Research in Neuroscience

p-ISSN: 2326-1226    e-ISSN: 2326-1234

2013;  2(3): 39-49


Non-Pharmacological Interventions for Enhancing Brain Plasticity and Promoting Brain Recovery: A Review

Farheen Farzana1, Yog Raj Ahuja1, Vemula Sreekanth2

1Department of Genetics and Molecular Medicine, Vasavi Medical and Research Center, Hyderabad, 500004, India

2Department of Neurology, Apollo Hospital, Hyderabad, 500034, India

Correspondence to: Farheen Farzana, Department of Genetics and Molecular Medicine, Vasavi Medical and Research Center, Hyderabad, 500004, India.


Copyright © 2012 Scientific & Academic Publishing. All Rights Reserved.


Despite the incredible advancements made in the field of neuroscience, neurodegenerative disorders arising from the pathological forms of neural plasticity, continue to remain the primary cause of increased death rate. While significant progress has been made in the introduction of novel pharmacological approaches for treating neurodegenerative disorders, minimizing the unpleasant adverse effects associated with these medications, still remains a far-fetched dream. This has led to numerous pre-clinical and clinical studies that have accumulated considerable amount of evidence, supporting the effectiveness of non-pharmacological interventions for slowing the progression of a wide range of neuropsychiatric disorders. The primary objective of this review is to provide scientific evidence on the efficacy of non-pharmacological interventions like environment enrichment, cognitive stimulation therapy, physical exercise, social interactions, dietary modifications and relaxation techniques that can be in co-operated in your lifestyle for preventing and reversing age-associated cognitive decline. It emphasizes the importance of adapting a combinatorial approach and utilizing the potential of both, drug-based and non-drug based therapies for managing the symptoms of neurodegenerative disorders, since these conditions are caused by an interplay between genetic and environmental factors.

Keywords: Neurodegenerative disorders, Non-pharmacological interventions, Cognitive decline, Brain plasticity

Cite this paper: Farheen Farzana, Yog Raj Ahuja, Vemula Sreekanth, Non-Pharmacological Interventions for Enhancing Brain Plasticity and Promoting Brain Recovery: A Review, Research in Neuroscience , Vol. 2 No. 3, 2013, pp. 39-49. doi: 10.5923/j.neuroscience.20130203.02.

1. Introduction

Over the last decade, the world has witnessed a rapid increase in the prevalence of neurodegenerative and psychiatric disorders[1], owing to the lack of access to drugs that target the underlying cause of the disease and cost-effective treatments for curing these disorders. Even though several drugs are available in the market for treating the symptoms of these disorders, the number of unpleasant and long term side-effects like cardiovascular and metabolic effects associated with these medications are phenomenal [2,3]. Furthermore, among the large proportion of patients who receive pharmacological treatments, only a small portion of the population experiences full remission while the others do not respond in the same manner. Hence, in order to overcome treatment resistance and the troublesome side-effects associated with these medications, introduction of non-drug based approaches, alone or in combination with drug-based therapies will serve as an effective strategy to guide and accelerate the natural process of brain recovery.
Even though, a number of randomized controlled trials have recorded the positive effects of a growing number of non-pharmacologic interventions that can promote nerve regeneration, they have received far less attention and funding than drug-based research[4]. Hence, the aim of this review article is to highlight the different non-drug based therapies including lifestyle changes that can enhance brain plasticity and improve the quality of life of patients suffering from age-associated neurological disorders.

2. Can Neural Plasticity be Enhanced in the Adult Brain?

Brain deterioration and a subsequent decline in cognitive and motor functions are considered to be common characteristics that accompany the normal process of ageing. However, contrary to the early dogma that the brain is fully formed during childhood and neurons once dead could never be substituted by new ones during adulthood, it is now known that the adult brain retains some plasticity, albeit to a lesser extent than the younger population and continues to modify its structural and functional organization and function, in response to an environmental stimulus[5]. Brain plasticity or neural plasticity is exhibited in two forms, namely synaptic plasticity, which refers to the strengthening and weakening of synapses that leads to learning and memory formation[6] and adult neurogenesis, a process by which new neurons are generated from neuronal progenitors to compensate for the lost or damaged neurons[7] (As shown in Figure 1).
Figure 1. Structural elements of brain plasticity. A, Synaptogenesis: Formation of synapses between two neurons. B, Neurogenesis: Generation of new neurons from neuronal stem cells
Decades of research have demonstrated the efficacy of brain-plasticity based approaches for slowing down the progression of a wide range of brain disorders in humans[8]. However, given the number of challenges that the brain faces as a part of normal ageing, maintaining brain plasticity in adulthood, continues to remain a major challenge faced by today’s world. Nevertheless, a recent innovative study conducted to examine the influence of age on the abolishment of brain plasticity revealed that the loss in number of neurons with age is compensated for, by an increase in dendritic branching, an essential component required for enhancing brain plasticity[9]. This has led to a considerable number of studies that have gathered substantial amount of evidence supporting the efficacy of non-drug based therapies for reversing brain decay, by utilizing the brain’s natural capacity for plasticity that is retained even during adulthood and old age[10].
Among the various molecular mediators that augment the process of neurogenesis in the adult brain, nerve growth regulators or neurotrophins especially, Brain-derived neurotrophic factor (BDNF) has been established as a candidate target molecule for enhancing neural plasticity[11]. Neurotrophins play an important role in the epigenetic regulation of neural plasticity by promoting the proliferation and differentiation of neural precursor cells into new neurons[12] and enhancing synaptic transmission, during brain development and at adulthood[13]. Many scientific studies have established a strong correlation between the dis-regulation of BDNF levels, impaired neurogenesis and an increased susceptibility to several neurological and psychiatric disorders[14] like Dementia[15], Alzheimer’s disease[16], Parkinson’s disease[17], Schizophrenia[18], Huntington’s disease[19], Autism[20] and Depression[21].

3. Non-Pharmacological Approaches for Enhancing Brain Plasticity

Over the past few decades, several lines of scientific evidence and clinical literature have established the beneficial effects of non-pharmacological therapies in enhancing the regenerative power of the brain, thereby promoting additional clinical research in this area[22-24]. However, lack of awareness in terms of the application of non-pharmacological therapies has limited their usage and hence, a review of the available scientific evidence supporting their efficacy and safety is important to place practice recommendations on a sound evidence-base. In the past few decades, research on brain plasticity and its induction by experience-related changes has rapidly gained momentum and attracted a great deal of public interest. Even though non-pharmacological interventions have been criticized for lack of vigor, there is growing evidence supporting the beneficial effects of these interventions for enhancing brain plasticity[25]. In this review, we summarize research supporting the benefits of non-pharmacological interventions for enhancing neural plasticity in the adult mammalian brain and reversing age-associated cognitive decline.
Figure 2. Non-Pharmacological Interventions for Enhancing Brain Plasticity. A. Cognitive Stimulation Therapy: Brain games, Video games and Indoor activities. B. Environment Enrichment (Adopted from Michael J. Meaney et. al, 1988). C. Social Interactions. D. Dietary modification: Fruits, Vegetables and Omega-3 fatty acids. E. Physical Exercise. F. Relaxation Techniques: Meditation, Yoga, Tai-chi, Aromatherapy

