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https://www.healthline.com/health/rewiring-your-brain

I picked this source because prevention, when it comes to health, is very important. I've heard that when the muscles of the body (and the brain) is trained there are a lot of long term affects that leave someone better off than a lot of other people after they've reached a certain age.

The link I provided was a link for exercises someone could do to keep their brain healthy for neuroplasticity.

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How to Rewire Your Brain: 6 Neuroplasticity Exercises

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It mind sound like something out of a sci-fi movie, but rewiring your brain is actually a thing, and it’s not as hard as you’d think.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128435/

Nathalia van Nimwegen

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These data provide additional confirmation for task-training induced lifelong plasticity. New motor and other skills can be acquired at any age even though the progress may be somewhat attenuated in older as compared to young populations. The importance of these results should not be underestimated.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510719/

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Abstract

Neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF) and other members of the neurotrophin family, are central mediators of the activity-dependent plasticity through which environmental experiences, such as sensory information are translated into the structure and function of neuronal networks. Synthesis, release and action of BDNF is regulated by neuronal activity and BDNF in turn leads to trophic effects such as formation, stabilization and potentiation of synapses through its high-affinity TrkB receptors. Several clinically available drugs directly activate neurotrophins and neuronal plasticity. In particular, antidepressant drugs rapidly activate TrkB signaling and gradually increase BDNF expression, and the behavioral effects of antidepressants are mediated by and dependent on BDNF signaling through TrkB at least in rodents. These findings indicate that antidepressants, widely used drugs, effectively act as TrkB activators. They further imply that neuronal plasticity is a central mechanism in the action of antidepressant drugs. Indeed, it was recently discovered that antidepressants reactivate a state of plasticity in the adult cerebral cortex that closely resembles the enhanced plasticity normally observed during postnatal critical periods. This state of induced plasticity, known as iPlasticity, allows environmental stimuli to beneficially reorganize networks abnormally wired during early life. iPlasticity has been observed in cortical as well as subcortical networks and is induced by several pharmacological and non-pharmacological treatments. iPlasticity is a new pharmacological principle where drug treatment and rehabilitation cooperate: the drug acts permissively to enhance plasticity and rehabilitation provides activity to guide the appropriate wiring of the plastic network. Optimization of iPlastic drug treatment with novel means of rehabilitation may help improve the efficacy of available drug treatments and expand the use of currently existing drugs into new indications.

Introduction

Neuronal plasticity is a process through which external and internal environment of an individual gradually becomes represented in neuronal structure and function during development and through learning. Although gross connectivity develops through genetically governed guidance, fine-tuning takes place through experience and activity-dependent plasticity, where neurons and connections that actively participate in network function are selected for stabilization and strengthened, whereas inactive contacts are weakened or eliminated ⁻.

Neuronal plasticity does not only involve trophic processes such as neurogenesis and synaptogenesis, but also includes atrophic processes, such as the elimination of inactive neurons and neuronal contacts. Although it is often thought that loss of neurons or synapses is harmful, elimination of connections that do not mediate useful information is, in fact, necessary for the optimal signal-to-noise ratio within the nervous system,. Indeed, most of the neurons and synapses formed during development are wiped out by adulthood,. Therefore, plasticity in itself does not have any particular direction; it is the experience-dependent activity within the neuronal network that determines which of the connections are strengthened and maintained and which ones are eliminated. Therefore, plasticity is adaptive when it is guided by beneficial environmental stimuli, but it can also be maladaptive, if the guiding experiences are adverse.

Neuronal plasticity is heightened during critical periods of postnatal development, which allows an efficient experience-driven fine-tuning of developing networks. After the closure of critical periods, neuronal plasticity and changes in network structure are more restricted. However, recent data indicate that several drugs used for the treatment of neuropsychiatric disorders can directly influence the plasticity and reactivate a critical period-like plasticity in the adult brain, a process known as induced plasticity (iPlasticity) ⁻.

To be translated into neuronal structure and function, neuronal activity needs molecular mediators and neurotropic factors are prime candidates for mediators between neuronal activity and plasticity,. In this review, we will first introduce the role of the neurotrophin family and especially on BDNF as a mediator of plasticity and drug effects. We will then discuss the role of neuronal plasticity in the mechanisms of action of drugs acting on the brain. Finally, we will review recent evidence that developmental-like plasticity, iPlasticity, can be activated in the adult brain and argue that iPlastic drugs should be combined with training, rehabilitation or psychotherapy to facilitate treatment outcome. For the role of other neurotrophic factors in neuronal plasticity, especially the family members of the glial cell line-derived neurotrophic factor (GDNF), fibroblast growth factor (FGF) and insulin-like growth factor (IGF), we refer to recent review articles ⁻.

Neurotrophins in Plasticity

The first neurotrophic factors, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were discovered through their ability to support the survival of neurons and neurites during development ⁻; other members of the neurotrophin family, neurotrophin-3 (NT-3) ⁻ and neurotrophin-4 (NT-4) ⁻ were then identified through sequence similarity to NGF and BDNF.

Neurotrophins act by binding to two types of receptors, Trk-family members ⁻ and the p75 neurotrophin receptor (p75NTR) ⁻. NGF binds to TrkA, BDNF and NT-4 to TrkB and NT-3 interacts mainly with TrkC receptors, whereas all neurotrophin family members bind to the p75NTR. Recent evidence suggests that mature forms of neurotrophins predominantly bind to Trk receptors to promote neuronal survival and plasticity, whereas intracellularly generated pro-forms of neurotrophins preferentially interact with the p75NTR to increase cell death and eliminate synapses,.

In the peripheral nervous system, neurotrophic factors are constitutively released in minute amounts by the target cells to regulate survival and process outgrowth of developing neurons. To act as a mediator of activity-dependent plasticity in the central nervous system (CNS), neurotrophins need to be released and to act in an activity-dependent manner,,. Levi-Montalcini and colleagues first found that hypothalamic Ngf mRNA levels in mice were regulated by behavioral activity, namely aggression, indicating the role for neurotrophins in the regulation of behavior. At the same time, Gall and coworkers showed that Ngf mRNA was regulated by neuronal activity induced by seizures. Subsequently, a similar activity-dependent regulation was observed for Bdnf mRNA ⁻, and subsequent studies showed that synthesis and release of BDNF and NGF, but not those of NT-3 and NT-4, are regulated by activity. Furthermore, TrkB, which is mostly localized within vesicles inside the cell, is translocated to plasma membrane through neuronal activity,. These data are consistent with a central role of neurotrophins as mediators of activity-dependent plasticity, ().

The first functional evidence for the role of neurotrophins in plasticity was obtained in the visual cortex, a classical model for developmental plasticity, when Maffei and colleagues showed that NGF prevents the effects of monocular deprivation during the critical period of visual development, (for a review, see,). These findings led the authors to propose an influential hypothesis that thalamic axons reaching the visual cortex compete for access to a neurotrophic factor that is regulated by activity. The observation that BDNF synthesis in the visual cortex is regulated by visual stimulation made BDNF the prime candidate for this activity-dependent regulated factor. Indeed, the presence of an excess of the TrkB ligands, BDNF and NT-4, prevented ocular column segregation during development ⁻, which is consistent with such a role. These studies demonstrate that neurotrophins are critical regulators of neuronal plasticity in the developing visual cortex; they also established visual cortex as an excellent model for studying the role of neurotrophic factors in neuronal plasticity ().

NGF and BDNF promote the outgrowth of axons and dendrites and increase synapse formation ⁻. The effect of BDNF on dendritic branching is dependent on neuronal activity, which again is consistent with the role of BDNF in activity-dependent plasticity.

BDNF also regulates synaptic plasticity. Long-term potentiation (LTP) is a widely used model of synaptic plasticity and BDNF has been demonstrated to be a critical regulator of the late, protein synthesis dependent stage of LTP,,. High-frequency stimulation that induces LTP increases BDNF production,. Furthermore, BDNF increases neurotransmitter release, promotes synaptic transmission and LTP in vitro⁻ as well as in vivo⁻. Mice deficient of BDNF fail to show LTP,, which can be rescued by exogenous BDNF administration ⁻. Similar findings have been found in mice carrying the Val66Met mutation in the Bdnf gene, which corresponds to a common human Bdnf gene polymorphism that alters the amino acid valine to methionine in the position 66 of the BDNF pro-region, leading to impaired activity-dependent BDNF release. Consistent with this, direct current stimulation promotes learning in homozygous BDNF val/val subjects, but not in met allele carriers, both in humans and mice. However, since long-term manipulations, such as transgenic mice, can have major effects on glutamate release and other basic synaptic properties that in turn alter the threshold for LTP and other forms of synaptic plasticity, it is not always clear whether the effects of neurotrophins on neuronal or synaptic plasticity are instructive or permissive,.

Mice deficient in TrkB also show blunted LTP and deficient learning,. These effects appear to be specifically mediated by signaling through the phospholipase Cγ (PLCγ) signaling pathway, since deletion of the tyrosine residue in TrkB mediating this signaling disrupts LTP. Furthermore, overexpression of TrkB occludes LTP in the hippocampal CA1 area, which is consistent with a critical role for TrkB signaling in LTP.

As noted above, plasticity is not only a trophic effect, but also includes atrophic processes such as apoptosis, axonal retraction, dendritic pruning, synapse loss and long-term depression. Interestingly, genes for neurotrophins produce mediators of both of these functions. While mature forms of neurotrophins activate Trk family receptors to promote trophic effects, pro-forms of neurotrophins bind to and activate the p75NTR to induce atrophic effects,,. p75NTR is widely expressed in cortical and hippocampal neurons during early development, but its expression is reduced during the first postnatal weeks, however, there is evidence that p75NTR is re-expressed in the cortex and hippocampus after injury,,. In addition, the BDNF pro-peptide that is released from pro-BDNF has recently been shown to possess biological effects on its own,. Pro-neurotrophins induce apoptosis in the absence of Trk receptors via interaction between sortilin and p75NTR,,,. Pro-BDNF binding to p75NTR has also been shown to induce pruning of axons and dendrites,⁻ and promote long-term depression (LTD) ⁻. There is evidence that the release of these competing signals derived from a single pro-neurotrophin is effectively utilized by neurons competing for target innervation to promote their own growth while inhibiting that of competing neighbors,⁻ ().

Neurotrophins and plasticity in drug responses

Since the discovery of BDNF and its receptor TrkB, efforts have been made to use BDNF as a therapeutic agent for neuropsychiatric disorders or to develop small-molecule pharmaceuticals that could increase the production of BDNF or activate TrkB in brain (for review, see,), and these efforts are still ongoing. It is, therefore, remarkable that there actually are safe and widely used drugs already in market that increase the production of BDNF or the activation of TrkB in brain. In particular, the effects of antidepressant drugs on BDNF synthesis and TrkB signaling have been well-characterized ⁻, yet these effects have been largely ignored by the pharmaceutical industry and clinical development. Given the meager outcome of the efforts to develop BDNF mimetics or TrkB agonists, one cannot escape contemplating that many of the scientists involved in these efforts ended up being treated with the very drugs they failed to discover.

Antidepressants activate BDNF signaling

Duman and coworkers were the first to observe that antidepressant drugs acting through diverse mechanisms increased Bdnf mRNA expression in the rat hippocampus. Later, multiple studies reported that chronic antidepressant treatment increases Bdnf mRNA expression ⁻ and triggers upregulation of genes associated with BDNF-induced plasticity ⁻. The antidepressant-induced increase in Bdnf mRNA expression can be further potentiated if the drug treatment is combined with voluntary exercise. Moreover, chronic antidepressant treatment can prevent the downregulation of Bdnf mRNA expression caused by stress,,. In addition, BDNF protein levels as well as the expression of genes associated with BDNF-induced plasticity are increased after chronic antidepressant treatment,. Acute antidepressant treatment, however, does not regulate BDNF expression,⁻. Studies on human subjects support the findings in rodents: BDNF expression is increased in post mortem samples of the hippocampus of depressed patients on antidepressant medication at the time of death. Furthermore, electroconvulsive shock treatment increases brain and serum BDNF levels in rats and depressed patients, respectively,. Conversely, BDNF and TrkB mRNA and protein levels are decreased in the frontal cortex and hippocampus of suicide victims when compared to controls.

