mechanism of action for nonpharmacological therapies for individuals with dementiaalio

1Research in Gerontological Nursing Vol. x, No. x, 20xx

State of the Science

Historically, the development of pharmacological ther-apies for dementia has consumed a majority of research re-sources and involvement of the scientific community. Con-comitantly, research testing nonpharmacological therapies has not fared well in meta-analyses assessing intervention efficacy for dementia, as addressed in a recent review of meta-analyses by Cohen-Mansfield et al. (2014). Yet, along with these current and historical trends, increased evi-dence and theoretical understandings have evolved from the physical sciences that offer support for nonpharma-

cological interventions designed to assist individuals with dementia to maintain function, slow disease progression, or both (Herring et al., 2009; Rodriguez & Verkhratsky, 2011). This increased support for nonpharmacological therapies comes at a time when emerging drug therapies have proven to be less effective than anticipated in ame-liorating the cognitive loss inherent in dementia (Lleo, Greenberg, & Growdon, 2006; Tschanz et al., 2011; Zec & Burkett, 2008). Increasingly, members of the scientific community are recognizing the need for multiple therapies

ABSTRACT

The current review addresses the need for increased use of evidence-based, nonpharmacological thera-pies for individuals with dementia. To facilitate understanding of the potential efficacy of nonpharmaco-logical therapies on cognitive functioning for individuals with dementia, the mechanisms of action for selected therapies are described, including the assessment method used to identify the mechanism. The strength of evidence supporting each therapy was evaluated, with some therapies demonstrating strong support and others only moderate support for their effectiveness and mechanism of action. Therapies with the strongest support include (a) cognitive training/stimulation, (b) physical exercise, and (c) music. Therapies with moderate support include (a) biofield, (b) meditation, (c) engagement with a naturally restorative environment, and (d) social engagement. Although the strength of evidence varies, together these therapies offer treatments designed to improve cognitive functioning, have low risks and adverse effects, and have the potential for widespread accessibility, thereby increasing the potential range of therapies for individuals with dementia.[Res Gerontol Nurs. 20XX; X(XX):XX-XX.]

Dr. Burgener is Associate Professor Emerita, College of Nursing, University of Illinois, Urbana, Illinois; Dr. Jao is Assistant Professor, College of

Nursing, Pennsylvania State University, Philadelphia, Pennsylvania; Dr. Anderson is Assistant Professor and Roberts Scholar, School of Nursing,

University of Virginia, Charlottesville, Virginia. Dr. Jao is also Adjunct Associate Professor, and Dr. Bossen is Postdoctoral Scholar, College of Nursing,

University of Iowa, Iowa City, Iowa.

The authors have disclosed no potential conflicts of interest, financial or otherwise.

Address correspondence to Sandy C. Burgener, PhD, RN, FAAN, Associate Professor Emerita, College of Nursing, University of Illinois, 210 S. Good-

win Street, Urbana, IL 61801; e-mail: [email protected].

doi:10.3928/19404921-20150429-02

Mechanism of Action for Nonpharmacological Therapies for Individuals With DementiaImplications for Practice and Research

Sandy C. Burgener, PhD, RN, FAAN; Ying-Ling Jao, PhD, RN; Joel G. Anderson, PhD, HTP; and Ann L. Bossen, PhD, RN

2 Copyright SLACK Incorporated

Burgener et al.

to effectively treat dementia (Foster, Rosenblatt, & Kuljis, 2011; Iqbal & Grundke-Iqbal, 2011).

Many nonpharmacological therapies share common theoretical underpinnings with evidence generated from basic science studies. In addition, basic science has identi-fied external factors (e.g., enriched stimulation) that influ-ence neuropathology and, consequently, impact cognitive function and reduce the risks of neurodegenerative dis-orders. However, these factors have been tested primarily in animal models and relatively few studies have evalu-ated the impact in clinical trials (Briones, Suh, Hattar, & Wadowska, 2005; Burke & Barnes, 2006; Kramer, Erickson, & Colcombe, 2006). On the other hand, nonpharmacolog-ical therapies have been applied and evaluated in clinical trials and have demonstrated positive outcomes at the phenotype level. However, the mechanisms underpinning those interventions are only beginning to be systematically described and linked to evidence.

To enhance use of and grant support for nonpharmaco-logical therapies, clinicians and researchers need to better understand the state of the science regarding (a) mecha-nisms of action, (b) strength of evidence, and (c) current trends in research. The most efficacious interventions are those that target specific behaviors and identify the mecha-nism of action. Individually, evidence for these therapies may have been presented in systematic reviews or meta-analyses, yet no published report was found that synthe-sized the evidence from multiple interventions while also addressing the strength of evidence for the mechanism of action for the therapy. Although many of these therapies have multiple outcomes, the focus of the current review centers on therapies designed to improve cognitive func-tioning. As such, the current report uniquely addresses the need for further understanding of the mechanisms of action specifically on cognitive outcomes in individuals with dementia and the strength of evidence supporting these effects. The current review is not intended to be a comprehensive synthesis or meta-analysis of the research, but rather a summary of representative studies examining mechanisms of action for each therapy and associated cog-nitive outcomes.

AGING- AND DEMENTIA-RELATED NEUROPATHOLOGY

Aging is associated with structural and functional changes in the brain, which can lead to poor cognitive function and neurodegenerative disorders in older adults (Arking, 2006). Brain changes in aging related to cogni-tive functioning include (a) decreased brain weight, size,

and synaptic density, resulting in decreased synaptic ac-tivity and complexity; (b) decreased expression of neuro-trophic factors, specifically decreased brain-derived neu-rotrophic factor (BDNF) in the hippocampus; (c) reduced neurotransmitters in the hippocampus, substantia nigra, striatal pathway, and thalamus, with changes in the hippo-campus being especially apparent; and (d) decreased neu-rogenesis, particularly in the dentate gyrus (Arking, 2006; Burke & Barnes, 2006; Mora, Segovia, & del Arco, 2007).