3.1. Environmental Enrichment

Environment enrichment takes into the account the crucial role played by the complex interaction between genetic factors and environmental modifiers in the etiology and progression of brain and psychiatric disorders[26]. Using a range of rodent models, environmental enrichment is often provided in the form of improvised housing conditions that enable an active lifestyle and a greater level of social, cognitive and sensorimotor stimulation, in order to promote neuro-rehabilitaion after brain damage[27]. Enriched cages are engineered to be larger than the standard cages to accommodate more animals for promoting social interaction and consist of running wheels for increasing physical exercise. In addition, in order to stimulate cognitive and exploratory behavior in rodents, these cages consist of diverse equipment of various sizes, shapes, color and composition like ladders, nesting material, cardboard boxes, numerous polycarbonate and plastic play tubes that are changed on a regular basis to provide novelty[28].
Several lines of evidence have established the role of stimulating environment in inducing significant synaptic changes[29] and morphological alterations in the dendate gyrus of the hippocampus[30], which manifest in the form of better performances in memory[31], learning and spatial navigational tasks in rodents[32]. Exposure of mice to an enriched environment have been shown to delay the progression of disease in genetic models of many neurodegenerative disorders like Alzheimer’s disease[33], Parkinson’s disease[34] and Huntington’s disease[35]. Moreover, environment enrichment has also been shown to improve cognitive functioning in transgenic mice over-expressing amyloid precursor protein and/or presenilin-1, thereby demonstrating the importance of education and cognitively demanding jobs on reducing the risk of dementia[36].
The positive aspects of environment enrichment, especially wheel running and learning have been strongly correlated with enhanced neural plasticity[37] and an increased rate of hippocampal neurogenesis, as shown by an increase in the number of new neurons in the hippocampal region of mice[38]. This increase in the rate of neurogenesis in enriched mice has been shown to be accompanied by a significant increase in the expression levels of Brain-derived neurotrophic factor, a member of the nerve growth family that is actively involved in enhancing neuronal plasticity in the adult brain[39]. In addition, environment enrichment promotes synaptic transmission by up-regulating the expression of genes involved in postsynaptic signal transduction and down-regulating the expression of genes associated with the reuptake of neurotransmitters at the presynaptic junction, thereby improving synaptic plasticity [40].
Even though adult hippocampal neurogenesis normally declines with age, adult mice exposed to enriched environment showed reduced levels of lipofuscin in the dentate gyrus, decreased age-dependent degeneration and a fivefold increase in adult hippocampal neurogenesis, when compared to mice housed in standard cages, indicating the sustained effect of environment enrichment on brain plasticity[41]. In humans, cognitive enrichment in the form of educational attainment and occupational status has been shown to induce neuroplasticity that not only strengthens the existing neural networks, but also recruits alternative neural networks to permit normal cognitive functioning in an injured brain[42]. Therefore, numerous studies have investigated the potential of psychological interventions, physical therapy at social interaction at providing an enriched environment and improving cognition and quality of life of patients suffering from brain disorders.

3.2. Cognitive Stimulation Therapy

Cognitive stimulation therapy (CST) aims at improving various aspects of neuropsychiatric symptoms such as mild to moderate cognitive impairment, impaired social interaction and communication skills and a poor quality of life in the elderly population suffering from dementia[43]. It is derived from Reality orientation therapy, a psychological intervention used in geriatric health care to improve cognition in the confused and disoriented elderly population suffering from dementia[44].
CST is a structured and cost-effective program[45] that is offered either on an individual basis[46] or in small groups of 4-5 people[47]. Based on the principle that lack of cognitive activity speeds up the process of cognitive decline, CST provides intensive training using a range of intellectually stimulating activities like puzzles, word games, team games, memory games, shape and color recognition, pattern recognition tasks, mazes, complex video games, group discussions and indoor activities like knitting, gardening and baking that can keep patients cognitively active, improve concentration and promote thinking and memory[48].
A study involving clinical evaluations of 700 elderly population, conducted over a period of five years revealed that cognitively inactive people are 2.6 times more likely to develop Alzheimer’s disease than cognitively active people, thereby establishing frequent cognitive activity during old age a means of reducing the risk of developing Alzheimer’s disease[49]. Besides establishing the role of CST in improving working memory and quality of life in Alzheimer’s patients, when conducted alone[50], researchers have also shown the additional benefits of CST when used in combination with the administration of acetylcholinesterase inhibitors for reversing the process of verbal and functional decline and decreasing negative emotional symptoms, thereby improving overall global performance in Alzheimer’s patients[51]. These studies support the hypothesis that there is considerable brain reserve and potential to improve cognitive functions in older adults and hence, cognitive stimulation therapy has gained wide acceptance for delaying cognitive decline associated with dementia.

