Mechanism of Action For Nonpharmacological Therapies For Individuals With Dementiaalio

State of the Science
Mechanism of Action for Nonpharmacological Therapies

for Individuals With Dementia
Implications 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
ABSTRACT
The current review addresses the need for increased use of evidence-based, nonpharmacological therapies for individuals with dementia. To facilitate understanding of the potential efficacy of nonpharmacological 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.]
Historically, the development of pharmacological therapies for dementia has consumed a majority of research resources and involvement of the scientific community. Concomitantly, 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 evidence 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 ameliorating 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
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. Goodwin Street, Urbana, IL 61801; e-mail: sburgenr@illinois.edu.
doi:10.3928/19404921-20150429-02
Research in Gerontological Nursing Vol. x, No. x, 20xx
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 identified external factors (e.g., enriched stimulation) that influence neuropathology and, consequently, impact cognitive
function and reduce the risks of neurodegenerative disorders. However, these factors have been tested primarily
in animal models and relatively few studies have evaluated the impact in clinical trials (Briones, Suh, Hattar, &
Wadowska, 2005; Burke & Barnes, 2006; Kramer, Erickson,
& Colcombe, 2006). On the other hand, nonpharmacological 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 nonpharmacological therapies, clinicians and researchers need to better
understand the state of the science regarding (a) mechanisms 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 mechanism of action. Individually, evidence for these therapies
may have been presented in systematic reviews or metaanalyses, yet no published report was found that synthesized 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 functioning. 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 cognitive 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 cognitive functioning include (a) decreased brain weight, size,
and synaptic density, resulting in decreased synaptic activity and complexity; (b) decreased expression of neurotrophic factors, specifically decreased brain-derived neurotrophic factor (BDNF) in the hippocampus; (c) reduced
neurotransmitters in the hippocampus, substantia nigra,
striatal pathway, and thalamus, with changes in the hippocampus being especially apparent; and (d) decreased neurogenesis, 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 cerebral blood flow; and a decreased number of working neurons, 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 impairment, 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, neurofibrillary tangles, and amyloid angiopathy (Savva et al.,
2009).
With aging, the role of stress hormones (i.e., cytokines and glucocorticoids) and dysregulation of the
hypothalamicpituitaryadrenal (HPA) axis are associated 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 response 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 regulation 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 cognitive function in individuals with dementia.
THEORIES OF NEUROLOGICAL REGENERATION

Research, primarily using animal models, suggests that
the brain, despite injury, is capable of extensive reorgani-
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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 information, 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 & Greenough, 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 counterbalance the effects of aging and dementia-related pathology
and consequently enhance plasticity and preserve cognitive 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 behavioral 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-yRita, 2003a,b). Studies using human subjects tested the
effectiveness of enriched environments on the preservation of neuronal function, including the slowing of cell
death (Bach-y-Rita, 2003b). Robertson and Murre (1999)
reviewed human studies regarding brain plasticity and concluded 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 metabolic impairment may contribute to neuronal dysfunction
and atrophy in dementia. Therefore, stimulation of neurons both pharmacologically and nonpharmacologically is
a promising strategy in the treatment of dementia.
Although some nonpharmacological therapies affect
cognitive function through neurophysiological mechanisms, 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 awareness of deficits being associated with an increased likelihood that an individual can benefit from cognitive rehabilitation (Clare, Wilson, Carter, Roth, & Hodges, 2004).
Evidence of brain plasticity and retained awareness and
ability for learning in dementia supports the potential benefits of nonpharmacological therapies.
NONPHARMACOLOGICAL THERAPIES
Widely 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 Evidence
Cognitive Training/Stimulation. Cognitive training
involves individual or group activities to stimulate an
individuals cognition through association and categorization (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.
TABLE 1
Scheme for Grading the Strength

and Consistency of Evidence
Grade
Evidence
A1
Evidence from well-designed meta-analysis or

