A combined DHA-rich fish oil and cocoa flavanols intervention does not improve cognition or brain structure in older adults with memory complaints: results from the CANN randomized, controlled parallel-design study.

BACKGROUND: There is evidence that both omega-3 long-chain polyunsaturated fatty acids (PUFAs) (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) and cocoa flavanols can improve cognitive performance in both healthy individuals and in those with memory complaints. However, their combined effect is unknown. OBJECTIVES: To investigate the combined effect of EPA/DHA and cocoa flavanols (OM3FLAV) on cognitive performance and brain structures in older adults with memory complaints. METHODS: A randomized placebo-controlled trial of DHA-rich fish oil (providing 1.1 g/d DHA and 0.4 g/d EPA) and a flavanol-rich dark chocolate (providing 500 mg/d flavan-3-ols) was conducted in 259 older adults with either subjective cognitive impairment or mild cognitive impairment. Participants underwent assessment at baseline, 3 mo, and 12 mo. The primary outcome was the number of false-positives on a picture recognition task from the Cognitive Drug Research computerized assessment battery. Secondary outcomes included other cognition and mood outcomes, plasma lipids, brain-derived neurotrophic factor (BDNF), and glucose levels. A subset of 110 participants underwent structural neuroimaging at baseline and at 12 mo. RESULTS: 197 participants completed the study. The combined intervention had no significant effect on any cognitive outcomes, with the exception of reaction time variability (P = 0.007), alertness (P < 0.001), and executive function (P < 0.001), with a decline in function observed in the OM3FLAV group (118.6 [SD 25.3] at baseline versus 113.3 [SD 25.4] at 12 mo for executive function) relative to the control, and an associated decrease in cortical volume (P = 0.039). Compared with the control group, OM3FLAV increased plasma HDL, total cholesterol ratio (P < 0.001), and glucose (P = 0.008) and reduced TG concentrations (P < 0.001) by 3 mo, which were sustained to 12 mo, with no effect on BDNF. Changes in plasma EPA and DHA and urinary flavonoid metabolite concentrations confirmed compliance to the intervention. CONCLUSIONS: These results suggest that cosupplementation with ω-3 PUFAs and cocoa flavanols for 12 mo does not improve cognitive outcomes in those with cognitive impairment. This trial was registered at clinicaltrials.gov as NCT02525198.

Investigating the Effects of a Multinutrient Supplement on Cognition, Mood and Biochemical Markers in Middle-Aged Adults with 'Optimal' and 'Sub-Optimal' Diets: A Randomized Double Blind Placebo Controlled Trial.

Background: Previous randomized controlled trials examining cognitive and mood effects of combination multivitamin supplements in healthy, non-clinical adults have reported mixed results. One purported explanation for this is that the dietary status of participants at the start of supplement interventions may influence the magnitude of the effect of supplementation. Methods: In this study, we evaluated the effect of a multinutrient formula containing B group vitamins, Bacopa monniera and Ginkgo biloba on memory, attention, mood and biochemical markers of nutrient status in middle-aged adults (M = 52.84 years, n = 141) with 'optimal' and 'sub-optimal' diets over 12 weeks. We hypothesised that active supplementation would differentially improve memory and attention in those with a 'sub-optimal' diet. Results: Mixed model, repeated measures analysis revealed that, in comparison to placebo, active treatment was associated with significant increases in B vitamin status (B1, B6, B12). Regarding behavioural outcomes there was no significant benefit to memory (F(1, 113.51) = 0.53, p = 0.470) nor attention (F(1,113.77) = 1.89, p = 0.171) in the whole cohort. Contrary to our hypothesis, there was a significant beneficial effect of supplementation on attentional performance in individuals with an 'optimal' diet prior to supplementation (F(1,57.25) = 4.94, p = 0.030). In the absence of a main effect of supplementation across the entire cohort, there were also a number of significant three-way interactions (treatment by time by diet group) detected in secondary outcomes including lower state anxiety and mental fatigue in those with an 'optimal' diet. Conclusion: These findings suggest that the cognitive benefit of B vitamin and herbal supplementation may be dependent on diet quality, supporting the concepts of 'co-nutrient optimisation' and interdependency of nutrients. This warrants further investigation. This study advocates characterising the diet of participants prior to supplementation as it may influence the effect of a nutraceutical intervention.

Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial.

BACKGROUND: Diabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial analgesic treatment for DPNP, but there is little comparative evidence on which one is best or whether they should be combined. We aimed to assess the efficacy and tolerability of different combinations of first-line drugs for treatment of DPNP. METHODS: OPTION-DM was a multicentre, randomised, double-blind, crossover trial in patients with DPNP with mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0-10) from 13 UK centres. Participants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisation schedule stratified by site using permuted blocks of size six or 12, to receive one of six ordered sequences of the three treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P), each pathway lasting 16 weeks. Monotherapy was given for 6 weeks and was supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. Both treatments were titrated towards maximum tolerated dose (75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin). The primary outcome was the difference in 7-day average daily pain during the final week of each pathway. This trial is registered with ISRCTN, ISRCTN17545443. FINDINGS: Between Nov 14, 2017, and July 29, 2019, 252 patients were screened, 140 patients were randomly assigned, and 130 started a treatment pathway (with 84 completing at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6·6 (SD 1·5) at baseline to 3·3 (1·8) at week 16 in all three pathways. The mean difference was -0·1 (98·3% CI -0·5 to 0·3) for D-P versus A-P, -0·1 (-0·5 to 0·3) for P-A versus A-P, and 0·0 (-0·4 to 0·4) for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was greater than in those who remained on monotherapy (1·0 [SD 1·3] vs 0·2 [1·5]). Adverse events were predictable for the monotherapies: we observed a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway. INTERPRETATION: To our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy. FUNDING: National Institute for Health Research (NIHR) Health Technology Assessment programme.

Patients with Epiglottic Collapse Are Less Adherent to Autotitrating Positive Airway Pressure Therapy for Obstructive Sleep Apnea.

Rationale: The anatomic orientation of the epiglottis is such that it points in the opposite direction to inspiratory flow, thereby potentially making positive airway pressure (PAP) treatment challenging in patients with epiglottic collapse. However, no previous studies have analyzed PAP adherence in these patients. Objectives: This study aimed to analyze adherence to autotitrating PAP (APAP) treatment in patients with epiglottic collapse. Methods: We performed an age- and sex-matched case-control study. On the basis of their overnight level-I polysomnogram, patients were prescribed APAP in a tertiary hospital between July 2018 and March 2019. The site of airway collapse was diagnosed with drug-induced sleep endoscopy. Demographic factors, sleep questionnaire, polysomnography, and APAP usage statistics were analyzed. Results: Eighteen patients with epiglottic collapse (epi-group) and 36 without epiglottic collapse (control group) were analyzed. We found that 22.8% of patients in the epi-group terminated APAP within 2 weeks, whereas only 2.8% of patients in the control group terminated APAP within 2 weeks (P = 0.048). The percentage of days with usage over 4 hours was significantly lower in the epi-group (64.6% vs. 75.6%; P = 0.008). In addition, the adherence failure rate was 66.7% in the epi-group and 33.3% in the control group (P = 0.039). Patients with epiglottic collapse were also found to have lower body mass index, which is an unfavorable predictor of APAP adherence. Conclusions: This study suggests that patients with epiglottic collapse have a higher APAP adherence failure rate than patients without epiglottic collapse. Thus, patients with epiglottic collapse should be followed closely during treatment, and alternative therapies should probably be considered for these patients.

Jet injection needle-free dental anaesthesia: Initial findings.

