for post-TBI depression; however, this approach may have some utility in improving cognitive function. Future research should focus on alternative rTMS treatment approaches for post-TBI depression and the direct investigation of rTMS as a treatment for cognitive impairment in TBI.

Obsessive-compulsive disorder (OCD) is a chronic disease that causes significant decline in the quality of life of those affected. Due to our limited understanding of the underlying pathophysiology of OCD, successful treatment remains elusive. Although many have studied the pathophysiology of OCD through electroencephalography (EEG), limited attempts have been made to synthesize and interpret their findings. To bridge this gap, we conducted a comprehensive literature review using Medline/PubMed and considered the 65 most relevant studies published before June 2018. The findings are categorised into quantitative EEG, sleep related EEG and event related potentials (ERPs). Increased frontal asymmetry, frontal slowing and an enhancement in the ERP known as error related negativity (ERN) were consistent findings in OCD. However, sleep EEG and other ERP (P3 and N2) findings were inconsistent. Additionally, we analysed the usefulness of ERN as a potential candidate endophenotype. We hypothesize that dysfunctional frontal circuitry and overactive performance monitoring are the major underlying impairments in OCD. Additionally, we conceptualized that defective fronto-striato-thalamic circuitry causing poor cerebral functional connectivity gives rise to the OCD behavioural manifestations. Finally, we have discussed transcranial magnetic stimulation and EEG (TMS-EEG) applications in future research to further our knowledge of the underlying pathophysiology of OCD., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Electroconvulsive therapy (ECT) is a very commonly used treatment for patients with severe and treatment-resistant depression. Although effective, this treatment is complicated by a number of side effects including cognitive impairment motivating attempts to develop treatment alternatives. Magnetic seizure therapy (MST) is a brain stimulation technique using a high-powered transcranial magnetic stimulation device to produce therapeutic seizures. Preliminary research suggests that MST has antidepressant activity in the absence of cognitive side effects. The aim of this study was therefore to investigate the therapeutic efficacy and cognitive profile of MST provided at high frequency (100 Hz) and potentially longer stimulation trains and longer treatment courses than have been previously investigated., Methods: Thirteen patients participated in an open-label clinical trial of up to 18 treatment sessions with 100-Hz MST. Assessments of depression severity and cognitive functioning were performed before and after treatment., Results: Of the 13 patients who completed the study, five met clinical response criteria at study end. There was an overall group reduction in depression severity and no evidence of any impairment of orientation, memory, or other elements of cognition after MST treatment. The major limitation of the study was its lack of sham control., Conclusions: In conclusion, MST shows antidepressant efficacy without apparent cognitive side effects. However, substantial research is required to understand the optimal conditions for stimulation and to compare MST to established treatments including ECT., (© 2012 Wiley Periodicals, Inc.)

Objective: A substantive body of research has demonstrated the efficacy of repetitive transcranial magnetic stimulation treatment (rTMS) in patients with depression. However, the parameters needed to optimize therapeutic efficacy remain unclear. The aim of this study was to investigate whether there is an advantage in efficacy of sequential bilateral rTMS compared to standard high-frequency left sided rTMS., Method: Sixty seven patients with treatment resistant depression were included in a randomised double-blind sham controlled trial of sequential bilateral rTMS compared to standard high-frequency left sided rTMS and sham rTMS over a three-week period. The study also included a further three week comparison of the two active treatment conditions. The primary outcome variable was scores on the 17-item Hamilton Depression Rating Scale (HAMD)., Results: In the three-week double-blind phase of the trial there was a greater antidepressant response to unilateral left sided rTMS compared with sham or bilateral rTMS. Across the full six weeks of active rTMS, there was also a consistent pattern of improved response in unilateral left compared to bilateral treatment. Response rates were low in both active groups., Conclusions: This study does not support the hypothesis that sequential bilateral rTMS is more effective than unilateral high-frequency left-sided rTMS., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Schizophrenia patients have been shown to be compromised in their ability to recognize facial emotion. This deficit has been shown to be related to negative symptoms severity. However, to date, most studies have used static rather than dynamic depictions of faces. Nineteen patients with schizophrenia were compared with seventeen controls on 2 tasks; the first involving the discrimination of facial identity, emotion, and butterfly wings; the second testing emotion recognition using both static and dynamic stimuli. In the first task, the patients performed more poorly than controls for emotion discrimination only, confirming a specific deficit in facial emotion recognition. In the second task, patients performed more poorly in both static and dynamic facial emotion processing. An interesting pattern of associations suggestive of a possible double dissociation emerged in relation to correlations with symptom ratings: high negative symptom ratings were associated with poorer recognition of static displays of emotion, whereas high positive symptom ratings were associated with poorer recognition of dynamic displays of emotion. However, while the strength of associations between negative symptom ratings and accuracy during static and dynamic facial emotion processing was significantly different, those between positive symptom ratings and task performance were not. The results confirm a facial emotion-processing deficit in schizophrenia using more ecologically valid dynamic expressions of emotion. The pattern of findings may reflect differential patterns of cortical dysfunction associated with negative and positive symptoms of schizophrenia in the context of differential neural mechanisms for the processing of static and dynamic displays of facial emotion.

Theoretical accounts suggest that mirror neurons play a crucial role in social cognition. The current study used transcranial magnetic stimulation (TMS) to investigate the association between mirror neuron activation and facial emotion processing, a fundamental aspect of social cognition, among healthy adults (n=20). Facial emotion processing of static (but not dynamic) images correlated significantly with an enhanced motor response, proposed to reflect mirror neuron activation. These correlations did not appear to reflect general facial processing or pattern recognition, and provide support to current theoretical accounts linking the mirror neuron system to aspects of social cognition. We discuss the mechanism by which mirror neurons might facilitate facial emotion recognition.

Impairments in social cognitive functioning are well documented in schizophrenia, however the neural basis of these deficits is unclear. A recent explanatory model of social cognition centers upon the activity of mirror neurons, which are cortical brain cells that become active during both the performance and observation of behavior. Here, we test for the first time whether mirror neuron functioning is reduced in schizophrenia. Fifteen individuals with schizophrenia or schizoaffective disorder and fifteen healthy controls completed a transcranial magnetic stimulation (TMS) experiment designed to assess mirror neuron activation. While patients demonstrated no abnormalities in cortical excitability, motor facilitation during action observation, putatively reflecting mirror neuron activity, was reduced in schizophrenia. Dysfunction within the mirror neuron system may contribute to the pathophysiology of schizophrenia.