Adverse Neurocognitive Effects Research Articles

A phase I trial of accelerated intermittent theta burst rTMS for amnestic MCI

BackgroundEmerging evidence suggests that repetitive transcranial magnetic stimulation (rTMS) enhances cognition in mild cognitive impairment (MCI). Accelerated intermittent theta burst stimulation (iTBS) rTMS protocols are promising as they substantially reduce...

Diagnosis and management of obstructive sleep apnoea in adults.

Obstructive sleep apnoea is the most common form of sleep-disordered breathing. It is characterised by recurrent occlusion of the airway during sleep. Ensuing apnoeas terminate in arousal from sleep and lead to non-restorative sleep, excessive daytime sleepiness and adverse cardiovascular and neurocognitive effects. A sleep study should be offered to patients reporting witnessed apnoeas or symptoms related to non-restorative sleep. It should also be considered in the presence of predisposing factors for obstructive sleep apnoea (e.g. obesity, tonsillar hypertrophy, retrognathia, refractory hypertension). Treatment should aim to improve symptoms and reduce cardiovascular and neurocognitive risk. The treatment approach should consider the symptom burden, severity, anatomical factors, and patient preference. Positive airway pressure is the most effective treatment option, although intolerance and non-adherence are common. Other options include positional therapy, oral appliances and upper airway surgery. Weight loss and optimisation of cardiovascular disease risk should be considered in selected patients.

Phencyclidine-Like Abuse Liability and Psychosis-Like Neurocognitive Effects of Novel Arylcyclohexylamine Drugs of Abuse in Rodents.

Abuse of novel arylcyclohexylamines (ACX) poses risks for toxicities, including adverse neurocognitive effects. In vivo effects of ring-substituted analogs of phencyclidine (PCP), eticyclidine (PCE), and ketamine are understudied. Adult male National Institutes of Health Swiss mice were used to assess locomotor effects of PCP and its 3-OH, 3-MeO, 3-Cl, and 4-MeO analogs, PCE and its 3-OH and 3-MeO analogs, and ketamine and its deschloro and 2F-deschloro analogs, in comparison with those of methamphetamine (METH), 3,4-methylenedioxymethamphetamine (MDMA), and two benzofuran analogs of MDMA. PCP-like interoceptive effects for all of these ACXs were determined using a food-reinforced drug discrimination procedure in adult male Sprague Dawley rats. A novel operant assay of rule-governed behavior incorporating aspects of attentional set-shifting was used to profile psychosis-like neurocognitive effects of PCP and 3-Cl-PCP in rats, in comparison with cocaine and morphine. PCP-like ACXs were more effective locomotor stimulants than the amphetamines, PCE-like ACXs were as effective as the amphetamines, and ketamine-like ACXs were less effective than the amphetamines. Addition of -Cl, -OH, or -OMe at the 3-position on the aromatic ring did not impact locomotor effectiveness, but addition of -OMe at the 4-position reduced locomotor effectiveness. Lethal effects were induced by drugs with -OH at the 3-position or -OMe at the 3- or 4-position. All novel ACXs substituted at least partially for PCP, and PCP and 3-Cl-PCP elicited dose-dependent psychosis-like neurocognitive deficits in the rule-governed behavior task not observed with cocaine or morphine. Novel ACXs exhibit substantial abuse liability and toxicities not necessarily observed with their parent drugs. SIGNIFICANCE STATEMENT: Novel arylcyclohexylamine analogs of PCP, PCE, and ketamine are appearing on the illicit market, and abuse of these drugs poses risks for toxicities, including adverse neurocognitive effects. These studies demonstrate that the novel ACXs exhibit PCP-like abuse liability in the drug discrimination assay, elicit varied locomotor stimulant and lethal effects in mice, and induce psychosis-like neurocognitive effects in rats.

