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Aging, Brain Plasticity, and Integrative Preventive Medicine 

Aging, Brain Plasticity, and Integrative Preventive Medicine
Chapter:
Aging, Brain Plasticity, and Integrative Preventive Medicine
Author(s):

Michael M. Merzenich

DOI:
10.1093/med/9780190241254.003.0016
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date: 29 November 2020

A large body of evidence has been generated to describe, in elaborate detail, the physical and functional decline of the brain as we age beyond the typical human peak performance epoch in the 3rd–4th decades of life.1,2,3 The predominant medical view is that the primary source of physical and functional deterioration in the brain derives from physical senescence. Those processes often culminate in a catastrophic end-stage expressed by emergent, progressive neuropathology (Alzheimer’s, Parkinson’s, etc.) associated with immune response and brain/vascular deterioration, and expressed by rapid physical dis-elaboration, demyelination, degeneration, and apoptosis. Enormous capital and scientific investment has been predicated on this view of age-related brain health, with a strong treatment focus directed toward chemically or electrically manipulating catastrophic end-stage pathologies.

Neuroscience studies now strongly support a compelling alternative perspective.4,5 By that view, the physical and functional changes described as brain aging arise, to a large extent, as a product of progressive active “negative” neuroplasticity. Those natural negative-change processes arise as a product of brain-use histories that, by their nature, destructively impact brain health—with ultimate pathological aging an expected end-stage of that long, degrading negative-plasticity progression. We also now know that there is a long list of medical vicissitudes that accelerate this negative brain plasticity, shortening the progression to dementia or to other neuropathological end-states. With little understanding of the forms of “brain exercise” required to actually sustain brain health, and with a limited understanding of how medical vicissitudes that plague our older-age populations contribute to accelerated decline, average modern citizens—and the medical professionals who care for them—understandably do a relatively poor job of sustaining the physical and functional integrity of this most important of human organs.

Importantly, while age-related deterioration in the background of life is, of course, an inexorable downhill path, lifestyle-driven physical and functional decline is not. Neuroplasticity science has shown that the negative neuroplasticity–driven changes that are a main source of age-related neurological limitations are, by their nature, reversible.4,5,6,7,8,9 By that alternative view, the focus of medicine in older adults should be directed far more strongly toward strengthening, managing, and sustaining organic brain health—as opposed to a current strong medical focus on treating substantially irreversible catastrophic end-stage pathology. We envision a transition in neurological health practices in aging akin to the development of modern approaches for monitoring and sustaining cardiovascular health. In that domain, physicians now almost universally apply simple, inexpensive, objective, and reliable indices of general cardiovascular health (measurements of blood pressure and pulse rates; blood oxygenation; blood chemistry including cholesterol titers; EKGs) that provide a primary basis for cardiovascular and cardiorespiratory health management. With ongoing monitoring, and with these elementary diagnostic tools backed up by a hierarchy of more sophisticated assessment strategies, the clinician can effectively prescribe first lifestyle advice then pharmaceutical medicines, and then intervene with surgical procedures to manage and sustain health—all designed to prevent or at least delay cardiovascular catastrophe.

We now have an increasingly clear understanding of how to define risks of progression to senility and end-stage neurodegenerative illness—and measure the risks of onset of many other emergent psychiatric and neurological clinical indications—to similarly inform positive brain-health management strategies, using equivalently simple, reliable, and inexpensive primary assessment strategies backed up by a hierarchy of more-elaborate physical and functional assessment tools. Just as importantly, we have an increasingly clear understanding of how we can restore and sustain organ health, both in the “normally aging” population and in an increasing number of other clinical indications now shown to accelerate the advance to dementia and other later-life catastrophes. Over the next few years, clinicians responsible for brain health management can be expected to widely exploit these new, rapidly emerging diagnostic and treatment approaches.

Our goal here is to review aging and the brain from this important, alternative, still-underappreciated scientific and medical perspective. After a brief description of the history of brain plasticity–related neuroscience, change processes that shape our brains in ways that ultimately distinguish the typical struggling older versus peak-performing younger and more vibrantly functioning brain are described. We then consider how and why processes that contribute to our personal growth at a younger age are commonly (but not always) thrown into reverse at an older age, on the path to cognitive loss, negative physical brain change, infirmity, and ultimately, neuropathological catastrophe. We review the development of new brain science–based tools that appear to throw the “plasticity switch” for brain health back in a corrective and strengthening direction, where change processes again support the growth and the more reliable maintenance of physical and functional brain health. Finally, we summarize how this translational science shall almost certainly evolve to enable a new, neuroscience-directed medical era of brain health management for our older-age populations.

A Brief History of Brain Plasticity-Related Neuroscience

Over an initial long epoch from the time of the historical origins of brain science and neurological medicine, investigators believed that the development of human ability must be a product of physical (“plastic”) changes in the brain. In the late 19th century, William James described those changes as being plausibly akin to the creation of a water channel by the continuous passage of water across a dry landscape.10 With repetition, the channel deepens, as the passage of water becomes more reliable, more predictable, more certain. Many studies in the late 19th and early 20th century appeared to support the view that the brain was continuously physically “plastic”—remodeling itself by use—as abilities were refined or new skills were developed across an animal or human lifespan.11

Beginning in the middle of the 20th century, this perspective was challenged by neuroscientists and neurologists who directly studied plasticity across the course of postnatal development using more advanced experimental methods. Those studies were interpreted as showing that neuronal wiring and the functional elements (for example, specific neuron and glial cell populations) of the cerebral cortex were modifiable on a substantial scale in the first weeks to months of mammalian postnatal life—then “froze”—became “hard-wired” into an “adult” form—at the end of an early-life “critical period.”12,13,14

This broad conclusion, arising from the mainstream of experimental neurology and neuroscience, had important negative and enduring societal and medical consequences. It led to a failure to understand, in medical practice, that specific forms of brain engagement were a primary determinant of the status of brain health and general physical health. Because almost every brain is continuously plastic, a remarkable capacity for brain change provides a basis for neurological improvement and possible recovery in almost every brain-struggling individual. Medical neurology still predominantly focuses on manipulating the dysfunctional or distorted brain by applying counterbalancing chemical or electrical or surgical interventions, underplaying the remarkable capacity that every brain has to change itself in an improving—and often, completely restorative—direction.

