December 2017
A number of important new study reports, ongoing trials, and industry news over the past several months continue to advance our community’s translational efforts in the development and delivery of computerized brain training to support individuals in need of help. Let’s dive in and talk about several of these interesting efforts.
A LITTLE NEWS
Dementia risk sharply reduced
Americans and world citizens are enjoying progressively longer lifespans — but, alas, without any matching extension of their brain-spans. Unless we do something about it, the majority of us now live just long enough to be pretty much assured that we’ll succumb to neurodegenerative diseases during our lifetimes. One of Posit Science’s great goals, from the time of establishment of BrainHQ, has been to sustain the brain’s happy, high-functioning, self-sustaining abilities to the very end of that longer human life.
Of course most of the collective neuroscientific effort over the past decades has been directed toward developing a pharmaceutical ‘magic bullet’ to address this great and growing human and societal problem, but the last time I counted them more than 450 drug trials designed to treat dementia had failed. 0 for 450 is a pretty low hit rate for the pharmaceutical giants amongst us — and represents a lot of treasure delivered straight down the rat-hole. No medicine, no neutra-ceutical, no exercise form — and for that matter, no other intervention — has been demonstrated to delay or prevent the onset of dementia by the standards of a believable (randomized; more than a handful of subjects) controlled trial.
That’s one reason why the just-published demonstration that the BrainHQ’s exercise Double Decision (originally developed by Drs. Karlene Ball and Daniel Roenker), showing that a brief epoch of training with this exercise alone sharply reduced the probability of the later development of dementia, is so important. Drs. Jerri Edwards, Fred Unverzagt and colleagues recorded that outcome via the analysis of the later-life fates of individuals who had received this training, in a 10-year follow-up of the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE; NCT00298558) Trial (Alzheimer’s & Dementia: Translational Research & Clinical Interventions, Nov 2017).
As most of you know, in ACTIVE, 2,832 community-dwelling volunteers were randomly assigned to one of three training groups (computerized speed, memory-class, reasoning-class training), or to a non-trained control group. A range of training sessions were administered with a maximum of 18 sessions in total–all delivered over the first 3 (of 10) study years. Dementia emerged in 260 participants over the 10-year study period (when the average subject age advanced to 84), as established with standardized interview- and performance-based criteria defining cognitive and functional status. The overall probability of dementia onset was 33% lower for computerized “speed-training” vs control subjects, when all dementia-related diagnostic criteria were included (HR = 0.67, 95%, CI = 0.49-0.91, p < .01), 29% lower when two criteria (institutionalization; deactivation due to family refusal) were removed (HR = 0.71, 95%, CI = 0.50-0.998, p < .05), and 48% lower when comparing the highest completion group of speed training (14-18 hours) to controls. Memory and Reasoning training programs applied for the same number of hours on the same schedule in a group setting in ACTIVE did not significantly reduce risk. Analyses examining dose showed a significant effect of training session (‘dose’), with each additional one-hour-long speed training session producing a 10% lower hazard for dementia (unadjusted HR = 0.90 per session delivered, 95% CI = 0.85-0.95, p < .001). The bottom line: Individuals who completed 14-18 hours of training, all over the first three ACTIVE trial years, were about half as likely to develop dementia over the trial decade.
These findings imply a potentially great and enduring value of this singular, simple, high-scalable form of computerized brain training for providing protection against dementia onset, and are important in at least two additional important ways. First, the intervention was remarkably simple and is relatively easily achieved in monitored subjects — and in this trial, was applied without any real consideration of the ‘dosing’ required to sustain protection. It is a virtual certainty that protection would have been better if a) subjects in the trial had been trained to achieve performance benchmarks marking a ‘safe’ organic brain health status; b) if they were monitored across this 10-year epoch, and administered additional doses as needed to sustain that benchmark; and c) if additional, training strategies had been applied to further restore other hypothetically important, deteriorating neurological assets.
Second, we were not surprised by these results because our animal studies have repeatedly shown that training in the general form achieved via Double Decision had broad, deep, physiologically generalized rejuvenative consequences. Those animal studies strongly indicate that the changes induced by training in this (and related) form(s) ARE the neurological basis of “cognitive reserve” — and given that interpretation, presumably show how doses of ‘cognitive reserve’ can be delivered to help any individual be stronger and safer, at any stage in their life (e.g., de Villers-Sidani et al., 2010).