3.3. Physical Exercise

Extensive research has been conducted on the profound effect that physical activity has on promoting brain health and plasticity[52] and its efficacy in preventing age-associated cognitive decline and neurodegenerative disorders[53]. A substantial amount of evidence has shown the impact of both, voluntary exercise in the form of wheel-running[54] and forced exercise in the form of regular treadmill running[55] on the rate of hippocampal neurogenesis and a subsequent improvement in performance in learning and memory tasks in adult mice. In addition to improving cognition and motor abilities in healthy older adults, physical activity has also been found to have a neuroprotective effect on cognitive functions[56], balance, strength and mobility[57] in elderly individuals suffering from dementia and related cognitive impairments.
However, these structural changes and an enhancement in synaptic plasticity were observed only in rats subjected to 56 days of long-term wheel-running, as opposed to 14 days of short-term wheel-running, which emphasizes the need for long-term periods of physical exercise to facilitate its structural and functional benefits on the brain[58]. Also, a study examining the effect of intensity of physical activity required to normalize corticomotor excitability and increase gait speed, stride length and step length in patients with early Parkinsons disease has demonstrated greater benefits using high-intensity exercise than low- and zero-intensity exercise[59]. Furthermore, a study conducted on older adults by Kramer et. al[60] has found that a six month intervention of moderate aerobic exercise in the form of walking as opposed to stretching and toning exercises, can dramatically enhance executive functions in the brain, thereby re-enforcing the view that plasticity or the potential for positive change is maintained even during adulthood.
While the molecular mechanisms by which exercise enhances brain plasticity have not been completely elucidated, evidence from numerous studies have established Brain-derived neurotrophic factor (BDNF) signaling as the candidate neural mechanism for facilitating exercise-dependant modulation of learning and memory and enhancing brain plasticity[61-63]. However, a meta-analytic study conducted by Colcombe and Krame[64] have reported that the effect of aerobic exercise on increasing BDNF levels and cognition have been found to be more pronounce in studies that included more women than in studies that included fewer women. This has been attributed to be the interaction between estrogen and BDNF, as supported by a study that showed no impact of aerobic exercise on the up-regulation of hippocampal BDNF levels in mice that were deprived of estrogen[65]. In addition, the same study showed that an increase in BDNF levels due to physical activity was found to be more pronounced in mice that underwent estrogen replacement therapy in combination with exercise than mice subjected to estrogen replacement therapy alone. This emphasizes the importance of physical exercise in post-menopausal women, especially in women undergoing hormone replacement therapy and may explain the benefits of estrogen replacement therapy in increasing the positive effects of exercise and mitigating the rate of brain atrophy in late adulthood. Moreover, physical exercise has also been shown to augment the effect of hormone therapy and offset the negative effects of prolonged hormone treatment replacement like memory impairment and irreversible neuronal damage[66].
Besides increasing BDNF levels, physical exercise has also been found to influence the gene expression profile of various other mediators of neuroplasticity in the adult brain such as Growth hormone (GH)[67], insulin-like growth factor I (IGF-I)[68], synapsin I[69] and Fibroblast growth factor-2 (FGF-2)[70] that aid in initiating molecular cascades that are crucial for the onset of neurogenesis in the adult brain. At the supramolecular level, physical exercise has been found to be effective in increasing dendritic length, spine density and neurogenic activity in dentate gyrus of the adult brain[71]. Evidence from numerous scientific studies have confirmed the role of physical activity in promoting brain vascularization[72], neuronal repair following brain injury[73] as well as reducing the risk of memory impairment and dementia in late adulthood by selectively reversing the loss of hippocampal volume with age[74].
Stress and elevated levels of glucocorticoids are known to inhibit neuronal growth and hippocampal neurogenesis in the adult brain[75]. There is presently a growing set of evidence that supports the positive effects of physical exercise in counteracting the effect of stress by reducing the levels of stress hormones[76] and increasing the availability of BDNF in the hippocampus, an important mediator of neurogenesis and plasticity in the adult brain[77]. On the other hand, a sedentary lifestyle in urban areas[78] and physical frailty[79] have been associated with an increased rate of cognitive decline and a higher risk of cognitive impairment in older adults. Hence, physical activity can act as a powerful effector of brain pathology by reversing stress-induced impairment of adult neurogenesis and increasing resistance to brain injury.

3.4. Social Interaction

Social interaction forms an integral part of our lives and is one of the most effective life style modifications that can bring about significant improvements in our cognitive abilities. In fact, a study has revealed that engaging in a 10 minute session of social interaction involving mentally stimulating conversations can enhance brain plasticity by improving cognitive abilities like learning, memory, attention and control[80].
Contrary to social interaction, isolation has deleterious effects. Oligodendrocytes are cells that actively participate in the formation of myelin sheaths around the neurons and promote nerve transmission[81]. Socially isolated rats showed a remarkable decrease in the density of oligodendrocytes in the prefrontal cortex, a region in the brain that governs emotional and cognitive behavior. Rats are, in general, highly motivated to be social; however when exposed to a novel rat after 8 weeks of isolation, they did not show any interest in interacting with the new rat, thus turning into a model of social avoidance and withdrawal[82]. Hence, social isolation can disrupt nerve transmission and affect brain plasticity to a great extent, thereby leading to many demyelinating and psychiatric disorders.
Moreover, it was found that the effect of social interaction on promoting brain recovery in mice, following ischemia, was superior to wheel-running and an enriched environment that comprised of free physical activity[83]. In addition, social isolation has been linked to increased susceptibility to stress, which in turn, attenuates the process of neurogenesis reduces the expression levels of brain plasticity markers in the hippocampus region and pre-frontal cortex[84].
In today’s world, owing to fewer social connections, decline in the number of organizations, family dinners and gatherings that involve one-on-one conversations, people have been finding it hard to establish a close relationship with someone to share their innermost feelings and thoughts. This has led to a gradual decline in cognitive abilities, thus reducing the sense of well-being and making socially inactive people, more prone to mental illnesses[85]. A study conducted by researchers at the Rush Alzheimer's Disease Center has established emotional isolation or loneliness as a potent risk factor for Alzheimers disease. Hence, people who stay persistently lonely become more susceptible to the devastating symptoms associated with age-related neuropathology[86]. Humans are biologically wired to be social creatures and therefore, need to stay socially active by maintaining close friendships and healthy relationships in order to improve brain health.