Specifically in dementia, cerebral neuropathological changes include cerebral atrophy; decreased regional cere-bral blood flow; and a decreased number of working neu-rons, synapses, and neurotransmitters in multiple cortical and subcortical regions (Reisberg, Franssen, Souren, Auer, & Kenowsky, 1998). Autopsy studies have shown that, in individuals with dementia, the brain often displayed cortical atrophy in the neocortex and hippocampus, which led to cognitive dysfunction, including memory impair-ment, poor executive function, and a deficit in spatial navigation (Gearing et al., 1995; Savva et al., 2009). In addition, several neuropathological changes are associated with Alzheimers disease, including neuritic plaques, neu-rofibrillary tangles, and amyloid angiopathy (Savva et al., 2009).

With aging, the role of stress hormones (i.e., cyto-kines and glucocorticoids) and dysregulation of the hypothalamicpituitaryadrenal (HPA) axis are associ-ated with cognitive impairments, including those seen in dementia (McEwen, 2006, 2007; Sotiropoulos et al., 2008). The brain plays a key role in determining organ stress, with the amygdala, hippocampus, and prefrontal cortex being affected by chronic stress responses (McEwen, 2006). In older adults and individuals with dementia, the stress re-sponse often becomes maladaptive due to disrupted or failed negative feedback loops, exposing the individual to high (i.e., toxic) levels of glucocorticoids (Sotiropoulos et al., 2011). Glucocorticoids are associated with regula-tion of mood and cognition and may result in cognitive disorders when secreted at high levels, such as those seen in stress responses with impaired HPA axis regulation (de Kloet, Joels, & Holsbeor, 2005). These collective changes in function and resulting cognitive decline set the stage for an increased understanding of the mechanisms of action for nonpharmacological therapies directed at improving cog-nitive function in individuals with dementia.

THEORIES OF NEUROLOGICAL REGENERATIONResearch, primarily using animal models, suggests that

the brain, despite injury, is capable of extensive reorgani-


Nonpharmacological Therapies for Individuals With Dementia

zation, termed brain plasticity. Plasticity is described as the brains ability to change its structure and function to allow the central nervous system to obtain new informa-tion, learn new skills, establish new neuronal networks in response to environmental stimulation, and recover from brain injuries (Mora et al., 2007; Silva et al., 2012). Results of animal studies reported since the mid-1980s provide evidence of plasticity and the brains capacity to respond structurally to external stimuli (Black, Sirevaag & Gre-enough, 1987; Briones, 2006; Fillit et al., 2002). Although the magnitude of plasticity in older adults is much lower than in young individuals, current literature suggests that neural plasticity does not disappear in aged brains (Aslan, et al., 2012; Fillit et al., 2002). Although plasticity decreases with age, external factors have been shown to counterbal-ance the effects of aging and dementia-related pathology and consequently enhance plasticity and preserve cogni-tive function in older adults with dementia (Mora et al., 2007). Enriched and varied stimulations (e.g., physical activity, cognitive-stimulating activity, social engagement, environmental enrichment) are widely supported behav-ioral and environmental factors. Specifically, theories of neurological functioning and regeneration support many of the therapies included in the current review.

In humans, the production of new neurons has been shown to continue even into later years. Based on animal studies and clinical trials in humans, plasticity theory suggests that both rehabilitative and pharmacological interventions may facilitate neuronal reorganization and recovery of function (Albensi & Janigro, 2003; Bach-y-Rita, 2003a,b). Studies using human subjects tested the effectiveness of enriched environments on the preserva-tion of neuronal function, including the slowing of cell death (Bach-y-Rita, 2003b). Robertson and Murre (1999) reviewed human studies regarding brain plasticity and con-cluded that the adult brain can undergo dramatic changes in neural structures, including dendritic and axonal sprouting. Swaab, Dubelaar, Scherder, van Someren, and Verwer (2003) examined evidence from a variety of studies that indicates neurons do not die in dementia, but instead in atrophy, indicating cells may continue to be stimulated. An increasing body of evidence also indicates that meta-bolic impairment may contribute to neuronal dysfunction and atrophy in dementia. Therefore, stimulation of neu-rons both pharmacologically and nonpharmacologically is a promising strategy in the treatment of dementia.

Although some nonpharmacological therapies affect cognitive function through neurophysiological mecha-nisms, some therapies require capacity of learning. Studies

have shown that individuals with dementia can learn (Bozoki, Grossman, & Smith, 2006; De Vreese, Neri, Fiorvanti, Belloi, & Zanetti, 2001), with increased aware-ness of deficits being associated with an increased likeli-hood that an individual can benefit from cognitive reha-bilitation (Clare, Wilson, Carter, Roth, & Hodges, 2004). Evidence of brain plasticity and retained awareness and ability for learning in dementia supports the potential ben-efits of nonpharmacological therapies.

NONPHARMACOLOGICAL THERAPIESWidely used therapies that have been shown to have

a potential positive impact on cognitive functioning are included in the current review, with most therapies being tested specifically with individuals with dementia. For each therapy presented, the research was reviewed if published from the early 1990s to the present and tested the effects of the therapy on cognitive functioning. From the reviewed research, published reports were then examined for testing and identification of a specific mechanism of action. The strength of the evidence (Table 1) for effects on cognitive functioning and identification of the mechanism of action were reviewed and rated. The strength of the evidence supporting each therapy is described and categorized as demonstrating either strong or moderate support for their effectiveness and mechanism of action. Reviewed therapies with the strongest support include (a) cognitive training/stimulation, (b) physical exercise, and (c) music. Therapies with moderate support include (a) biofield, (b) meditation, (c) engagement with a naturally restorative environment (NRE), and (d) social engagement. These therapies have identified mechanisms of action that support their effects on cognitive and neuronal functioning, including potential neurogenesis. An overview of the mechanisms of action specific to each treatment is found in Table 2.

Therapies With Strongest EvidenceCognitive Training/Stimulation. Cognitive training

involves individual or group activities to stimulate an individuals cognition through association and categoriza-tion (Olazaran et al., 2010). In addition, cognitive training often involves teaching strategies with an emphasis on problem solving to enhance specific cognitive function (e.g., memory, reasoning, processing speed) and has been widely tested with individuals with dementia (Aguirre, Woods, Spector, & Orrell, 2013; Hopper et al., 2013; Olazaran et al., 2010; Sitzer, Twamley, & Jeste, 2006).