This misunderstanding contributed to the false presumption that the basis of success in school and in life was fundamentally genetically determined—that the abilities of the child determined at the time they entered the schoolhouse door, given their immutable brain hardware, deterministically defined their potential for achievement and success. It led to the still widely held societal belief that as custodians of our health and welfare, while physical exercise clearly matters for us, changes in our neurological abilities are beyond any very significant powers of self-repair.

Almost nothing could be further from the truth.

Importantly, even across the period of the 1950s through the 1980s, when this perspective of the brain as being “hard-wired” in early childhood began to dominate medical and social perspectives, investigators on the periphery of the medical neuroscience mainstream were actively demonstrating that the adult brain was very plastic. That counterargument initially came from physiological psychologists who were sharply focused on documenting the changes accounting for Pavlovian (“classical”) behavioral conditioning. They repeatedly showed that pairing a stimulus with a following reward or punishment à la Pavlov and his contemporaries resulted in magnified representations of (1) that stimulus, (2) that reward or punishment, and (3) the “conditioned” responses that manifested the expectation of reward or punishment, demonstrating the establishment of neurological association.15,16,17,18 Importantly, investigators showed that these broadly expressed neurological changes could be “reversed” by deconditioning an animal (“extinguishing” the association between the stimulus and the reward/punishment), achieved by repeatedly delivering formerly “conditioned” stimuli without associated rewards or punishments. Plasticity in adult brains, by its nature and at least in this elementary model, appeared to be strongly in play, and by its nature, reversible.

Beginning in the 1980s, we and others began to conduct studies that helped bring these findings into the medical neuroscience mainstream. Specifically, we showed that the brain undergoes large-scale remodeling following the manipulation of inputs associated with peripheral injury and loss,19,20,21,22,23 studies that were rapidly extended to the human model. We documented large-scale changes achieved via operant conditioning (the predominant behavioral basis of human skill acquisition) that almost certainly account for our improvements and refinements of ability, and for the acquisition of any new skill.24,25,26,27,28,29 We showed that the fundamental processing unit of the mammalian cerebral cortex (the cortical minicolumn) was “plastic,” subject to large-scale positive or negative revision via specific forms of training, at any age.25,29,30 We and others showed that plasticity followed (to the level of first approximation) a “Hebbian rule” (coincident input–dependent synaptic strengthening), which defined how changes related to task structures and demands, and with an understanding of the time and space constants involved, revealed to us how we could drive specific bidirectional changes in behavior or in brain machinery operations, at will.22,23,31,32,33,34 We repeatedly showed that both temporal and spatial (or sound-frequency) aspects of stimulus-response selectivity and the refined neurological representations of simple and complex incoming information were plastic.31,32,35,36 Large-scale remodeling of brain systems was easily achieved in adult primates, by engaging them in simple, progressive natural behaviors. We showed that it was possible to “grow” sequenced behaviors and the expectation or predictions that supported complex “mental” and physical actions, via appropriate forms of rule-based training.37,38,39 We showed that we could drive large-scale plasticity that accounted for evident recovery of function in primate models of brain injury and stroke.40,41 And we showed that every tested aspect of change appeared to be “reversible.”42,43,44,45,46,47 By progressive training, changes could be easily driven in a positive (improving) or negative (degrading) direction—paralleled by corresponding behavioral improvements or losses.

Thus, for example, training an adult monkey on one form of a behavioral task led to the predicted elaboration, refinement, and expansion of the cortical machinery supporting (for example) more facile hand use in stimulus identification or manually dexterous digital manipulation.48,49 Training an adult monkey in a second form of the same task slowly diselaborated, degraded, and reduced the hand representation, dramatically shrinking the cortical territory dedicated to hand “representation” in the cerebral cortex, and ultimately catastrophically destroying the functional control of the hand.29,50-52

The demonstration that a medical condition like a focal hand dystonia could be induced by training—or more generally, that the cortical machinery that supports refined behaviors are, by their nature, easily driven in either a positive or negative direction—bore the very important implications that neurological and psychiatric disease progressions are (1) actually substantially manifesting natural, negative-plasticity progressions, and (2) are potentially subject to plastic reversal.3,4,7,48

On a Path to Developing Computerized Training Strategies to Drive Positive Changes in Neurological Ability

Those observations led us to direct our research efforts toward “harnessing the genie” of postcritical period (“adult”) plasticity for the potential benefit of struggling human child and adult populations. In the initial phase of these efforts, we and others investigated the neurological mechanisms that control plastic change, because we knew that optimizing learning-enabling processes would be important for achieving efficient corrective brain remodeling in medical therapeutics. The key plasticity-enabling roles of neuromodulatory neurotransmitters and the operational rules that govern the machinery that controls their release and their cortical and subcortical actions have been richly elucidated by thousands of research studies over the subsequent several decades. We now understand the plasticity-enabling roles of acetylcholine, noradrenaline, serotonin, dopamine, and other modulatory neurotransmitters.53,54,55,56,57,58,59,60,61 All have been shown to be expressed by machinery that is itself plastic; and the expression of these neurotransmitters in a learning context has been elucidated in ways that have helped us optimize training effectiveness, by appropriately controlling the timed activation and release of these crucial agents of change. These studies also helped explain one major source of confusion about plasticity in critical-period versus older brains. Scientists studying synaptic plasticity in the older brain had not fully appreciated the fact that the brain positively evolves its control of brain change across the early life of the brain. In the post-critical-period brain, changes are modulated as a function of both behavioral state and outcome, by a brain that can now “keep in mind” (hold, in “working memory”) and evaluate whether or not it has achieved a training goal.3,62 In the very young brain, these powerful plasticity-controlling processes are not yet functionally established, and mere exposure to a stimulus is sufficient for plastically modifying brain connections. By contrast, nonattended or behaviorally meaningless stimuli do not drive enduring, large-scale plastic change in the older brain because the older brain controls its remodeling, limiting change, in a sense, to those experiential or learning moments that it “judges to be good for it.”4,62

This “purposeful” plasticity underlying the refinement of brain machinery and acquired skills and abilities, in place from early childhood forward to the end of life, is a more (not less) powerful and sophisticated mode of brain remodeling than is the “anything goes,” substantially unregulated competitive plastic change processes in play in fetal and infant life.