OBJECTIVES: We evaluated patient preference and reported levels of anxiety and discomfort of participants treated with a new needle-free electric motor-driven device vs. conventional local anaesthetic for dental extractions in a proof-of-principle study. Healing and response of gingival tissues to injection were also evaluated at 1, 3- and 7-days post-procedure. METHODS: After informed consent, eight participants who required bilateral maxillary extractions were included in the trial. The side and order of placement for the needle-free and conventional anaesthetic were randomized. The same operator delivered anaesthesia and ensured teeth were anaesthetized on both sides. Another operator, unaware of order and type of anaesthesia placed, performed the extractions. RESULTS: Participant's average discomfort scores were low for both techniques, and lower for the needle-free injection at all timepoints. Needle-free local anaesthesia was the preferred technique by most participants at most timepoints. The average volume of anaesthetic dispensed was similar between techniques. Successful anaesthesia with the needle-free device was achieved in 6 out of 8 participants. Healing of the extraction sockets and adjacent oral mucosa progressed normally for all participants, with no evidence of infection, trauma or hematoma in the injection sites of the test and conventional sides. CONCLUSIONS: The needle-free local anaesthetic technique investigated achieved sufficient anaesthesia for tooth extractions in the maxilla in 75% of the subjects. A larger clinical trial is needed to further validate the technique tested and to investigate whether needle-free local anaesthesia can be successfully applied to the provision of restorative therapy. CLINICAL SIGNIFICANCE: The results of this study can be used by clinicians treating patients who suffer from dental anxiety and needle-phobia.

EEG signatures change during unilateral Yogi nasal breathing.

Airflow through the left-and-right nostrils is said to be entrained by an endogenous nasal cycle paced by both poles of the hypothalamus. Yogic practices suggest, and scientific evidence demonstrates, that right-nostril breathing is involved with relatively higher sympathetic activity (arousal states), while left-nostril breathing is associated with a relatively more parasympathetic activity (stress alleviating state). The objective of this study was to further explore this laterality by controlling nasal airflow and observing patterns of cortical activity through encephalographic (EEG) recordings. Thirty subjects participated in this crossover study. The experimental session consisted of a resting phase (baseline), then a period of unilateral nostril breathing (UNB) using the dominant nasal airway, followed by UNB using the non-dominant nasal airway. A 64-channel EEG was recorded throughout the whole session. The effects of nostril-dominance, and nostril-lateralization were assessed using the power spectral density of the neural activity. The differences in power-spectra and source localization were calculated between EEG recorded during UNB and baseline for delta, theta, alpha, beta and gamma bands. Cluster-based permutation tests showed that compared to baseline, EEG spectral power was significantly (1) decreased in all frequency bands for non-dominant nostril UNB, (2) decreased in alpha, beta and gamma bands for dominant nostril UNB, (3) decreased in all bands for left nostril UNB, and (4) decreased in all bands except delta for right nostril UNB. The beta band showed the most widely distributed changes across the scalp. our source localisation results show that breathing with the dominant nostril breathing increases EEG power in the left inferior frontal (alpha band) and left parietal lobule (beta band), whereas non-dominant nostril breathing is related to more diffuse and bilateral effects in posterior areas of the brain.These preliminary findings may stimulate further research in the area, with potential applications to tailored treatment of brain disorders associated with disruption of sympathetic and parasympathetic activity.

APOE ε4 alters associations between docosahexaenoic acid and preclinical markers of Alzheimer's disease.

Docosahexaenoic acid is the main long-chain omega-3 polyunsaturated fatty acids in the brain and accounts for 30-40% of fatty acids in the grey matter of the human cortex. Although the influence of docosahexaenoic acid on memory function is widely researched, its association with brain volumes is under investigated and its association with spatial navigation is virtually unknown. This is despite the fact that spatial navigation deficits are a new cognitive fingerprint for symptomatic and asymptomatic Alzheimer's disease. We investigated the cross-sectional relationship between docosahexaenoic acid levels and the major structural and cognitive markers of preclinical Alzheimer's disease, namely hippocampal volume, entorhinal volume and spatial navigation ability. Fifty-three cognitively normal adults underwent volumetric magnetic resonance imaging, measurements of serum docosahexaenoic acid (DHA, including lysophosphatidylcholine DHA) and APOE ε4 genotyping. Relative regional brain volumes were calculated and linear regression models were fitted to examine DHA associations with brain volume. APOE genotype modulated serum DHA associations with entorhinal cortex volume and hippocampal volume. Linear models showed that greater serum DHA was associated with increased entorhinal cortex volume, but not hippocampal volume, in non APOΕ Îµ4 carriers. APOE also interacted with serum lysophosphatidylcholine DHA to predict hippocampal volume. After testing interactions between DHA and APOE on brain volume, we investigated whether DHA and APOE interact to predict spatial navigation performance on a novel virtual reality diagnostic test for Alzheimer's disease in an independent population of APOE genotyped adults (n = 46). APOE genotype modulated DHA associations with spatial navigation performance, showing that DHA was inversely associated with path integration in APOE ε4 carriers only. This exploratory analysis suggests that interventions aiming to increase DHA blood levels to protect against cognitive decline should consider APOE ε4 carrier status. Future work should focus on replicating our initial findings and establishing whether a specific dose of supplementary DHA, at a particular time in the preclinical disease course can have a positive impact on Alzheimer's disease progression in APOE ε4 carriers.