well-done systematic review with results that
consistently support a specific action (e.g., assessment, intervention, treatment)
A2
Evidence from one or more randomized controlled 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
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.
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 performances) (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 cognitively stimulating therapies (Schwindt & Black, 2009).
The concept of use it or lose it has been applied to
cognitive aging and suggests that specific cognitive functions 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 function, and the benefits are seen in individuals at any age (i.e.,
older adults, individuals with dementia, nursing home residents with more advanced disease) (Frick & Benoit, 2010;
Spector et al., 2003). Recent meta-analyses indicate common outcomes of cognitive therapies include (a) improved
memory and mental ability; (b) errorless learning achievement; (c) verbal and visual learning; (d) improved executive functioning, language, and attention; (e) improved
functioning in activities of daily living; and (f) lower depression (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 controls 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 damaged 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 measures of cortical imaging (i.e., functional magnetic resonance imaging [fMRI] and positron emission tomography
[PET] scans), cerebral blood flow, and diffusion tensor
imaging for assessing white matter tracts as well as performance 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 temporal 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, including 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 pattern recall (Grn, Bittner, Schmitz, Wunderlich, & Riepe,
2002), free word recall (Becker et al., 1996), attenuated decline (Mini-Mental State Exam [MMSE] and Alzheimers
Disease Assessment Scale-cog), and word recall for patients with MCI (Belleville et al., 2011; Forster et al., 2011).
Specific to individuals with MCI, a systematic review of 20
Non-impaired older
adults
Adults with MCI and
mild to advanced dementia
Increased neurogenesis, specifically in the dentate gyrus and hippocampus

Increased insulin-like growth factor (IGF-1)
sol, and IGF-1 levels;
brain autopsy
Neurotransmitter
secretion analysis;
cytokine, melatonin,
salivary cortisol, CgA,
and immunoglobulin levels; PET and
fMRI scans
Salivary cortisol and

IgA; EEG; heart rate
variability; natural
killer cell activity and
number; neuropsychological testing
Music therapies
Biofield therapies
MRI and fMRI scans;
Increased BDNF secretion
Serum BDNF, corti-
Increased alpha-band activity in the frontoparietal lobes
Increased immune function leading to reduction in neuroendocrine stress responses
Buffers the hyper-secretion of the corticosteroid associated with

stress and impaired HPA axis regulation
3. Activates neurotransmitter secretion
2. Buffers the hyper-secretion of the corticosteroid associated with

stress and impaired HPA axis regulation
1. Modulated immune response
Increased synaptic connectivity
Increased hippocampal volume
Diminished stress responses; decreased cortisol secretion
Anti-inflammatory effects
Increased clearance and delayed accumulation of brain amyloid

(A)
Adults with mild to

moderate dementia and
MCI
Cellular studies
Adults with mild to

advanced dementia
Non-impaired older
adults
Animal models
Non-impaired older
adults with MCI and mild
to moderate dementia
Physical exercise
Increased connectivity (white matter)
Increased blood flow to specific brain regions
basal ganglia, and prefrontal cortex
occipito-parietal, frontal, and temporal lobes, and the cerebellum,
Increased activation to brain regions, including the parietal,
MRI, fMRI, PET, and

FDG-PET scans
Population Studied
Cognitive training/
stimulation
Mechanisms of Action
Assessment Methods
for Mechanism
Nonpharmacological
Therapy
B2, A2
A2
A1
A1
Evidence
Grading
Improved mood and cognitive scores (MOCA; AMMSE),

and decreased behavioral
and psychological symptoms (RMBPC) and agitation
Improved short-term recall

and language abilities (improved MMSE scores)
Increased verbal fluency and

verbal communication, and
improved executive function
Improved word recall, face

name association encoding,
attenuating mental decline
(MCI), visuospatial paired
learning, and abstract pattern recall
Cognitive Domains of
Improvement
Mechanism of Action, Population Studied, and Effects on Cognition for Nonpharmacological Therapies
TABLE 2
Assessment Methods
for Mechanism
Brain autopsy; MRI

and fMRI scans;
electrophysiology
Non-impaired adults
and older adults
Adults with mild to
advanced dementia
Animal models
Increased synaptic plasticity in the hippocampus
Non-impaired older
adults and adults with
mild to advanced dementia
Non-impaired adults and