Genetic studies have demonstrated that BDNF signaling is required for the behavioral effects of antidepressant drugs. In BDNF heterozygous knockout mice and BDNF conditional knockout mice, the behavioral response to antidepressant drugs in the forced swim test is abolished,,. Moreover, after chronic mild stress, BDNF heterozygous knockout mice did not respond to chronic imipramine treatment in the novelty suppressed feeding test. On the other hand, administration of BDNF directly into the midbrain region or hippocampus is sufficient to induce antidepressant-like behavior and neurogenesis,.

The increase in BDNF expression takes several days of antidepressant treatment to develop, but a single acute administration of many different antidepressants rapidly increases the phosphorylation of TrkB ⁻. This delayed increase in BDNF expression may be mediated by TrkB activation, since BDNF is known to regulate its own expression through TrkB,. Antidepressants increase TrkB phosphorylation at the PLCγ binding site (Y816), but not at the Shc binding tyrosine (Y515) and the phosphorylation takes place independent of BDNF, indicating TrkB transactivation. Interestingly, fluoxetine activated TrkB receptor similarly in wild type mice and mice lacking the serotonin transporter, the main target of fluoxetine. TrkB receptor overexpression, which results in increased TrkB signaling, is sufficient to produce antidepressant-like behavioral effect in the forced swim test. Intact TrkB signaling is required for the behavioral effects of antidepressant drugs, since mice overexpressing the dominant-negative truncated form of the TrkB receptor do not respond to antidepressant drugs in the forced swim test. Moreover, the behavioral effects of chronic antidepressant treatment were blunted in mice lacking TrkB in the newly born hippocampal neurons. In addition to activating TrkB receptor signaling, chronic treatment with antidepressant drugs increases Trkb mRNA expression.

Chronic stress is an important precipitating factor for depression and has been shown to induce atrophic changes in dendritic complexity and thus affect neuronal network function. Interestingly, in animal models antidepressant treatment during the chronic stress paradigm can counteract the effects of stress on dendritic spines via a mechanism that includes regulation of glucocorticoid receptor phosphorylation by BDNF. Specifically, BDNF through TrkB activation regulates the functional consequences of the glucocorticoid receptor activation following stress.

Taken together, these data convincingly demonstrate that antidepressant drugs activate TrkB signaling and subsequently increase BDNF levels in brain, and that BDNF signaling is critical for the behavioral effects of antidepressants. Therefore, effective TrkB agonists exist and are therapeutically used by millions of patients.

Antidepressants and neuronal plasticity

The finding that BDNF expression is increased by antidepressants was the trigger for the hypothesis that neuronal plasticity is involved in the antidepressant drug action. Since then, several lines of data indicate that antidepressant drugs activate and act through neuronal plasticity. Neurogenesis in adult animals is restricted to the subventricular zone of lateral ventricles and to the dentate gyrus of the hippocampus. Hippocampal neurogenesis is sensitive to a variety of environmental stimuli, including exercise, enrichment and antidepressant treatment. Essentially all antidepressant drugs increase hippocampal neurogenesis after about 2 weeks of treatment in rodents ⁻ and neurogenesis appears to be required for many, although not all the behavioral effects of antidepressant drugs,,. The effects of antidepressants on neurogenesis are dependent on the intact BDNF signaling through TrkB,.

In addition to hippocampal neurogenesis, antidepressants increase remodeling of axons and dendrites in the hippocampus, as well as in the prefrontal cortex. Antidepressants also increase synaptogenesis apparently by increasing spine turnover,,. Furthermore, antidepressants promote long-term potentiation (LTP) in the hippocampus, cortex and amygdala,,, and propagation of signals through hippocampal circuitry,. While the effects of antidepressants on dendritic remodeling in the dentate gyrus are associated with ongoing neurogenesis, in other parts of the hippocampus and in the prefrontal cortex these effects are independent of neurogenesis.

Ketamine

Ketamine has recently received a lot of attention as a rapid-acting antidepressant drug (for a review, see). A single dose of ketamine alleviates depression within an hour, but the effect lasts for a week or more, even though the half-life of ketamine and its metabolites is only a few hours,. This temporal discrepancy between the effects and kinetics of ketamine suggests that neuronal plasticity may be behind the long-lasting effects. Indeed, ketamine promotes synaptogenesis in the rodent prefrontal cortex,. Ketamine has also been reported to promote hippocampal neurogenesis,, but neurogenesis does not appear to be necessary for the antidepressant effects of this drug.

BDNF and TrkB have been linked to the mechanism of the antidepressant actions of ketamine,. BDNF val66met polymorphism can affect the responsiveness to ketamine in humans and rodents. The ability of ketamine to induce dendritic spine formation was abolished in BDNF met/met mice and the mice failed to respond to ketamine in FST. Depressed human patients carrying the met allele did not respond to ketamine as effectively as the val/val carriers. These results suggest that the activity-dependent secretion, which is impaired in BDNF met/met carriers, is involved in the mechanism of ketamine action. In cultured neurons, ketamine stimulation indeed increases BDNF secretion.

The ketamine metabolite, (2R,6R)-hydroxynorketamine (HNK), can reproduce the behavioral effects of ketamine in animal models, although it does not bind to NMDA receptors that are thought to be the main targets mediating the effects of ketamine. Instead, (2R,6R)-HNK increases AMPA-mediated currents and BDNF expression. The NMDA receptor-independent actions of (2R,6R)-HNK suggest that mechanisms other than NMDA antagonism, such as the effects mediated by BDNF and TrkB, can be crucial in the antidepressant effects of ketamine. This hypothesis is supported by findings from Autry et al. that a single ketamine injection rapidly increases the TrkB receptor activation and the translation of BDNF via eukaryotic elongation factor 2 (eEF2) in the mouse hippocampus, effects that are also seen after chronic fluoxetine treatment. Furthermore, the antidepressant-like behavioral effects of ketamine were lost in mice lacking BDNF or TrkB or if BDNF function blocking antibody was infused into the medial prefrontal cortex of rats,. In BDNF heterozygous knockout mice, however, the response to ketamine in FST is preserved, suggesting that ketamine is able to produce antidepressant effects in situations where BDNF expression is reduced but not completely lost.

Fingolimod

Fingolimod is a sphingosine-1-phosphate receptor modulator that is clinically used for multiple sclerosis, but it has been suggested for the treatment of several neurological disorders, including Huntington's disease and Rett syndrome, where BDNF signaling has been implicated. Indeed, fingolimod increases BDNF levels in cultured neurons and in brain and rescues reduced BDNF levels in the brain of Rett syndrome model mice. In addition, fingolimod has been shown to increase memory and prevent the upregulation of p75NTR in Huntington's disease model mice. Finally, fingolimod has antidepressant-like effects, which is consistent with the critical role of BDNF signaling in the antidepressant drug action.

Drug-induced Trk receptor transactivation

TrkB receptors can be activated independently of BDNF via transactivation through other receptors. TrkB receptor appears to mediate, in particular, the neuronal survival-promoting effects of compounds able to transactivate TrkB. For example, the adenosine A2 and PACAP receptors that belong to the family of G-protein coupled receptors can transactivate Trk receptors,. In vivo, the effects of adenosine 2A receptor agonists on survival of motoneurons were mediated via TrkB receptor transactivation. In addition to transactivation via G-protein coupled receptors, TrkB receptor activation and signaling can be induced by glucocorticoids, for example dexamethasone, to mediate their effects on neuronal survival.

Drugs of abuse

Drugs of abuse produce long-lasting memories, typically persisting for life and neuronal plasticity has been for a long time implicated in the formation and maintenance of these memories (for a thorough discussion of this area, see ⁻). The first evidence for long-term plastic changes in response to an addictive drug was observed in the dopaminergic neurons originating from the ventral tegmental area and forming synapses in the nucleus accumbens (NAc). A single cocaine administration induced an LTP in this synapse that was observed 24 h after the cocaine administration but no longer at one week after. Repeated cocaine injection also induces production of new synapses in the excitatory projections to NAc, which remain silent expressing only NMDA receptors and having no AMPA-receptor mediated currents. Subsequently, during withdrawal, AMPA-receptors are gradually recruited to these silent synapses, which converts them to mature synaptic contacts.

The role of neurotrophins in addiction has been extensively studied, particularly by Nestler and coworkers. BDNF is expressed in dopamine neurons as well as in excitatory neurons projecting to the NAc and TrkB is expressed in both dopamine D1 and D2 receptor expressing neurons in the NAc,. Expression of both BDNF and TrkB is increased by cocaine exposure, and inhibition of BDNF-TrkB signaling reduces the rewarding effects of cocaine. Interestingly, TrkB signaling within the D2 expressing NAc neurons promotes reward to cocaine, whereas TrkB in the D1 neurons suppresses it. In contrast, chronic morphine administration reduces BDNF expression in the ventral tegmental area and suppression of BDNF signaling in the NAc promotes morphine reward. Therefore, BDNF as well as other neurotrophic factors (for a review of the role of GDNF, see) play a critical, though complex, role in the neuronal plasticity leading to addiction.

It has been proposed that addictive drugs of abuse "hijack" a process of neuronal plasticity that normally takes place during development. Nestler and coworkers have proposed a neural rejuvenation hypothesis of addiction, which suggests that repeated exposure to cocaine reactivates developmental processes that normally occur in the juvenile brain. It will be important to explore whether rejuvenation and iPlasticity in fact represent a common mechanism through which developmental plasticity is activated in the adult brain through drugs or experiences to promote adaptive or maladaptive plasticity.

Role of iPlasticity in drug responses

Plasticity is adaptation of the nervous system to environmental experiences, and since exposure to a drug is an experience, it is to be expected that drugs acting on the CNS involve plasticity. However, recent evidence suggests that central processes of developmental plasticity, such as critical periods, neurogenesis and synaptic plasticity, can be direct targets of drug treatments.

Postnatal critical or sensitive periods are phases of heightened neuronal plasticity during which a certain network is particularly sensitive to environmental input and experiences have a large impact on the subsequent structure and function of the network. A classical experimental setup for the investigation of critical periods is the development of the mammalian visual cortex, (). In this process a perfectly healthy eye that has grown its projections to the visual cortex normally, may lose its connectivity and become permanently deficient only because it is deprived of activation during the critical period. Critical periods are ubiquitous and also govern the development of, for example, motor learning, language and social interactions ⁻. Therefore, abnormal experiences during early life can guide maladaptive wiring of many cortical networks, including those governing social interactions, and this wiring becomes permanent after the closure of the corresponding critical period, impeding normal adaptation of the network function. Critical periods typically have a relatively well-defined boundaries and it is known that GABA-mediated signaling as well as BDNF are central regulators of the opening and closure of these boundaries,,. Drugs acting on GABA receptors, such as benzodiazepines and anesthetics, are occasionally used in children and adolescents, but so far very little is known about the impact of these drug treatments on the opening and closure of critical period, a field that clearly would benefit from more attention.

iPlasticity: induced critical period-like plasticity in the adult brain

It had been considered that once closed, critical periods remain closed. However, recent evidence has demonstrated that it is possible to reactivate a state of plasticity in the adult cerebral cortex closely resembling that observed at the peak of postnatal critical periods,,,. This iPlasticity creates a window of opportunity for better rewiring of abnormally connected or injured neuronal networks, which has obvious potential in the treatment of neuronal trauma and psychiatric disorders (). Furthermore, since natural critical periods coincide with a period of brain growth when many experimental procedures such as brain imaging are complicated, iPlasticity that can be induced in the adult brain facilitates investigations of the molecular and cellular mechanisms of enhanced plasticity.