Cognitive stimulation refers to the characteristics of an individuals continuous learning and adaption to environ-


Burgener et al.

mental stimuli (Yevchak, Loeb, & Fick, 2008). It is suggested that the elements of cognitively stimulating activities require (a) multiple function involvement, (b) attention control, and (c) complicated tasks (Yevchak et al., 2008). This type of activity can refer to professional work (e.g., driving a taxi, teaching, conducting research) or leisure activities (e.g., travel, extensive reading, watching perfor-mances) (Frick & Benoit, 2010). Specific to individuals with dementia, the encoding and retrieval tasks have been most consistently examined in relation to identifying the mechanisms underlying therapeutic responses to cogni-tively stimulating therapies (Schwindt & Black, 2009).

The concept of use it or lose it has been applied to cognitive aging and suggests that specific cognitive func-tions are more likely to be promoted or preserved when individuals experience more cognitive stimulation and frequently operate that specific function (Kramer et al., 1999; Yevchak et al., 2008). In fact, research suggests that decreased cognitive performance in older adults is not due to the brains inability to change, but rather a result of a lack of stimulation (i.e., training) or insufficient interaction with the environment (Yevchak et al., 2008). The extant literature supports this concept, including findings that

cognitive stimulation significantly benefits cognitive func-tion, and the benefits are seen in individuals at any age (i.e., older adults, individuals with dementia, nursing home res-idents with more advanced disease) (Frick & Benoit, 2010; Spector et al., 2003). Recent meta-analyses indicate com-mon outcomes of cognitive therapies include (a) improved memory and mental ability; (b) errorless learning achieve-ment; (c) verbal and visual learning; (d) improved execu-tive functioning, language, and attention; (e) improved functioning in activities of daily living; and (f) lower de-pression (Aguirre et al., 2013; Hopper et al., 2013; Olazaran et al., 2010). Long-term benefits have also been described, including improved cognitive abilities compared to con-trols specific to training as long as 5 years after treatment (Willis et al., 2006). However, findings from these analyses did not include reports of physical findings or mechanisms of action.

Bach-y-Rita (2003a,b) reported findings that support that the human brain can reorganize after being dam-aged and result in functional improvement. Mechanisms through which this reorganization can occur have been identified through studies of individuals with both mild cognitive impairment (MCI) and dementia that use mea-sures of cortical imaging (i.e., functional magnetic reso-nance imaging [fMRI] and positron emission tomography [PET] scans), cerebral blood flow, and diffusion tensor imaging for assessing white matter tracts as well as perfor-mance on measures of cognitive functioning (Aslan et al., 2012; Belleville et al., 2011; Forster et al., 2011; Schwindt & Black, 2009). Reported findings from imaging studies reveal increased activation of specific brain regions, including areas of the parietal, occipital, frontal, and tem-poral lobes (Belleville et al., 2011; Nyberg et al., 2003; Schwindt & Black, 2009), prefrontal cortex, cerebellum, and basal ganglia (Belleville et al., 2011). Increased blood flow to specific brain regions has also been identified, in-cluding the parahippocampal gyrus and bilateral inferior frontal gyri, as well as increased connectivity (i.e., white matter) in the uncinate fasciculus and forceps minor (Aslan et al., 2012). Positive cognitive outcomes reported in these studies include facename associative encoding (Celone et al., 2006; Diamond et al., 2007), visuospatial paired associate learning (Gould et al., 2006), abstract pat-tern recall (Grn, Bittner, Schmitz, Wunderlich, & Riepe, 2002), free word recall (Becker et al., 1996), attenuated de-cline (Mini-Mental State Exam [MMSE] and Alzheimers Disease Assessment Scale-cog), and word recall for pa-tients with MCI (Belleville et al., 2011; Forster et al., 2011). Specific to individuals with MCI, a systematic review of 20

TABLE 1

Scheme for Grading the Strength and Consistency of Evidence

Grade EvidenceA1 Evidence from well-designed meta-analysis or

well-done systematic review with results that consistently support a specific action (e.g., assess-ment, intervention, treatment)

A2 Evidence from one or more randomized con-trolled trials with consistent results

B1 Evidence from high-quality, evidence-based practice guideline

B2 Evidence from one or more quasi-experimental studies with consistent results

C1 Evidence from observational studies with consistent results (e.g., correlational, descriptive studies)

C2 Inconsistent evidence from observational studies or controlled trials

D Evidence from expert opinion, multiple case reports, or national consensus reports

Note. A1 and A2 = strong evidence; B1 and B2 = moderate evidence; C1, C2, and D = weak evidence. Reprinted with permission from The University of Iowa Nursing Interventions Research Center Research Translation and Dissemination Core, 11/0.



TAB

LE 2

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f Act

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Pop

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Stud

ied,

and

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on

Cogn

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n fo

r Non

phar

mac

olog

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npha

rmac

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Ther

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ssm

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etho

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echa

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M

echa

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s of A

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ion S

tudi

edEv

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ce

Grad

ing

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itive

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ains

of

Impr

ovem

ent

Cogn

itive

trai

ning

/st

imul

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RI, f

MRI

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, and

FD

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cans

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reas

ed a

ctiv

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n to

bra

in re

gion

s, in

clud

ing

the

parie

tal,

occi

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d te

mpo

ral l

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the

cere

bellu

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glia

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pre

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tal c

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reas

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flow

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peci

fic b

rain

regi

ons

Inc

reas

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onne

ctiv

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hite

mat

ter)

Non

-impa

ired

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ults

with

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and

mild

to

mod

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e de

men

tia

A1

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oved

wor

d re

call,

face

na

me

asso

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tenu

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line

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ical

exe

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rum

BD

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dec

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gA,

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the

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Burgener et al.

TAB

LE 2

Mec

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Pop

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and

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on

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phar

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echa

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tudi

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ains

of

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ovem

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itatio

n th

erap

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; MRI

; ser

um

mel

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in, s

ero-

toni

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y co

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amm

a-ba

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the

med

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icity

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f dem

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studies revealed fMRI findings indicating changes in brain activation specific to areas associated with memory (i.e., frontal, temporal, and occipital lobes), as well as increased connectivity in the medial temporal gyrus and precuneus (Simon, Yokomizo, & Bottino, 2012). These meta-analyses and reports of imaging studies provide support for cog-nitive training and stimulation therapies as beneficial for individuals with MCI and mild dementia, although the po-tential also exists for benefits for individuals at later disease stages.