The Complex Nature of Reversible Brain Plasticity

Plasticity is usually described in positive connection-remodeling terms. Indeed, on the most elementary level, selective synaptogenesis and synaptic strengthening for inputs that provide the basis for skill acquisition and refinement are core achievements of positive plastic remodeling, and the processes underlying these positive connection-change processes have been exhaustively studied.63,64,65,66 At the same time, in brain change processes, nonselected (task-irrelevant) synapses weaken or turn over, as task-relevant synapses strengthen or emerge—and positive and negative changes in synaptic connection strengths represent just one of many aspects of experience-induced remodeling that contribute to evolving brain function and organic brain health.

Beginning about a decade ago, we asked, What large-scale physical, chemical, and functional differences distinguish high-performing from struggling brains? 6,7,9 Studies were conducted in the brains of animals in the prime of life, compared with the brains of animals struggling with aging-related deficits near the end of life. In those rat model experiments and in follow-on studies, we (and others) ultimately documented the status of more than 20 major physical, chemical, and functional aspects of brain function and organic brain health. Those indices include (1) receptive field sizes and complex-feature extraction; (2) the orderliness of cortical “maps” (representational topographies); (3) stimulus-evoked excitatory- and inhibitory-response magnitudes; (4) coordination of local neuronal responses underlying controlled, reliable cortical system functioning; (5) excitatory and inhibitory response dynamics; (6) processing speed (cortical “sampling rate”); (7) responses to modulated stimuli; (8) the fidelity and reliability of representation of temporal structure (stimulus durations, intervals, sequences); (9) receptors and receptor subunits controlling specific excitatory and inhibitory responses; (10) intracortical and subcortical tract myelination; (11) numbers and morphologies of parvalbumin inhibitory interneurons; (12) elaboration of dendritic processes of excitatory pyramidal cells;68 (13) numbers and morphologies of somatostatin interneurons;69 (14); expression of a brain-derived neurotrophin (BDNF); (15) background neuronal process noise (spontaneous activity; “neuronal chatter”); (16) response adaptation strength, and dynamics; (17) responses to “distractors” in an attended behavioral state; (18) integrity and levels of expression of the neuromodulators of plasticity (acetylcholine; norepinephrine; serotonin; dopamine); and (19) neurotransmitter transporter expression; (20) among other measures.

All of these indices of brain health were shown to substantially differ in aged infirm versus young, vigorous animals. Every difference substantially disadvantaged the older adult.

In those older animals, we asked, How many of these now-negative indices of physical, functional, and chemical brain function and health are reversible? And how complex would training engagement have to be, with what dosing, to drive changes sharply back in a rejuvenating direction? The answer: All of them were reversible. In this animal (rat) model, every physical, chemical, and functional difference that differentiated a struggling older brain from a healthy young adult brain was reversed to a status that approached or equaled that of “young, healthy-adult normalcy” by applying only two simple, specific forms of progressive computer-controlled training over a training epoch of about 1 month (about 25 training hours).6,7,9

It might be noted that the intensive, progressive, computer-controlled exercises applied in these rat studies were not conventional “cognitive training tasks.” One focused on progressively improving the accuracy of distinguishing elementary incoming signals from increasingly confusable background stimuli, at speed. The second required the animal to first identify (by its behavioral responding) an elementary target stimulus—then hold that stimulus in working memory for long continuously attended epochs, correctly signaling its random recurrence when it was presented in the presence of progressively more confusable background distractors. For us, these training tasks are “brain training” vehicles—as compared with higher-level performance task training usually applied in “cognitive training” programs.

Accelerating Aging

The fundamental reversibility of changes generated by natural plasticity processes demonstrated by these studies was further illustrated by an additional experiment in which brain aging was accelerated, simply by maintaining vigorous young adult rats in high-acoustic-noise environments. In that setting, levels of background spontaneous activity—meaningless background “chatter” in the auditory brain—were substantially elevated. Surprisingly rapid negative plastic changes were induced, and within a few weeks in these animals, the physical and functional status of their brains again matched, for all recorded indices, those documented in physically deteriorated near-end-of-life animals.67 This is one of several indications that brain noise—meaningless neuronal response chatter—or, from another perspective, the degradation of local response coordination resulting from a continuous bombardment of a brain system by unstructured background activity—has a strong direct or indirect controlling impact on the remarkable changes in gene expression that must underlie this coordinated, multifaceted, reversible plasticity. Initiate the right forms of training in the old rat, and hundreds of genes must change their expression together, on the turn of a dime, with all processes changing in a coordinated way to “shift” from the negative (“clastic”) progression that characterizes aging, to a positive rejuvenating (“blastic”) direction. Bombard a brain system at the peak of a performance growth (blastic) life phase—in this case in healthy, vigorous prime-of-life adulthood—with continuous ongoing meaningless noise, and all of those same genes change their expressions, on the turn of a dime, to progress in the opposite clastic direction, again in a remarkably coordinated manner.

These broad, coordinated, bidirectional experience-driven changes in elemental neurology related to brain function and its organic health are at the center of any consideration of brain health growth or maintenance—or decline—in human populations.