The first chemical treatment that was shown to induce critical period-like plasticity in the adult brain was the enzyme chondroitinase ABC (ChABC) that, upon intracerebral infusion, degrades perineuronal nets (PNN), extracellular matrix structures preferentially encasing parvalbumin-expressing interneurons. Intracerebral infusion of ChABC was shown to reactivate a critical period-like ocular dominance (OD) plasticity after monocular deprivation (MD) in the rat visual cortex. Degradation of PNNs has been shown to reactivate early life-like plasticity also in the spinal cord and fear circuitry,. Subsequently, several pharmacological treatments () and environmental manipulations,⁻, as well as genetic means, have been used to induce iPlasticity in several model systems and also in humans. Clearly, iPlasticity is an increasingly recognized pharmacological principle with a wide range of potential applications.

iPlasticity induced by antidepressant drugs

Intracortical infusion of ChABC is an invasive procedure and not feasible for human use. However, recent findings have shown that the antidepressant fluoxetine activates iPlasticity in the adult rat visual cortex in a manner very similar to that found at the peak of the natural critical period and to that produced by ChABC or enriched environment,,. During chronic treatment by fluoxetine, critical period-like plasticity is reactivated and monocular deprivation induces a shift in ocular dominance in the visual cortex of adult rats (). Further, in rats rendered amblyopic through MD from early life onwards, opening of the weak eye and patching of the healthy eye in adulthood restores vision to the amblyopic eye only when fluoxetine is given during the patching procedure. BDNF levels are increased by fluoxetine in the visual cortex and BDNF signaling through TrkB is required for iPlasticity. Furthermore, fluoxetine reduces intracortical inhibition and diazepam that potentiates GABA-mediated inhibition, prevents its effects on visual plasticity. Finally, serotonin through 5HT1A receptors is involved in iPlasticity. Fluoxetine has also been shown to produce enhanced structural plasticity in the mouse visual cortex, promoting turnover of synaptic sites. Essentially all antidepressant drugs increase TrkB signaling in brain, but it is not clear whether iPlasticity is produced by other antidepressants than fluoxetine. However, preliminary data show that tianeptine, an antidepressant that does not inhibit monoamine reuptake, readily reactivates OD plasticity in the adult rat visual cortex (J.F. Maya-Vetencourt, A. Cattaneo and E. Castrén, unpublished observations), which suggests that iPlasticity might be induced by other antidepressant drugs as well. It should be emphasized that fluoxetine treatment alone has no effects on the vision in rats; the effects on visual acuity only become apparent when the promoted plasticity is combined with a manipulation (such as MD) that produces a new pattern of activity within the plastic networks.

iPlasticity produced by fluoxetine is not restricted to the visual cortex. Chronic peroral fluoxetine exposure induces markers of critical period-like plasticity and promotes LTP in the amygdala, which is indicative of iPlasticity,. These effects also reactivate the ability to suppress fearful memories when fluoxetine treatment is combined with extinction training. Similar iPlastic effects have also been shown after injection of ChABC into the amygdala in adult mice. As was the case for iPlasticity in the visual cortex, the effects of fluoxetine on fear extinction were also dependent on BDNF signaling and were apparent only when fluoxetine treatment was combined with rehabilitation, in this case extinction training. Taken together, iPlasticity may constitute a neurobiological basis for the observation that the combination of antidepressant treatment and psychotherapy works better than either treatment alone.

In the adult hippocampal dentate gyrus, fluoxetine reverts the molecular and functional properties of granule neurons to an immature state, a phenomenon coined dematuration,. Although dematuration coincides with iPlasticity in other cortical regions, it is currently unclear whether these two phenomena share the same molecular and cellular background.

Fluoxetine has recently been found to promote recovery from stroke and from brain trauma ⁻. It is possible that iPlasticity plays a significant role in these actions. In rats, iPlasticity induced either by ChABC or fluoxetine improves recovery from spinal cord lesion,. If iPlasticity was the underlying mechanism, fluoxetine (promoting plasticity) and rehabilitation (guiding plasticity by activity) together should produce an even better response than either treatment alone; this should be taken into consideration in patient care and in the design of future clinical trials.

Taken together, these data demonstrate that a safe and widely used drug fluoxetine can reactivate critical period-like plasticity in many cortical regions and promote recovery of vision in an amblyopic eye in adult rodents, but whether similar effects are produced in humans is not clear. Normann and colleagues showed that a 3-week treatment with the antidepressant sertraline increases visually evoked potentials in response to a strong visual stimulation in healthy humans, which is reminiscent of the increased LTP produced by fluoxetine in rats, indicating that fluoxetine influences human visual cortex. However, in a recent clinical trial in amblyopic patients, fluoxetine and placebo were equally effective in improving the acuity of the amblyopic eye when given together with a daily eye patching and a computer game-based training of the weaker eye (H. Huttunen, M. Palva, L. Lindberg, S. Palva, V. Saarela, J. Liinamaa, E. Karvonen, M.-L. Latvala, S. Booms, E Castrén and H Uusitalo, unpublished observations). Therefore, it remains unclear to what extent iPlasticity contributes to the clinical effects of antidepressant drugs in humans.

iPlasticity induced by other drug treatments

Experiences have long-lasting effects on gene expression through the epigenetic regulation of chromatin structure and DNA methylation,. Histone acetylation is one of the key epigenetic mechanisms promoting the open chromatin state and regulating gene expression. Histone acetylation can be increased by inhibitors of histone deacetylase (HDAC) and several drugs in clinical use act as HDAC inhibitors. Since activity-dependent plasticity requires changes in gene expression and protein synthesis, HDAC inhibitors might activate iPlasticity. Indeed, HDAC inhibition increases the expression of plasticity-related factors and promotes OD plasticity in the visual cortex,,. Treatment with the HDAC inhibitor valproate also reactivates the plasticity related to music preference in mice through activation of plasticity in a network including the prefrontal cortex. Interestingly, valproate promotes auditory pitch recognition in human volunteers; since development of perfect pitch has a postnatal critical period, this finding is consistent with valproate-activated iPlasticity in the auditory pitch circuitry in humans.

Cholinergic innervation has been known for a long time to regulate critical period plasticity. The cholinesterase inhibitor physostigmine was recently demonstrated to induce OD plasticity in the adult mouse visual cortex and to reverse amblyopia in adulthood when given together with patching of the better eye, suggesting that cholinesterase inhibitors induce iPlasticity. Since physostigmine has side effects, it would be important to investigate whether other cholinesterase inhibitors with fewer side effects, such as donepezil, which is widely used for dementia, also activate iPlasticity. Indeed, a clinical trial is ongoing to test whether donepezil together with patching of the better eye can be used for the treatment of residual amblyopia after the closure of the natural critical period in humans (https://clinicaltrials.gov/ct2/show/ NCT01584076).

Finally, it should be kept in mind that iPlasticity can also be achieved in the visual cortex with purely environmental manipulations, such as environmental enrichment or food restriction in the visual cortex,⁻. iPlasticity induced by fluoxetine and enriched environment closely resemble each other and they both share electrophysiological properties with the naturally occurring critical period. iPlasticity induced by cortical injection of IGF-1 was occluded by the simultaneous exposure to enriched environment; one explanation of this finding is that both treatments share the same core mechanisms. However, iPlasticity induced by calorie restriction is not dependent on BDNF. Plasticity induced by transcranial magnetic stimulation is more pronounced in BDNF Val66Val subjects than in met allele carriers, suggesting that iPlasticity may also be involved in the TMS-induced plasticity. Clearly, more information is needed about the cellular and molecular mechanisms that govern iPlasticity and to which extent these mechanisms recapitulate those in play during the natural critical periods. Nevertheless, the fact that critical periods are ubiquitous suggests that iPlasticity could be beneficial in the treatment of many neurological and psychiatric disorders, especially when combined with rehabilitation.

Conclusions

Neurotrophins are regulated by several classes of drugs used in clinical practice. Many of these drugs also induce iPlasticity, a newly recognized pharmacological principle where drugs can be used to directly promote neuronal plasticity. If iPlasticity is induced by drugs that are consumed by millions of people, why has it not been recognized before? One possibility is that iPlasticity is a central mechanism producing the expected clinical effects these drugs, such as mood recovery in the case of antidepressants. The disorders being treated by iPlastic drugs, such as depression, may also themselves restrict neuronal plasticity and thereby limit the observable plastic effects. Another potential reason is that although iPlasticity has now been recognized in several species of experimental animals, iPlasticity may not take place in the human brain. Finally, it must be emphasized that iPlastic drugs need to be combined with rehabilitation to guide the plastic networks towards a new function. Such rehabilitation may not be a prominent component of current treatment strategies, but with the advent of smart phones and virtual reality, it is possible to design novel and inexpensive rehabilitation programs that combined with iPlasticity may significantly potentiate the effects of currently available drugs. Such combinations of iPlasticity and rehabilitation could also extend the utility of available drugs into new clinical indications and might have a significant impact on the recovery from, for example, neurological insults. There is already evidence for this.

Acknowledgments

We would like to thank the Trophin lab members for stimulating discussions, Jussi Kupari for help with the figures and Adrian Goldman and Johanna Ratia for language revision. The original research in our lab has been supported by the ERC grant No 322742 - iPLASTICITY, the Sigrid Jusélius foundation and Academy of Finland grants # 294710 and # 307416.

Footnotes

Conflict of interest statement: The authors declare no conflict of interest.

References

# data[].attributes.attachment_link.title
Neuronal plasticity and neurotrophic factors in drug responses

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Neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF) and other members of the neurotrophin family, are central mediators of the activity-dependent plasticity through which environmental experiences, such as sensory information are translated into the structure and function of neuronal networks.

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Abstract

Impulse control disorders (ICDs) represent an important medical challenge. The authors of the present paper restricted themselves to present an overview of the neurocircuitry that is involved in ICDs and to present information about the mechanisms of neuroplasticity that are the substrate of the ICDs. Understanding the networks involved in ICDs at the level of the cellular and molecular mechanisms of neural and synaptic plasticity may facilitate the understanding of the ways in which various conditions favour the habit formation and compulsivity that are associated with neurological disorders. The psychological, sociological and forensic dimensions of ICDs are beyond the scope of this paper.

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Neuroplasticity and impulse control disorders

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Impulse control disorders (ICDs) represent an important medical challenge. The authors of the present paper restricted themselves to present an overview of the neurocircuitry that is involved in ICDs and to present information about the mechanisms of neuroplasticity that are the substrate of the ICDs.

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https://www.sciencedirect.com/science/article/abs/pii/S0010945214001543

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Abstract

The brain has an extraordinary ability to functionally and physically change or reconfigure its structure in response to environmental stimulus, cognitive demand, or behavioral experience. This property, known as neuroplasticity, has been examined extensively in many domains. But how does neuroplasticity occur in the brain as a function of an individual's experience with a second language? It is not until recently that we have gained some understanding of this question by examining the anatomical changes as well as functional neural patterns that are induced by the learning and use of multiple languages. In this article we review emerging evidence regarding how structural neuroplasticity occurs in the brain as a result of one's bilingual experience. Our review aims at identifying the processes and mechanisms that drive experience-dependent anatomical changes, and integrating structural imaging evidence with current knowledge of functional neural plasticity of language and other cognitive skills. The evidence reviewed so far portrays a picture that is highly consistent with structural neuroplasticity observed for other domains: second language experience-induced brain changes, including increased gray matter (GM) density and white matter (WM) integrity, can be found in children, young adults, and the elderly; can occur rapidly with short-term language learning or training; and are sensitive to age, age of acquisition, proficiency or performance level, language-specific characteristics, and individual differences. We conclude with a theoretical perspective on neuroplasticity in language and bilingualism, and point to future directions for research.