Cognitive and Functional Connectivity Outcomes from a Phase I Trial of Accelerated High‐Dose Repetitive Transcranial Magnetic Stimulation in Amnestic MCI

AbstractBackgroundRepetitive transcranial magnetic stimulation (rTMS), most widely used to treat depression, may have secondary benefits for cognition. Accelerated high‐dose protocols such as intermittent theta burst (iTBS)‐rTMS shorten the treatment course by >50%, potentially improving the feasibility of use in patients with cognitive impairments. Here, we present the results of a phase I trial of iTBS‐rTMS for improving cognition in individuals with amnestic mild cognitive impairment (aMCI) and we explore whether functional brain changes relate to improved cognition.MethodTwenty‐two patients with clinically diagnosed aMCI received 24 sessions of open‐label iTBS‐rTMS to left dorsolateral prefrontal cortex (l‐dlPFC) over 3 days. Nineteen had complete brain MRI and cognitive testing pre‐ and immediately post‐treatment. The primary cognitive outcome was the norm‐adjusted fluid cognition composite T‐score from the NIH Toolbox Cognition Battery. Resting‐state functional connectivity was computed from subject‐specific parcellations mapped to each individual’s functional topology. We examined changes in connectivity within and between the FPN (of with the l‐dlPFC is a hub) and networks implicated in cognition (FPN, dorsal and ventral attention, limbic, default mode). We assessed whether connectivity changes (post minus pre) related to change in fluid cognition.ResultWe achieved a high retention rate of 95%. Treatment with iTBS‐rTMS was safe, with no adverse neuroradiological, neuropsychiatric, or neurocognitive effects. Side effects were minimal and acceptability ratings were high. Treatment produced significant, large effect size (d = 0.98) improvements in fluid cognition (Fig. 1A), and we observed preliminary evidence of related changes in functional connectivity. Specifically, there was a numerical increase in within‐FPN connectivity and a marginally significant increase in connectivity between cognitive networks (Fig. 1B). Further, there was a medium‐strength and marginally significant association between increased within‐FPN connectivity and improved fluid cognition (Fig. 1C).ConclusionThis phase I trial demonstrated that iTBS‐rTMS is safe, feasible, and acceptable in aMCI. Although not dosed for efficacy, we observed large improvements in fluid cognition and preliminary evidence of increased functional connectivity in expected brain networks that related to improved cognition. These promising results support iTBS‐rTMS as potentially efficacious in improving cognition in aMCI, directly informing larger, planned follow‐up randomized controlled phase II trials.

74 A Phase I Trial of Accelerated, HighDose Repetitive Transcranial Magnetic Stimulation to Improve Cognition in Amnestic MCI

Objective:Repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation therapy most widely used in depression, has shown evidence of secondary benefits for cognition in both neurologic and neuropsychiatric conditions. The recent development of more efficient stimulation protocols, such as accelerated high-dose intermittent theta burst (iTBS)-rTMS, has substantially reduced treatment burden by shortening the treatment course by >50%. This study aimed to establish the safety, feasibility, acceptability, and preliminary efficacy of iTBS-rTMS as a tool for bolstering cognition in individuals with amnestic mild cognitive impairment (aMCI).Participants and Methods:Twenty-four patients with aMCI were enrolled in an open-label phase I trial of iTBS-rTMS; 2 withdrew prior to initiating treatment due to personal circumstances. All participants had received a diagnosis of MCI due to possible AD from a healthcare provider (i.e., neurologist or neuropsychologist) and met actuarial neuropsychological criteria for aMCI. This sample of older adults (range: 61.5-85.2 years, M = 74.1, SD = 5.71) was predominantly White/non-Hispanic (n = 23; Black/non-Hispanic: n = 1), roughly half female (n = 13), with a college education (range: 12-20 years, M = 15.9, SD = 2.5). Participants received 24 sessions of iTBS-rTMS to the left dorsolateral prefrontal cortex over 3 days (8 sessions each, lasting roughly 2 hours per day). Participants rated their perceptions and experience of common side effects during and after each treatment session as well as retrospectively at post-treatment and 4-week follow-up. They completed structural and functional brain MRI, neuropsychiatric evaluations, and neuropsychological assessments before and after treatment and were administered a subset of these measures at 4-week follow-up. MoCA scores were used to monitor for adverse neurocognitive effects, and the fluid cognition composite score from the NIH Toolbox Cognition Battery was used to test preliminary efficacy.Results:We achieved a high retention rate (95%), with 21 of the 22 participants completing all study procedures. There were no clinically significant adverse neuroradiological, neuropsychiatric, or neurocognitive effects of treatment. Participant reports indicated high tolerability and acceptability, with a modal rating of 0 (on a scale from 0=not at all to 10=extremely) for six common side effects (i.e., headache, pain, scalp irritation, facial twitching, fatigue, fear/anxiety), assessed both during and after each treatment session. They reported very low desire to quit despite some participants rating the treatment as moderately tiring. We observed significant, large effect-size (d = 0.98) improvements in fluid cognition from pre- to post-treatment.Conclusions:Our findings support the safety, feasibility, and acceptability of iTBS-rTMS treatment in patients with aMCI. Further, although not explicitly dosed for efficacy, we provide preliminary evidence of improved fluid cognition as a function of treatment, highlighting the potential of this treatment for improving trans-domain cognitive impairment. These promising results can directly inform future trials aimed at optimizing treatment parameters, broadening the indication to other MCI subtypes, and testing the augmentation of established cognitive rehabilitation interventions when combined with rTMS.

