A systematic review and meta-analysis of neuromodulation therapies for substance use disorders.

While pharmacological, behavioral and psychosocial treatments are available for substance use disorders (SUDs), they are not always effective or well-tolerated. Neuromodulation (NM) methods, including repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS) and deep brain stimulation (DBS) may address SUDs by targeting addiction neurocircuitry. We evaluated the efficacy of NM to improve behavioral outcomes in SUDs. A systematic literature search was performed on MEDLINE, PsychINFO, and PubMed databases and a list of search terms for four key concepts (SUD, rTMS, tDCS, DBS) was applied. Ninety-four studies were identified that examined the effects of rTMS, tDCS, and DBS on substance use outcomes (e.g., craving, consumption, and relapse) amongst individuals with SUDs including alcohol, tobacco, cannabis, stimulants, and opioids. Meta-analyses were performed for alcohol and tobacco studies using rTMS and tDCS. We found that rTMS reduced substance use and craving, as indicated by medium to large effect sizes (Hedge's g > 0.5). Results were most encouraging when multiple stimulation sessions were applied, and the left dorsolateral prefrontal cortex (DLPFC) was targeted. tDCS also produced medium effect sizes for drug use and craving, though they were highly variable and less robust than rTMS; right anodal DLPFC stimulation appeared to be most efficacious. DBS studies were typically small, uncontrolled studies, but showed promise in reducing misuse of multiple substances. NM may be promising for the treatment of SUDs. Future studies should determine underlying neural mechanisms of NM, and further evaluate extended treatment durations, accelerated administration protocols and long-term outcomes with biochemical verification of substance use.

Managing substance use in patients receiving therapeutic repetitive transcranial magnetic stimulation: A scoping review.

Repetitive Transcranial Magnetic Stimulation (rTMS) is an invaluable treatment option for neuropsychiatric disorders. Co-occurring recreational and nonmedical substance use can be common in those presenting for rTMS treatment, and it is unknown how it may affect the safety and efficacy of rTMS for the treatment of currently approved neuropsychiatric indications. This scoping review aimed to map the literature on humans receiving rTMS and had a history of any type of substance use. The search identified 274 articles providing information on inclusion/exclusion criteria, withdrawal criteria, safety protocols, type of rTMS and treatment parameters, adverse events and effect on primary outcomes that related to substance use. There are neurophysiological effects of substance use on cortical excitability, although the relevance to clinical rTMS practice is unknown. The current literature supports the safety and feasibility of delivering rTMS to those who have co-occurring neuropsychiatric disorder and substance use. However, specific details on how varying degrees of substance use alters the safety, efficacy, and mechanisms of rTMS remains poorly described.

GABAergic signaling in alcohol use disorder and withdrawal: pathological involvement and therapeutic potential.

Alcohol is one of the most widely used substances. Alcohol use accounts for 5.1% of the global disease burden, contributes substantially to societal and economic costs, and leads to approximately 3 million global deaths yearly. Alcohol use disorder (AUD) includes various drinking behavior patterns that lead to short-term or long-lasting effects on health. Ethanol, the main psychoactive molecule acting in alcoholic beverages, directly impacts the GABAergic system, contributing to GABAergic dysregulations that vary depending on the intensity and duration of alcohol consumption. A small number of interventions have been developed that target the GABAergic system, but there are promising future therapeutic avenues to explore. This review provides an overview of the impact of alcohol on the GABAergic system, the current interventions available for AUD that target the GABAergic system, and the novel interventions being explored that in the future could be included among first-line therapies for the treatment of AUD.

Efficacy of insula deep repetitive transcranial magnetic stimulation combined with varenicline for smoking cessation: A randomized, double-blind, sham controlled trial.