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Neuroplasticity as a function of second language learning: Anatomical changes in the human brain

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The brain has an extraordinary ability to functionally and physically change or reconfigure its structure in response to environmental stimulus, cognitive demand, or behavioral experience. This property, known as neuroplasticity, has been examined extensively in many domains. But how does neuroplasticity occur in the brain as a function of an individual's experience with a second language?

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296269/

This study makes an interesting connection between physical exercise and neuroplasticity, which they also found to delay Alzheimer's disease

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INTRODUCTION

In line with population aging, the number of people living with dementia worldwide is set to increase. According to the World Alzheimer Report 2016, there are about 47 million people worldwide living with dementia and this number may reach 74.7 million in 2030 and 131.5 million in 2050 (Alzheimer's Disease International. World Alzheimer report 2016: Improving healthcare for people living with dementia. https://www.alz.co.uk/research/world-report-2016). Alzheimer's disease (AD) is the most common form of dementia and possibly contributes to 60-70% of dementia cases (WHO and Alzheimer's Disease International. Dementia: a public health priority. Geneva, Switzerland: World Health Organization, 2012). The pathological features of AD are characterized by extracellular depositions of amyloid plaques, which are primarily composed of 39-43 amino acids long A β peptides, and intracellular accumulations of neurofibrillary tangles, which are mainly composed by hyperphosphorylated tau protein [ 1]. Accumulations of amyloid plaques and neurofibrillary tangles in the brain have been hypothesized to cause deleterious responses in neuronal function in several brain regions related to cognition, such as the hippocampus and entorhinal cortex [ 1]. To date, there is no promising pharmacologic treatment (medication) that can halt AD. Therefore, nonpharmacological interventions that could improve or maintain cognitive function have become alternative options for the prevention and treatment of AD.

Epidemiological evidence has suggested that some lifestyle factors, such as regular exercise and cognitive activity, may delay age-related memory impairment and decrease risk of AD [ 2-4]. A meta-analysis examining the relationship between physical activity and the risk of neurodegenerative disease reported that engaging in physical activity reduces the risk of dementia and AD by 28% and 45%, respectively [ 5]. Higher levels of total daily physical exercise is associated with a lower risk of developing AD [ 6, 7]. Exercise can have a positive effect on multiple aspects of the brain, such as an increase in synaptic and cerebrovascular plasticity [ 8], a decrease in neuropathology [ 9], and an attenuation in neuroinflammation [ 10]. The wide variety of beneficial effects induced by exercise enhances overall brain health, which in turn helps to preserve neuronal function and protect against aging-associated loss of cognition. In this review, we summarize the recent advances in the beneficial effects of exercise on brain function and highlight some potential mechanisms.

BENEFICIAL EFFECTS OF EXERCISE ON BRAIN FUNCTION

Behavior level - learning and memory function

A growing number of studies support the idea that physical exercise increases brain function throughout life [ 11, 12]. In a meta-analysis that included a total of 59 studies (from 1947 to 2009) examining the relationship between physical activity and academic achievement in school-age children, the authors demonstrated significant and positive correlations between physical activity and cognitive outcomes [ 13]. In another meta-analytic review of 29 randomized controlled trials examining the association between aerobic exercise and neurocognitive performance in a group with a mean age of≥18 years of age, positive association between exercise with attention, processing speed, and executive and memory function was also evident [ 14]. Particularly, exercise enhances pattern separation in humans, which is defined as a process to remove redundancy from similar input patterns so that events can be separated from each other and interference can be minimized [ 15]. An acute bout of moderate intensity aerobic exercise improves the pattern separation in young adults [ 16]. This mnemonic discrimination ability is highly correlated with aerobic fitness. The higher fitness group (i.e., high endurance capacity during exercise) had better performance in the pattern separation test compared with the lower fitness group [ 17]. The memory-enhancing effect of exercise on young adults has also been demonstrated in a series of hippocampal-associated learning and memory tests designed for rodents. Almost all young animal studies confirmed the memory-facilitating effect (i.e., acquisition and retention) of exercise. These tests included novel object recognition [ 18, 19], object displacement [ 19], Morris water maze [ 18, 20-22], radial arm water maze [ 23], Y-maze [ 24], passive avoidance [ 25, 26] and contextual fear conditioning [ 27-29].

In addition to benefiting healthy young adults, physical exercise is known to delay age-related cognitive decline. A randomized, controlled trial study that evaluated the association between exercise and cognitive function in 120 healthy participants aged over 65 showed that 6 months of exercise reversed age-related loss in hippocampus volume and improved performance in a computerized spatial memory task [ 30]. A meta-analysis including 42 studies (from 1966 and 2010) of cognitive interventions of exercise in 3,781 healthy older adults aged 55 and older concluded that aerobic fitness training improves cognitive performance [ 31]. Similar findings have also been obtained in aged animals. For example, it has been shown that 6-weeks of treadmill exercise ameliorates age-induced losses in short-term (tested by step-down avoidance task) and long-term memory (tested by radial 8-arm maze) functions in 24-month-old rats [ 32]. Another study demonstrated that one week of mild treadmill exercise was enough to improve spatial learning and memory ability, which was tested by the Morris water maze in 23-month-old rats [ 33]. These results suggest that exercise not only enhances learning and memory in young adults but also protects aged individuals from age-related cognitive impairment.

Although the beneficial effects of exercise on learning and memory have been well-documented in numerous studies, some studies of rodents failed to find such an association. This discrepancy may be due to the different exercise intensities and durations employed in each study. For example, high levels of running exercise are known to impair hippocampus-dependent spatial memory [ 34, 35] and other types of memory [ 36]. It has been speculated that the exercise intensity affects cognitive performance in a reversed U-shaped fashion. In other words, cognition improvement is most effective at moderate-intensity exercise, whereas exercise at low-intensity is less effective and at high-intensity would induce high levels of stress responses, hence impairing cognitive performance [ 37, 38].

Behavior level - mental function

The beneficial effects of exercise extend beyond cognitive function. A plethora of evidence supports the notion that exercise can prevent or delay the onset of various mental disorders such as anxiety, depression, and posttraumatic stress disorder [ 39, 40]. Several meta-analysis studies suggest that exercise could reduce depressive and anxiolytic symptoms in adolescents with clinical levels of mental illness [ 41, 42]. The effects of exercise on mental health are dose-dependent. In adults, a moderate amount of exercise exerts greater benefits in the mental health than low or high doses of exercise [ 43].

The positive effects of exercise on mood disorders have been examined in various animal models. It has been shown that a 2-week period of treadmill exercise effectively decreased anxiety-like (tested by elevated plus maze) and depressive-like (tested by sucrose preference test) behaviors in a single-prolonged stress-induced post-traumatic stress disorder rat model [ 44]. Besides stress, mood disorders commonly occur secondary to medical conditions such as obesity and stroke. In high-fat diet induced obesity, and middle cerebral artery occlusion-induced stroke animal models, exercise was also capable of attenuating depression- and anxiety-like behaviors in the modeled animals [ 45, 46].

Behavior level - motor function

Exercise has a profound effect on motor function. It has been demonstrated that a single session of exercise not only significantly improves performance in a motor learning task during the training session [ 47] but also leads to longer retention of said motor skills than the control group. This is especially clear when motor memory is assessed one day after practice [ 48]. In the animal studies, both wheel and treadmill exercise enhanced animals' motor performance in foot fault-placing and parallel bar-crossing, as well as the staircase reaching task [ 49], rota-rod test [ 50], beam walking and cylinder tests [ 51], and ladder-climbing tests [ 52], after ischemic or hemorrhagic stroke. Furthermore, wheel-running and treadmill exercise can also rescue motor behaviors (e.g., rotarod performance test, rotational behavior test, ladder rung walking task, and gait parameters) that are impaired by different dopamine-depletion methods such as LPS, 6-OHDA and MPTP [ 53-55].

Cellular level - neurons

Neuroplasticity is a continuous process that modifies existing neural networks by mediating structural and functional adaptations of synapses in response to changes in behavior. Exercise-induced structural and functional changes in the brain have been reported in both human and animal studies.

Cellular level - glial cells

In parallel with the effects of exercise on neurons, exercise is also known to have multiple effects on glial cells. Astrocytes, the major glial cells in the brain, play a vital role in the regulation of brain energy transmissions from the vasculatures to the neurons [ 88, 89]. Because proper and efficient astrocyte function is essential for supporting neuronal function [ 88], it has been suggested that exercise-induced enhancement of neuronal function may occur via the adaptation of astrocyte behavior. Exercise induces widespread plasticity in astrocytes [ 90]. It has been shown that one month of treadmill exercise increases GFAP-labeled cell numbers and the improvement of astrocyte plasticity in the CA1 area [ 91]. Furthermore, immunostaining signals of S100 β and aquaporin-4, two astrocyte-specific markers, in various brain regions related with cognitive function, such as the hippocampus, medial prefrontal cortex, and orbitofrontal cortex, increased after 12 days of wheel-running in rats [ 90]. In mice, 4 weeks of physical exercise (a combination of treadmill and running wheel) increased the average length and the area enclosed by each astrocytic projection in the hippocampus [ 92]. The exercise also changed the orientation of astrocytic projections towards DG in the hippocampus, the region with significant increase in neurogenesis following the exercise [ 92].

The structure and function of microglia, the major immune cells in the central nervous system, are also affected by exercise. Exercise has been reported to decrease the aging-induced activation and proliferation of microglia in the hippocampus [ 93, 94]. In parallel to the in vivo findings, microglia isolated from aged rodents that participated in chronic wheel-running exercise have a lower basal level of IL-1 β and TNF- α when compared to the microglia isolated from their sedentary littermates [ 95-97]. Similarly, when stimulating these microglia with LPS, the production of IL-1 β was also lower in the chronic wheel-running group. In addition to the inflammatory cytokines, neuron-microglia contact signaling, an important regulator of microglial activation, is affected by exercise. For example, CX3CL1 and CD200 are immunomodulatory factors expressed by neurons to inhibit microglial activation through binding with the CX3CL1 and CD200 receptor on microglia, respectively [ 98]. Chronic exercise is known to upregulate the expression of the CX3CL1 gene [ 99] and the CD200/CD200R proteins in the brain [ 100], supporting that exercise may inhibit microglial activation via the enhancement of neuron-microglia contact signaling.

Molecular level - brain-derived neurotrophic factor (BDNF)

The mechanisms underlying exercise-induced neuroplasticity involve, at least in part, several neurotrophic and growth factors. Among them, BDNF is a well-characterized mediator of neuronal growth [ 101], plasticity [ 102, 103], and survival [ 99]. Human and animal studies collectively suggest that exercise is an active strategy to upregulate the expression of BDNF, which plays an essential role in exercise-induced neuroplasticity [ 104, 105]. Different types of exercise (i.e., voluntary wheel-running and mandatory treadmill running) all seem to be capable of enhancing the production of BDNF in the hippocampus of young and aged animals [ 22, 28, 106-108]. It is believed that BDNF binds to its receptor, tropomyosin receptor kinase B (TrkB), which increases the phosphorylation levels of cAMP response-element-binding (CREB) and the translation of synaptic-plasticity related proteins [ 22, 28, 103, 109, 110], and finally enhances neuroplasticity. It has been demonstrated that animals with higher levels of BDNF and TrkB receptor in the hippocampus exhibit better performance in radial water mazes [ 23] and passive avoidance tasks [ 26]. On the contrary, blocking the TrkB receptor with a TrkB receptor-IgG chimera or antagonist inhibits the efficacy of exercise-induced upregulation of synaptic plasticity-related proteins significantly [ 103, 109], resulting in a disruption of benefits on cognitive function. Behavior tests in the Morris water maze, passive avoidance, and contextual fear condition also suggest that the learning and memory abilities enhanced by exercise are reduced to sedentary levels after treating the animals with TrkB receptor blockers [ 26, 28, 111].