A novel application of spectrograms with machine learning can detect patient ventilator dyssynchrony

Patients in intensive care units are frequently supported by mechanical ventilation. There is increasing awareness of patient-ventilator dyssynchrony (PVD), a mismatch between patient respiratory effort and assistance provided by the ventilator, as a risk factor for infection, narcotic exposure, lung injury, and adverse neurocognitive effects. One of the most injurious consequences of PVD are double cycled (DC) breaths when two breaths are delivered by the ventilator instead of one. Prior efforts to identify PVD have limited efficacy. An automated method to identify PVD, independent of clinician expertise, acumen, or time, would potentially permit early, targeted treatment to avoid further harm. We performed secondary analyses of data from a clinical trial of children with acute respiratory distress syndrome. Waveforms of ventilator flow, airway pressure and esophageal manometry were annotated to identify DC breaths and underlying PVD subtypes. Spectrograms were generated from those waveforms to train Convolutional Neural Network (CNN) models in detecting DC and underlying PVD subtypes: Reverse Trigger (RT) and Inadequate Support (IS). The DC breath detection model yielded AUROC of 0.980, while the multi-target detection model for underlying dyssynchrony yielded AUROC of 0.980 (RT) and 0.976 (IS). When operating at 75% sensitivity, DC breath detection had a number needed to alert (NNA) 1.3 (99% specificity), while underlying PVD had a NNA 1.6 (98.5% specificity) for RT and NNA 4.0 (98.2% specificity) for IS. CNNs using spectrograms of ventilator waveforms can identify DC breaths and detect the underlying PVD for targeted clinical interventions.

Maternal exposure to neonicotinoid insecticides and fetal growth restriction: A nested case-control study in the guangxi Zhuang birth cohort

