Towards a lifelong personalized brain health program:empowering individuals to define, pursue, and monitor meaningful outcomes

Incorporating person-centered outcomes into clinical trials for neurodegenerative diseases has been challenging due to a deficiency in quantitative measures. Meanwhile, the integration of personally meaningful treatment targets in clinical practice remains qualitative, failing to truly inform evaluations, therapeutic interventions and longitudinal monitoring and support. We discuss the current advances and future directions in capturing individualized brain health outcomes and present an approach to integrate person-centered outcome in a scalable manner. Our approach stems from the evidence-based electronic Person-Specific Outcome Measure (ePSOM) program which prompts an individual to define personally meaningful treatment priorities and report level of confidence in managing items that matter to the individual the most (e.g., "Do I feel confident in my ability to contribute to a conversation?"). Deployed either as a single version (person only) or a dyad version (person and care partner), our proposed tool could be used as an endpoint in clinical trials, offering proof of meaningful intervention benefits and in clinical practice, by establishing an anchor for the therapeutic objectives sought by the individual.</p

Exercise engagement drives changes in cognition and cardiorespiratory fitness after 8 weeks of aerobic training in sedentary aging adults at risk of cognitive decline

BackgroundWith our aging population, many individuals are at risk of developing age-related cognitive decline. Physical exercise has been demonstrated to enhance cognitive performance in aging adults. This study examined the effects of 8 weeks of aerobic exercise on cognitive performance and cardiorespiratory fitness in sedentary aging adults at risk for cognitive decline.MethodsFifty-two participants (age 62.9 ± 6.8, 76.9% female) engaged in eight weeks of moderate-to high-intensity exercise (19 in-person, 33 remotely). Global cognition was measured by the Repeatable Battery for the Assessment of Neuropsychological Status, the Delis-Kaplan Executive Function System, and the Digit Span subtest of the Wechsler Adult Intelligence Scale (WAIS) Fourth Edition. Cardiorespiratory fitness was measured via heart rate recovery at minute 1 (HRR1) and 2 (HRR2), and exercise engagement (defined as percent of total exercise time spent in the prescribed heart rate zone). We measured pre and post changes using paired t-tests and mixed effects models, and investigated the association between cardiorespiratory and cognitive performance using multiple regression models. Cohen's d were calculated to estimate effect sizes.ResultsOverall, 63.4 % of participants demonstrated high engagement (≥ 70% total exercise time spent in the prescribed heart rate zone). There were significant pre-post improvements in verbal fluency and verbal memory, and a significant decrement in working memory, but these were associated with small effect sizes (Cohen's d &lt;0.5). Concerning cardiorespiratory fitness, there was a pre-to-post significant improvement in HRR1 (p = 0.01, d = 0.30) and HRR2 (p &lt; 0.001, d = 0.50). Multiple regressions revealed significant associations between cardiorespiratory and cognitive performance, but all were associated with small effect sizes (Cohen's d &lt; 0.5). Interestingly, there were significant between-group differences in exercise engagement (all p &lt; 0.001), with remote participants demonstrating greater exercise engagement than in-person participants.ConclusionImprovements in cognition and cardiorespiratory fitness were observed after 8 weeks of moderate to high-intensity exercise in aging adults. These results suggest that committing to a regular exercise regimen, even for a brief two-month period, can promote improvements in both cardiorespiratory fitness and cognitive performance, and that improvements are driven by exercise engagement

Recommending Physical Activity to Your Aging Patients? What Clinicians Need to Know to Increase Adherence From the Older Adult Perspective

A wealth of scientific evidence supports that being physically active may prevent or delay the onset of cognitive impairment and dementia. However, a critical barrier is that while most clinicians recommend physical activity (PA) and older adults recognize its health benefits, most older adults fail to regularly practice PA. Thus, it is necessary to explore and disseminate knowledge on how to help clinicians truly partner with people and help them to change their behavior and become more active. Clinical and scientific efforts are underway to establish dose-specific PA recommendations for cognitive brain health. However, an important knowledge gap is how to develop effective strategies to increase PA adherence in aging. To better understand the perspective of older adults, we undertook a mixed-method study on sixty-five sedentary older adults at risk for cognitive decline. Participants answered a questionnaire battery related to PA engagement, and a subcohort participated in a remote focus group. Our findings revealed four main themes: First, age and aging are determinants in PA practice. Second, maintaining both an active mind and autonomy are priorities, but planned PA is not usually related as part of being “active.” Third, motivational challenges in PA engagement were noted. And fourth, they emphasized a call for tailored recommendations. Therefore, we present a multidimensional model of PA adherence to maximize brain health in older adults and suggest a tool kit and key questions to effectively screen sedentary aging adults and translate current guidelines into the needs of the individual by using behavior change strategies

Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies

Background: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. Methods: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. Findings: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42\ub74% vs 44\ub72%; absolute difference \u20131\ub769 [\u20139\ub758 to 6\ub711] p=0\ub767; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5\u20138] vs 6 [5\u20138] cm H2O; p=0\ub70011). ICU mortality was higher in MICs than in HICs (30\ub75% vs 19\ub79%; p=0\ub70004; adjusted effect 16\ub741% [95% CI 9\ub752\u201323\ub752]; p&lt;0\ub70001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0\ub780 [95% CI 0\ub775\u20130\ub786]; p&lt;0\ub70001). Interpretation: Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status. Funding: No funding

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Using Stimulation and Repetitive Task Practice to Promote Neuroplasticity Targeted at Improving Hand Function in Individuals with Chronic Tetraplegia.