Molecular level - insulin-like growth factor 1 (IGF-1)

IGF-1 is also a key modulator of neuronal functions in the central nervous system, including synaptic plasticity, synapse density, neurotransmission, neurogenesis and neuron differentiation [ 112-114]. Chronic exercise-enhanced adult hippocampal neurogenesis, learning, and memory performance have been attributed to IGF-1 signaling in the hippocampus [ 115-117]. The levels of IGF-1 in the blood positively correlated with the time animals spent in the target quadrant during the probe trial of the Morris water maze [ 115]. The levels of IGF-1 in the brain are also increased after exercise, which is a result of uptake in circulating IGF-1 [ 118]. Infusion of anti-IGF-I antiserum or neutralization of hippocampal IGF-1 receptor inhibits the exercise-induced brain uptake of circulating IGF-I, disrupts neurogenesis, and lessens the effects of exercise on memory retention [ 116, 117, 119]. Exercise-induced upregulation of BDNF may be partially affected by the IGF-1 pathway. Blockade of the IGF-I receptor during exercise inhibits the ability of exercise to enhance the expressions of pro-BDNF and BDNF in the hippocampus [ 119].

Molecular level - vascular endothelial growth factor (VEGF)

VEGF, an angiogenic protein, is known to have neuroprotective and neurotrophic functions [ 120]. VEGF can be synthesized and released by peripheral vascular endothelial cells and brain cells, including astrocytes, ependymal cells, and neuronal stem cells [ 121]. Intracerebroventricular injection of VEGF or gene transfer of VEGF in the hippocampus increases the number of BrdU labeling cells in the subventricular zone and the subgranular zone of the DG, suggesting an intimate association between angiogenesis and neurogenesis [ 122, 123]. The changes in the vascular niche promotes local signaling that directly regulates or indirectly activates other regulatory factors to stimulate the proliferation, differentiation, and survival of newborn neurons [ 124]. Voluntary exercise is known to increase the expressions of VEGF receptors, fms-like tyrosine kinase (Flt-1/VEGF1), and fetal liver kinase (Flk-1 or VEGFR2) in the hippocampus [ 125]. The activation of the intracellular tyrosine kinase domains of the VEGF receptors induces the activation of several downstream signaling pathways which in turn enhances the proliferation of neuron precursors [ 126, 127]. Peripheral VEGF seems to play an essential role in exercise-induced adult hippocampal neurogenesis [ 128, 129]. Blockade of VEGF signaling by intravenous injection of adenoviruses carrying the chimeric VEGFR1 receptor or conditionally knocking down skeletal myofiber-specific VEGF gene nullifies running-induced adult hippocampal neurogenesis [ 128, 129].

Molecular level - nerve growth factor (NGF)

NGF also plays a role in promoting neuronal function, especially the survival of neural progenitors [ 130]. Results gathered from microarray and nuclease protection assays indicate that the expression of hippocampal NGF is increased after wheel- running, with a peak at 2 to 3 days after exercise [ 87, 131]. The expressions of hippocampal NGF and one of its receptors, tropomyosin receptor kinase A (TrkA), are increased after 8-weeks of treadmill running in rodents. Similar to BDNF/TrkB signaling, the binding of NGF to TrkA stimulates the downstream transcription factor, CREB, and induces various gene transcriptions related to cell survival and neuroplasticity [ 132].

PHYSICAL ACTIVITY, AGING, AND AD

Physical activity and aging

Aging is an irreversible and inescapable process. Age alone increases the risk of dementia and AD [ 133]. Even in the absence of overt disease symptom, increasing age is associated with decreasing cognitive function of varying severity in human beings. The hippocampus is considerably vulnerable to aging and is involved in the development of aging-related deficits of neuroplasticity and memory functions [ 134]. Aging-associated memory deficits are accompanied by abnormal structural and functional changes in the hippocampus. Aging also reduces hippocampus size, induces hippocampal neuron loss [ 135, 136], suppresses dendritic arbors and spine density of the hippocampal neurons [ 137-139], decreases the degrees of DG neurogenesis [ 140, 141], and represses the field excitatory postsynaptic potentials [ 142, 143] and LTP induction [ 144] in the hippocampus.

Several lines of evidence indicate that exercise can ameliorate the structural and functional changes in the brain during aging. In the pioneer study, Samorajski et al. showed that exercise (spontaneously wheel-running) significantly increased recent memory in the passive avoidance test in adults (10-14 month), middle-aged (20-24 month), and old (28-30 month) C57BL/6J male mice [ 145]. Later studies also demonstrated that physical activity increases the cognitive reserve and prevents aging-related memory decline [ 108, 146, 147]. Regular aerobic exercise increases the hippocampal volume by 2%, effectively countering age-related loss in volume in older adults (55-80 years old) without dementia [ 30]. Six-weeks of moderate treadmill training reverses the age-related declines in the complexity of dendritic arbors and the density of the dendritic spines of hippocampal CA1 pyramidal neurons in mice [ 139]. Furthermore, six-weeks of moderate-intensity running enhanced the LTP induced by high-frequency stimulation in the CA1 regions and hippocampal memory in mice of different ages, even when the memory impairment had progressed to an advanced stage [ 139]. It is widely accepted that exercise enhances the adult hippocampal neurogenesis that is critical for hippocampal memory functions [ 21, 148-150]. The decline in neurogenesis in aged (19 months of age) mice is reversed to 50% of young (3 months of age) control levels by 45-days of voluntary wheel-running [ 141]. Yang et al. demonstrated that the hippocampal neurogenesis dramatically decreased by the time mice reached nine months of age and 5-weeks of treadmill running attenuated the decrease of the number of neural stem/progenitor cells during aging and enhanced the maturation of newborn neurons [ 66].

Physical activity and AD - neuroprotection

It is well known that neurotrophic and growth factors (BDNF, IGF-1, VEGF, NGF) are attenuated in AD [ 151-154]. Therefore, one of the potential mechanisms for exercise to protect the brain against AD may be via the upregulations of neurotrophic and growth factors. In the following section, we will discuss exercise-induced neuroprotection against AD with focuses on the four trophic factors.

Both clinical and basic research documents that BDNF mRNA and proteins, including proBDNF, are severely decreased in AD, especially in the hippocampus [ 155-157]. Several lines of evidence have suggested that decreases in brain BDNF and NGF levels contribute to AD pathology [ 158, 159]. On the contrary, administration of lentiviral vectors to constitutively express BDNF in the hippocampus can prevent cell death, reverse neuronal atrophy, and ameliorate behavioral deficits, hence delaying the development of AD [ 160]. As a physiological approach to increase the production of neurotrophic factors, exercise has been reported to alleviate hippocampal functional impairment in AD through the induction of BDNF expression in the hippocampus [ 71, 105]. Exercise-induced BDNF signaling activation has been applied to a variety of AD models, including the A β injection-induced non-Tg AD model [ 161], APP/PS1 [ 71, 162], APOE4 [ 163], NSE/APPsw [ 164] and NSE/PS2 m [ 165, 166] Tg animal models. Increased BDNF signaling due to exercise is suggested to protect against AD-induced learning and memory deficits through enhancing neurogenesis [ 167] and LTP expression [ 161, 162], modulating dendritic morphology [ 71], and reversing A β-induced neurotoxicity [ 168].

Neurotrophic signaling not only directly enhances neuronal function but also decreases AD pathological burden. An in-vitro study suggests that APP processing shifts towards the non-amyloidogenic α-secretase pathway in response to BDNF treatment [ 169], which is known to reduce the production of A β 1 - 40 and A β 1 - 42. Beyond amyloid pathology, BDNF also affects the tau pathology through mediating tau phosphorylation. In P19 neurons, BDNF stimulation induces a rapid decrease in tau phosphorylation [ 170]. The effects of BDNF on tau dephosphorylation is known to be TrkB dependent. TrkB activation induces AKT-dependent phosphorylation of GSK-3 β at the Ser9 site, resulting in the inhibition of tau phosphorylation [ 171]. The K252a treatment, a Trk receptor inhibitor, attenuates the effect of BDNF stimulation on tau dephosphorylation [ 170].

The reduction of the cerebrospinal fluid/plasma IGF-I ratio has been found in AD patients and AD model mice [ 172, 173], reflecting an impaired uptake of IGF-I from the serum to the CSF. Exercise is known to increase the uptake of IGF-1 in the central nervous system [ 118]. Elevated IGF-1 not only benefits neuronal functions but also influences the production of A β and the formation of neurofibrillary tangles [ 174]. IGF-1 also affects brain amyloidosis [ 175, 176]. Crossing APPswe/PS1dE9 Tg mice with serum IGF-I deficient LID mice accelerates brain amyloidosis significantly [ 175]. Conversely, increases of serum IGF-1 levels decrease the A β load in the brain of aged APP/PS2 Tg mice [ 176]. IGF-1-induced inhibition of amyloidosis could be due to, at least in part, an increase of A β clearance. This is because IGF-1 increases the levels of A β carrying proteins, such as apolipoprotein J, transthyretin, and albumin, which are all known to facilitate A β clearance via blood-brain barrier (BBB) transportation [ 176, 177]. Antagonization of IGF-1 by TNF- α reduces IGF-I signaling at the BBB, resulting in a decrease of the expression of A β-carrying proteins and an increase of A β levels in the brain [ 177]. Furthermore, in vitro cell culture studies (i.e., NT2N cells and rat primary cortical neurons) reveal that IGF-1 induces the phosphorylation of GSK3 α (ser21)/ β (ser9) and attenuates tau phosphorylation through activating IRS1/PI3K/AKT/mTOR pathway [ 178, 179]. It has been reported that exercise increases the activity in the IRS/PI3/AKT pathway to dephosphorylate GSK-3 α/ β [ 180] and inhibit tau phosphorylation in APP/PS1 [ 181] and NSE/htau23 Tg mice [ 182] as well as in the ICV-STZ non-Tg AD model [ 183]. This supports the assertion that exercise-induced IGF-1 signaling plays an important role in preventing pathologies associated with AD.

Exercise elevates VEGF transcription, mRNA, and protein in the brain [ 184]. In addition to supporting neurogenesis, VEGF could protect neurons against AD via the following potential mechanisms. Firstly, VEGF increases angiogenesis to help the maintenance of BBB integrity [ 185, 186], which is essential in preventing the entry of systemic A β [ 187]. Secondly, VEGF regulates the expression of A β transporters on the BBB [ 188]. It has been shown that an implant of VEGF-secreting fibroblast microcapsules into the brain of APP/PS1 mice not only enhances brain vessel density but also increases the level of LRP-1 expression, which is an A β efflux transporter on the BBB, accompanied by a reduction of A β deposition in the brain [ 189]. Thirdly, VEGF directly affects APP processing by decreasing β-secretase activity [ 190, 191]. Applying VEGF to Tg2576 mouse brain slices decreases β-secretase activity and production of both soluble A β 1 - 40 and A β 1 - 42 [ 190]. Finally, VEGF directly binds to A β and eliminates A β toxicity. VEGF contains a heparin-binding domain that can be recognized by A β [ 192]; therefore, it is capable of binding to A β (at around the 26-35 amino acid region), hence inhibiting A β aggregation and A β neurotoxicity [ 192].