3.5. Dietary Modifications

Many years of research have demonstrated the beneficial effects of dietary modifications that incorporate calorie restriction, on reversing age-associated cognitive decline in both wild-type[87] and experimental models of Alzheimer’s disease[88], Parkinson’s disease[89] and Stroke[90]. Intake of proper diet leads to a reduction in oxidative stress that is primarily responsible for senescence-related loss of brain functions in neurodegenerative disorders[91]. At the molecular level, dietary restriction have been found to exert a neuroprotective effect by altering synaptic homeostasis[92], signalling cascades and long-term brain plasticity[93], thereby increasing resistance to withstand oxidative and metabolic insults.
Most importantly, dietary restriction has been found to alter the expression of neurotrophins like Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), which play a major role in increasing the rate of adult neurogenesis and enhancing brain plasticity, thereby slowing down the progression of neurodegeneration and increasing resistance to brain injury[94]. This has been supported by another study conducted in mice that has established the role of a diet rich in high saturated fat and refined sugar, a typical diet of many urbanized countries, in lowering hippocampal levels of Brain-derived neurotrophic factor (BDNF) and its downstream effectors like synapsin I, cyclic AMP-response element-binding protein (CREB) and growth-associated protein 43; factors that are crucial for maintaining neuronal growth, neurotransmitter release, and synaptic plasticity[95].
Hence, calorie restriction, in conjunction with dietary modification, involving the incorporation of fruits, vegetables and foods that are enriched with nutrients that influence brain health and cognition[96], constitute an effective strategy for both preventing and reversing the progression of neurological and psychiatric disorders.
3.5.1. Diet Rich in Omega-3 Fatty Acids
Long-chain Omega-3 polyunsaturated fatty acids namely docosahexaenoic acid and eicosapentaentoic acid form an important constituent of neuronal membranes and play a crucial role in maintaining cognitive abilities in late adulthood[97]. Decreased levels of Omega-3 fatty acids have been strongly linked with an increased rate of cognitive impairment, dementia and Alzheimer’s disease[98] and other neuropsychiatric disorders like schizophrenia, depression and attention deficit hyperactivity disorder (ADHD) [99,100].
A study conducted by Wu A[101] has shown that a diet rich in Omega-3 fatty acids fed to mice, for a period of 4 weeks, not only improved the speed of nerve impulse transmission, but also protected neurons from oxidative damage induced by mild fluid percussion injury (FPI). The neuroprotective effect conferred by Omega-3 fatty acids against reduced plasticity and impaired learning and memory was found to be a result of the normalization of the levels of BDNF and its downstream effectors namely, synapsin I, and cAMP responsive element-binding protein (CREB).
Hence, supplementation of Omega-3 fatty acids through a diet rich in fish, fish oils, sardines, walnuts, flax seeds, tofu, soybeans, olive oil, canola oil has been implicated to improve learning and memory and delay age-associated cognitive decline.
3.5.2. Diet Rich in Iron
Given the vital role played by iron in brain oxygen transport, myelin production, morphology of neural networks and synthesis of neurotransmitters, iron deficiency in early stages of life can lead to irreversible alterations in brain development and neuronal functioning[102]. While iron overload also has been strongly associated with the pathophysiology of many neurodegenerative disorders[103], early-life iron deficiency has been shown to alter hippocampal volume by impairing hippocampal neurogenesis and reducing the expression levels of Brain-derived neurotrophic factor[104].
During normal aging and age-related neurodegenerative diseases like Alzheimer’s and Parkinson’s disease, dyshomeostasis of iron has been commonly observed[105]. Hence, intake of foods rich in iron like dark leafy greens, beans, lentils, chickpeas, tofu, red meat, chicken, turkey, egg yolk, liver, oysters, dates, nuts and raisins can maintain optimum levels of iron that in turn, up-regulates the levels of BDNF and slows down the rate of age-associated neurodegeneration in the brain.
3.5.3. Diet Rich in Zinc
Zinc has been found to play a critical role in regulating communication between nerve cells in the hippocampus, thereby maintaining cognitive stability and improving learning and memory[106]. Highly concentrated in the cortex, hippocampus and amygdala, zinc acts as a cofactor for many enzymes and zinc metalloproteins that are essential for synaptic neurotransmission and cellular signalling cascades[107].
Alterations of zinc dyshomeostasis both in the form of zinc accumulation and zinc deficiency have been considered an important factor for the onset of Alzheimer’s disease, depression other age-related neuropsychiatric disorders[108]. Indeed, zinc deficiency has been strongly linked with reduced hippocampal neurogenesis and increased neuronal death, thus leading to the impairment of synaptic plasticity and learning and memory deficits[109]. Also, a growing number of studies conducted in humans and rodents support the involvement of zinc deficiency in the pathogenesis of depression[110]. While zinc deficiency has been found to be a potent risk factor for treatment resistance to anti-depressants[111], zinc treatment in mice has been shown to mimick the activity of anti-depressants by increasing the expression of BDNF[112]. Hence, ensuring adequate intake of foods rich in zinc like nuts, seeds, liver, red meat, shellfish, oats and green peas can enhance brain plasticity and can have a great impact on brain health.
3.5.4. Diet Rich in Vitamin E
Owing to its potent anti-oxidant activity, Vitamin E aids in scavenging toxic free radicals, thus counteracting the effect of oxidative damage on neuronal cells[113]. Elevated serum levels of two natural forms of vitamin E, namely tocopherols and tocotrienols, have been associated with a reduced risk of cognitive impairment in older adults[114]. Palm oil-derived alpha-tocotrienol, a natural Vitamin E molecule has been found to have the potential of attenuating the process of oxidative metabolism of arachidonic acid, a common mechanism that leads to the onset of several neurodegenerative disorders[115]. The anti-oxidant property of vitamin E has been linked to its ability of normalizing the levels of BDNF, and its downstream effectors like synapsin I and cyclic AMP-response element-binding protein (CREB) that are important modulators of neuronal and behavioural plasticity[116].
Therefore, frequent consumption of foods rich in Vitamin E like tofu, spinach, avocados, broccoli, red bell peppers, tropical fruits, nuts, seeds, fish, olive oil and palm oil can enhance neuroprotection and delay the development of neurodegenerative disorders like Alzheimer’s disease[117].

4. Relaxation Therapies

There is considerable epidemiological evidence supporting the association between chronic stress and impaired neuroplasticity[118]. Brain-derived neurotrophic factor (BDNF) and Neurotrophin-3, the two neurotrophic factors that play an important role in enhancing brain plasticity and preventing neuronal death, have been found to be lowered in rats that were exposed to chronic stress[119]. This has been supported by data obtained from human and animal studies that suggest an inverse relationship between stress hormones and BDNF levels[120]. Hence, abnormally high levels of stress hormones and a simultaneous reduction in the expression of BDNF plays an important role in stress-mediated changes in neuroplasticity and cognition [121].
In order to relieve stress, several researcher have shown the benefits of various relaxation techniques like deep breathing meditation, yoga, Tai chi, aromatherapy and music therapy for ameliorating cognitive impairment associated with increases stress. Tai chi, a non-aerobic exercise originally developed as a means of self-defence, has now evolved as a powerful technique for promoting psychological well-being by reducing stress, anxiety and depression[122]. In fact, a study conducted by James A Mortimer et. al showed an increase in the brain volume and cognitive improvement in healthy individuals practicing Tai chi[123]. Meditation has been shown to have a neuroprotective effect through its ability to strengthen neuronal circuits, delay the process of neurodegeneration and reduce the risk of age-associated cognitive decline[124]. Indeed, yoga meditation have been associated with neuroplastic changes in the brain, as evident by an increase in grey matter volume[125] and elevated serum BDNF levels in depressed individuals[126].
There is also a growing body of evidence on the beneficial effects of aromatherapy in reducing stress levels, as shown by a studies demonstrating the effect of lavender oil on reducing stress levels and pain intensity[127]; essential oils of salvia species on improving the quality of memory and mood[128] and aromas of peppermint showing a significant improvement in cognitive performance and mood levels in healthy individuals[129]. In addition, an interesting study conducted using a rat model of Alzheimer’s disease have shown the positive effects of the essential oils of Chamaecyparis obtuse in reversing neuronal apoptosis and memory deficits[130]. Hence relaxation techniques incorporated in one’s lifestyle can not only prevent the onset of neurodegenerative disorders, but can also suppress the progression of the disease by promoting adult neurogenesis during pathological conditions.

5. Conclusions

Given the available evidence, we conclude that non-pharmacological interventions show promising results in reducing age-associated cognitive decline and offer hope to target the underlying cause of brain disorders by augmenting neurogenesis and preventing neuronal death, thereby stimulating neuronal regeneration in the adult brain. Besides promoting neuro-rehabilitation in pathological conditions, these therapies can also be adapted by the younger generation as preventive measures to delay the onset of neurodegenerative disorders in adulthood.
Considering the fact that brain plasticity is maintained well into adulthood and old age, when devising strategies to combat age-related neurological disorders, it is best to adapt a combinatorial approach involving drug-based therapies, psychological interventions and lifestyle modifications to overcome the adverse effects of medications and facilitate plastic changes in the brain to speed up the process of recovery.