BACKGROUND: Current smoking cessation treatments are limited in terms of efficacy, particularly with regards to long term abstinence. There is a large amount of evidence implicating the insula in nicotine addiction. OBJECTIVE: To examine the efficacy of bilateral repetitive transcranial magnetic stimulation (rTMS) directed to the insular cortex with the H11 coil, relative to sham stimulation, on smoking abstinence and smoking outcomes in smokers who are receiving standard varenicline treatment. METHODS: This randomized, double-blind, sham controlled trial recruited 42 participants who were randomized to receive either active (n = 24) or sham (n = 18) high frequency rTMS directed to the insula (4 weeks), while receiving varenicline treatment (12 weeks). The primary outcome was 7-day point prevalence abstinence at the end of 12 weeks. RESULTS: Smokers in the active group had significantly higher abstinence rates than those in the sham group (82.4% vs. 30.7%, p = 0.013) at the end of treatment (Week 12). Secondary outcome measures of abstinence rate at the end of rTMS treatment (Week 4), abstinence rate at 6 months, and smoking outcomes (e.g., craving, withdrawal) showed no significant differences between groups. No differences were found in adverse events reported between the groups. CONCLUSION: This study provides evidence of the potential benefit of having a combined treatment for smoking cessation using insula rTMS with the H11 coil and varenicline. Maintenance rTMS sessions and continuation of varenicline for those in abstinence may induce longer-term effects and should be considered in future studies.

SaeR as a novel target for antivirulence therapy against Staphylococcus aureus.

Staphylococcus aureus is a major human pathogen responsible for a wide range of clinical infections. SaeRS is one of the two-component systems in S. aureus that modulate multiple virulence factors. Although SaeR is required for S. aureus to develop an infection, inhibitors have not been reported. Using an in vivo knockdown method, we demonstrated that SaeR is targetable for the discovery of antivirulence agent. HR3744 was discovered through a high-throughput screening utilizing a GFP-Lux dual reporter system driven by saeP1 promoter. The antivirulence efficacy of HR3744 was tested using Western blot, Quantitative Polymerase Chain Reaction, leucotoxicity, and haemolysis tests. In electrophoresis mobility shift assay, HR3744 inhibited SaeR-DNA probe binding. WaterLOGSY-NMR test showed HR3744 directly interacted with SaeR's DNA-binding domain. When SaeR was deleted, HR3744 lost its antivirulence property, validating the target specificity. Virtual docking and mutagenesis were used to confirm the target's specificity. When Glu159 was changed to Asn, the bacteria developed resistance to HR3744. A structure-activity relationship study revealed that a molecule with a slight modification did not inhibit SaeR, indicating the selectivity of HR3744. Interestingly, we found that SAV13, an analogue of HR3744, was four times more potent than HR3744 and demonstrated identical antivirulence properties and target specificity. In a mouse bacteraemia model, both HR3744 and SAV13 exhibited in vivo effectiveness. Collectively, we identified the first SaeR inhibitor, which exhibited in vitro and in vivo antivirulence properties, and proved that SaeR could be a novel target for developing antivirulence drugs against S. aureus infections.

Treatment outcomes in major depressive disorder in patients with comorbid alcohol use disorder: A STAR*D analysis.

INTRODUCTION: Guidance on Major Depressive Disorder (MDD) treatment in those with comorbid Alcohol Use Disorder (AUD) is limited. We performed a secondary analysis on the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, examining the association between comorbid AUD and depression outcomes. METHODS: STAR*D was a real-world effectiveness trial starting with citalopram in level 1. Non-responding participants progressed through 3 other sequential treatment levels with different switch or augmentation options. Antidepressant outcomes were compared between MDD (n = 2826) and comorbid MDD and AUD (n = 864). Logistic regressions were performed to evaluate remission and response predictors in the total STAR*D sample and the AUD-comorbidity interaction. RESULTS: Chi-squared tests showed no significant difference in response or remission rates from depression between groups across treatment levels. Higher Hamilton Rating Scale for Depression (HRSD) score was associated with overall lower odds of remission in treatment level 1 (OR = 0.93, p < 0.001) and 2 (OR = 0.95, p < 0.001), with no significant interaction with comorbid AUD. Higher baseline suicidality had overall lower odds of remission in level 1 (OR = 0.82, p < 0.001) and 2 (OR = 0.1, p < 0.001), but with comorbid AUD compared to no AUD, suicidality increased odds of level 1 remission (OR = 1.30, p = 0.012). In comorbid AUD in level 2, venlafaxine was associated with lower odds of remission (OR = 0.13, p = 0.013) and response (OR = 0.12, p = 0.006); bupropion with lower odds of response (OR = 0.22, p = 0.024). LIMITATIONS: Open label study design and lack of alcohol use data. CONCLUSIONS: Comorbid AUD may interact with predictors of antidepressant response in MDD and using venlafaxine or bupropion may be less effective. Addressing this comorbidity requires unique assessment and treatment approaches.