Decreases in mature NGF expression as well as increases in Pro-NGF expression have been found in postmortem AD brains [ 152, 193, 194], suggesting that diminished conversion of pro-NGF to mature NGF and increased degradation in the activity of mature NGF in AD brains [ 152]. It is known that proNGF preferentially binds to p75NTR and initiates the activation of apoptotic pathways, which may contribute to AD neurodegeneration [ 195, 196]. Increased mature NGF due to exercise could protect neurons against AD pathologies through acting on the trkA receptor to promote neurite generation, neuronal survival, and synapse formation [ 197, 198]. It has been reported that exercise-induced increases of mature NGF expression and decreases of Bax expression, the downstream molecule of p75 NTR, are involved in the inhibition of neuronal death during AD development [ 165]. An in-vivo study of Tg mice expressing a neutralizing antibody directed against NGF showed a progressive development of amyloid deposition and neurofibrillary pathology in the brain [ 199, 200]. An in-vitro study using PC12 differentiated cells revealed that withdrawal of NGF caused the overproduction of A β peptides, increasing tau phosphorylation and neurite degeneration [ 201, 202]. Similar to BDNF, mature NGF increases the metabolism of APP from amyloidogenic towards non-amyloidogenic processing through binding to the TrkA receptor [ 203, 204]. Mature NGF is also able to decrease the hyperphosphorylation of tau via increasing the phosphorylation of GSK3 β at the Ser 9 site [ 204].

Physical activity and AD - glia cells regulations

Accumulated evidence suggests a strong association between risk factors of cerebrovascular disorders, such as hypertension, diabetes, hypercholesterolaemia, hyperhomocysteinaemia, and APOE4, with AD [ 205]. Astrocytes play an important role in maintaining neurovascular function [ 205]. The prodromal stage of AD has been linked to dysregulated astrocytes in the neurovascular unit, which may then cause disruptions of neuronal metabolic support, impairment of synaptic functions, onset of neuronal death, and decreases of degradation and clearance of A β [ 206-208]. One of the exercise-induced neuroprotective pathways is mediated by astrocytes. For example, S100B, a calcium-binding protein, is predominantly secreted by astrocytes and acts as a neurotrophic factor to support neuronal survival. In the sporadic AD animal model, five weeks of treadmill exercise could reverse the reduced extracellular levels of S100B [ 209], suggesting that exercise can alleviate neuronal dysfunction via controlling astrocyte signaling. Furthermore, exercise increases the A β clearance abilities of astrocytes in the AD brain. The recently identified glymphatic pathway, which critically relies on AQP4 in astrocytes, contributes to A β clearance. Mice lacking the AQP4 in astrocytes exhibit slower paravascular cerebrospinal fluid-interstitial fluid exchange and lower A β1-40 clearance rate than those of intact mice [ 210, 211]. Chronic exercise can increase A β clearance through the glymphatic pathway [ 212]. Two-photon imaging reveals that six weeks of wheel-running increases AQP4 expression in the perivascular region and increases the rate of paravascular cerebrospinal fluid-interstitial fluid exchange in the brain of aged mice; this is accompanied by a decrease of A β accumulation in the cortex and hippocampus [ 212].

In addition to amyloid plaque and neurofibrillary tangle deposition, neuroinflammation is considered a key feature of AD pathology. AD inflammation is characterized by the presence of reactive astrocytes and activated microglia surrounding amyloid plaques. Chronic exercise has been reported to decrease neuroinflammation in AD. In the Tg animal models, wheel-running and treadmill exercise decreased the levels of hippocampal pro-inflammatory cytokines (i.e., IL-1 β and TNF- α) of Tg2576 AD mice and NSE/htau23 Tg mice to levels indistinguishable from wild-type mice [ 213, 214].

Physical activity and AD - Aβ transportation and degradation

LRP-1 and RAGE are major A β carrier proteins that regulate A β efflux and influx, respectively, in transportation across the BBB [ 215, 216]. The expression of LRP-1 and RAGE can be detected in both neurons and glial cells [ 215, 216]. It has been demonstrated that exercise increases LRP-1 and decreases RAGE expression in the hippocampus of Tg2576 [ 217] and APP/PS1 [ 71, 181] mice, suggesting enhanced brain-to-blood A β transportation after exercise. Also, exercise can increase the activity of A β degradation enzymes that prevent the aggregation of A β. Tg2576 mice given a 12-week period of exercise significantly increased hippocampal levels of neprilysin, insulin-degrading enzyme, and matrix metallopeptidase 9; all of which are A β proteolytic enzymes [ 217]. Interestingly, exercise-induced changes in the expression levels of A β transport proteins and proteolytic degrading enzymes depend on the intensity of exercise training [ 217].

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Physical Exercise Enhances Neuroplasticity and Delays Alzheimer's Disease

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In line with population aging, the number of people living with dementia worldwide is set to increase. According to the World Alzheimer Report 2016, there are about 47 million people worldwide living with dementia and this number may reach 74.7 million in 2030 and 131.5 million in 2050 (Alzheimer's Disease International.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4960264/

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Abstract

The focus of this review is on driving neuroplasticity in a positive direction using evidence-based interventions that also have the potential to improve general health. One goal is to provide an overview of the many ways new neuroscience can inform treatment protocols to empower and motivate clients to make the lifestyle choices that could help build brain power and could increase adherence to healthy lifestyle changes that have also been associated with simultaneously enhancing vigorous longevity, health, happiness, and wellness. Another goal is to explore the use of a focus in clinical practice on helping clients appreciate this new evidence and use evolving neuroscience in establishing individualized goals, designing strategies for achieving them and increasing treatment compliance. The timing is urgent for such interventions with goals of enhancing brain health across the lifespan and improving statistics on dementia worldwide.

Keywords: neuroplasticity, brain plasticity, neurogenesis, health psychology, healthy aging, cognitive, computerized cognitive training, cognition

Introduction

Since 2011, our Director of NIMH has encouraged "the 21st century discipline of clinical neuroscience" to include brain-plasticity based strategies in providing clinical care ( White, 2011). Neuroplasticity, the capacity of brain cells to change in response to intrinsic and extrinsic factors, can have negative or positive influence at any age across the entire lifespan. How can these factors be influenced in clinical settings? In keeping with the increasing shift in focus from illness to what maximizes wellness, psychologists are uniquely trained to use evidence based behavioral techniques as effective methods for driving neuroplasticity in a positive direction.

Search efforts for this review were primarily focused within the PubMed database using combinations of keywords listed above as well as names of prominent researchers in the field. Also, bibliographies of these articles and related reviews were searched. Studies accepted for review included animal as well as human studies. Studies reviewed met rigorous scientific standards, were almost exclusively broad review articles or random controlled trials, and were included without a specified time span. Periodic searches of this nature were conducted between 2005 and 2016.

It has been estimated that dementia has been detected at the rate of one new person about every 7 s around the world ( Ferri et al., 2005). Brookmeyer et al. (2007) estimate that success in delaying the onset of dementia by as little as a year could reduce the global burden of Alzheimer's disease by as much as 9,200,000 cases in 2050, a number that makes driving brain plasticity in a positive direction a top priority worldwide.

The focus of this article is to review the scientific foundation and recent progress in research of neuroplasticity; relate that to the various ways these findings can influence treatment; propose ways treatment protocols could increase adherence to brain plasticity based therapeutics; and suggest research questions going forward. Before proceeding on how to impact the so called "normal age-related cognitive decline," it is important to consider recent research on the myth of cognitive decline ( Ramscar et al., 2014). While noting that there are changes in performance on many psychometric tasks with aging, the results of this long series of studies indicate that these changes reflect the "consequences of learning on information processing, and not cognitive decline." Across the years adults develop a greater sensitivity to small details of differences in stimuli, accumulate more acquired knowledge, and, as a result, have more and different demands in their memory search "which escalate as experience grows." These researchers concluded that the performance of older adults is a reflection of predictable outcomes of increased learning on information processing and is not an indication of cognitive decline. Viewing cognitive differences across the lifespan as related to better awareness of details and accumulated learning is an example of a hopeful perspective which could effectively empower any individual to factor neuroplasticity into their efforts to promote improved business and health behaviors.

Researchers have referred to Michael Merzenich as the "father of plasticity" because he enjoyed a long career that established that the human brain is highly plastic and that led Merzenich to develop science-based novel interventions to drive improvements. Because of her decades of research preceding that of Merzenich, let us consider Marian Diamond to be the "mother of neuroplasticity." Her work influenced a paradigm shift for scientists when she was the first to prove that the brain shrinks with impoverishment and grows in an enriched environment at any age ( Diamond et al., 1971, 1984; Malkasian and Diamond, 1971). Fred Gage brought science another paradigm shift with the proof of neurogenesis in humans ( Eriksson et al., 1998); showing how animals could sustain fivefold induction of neurogenesis ( Kempermann et al., 2002); demonstration of how humans can increase neurogenesis ( Pereira et al., 2007); and using human induced pluripotent stem cells to model neurogenesis in the hippocampus ( Yu et al., 2014). Richard Davidson's research found that thought alone was associated with neuroplastic gains ( Davidson and Lutz, 2008; Davidson and McEwen, 2012) and improved immune response ( Davidson et al., 2003; Kaliman et al., 2014).

There is a growing corpus of literature on ways to drive brain plasticity in a positive direction that could contribute more powerfully in strategies of intervention for healing and enhancement of function than would research on what drives loss. These findings coupled with recent neuroscience clearly showing the potential for improving brain plasticity ( Goh and Park, 2009) could give humans unprecedented hope for personal empowerment. Neuroplasticity research has fleshed out what these chemical, anatomical, and performance gains could include.

Healthcare providers including psychologists ( Cramer et al., 2011) need to address all of the essentials identified by Diamond as well as other lifestyle choices such as sleep ( Jacobs et al., 2004; Guzman-Marin and McGinty, 2006; Zhu et al., 2012; Castronovo et al., 2014; Irwin, 2014), reducing inflammation ( Kohman and Rhodes, 2012; Rosano et al., 2012; Irwin, 2014) and turning stress into power ( Sapolsky, 2004; Zucconi et al., 2006). Psychology is uniquely positioned to maximize the "revolution which is set to transform the diagnosis and treatment of mental illness and reverse the lack of major progress made in curbing associated ill health and death over the past 100 years" ( White, 2011). This specialty can influence "the development of a credible risk score coupled with some, or all of, cognitive training, psychosocial approaches, education, and the use of specially designed video and computer games" as well as promoting choices that can enhance neuroplasticity for, per Marian Diamond, "Enriching Heredity."

Applying interventions in positive ways to enhance neuroplasticity is the model proposed herein because it captures changes made in the Diamond lab; the only change in their enriched environment was having lab workers hold and talk with the rats; that "TLC" resulted in fifty percent increase in longevity while maintaining plastic gains even in animals that lived to the equivalent of ninety human years ( Diamond et al., 1984). Diamond opined these plastic gains could be enjoyed by humans at any age. She identified five essentials for a healthy brain: newness, challenge, exercise, diet, and love.

Newness and Challenge

Animal and human research have shown that environmental stimulation is critical for enhancing and maintaining cognitive function. Novelty, focused attention and challenge are essential components of enhancing cognitive function ( Mahncke et al., 2006a, b; Houillon et al., 2013). Perceived challenge is associated with enjoyment of the task ( Abuhamden and Csikszentmihalyi, 2012); it functions as reinforcement for humans.