BackgroundFetal growth restriction (FGR) is a major determinant of perinatal morbidity and mortality, with adverse long-term neurocognitive effects in childhood and adulthood. Prenatal exposure to environmental pollutants has been reported to be associated with FGR. Neonicotinoids (NEOs) are extensively used insecticides worldwide and are suggested to have embryonic and developmental neurotoxicity. However, the effects of NEOs exposure on FGR is unknown. ObjectivesWe aimed to quantify the single and combined associations of maternal exposure to NEOs and FGR. MethodsWe conducted a nested case-control study based on the Guangxi Zhuang Birth Cohort, China. A total of 387 with FGR cases and 1096 without- FGR controls were included between 2015 and 2018. Ten NEOs were measured by UPLC-MS from the maternal blood samples were pre-collected in the first trimester. After adjusting for potential confounders, multivariable logistic regressions, weighted quantile sum regression and quantile g-computation were performed for individual and NEOs mixtures. ResultsIn the individual exposure models, each 1-standard deviation increment of the natural-log in dinotefuran and acetamiprid concentrations were significantly associated with odds ratios of 1.93 (95% CI: 1.69, 2.20) and 1.31 (95% CI: 1.07, 1.59) higher odds of FGR, respectively. However, the FGR risk was negatively associated with thiacloprid, sulfoxaflor, and nitenpyram (OR = 0.23, 95%CI: 0.15, 0.34; OR = 0.48, 95%CI: 0.41, 0.56; OR = 0.86, 95%CI: 0.80, 0.93; respectively). Similar findings were found in the combined exposure analysis. Dinotefuran was the most strongly attributable to increase FGR, while sulfoxaflor and thiacloprid contributed the highest negative weighted on FGR. Furthermore, each quintile increase in all ten NEOs exposures was associated with FGR (OR = 0.21, 95% CI: 0.08, 0.54). ConclusionOur findings suggest that maternal single and combined exposures to NEOs were associated with varying FGR risks. They contribute to the mounting evidence on serum NEOs exposure impact on FGR. However, a replication of these associations in other populations is warranted.

The risk of radiation-induced neurocognitive impairment and the impact of sparing the hippocampus during pediatric proton cranial irradiation

Background and purpose Hippocampus is a central component for neurocognitive function and memory. We investigated the predicted risk of neurocognitive impairment of craniospinal irradiation (CSI) and the deliverability and effects of hippocampal sparing. The risk estimates were derived from published NTCP models. Specifically, we leveraged the estimated benefit of reduced neurocognitive impairment with the risk of reduced tumor control. Material and methods For this dose planning study, a total of 504 hippocampal sparing intensity modulated proton therapy (HS-IMPT) plans were generated for 24 pediatric patients whom had previously received CSI. Plans were evaluated with respect to target coverage and homogeneity index to target volumes, maximum and mean dose to OARs. Paired t-tests were used to compare hippocampal mean doses and normal tissue complication probability estimates. Results The median mean dose to the hippocampus could be reduced from 31.3 GyRBE to 7.3 GyRBE (p < .001), though 20% of these plans were not considered clinically acceptable as they failed one or more acceptance criterion. Reducing the median mean hippocampus dose to 10.6 GyRBE was possible with all plans considered as clinically acceptable treatment plans. By sparing the hippocampus to the lowest dose level, the risk estimation of neurocognitive impairment could be reduced from 89.6%, 62.1% and 51.1% to 41.0% (p < .001), 20.1% (p < .001) and 29.9% (p < .001) for task efficiency, organization and memory, respectively. Estimated tumor control probability was not adversely affected by HS-IMPT, ranging from 78.5 to 80.5% for all plans. Conclusions We present estimates of potential clinical benefit in terms of neurocognitive impairment and demonstrate the possibility of considerably reducing neurocognitive adverse effects, minimally compromising target coverage locally using HS-IMPT.

Epilepsija kod pacijenata sa supratentorijalnim meningeomima

Meningiomas are the most common primary intracranial tumors. They are mostly slow-growing and of benign histopathology rendering them curable by surgery alone. Symptomatic lesions depend on the location with signs of focal neurological deficits or increased intracranial pressure. Seizures are the presenting symptoms in approximately 30% of supratentorial meningiomas. Epileptogenesis in these patients is not yet clearly defined. Epilepsy negatively affects the quality of life, limits independence, and impairs cognition, as well as increases the risk for psychiatric comorbidities including depression. Although surgical resection may offer seizure freedom in more than 60% of meningiomas, seizures persist after surgical resection in a significant number of patients. The potential preoperative and postoperative predictors for seizures in meningioma patients have been analyzed in multiple studies. Antiseizure medications are employed in the treatment of these patients, however, their application is often followed by adverse neurocognitive side effects and inefficacy in some patients. Understanding various clinical, histopathological, and surgical factors potentially associated with epilepsy can help guide more effective seizure control and allow for better assessment of risk before and after surgery. Patients with persistent seizures may benefit from referral to an epilepsy center for evaluation.