Physical Brain Changes Recorded in Aging Humans Are Substantially a Product of “Negative” Brain Plasticity

It should be noted that all of the changes recorded above are expressed, of course, by physical brain alterations.3,4-9 As the brain elaborates its dendrites and axonal arbors and astrocytic processes through intensive engagement, cortical volumes grow. As the brain increases local response coordination and sharpens all of the fast excitatory and inhibitory processes in cortical networks, it grows myelin and positively enables physically more powerful local and system connectivities. Progressive changes in speed of processing and temporal precision necessarily derive from chemical changes in receptors and from physical changes in synapses and networks, neuropil elaboration, and in physical changes that underlie the powers of action of specific excitatory and inhibitory neuron—and astrocyte—populations. Changes in response coordination arising from this physical remodeling directly impact feedforward coincidence-dependent plasticity, thereby generating a cascade of functional and physical changes at every “higher” brain system level.

Coordinated changes in the “negative” direction are expressed as slowly, progressively degrading physical changes that culminate in the physically shrunken and disconnected brain of most near-end-of-life individuals. In this clastic progression, the brain weakens its connections, down-regulates metabolic processes in progressively disengaged forebrain machinery, slowly diselaborates dendritic and axonal arbors, progressively simplifies and shrinks its neuropil, degrades the integrity of the blood-brain barrier and the reactive hyperemia and immune response powers supported by deteriorating astrocyte populations, slowly loses its inhibitory powers, necessarily changes its chemistry to support now-sluggish operations, down-regulates neurotrophins, and slowly disconnects and down-regulates the neuromodulatory machinery that controls plasticity itself—among other documented natural physical neuroclastic changes. The folly of believing that all these changes could be expected to be reversed at a late stage of what is usually a decades-long clastic progression by any singular pharmaceutical redistortion, has been repeatedly borne out by the numerous failed attempts to overcome this grand panoply of negative changes via any simple chemical agency. True restoration of function requires that the plasticity “switch” be thrown back in a blastic direction. From a neuroplasticity perspective, even after that switch is thrown, necessary restorative changes can only be achieved through intensive, positive, progressive, natural brain machinery remodeling.

Onset of Alzheimer’s, Parkinson’s, and Other Neurodegenerative Disorders as an Expected Catastrophic End-Stage of Progressive Neurological Deterioration

As the brain progressively disassembles itself via negative plasticity, the immune-response machinery in brain tissues is challenged both to clear cellular debris and to rise to protect the brain from blood-borne agents that can “invade” it via an increasingly “leaky” blood-brain barrier.71,72,73 In parallel, immunoreactive glial cells and the brain machinery that modulates their actions are functionally degraded because their integrity is also almost certainly a product of coordinated negative brain plasticity. In the face of these complex changes, experimental neurologists have posited many theories, expressed via several hundred specific posited variations, about the causes of neuropathological degeneration and collapse defined as Alzheimer’s disease. Frequently described causes, not considered in any detail here, include (1) accelerated biological aging; (2) progressive brain system disconnection; (3) cholinergic and other modulation system failures; (4) weakened expression of trophic factors supporting processes of regeneration and renewal; (5) a leaky blood-brain barrier enabling access for infectious and other agents from blood or cerebrospinal fluid compartments; (6) a deterioration in reactive hyperemia supporting brain nutrition and blood-based immune responses; (7) immune system dysfunction for processes intrinsic for brain tissues; (8) environmental factors (head injury, poisons, and many others); (9) genetic factors, for example, resulting in amyloid precursor protein formation, in presenilin, and/or in allelic variations in apolipoprotein E; (10) oxidative metabolism (mitochrondrial) dysfunction; (11) and others.74,75

From a neuroplasticity perspective, in a negative plasticity–driven scenario, all of these factors are expected to be progressively clastically changing, because declining individuals’ environmentally driven experiential activities do not effectively support the positive maintenance of their brain health. As a result, brain systems are progressively disconnecting, acetylcholine expression and the metabolic status of neurons in the basal nucleus of Meynert (and for other modulatory neurotransmitters, in the dorsal raphe nucleus, the locus coeruleus, the ventral tegmental area, and substantia nigra) are down-regulated, the blood-brain barrier is leaky, reactive hyperemia is compromised, and intrinsic immune response actions are degraded because of both negative astrocytic and neuromodulatory changes. Environmental factors add to risks of onset specifically because they add to the brain noise (“chatter”) that accelerates negative change. Genetic weaknesses specifically accelerate amyloid poisoning, with resulting differential inhibitory cell apoptosis and disconnection again directly amplifying neuronal “chatter” (reducing the capacity for sustaining local response-coordination powers). In progressively degenerating brain systems, the correlated patterns of action are most difficult to sustain at “highest” system levels. Their deterioration presages later brain-wide disaster.

It is important to understand that in the months, years, or decades preceding this emergent catastrophe, at least most of these negative changes were reversible. The negative expressions and neurological change consequences in what is usually a long, slow progression of all of these “causes” can be positively altered by coordinated plastic remodeling driven by simple, intensive forms of brain engagement. As for genetics, because few if any inherited weaknesses confer a certain progression to dementia onset,76 appropriate intensive training driving blastic changes might be expected to at least delay the onset of emergent neuropathology

Living a Life to the Disadvantage of Your Brain

Why does “chatter” grow in the brain as you grow older? The elemental processing of information by the brain is an achievement in the extraction of details against environmental and intrinsic brain activities, from the brain’s representation of information delivered from our senses and upstream input sources within cortical systems. We progressively challenge our brain to extract more refined, higher-speed, and more complexly received information in the early phase of our lives, as we slowly advance the machinery that supports our growing neurobehavioral capabilities. “Adult” plasticity contributing to extraction of details with high accuracy at speed is controlled by our capacity for “selective attention” (a neurological process that is often confusedly called “working memory” or “prediction” by cognitive psychologists). As we process information in progressively more complicated ways in our operations in guided behavior and thought, we slowly refine and strengthen this higher-level plasticity-controlling machinery. This progressive refinement is marked by the “completion” of the myelination of cortico-cortical connections to “highest” brain levels at circa age 20.77,78 Why do the performance characteristics of our neurological processing machinery then usually lead to that slow, progressive decline from the broad neuroblastic peak of young adulthood to the infirmities of an older age?