Healthy brain, healthy body
Independent researchers using BrainHQ have been documenting clinical and cognitive improvements in what are nearly always interpreted as body-based ‘non-neurological’ conditions — heart failure, focal dystonia, breast cancer, and in autoimmune disease such as Multiple Sclerosis — to name a few. This line of work has been recently extended to childhood kidney disease is an interesting review by Javalkar and colleagues (Pediatric Nephrology, Feb 2017), who recommend that therapeutical brain training be used to help patients overcome disease-associated cognitive deficits. Kidney-disease induced impairments in neurocognitive function are a key aspect of these maladies. If untreated, performance losses accelerate, and often grow to be devastating over time. Based on available data of brain training in children, the authors recommend that BrainHQ and Captain’s Log be deployed to help children without attentional deficits, and recommend CogMed, Cognitive Remediation Program (CRP), Amsterdam Memory and Attention Training for Children (AMAT-C), and Captain’s Log for children with ADHD-related deficits. A computerized, low-cost and easily-accessible brain training therapeutic that does not require a visit to a doctor or pharmacy is a useful class of tool to apply to help a young population with chronic disease who should have nothing much more burdensome to do than schoolwork.
This study is among a rapidly growing number that remind us, once again, that the brain often plays an active role in the genesis and expression of ‘physical’ illness. A healthier organic brain achieved via training or lifestyle adjustments commonly impacts pathological processes via the brain’s direct control of physical and chemical functions, and its strong influences on regulating hormonal, autonomic, vascular, digestive, physical action control and other body process. At Posit, we are now routinely including non-brain indices of brain training impacts to further document these many brain-to-body impacts, including measures of disease relapse, time-to-remission, blood and hormone profiles, immune response, autonomic response powers, numbers of hospitalizations, mortality, medical expenditures, and chemical analyses of blood and cerebrospinal fluids, and of skin and stool microbiomes. We have a great deal to learn about the brain’s important contributions to disease genesis and expression. Help us accelerate the process of answering that long list of brain-to-body questions that can impact so many issues of medical health. Brain training has a very big role to play, in this extended medical domain.
Meta-analysis of brain training in healthy aging and MCI
In a recent meta-analysis on the effectiveness of brain training in 60+ yo older healthy or mildly impaired individuals, Drs. Catherine Mewborn, Cutter Lindbergh, and Stephen Miller (Neuropsychol Rev, 2017) report that training results in significant cognitive improvement relative to placebo (Hedges g = .298; p < .001) with significant near (g = .438; p < .001) and far transfer effects (g = .145; p < .001). Ninety-seven studies were included in this meta-analysis, all of which were controlled and randomized, with all including both a cognitive intervention and a comparison active control group. All studies used broadly accepted, standardized assays of cognitive functioning and assessment immediately post-intervention. Significant moderators of effects included intervention domain (working memory training vs other), degree of transfer (near vs far), and selection bias (unclear methodological risk vs low methodological risk). The first value in each parenthetical yielded larger effect sizes over the second.
Just as combining the vehicle inspection results of all cars across all automobile manufacturers will give you an imprecise estimate of quality, indiscriminate pooling across all brain training programs necessarily dilutes overall achievable effect sizes. Brain training programs have varying degrees of potency. Training exercises across programs are constructed with respect to the company’s (or researcher’s) theoretical framework, which may deviate from the most accurate implementation of the core principles that drive neuroplastic change. Furthermore, most brain training programs on the market have no empirical support (Shah et al., 2017). The work by Mewborn et al (2017) is a solid beginning for addressing the resulting ongoing controversies in our field. In the future we’d like to see all meta-analyses focus on appropriately vetted programs, with the specific programs assigned as moderators. We predict that such an analysis would account for the significant heterogeneity in observed effects sizes that survived Mewborn et al (2017) post-moderator analysis. A more complete consideration of differences in program design should result, could result, in a rapid further clarification of the key relationships between program designs and efficacies.
TRIALS UNDERWAY
I’ve rather arbitrarily chosen to introduce you to a few of the several hundred randomly-assigned controlled trials deploying computer-delivered brain training programs that we are aware of that are now underway. Let me know about yourown special projects so that we can tell other professionals in our research family about your work in future newsletters.