Exercise Therapies. Substantial evidence suggests that physical activity and exercise, primarily aerobic exercise (e.g., walking, jogging, bicycling) and activities that require a memory for muscle movement (e.g., Tai Chi, dance), im-prove cognitive outcomes in older adults and individuals with dementia. A number of epidemiological studies have also supported the benefits of exercise for risk reduction for dementia, with significantly lower dementia rates for older adults who exercised more than three times per week, controlling for dementia risk factors such as APOE genetic predispositions (Larson et al., 2006; Podewils et al., 2005; Scarmeas et al., 2011; Yaffe, Barnes, Nevitt, Lui, & Covinsky, 2001). Mechanisms of action have been ex-amined to identify the cellular and molecular pathways to explain these positive exercise effects on the brain.

Several meta-analyses and systematic reviews describe the effects of exercise on the brain using animal models. The complexity of the mechanisms underlying exercise-induced cognitive plasticity is supported by a recent re-view by Foster et al. (2011). Some of the basic exercise ef-fects identified through animal studies include increased length and number of dendritic connections (Cotman & Berchtold, 2002); neurogenesis in the dentate gyru; in-creased BDNF levels in the hippocampus and dentate gyrus (Adlard, Engesser-Cesar, & Cotman, 2011; Berchtold, Cas-tello, & Cotman, 2010); increased brain uptake of insulin-like growth factor (IGF-1) (Trejo, Carro, & Torres-Aleman, 2001); and mediation of inflammatory processes (Nie-man et al., 2006). Exercise has also been reported to de-lay amyloid (A) accumulation and improve memory in transgenic mice (Lazarov et al., 2005). Although primarily aerobic exercise has been studied, acrobatic exercise was another exercise type with positive effects on neurogenesis and synaptic plasticity, requiring motor learning com-pared to forced exercises (e.g., running, exercising on a treadmill) (Ball & Birge, 2002). These findings suggest that forms of exercise that require attention or motor learning, such as Tai Chi or dance, may positively affect cognitive functioning.

A number of human studies have examined the neu-ropathological mechanisms of physical activity on cog-nitive function; however, most studies, including meta-analyses, have included older adults without dementia (Colcombe & Kramer, 2003; Erickson et al., 2009; Foster et al., 2011; Kramer et al., 2006; Rockwood & Middleton, 2007). Colcombe et al. (2006) examined the association between aerobic exercise and brain structure using MRI. Study findings included increases in the volume in gray matter brain areas in the exercise group but not in the con-trol group. Similar findings were reported by Erickson et al. (2009, 2011) when testing the effects of aerobic exer-cise on hippocampal volume and spatial memory in older adults. The researchers reported that a higher exercise level was positively correlated to higher hippocampal volume (increased by 2%) and increased BDNF serum levels after controlling for demographic characteristics. In addition, higher exercise and hippocampal volumes were correlated to better spatial memory. In older adults (mean age = 67.3), improved executive functioning was found following a 12-month walking exercise, along with increased con-nectivity between frontal, posterior, and temporal cortices using fMRI data (Voss et al., 2010). Improved immune function with exercise has also been suggested in older adults participating in cardiovascular exercise training (Woods et al., 2009). These protective effects suggest ex-ercise may help preserve cognitive function in older adults (Graff-Radford, 2011).

In studies including individuals with dementia, Heyn, Abreu, and Ottenbacher (2004) examined the positive ef-fects of exercise training and found a significant effect size for cognitive performance across studies; however, none of the studies reviewed assessed potential mechanisms of action congruent with the cognitive outcomes. Reported cognitive benefits were minimal, with primary outcomes being improvements in word fluency and verbal commu-nication (Friedman & Tappen, 1991; Molloy, Richardson, & Crilly, 1988). In individuals with MCI, high-intensity aerobic exercise has resulted in improved executive functioning and glucose metabolism and reduced cor-tisol secretion for women only, with increased IGF-1 for men only (Baker et al., 2010). Conversely, Podewils et al. (2007) found no associations between physical activity and white matter lesions using MRI data in a sample of older adults, including individuals with dementia and MCI. Sys-tematic studies including animals and older adults with-out dementia provide support for benefits of exercise on cognitive functioning. However, the need exists for more systematic studies that examine exercise effects and the


Burgener et al.

mechanism of action, specifically with individuals with MCI or dementia.

Music Therapy. Music therapy is an individual or group intervention that has the potential to affect neuropsychiatric disorders, including organic disorders (e.g., dementia). Music therapies have been designed to improve self-reported quality of life of individuals with dementia in var-ious domains, including cognitive functioning and using music experiences (e.g., singing, listening to and discussing music, moving to music) (Simmons-Stern, Budson, & Ally, 2010). Music therapy can be performed in a group setting or on a one-on-one basis using either relaxing music or the individuals preferred music. The music therapy model is based on neuroscience called neurological music therapy (NMT). NMT is defined as the influence of music on changes in nonmusical brain and behavior functions. In other words, NMT (a) studies how the brain is with and without music stimuli, (b) measures the differences, and (c) uses these differences to document changes in the brain through music that will eventually affect the individual with dementia nonmusically (Boso, Politi, Barale, & Enzo, 2006).

Several reviews of the effects of music therapy have found positive effects on older adults and individuals with dementia (Boso et al., 2006; Fukui & Toyoshima, 2008; Lin et al., 2011; McDermott, Crellin, Ridder, & Orrell, 2013). Studies have been conducted with community-based older adults (i.e., generally outpatient settings) and nursing home residents, with most studies using randomized, con-trolled study designs, although sample sizes have tended to be small (i.e., N = 20 to 87). Specific to individuals with dementia, studies have been conducted across the disease stages; however, no studies were found specific to individ-uals with MCI. Positive outcomes across studies have in-cluded (a) reductions in behavioral symptoms (Sakamoto, Ando, & Tsutou, 2013), anxiety, and depression (Chu et al., 2013; Raglio et al., 2010); (b) increased engagement, socialization, attention, and verbalization (Thompson, Moulin, Hayre, & Jones, 2005); and (c) heightened or im-proved hormonal and physiological parameters, including modulated stress responses (Khalfa, Bella, Roy, Peretz, & Lupien, 2003). Most recently, in individuals with advanced dementia, music interventions have been shown to in-crease short-term parasympathetic activity and reduce behavioral symptoms, suggesting continuing benefits of music therapies into the later disease stages (Sakamoto et al., 2013). One brief analysis also suggested positive cost benefits of music therapies (Bellelli, Raglio, & Trabucchi, 2012).