Mendelian Randomization Study of PCSK9 and HMG-CoA Reductase Inhibition and Cognitive Function

BackgroundLipid-lowering therapy with statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition are effective strategies in reducing cardiovascular disease risk; however, concerns remain about potential long-term adverse neurocognitive effects. ObjectivesThis genetics-based study aimed to evaluate the relationships of long-term PCSK9 inhibition and statin use on neurocognitive outcomes. MethodsWe extracted single-nucleotide polymorphisms in 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and PCSK9 from predominantly European ancestry-based genome-wide association studies summary-level statistics of low-density lipoprotein cholesterol and performed drug-target Mendelian randomization, proxying the potential neurocognitive impact of drug-based PCSK9 and HMGCR inhibition using a range of outcomes to capture the complex facets of cognition and dementia. ResultsUsing data from a combined sample of ∼740,000 participants, we observed a neutral cognitive profile related to genetic PCSK9 inhibition, with no significant effects on cognitive performance, memory performance, or cortical surface area. Conversely, we observed several adverse associations for HMGCR inhibition with lowered cognitive performance (beta: –0.082; 95% CI: –0.16 to –0.0080; P = 0.03), reaction time (beta = 0.00064; 95% CI: 0.00030-0.00098; P = 0.0002), and cortical surface area (beta = –0.18; 95% CI: –0.35 to –0.014; P = 0.03). Neither PCSK9 nor HMGCR inhibition impacted biomarkers of Alzheimer’s disease progression or Lewy body dementia risk. Consistency of findings across Mendelian randomization methods accommodating different assumptions about genetic pleiotropy strengthens causal inference. ConclusionsUsing a wide range of cognitive function and dementia endpoints, we failed to find genetic evidence of an adverse PCSK9-related impact, suggesting a neutral cognitive profile. In contrast, we observed adverse neurocognitive effects related to HMGCR inhibition, which may well be outweighed by the cardiovascular benefits of statin use, but nonetheless may warrant pharmacovigilance.

Fetal Disseminated Malignant Rhabdoid Tumor.

Fetal Disseminated Malignant Rhabdoid Tumor.

Polypharmacy Is Associated With Falls in Women With and Without HIV.

Aging in people with HIV is associated with increased risk of developing synergistic conditions such as neurocognitive impairment, polypharmacy, and falls. We assessed associations between polypharmacy (use of 5 or more non-ART medications), use of neurocognitive adverse effects (NCAE) medications, and odds of falls in women with HIV (WWH) and without HIV (HIV-). Self-reported falls and medication use data were contributed semiannually by 1872 (1315 WWH and 557 HIV-) Women's Interagency HIV Study participants between 2014 and 2016. Polypharmacy and NCAE medication use were evaluated separately and jointly in multivariable models to assess their independent contributions to single and multiple falls risk. The proportion of women who reported any fall was similar by HIV status (19%). WWH reported both greater polypharmacy (51% vs. 41%; P < 0.001) and NCAE medication use (44% vs. 37%; P = 0.01) than HIV- women. Polypharmacy conferred elevated odds of single fall [adjusted odds ratio (aOR) 1.67, 95% CI: 1.36 to 2.06; P < 0.001] and multiple falls (aOR 2.31, 95% CI: 1.83 to 2.93; P < 0.001); the results for NCAE medications and falls were similar. Both polypharmacy and number of NCAE medications remained strongly and independently associated with falls in multivariable models adjusted for HIV serostatus, study site, sociodemographics, clinical characteristics, and substance use. Polypharmacy and NCAE medication use were greater among WWH compared with HIV-, and both were independently and incrementally related to falls. Deprescribing and avoidance of medications with NCAEs may be an important consideration for reducing fall risk among WWH and sociodemographically similar women without HIV.

Integrated Multi-Omics Analysis Reveals the Effect of Maternal Gestational Diabetes on Fetal Mouse Hippocampi.