6. Future Research

Even though the effectiveness of non-pharmacological interventions in enhancing brain plasticity has been well established, there are many unanswered questions with regard to the implementation of these therapies in real-life settings. Furthermore, there is a clear need for more randomized controlled trials and funding to systematically address the long term benefits of non-pharmacological intervention for enhancing brain plasticity.
Also, a common or different molecular mechanisms underlying the beneficial effects of non-pharmacological interventions in enhancing brain plasticity still remain to be satisfactorily elucidated. Therefore, further investigations linking the benefits of non-pharmacological interventions for improving cognition, mood, quality of life, behavior and day-to-day functioning, with the measurement of the changes in the levels of molecular mediators of adult neurogenesis, can strengthen the existing evidence and support the theoretical basis of these non-drug based therapies.


[1]  Mayeux R. Epidemiology of neurodegeneration. Annu Rev Neurosci. 2003;26:81-104.
[2]  Misra A, Ganesh S, Shahiwala A. Drug delivery to the central nervous system: a review. Pharm Pharmaceut Sci. 2003;6: 252-273.
[3]  Michelsen JW, Meyer JM. Cardiovascular effects of antipsychotics. Expert Rev Neurother. 2007 Jul;7(7):829-39.
[4]  Gardette V, Coley N, A Sandrine. Non Pharmocological therapies: A different Approach to AD, The Canadian Review of Alzheimer’s Disease and Other Dementias. 2010;13:13-22.
[5]  Colcombe S, Kramer AF. Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychol Sci. 2003;14(2):125-30.
[6]  Burke SN, Barnes CA. Neural plasticity in the ageing brain. Nature Reviews Neuroscience. 2006;7:30-40.
[7]  Zhao C, Deng W, Gage FH, Mechanisms and Functional Implications of Adult Neurogenesis. Cell. 2008;132:645-60.
[8]  Ganguly K, Poo MM. Activity-dependent neural plasticity from bench to bedside. Neuron. 2013;80(3):729-41.
[9]  Buell SJ, Coleman PD. Quantitative evidence for selective dendritic growth in normal human aging but not in senile dementia. Brain Research. 1981;214:23-41.
[10]  Christopher Hertzog, Arthur F. Kramer, Robert S, Wilson and Ulman Lindenberger Enrichment Effects on Adult Cognitive Development: Can the Functional Capacity of Older Adults Be Preserved and Enhanced? Psychological Science in the Public Interest. 2008;9: 1-65.
[11]  Branchi I, Francia N, Alleva E. Epigenetic control of neurobehavioural plasticity: the role of neurotrophins. Behav Pharmacol. 2004;15(5-6):353-62.
[12]  Waterhouse EG, An JJ, Orefice LL, et al. BDNF promotes differentiation and maturation of adult-born neurons through GABAergic transmission. Neuroscience. 2012;32:14318-30.
[13]  Carter AR, Chen C, Schwartz PM, Segal RA. Brain-Derived Neurotrophic Factor Modulates Cerebellar Plasticity and Synaptic Ultrastructure. Neuroscience. 2002;22:1316-27.
[14]  Balaratnasingam S, Janca A. Brain Derived Neurotrophic Factor: A novel neurotrophin involved in psychiatric and neurological disorders. Pharmacol Ther. 2012;134:116-24.
[15]  Lee JG, Shin BS, You YS, Kim JE, Yoon SW, Jeon DW, Baek JH, Park SW, Kim YH.Decreased serum brain-derived neurotrophic factor levels in elderly korean with dementia. Psychiatry Investig. 2009 Dec;6(4):299-305
[16]  O'Bryant SE, Hobson VL, Hall JR, Barber RC, Zhang S, Johnson L, Diaz-Arrastia R. Serum brain-derived neurotrophic factor levels are specifically associated with memory performance among Alzheimer's disease cases. Dement Geriatr Cogn Disord. 2011;31:31-6.
[17]  Howells DW, Porritt MJ, Wong JY, et al. Reduced BDNF mRNA expression in the Parkinson's disease substantia nigra. Experimental Neurology. 2000;166:127-35.
[18]  P Muglia, A M Vicente, M Verga, N King, F Macciardi, J L Kennedy. Association between the BDNF gene and schizophrenia. Molecular Psychiatry. 2002;8:146–147.
[19]  Ferrer I, Goutan E, Marín C, Rey MJ, Ribalta T. Brain-derived neurotrophic factor in Huntington disease. Brain Research. 2000;866:257-61.
[20]  Garcia KL, Yu G, Nicolini C, et al. Altered Balance of Proteolytic Isoforms of Pro–Brain-Derived Neurotrophic Factor in Autism. Neuropathology and Experimental Neurology. 2012;71:289-97.
[21]  Castrén E, Rantamäki T. The role of BDNF and its receptors in depression and antidepressant drug action: Reactivation of developmental plasticity. Developmental Neurobiology. 2010;70:289-97.
[22]  Hindle JV, Petrelli A, Clare L, Kalbe E. Nonpharmacological enhancement of cognitive function in Parkinson's disease: a systematic review. Mov Disord. 2013;28(8):1034-49.
[23]  Olazarán J, Reisberg B, Clare L, et. Al. Nonpharmacological therapies in Alzheimer's disease: a systematic review of efficacy. Dement Geriatr Cogn Disord. 2010;30(2):161-78.
[24]  Zec RF, Burkett NR. Non-pharmacological and pharmacological treatment of the cognitive and behavioral symptoms of Alzheimer disease. NeuroRehabilitation. 2008; 23(5): 425-38.
[25]  Conn DK, Seitz DP. Advances in the treatment of psychiatric disorders in long-term care homes. Curr Opin Psychiatry. 2010;23(6):516-21.
[26]  Burrows EL, McOmish CE, Hannan AJ. Gene-environment interactions and construct validity in preclinical models of psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(6):1376-82.
[27]  Nithianantharajah J, Hannan AJ. Enriched environments, experience dependent plasticity and disorders of the nervous system. Nature. 2006;7:697-709.
[28]  Fares RP, Belmeguenai A, Sanchez PE, Standardized environmental enrichment supports enhanced brain plasticity in healthy rats and prevents cognitive impairment in epileptic rats. PLoS One. 2013;8(1):e53888.
[29]  Rampon C, Tang YP, Goodhouse J, Shimizu E, Kyin M, Tsien JZ. Enrichment induces structural changes and recovery from non-spatial memory deficits in CA1 NMDAR1-knockout mice. Nature Neuroscience. 2000;3: 238-44.
[30]  Faherty CJ, Kerley D, Smeyne RJ. Golgi-Cox morphological analysis of neuronal changes induced by environmental enrichment. Brain Res. Dev. 2003;141:55-61.