We have argued that our younger lives are a skill-learning and abilities-refinement epoch, which strongly supports continuous positive plasticity. In the middle years of life, we begin to rely more heavily on well-learned abilities acquired earlier, operating over progressively more hours in the day deploying mastered (automatized) behaviors supported by nondeclarative (habit-supporting) memories. As we operate with greater automaticity and on greater schedules of mental abstraction, we pay progressively less attention to the details of our refined neurological operations—for example, to what we hear or feel or see. With that neglect, the encoding of those details—the platform abilities that support all higher-order actions—slowly, inexorably diselaborate. We hypothesize that the basic change in course from a blastic to a clastic phase arises from a slow inexorable growth of process noise (or, expressed in an alternative way, from coherent-response discoordination) in the middle decades of life. Neurons now respond in a progressively less coordinated way; less salient cortical signaling is more prone to error. As error rates grow, negative plastic changes that assure sustained functional control (“getting the answer right”) slowly, broadly, negatively impact brain health status.

We have likened these changes to those that occur in a professional musician who has acquired her elaborate, specialized instrumental performance skills through intensive practice.4 If such an individual attenuates the practicing required to sustain their high-level skills, noise (manifested by imprecision in performance control) slowly grows in their brain and their performance ability necessarily declines—ultimately to a level in which they can no long perform at a professional level. At the same time, any new intense extended practice epoch in just the right forms in such a professional can bring their refined abilities (neuroblastically) all the way back to a high performance level—because the underlying governing plasticity in their (in every) brain is, by its nature, reversible.

Other lifestyle changes that often apply for older lives are especially important to understand. For example, many older people substantially voluntarily withdraw from new-skill learning or experiential challenges. In their stereotypical behavioral realm, little positive plastic change occurs and the unexercised machinery that controls sustained attention and plasticity itself slowly down-regulates. Close attention in a task environment in which an attending brain recognizes performance advances is a prerequisite for positive, health-sustaining plastic change.

A second neurological aspect of “just taking it easy” in a stereotypic life involves the broader engagement on tasks that are errorless. In animal models, errorless tasks have no impact on brain health status.28,79,80 On the other hand, tasks that continually challenge performance ability while assuring a reasonable level of (but never certain) success strongly enable positive brain-healthy change.

Note that maintaining high functionality in the machinery that controls brain change is a key. This modulatory control machinery is up-regulated in a life that is marked by continuous new skill learning and by a rich schedule of positive novel experiences. Predominantly applied skills that were mastered and reduced to automaticity decades before (e.g., reading) have value to the individual in their ongoing personal self-development, but only limited value for the maintenance of brain health. To sustain its physical and functional integrity, the brain requires a life marked by continuous skill learning extending down to the most elemental levels of signal reception and manipulation.

Unfortunately, from the perspective of our plastic brains, modern environments are designed to minimize the necessity of our operating with high input resolution and speed, especially in elementary (platform) skill domains. The average citizen spends the majority of their waking hours in a sitting posture, grossly limiting conditions for natural input refinement, and grossly underexercising the translation of neurological operations into action. Many hours are spent as relatively passive receivers of inputs delivered on screens and audio speakers, again minimizing the translation of neurological operations into actions beyond emotional responding. Our world is paved, and movement through it is largely automatized. In a natural world, every footfall is uncertain. The modern human is thereby deprived of thousands of moments of adjustments in fast vision and in posture that were everyday brain exercise in our human ancestors. In our modern world, we increasingly more often look up answers rather than probe our memories or exercise our reasoning powers to find them. We rely on machines in our navigation, curtailing our practice at closely attending to and recording landmarks mounted on a serial framework of time and place, so important for sustaining organic brain health. Modern humans operate on a higher level of self-directed abstraction, “buried” in their thoughts or in their narrow interactions with their hand-held devices.

All of these modern “advances” advantage our higher-order human operations. At the same time, when carried to excess, they separately and collectively make a substantial contribution to the growth of “chatter” in our neurological machinery.

In addition to lifestyle contributions, there is a very long list of other things that can happen in an adult life that add to brain “noise,” accelerating and increasing the risks of a passage to dementia. Brain infections, brain poisoning, antipsychotic and antidepressant drugs, a history of mental illness, numerous historic developmental impairments, historic or concurrent concussive and other traumatic brain injuries, brain bleeds, subdural hematomas, blood-brain barrier compromise associated with ICU delirium, heart failure, multiple sclerosis, diabetes, extended grief, auto-immune disease, loss of mobility, an extended period of high stress, dysregulated sleep, atherosclerosis, multiple sclerosis, and a long list of genetic disorders are just a few of more than a hundred epidemiologically documented examples. Importantly, all of these conditions plausibly result in increased noisiness in cortical processes in the brain that can be expected to result in (and have often been directly shown to result in) associated negative changes in what we view as indices of organic brain health status (for example, processing speed).4

Applying This Science to Improve Brain Health in Normal and Struggling Human Populations

We began practical studies for applying this science to help struggling brains by creating programs designed to restore more normal neurological functioning in children that struggled in school because of impairments in speech and language that usually led to reading failure.4,76,81 We’ve successfully helped several million children overcome these impairments, through intensive, progressive computerized training. While it is beyond our ability to consider these programs in detail here, that training has been shown to generalize in neurological impact to drive broad, corrective behavioral and neurological changes in the great majority of children who have used it.