A multimodal lifestyle intervention to improve an incurable disease
If you ask someone over the age of 60 about their greatest health concern is, most identify losing their memories, losing their independence, and losing the essence of what makes them them at or near the top of their list. Because the predominant medical opinion says there’s nothing we can do to prevent decline, dementia has become synonymous with doom. While there is no established ‘cure’ at this time, Dr. Dale Bredesen’s has published several studies reporting a reversal of cognitive decline resulting from the optimization of nutrition, sleep, stress, physical exercise and brain training in patients with MCI or dementia (e.g., Bredesen, 2014; Bredesen et al., 2016). Importantly, his studies have documented strong improvements in cognitive abilities in MCI and Alzheimers cohorts.
Bredesen’s integrated-health protocol is now being implemented in a longitudinal RCT (Four Winds Study) conducted with several hundred patients diagnosed with MCI or early dementia. These projects involve a collaboration between MPI Cognition and Drs. Leroy Hood and Nathan Price from the Institute for Systems Biology (ISB). BrainHQ is the brain training component of the intervention. Participants will intensively train on BrainHQ while also actively taking steps to optimize sleep, nutrition, stress and physical exercise.
Another multimodal longitudinal multisite RCT is called the Coaching for Cognition in Alzheimer’s (COCOA trial). It will randomize 200 patients will MCI or early dementia into a lifestyle intervention inspired by the Bredesen protocol that includes BrainHQ, diet, and exercise, with outcomes related to those in an active control group. Participants will intensively train on BrainHQ 30 minutes a day, 3-7 times per week for 2 years. This project involves a collaboration between Institute for Systems Biology (ISB), Hoag Neurosciences Institute, Arivale, and the Shankle Clinic led by Drs. Jared Roach, Rod Shankle, Deborah Fridman, Junko Hara, and Jennifer Lovejoy. Recruitment of participants will be through eligible patients at either the Shankle Clinic or the Hoag Medical Group. We are excited to learn more about these trials as they unfold and even more excited to approach a new era in which a diagnosis of dementia may – for the first time in history – not be the beginning of the end.
Exercising brain and body in MCI
Congratulations are in order for Dr. Vankee Lin from the University of Rochester, who has received yet another R01 to study the effects of a 6-month BrainHQ and aerobic exercise intervention in older adults with mild cognitive impairment. In this multisite RCT, called AeroCogT, participants will be randomized to cycling only, BrainHQ speed of processing training, both cycling and BrainHQ, or to a control of stretching and leisure mental stimulation. The study is designed to assess the efficacy and synergistic interactions of this brain and body intervention on cognition, fitness, and rate of conversion to Alzheimer’s Disease (AD). Underlying mechanisms of the intervention will be assessed through MRI. Measurements of cognition and fitness will be taken at baseline, 3 months, post-test, and at 12 and 18 month follow-up benchmarks with MRI measurements taken at baseline, post-test, and at both benchmarks. Congratulations, Vankee, on this wonderful and much-needed project!
BrainHQ in Alcohol Use Disorders and PTSD
Approximately one-third of individuals in treatment for Alcohol Use Disorder (AUD) also have Post Traumatic Stress Disorder (PTSD). The co-occurrence of PTSD with AUD is marked by poorer occupational, psychosocial, and health outcomes, lower quality of life, increased interpersonal problems, higher rates of hospitalization, and greater risks of suicide and mortality. Dr. Kyu Lee from Posit Science in collaboration with the Palo Alto VA Health Care System has received a Phase I award from NIH NIAAA to develop and evaluate the feasibility of mobile BrainHQ cognitive control training program for the treatment of those who are suffering from co-morbid AUD and PTSD. The program goals are three-fold. It will broadly assess cognitive and functional abilities in this population, train deficient cognitive abilities with the specific goal of strengthening systems that mediate core deficits in AUD and PTSD, and continuously inform clinicians about patient adherence and treatment progress via a Cloud-based patient-to-clinician portal. Given the ease of access of mobile-based training and online monitoring of AUD-PTSD status, this project should result in the development of a new, powerful tool to provide effective adjunctive therapy that results in far greater treatment outcome among individuals with co-occurring AUD and PTSD.