Growing evidence suggests that adverse intrauterine environments could affect the long-term health of offspring. Recent evidence indicates that gestational diabetes mellitus (GDM) is associated with neurocognitive changes in offspring. However, the mechanism remains unclear. Using a GDM mouse model, we collected hippocampi, the structure critical to cognitive processes, for electron microscopy, methylome and transcriptome analyses. Reduced representation bisulfite sequencing (RRBS) and RNA-seq in the GDM fetal hippocampi showed altered methylated modification and differentially expressed genes enriched in common pathways involved in neural synapse organization and signal transmission. We further collected fetal mice brains for metabolome analysis and found that in GDM fetal brains, the metabolites displayed significant changes, in addition to directly inducing cognitive dysfunction, some of which are important to methylation status such as betaine, fumaric acid, L-methionine, succinic acid, 5-methyltetrahydrofolic acid, and S-adenosylmethionine (SAM). These results suggest that GDM affects metabolites in fetal mice brains and further affects hippocampal DNA methylation and gene regulation involved in cognition, which is a potential mechanism for the adverse neurocognitive effects of GDM in offspring.

Adjunctive Magnetic Seizure Therapy for Schizophrenia: A Systematic Review

Objective: The efficacy and safety of adjunctive magnetic seizure therapy (MST) for patients with schizophrenia are unclear. This systematic review was conducted to examine the efficacy and safety of adjunctive MST for schizophrenia.Methods: Chinese (WanFang and Chinese Journal Net) and English (PubMed, EMBASE, PsycINFO, and the Cochrane Library) databases were systematically searched.Results: Two open-label self-controlled studies (n = 16) were included and analyzed in this review. In these studies, the Positive and Negative Syndrome Scale (PANSS) total scores and Brief Psychiatric Rating Scale (BPRS) total scores significantly decreased from baseline to post-MST (all Ps < 0.05), without serious adverse neurocognitive effects. Mixed findings on the neurocognitive effects of adjunctive MST for schizophrenia were reported in the two studies. A discontinuation rate of treatment of up to 50% (4/8) was reported in both studies. The rate of adverse drug reactions (ADRs) was evaluated in only one study, where the most common ADRs were found to be dizziness (25%, 2/8) and subjective memory loss (12.5%, 1/8).Conclusion: There is inconsistent evidence for MST-related adverse neurocognitive effects and preliminary evidence for the alleviation of psychotic symptoms in schizophrenia.

Prophylactic progesterone prevents adverse behavioural and neurocognitive effects of neonatal anaesthesia exposure in rat

BackgroundEvidence from animal models and human studies suggests an association between early general anaesthesia exposure and development of long-lasting neurocognitive problems including learning and memory impairments and an anxious phenotype. Because millions of children each year undergo procedures that require anaesthesia, it is important to investigate ways to protect the vulnerable developing brain. We evaluated whether progesterone treatment administered before general anaesthesia exposure could prevent long-term anaesthesia-induced neurocognitive and behavioural changes. MethodsFemale and male Long–Evans rat pups were repeatedly exposed to 2 h of sevoflurane or control procedures at postnatal days 7, 10, and 13. Subcutaneous injections of progesterone or vehicle were administered immediately before general anaesthesia exposure or control procedures. Neurobehavioural and cognitive outcomes were evaluated using elevated plus maze and Morris water maze tests. ResultsProphylactic progesterone treatment attenuated the chemokine (C-X-C motif) ligand 1 (CXCL1) response to sevoflurane exposure. Rats given vehicle treatment with general anaesthesia exposure exhibited increased anxiety on the elevated plus maze and learning and memory impairments on the Morris water maze. However, rats treated with progesterone before general anaesthesia lacked these impairments and performed in a similar manner to controls on both tasks. ConclusionsProgesterone attenuated the anaesthesia-induced, acute peripheral inflammatory response and prevented cognitive and behavioural alterations associated with early repeated general anaesthesia exposure. Importantly, our results suggest that progesterone treatments given before general anaesthesia may help to protect the developing brain.