With the benefits of this early experience in training child populations, we applied the same science to create the BrainHQ computer training platform82 to address neurological and psychiatric limitations and distortions in many clinical indications impacting mature individuals. In parallel, a growing number of other scientists have created “cognitive training” tools that have been widely applied in humans. For us, strengthening and sustaining the neurological status of normal older individuals ultimately at risk for dementia onset has been a primary objective. In this respect, our approach differs from that applied by at least most other providers of “cognitive training” tools because our primary goal is to rejuvenate or normalize the neurological assets that support organ function. This approach is predicated on the assumption that with appropriate more-elementary neurological strengthening and recovery of function, more complex behavioral abilities (the primary target of most “cognitive training” tools) and the capacity for new learning can be expected to be broadly positively advanced.

In application, these adaptive, progressive brain-training tools demonstrate that at least most of the rejuvenating changes documented in animal studies of reversible neuroplasticity must also apply for humans. We have engaged tens to hundreds of thousands of individuals on more than 30 elementary training tasks, documenting their performance gains for individuals of all ages. In humans as in rats, performance at every elementary ability rises to a peak across the second into the third decade of life, then systematically and progressively declines out to the end of life. After training, performance abilities in the 8th decade of life (for example) come close to matching—or can exceed—the ability recorded in untrained young peak-performing adults for every elementary neurological ability. These changes in signal resolution, speed of processing, identification and manipulation of rapidly successive inputs, phasic and sustained attention, divided attention, and others, require progressive, positive coordinated physical changes in their brain, akin if not identical to the coordinated physical changes recorded in our animal models. Collectively, those presumptive blastic changes manifest a substantial training-driven improvement of organic brain health.

Applying Computerized Brain Training to Strengthen Then Sustain Brain Health-Relevant Neurological Ability in Older-Aged Individuals

Studies of training designed to grow and sustain brain health conducted in animal and human models have evolved into computerized strategies for driving these changes with relatively high efficiency via a game-like software platform. Training exercises at BrainHQ.com are adaptive, adjusting in difficulty as a function of performance ability, and advancing progressively in difficulty as gains are achieved in training. By controlling task difficulty to assure general performance success while sustaining a continuously demanding task level, enduring improvements can be generated with relatively high efficiency. Tasks are organized in an “Angry Birds” format, in which a trainee is asked to progressively improve at an elemental skill or ability within several-minute-long training blocks, at a series of 20–80 progressively more difficult training levels. Most tasks are progressively speed challenged; as each new training “box” (level) is “unlocked,” judgments must be made about progressively briefer or more rapidly sequential stimulus events, and responding must be speeded. Note that (1) improvements in accurately identifying successive stimuli at speed engender positive changes in most of the dimensions of brain health described earlier for animal and human studies; (2) the progressive degradation in processing speed is a signature deficit in aging;83,84 and (3) processing speed is the largest single factor contributing to the variance in complex human performance ability—for example, to fluid intelligence.85,86

Tasks are also specifically designed to progressively up-regulate elementary processes controlling plasticity itself. With appropriate training, the slower learning rates and the greater number of “false positive responses” again long identified as a signature problem in aging can usually be restored to a substantially more youthful level.87 Importantly, recovery of the powers of modulatory control provide a basis for strengthening other elemental aspects of brain health: increased up-regulation of norepinephrine, serotonin, acetylcholine, somatostatin, dopamine, and other modulatory neurotransmitters contribute importantly (1) to recovering and sustaining the integrity of the blood-brain barrier, and facile reactive hyperemia; (2) to modulating the brain’s immune response; (3) to the regulation of sleep; (4) to baseline levels of brightness/arousal; and (5) to the regulation of mood.

Task achievements also progress in other dimensions that can only be accounted for by more refined neurological processing. One set of tasks is specifically designed to accelerate input sampling rates in listening and in vision, in the latter case by driving improvements in saccade (fast-eye-movement) rates in active visual exploration. One set is designed to expand an individual’s command of the visual horizon, and to sharpen their monitoring of unexpected, changing, and often-subtle visual or auditory events in their local environment. One set is designed to elevate attentiveness, and at the same time magnify the suppression of responses to meaningless distractors—together, keys to sustained attending. One set is designed to clarify the representation of the fast-changing details of what you see or hear, on the path to improving your ability to indelibly record (remember) them. One set is designed to specifically sharpen elemental aspects of your social cognitive ability; another to recover navigation abilities—together, keys for sustaining control of social and physical landscapes.

These Brain Plasticity-Based Strategies Have Been Shown to Be Effective for Improving the Elementary Neurological Abilities of Individuals of All Ages

For every training task, strong, expected improvements in ability are recorded as a rule. Importantly, training is not designed only to improve an individual’s fundamental neurological machinery. A second equally important goal is to drive general improvements in brain health by driving positive changes in the operational characteristics of the processing machinery of the brain that support general, broad gains in performance ability. Many studies have now documented generalized (“real life”) gains in abilities resulting from this training, in normally aging and in variously neurologically struggling adult populations.

In the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) trial,88 an older-age population of more than 700 subjects (mean age 74) versus 700 controls was trained at a computerized visual task that had many of the core speed, accuracy, attention, and sequence-reconstruction challenges described earlier as important contributors to brain health status. The BrainHQ version of this “useful field of view” (UFOV) task (Double Decision) was originally developed by Karlene Ball and Daniel Roenker89 to address peripheral vision and fast-responding deficits that increased the crash risks for older drivers. In their task, subjects are required to identify brief, confusable stimuli near the center of visual gaze, then report on the location of a second briefly flashed stimulus presented in the visual surround. Task variables were stimulus durations for both central and peripheral stimuli, interstimulus intervals separating central and peripheral stimuli, magnitudes of differences between target and foil stimuli, the confusability of target stimuli with visual backgrounds, and the eccentricity of peripherally flashed stimuli. The reliably achieved goals of this computerized training were (1) an expansion of the “useful field of view” (which progressively contracts in normal aging); (2) the recovery of fast recognition speed and fast responding; and (3) the restoration of attention-based visual monitoring, response amplification, and attention network operations.