Unlike previous AUD interventions that may overlook the role of co-occurring psychopathology, those that target “trans-disease” cognitive deficits for remediation represent an innovative and potentially high-yield approach for optimizing recovery outcomes. With the successful completion of Phase I, Dr. Lee and colleagues will have a commercial mobile application for remediation in this population.
CURRENT PERSPECTIVES
What if we managed brain health as we now manage general (e.g., cardiovascular) health, following strategies that could more reliably sustain this most important of organs far closer to the end of an even longer natural life?
At present, brain health evaluation is not a standard component of routine medical check-ups, and clinicians stand little chance of detecting early warning signs of medically serious cognitive impairments. By contrast, simple but effective early detection measures have been in place to identify risk of cardiovascular disease for many decades (via the measurement of blood pressure, cholesterol, and weight), and are estimated to have prevented millions of premature deaths. Coupling early identification with early intervention is the best strategy for reducing the cumulative effects of damage before the damage becomes too extensive, too costly, or too precarious to treat. We will also be better equipped to track the developmental trajectories of these diseases throughout the pre-clinical, manifestation, and maturation stages.
We envisage a new medical era in which the brain health of every older citizen is regularly assessed. The toolbox necessary to achieve this transformative goal includes improvements in diagnosis and treatments. A new set of diagnostic tools will include 1) genetic definition of the inherent biological strengths and weaknesses of every older citizen to guide us in defining patient risks and assets; 2) neuroscience-guided use of special biomarkers designed to index the status of key neurological assets; 3) computerized assessments applied continuously to rapidly evaluate the functional status of key brain systems; and 4) medical-records and health-history ‘mining’ to further define factors in each individual (developmental disorders, depression, anxiety disorders, traumatic brain injuries, brain infections, poisons, addictions, medications, neurological disease, diabetes – among several hundred others) that contribute to risk for earlier-onset disease. Treatment tools will include 1) brain-training programs applied in a form that has been shown to restore key aspects of brain health and delay the onset of dementia; 2) customized programs designed to delay the onset of neurodegenerative disorders; 3) customized chemical therapeutics; and 4) a health monitoring app that provides ongoing indices of brain health status and that links all individuals to the medical professionals responsible for their care.
A powerful example of how new tools will change the landscape of clinical research and medical practice will be the use of smartphone apps for documenting cognitive decline. These apps hold the potential to capture many neurophysiological changes during the course of aging and on the path to dementia that begin many years before a mild cognitive impairment or dementia diagnosis. Much of this dementia may in fact be avoidable – a huge cost saving to health care and, especially, a boon for quality of life for many people. Importantly, the same computerized assessment tools provide a simple basis for broadly determining the effectiveness of treatments designed to rejuvenate the cognitively challenged brain. Using modern technological approaches, studies of rejuvenation can be conducted on an unprecedented scale, with an evaluation of lifestyle keys and medical advances rapidly generated by applying large-trial/big-data analytic approaches.
Initiating trials that can result in the rapid fulfillment of that promise, using affordable, scalable strategies that are already largely in hand, would transform society and the world. If together with others we achieve this overarching goal, we will not only transform the quality of the final decades of the average citizen’s life, but will also impact their entire lifespan. Particular benefits from diagnosing and initiating current and future treatments for cognitive decline will allow aging individuals work longer, conserve finances, live happier and less worrisome lives; and be much more likely to end their natural lives compos mentis. As cognitive health screening becomes a mainstay of routine medicine, we can anticipate large-scale health benefits and enormous costs savings for American (and world) citizens.
We must bring the fruits of the past four decades of neurological and biological research to bear – by creating a new epoch in medicine in which brain health is managed to assure healthier organ status to far nearer the ends of longer and more vibrant and independent lives. In this new brain-health therapeutic environment, we will be able to intervene with guidance personalized to diagnoses derived from both cognitive and molecular biomarkers. Risks of onsets of psychiatric and neurological illness will be more reliably detected, treatments applied in prodromal individuals will more often result in disease prevention, and brain health management can minimize a continuance or recurrence of neurological struggles.
A shared publication database
The scientific literature in our field is scattered across many journals. We try to keep up with it, and am committed to making our efforts public. We ask you to help us keep up with this fast-moving feast! You can see our shared database of published randomized controlled trials in brain training online. It’s worth taking a look, as you might find something you weren’t aware of before that can be helpful for you. As always, please email us any papers that you know about that you find to be missing from this compendium.