In studies examining the mechanisms of action for music therapies specifically in individuals with dementia, positive outcomes have been documented using primarily PET or fMRI (Fukui & Toyoshima, 2008); neurotransmitter secretion analysis (Kumar et al., 1999; Sakamoto et al., 2013); cytokine levels (Okada et al., 2009); melatonin levels (Kumar et al., 1999); and salivary cortisol, immuno-globulin, and Chromogranin A measures (Chu et al., 2013; Khalfa et al., 2003; Suzuki, Kanamori, Nagasawa, Tokiko, & Takayuki, 2007; Takahashi & Matsushita, 2006). Find-ings from these studies suggest that music therapies may benefit cognitive functioning through their modulation of the stress response, buffering the hyper-secretion of the corticosteroid associated with stress and impaired HPA axis regulation, as described previously (de Kloet et al., 2005). Increased secretion of melatonin and neurotrans-mitters associated with autonomic activation (i.e., norepi-nephrine and epinephrine) are proposed to result in both relaxing and activating responses (Kumar et al., 1999). In studies measuring the mechanism of action and cogni-tive outcomes, positive outcomes have included improved short-term recall (Chu et al., 2013) and improved language ability using the MMSE language subscale (Suzuki et al., 2004) in addition to improved behavioral outcomes (Saka-moto et al., 2013; Suzuki et al., 2007). In systematic studies conducted with individuals with dementia, findings sug-gest several mechanisms of action for the positive effects of music therapies, with an identified need for further stud-ies, including additional measures (e.g., electroencepha-lography [EEG]), to document specific areas of the brain stimulated through music therapies (Boso et al., 2006).

Therapies With Moderate EvidenceBiofield Therapy. Historical accounts of hands-on

healing and energy-based interventions have been found in numerous cultures around the world (Jain & Mills, 2010; Wang & Hermann, 2006). Termed biofield thera-pies, these interventions involve a practitioner using his or her hands, either on or off an individuals body, to fa-cilitate general health and well-being through modifica-tion of the human energy field by the direction of healing energy (Jain & Mills, 2010). These therapies include Reiki, Therapeutic Touch, Healing Touch, and others, many of which are practiced by health care professionals, particu-larly nurses (Anderson & Taylor, 2011). Requiring no ef-fort on the part of the patient, biofield therapies may be an appropriate intervention for individuals with dementia over more cognitive interventions (e.g., guided imagery, meditation). Recent reviews have found that earlier studies



of biofield therapies lack adequate design features, such as appropriate controls, blinding, and sufficient sample sizes; however, results of these studies are promising and war-rant further research (Anderson & Taylor, 2011; Jain & Mills, 2010). More recent studies of biofield therapies have started to address these issues, enhancing study rigor (Lu, Hart, Lutgendorf, Oh, & Schilling, 2013). Because of the variability in methodology, the aspects of the intervention that need to be present, including dosage and duration, remain to be established in specific patient populations, including those with dementia.

In vitro studies have begun to elucidate cellular mecha-nisms involved in mediating the effects of biofield thera-pies. Biofield therapy significantly reduced cytotoxicity induced by oxidative damage in primary retinal neurons, offering a protective effect, and increased the gene expres-sion of IGF-1 (Yan et al., 2004). As previously discussed, IGF-1 is believed to mediate the effects of BDNF as well as increase the clearance of A. Studies by Kiang, Marotta, Wirkus, and Jonas (2002) and Kiang, Ives, and Jonas (2005) have demonstrated that biofield therapies increase intra-cellular Ca2+ concentrations in leukemic Jurkat cells via L-type calcium channels (LTCCs). LTCCs are essential for synaptic plasticity and spatial memory in the hippocampus (Anekonda & Quinn, 2011). Aging and A promote the influx of Ca2+ into neurons via LTCCs, leading to impaired neuronal function, adversely affecting synaptic functions in Alzheimers disease. Moreover, dysregulation of intra-cellular Ca2+ may contribute directly to the expression of clinical symptoms in Alzheimers disease (Anekonda & Quinn, 2011). Although speculative, biofield therapies may positively affect the homeostatic regulation of calcium in hippocampal neurons, thereby improving cognitive function. In a pilot study by Uchida, Iha, Yamaoka, Nitta, and Sugano (2012), biofield therapy increased mean power spectral values in the alpha range versus placebo in the frontal and central cortical regions (i.e., brain regions as-sociated with cognitive function and the stress response) (McEwen, 2006).

Reports of studies in other chronic disease popula-tions measuring physiological parameters in response to biofield therapies reflect positive changes in heart and respiratory rates and blood pressure (Post-White et al., 2003), and heart rate variability (Kemper, Fletcher, Ham-ilton, & McLean, 2009); these changes suggest relaxation is reflected in the reduction of sympathetic tone and a shift to a more parasympathetic response, influencing activity of the HPA axis, which plays a role in the stress response (as described previously), as well as in exacerbat-

ing the behavioral and psychological symptoms expressed by individuals with dementia. Biofield therapies appear to exert effects through a psychoneuroimmunological frame-work by reducing stress and improving immune function. Biofield therapies have been reported to increase salivary immunoglobulin A (Wilkinson et al., 2002) and increase the activity (Lutgendorf et al., 2010) and number of natural killer cells (Coakley & Duffy, 2010). Moreover, as biofield therapies often involve touch and nontouch techniques, positive effects on the immune system may be secondary to the documented beneficial effects of physical contact on both the immune response and neuroendocrine stress hor-mones by manual therapies (e.g., massage) (Post-White et al., 2003), leading to a decrease in HPA activity.