[31]  Baraldi T, Schöwe NM, Balthazar J, Monteiro-Silva KC, Albuquerque MS, Buck HS, Viel TA. Cognitive stimulation during lifetime and in the aged phase improved spatial memory, and altered neuroplasticity and cholinergic markers of mice. Exp Gerontol. 2013;48(8):831-8.
[32]  Leggio MG, Mandolesi L, Federico F, et al. Environmental enrichment promotes improved spatial abilities and enhanced dendritic growth in the rat. Behav. Brain Res. 2005;163: 78-90.
[33]  Costa DA, Cracchiolo JR, Bachstetter AD, Hughes TF, Bales KR, et al. Enrichment improves cognition in AD mice by amyloid-related and unrelated mechanisms. Neurobiol Aging 2007;28: 831–844.
[34]  Faherty CJ, Shepherd KR, Herasimtschuk A, Smeyne RJ. Environmental enrichment in adulthood eliminates neuronal death in experimental Parkinsonism. Molecular Brain Research 2005;134: 170–179.
[35]  Van Dellen A, Blakemore C, Deacon R, York D, Hannan AJ. Delaying the onset of Huntington's in mice. Nature. 2000;404 (6779):721-2.
[36]  Jankowsky JL, Melnikova T, Fadale DJ, Xu GM, Slunt HH, Gonzales V. Environmental Enrichment Mitigates Cognitive Deficits in a Mouse Model of Alzheimer’s Disease. Neuroscience. 2005;25:5217-24.
[37]  Van Praag H, Kempermann G, Gage FH. Neural consequences of environmental enrichment. Nat Rev Neurosci. 2000 Dec;1(3):191-8.
[38]  Kempermann G, Kuhn HG, Gage FH. More hippocampal neurons in adult mice living in an enriched environment. Nature.1997;386:493-5.
[39]  Rossi C, Angelucci A, Costantin L, Braschi C, Mazzantini M, Babbini F, Fabbri ME, Tessarollo L, Maffei L, Berardi N, Caleo M. Brain-derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis following environmental enrichment. Eur J Neurosci. 2006; 24(7):1850-6.
[40]  Lee MY, Yu JH, Kim JY, Seo JH, Park ES, Kim CH, Kim H, Cho SR. Alteration of synaptic activity-regulating genes underlying functional improvement by long-term exposure to an enriched environment in the adult brain. Neurorehabil Neural Repair. 2013;27(6):561-74.
[41]  Kempermann G, Gast D, Gage FH. Neuroplasticity in Old Age: Sustained Fivefold Induction of Hippocampal Neurogenesis by Long-term Environmental Enrichment. Annals of Neurology. 2002;52:135-43.
[42]  Petrosini L, De Bartolo P, Foti F, Gelfo F, Cutuli D, Leggio MG, Mandolesi L. On whether the environmental enrichment may provide cognitive and brain reserves. Brain Res Rev. 2009;61(2):221-39.
[43]  Leach L. Cognitive stimulation therapy improves cognition and quality of life in older people with dementia. Evid Based Ment Health. 2004;7(1):19.
[44]  M. Carol Bowlby. Reality orientation thirty years later: Are we still confused? Canadian Journal of Occupation Therapy. 1991; 58(3): 114-122.
[45]  Knapp M, Thorgrimsen L, Patel A, Spector A, Hallam A, Woods B, Orrell M.Cognitive stimulation therapy for people with dementia: cost-effectiveness analysis. Br J Psychiatry. 2006;188:574-80.
[46]  Orrell M, Yates LA, Burns A, et al. Individual Cognitive Stimulation Therapy for dementia (iCST): study protocol for a randomized controlled trial. Trials. 2012;13:172.
[47]  Woods B, Aguirre E, Spector AE, Orrell M. Cognitive stimulation to improve cognitive functioning in people with dementia. Cochrane Database Syst Rev. 2012;2:CD005562.
[48]  Yuill N, Hollis V. A systematic review of cognitive stimulation therapy for older adults with mild to moderate dementia: an occupational therapy perspective. Occup Ther Int. 2011;18(4):163-86.
[49]  Wilson RS, Scherr PA, Schneider JA, Tang Y, Bennett DA. Relation of cognitive activity to risk of developing Alzheimer disease. Neurology. 2007;69:1911-20.
[50]  Spector A, Thorgrimsen L, Woods B, Royan L, Davies S, Butterworth, M, Orrell M: Efficacy of an evidence-based cognitive stimulation therapy programme for people with dementia: randomised controlled trial. Br J Psychiatry 2003; 183:248–254.
[51]  Schecker M, Pirnay-Dummer P, Schmidtke K, Hentrich-Hesse T, Borchardt D. Cognitive interventions in mild Alzheimer's disease: a therapy-evaluation study on the interaction of medication and cognitive treatment. Dement Geriatr Cogn Dis Extra. 2013;3(1):301-11.
[52]  Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 2002;25(6):295-301.
[53]  Bherer L, Erickson KI, Liu-Ambrose T. A Review of the Effects of Physical Activity and Exercise on Cognitive and Brain Functions in Older Adults. J Aging Res. 2013; 2013: 657508.
[54]  Bednarczyk MR, Aumont A, Décary S, Bergeron R, Fernandes KJ. Prolonged voluntary wheel-running stimulates neural precursors in the hippocampus and forebrain of adult CD1 mice. Hippocampus. 2009;19(10):913-27.
[55]  Li H, Liang A, Guan F, Fan R, Chi L, Yang B. Regular treadmill running improves spatial learning and memory performance in young mice through increased hippocampal neurogenesis and decreased stress. Brain Res. 2013;1531:1-8.
[56]  Heyn P, Abreu BC, Ottenbacher KJ. The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis. Arch Phys Med Rehabil. 2004; 85(10):1694-704.
[57]  Blankevoort CG, van Heuvelen MJ, Boersma F, Luning H, de Jong J, Scherder EJ. Review of effects of physical activity on strength, balance, mobility and ADL performance in elderly subjects with dementia. Dement Geriatr Cogn Disord. 2010;30(5):392-402.
[58]  Patten AR, Sickmann H, Hryciw BN, Kucharsky T, Parton R, Kernick A, Christie BR. Long-term exercise is needed to enhance synaptic plasticity in the hippocampus. Learn Mem. 2013;20(11):642-7.
[59]  Fisher BE, Wu AD, Salem GJ, The effect of exercise training in improving motor performance and corticomotor excitability in people with early Parkinson's disease. Arch Phys Med Rehabil. 2008;89(7):1221-9.
[60]  Kramer AF, Erickson KI, Colcombe SJ. Exercise, cognition, and the aging brain. J Appl Physiol. 1985;101(4):1237-42.
[61]  Neeper SA, Gómez-Pinilla F, Choi J, Cotman CW. Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain. Brain Res. 1996;726(1-2):49-56.
[62]  Alomari MA, Khabour OF, Alzoubi KH, Alzubi MA. Forced and voluntary exercises equally improve spatial learning and memory and hippocampal BDNF levels. Behav Brain Res. 2013;247:34-9.