Neti pot irrigation volume filling simulation using anatomically accurate in-vivo nasal airway geometry.

Nasal saline irrigation is frequently utilised in rhinosinusitis management, and after nasal and sinus surgery. Nasal saline irrigation improves mucociliary transport and assists inflammatory mediator and post-surgical debris removal. The aim of this study was to assess the influence different head positions, irrigation inflow nostril, and the nasal cycle have on Neti pot nasal saline volume filling within the nasal passages and maxillary sinuses. Computational fluid dynamics modelling using anatomically correct nasal geometry found only minor difference in nasal cavity volume filling with inflow from either side of the nose however both head position and inflow direction were both found to have a major influence on maxillary sinus volume filling. Computational modelling flow velocity results at the nasopharynx were validated using particle image velocimetry. It was also found that directing irrigation inflow into the patent side of the nose while in the head-back position achieved the highest volume filling of both maxillary sinuses.

Effects of Panax quinquefolius (American ginseng) on the steady state visually evoked potential during cognitive performance.

OBJECTIVE: To investigate the effects of acute Panax quinquefolius (American ginseng) administration on steady state visually evoked potentials (SSVEPs) during completion of working memory and continuous performance tasks. METHODS: A randomised, double-blind, placebo controlled, balanced, cross-over trial was conducted in middle-aged volunteers aged between 40 and 60 years. Participants were administered 200 mg P. quinquefolius and placebo on two separate testing sessions. Six-h post-dose participants completed spatial working memory (SWM) and continuous performance (CP) tasks while SSVEP from a diffuse task-irrelevant 13 Hz flicker was recorded. RESULTS: During SWM retrieval, P. quinquefolius was associated with significantly reduced prefrontal SSVEP latency. There were no significant treatment effects on CP nor behavioural performance of either task. CONCLUSIONS: These findings provide preliminary evidence of increased recruitment of prefrontal brain regions during working memory processing following a single acute dose of P. quinquefolius.

Further Evidence of Benefits to Mood and Working Memory from Lipidated Curcumin in Healthy Older People: A 12-Week, Double-Blind, Placebo-Controlled, Partial Replication Study.

Curcumin (a flavonoid isolated from turmeric) affects several processes involved in neurocognitive aging. We have previously reported that short term (4-weeks) administration of a highly bioavailable curcumin preparation (Longvida©) improved working memory and reduced fatigue and stress reactivity in a healthy older cohort. The present trial (ACTRN12616000484448) was a partial replication study, evaluating similar effects at 4 and 12-weeks Longvida© supplementation. A double-blind, placebo-controlled, parallel-groups trial was conducted. Eighty participants aged 50-80 years (mean = 68.1, SD = 6.34) were randomised to receive Longvida© (400 mg daily containing 80 mg curcumin) or a matching placebo. Assessment took place at baseline then following 4 and 12 weeks treatment. Outcome measures included cognitive performance, mood and biomarkers. Compared with placebo, curcumin was associated with several significant effects. These included better working memory performance at 12-weeks (Serial Threes, Serial Sevens and performance on a virtual Morris Water Maze), and lower fatigue scores on the Profile of Mood States (POMS) at both 4 and 12-weeks, and of tension, anger, confusion and total mood disturbance at 4-weeks only. The curcumin group had significantly elevated blood glucose. These results confirm that Longvida© improves aspects of mood and working memory in a healthy older cohort. The pattern of results is consistent with improvements in hippocampal function and may hold promise for alleviating cognitive decline in some populations.