Relaxation, decreased anxiety and stress, and im-proved mood are the most common effects and hallmarks of biofield therapies, and frequently have been reported in various study populations, including individuals with dementia (Anderson & Taylor, 2011; Jain & Mills, 2010; Lutgendorf et al., 2010). In studies involving individuals with dementia, biofield therapies have been shown to de-crease agitation (Hawranik, Johnston, & Deatrich, 2008) and salivary cortisol (Wang & Hermann, 2006; Woods & Dimond, 2002). By reducing cortisol levels, biofield therapies may have a positive impact on cognitive func-tion. Using a quasi-experimental design, a 4-week biofield therapy intervention improved cognitive function and be-havioral and psychological symptoms of individuals with dementia (Crawford, Leaver, & Mahoney, 2006). More recently, a 6-month biofield therapy intervention using a randomized controlled trial design was shown to reverse cognitive decline and improve mood significantly in indi-viduals with dementia (Lu et al., 2013).

Meditation Therapies. The effects of meditation on cog-nitive functioning have been increasingly studied in older adults, with findings suggesting potential benefits for im-proved or sustained cognitive functioning, including po-tential benefits for individuals with dementia. Models sup-porting the efficacy of meditation therapies have focused on the positive effects on attention and information pro-cessing, including activation of specific areas of the brain (Hu, Chang, Prakash, & Chaudhury, 2011). Several types of meditation practices have been examined in adult pop-ulations, including objectless mindfulness (Davidson et al., 2003; Lutz, Greischar, Rawlings, Ricard, & Davidson, 2004), insight meditation (Lazar et al., 2005), Sahaja and Vihangam yoga (Aftanas & Golosheykin, 2005; Prakash et al., 2010; Prakash et al., 2012), Zen meditation (Pagnoni & Cekic, 2007), and transcendental meditation (TM) (Walton


Burgener et al.

et al., 2004). As described in a review of meditation thera-pies, the effects on cognition have been studied across age groups, including older adults (Xiong & Doraiswamy, 2009). These studies included both advanced and begin-ning practitioners, with some controlling for length of total meditation experience (Davidson et al., 2003).

Study methods have varied and included testing meditation interventions over 8 to 12 weeks (Alexander, Chandler, Langer, Newman, & Davies, 1989; Davidson et al., 2003; Holzel et al., 2011) to comparing long-term meditation practitioners to untrained controls, with long-term practitioners often engaging in meditation daily (Lazar et al., 2005; Walton et al., 2004). Studies have pri-marily taken place in community settings, although older adults in nursing and retirement home settings have also been included (Alexander et al., 1989). Across studies, the cognitive benefits of meditation therapies have been documented using a wide range of standardized tests. In an early study, Alexander et al. (1989) demonstrated that, in older adult participants (mean age = 81), transcendental meditation resulted in improved cognitive flexibility and paired associate learning. Positive cognitive outcomes for yoga meditation practices have included increased atten-tion, processing speed, alternation ability, and performance on interference tests (Prakash et al., 2010; Prakash et al., 2012), whereas Zen meditation has resulted in improved attentional processes (Pagnoni & Cekic, 2007). Sustained or improved attention has also been found in practitioners of Buddhist-style concentrative meditation (Valentine & Sweet, 1999).

A range of mechanisms of action have been identi-fied across the types of meditation practices. Analyses of MRIs, EEGs, and melatonin, serotonin, and cortisol levels have been used primarily as indicators of positive effects. Positive neurophysiological outcomes included higher gamma-band activity in the medial frontoparietal lobes on EEG in advanced practitioners compared to controls (Lutz et al., 2004). In a study of an 8-week training pro-gram, mindfulness-based meditation was found to in-crease left-sided anterior activation on EEG (participants mean age = 36) (Davidson et al., 2003). Using MRI, struc-tural changes in the brain have been reported, with the prefrontal cortex and right anterior insula being thicker in long-term practitioners using insight meditation (mean age = 38), with more pronounced effects in older practitio-ners (Lazar et al., 2005). These brain regions are associated with attention and sensory processing, which is consistent with findings of increased attentional capacity in medita-tion practitioners. In addition, the thickness of the infe-

rior occipitotemporal visual cortex was correlated with years of meditation experience, controlling for age and average thickness of the right hemisphere. More recently, in meditation-nave participants (i.e., non-dementia), mindfulness-based stress reduction practitioners (8-week treatment) demonstrated MRI structural changes, includ-ing increased gray matter concentrations in the left hip-pocampus, posterior cingulated cortex, temporo-parietal junction, cerebellum (Holzel et al., 2011), and putamen (Pagnoni & Cekic, 2007) compared to controls.

Metabolic stressors have also been examined, with melatonin secretion being greater in TM practitioners compared to controls; however, melatonin secretion began to decline in TM practitioners after long meditationan effect that was not explained (Solberg et al., 2004). In post-menopausal women (mean age = 75), following an administered metabolic stressor (glucose), long-term TM practitioners displayed significantly lower cortisol levels compared to non-practicing, age-matched controls (Walton et al., 2004). Interestingly, along with activation of specific brain regions, increases in antibody titer following an influenza vaccination were also found in practitioners compared to controls, suggesting positive effects on im-mune functioning (Davidson et al., 2003).

Although studies are lacking meditation specifically with individuals with dementia, these findings have identi-fied mechanisms of action with the potential to positively impact cognitive functioning, including changes in brain structure and stress responses. As cortical thinning occurs with aging and more aggressively in dementia, the pres-ervation of cortical thickness in specified brain regions may buffer or attenuate this thinning in individuals with dementia (Hu et al., 2011). The positive effects of TM on cortisol response and melatonin secretion may reduce the well-documented harmful effects of stress-induced cortisol secretion in the hippocampus, including atrophy. EEG findings suggest a second, positive effect on improved at-tentional capacity and the ability to regulate negative emo-tions, further lowering autonomic arousal and decreasing the cortisol response. Although cost-effectiveness studies have not been conducted, one study reported higher levels of mindbody therapies in adults with neurological con-ditions, including dementia, supporting the potential ac-ceptance of these therapies by individuals with dementia (Wells, Phillips, & McCarthy, 2011).