[63]  Korol DL, Gold PE, Scavuzzo CJ. Use it and boost it with physical and mental activity. Hippocampus. 2013;23(11): 1125-35.
[64]  Colcombe S, Kramer AF. Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychol Sci. 2003;14(2):125-30.
[65]  Berchtold NC, Kesslak JP, Pike CJ, Adlard PA, Cotman CW. Estrogen and exercise interact to regulate brain-derived neurotrophic factor mRNA and protein expression in the hippocampus. Eur J Neurosci. 2001;14(12):1992-2002.
[66]  Erickson KI, Colcombe SJ, Elavsky S, McAuley E, Korol DL, Scalf PE, Kramer AF. Interactive effects of fitness and hormone treatment on brain health in postmenopausal women. Neurobiol Aging. 2007;28(2):179-85.
[67]  Blackmore DG, Vukovic J, Waters MJ, Bartlett PF. GH mediates exercise-dependent activation of SVZ neural precursor cells in aged mice. PLoS One. 2012;7(11):e49912.
[68]  Carro E, Trejo JL, Busiguina S, Torres-Aleman I. Circulating insulin-like growth factor I mediates effects of exercise on the brain. Neuroscience. 2000;21:5678-84.
[69]  Vaynman S, Ying Z, Gómez-Pinilla F. Exercise induces BDNF and synapsin I to specific hippocampal subfields. J Neurosci Res. 2004;76(3):356-62.
[70]  Eliakim A, Oh Y, Cooper DM. Effect of single wrist exercise on fibroblast growth factor-2, insulin-like growth factor, and growth hormone. Am J Physiol Regul Integr Comp Physiol. 2000;279:R548-53.
[71]  Eadie BD, Redila VA, Christie BR. Voluntary exercise alters the cytoarchitecture of the adult dentate gyrus by increasing cellular proliferation, dendritic complexity, and spine density. J Comp Neurol. 2005 May 23;486(1):39-47.
[72]  Isaacs KR, Anderson BJ, Alcantara AA, Black JE, Greenough WT. Exercise and the brain: angiogenesis in the adult rat cerebellum after vigorous physical activity and motor skill learning. Cerebral Blood Flow Metab. 1992;12: 110-9.
[73]  Stummer W, Weber K, Tranmer B, Baethmann A, Kempski O. Reduced mortality and brain damage after locomotor activity in gerbil forebrain ischemia. Stroke. 1994;25: 1862-9.
[74]  Erickson KI, Voss MW, Prakash RS, Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A. 2011;108(7):3017-22.
[75]  Schoenfeld TJ, Gould E. Differential effects of stress and glucocorticoids on adult neurogenesis. Curr Top Behav Neurosci. 2013;15:139-64.
[76]  Nabkasorn C, Miyai N, Sootmongkol A, Junprasert S, Yamamoto H, Arita M, Miyashita K. Effects of physical exercise on depression, neuroendocrine stress hormones and physiological fitness in adolescent females with depressive symptoms. Eur J Public Health. 2006 ;16(2):179-84.
[77]  Gómez-Pinilla F, Ying Z, Roy RR, Molteni R, Edgerton VR. Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. J Neurophysiol. 2002;88(5): 2187-95.
[78]  Uysal N, Kiray M, Sisman A, Effects of exercise and poor indoor air quality on learning, memory and blood IGF-1 in adolescent mice. Biotech Histochem. 2013.[Epub ahead of print.
[79]  Boyle PA, Buchman AS, Wilson RS, Leurgans SE, Bennett DA. Physical frailty is associated with incident mild cognitive impairment in community-based older persons. J Am Geriatr Soc. 2010;58(2):248-55.
[80]  Ybarra O, Burnstein E, Winkielman P , et al. Mental Exercising Through Simple Socializing: Social Interaction Promotes General Cognitive Functioning. Personality and Social Psychology Bulletin. 2012;34:248-59.
[81]  Bradl M, Lassmann H. Oligodendrocytes: biology and pathology. Acta Neuropathol. 2010;119(1):37-53.
[82]  Jia Liu, Karen Dietz, Jacqueline M DeLoyht , et al. Impaired adult myelination in the prefrontal cortex of socially isolated mice. Nature Neuroscience. 2012;15,1621-1623.
[83]  Johansson BB, Ohlsson AL. Environment, social interaction, and physical activity as determinants of functional outcome after cerebral infarction in the rat. Exp Neurol. 1996;139:322-7.
[84]  Djordjevic J, Djordjevic A, Adzic M, Radojcic MB. Effects of chronic social isolation on Wistar rat behavior and brain plasticity markers. Neuropsychobiology. 2012;66:112-9.
[85]  Gladstone GL, Parker GB, Malhi GS, Wilhelm KA. Feeling unsupported? An investigation of depressed patient’s depression. Affective Disorders. 2007;103:147-54.
[86]  Wilson RS, Krueger KR, Arnold SE, et al. Loneliness and Risk of Alzheimer Disease. Arch Gen Psychiatry. 2007; 64:234-40.
[87]  Bruce-Keller AJ, Umberger G, McFall R, Mattson MP. Food restriction reduces brain damage and improves behavioral outcome following excitotoxic and metabolic insults. Ann Neurol. 1999;45(1):8-15.
[88]  Maruszak A, Pilarski A, Murphy T, Branch N, Thuret S. Hippocampal neurogenesis in Alzheimer's disease: is there a role for dietary modulation? J Alzheimers Dis. 2014;38(1): 11-38.
[89]  Duan W, Mattson MP. Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson's disease. J Neurosci Res. 1999;57(2):195-206.
[90]  Yu ZF, Mattson MP. Dietary restriction and 2-deoxyglucose administration reduce focal ischemic brain damage and improve behavioral outcome: evidence for a preconditioning mechanism. J Neurosci Res. 1999;57(6):830-9.
[91]  Dubey A, Forster MJ, Lal H, Sohal RS. Effect of age and caloric intake on protein oxidation in different brain regions and on behavioral functions of the mouse. Arch Biochem Biophys. 1996;333(1):189-97.
[92]  Guo Z, Ersoz A, Butterfield DA, Mattson MP. Beneficial effects of dietary restriction on cerebral cortical synaptic term nals: preservation of glucose and glutamate transport and mitochondrial function after exposure to amyloid beta-peptide, iron, and 3-nitropropionic acid. J Neurochem. 2000;75(1):314-20
[93]  Gomez-Pinilla F, Tyagi E. Diet and cognition: interplay between cell metabolism and neuronal plasticity. Curr Opin Clin Nutr Metab Care. 2013;16:726-733.
[94]  Lee J, Seroogy KB, Mattson MP. Dietary restriction enhances neurotrophin expression and neurogenesis in the hippocampus of adult mice. J Neurochem. 2002;80(3):539-47
[95]  Molteni R, Barnard RJ, Ying Z, Roberts CK, Gómez-Pinilla F. A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning. Neuroscience. 2002;112:803-14.
[96]  Fernando Gómez-Pinilla, Brain foods: the effects of nutrients on brain function. Nature Reviews Neuroscience. 2008; 9, 568-578.