older adults
Population Studied
Increased hippocampal neurogenesis
Restored attention capacity
Faster recovery from sympathetic activation
Decreased cortisol levels
Activation of specific neural regions including: superior and middle

frontal gyri, superior parietal gyrus, precuneus, basal ganglia,
superior occipital gyrus, anterior cingulate gyrus, superior temporal
gyrus, and insula
Increased alpha activation indicating relaxation; decreased autonomic arousal
Reduced urinary cortisol in TM practitioners
Increased antibody titers
Increased melatonin compared to controls
Increased gray matter in the left hippocampus, posterior cingulated

cortex, temporoparietal junction, cerebellum, and putamen
Thickening of the prefrontal cortex and right anterior insula
Increased left-sided anterior activation
Higher gamma-band activity in the medial frontoparietal lobes
Mechanisms of Action
A2, C1
B2, B2
A2
Evidence
Grading
Decreased risk of dementia

and improved global cognitive function, semantic and
working memory, spatial
learning, and functional level
Increased attention capacity

and speed of processing;
improved memory, calculation, semantic word fluency,
orientation, and mood; and
decreased agitation
Increased attentional performance and decreased negative affect and autonomic

arousal
Cognitive Domains of
Improvement
Note. MRI = magnetic resonance imaging; fMRI = functional magnetic resonance imaging; FDG = Fluorine-18-Fluorodeoxyglucose; PET = positron emission tomography; MCI = mild cognitive impairment; BDNF = brain-derived neurotrophic factor; HPA
= hypothalamicpituitaryadrenal; CgA = Chromogranin A; MMSE = Mini-Mental State Exam; EEG = electroencephalography; MOCA = Montreal Cognitive Assessment; AMMSE = Annotated Mini-Mental State Exam; RMBPC = Revised Memory and
Behavior Problems Checklist; TM = transcendental meditation; EKG = electrocardiogram; HR = heart rate.
Social engagement
Natural environment fMRI scans; salivary

interactions
cortisol levels; EEG
and EKG (HR); skin
conduction; neuropsychological testing
Meditation therapies EEG; MRI; serum