Interacting With the Natural Environment. Multiple studies have shown that interacting with the natural en-vironment produces attention-restoration effects, thus im-proving cognitive function (Hartig, Evans, Jamner, Davis,



& Garling, 2003; Kaplan, 1995, 2001). Interactions with na-ture may include any activity that stimulates one or more of the senses either through natural or man-made stimuli (Gibson, Chalfont, Clarke, Torrington, & Sixsmixth, 2007; Herzog, Chen, & Primeau, 2002). Natural environments have been shown to improve attention and memory more effectively than built environments (Korpela & Hartig, 1996; Lauman, Garling, & Stormark, 2003). The NRE can be experienced indoors or outdoors and can include gardening, aromatherapy, light therapy, a walk in nature, viewing nature through windows, and listening to bird or water sounds. NRE interactions provide cognitive, physi-cal, and emotional stimulation and spiritual enhancement (Cox, Burns, & Savage, 2004; Lee & Kim, 2008; Ottosson & Grahn, 2005). NRE elements are a rich source of mul-tisensory stimulation and range from physically passive to active engagement and individual or social stimulation (Bengtsson & Carlsson, 2005; Sugiyama & Ward-Thomp-son, 2007).

As noted previously, studies demonstrate that attention control is an important mechanism in cognition, especially for individuals with dementia (Baddeley, Baddeley, Bucks, & Wilcock, 2001; Gorus, De Raedt, Lambert, Lemper, & Mets, 2006; Perry & Hodges, 1999). Attention has been correlated with memory, executive functions (e.g., plan-ning, decision making), motor function, and way-finding (Baddeley et al., 2001; Parasuraman & Haxby, 1993; Perry & Hodges, 1999). Selective or directed attention is the ability that allows directing responses to salient stimuli and processing information without interference from irrelevant stimuli (Perry & Hodges, 1999). The control of cognition (i.e., executive functioning) and emotions (i.e., self-regulation) share limited resources (Baumeister, Vohs, & Tice, 2007; Kaplan & Berman, 2010). This finding is sup-ported by neuroimaging data in that both executive func-tioning and self-regulation are heavily reliant on the func-tioning of the anterior cingulate cortex (Posner, Rothbart, Sheese, & Tang, 2007).

In studies using attention restoration therapy (ART), which is theory-based interventions involving interactions with NRE, the authors found that by spending time in or being exposed to the natural environment, a soft fascina-tion occurs that promotes relaxation and allows for resto-ration of attention capacity (versus hard fascination [e.g., sirens, bright and flashing lights], which requires attention to process) (Kaplan, 1995). Using fMRI, Kim et al. (2010) showed differential brain activation patterns between nat-ural and urban scenic views. The predominant activation areas stimulated by natural scenery were contrasted with

urban views and less aversively arousing and more pleasant (Kim et al., 2010). For example, the precuneus, activated by natural scenery, is related to regulation of tasks with cog-nitive and affective components (e.g., episodic memory).

Neural mediation of stress promotes cognitive reserve, thus enhancing task performance and cognitive capacity (Petrosini et al., 2009; Stern, 2009). NRE therapies have been demonstrated to mitigate the effects of stress, spe-cifically the hypersecretion of glucocorticoids common in older adults and individuals with dementia (Kemperman, Gast, & Gage, 2002; Rodiek, 2002). The natural environ-ment, specifically gardening, was shown to decrease sali-vary cortisol levels, self-reported stress, and increased pos-itive mood in a population of middle- to old-age healthy adults (Van den Berg & Custers, 2011). Van den Berg and Custers (2011) found that levels of salivary cortisol re-turned to normal levels when participants were allowed 30 minutes of gardening activities after having been inten-tionally stressed (Stroop test with social comparison), pro-viding support acute stress reduction from NRE activities. Research findings suggesting physiological stress reduc-tion include galvanic skin response and electromyogram, and decreases in heart rate and blood pressure (Ulrich et al., 1991). This study showed increases in alpha activity when viewing nature scenes. High alpha activity is associ-ated with lower levels of physiological arousal and feelings of wakeful relaxation (Teplan, 2002).

Other studies not using a dementia sample have found correlations between improved attention capacity and in-terventions using nature with use of backward digit span testing or attention network task tests (Berman, Jonides, & Kaplan, 2008; Cimprich, 1993; Cimprich & Ronis, 2001, 2003; Herzog et al., 2002; Tennessen & Cimprich, 1995). Lauman et al. (2003) demonstrated decreased autonomic arousal by viewing natural versus urban settings by mea-suring inter-beat intervals (via EKG) and improved orienting task performance.

There have been fewer studies for populations with dementia, but they still show evidence of cognitive ben-efits. Using indoor gardening activities, Lee & Kim (2008) demonstrated significant improvements in cognitive scores on the Revised Hasegawa Dementia Scale. Support for positive cognitive effects in individuals with dementia was demonstrated in a quasi-experimental study by Tse (2010). NRE therapies have demonstrated a variety of ad-ditional benefits for individuals with dementia, including decreases in agitation (Cohen-Mansfield, 2007; Detwei-ler, Murphy, Kim, Myers, & Ashai, 2009; La Garce, 2002; Mather, Nemecek, & Oliver, 1997; Mooney & Nicell, 1992;


Burgener et al.

Riemersma-van der Lek et al., 2008; Whall et al., 1997); de-creased psychotropic drug use and falls (Detweiler, Mur-phy, Myers, & Kim, 2008; Detweiler et al., 2009); circadian rhythm normalization (i.e., sleep patterns and quality) (Lee & Kim, 2008); as well as increased socialization, life satisfaction, and positive affect (Heyn et al., 2004; Jarrott & Gigliotti, 2010; Rappe & Topo, 2007; Tse, 2010).

In summary, growing evidence supports NRE thera-pies as having benefits for cognitive functioning for older adults, including individuals with dementia. The mecha-nism showing the most robust support is that of stress mediation, although due to the multidimensionality of NRE interventions, other mechanisms may contribute to the overall effects. Components of chronobiology, physical activity, social interactions, sensory stimulation, practicing remembered skills/hobbies, and sense of accomplishment and meaningfulness may play a role in the influence of NRE on cognition. NRE interventions are multidimen-sional activities; therefore, identifying the precise mecha-nisms of action for NRE need to be viewed in light of the overall impact.