A Pilot Study of Low-Dose Craniospinal Irradiation in Patients With Newly Diagnosed Average-Risk Medulloblastoma.

PurposeMedulloblastoma is one of the most common malignant brain tumors in children. To date, the treatment of average-risk (non-metastatic, completely resected) medulloblastoma includes craniospinal radiation therapy and adjuvant chemotherapy. Modern treatment modalities and now risk stratification of subgroups have extended the survival of these patients, exposing the long-term morbidities associated with radiation therapy. Prior to advances in molecular subgrouping, we sought to reduce the late effects of radiation in patients with average-risk medulloblastoma.MethodsWe performed a single-arm, multi-institution study, reducing the dose of craniospinal irradiation by 25% to 18 Gray (Gy) with the goal of maintaining the therapeutic efficacy as described in CCG 9892 with maintenance chemotherapy.ResultsTwenty-eight (28) patients aged 3-30 years were enrolled across three institutions between April 2001 and December 2010. Median age at enrollment was 9 years with a median follow-up time of 11.7 years. The 3-year relapse-free (RFS) and overall survival (OS) were 79% (95% confidence interval [CI] 58% to 90%) and 93% (95% CI 74% to 98%), respectively. The 5-year RFS and OS were 71% (95% CI 50% to 85%) and 86% (95% CI 66% to 94%), respectively. Toxicities were similar to those seen in other studies; there were no grade 5 toxicities.ConclusionsGiven the known neurocognitive adverse effects associated with cranial radiation therapy, studies to evaluate the feasibility of dose reduction are needed. In this study, we demonstrate that select patients with average-risk medulloblastoma may benefit from a reduced craniospinal radiation dose of 18 Gy without impacting relapse-free or overall survival.Clinical Trial RegistrationClinicalTrials.gov identifier: NCT00031590

Raw and processed electroencephalography in modern anesthesia practice: a brief primer on select clinical applications.

The evidence supporting the intraoperative use of processed electroencephalography (pEEG) monitoring to guide anesthetic delivery is growing rapidly. This article reviews the key features of electroencephalography (EEG) waveforms and their clinical implications in select patient populations and anesthetic techniques. The first patient topic reviewed is the vulnerable brain. This term has emerged as a description of patients who may exhibit increased sensitivity to anesthetics and/or may develop adverse neurocognitive effects following anesthesia. pEEG monitoring of patients who are known to have or are suspected of having vulnerable brains, with focused attention on the suppression ratio, alpha band power, and pEEG indices, may prove useful. Second, pEEG monitoring along with vigilant attention to anesthetic delivery may minimize the risk of intraoperative awareness when administering a total intravenous anesthesia in combination with a neuromuscular blockade. Third, we suggest that processed EEG monitoring may play a role in anesthetic and resuscitative management when adverse changes in blood pressure occur. Fourth, pEEG monitoring can be used to better identify anesthesia requirements and guide anesthetic titration in patients with known or suspected substance use.

Dose-response analyses of the 27 human developmental neurotoxicity studies ranked highest quality by National Toxicology Program (NTP) systematic review