[97]  Yehuda S, Rabinovitz S, Carasso RL, Mostofsky DI. The role of polyunsaturated fatty acids in restoring the aging neuronal membrane. Neurobiol Aging. 2002;23(5):843-53.
[98]  Conquer JA, Tierney MC, Zecevic J, Bettger WJ, Fisher RH. Fatty acid analysis of blood plasma of patients with Alzheimer's disease, other types of dementia, and cognitive impairment. Lipids. 2000;35(12):1305-12.
[99]  Young G, Conquer J. Omega-3 fatty acids and neuropsychiatric disorders. Reprod Nutr Dev. 2005;45:1-28.
[100]  Ortega RM, Rodríguez-Rodríguez E, López-Sobaler AM. Effects of omega 3 fatty acids supplementation in behavior and non-neurodegenerative neuropsychiatric disorders. Br J Nutr. 2012;107 Suppl 2:S261-70.
[101]  Wu A, Ying Z, Gomez-Pinilla F. Dietary Omega-3 Fatty Acids Normalize BDNF Levels, Reduce Oxidative damage and Counteract Learning Disability after Traumatic Brain Injury in Rat. Neurotrauma. 2004;21:1457-67.
[102]  Beard J. Iron deficiency alters brain development and functioning. J Nutr.2003;133(5 Suppl 1):1468S-72S.
[103]  Kruer MC. The neuropathology of neurodegeneration with brain iron accumulation. Int Rev Neurobiol. 2013;110: 165-94.
[104]  Tran PV, Carlson ES, Fretham SJ, Georgieff MK. Early-life iron deficiency anemia alters neurotrophic factor expression and hippocampal neuron differentiation in male rats. Nutrition. 2008;138:2495-501.
[105]  Fairweather-Tait SJ, Wawer AA, Gillings R, Jennings A, Myint PK. Iron status in the elderly. Mech Ageing Dev. 2013; S0047-6374(13)00124-3.
[106]  Frederickson CJ, Suh SW, Silva D, Frederickson CJ, Thompson RB. Importance of zinc in the central nervous system: the zinc-containing neuron. J Nutr. 2000;130(5S Suppl):1471S-83S.
[107]  Takeda A. Movement of zinc and its functional significance in the brain. Brain Res Brain Res Rev. 2000;34(3):137-48.
[108]  Takeda A. Movement of zinc and its functional significance in the brain. Brain Res Brain Res Rev. 2000;34(3):137-48.
[109]  Takeda A. Movement of zinc and its functional significance in the brain. Brain Res Brain Res Rev. 2000;34(3):137-48.
[110]  Swardfager W, Herrmann N, McIntyre RS, Potential roles of zinc in the pathophysiology and treatment of major depressive disorder. Neurosci Biobehav Rev. 2013;37(5): 911-29.
[111]  Młyniec K, Nowak G. Zinc deficiency induces behavioral alterations in the tail suspension test in mice. Effect of antidepressants. Pharmacol Rep. 2012;64(2):249-55.
[112]  Sowa-Kućma M, Legutko B, Szewczyk B, et al. Antidepressant-like activity of zinc: further behavioral and molecular evidence. Neural Transmission. 2008;115:1621-8.
[113]  Aiguo Wu, Zhe Ying, Gomez-Pinilla F. Vitamin E Protects Against Oxidative Damage and Learning Disability After Mild Traumatic Brain Injury in Rats. Neurorehabil Neural Repair. 2010;24:290-8.
[114]  Mangialasche F, Solomon A, Kåreholt I, Serum levels of vitamin E forms and risk of cognitive impairment in a Finnish cohort of older adults. Exp Gerontol. 2013;48(12): 1428-35.
[115]  Sen CK, Rink C, Khanna S. Palm oil-derived natural vitamin E alpha-tocotrienol in brain health and disease. J Am Coll Nutr. 2010;29(3 Suppl):314S-323S.
[116]  Wu A, Ying Z, Gomez-Pinilla F. The interplay between oxidative stress and brain-derived neurotrophic factor modulates the outcome of a saturated fat diet on synaptic plasticity and cognition. Eur J Neurosci. 2004; 19: 1699-707.
[117]  Kontush K, Schekatolina S. Vitamin E in neurodegenerative disorders: Alzheimer's disease. Ann N Y Acad Sci. 2004; 1031:249-62.
[118]  Lynch JW, Kaplan GA, Shema SJ. Cumulative impact of sustained economic hardship on physical, cognitive, psychological, and social functioning. N Engl J Med. 1997;337(26):1889-95.
[119]  Smith MA, Makino S, Kvetnansky R, Post RM. Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci. 1995;15(3 Pt 1):1768-77.
[120]  Issa G, Wilson C, Terry AV Jr, Pillai A. An inverse relationship between cortisol and BDNF levels in Schizophrenia: Data from human postmortem and animal studies. Neurobiology of disease. 2010;39:327-33.
[121]  Licinio J, Wong M-. Brain-derived neurotrophic factor (BDNF) in stress and affective disorders. Mol Psychiatry. 2002;7(6):519.
[122]  Wang F, Lee EK, Wu T, Benson H, Fricchione G, Wang W, Yeung AS. The Effects of Tai Chi on Depression, Anxiety, and Psychological Well-Being: A Systematic Review and Meta-Analysis. Int J Behav Med. 2013.[Epub ahead of print].
[123]  Mortimer JA, Ding D, Borenstein AR, et. al. Changes in brain volume and cognition in a randomized trial of exercise and social interaction in a community-based sample of non-demented Chinese elders. J Alzheimers Dis. 2012;30(4): 757-66.
[124]  Xiong GL, Doraiswamy PM. Does meditation enhance cognition and brain plasticity? Ann N Y Acad Sci. 2009;1172: 63-9.
[125]  Froeliger B, Garland EL, McClernon FJ. Yoga meditation practitioners exhibit greater gray matter volume and fewer reported cognitive failures: results of a preliminary voxel-based morphometric analysis. Evid Based Complement Alternat Med. 2012;2012:821307.
[126]  Naveen GH, Thirthalli J, Rao MG, Varambally S, Christopher R, Gangadhar BN. Positive therapeutic and neurotropic effects of yoga in depression: A comparative study. Indian J Psychiatry. 2013;55(Suppl 3):S400-4.
[127]  Kim S, Kim HJ, Yeo JS, Hong SJ, Lee JM, Jeon Y. The effect of lavender oil on stress, bispectral index values, and needle insertion pain in volunteers. J Altern Complement Med. 2011 Sep;17(9):823-6.
[128]  Moss L, Rouse M, Wesnes KA, Moss M. Differential effects of the aromas of Salvia species on memory and mood. Hum Psychopharmacol. 2010;25(5):388-96.
[129]  Moss M, Hewitt S, Moss L, Wesnes K. Modulation of cognitive performance and mood by aromas of peppermint and ylang-ylang. Int J Neurosci. 2008;118(1):59-77.
[130]  Bae D, Seol H, Yoon HG, Na JR, Oh K, Choi CY, Lee DW, Jun W, Youl Lee K, Lee J, Hwang K, Lee YH, Kim S. Inhaled essential oil from Chamaecyparis obtuse ameliorates the impairments of cognitive function induced by injection of β-amyloid in rats. Pharm Biol. 2012;50(7):900-10.