Repetitive transcranial magnetic stimulation for smoking cessation: Next steps for translation and implementation into clinical practice.

Tobacco smoking is a significant determinant of preventable morbidity and mortality worldwide. It is now possible to modulate the activity of the neurocircuitry associated with nicotine dependence using repetitive Transcranial Magnetic Stimulation (rTMS), a non-invasive neurostimulation approach, which has recently demonstrated efficacy in clinical trials and received regulatory approval in the US and Canada. However there remains a paucity of replication studies and real-world patient effectiveness data as access to this intervention is extremely limited. There are a number of unique challenges related to the delivery of rTMS that need to be addressed prior to widespread adoption and implementation of this treatment modality for smoking cessation. In this paper, we review the accessibility, scientific, technological, economical, and social challenges that remain before this treatment can be translated into clinical practice. By addressing these remaining barriers and scientific challenges with rTMS for smoking cessation and delineating implementation strategies, we can greatly reduce the burden of tobacco-related disease worldwide.

Evaluating the effect of electroconvulsive therapy (ECT) on post-traumatic stress disorder (PTSD): A systematic review and meta-analysis of five studies.

ECT has been proposed as a potential treatment for PTSD. There is a small number of clinical studies to date, but no quantitative review of the efficacy has been conducted. We performed a systematic review and meta-analysis to evaluate the effect of ECT in reducing PTSD symptoms. We followed the PICO and the PRISMA guidelines and searched PubMed, MEDLINE (Ovid), EMBASE (Ovid), Web of Science, and the Cochrane Central Register of Controlled Trials (PROSPERO No: CRD42022356780). A random effects model meta-analysis was conducted with the pooled standard mean difference, applying Hedge's adjustment for small sample sizes. Five within-subject studies met the inclusion criteria, containing 110 patients with PTSD symptoms receiving ECT (mean age 44.13 ± 15.35; 43.4% female). ECT had a small but significant pooled effect on reducing PTSD symptoms (Hedges' g = -0.374), reducing intrusion (Hedges' g = -0.330), avoidance (Hedges' g = -0.215) and hyperarousal (Hedges' g = -0.171) symptoms. Limitations include the small number of studies and subjects and the heterogeneity of study designs. These results provide preliminary quantitative support for the use of ECT in the treatment of PTSD.

Identification of a Small Molecule Compound Active against Antibiotic-Tolerant Staphylococcus aureus by Boosting ATP Synthesis.

Antibiotic tolerance poses a threat to current antimicrobial armamentarium. Bacteria at a tolerant state survive in the presence of antibiotic treatment and account for persistence, relapse and recalcitrance of infections. Antibiotic treatment failure may occur due to antibiotic tolerance. Persistent infections are difficult to treat and are often associated with poor prognosis, imposing an enormous burden on the healthcare system. Effective strategies targeting antibiotic-tolerant bacteria are therefore highly warranted. In this study, small molecule compound SA-558 was identified to be effective against Staphylococcus aureus that are tolerant to being killed by conventional antibiotics. SA-558 mediated electroneutral transport across the membrane and led to increased ATP and ROS generation, resulting in a reduction of the population of antibiotic-tolerant bacteria. In a murine chronic infection model, of which vancomycin treatment failed, we demonstrated that SA-558 alone and in combination with vancomycin caused significant reduction of MRSA abundance. Our results indicate that SA-558 monotherapy or combinatorial therapy with vancomycin is an option for managing persistent S. aureus bacteremia infection and corroborate that bacterial metabolism is an important target for counteracting antibiotic tolerance.

Systematic review of structured care pathways in major depressive disorder and bipolar disorder.