In this component of the large, multifaceted ACTIVE trial,88 subjects who were trained adaptively for 5 hours at this computer-delivered task (following 5 hours of nonadaptive engagement) had a roughly twofold increase in their neurological “speed of processing.” Trainees completed timed independent activities of daily living (IADLs) at correspondingly faster rates.90,91 When subjects completed brief “booster training” sessions at +1 and +3 years, stronger and longer-sustained gains in speed of processing (SOP) and larger and stronger timed IADL gains were recorded; scientists concluded that maintaining full benefits from the initial training epoch would require about 1 hour of additional UFOV “booster training” per annum.92

As a result of this limited epoch of computerized training, these (average) 74-year-olds aging to 84-year-olds had about half as many driver-caused traffic accidents over at least the first 6 trial years.93,94 They were more successful is sustaining their driving mobility, and drove more confidently over longer distances in their more active everyday lives.95,96,97 Trainees were significantly less likely to develop “senior depression” following training.98,99 If depression did arise, it was in a less severe form.100 The confidence that trainees could manage their own affairs was higher over the initial 5-year post-training epoch.101 Self-rated health and quality of life were significantly better in trained than in untrained individuals.102,103 Medical costs savings in the trained cohort were estimated to be about $1,000/subject over the initial 5 years of the study. At a +10-year benchmark (7 years following the completion of the very limited booster “doses” of computerized training) individuals that had completed booster sessions had processing speeds—again, a signature deficit of aging correlated strongly with aged infirmity83,84—that were still higher than before training initiation a decade earlier.104 These speed of processing benefits transferred to timed-IADL scores that still distinguished trainees from controls at the +10-year benchmark.

Given these compelling demonstrations of enduring and generalized neurobehavioral impacts, it was not surprising that these investigators have more recently shown that engaging in this single, simple progressive, attention-demanding, computerized visual task for 10–18 hours (again, with only 5–13 hours of that training delivered in a progressively challenging form, as in Double Decision on BrainHQ), resulted in a lower probability of dementia onset over the 10-year period following training initiation.105,106 Protection against dementia onsets was dose-related. For the entire computer task-trained population, risks were about one-third as high as risks recorded for randomly assigned untrained control cohort. For individuals who had completed brief “booster sessions” at +1-year and +3-year benchmarks risks of dementia onset recorded across this 10-year epoch—in which the average age of trial participants advanced from 74 to 84—were roughly cut in half.105,106 This is the first randomized controlled trial applying any intervention that has been shown to provide apparent protection against dementia onset on this scale.

It is difficult to imagine how time could have been better spent, for these older volunteers, than at this 10 to 18 hours of computerized training at this progressive, elementary inherently neuroblastic exercise. It is almost certain that even modestly higher and more regular dosing could have increased and extended the duration of this apparent intensive-training-provided protection.

It might be noted that two other cohorts that were trained with equal intensity in ACTIVE using noncomputerized classroom strategies to improve memory and reasoning/cognitive skills designed to be habitually deployed in their older lives also very clearly benefited from training—but with no significant benefits with regard to protection from dementia onset over this 10-year epoch.88,104-106 It should also be noted that positive training impacts have been shown, in other studies, to be substantially independent of age, and independent of whether or not training is self-administered at home on an Internet-connected device or completed in a supervised classroom setting as in ACTIVE.106,107,108

In part because the long-running ACTIVE trial was initiated more than a decade ago, only limited longitudinal brain recording and imaging analyses have been conducted in individuals trained over these durations with this multifaceted (divided attention; speed; reception accuracy; restoration of peripheral vision) elemental visual signal processing task. Those limited studies documented a clear up-regulation of attention modulation and attention network status.109,110

Many other randomly assigned, controlled outcomes studies have recorded positive changes in abilities that can be viewed as indices of brain health status, both in normally aging individuals and in subject populations at higher risks for early dementia onset. In the Improvement in Memory with Plasticity-Based Adaptive Cognitive Training (IMPACT) trial, nearly 500 subjects were engaged by either adaptive computerized listening training (BrainHQ) programs or alternative (control) computer games and exercises, over a 40-hour-long training period.108,111,112 In this elemental listening speed and accuracy training study, gains in trained versus control groups documented strong exercise-driven impacts, and recorded extensive generalization to nontrained abilities extending to general improvements in quality of life. Speed of processing for listening—an elemental ability manifesting necessarily broad neuroblastic remodeling—increased roughly threefold, which translated to a rejuvenation to match the performance level on this assessment of an individual in their 20s or 30s. Gains at higher-level cognitive abilities translated to a reversal in age-related performance on the broader RBANS battery and on memory-for-speech assessments, in an intent-to-treat analysis, that was equivalent to an 11- to 13-year rejuvenation. If a small noncompliant trainee cohort was removed from the analysis, benefits for completers translated to 15- to 18-year “age-performance reversal.” At the same time, benefits appeared to fall back toward the baseline more rapidly than in the intensive visual training applied in ACTIVE.113 This and other studies indicate that sustaining higher-level listening abilities may require a more significant level of ongoing training engagement.

The major behavioral outcomes of these studies were broadly confirmed in other randomly assigned, controlled trials that applied the same multifaceted listening training programs.114,115,116,117,118,119 Kraus and colleagues extended these findings by showing that training positively impacted aural speech reception in acoustic noise. With plastic remodeling, auditory brainstem responses representing the spectral and temporal details of speech-related acoustic inputs were renormalized in trained older individuals. These investigators also documented a fall-off in training-generated benefits over time; at a +6-month benchmark, the brainstem still more sharply represented acoustic inputs, but earlier improvements documented for listening in noise were significantly reduced.120 These studies indicate, again, that more consistent “booster training” may be required to sustain ongoing performance (and brain health?) benefits in the listening modality in humans.