Translation of the Frailty Paradigm from Older Adults to Children with Cardiac Disease.

Children and adolescents with cardiac disease (CCD) have significant morbidity and lower quality of life. However, there are no broadly applicable tools similar to the frailty score as described in the elderly, to define functional phenotype in terms of physical capability and psychosocial wellbeing in CCD. The purpose of this study is to investigate the domains of the frailty in CCD. We prospectively recruited CCD (8-17.5 years old, 70% single ventricle, 27% heart failure, 12% pulmonary hypertension; NYHA classes I, II and III) and age and gender matched healthy controls (total n = 56; CCD n = 34, controls n = 22; age 12.6 ± 2.6 years; 39.3% female). We measured the five domains of frailty: slowness, weakness, exhaustion, body composition and physical activity using developmentally appropriate methods. Age and gender-based population norms were used to obtain Z scores and percentiles for each measurement. Two-tailed t-tests were used to compare the two groups. The CCD group performed significantly worse in all five domains of frailty compared to healthy controls. Slowness: 6-min walk test with Z score -3.9 ± 1.3 vs -1.4 ± 1.3, p < 0.001; weakness: handgrip strength percentile 18.9 ± 20.9 vs 57.9 ± 26.0, p < 0.001; exhaustion: multidimensional fatigue scale percentile 63.7 ± 13.5 vs 83.3 ± 14.4, p < 0.001; body composition: height percentile 43.4 ± 29.5 vs 71.4 ± 25.2, p < 0.001, weight percentile 46.0 ± 36.0 vs 70.9 ± 24.3, p = 0.006, BMI percentile 48.4 ± 35.5 vs 66.9 ± 24.2, p = 0.04, triceps skinfold thickness 41.0 ± 24.0 vs 54.4 ± 22.1, p = 0.04; physical activity: pediatric activity questionnaire score 2 ± 0.6 vs 2.7 ± 0.6, p < 0.001. The domains of frailty can be quantified in children using developmentally appropriate methods. CCD differ significantly from controls in all five domains, supporting the concept of quantifying the domains of frailty. Larger longitudinal studies are needed to study frailty in CCD and examine if it predicts adverse health outcomes.Clinical Trial Registration: The ClinicalTrials.gov identification number is NCT02999438. https://clinicaltrials.gov/ct2/show/NCT02999438.

Interventions to promote oral nutritional behaviours in people living with neurodegenerative disorders of the motor system: A systematic review.

BACKGROUND & AIMS: Weight loss is common in people with neurodegenerative diseases of the motor system (NDMS), such as Parkinson's disease and Amyotrophic Lateral Sclerosis, and is associated with reduced quality of life, functional ability and survival. This systematic review aims to identify interventions and intervention components (i.e. behaviour change techniques [BCTs] and modes of delivery [MoDs]) that are associated with increased effectiveness in promoting oral nutritional behaviours that help people with NDMS to achieve a high calorie diet. METHODS: Eight electronic databases including MEDLINE and CINAHL were searched from inception to May 2018. All interventions from included studies were coded for relevant BCTs and MoDs. Methodological quality of studies was assessed using the Cochrane risk of bias tool. RESULTS: Fourteen studies were included. Of these, eight studies reported interventions to assist with swallowing difficulties and six studies reported interventions targeting dietary content. Beneficial effects in managing swallowing difficulties were observed with video assisted swallowing therapy, lung volume recruitment and swallowing management clinics with outpatient support. In contrast, studies reporting effectiveness of chin down posture, use of thickened liquids and respiratory muscle training were inconclusive. Positive effects in interventions targeting dietary content included the use of food pyramid tools, individualised nutritional advice with nutritional interventions, electronic health applications, face-to-face dietary counselling and high fat, high carbohydrate and milk whey protein supplements. Individualised nutritional advice with weekly phone contact did not appear to be effective. Most frequently coded BCTs were 'instructions on how to perform the behaviour', 'self-monitoring' and 'behavioural practice/rehearsal'. Most commonly identified MoDs were 'human, face-to-face' and 'somatic therapy'. However, the robustness of these findings are low due to the small number of studies, small sample sizes and large between-study variability. CONCLUSIONS: Despite the limited evidence, these findings may help inform the development of more effective interventions to promote oral nutritional behaviours in people with NDMS. However, further research is needed to demonstrate which interventions, or intervention components, yield most benefit.