BACKGROUND: Structured care pathways (SCPs) consist of treatment algorithms that patients advance through with the goal of achieving remission or response. These SCPs facilitate the application of current evidence and adequate treatment, which potentially benefit patients with mood disorders. The aim of this systematic review was to provide an updated synthesis of SCPs for the treatment of depressive disorders and bipolar disorder (BD). METHOD: PubMed, PsycINFO, and Embase were searched through June 2022 for peer-reviewed studies examining outcomes of SCPs. Eligibility criteria included being published in a peer-reviewed journal in the English language, reporting of intervention used in the SCP, and having quantitative outcomes. Studies Cochrane risk of bias tool was used to assess quality of RCTs. RESULTS: Thirty-six studies including 15,032 patients were identified for qualitative synthesis. Six studies included patients with BD. The studies were highly heterogeneous in design, outcome measures, and algorithms. More than half of the studies reported superiority of SCPs over treatment as usual, suggesting that the standardized structure and consistent monitoring inherent in SCPs may be contributing to their effectiveness. We also found accumulating evidence supporting feasibility of SCPs in different settings, although dropout rates were generally higher in SCPs. The studies included were limited to being published in peer-reviewed journals in English language. The heterogeneity of studies did not allow quantitative evaluation. CONCLUSIONS: The findings of our study suggest that SCPs are equally or more effective than treatment as usual in depression and BD. Further studies are required to ascertain their effectiveness, particularly for BD, and to identify factors that influence their feasibility and success.

Diagnostic accuracy of a commercially available deep-learning algorithm in supine chest radiographs following trauma.

OBJECTIVES: Trauma chest radiographs may contain subtle and time-critical pathology. Artificial intelligence (AI) may aid in accurate reporting, timely identification and worklist prioritisation. However, few AI programs have been externally validated. This study aimed to evaluate the performance of a commercially available deep convolutional neural network - Annalise CXR V1.2 (Annalise.ai) - for detection of traumatic injuries on supine chest radiographs. METHODS: Chest radiographs with a CT performed within 24 h in the setting of trauma were retrospectively identified at a level one adult trauma centre between January 2009 and June 2019. Annalise.ai assessment of the chest radiograph was compared to the radiologist report of the chest radiograph. Contemporaneous CT report was taken as the ground truth. Agreement with CT was measured using Cohen's κ and sensitivity/specificity for both AI and radiologists were calculated. RESULTS: There were 1404 cases identified with a median age of 52 (IQR 33-69) years, 949 males. AI demonstrated superior performance compared to radiologists in identifying pneumothorax (p = 0.007) and segmental collapse (p = 0.012) on chest radiograph. Radiologists performed better than AI for clavicle fracture (p = 0.002), humerus fracture (p < 0.0015) and scapula fracture (p = 0.014). No statistical difference was found for identification of rib fractures and pneumomediastinum. CONCLUSION: The evaluated AI performed comparably to radiologists in interpreting chest radiographs. Further evaluation of this AI program has the potential to enable it to be safely incorporated in clinical processes. ADVANCES IN KNOWLEDGE: Clinically useful AI programs represent promising decision support tools.

Endothelial dysfunction after androgen deprivation therapy and the possible underlying mechanisms.

INTRODUCTION: Androgen deprivation therapy (ADT) is a key treatment modality in the management of prostate cancer (PCa), especially for patients with metastatic disease. Increasing evidences suggest that patients who received ADT have increased incidence of diabetes, myocardial infarction, stroke, and even mortality. It is important to understand the pathophysiological mechanisms on how ADT increases cardiovascular risk and induces cardiovascular events, which would provide important information for potential implementation of preventive measures. METHODS: Twenty-six 12-week-old male SD rats were divided into four groups for different types of ADTs including: the bilateral orchidectomy group (Orx), LHRH agonist group (leuprolide), LHRH antagonist group (degarelix), and control group. After treated with drug or adjuvant injection every 3 weeks for 24 weeks, all rats were sacrificed and total blood were collected. Aorta, renal arteries, and kidney were preserved for functional assay, immunohistochemistry, western blot, and quantitative reverse-transcription polymerase chain reaction. RESULTS: In vascular reactivity assays, aorta, intrarenal, and coronary arteries of all three ADT groups showed endothelial dysfunction. AT1R and related molecules at protein and messenger RNA (mRNA) level were tested, and AT1R pathway was shown to be activated and played a role in endothelial dysfunction. Both ACE and AT1R mRNA levels were doubled in the aorta in the leuprolide group while Orx and degarelix groups showed upregulation of AT1R in the kidney tissues. By immunohistochemistry, our result showed higher expression of AT1R in the intrarenal arteries of leuprolide and degarelix groups. The role of reactive oxygen species in endothelial dysfunction was confirmed by DHE fluorescence, nitrotyrosine overexpression, and upregulation of NOX2 in the different ADT treatment groups. CONCLUSION: ADT causes endothelial dysfunction in male rats. GnRH receptor agonist compared to GnRH receptor antagonist, showed more impairment of endothelial function in the aorta and intrarenal arteries. Such change might be associated with upregulation and activation of AngII-AT1R-NOX2 induced oxidative stress in the vasculature. These results help to explain the different cardiovascular risks and outcomes related to different modalities of ADT treatment.