Other randomly assigned, controlled outcomes trials have documented benefits of training that appear to manifest positive neuroclastic change, and that often directly document (in a piecemeal way) evidence of physical remodeling. Those studies have targeted patients with mild cognitive impairment,121,122,123,124,125 older-age individuals who have endured long-standing HIV-AIDS infections,126,127 cancer patients who have undergone intensive chemotherapy,128 stroke patients,129,130,131,132,133 patients with major depressive disorder99 or schizophrenia,134,135,136,137,138,139,140 in patients following heart failure141,142 or multiple sclerosis143—among other clinical indications. All studies provide evidence of positive improvements in elemental performance abilities (e.g., gains in processing speed and accuracy) that infer that training is driving positive neuroblastic growth. In most of these studies, the training of more elementary neurological abilities transferred to documented gains in everyday skills indexing these patients’ qualities of life.

Beyond Training on a Computer: An Integrated Approach to Sustaining Brain Health

In parallel with our efforts to create neuroscience-inspired brain exercise strategies, other scientists have repeatedly documented the brain-health benefits of other older-age life-style practices. Living your life to the advantage of your brain obviously extends beyond intensive, progressive brain exercises!

For example, there are many hundreds of studies demonstrating the value of adopting a brain-healthy diet144,145 and for intelligently supplementing or restricting that diet to meet brain health146 and brain-age-related147 nutritional needs. Many studies have shown clear benefits of a regular program of physical exercise and balance training extending beyond the support of general health and mobility to reveal specific, positive impacts on neurological health and cognitive (e.g., attention control) ability.148,149,150,151,152,153 Social engagement on a level that assures the maintenance of the machinery that supports social cognition and positive mood has also been repeatedly confirmed to contribute to an individual’s “cognitive reserve” and to support positive changes and the healthy maintenance of cognitive and action-control abilities.154,155,156 Maintaining healthy sleep schedules has also been directly related to sustaining organic brain health.157,158

Physical exercises and nutritional supplementation can be of especially high value to the mature brain.146,148 Sustaining unimpaired mobility, if at all possible, is obviously important for enabling an active brain-healthy experiential engagement with the world. From a neuroplasticity perspective, physical exercise strategies that engage and continuously elaborate the neurological control of actions in a closely attended task setting is an important aspect of any well-ordered older life. Note that progressively exercising the “master movement controller” capabilities of your brain is very different from physical exercise in a typical structured gym environment, or in any conventional form of relatively stereotypical exercise. From the perspective of brain health, the most valuable forms of physical exercise require that you engage in active, progressive, challenging physical skill learning. If such exercises are undertaken with appropriate energy and enthusiasm, they can also provide an individual with the additional benefits attributed to aerobics, which by itself is argued to have positive impacts on neuromodulatory and attention-related processes in the brain.148,149

For most individuals, all of these goals can be achieved by engaging in physical activities that do not employ stereotypic (e.g., exercise machine–implemented) exercise strategies, that are richly and continuously variable in the action control that they command, that by their nature naturally provide a basis for social interaction, and that provide a basis for progressive motor skill improvement over an extended period of time. Aerobically demanding, fast-responding net games (like tennis, pickle ball, badminton, table tennis), off-road bicycling, off-the-sidewalk walking (hiking, rock climbing, bird-watching, etc.), field games, afoot on the golf course or the trout stream working very hard to improve your skills, ball-room dancing, singing then choir practice—or a hundred other activities—can help fulfill these real-life brain-healthy physical exercise goals.

As we consider the likely scenarios for the medical management of brain health, we envisage a tiered approach beginning with lifestyle adjustments, on the path to assuring that simple behavioral biomarkers are being sustained within safe bounds. While many contemporary practitioners argue for the specific importance of dietary adjustments, or social or physical activities to grow cognitive reserve and sustain brain health, all of these factors can be expected to play a role in integrated brain health management programs. At the same time, it must be remembered that the deterioration and progressive distortion of brain wiring in the aging brain can only be restored to normalcy—and ultimately, can only be sustained—via progressive brain exercises.

Summary and Conclusions

Scientists have now richly documented the fact and nature of adult brain plasticity, through many thousands of research studies conducted in animal and human models. We now know that almost every aspect of fundamental neurology related to brain performance and organic brain health is plastic, that the processes underlying brain change are remarkably reversible, and that positive growth and negative reductive phases involve broadly coordinated remodeling. Importantly, we understand at a first level how to “throw the switch” to drive changes in a “negative” clastic or a “positive” clastic direction. Broadly expressed changes in elementary functional status and organic brain health status are a product of surprisingly elementary forms of intensive training.

Although data documenting the long-term benefits of these therapeutic strategies are still limited, two large controlled trials have now documented broadly beneficial impacts resulting from limited training doses. Their positive outcomes directly inspire the implementation of new strategies for managing organic brain health. We now know that a determination of processing speed and accuracy, attention control, and distractor suppression powers collectively index the status of a complex array of coordinated physical-chemical processes. Measuring their status can be achieved at low cost, at a first level, in a 20- to 30-minute-long procedure on any smart device, delivered and controlled via the cloud. Those assessment data can be easily conveyed to attending physicians and therapists, to help them manage their patients’ brain health. Our research efforts are now directed toward determining what constitutes “safe” performance levels, indexing the status of organic brain health. We envision the use of these simple biomarkers as a primary screening tool for evaluating brain health status.

Brain medicine shall now almost certainly evolve from its focus on the treatment of neurological catastrophe in all of its psychiatric and neuropathological forms to a far stronger emphasis on prophylaxis and prevention, guided by ongoing assessment strategies that both help secure enduring patient safety and continuously document treatment effectiveness. A crucial aspect of this transformation shall be the growing understanding of how lifestyle factors (including dietary supplement and nutritional strategies and physical activities) contribute positively (and negatively) to brain health status, because as in other domains of medicine, the first line of defense for sustaining brain health shall be to ask the patient to live their life to the advantage of the health of this most important of their human organs—because when it dies, now far too often before the body dies, the person that that brain has so magically created is lost to the world.

The adoption of these neuroscience-informed brain health management strategies can be expected to radically transform brain health–related medicine over the next decade.

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