Nasal saline irrigation - A review of current anatomical, clinical and computational modelling approaches.

Nasal saline irrigation is frequently utilised in allergic rhinitis and rhinosinusitis management, and after nasal and sinus surgery. Anatomical modelling, clinical and computational studies guide treatment optimisation. This review offers a comprehensive summary of the modelling methodologies used in previous nasal irrigation studies by undertaking a systematic analysis of anatomical, clinical and computational investigations that assessed nasal saline irrigation using Medline, EMBASE, and Cochrane Review databases. Both procedural and assessment methods were reviewed. It was found that all twenty-four publications reviewed did not discuss the influence of the nasal cycle on internasal geometry and nasal resistance. Cadaver studies misrepresent in vivo nasal geometry. Irrigation pressure and shear forces, which could influence mucociliary transport and postoperative cleaning, were not evaluated. Previous studies focus on irrigation coverage and have not considered the nasal cycle which influences unilateral nasal resistance and thus pressure/ flow relationships and may also increase nasal air-locking. New computational fluid dynamic models could better inform nasal irrigation clinical practice.

A Systematic Review and Meta-Analysis of B Vitamin Supplementation on Depressive Symptoms, Anxiety, and Stress: Effects on Healthy and 'At-Risk' Individuals.

A systematic review and meta-analysis was undertaken to examine and quantify the effects of B vitamin supplementation on mood in both healthy and 'at-risk' populations. A systematic search identified all available randomised controlled trials (RCTs) of daily supplementation with ≥3 B group vitamins with an intervention period of at least four weeks. Random effects models for a standardized mean difference were used to test for overall effect. Heterogeneity was tested using the I2 statistic. Eighteen articles (16 trials, 2015 participants) were included, of which 12 were eligible for meta-analysis. Eleven of the 18 articles reported a positive effect for B vitamins over a placebo for overall mood or a facet of mood. Of the eight studies in 'at-risk' cohorts, five found a significant benefit to mood. Regarding individual facets of mood, B vitamin supplementation benefited stress (n = 958, SMD = 0.23, 95% CI = 0.02, 0.45, p = 0.03). A benefit to depressive symptoms did not reach significance (n = 568, SMD = 0.15, 95% CI = -0.01, 0.32, p = 0.07), and there was no effect on anxiety (n = 562, SMD = 0.03, 95% CI = -0.13, 0.20, p = 0.71). The review provides evidence for the benefit of B vitamin supplementation in healthy and at-risk populations for stress, but not for depressive symptoms or anxiety. B vitamin supplementation may particularly benefit populations who are at risk due to (1) poor nutrient status or (2) poor mood status.

Closed-loop system to enhance slow-wave activity.

OBJECTIVE: Recent evidence reports cognitive, metabolic, and sleep restoration benefits resulting from the enhancement of sleep slow-waves using auditory stimulation. Our objective is to make this concept practical for consumer use by developing and validating an electroencephalogram (EEG) closed-loop system to deliver auditory stimulation during sleep to enhance slow-waves. APPROACH: The system automatically detects slow-wave sleep with 74% sensitivity and 97% specificity and optimally delivers stimulation in the form of 50 ms-long tones separated by a constant one-second inter-tone interval at a volume that is dynamically modulated such that louder tones are delivered when sleep is deeper. The system was tested in a study involving 28 participants (18F, 10M; 36.9 ± 7.3 years old; median age: 40 years old) who used the system for ten nights (five nights in a sham condition and five in a stimulation condition). Four nights in each condition were recorded at-home and the fifth one in-lab. MAIN RESULTS: The analysis in two age groups defined by the median age of participants in the study shows significant slow wave activity enhancement (+16.1%, p < 0.01) for the younger group and absence of effect on the older group. However, the older group received only a fraction (57%) of the stimulation compared to the younger group. Changes in sleep architecture and EEG properties due to aging have influenced the amount of stimulation. The analysis of the stimulation timing suggests an entrainment-like phenomenon where slow-waves align to the stimulation periodicity. In addition, enhancement of spindle power in the stimulation condition was found. SIGNIFICANCE: We show evidence of the viability of delivering auditory stimulation during sleep, at home, to enhance slow wave activity. The system ensures the stimulation delivery to be at the right time during sleep without causing disturbance.