The timing of enrichment has also been the focus of studies with humans such as the Mayo Clinic Study of Aging ( Vemuri et al., 2014) showing that academic and career achievements in the 75th percentile showed higher levels of cognition with a delay of cognitive impairment of 8.7 years as compared to individuals in the 25th percentile. This research involved 1,995 people without dementia aged 70-89, of whom only 277 had mild cognitive impairment (MCI). Since people whose intellectual enrichment was focused in midlife also showed significant gains, newness and challenge can be seen as a powerful way to lengthen the "healthy lifespan."

In the Rush Memory and Aging Project the 964 individuals without cognitive impairment had an average age of 78.7 years and an average of 14.6 years of education when they agreed to annual evaluation and brain autopsy at their death ( Wilson et al., 2014). In the beginning of the study they were asked if by the age of 18 they had foreign language instruction; if they had any music lessons; and if so, how many years of each. Over the course of about 6 years of annual examinations, 396 individuals developed MCI. The risk of MCI was about 30% less in those who before the age of 18 had had more than 4 years of foreign language training; the same finding was true of those who prior to 18 years of age had had more than 4 years of music lessons. When compared to people who had neither foreign language training nor music lessons before turning 18, the risk of MCI was about 60% less in individuals who had more than 4 years of both foreign language instruction and music lessons in their early years. It is unknown how much of this could have been mediated by the extent to which individuals used these skills during the intervening years between youth and being in the study.

Japanese individuals 65 and older enjoyed physical exercise with musical accompaniment for 1 h once a week completing 40 h in 1 year ( Satoh et al., 2014). With each session the exercise intensity was gradually increased. Half of the group heard the music played in harmony with the exercise. The other half only heard percussion that kept the beat while the people read the lyrics without music while exercising. While both groups may have appreciated gains in psychomotor speed, only the music group had significant improvement in visuospatial function. These scientists believe that cognitive functioning in elders can be enhanced when music is combined with physical exercise.

To what extent is neurogenesis relevant to information processing? New brain cells in the dentate gyrus are essential for discriminating fine differences in experiences and sensory inputs ( Jessberger and Gage, 2014). It is this awareness of differences in small details that picks up newness. It is during their sixth to eighth week that new neurons are more excitable than mature brain cells ( Ge et al., 2007) permitting the plastic response of stimulated adult-born new brain cells while preserving existing neuronal function. This important period is when the per cent of new brain cells that survive and get integrated ( Tashiro et al., 2007) can be influenced by intrinsic and extrinsic factors ( Dranovsky et al., 2011). It is also when less strong exciting currents are essential to cause a plastic response such as survival, integration, memory, or long term potentiation. These new brain cells are also thought to hold associations between time-related experiences that may not be related in content like those that occur during memory flashbacks.

In their first few days of life new brain cells grow dendrites that reach into the dentate gyrus and axons are evident. It is during this young and excitable period that new neurons require experiences such as physical activity and learning that includes challenge and newness to become integrated and stable in the dentate gyrus. Although the many steps between birth and the connectivity that includes synaptic integration are still awaiting definition, there is largely no difference between mature brain cells and newborn ones by the time new neurons are about 8 weeks old ( Deshpande et al., 2013). While many of the steps and mechanisms of such rapid maturity are still being studied ( Jessberger and Gage, 2014), "current hypotheses suggest that it will depend on both intrinsic signaling pathways and extrinsic regulators and local network activity."

Working with adults aged 60-89 using a computer training program, the duration of and presentation speed of stimuli adapted to the skill level of the person in order to maintain a degree of challenge ( Berry et al., 2010). As a result of practice and challenge, individuals had improved working memory for tasks they had not been trained on. Pre-training and post-training electroencephalography also showed functional brain plasticity. The sample size was small ( N = 32) and well educated (13-21 years of education). Further research is indicated on how to maximize transfer of gains from training programs that are computer based, provide adaptive challenge and can reinforce progress with greater accuracy and effectiveness than could ever be managed by human trainers.

Exercise

Regular exercise can reinvigorate the immune system ( Simpson et al., 2012). In elders without known cognitive impairment exercise can improve cognitive performance ( Angevaren et al., 2008). Being aerobic up to 60 min can improve information processing. A recent review suggests that different types of physical activity and a high level of physical fitness can decrease the so called "normal age-related" atrophy of the hippocampus and increase volume of the hippocampus ( Niemann et al., 2014). With elders whose average age was 83, it predicted greater integrity in microstructures in brain networks related to memory ( Tian et al., 2014). It can result in greater health of brain white matter in people aged 60-78 ( Burzynska et al., 2014). Exercise energizes motor responses to improve the speed of reaction ( Audiffren et al., 2008). Aerobic exercise has been associated with increased neurogenesis in humans ( Pereira et al., 2007). Exercise influences survival and maturation of adult born neurons ( Snyder et al., 2009). In community dwellers between the ages of 55 and 80, physical exercise was a powerful method to increase gray matter volume in the hippocampus and prefrontal cortex "effectively reversing age-related loss in volume by 1-2 years" with related improvements in memory performance ( Erickson et al., 2011). Six months of high intensity aerobic exercise with women between the ages of 55 and 85 who had mild cognitive decline was a potent non-pharmacologic treatment that improved their performance on multiple tests of executive functioning ( Baker et al., 2010). A review of random controlled trials suggested that physical exercise could be a powerful way to increase gray brain matter in elders such that cognitive losses and behavioral problems associated with brain atrophy can be prevented ( Erickson et al., 2014). It may have pervasive benefits that could translate into less risk in humans for Alzheimer's disease ( Voss et al., 2013).

All things considered it is URGENT to prescribe exercise at any age ( Colcombe and Kramer, 2003) because it can be considered beneficial for body and brain ( Diamond et al., 1971; Malkasian and Diamond, 1971; Eriksson et al., 1998; Gage, 2002; Pereira et al., 2007; Angevaren et al., 2008; Larson, 2008; Snyder et al., 2009; Lojovich, 2010; Voss et al., 2010, 2013; Erickson et al., 2011, 2014; Kohman and Rhodes, 2012; Simpson et al., 2012; Hallal and Lee, 2013; Barnard et al., 2014; Burzynska et al., 2014; Jessberger and Gage, 2014; Nagamatsu et al., 2014; Tian et al., 2014; Gajewski and Falkenstein, 2016; Ryan and Nolan, 2016). There is no reason to hold back on these prescriptions while evolving research attempts to establish guidelines on preferred dose, timing and method.

In the Cardiovascular Health Study, calorie expenditure was measured along with assessments of cognitive functioning and MRI measurements of brain volume ( Raji et al., 2016) in individuals with an average age of 78.3. Their findings suggest "that simply caloric expenditure, regardless of type or duration of exercise, may alone moderate neurodegeneration and even increase GM volume in structures of the brain central to cognitive functioning."

Diet and Inflammation

Calorie restriction with adequate nutrients has been associated with health benefits through increased longevity in organisms from yeast to flies, worms, and mammals. Research suggests that hara hachi bu, or "eat until you are 80% full," has been an important factor in exceptional longevity with increased health span for one human population ( Willcox et al., 2014). Reducing calories 30% was associated with an average of 20% improvement in verbal memory after 3 months ( Witte et al., 2009). Some of these cognitive and general health benefits of calorie restriction in humans are thought to be related to the reduction of inflammation and oxidative damage. The brain and body interaction in response to the restriction of calories could influence the sleep cycle which has been associated with inflammation; and it might be related to "the global metabolic reprogramming of the central biological clock" ( Fusco and Pani, 2013). Still, the molecular nuances of the calorie restriction remains poorly understood. The problem with low grade inflammation that can be chronic as well as undiagnosed is that it can be associated with decreased cognitive functioning with aging ( Marioni et al., 2009; Calcada et al., 2014).

Neither calorie restriction nor intermittent fasting should be taken lightly. Each require healthy nutrition. Whether that uses the Okinawan Diet, that was one of the factors in the lives of high-functioning centenarians ( Willcox et al., 2014), or the Mediterranean Diet, which has some evidence for being "a potential strategy to reduce cognitive decline in older age" ( Knight et al., 2016), is discretionary. Since both emphasize vegetables, fruits, fish as a source of protein, and low glycemic load, both would be rich in polyphenols and the healthier polyunsaturated fats and would have antioxidant and anti-inflammatory benefits.

Interestingly, the polyphenol resveratrol also increases longevity ( Dauncey, 2014; Witte et al., 2014) while preserving memory and hippocampal microstructure. This polyphenol occurs naturally in grapes, purple grape juice and some berries such as blueberries and cranberries.

Other invaluable polyphenols that get much wider dietary acceptance are the flavonoids found in cocoa which are noted for powerful anti-inflammatory as well as antioxidant effects. The added benefits of these flavonoids are the dose dependent improved blood flow to the brain as well as increased health and flexibility of blood vessels ( Monahan et al., 2012). A recent review ( Nehlig, 2013) of the neuroprotective effects of the flavonoids in cocoa suggested that they "provoke angiogenesis, neurogenesis and changes in neuron morphology, mainly in regions involved in learning and memory." Another review ( Latif, 2013) similarly found that cocoa flavonoids are neuroprotective and can enhance mood and cognitive function. Humans aged 50-69 years who consumed 900 mg of cocoa flavanols daily for 3 months enjoyed improved dentate gyrus performance on cognitive testing as well as on fMRI ( Brickman et al., 2014).

Also crucial to optimal central nervous system structure and function are the essential omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA; Barberger-Gateau, 2014) which humans cannot create. Primary sources include fish and plant foods. Interestingly, in the parts of the brain essential to cognition and memory one study found increased gray matter volumes that were associated with fish consumption and independent of plasma measures of omega-3 fatty acids ( Raji et al., 2014), highlighting the complexity of, and interactions of, dietary impact in humans. An animal study ( Tyagi et al., 2015) found that a diet early in life that was high in omega-3 fatty acids protected brain cells from environmental challenges later in life. When these animals were transitioned from high omega-3s to a Western diet, the "epigenetic memory" protected these animals from cognitive decline. In the Framingham Heart Study people whose DHA level was in the top quartile had a highly significant 47% lower risk for developing dementia ( Schaefer et al., 2006).

A random controlled trial ( Boespflug et al., 2016) that supplemented with fish oil found "increased red blood cell omega-3 content, working memory performance, and BOLD signal in the posterior cingulate cortex during greater working memory load in older adults with subjective memory impairment." Thus they suggested that supplementing with omega-3 fish oil could enhance brain cell response to challenges in working memory.

A research review suggests that a high brain concentration of DHA can optimize synaptic plasticity and efficiency and help maintain homeostasis in the synapses ( Denis et al., 2013). For efficient transmission of data between brain cells, the plasma membrane must remain fluid. DHA is a component of this membrane. Rats maintained on a mixture of alpha-linolenic and linoleic acid showed enhanced learning that the researchers opined was due to the fatty acids changing the amount of cholesterol in the membrane of the neurons ( Yehuda et al., 1998). Adequate intake of the essential fatty acids is crucial to maintaining the fluid transmission of molecules across neuronal membranes because this is where much of the action takes place for such core brain functions as learning, memory, and sleep ( Yehuda et al., 2002). They are also essential in building the myelin sheath that enhances efficient processing of information ( Yehuda et al., 2005).

The finding that DHA is vulnerable to oxidative damage underscores both the need for polyphenols as well as the complexity of the interactive neuroplastic influence of the several components of the dietary intervention matrix which also needs to consider essential vitamins and minerals. For example, since brain health requires adequate Vitamin B ₁₂, episodic measures of this status are recommended ( Barnard et al., 2014).