Continuation Magnetic Seizure Therapy for Treatment-Resistant Unipolar or Bipolar Depression.

Objective: Electroconvulsive therapy (ECT) is highly effective for treatment-resistant depression (TRD) but may be associated with adverse cognitive effects. Magnetic seizure therapy (MST) is a promising alternative convulsive treatment with a safer cognitive profile. Although there is emerging evidence for the efficacy of MST for TRD as an acute treatment, there are no published studies of continuation MST for the prevention of relapse.Methods: Patients with TRD with a DSM-IV diagnosis of major depressive disorder or bipolar disorder who met response criteria after acute MST were offered continuation MST in a prospective, open-label trial between February 2012 and June 2019. They received 12 continuation MST sessions with decreasing frequency over the course of 6 months, with additional booster sessions if their depression symptoms started to worsen. The primary outcome was relapse of depression or psychiatric hospitalization. Secondary outcomes included relapse of suicidal ideation and neurocognitive outcomes.Results: Thirty participants completing at least one assessment during continuation MST were included in the analysis; 10 (33.3%) relapsed, with no significant differences in survival distributions between unipolar and bipolar groups (χ2 = 0.3, P = .58). Mean (SD) survival time was 18.6 (1.6) weeks. All 17 participants who achieved resolution of baseline suicidality after acute MST remained free of suicidality during the continuation phase. Except for improvement in verbal fluency, neurocognitive test scores did not change during continuation MST.Conclusions: During 6 months of continuation MST, two-thirds of participants sustained improvements in depressive symptoms without any adverse cognitive effects. Future studies of continuation MST are warranted, particularly in comparison to ECT.Trial Registration: ClinicalTrials.gov identifier: NCT01596608.

Electroconvulsive therapy with a memory reactivation intervention for post-traumatic stress disorder: A randomized controlled trial.

BACKGROUND: Post-traumatic Stress Disorder (PTSD) often does not respond to available treatments. Memories are vulnerable to disruption during reconsolidation, and electroconvulsive therapy (ECT) has amnestic effects OBJECTIVE/HYPOTHESIS: To test the use of ECT to disrupt the reconsolidation of traumatic memories as a potential treatment for PTSD METHODS: Participants were adults from the civilian population and were referred for ECT treatment for severe depression with comorbid PTSD symptoms. Twenty-eight participants were randomly assigned to reactivation of a traumatic or non-traumatic memory using audio script driven imagery prior to each ECT treatment. Primary outcomes were change in scores on the Modified PTSD Symptom Scale - Self Report (MPSS-SR) and the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). Secondary outcomes included a comparison of the change in heart rate while listening to the script RESULTS: Twenty-five female patients who completed a post-ECT assessment were included in the analysis. No significant group differences were found in the MPSS-SR or CAPS-5 scores from pre-ECT to post-ECT or 3-month follow-ups. However, both groups improved at post-ECT and 3-month follow up. Partial eta squared estimates of effect size showed large effect sizes for all outcomes (η2 > 0.13). Changes in heart rate were not significantly different between groups or over time CONCLUSIONS: ECT paired with pre-treatment traumatic memory reactivation was not more effective for treating PTSD symptoms than ECT with non-traumatic memory reactivation. While our primary hypothesis was not supported, our data provides further support for the efficacy of ECT for improving symptoms of PTSD with comorbid depression. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04027452. IDENTIFIER: NCT04027452.