Glycerophospholipid Supplementation as a Potential Intervention for Supporting Cerebral Structure in Older Adults.

Modifying nutritional intake through supplementation may be efficacious for altering the trajectory of cerebral structural decline evident with increasing age. To date, there have been a number of clinical trials in older adults whereby chronic supplementation with B vitamins, omega-3 fatty acids, or resveratrol, has been observed to either slow the rate of decline or repair cerebral tissue. There is also some evidence from animal studies indicating that supplementation with glycerophospholipids (GPL) may benefit cerebral structure, though these effects have not yet been investigated in adult humans. Despite this paucity of research, there are a number of factors predicting poorer cerebral structure in older humans, which GPL supplementation appears to beneficially modify or protect against. These include elevated concentrations of homocysteine, unbalanced activity of reactive oxygen species both increasing the risk of oxidative stress, increased concentrations of pro-inflammatory messengers, as well as poorer cardio- and cerebrovascular function. As such, it is hypothesized that GPL supplementation will support cerebral structure in older adults. These cerebral effects may influence cognitive function. The current review aims to provide a theoretical basis for future clinical trials investigating the effects of GPL supplementation on cerebral structural integrity in older adults.

Development of a Functional Observational Battery in the Minipig for Regulatory Neurotoxicity Assessments.

A functional observational battery (FOB) is recommended as the first-tier neurotoxicity screening in the preclinical safety pharmacology testing guidelines. Minipigs have increasingly been used in regulatory toxicology studies; however, no current FOB protocol is available for neurotoxicity testing in these species. Hence, a minipig FOB instrument was developed. A complete crossover study with Sinclair minipigs was performed to evaluate physiologic, neurologic, and behavioral effects of amphetamine, ketamine, and diazepam. The treated minipigs were first observed in their home cage, were video-recorded for 10 minutes in an open field, and then went through a complete neurologic examination. Both ketamine and diazepam were shown to reduce the freezing and behavior shifts of treated minipigs, while increasing their exploratory behaviors. Both drugs also caused muscular and gait impairment. The effects of ketamine and diazepam were consistent with their roles as central nervous system (CNS) suppressants. Unique effects were also observed with ketamine and diazepam treatments, which may reflect their unique mechanisms of action. Consistent with its role as a CNS stimulant, amphetamine caused the treated minipigs to be hyperactive and to display increased freezing and behavior shifts and reduced exploring activities. These effects of amphetamine were opposite to those observed with ketamine and diazepam. Amphetamine also increased locomotion in the treated minipigs. The present effects of amphetamine, ketamine, and diazepam are in agreement with observations by others. In conclusion, the minipig is a suitable species for FOB evaluation of pharmaceuticals in preclinical safety pharmacology testing.

The effect of a single dose of multivitamin and mineral combinations with and without guaraná on functional brain activity during a continuous performance task.

OBJECTIVES: Relatively few studies have explored the possibility of acute cognitive effects of multivitamin ingestion. This report explores the acute brain electrophysiological changes associated with multivitamin and mineral supplementation, with and without guaraná, using the steady-state visually evoked potential (SSVEP). METHODS: Based on the known SSVEP correlates of A-X continuous performance task (CPT) performance, and sensitivity to acute psychopharmacological manipulations, the A-X CPT was adopted as a task paradigm to explore treatment-related neurophysiological changes in attentional processing. Twenty healthy non-smoking adults aged 21-39 years (mean age = 28.35 years, SD = 5.52) took part in this double-blind, placebo-controlled, randomized, balanced crossover design study. RESULTS: The study demonstrated both transient and tonic changes in the SSVEP response during completion of the A-X CPT following multivitamin and mineral treatment both with and without guaraná. Transient changes in SSVEP response in prefrontal regions were observed after a single dose of a multivitamin and mineral preparation indicative of enhanced activity within brain regions engaged by the attentional demands of the task. This pattern of change in frontal regions was correlated with improved behavioural performance after treatment with the multivitamin and mineral combination. Where tonic shifts in SSVEP response were investigated, multivitamin and mineral treatment was associated with a pattern of increased inhibition across posterior regions, with enhanced excitatory processing in prefrontal regions. In contrast, multivitamin and mineral treatment with additional guaraná showed a tonic shift towards greater excitatory processes after a single treatment, consistent with the caffeine content of this treatment. DISCUSSION: While preliminary in nature, these findings suggest a single multivitamin/mineral dose is sufficient to impact on functional brain activity in task-related brain regions.