Love, Perception, and Reduced Stress

Perhaps love is one of the most valuable intentional emotional experiences humans can produce to drive brain plasticity in a positive direction. It is significant that the only change in experimental paradigm in the Diamond research lab was the addition of "TLC" in holding and talking with rats ( Diamond et al., 1984) and that this TLC resulted in continued production of neuroplastic gains through a 50% increase in lifespan to the human equivalent of 90 years.

Diamond believed that the same gains could be appreciated in older humans but a confounding variable to consider is human perception. In the Baltimore Longitudinal Study of Aging stereotypes were assessed in people without dementia decades prior to when annual magnetic imaging and brain autopsies were done ( Levy et al., 2016). Their findings were rather motivating (or sobering, depending on your perspective): "Those holding more-negative age stereotypes earlier in life had significantly steeper hippocampal volume loss and significantly greater accumulation of neurofibrillary tangles and amyloid plaques, adjusting for relevant covariates." The cognitive skills of verbal fluency and memory ( Robertson et al., 2016) were also found to decline over 2 years associated with "negative perceptions of aging." The impact of stress that would be associated with negative perceptions was not addressed in these studies.

A rich social network of friends and family stimulates and enhances healthy aging. In contrast, neurogenesis in animals is reduced with stress and depression. In humans hippocampal volume loss is predicted by depression but not age ( Sheline et al., 1999). Training such as cognitive therapy and meditation could enhance wellbeing and other prosocial elements of the human experience and positive plasticity ( Davidson and McEwen, 2012).

Sleep

A study of 6,050 adults aged 65 or older ( Spira et al., 2014) found greater quality of life and independent functioning in individuals who had adequate sleep as compared to those who reported insomnia. Chronic insomnia in humans was associated with hippocampal atrophy that suggests decreased neurogenesis; this was associated with cognitive deficits ( Joo et al., 2014). In a population of 2,822 men aged 67 and older, measured and reported sleep disturbance was associated with cognitive decline.

Chronic sleep deprivation in animals resulted in increased inflammatory molecules and decreased BDNF which is crucial to many components of neuroplasticity ( Zielinski et al., 2014). A recent review of animal research ( da Costa Souza and Ribeiro, 2015) concludes that the major physiological challenge created by sleep deprivation can include "cognitive deficits, inflammation, general impairment of protein translation, metabolic imbalance, and thermal deregulation." Sleep is essential for removal of waste and distribution of "glucose, lipids, amino acids, growth factors, and neuromodulators" ( Jessen et al., 2015). One of the neuroprotective mechanisms of adequate sleep may be its reduction of inflammation that can be associated with aging ( Irwin, 2014) as well as with decreased neurogenesis as observed in animal models ( Guzman-Marin and McGinty, 2006). However, when one night of sleep deprivation in rats included gentle handling to prevent sleep, neurogenesis increased significantly initially as well as 15 and 30 days later ( Zucconi et al., 2006).

Discussion

An example of neuroplastic flexibility in humans is the "significant improvements involving memory, attention, and executive-functioning" after 1 year of compliance with CPAP treatment in people whose previous non-compliance with treatment of sleep apnea showed "diffuse reduction" in white brain matter integrity that was associated with cognitive dysfunction ( Castronovo et al., 2014). Even though this was a small sample, it might help clinicians influence motivation and empower clients to increase healthy sleep for brain health. Essential molecules for health must circulate in adequate supply to the brain and waste products that could have toxic impact must be removed for best brain performance and maintenance. That is part of the critical function of sleep as shown in research on the glymphatic system ( Jessen et al., 2015).

Although calorie restriction and some nutrients have been associated with increased healthy longevity in many species, this could require greater creativity in motivating individuals to eat less and eat differently. Educating people that some cognitive and general health benefits could be related to the resultant reduction in inflammation and oxidative damage may not be enough. More research on the Okinawa Program should be encouraged because the World Health Organization declared Okinawa a centenarian center of the world based on the percentage of Okinawans that remained physically, socially and cognitively intact well past the age of 100, a distinction that persisted until Western lifestyle choices markedly changed that demographic. With the growing global burden of obesity and associated negative health impacts, clinicians could play pivotal roles in empowering people to celebrate benefits of hara hachi bu for their brain health; to structure reinforcement schedules for adherence to healthier food choices; and to learn from the Okinawan model that led to remarkable vigorous longevity.

Extensive work by Karlene Ball and Michael Merzenich has used behavioral techniques in computer software training that could adapt to the current level of functioning such that positive reinforcement was predominant. Merzenich has repeatedly shown that brain plasticity can be influenced in positive ways that can enrich human experience ( Merzenich, 2013) suggesting that "age-related cognitive decline may be slowed, arrested, or even reversed" ( Mahncke et al., 2006a). Both Ball and Merzenich have found significant gains in skills that were trained. It is especially significant that these enduring positive effects of neuroplasticity based computerized cognitive training have been found to impact such important issues as quality of life ( Wolinsky et al., 2014), driving mobility ( Edwards et al., 2009), independence ( Jobe et al., 2001), improved memory and attention in humans aged 65 and older ( Smith et al., 2009; Zelinski et al., 2011), and reduced risk of increased depression 1 and 5 years after baseline training ( Wolinsky et al., 2009). Thus, ample research exists to indicate the need for behavioral techniques in neuroplasticity based computerized programs in healthcare. The finding of Ball and associates that some gains persisted up to 10 years highlights the need for research on dose, timing, and how broadly these gains might influence other factors such as memory, judgment, and prosocial behaviors.

Since computerized complex new learning coupled with aerobic exercise has shown increased gains over either intervention alone in early research ( Anderson-Hanley et al., 2012), ballroom dancing could be another research avenue for measuring cognitive gains in an activity that combines at least physical and cognitive elements; add social aspects when dancing with others. A recent review ( Gajewski and Falkenstein, 2016) suggests that combining cognitive training with aerobic exercise in natural activities like dancing might be the most beneficial because it is multilevel with both physical and cognitive coordination required.

Since aerobic exercise is associated with increased neurogenesis in humans, integration of these new brain cells requires newness and challenge, research has shown increased survival rates of new brain cells in animals afforded an enriched environment, and type of stimulation during aerobic exercise can influence the site of integration as well as improved cognition related to those efforts, the timing is right for increased research to develop computerized interventions that can be used in association with aerobic activity, whether on the dance floor or cardio machine, to assess potential academic, cognitive, prosocial, and business benefits across a healthier longevity.

Some humans increase their probability of retaining brain architecture and performance while thriving on hope and purpose whereas others maintain "more negative age stereotypes earlier in life" with the unfortunate result of "significantly steeper hippocampal-volume loss and significantly greater accumulation of neurofibrillary tangles and amyloid plaques, adjusting for relevant covariates" with associated decline over 2 years in verbal fluency and memory ( Robertson et al., 2016). In contrast a small study that embedded purposeful activity within a program in which elders volunteered to support the academic success of children "forestalled and possibly reversed age-related declines in annual rates of atrophy" in the "cortical and hippocampal volumes" of the participants compared to controls ( Carlson et al., 2015). This is another example of an intervention that encourages further research on purpose, service, and potentially confounding variables such as the increased physical and social activity.

Age alone does not explain individual differences in cognitive decline, volume in specific brain areas, nor the association between these variables and quality of life and survival. Many factors have been associated with driving neuroplasticity in a positive direction. By empowering clients to use these evidence based interventions, we have the potential to increase health span as well. Much of the research referenced herein can be seen as capturing the perspective of positive psychology which "studies what makes life most worth living" and "is a call for psychological science and practice to be as concerned with strength as with weakness; as interested in building the best things in life as in repairing the worst; and as concerned with making the lives of normal people fulfilling as with healing pathology ( Peterson, 2008)."

What has become clear is that human brains remain plastic, i.e., responsive to intrinsic and extrinsic stimulation, throughout our lifespan. Very complex interactions exist between physiology, function, social, and psychological factors.

Baker et al. (2012) noted that, although high intensity physical exercise resulted in normal adults being "less vulnerable to the pathological effects of an unhealthy diet," individuals with MCI appreciated even greater benefit from a "healthy diet on Aβ modulation" when they also included high intensity physical exercise in their efforts. These researchers concluded that exercise "may thus interact with diet to alter pathological processes that ultimately modify AD risk." That is particularly empowering in light of the later study ( Baker, 2015) in which individuals aged 70 or older who maintained 70-80% of their maximum heart range for 45 min a day, 4 days a week for 6 months appreciated reduced phosphorylated tau levels in their cerebrospinal fluid with associated cognitive skill gains compared to a group whose exercise protocol was to stretch.

The complexity of all of these interactions needs to be acknowledged, even emphasized. This is eloquently stated by Aimone et al. (2014): "In short, while the technological advances of the last couple of decades have revealed most of what we know about adult neurogenesis, we may yet learn that we still know very little."

The timing is urgent for humans worldwide to apply new neuroscience even while many of these promising research advances are in their infancy. With increasing lifespan has come the increase in the number of people suffering cognitive decline. Within the so-called "normal age-related cognitive decline" there is reason to separate the myth ( Ramscar et al., 2014) from the serious losses. The goals of our time can be to add dignity to the human condition at any age; to emphasize science based interventions with potential for enriching heredity, reversing losses and empowering individuals to drive neuroplasticity in a positive direction; to maximize human potential in ways previously unimagined; and to enjoy influencing human intelligence to evolve in a positive direction with the goal of creating more Outliers ( Gladwell, 2011) who celebrate cerebral successes throughout vigorous longevity. If these efforts succeed in delaying the onset of dementia by as little as 1 year ( Brookmeyer et al., 2007), the worldwide burden of Alzheimer's disease could be reduced by as much as 9,200,000 by 2050.

Perhaps the ideal research now would be multifaceted. It would begin with informing individuals in our global community about the potential gains in brain chemistry, architecture and performance suggested in the current neuroscience database. Include the fact that even the gold standard random controlled trial is only a probability statement. Devise an easy manner of assessing in a community the current level of that community's functioning, knowledge about this research, unique values and current use of any of the elements of these findings toward their specific goals. Encourage healthcare oversight for modifications that reflect their unique situation. Train interested individuals in how to use positive reinforcement of successive approximation of the several interventions that their community endorses. Develop measures to assess baseline and progress in the community as well as in the trainers given the finding of the Baltimore study that purpose-driven service can also include neuroplastic benefits in trainers ( Carlson et al., 2015).

Current estimates may be significantly below actual occurrence of dementia since they tend to only capture the data of clinicians aware of the need to screen for dementia in the fraction of the population that accessed care. However, it is conceivable that an effective program of teaching and training trainers in the use of positive behavioral techniques and perspectives to increase knowledge and compliance with the several evidence-based interventions thus far identified could improve the global statistics on cognition.

The message of hope and empowerment is well stated by Jessberger and Gage (2008): "Despite the dramatic reductions in hippocampus-dependent function that accompany advancing age, there is also striking evidence that even the aged brain retains a high level of plasticity. Thus, one promising avenue to reach the goal of successful aging might be to boost and recruit this plasticity, which is the interplay between neural structure, function, and experience, to prevent age-related cognitive decline and age-associated comorbidities."

The timing is urgent for clinicians to use positive behavioral techniques, measure, motivate, strategize, and increase compliance with new neuroscience associated with driving neuroplasticity in a positive direction.

Author Contributions

The author confirms being the sole contributor of this work and approved it for publication.

Conflict of Interest Statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Neuroplasticity and Clinical Practice: Building Brain Power for Health

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The focus of this review is on driving neuroplasticity in a positive direction using evidence-based interventions that also have the potential to improve general health. One goal is to provide an overview of the many ways new neuroscience can inform treatment ...