Injury to the cervical segments of the spinal cord causes significant functional deficits to the upper extremities, affecting the performance of daily life activities and quality of life. Functional impairments following a cervical spinal cord injury (SCI) are primarily attributed to the damage to ascending and descending tracts that hinders the flow of information to and from supraspinal centers and the hand muscles, but there is also evidence that post-injury patterns of cortical reorganization can also play an important role. This thesis explored the influence of different approaches used to activate the motor cortex combined with repetitive task practice, and assessed their effects on hand function and corticomotor excitability. In chapter 1, we explored the literature regarding the primary processes (the lesion itself) and secondary processes (cortical reorganization and anatomical changes) that may further contribute to deficits in hand function after tetraplegia. In addition, we explored the evidence regarding the use of stimulation approaches that either target the motor cortex directly (repetitive transcranial magnetic stimulation [rTMS] and transcranial direct current stimulation [tDCS]), or indirectly (transcutaneous electrical nerve stimulation [TENS] and peripherally applied vibration [VIB]) for their effects on hand function and corticomotor excitability and thus, their potential as adjunct tools in neurorehabilitation. In the study described in chapter 2, we assessed the safety and late effects of a multi-day intervention consisting of a novel electrode montage using tDCS aimed at increasing bi-hemispheric cortical excitability (and thus, targeting the bimanual motor deficits observed after SCI and the cortical activation that exists in bimanual movements) interleaved with bimanual typing task performance in neurologically healthy participants. We found that a multi-day intervention consisting of 5 days of BAC-tDCS was associated with significantly greater gains in bimanual typing performance when compared with sham-tDCS, which was not retained after one week. In chapter 3, we describe a study where we assessed the late effects of a 3-day intervention of 10 Hz rTMS (a frequency that is associated with increased corticomotor excitability) interleaved with performance of a fine motor task on hand function and cortical excitability in individuals with tetraplegia and neurologically healthy controls. We found that participants who received rTMS made greater improvements in skilled hand function and assessed by the Jebsen-Taylor Hand Function Test and grasp force than participants who received sham-rTMS. The improvement in skilled hand function was not accompanied by changes in pinch grip force or corticomotor excitability. In Chapter 4, we undertook a study to assess whether there are differences in outcomes of repetitive task practice when combined with each of the clinically accessible approaches to increase corticomotor excitability either directly (tDCS) or indirectly (TENS, VIB) . Individuals with tetraplegia participated in this crossover study consisting of one session of each stimulation approach, simultaneously delivered with repetitive task practice. We found transient increases in pinch force in the VIB condition, and increases in skilled hand function measured by the Nine-hole Peg Test with the TENS and tDCS conditions. In addition, TENS and tDCS seemed to have shared similarities in terms of early increases in corticomotor excitability, whereas VIB seemed to follow a different pattern characterized by late increases in corticomotor excitability. Finally, in chapter 5 we explore discuss the results of these studies and their applicability to upper extremity rehabilitation of individuals with tetraplegia

Non-invasive Brain Stimulation: Probing Intracortical Circuits and Improving Cognition in the Aging Brain

The impact of cognitive aging on brain function and structure is complex, and the relationship between aging-related structural changes and cognitive function are not fully understood. Physiological and pathological changes to the aging brain are highly variable, making it difficult to estimate a cognitive trajectory with which to monitor the conversion to cognitive decline. Beyond the information on the structural and functional consequences of cognitive aging gained from brain imaging and neuropsychological studies, non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) can enable stimulation of the human brain in vivo, offering useful insights into the functional integrity of intracortical circuits using electrophysiology and neuromodulation. TMS measurements can be used to identify and monitor changes in cortical reactivity, the integrity of inhibitory and excitatory intracortical circuits, the mechanisms of long-term potentiation (LTP)/depression-like plasticity and central cholinergic function. Repetitive TMS and tDCS can be used to modulate neuronal excitability and enhance cortical function, and thus offer a potential means to slow or reverse cognitive decline. This review will summarize and critically appraise relevant literature regarding the use of TMS and tDCS to probe cortical areas affected by the aging brain, and as potential therapeutic tools to improve cognitive function in the aging population. Challenges arising from intra-individual differences, limited reproducibility, and methodological differences will be discussed

Bihemispheric Anodal Corticomotor Stimulation Using Transcranial Direct Current Stimulation Improves Bimanual Typing Task Performance

Transcranial direct current stimulation (tDCS) is associated with improved unimanual skilled hand use. The authors assessed effects of bihemispheric anodal corticomotor tDCS (BAC-tDCS) on bimanual skilled hand use. Twenty-eight nondisabled subjects were randomized to either BAC-tDCS or sham-tDCS, 20 min daily for 5 consecutive days. Performance on a bimanual typing (BT) task and a short-term memory (STM) task was assessed daily and at 1-week follow-up. Mean change between Day 1 and Day 5 in BT score with BAC-tDCS (19.4 points; 95% CI [12.82, 25.99]) was significantly greater (p =.04) than change with sham-tDCS (12.5 points; 95% CI [7.6, 17.3]). Neither group retained improvements in BT score at follow-up. BAC-tDCS had no effect on STM. These results may have implications for interventions to improve hand function in persons with bilateral hand dysfunction