Functional Brain Activity Changes after 4 Weeks Supplementation with a Multi-Vitamin/Mineral Combination: A Randomized, Double-Blind, Placebo-Controlled Trial Exploring Functional Magnetic Resonance Imaging and Steady-State Visual Evoked Potentials during Working Memory.

This study explored the neurocognitive effects of 4 weeks daily supplementation with a multi-vitamin and -mineral combination (MVM) in healthy adults (aged 18-40 years). Using a randomized, double-blind, placebo-controlled design, participants underwent assessments of brain activity using functional Magnetic Resonance Imaging (fMRI; n = 32, 16 females) and Steady-State Visual Evoked Potential recordings (SSVEP; n = 39, 20 females) during working memory and continuous performance tasks at baseline and following 4 weeks of active MVM treatment or placebo. There were several treatment-related effects suggestive of changes in functional brain activity associated with MVM administration. SSVEP data showed latency reductions across centro-parietal regions during the encoding period of a spatial working memory task following 4 weeks of active MVM treatment. Complementary results were observed with the fMRI data, in which a subset of those completing fMRI assessment after SSVEP assessment (n = 16) demonstrated increased BOLD response during completion of the Rapid Visual Information Processing task (RVIP) within regions of interest including bilateral parietal lobes. No treatment-related changes in fMRI data were observed in those who had not first undergone SSVEP assessment, suggesting these results may be most evident under conditions of fatigue. Performance on the working memory and continuous performance tasks did not significantly differ between treatment groups at follow-up. In addition, within the fatigued fMRI sample, increased RVIP BOLD response was correlated with the change in number of target detections as part of the RVIP task. This study provides preliminary evidence of changes in functional brain activity during working memory associated with 4 weeks of daily treatment with a multi-vitamin and -mineral combination in healthy adults, using two distinct but complementary measures of functional brain activity.

ARQiv-HTS, a versatile whole-organism screening platform enabling in vivo drug discovery at high-throughput rates.

The zebrafish has emerged as an important model for whole-organism small-molecule screening. However, most zebrafish-based chemical screens have achieved only mid-throughput rates. Here we describe a versatile whole-organism drug discovery platform that can achieve true high-throughput screening (HTS) capacities. This system combines our automated reporter quantification in vivo (ARQiv) system with customized robotics, and is termed 'ARQiv-HTS'. We detail the process of establishing and implementing ARQiv-HTS: (i) assay design and optimization, (ii) calculation of sample size and hit criteria, (iii) large-scale egg production, (iv) automated compound titration, (v) dispensing of embryos into microtiter plates, and (vi) reporter quantification. We also outline what we see as best practice strategies for leveraging the power of ARQiv-HTS for zebrafish-based drug discovery, and address technical challenges of applying zebrafish to large-scale chemical screens. Finally, we provide a detailed protocol for a recently completed inaugural ARQiv-HTS effort, which involved the identification of compounds that elevate insulin reporter activity. Compounds that increased the number of insulin-producing pancreatic beta cells represent potential new therapeutics for diabetic patients. For this effort, individual screening sessions took 1 week to conclude, and sessions were performed iteratively approximately every other day to increase throughput. At the conclusion of the screen, more than a half million drug-treated larvae had been evaluated. Beyond this initial example, however, the ARQiv-HTS platform is adaptable to almost any reporter-based assay designed to evaluate the effects of chemical compounds in living small-animal models. ARQiv-HTS thus enables large-scale whole-organism drug discovery for a variety of model species and from numerous disease-oriented perspectives.