Social Engagement. Social engagement is conceptually defined as staying socially connected, frequently partici-pating in social activities, and a feeling of being socially supported (Cacioppo & Hawkley, 2009). It is gener-ally accepted that individuals with higher social engage-ment have higher cognitive function and are less likely to have dementia, whereas social isolation and loneliness contribute to impaired learning and executive functions and increased risks for cognitive decline and dementia (Cacioppo & Hawkley, 2009). The positive effects of so-cial engagement have been supported in both animal and human studies.

In animal models, rats housed in groups performed better on spatial learning tasks compared to socially iso-lated rats (Lu et al., 2003). In addition, the study by Lu et al. (2003) revealed that group-housed rats had significantly increased neuron proliferation in the dentate gyrus of the hippocampus and synaptic plasticity in the hippocampus. Some recovery of cognitive function also was found, with the rats previously isolated for 4 weeks and then subse-quently reared in groups for another 4 weeks, showing recovered performance in spatial learning tasks (Lu et al., 2003). These early findings were supported by a later study by Madroal et al. (2010), in which increased hippocampal neurogenesis was observed in young mice (age =



that a variety of mechanisms from nonpharmacological interventions impact cognition, with many addressing age- and dementia-related neuropathic changes described previously. For example, increases in actual brain size and cortical thickness were demonstrated in studies testing the effects of cognitive training, physical exercise, and so-cial engagement, whereas neurotrophic factors, including increased BDNF, were found to be modulated following physical exercise and music therapies. Changes (i.e., in-creases) in cerebral blood flow have also been found fol-lowing cognitive therapies. Impaired HPA axis function was also positively affected by a number of therapies, in-cluding music, biofield, physical exercise, meditation, and interacting with a natural environment. The current review identifies the links between nonpharmacological therapies and their effects on specific mechanisms of action and cog-nitive function, many of which have been identified as be-ing associated with aging and cognitive decline (Arking, 2006; Burke & Barnes, 2006; Mora et al., 2007). These find-ings underscore the understanding that many nonphar-macological interventions designed to improve cognitive functioning are theory-driven and supported by empirical research findings.

Findings from the current review also have relevance for clinical practice. By increasing our understanding of the potential benefits of nonpharmacological therapies, the implicit hope is to advance support for combined therapies for individuals with dementia, using drug and non-drug

therapies with identified positive effects on neuronal func-tioning. Although medication therapies have been avail-able to treat dementia for approximately two decades, the limits of these drugs have been well-established, increasing the potential importance of adding non-drug therapies to treatment plans (Tschanz et al., 2011; Zec & Burkett, 2008).

As many of these therapies (i.e., cognitive training, exercise, and meditation) have preventive actions, they provide the older adult with choices for self-care actions, with benefits for disease prevention as well as maintenance of cognitive functioning. For those newly diagnosed with dementia, these therapies provide the opportunity to se-lect treatment options that fit with the individuals prefer-ences and previous activities. Clinically, recommending dual therapies allows the patient more treatment options, including therapies that can be individualized, based on an individuals domain of cognitive impairment and prefer-ences, with a possible non-drug treatment plan (Table 3). As most non-drug therapies have no or few adverse effects and can be made available in many community settings, the potential benefits of incorporating non-drug therapies may far exceed the potential costs, as many of these thera-pies are also considered pleasant activities (e.g., music, social engagement, interacting with the natural environ-ment).

The implications of these findings for research are evident, including the need for head-to-head studies examining the effects of dual therapies compared to

Figure. Mechanisms for action for selected nonpharmacological therapies for individuals with dementia. Note. BDNF = brain-derived neurotrophic factor; IGF-1 = insulin-like growth factor-1; neurogenesis = social engagement, cognitive training, and exercise therapies; hormonal changes = natural environment intervention, music, biofield, exercise, and meditation therapies; brain regions and activity affected = music, meditation, cognitive training, and biofield therapies; amyloid B-related changes = exercise therapies; neurotrophic factor changes = exercise and music therapies.


Burgener et al.

medication-only therapies, especially in individuals with MCI or early-stage dementia. Research that includes samples of individuals with MCI or early-stage dementia diagnoses are especially lacking in biofield and medita-tion therapies, indicating the need to increase controlled, randomized trials testing these two therapies. Studies examining combined therapies (i.e., multi-modal studies) are also indicated as suggested by the rather unique mech-anisms of action found for some therapies. For example, the mechanisms of action identified for cognitive therapies have little overlap with those identified for music therapies, suggesting that these combined therapies may produce a synergistic effect on cognitive functioning. Cost-effec-tiveness studies are indicated as well, given the potential to improve overall functioning and decrease the need for assistive care. These findings also suggest the importance of examining the mechanism of action underlying any nonpharmacological therapy to better understand the ef-fects on the brain and assure the therapy has the potential to positively impact cognitive functioning in older adults, especially individuals with cognitive impairment.

CONCLUSIONThe current analysis and overview provides a begin-

ning understanding of the potential positive effects of a variety of nonpharmacological interventions on neuropa-thology and cognitive function. Collectively, the variety of therapies reviewed allows for tailoring of a treatment plan based on individual strengths and preferences, providing a guide for health care providers to use in recommending nonpharmacological therapies. The current findings add

to the growing body of re-search identifying protec-tive or preventive factors and therapies that may be beneficial prior to the on-set of memory loss or de-mentia. Findings may also point to the importance of future research testing non-pharmacological therapies to ameliorate pathology and potentially improve cognitive functioning in individuals with dementia.

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TABLE 3

Treatment Plan for Nonpharmacological TherapiesTherapy Treatment PlanPhysical exercise Preferably aerobic exercises if tolerated, including walking. If

walking or aerobic exercises cannot be tolerated, then exercises that are less strenuous yet require a memory for muscle move-ment, such as Tai Chi or dance, are recommended.

Cognitive therapies Preferably diverse therapies that use cognitive training and stimulation as the focus of the training.

Mediation therapies May include: transcendental meditation, mindfulness meditation, insight meditation, Sahaja yoga

Biofield therapies May include: Healing Touch, Therapeutic Touch, Reiki, polarity therapy

Environmental/recreational therapies

May include: social engagement, interacting with the natural environment, music therapy



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