BACKGROUND AND AIM: The National Toxicology Program (NTP) has been conducting a systematic review of the evidence for fluoride’s neurotoxicity. Drafts of the NTP report conclude fluoride is a presumed hazard for developmental neurotoxicity, but have not included rigorous dose-response analyses to estimate a safe dose. This is of great public health importance because millions of people are exposed to fluoride added to public water supplies or table salt; or naturally elevated fluoride in drinking water. METHODS: We conducted several dose-response analyses using data extracted by NTP from 27 human studies NTP ranked high quality. The number of studies finding adverse effects were counted at three exposure levels: 0.7, 0.7–1.5, 1.5mg/L. Meta-analyses were performed with the 14 studies having individual-level exposure data, in two subgroups by mean exposure: ≤1.5mg/L or 1.5mg/L. The same 14 studies were then assessed using meta-regression of IQ loss at mean exposure against mean exposure. RESULTS:Of the 27 higher quality studies, 25 found adverse neurocognitive effects with 11 at exposures below 0.7mg/L; 4 at 0.7–1.5mg/L; and 10 at 1.5mg/L. None found significant beneficial effects. In the meta-analysis, all 14 studies found loss of IQ, including the 7 in subgroup ≤1.5mg/L which had a pooled effect size of -4.0 (95%CI -6.03, -2.05) IQ points per 1mg/L fluoride. The meta-regression fit a linear dose-response with pooled effect size of -2.94 (95%CI -4.03, -1.84) IQ points per 1mg/L. CONCLUSIONS:Dose-response analyses of 27 studies ranked high quality by NTP found a remarkable consistency of adverse effects down to very low doses. The magnitude of predicted IQ loss is of considerable concern. Pregnant women and infants should limit exposure to fluoride. KEYWORDS: fluoride, developmental neurotoxicity, dose-response, IQ, National Toxicology Program, meta-analysis

Adjunctive Nonconvulsive Electrotherapy for Patients with Depression: a Systematic Review.

The efficacy and safety of adjunctive nonconvulsive electrotherapy (NET) for patients with depression are undetermined. This systematic review was conducted to examine the efficacy and safety of adjunctive NET for patients with depression. Chinese (WanFang and Chinese Journal Net) and English (PubMed, EMBASE, PsycINFO and the Cochrane Library) databases were systematically searched from their inception until Jan 27, 2021 by three independent investigators. One randomized controlled trial (RCT) with 3 treatment arms (n = 108) and two observational studies (single-group, before-after design, n = 31) were included. In the RCT,the antidepressant efficacy of NET on depression was similar to that of electroconvulsive therapy (ECT) (P > 0.05) but with significantly fewer neurocognitive impairments as measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (P < 0.05). In two observational studies, the 17-item Hamilton Depression Rating Scale (HAMD-17) scores decreased significantly from baseline to post-NET (all Ps < 0.05), without adverse neurocognitive effects. In the RCT, adverse drug reactions (ADRs) were not separately reported among the 3 treatment arms but a similar rate of discontinuation was reported. The currently available limited evidence from 3 studies suggests that NET as an adjunctive treatment may be a safe, well-tolerated, effective therapy for depression without serious neurocognitive impairments.

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors and the risk for neurocognitive adverse events: A systematic review, meta-analysis and meta-regression

BackgroundIt has been suggested that lipid lowering therapy causes impaired cognitive changes. The association between the use of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors and the risk of neurocognitive adverse events remains unclear. This meta-analysis aims to assess neurocognitive safety of PCSK9 inhibitors in randomized controlled trials (RCTs). Methods and resultsThe research was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). PubMed (MEDLINE), Embase and Cochrane library were searched through September 2019. Selection criteria included RCTs that addressed to neurocognitive adverse events of participants using Alirocumab, Evolocumab or Bococizumab, with a follow up duration of at least 6 months. The search results were screened by two independent reviewers. Safety data from included papers were extracted. Random effects meta-analysis was used to pool results, and meta-regression was utilized when applicable. Twenty-one studies were included. Among 59,733 patients, 31,611 were treated with PCSK9 inhibitors. The follow-up period ranged from 24 weeks to 48 months. No significant difference in the incidence of neurocognitive adverse effects between the groups was identified (RR = 1.01, 95% CI: 0.86–1.19, I2 = 3%). Similar results were seen in subgroup analysis for each of the medications (alirocumab- RR = 0.88, 95% CI: 0.72–1.08, I2 = 0%, evolocumab- RR = 1.42, 95% CI: 0.74–2.73, I2 = 55%). A meta-regression analysis for evolocumab revealed that prolonged study duration was associated with decreased risk for neurocognitive adverse events (βweek = −0.0037, p-value = 0.03). ConclusionsPooled results of our meta-analysis and meta-regression show that exposure to PCSK9 inhibitors is not associated with an increased risk of neurocognitive adverse effects.