melatonin, serotonin, and urinary
cortisol levels
Nonpharmacological
Therapy
Mechanism of Action, Population Studied, and Effects on Cognition for Nonpharmacological Therapies
TABLE 2 (CONTINUED)
Burgener et al.
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 cognitive training and stimulation therapies as beneficial for
individuals with MCI and mild dementia, although the potential 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), improve 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 examined 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 exerciseinduced cognitive plasticity is supported by a recent review by Foster et al. (2011). Some of the basic exercise effects identified through animal studies include increased
length and number of dendritic connections (Cotman &
Berchtold, 2002); neurogenesis in the dentate gyru; increased BDNF levels in the hippocampus and dentate gyrus
(Adlard, Engesser-Cesar, & Cotman, 2011; Berchtold, Castello, & Cotman, 2010); increased brain uptake of insulinlike growth factor (IGF-1) (Trejo, Carro, & Torres-Aleman,
2001); and mediation of inflammatory processes (Nieman et al., 2006). Exercise has also been reported to delay 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 compared 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 neuropathological mechanisms of physical activity on cognitive function; however, most studies, including metaanalyses, 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 control group. Similar findings were reported by Erickson et
al. (2009, 2011) when testing the effects of aerobic exercise 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 connectivity 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 exercise 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 effects 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 communication (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 cortisol 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. Systematic studies including animals and older adults without 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 selfreported quality of life of individuals with dementia in various 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, controlled 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 individuals with MCI. Positive outcomes across studies have included (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 improved 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 increase 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, immunoglobulin, and Chromogranin A measures (Chu et al., 2013;
Khalfa et al., 2003; Suzuki, Kanamori, Nagasawa, Tokiko,
& Takayuki, 2007; Takahashi & Matsushita, 2006). Findings 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 neurotransmitters associated with autonomic activation (i.e., norepinephrine and epinephrine) are proposed to result in both
relaxing and activating responses (Kumar et al., 1999). In
studies measuring the mechanism of action and cognitive 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 (Sakamoto et al., 2013; Suzuki et al., 2007). In systematic studies
conducted with individuals with dementia, findings suggest several mechanisms of action for the positive effects of
music therapies, with an identified need for further studies, including additional measures (e.g., electroencephalography [EEG]), to document specific areas of the brain
stimulated through music therapies (Boso et al., 2006).
Therapies With Moderate Evidence
Biofield 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 therapies, these interventions involve a practitioner using his
or her hands, either on or off an individuals body, to facilitate general health and well-being through modification 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, particularly nurses (Anderson & Taylor, 2011). Requiring no effort 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 warrant 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 mechanisms involved in mediating the effects of biofield therapies. Biofield therapy significantly reduced cytotoxicity
induced by oxidative damage in primary retinal neurons,
offering a protective effect, and increased the gene expression 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 intracellular 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 intracellular 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 associated with cognitive function and the stress response)
(McEwen, 2006).
Reports of studies in other chronic disease populations 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, Hamilton, & 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 framework 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 hormones by manual therapies (e.g., massage) (Post-White et
al., 2003), leading to a decrease in HPA activity.
Relaxation, decreased anxiety and stress, and improved 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 decrease 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 function. Using a quasi-experimental design, a 4-week biofield
therapy intervention improved cognitive function and behavioral 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 individuals with dementia (Lu et al., 2013).
Meditation Therapies. The effects of meditation on cognitive functioning have been increasingly studied in older
adults, with findings suggesting potential benefits for improved or sustained cognitive functioning, including potential benefits for individuals with dementia. Models supporting the efficacy of meditation therapies have focused
on the positive effects on attention and information processing, including activation of specific areas of the brain
(Hu, Chang, Prakash, & Chaudhury, 2011). Several types
of meditation practices have been examined in adult populations, 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 therapies, the effects on cognition have been studied across
age groups, including older adults (Xiong & Doraiswamy,
2009). These studies included both advanced and beginning 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 longterm practitioners often engaging in meditation daily
(Lazar et al., 2005; Walton et al., 2004). Studies have primarily 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 attention, 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 identified 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 program, mindfulness-based meditation was found to increase left-sided anterior activation on EEG (participants
mean age = 36) (Davidson et al., 2003). Using MRI, structural 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 practitioners (Lazar et al., 2005). These brain regions are associated
with attention and sensory processing, which is consistent
with findings of increased attentional capacity in meditation practitioners. In addition, the thickness of the infe-
10
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, including increased gray matter concentrations in the left hippocampus, 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 meditation
an 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 immune functioning (Davidson et al., 2003).
Although studies are lacking meditation specifically
with individuals with dementia, these findings have identified 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 preservation 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 attentional capacity and the ability to regulate negative emotions, 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 conditions, including dementia, supporting the potential acceptance 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 environment produces attention-restoration effects, thus improving cognitive function (Hartig, Evans, Jamner, Davis,
& Garling, 2003; Kaplan, 1995, 2001). Interactions with nature 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, physical, and emotional stimulation and spiritual enhancement
(Cox, Burns, & Savage, 2004; Lee & Kim, 2008; Ottosson
& Grahn, 2005). NRE elements are a rich source of multisensory stimulation and range from physically passive
to active engagement and individual or social stimulation
(Bengtsson & Carlsson, 2005; Sugiyama & Ward-Thompson, 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., planning, 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 supported by neuroimaging data in that both executive functioning and self-regulation are heavily reliant on the functioning 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 fascination occurs that promotes relaxation and allows for restoration 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 natural 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 cognitive 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, specifically the hypersecretion of glucocorticoids common in
older adults and individuals with dementia (Kemperman,
Gast, & Gage, 2002; Rodiek, 2002). The natural environment, specifically gardening, was shown to decrease salivary cortisol levels, self-reported stress, and increased positive 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 returned to normal levels when participants were allowed
30 minutes of gardening activities after having been intentionally stressed (Stroop test with social comparison), providing support acute stress reduction from NRE activities.
Research findings suggesting physiological stress reduction 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 associated 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 interventions 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 measuring 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 benefits. 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 additional benefits for individuals with dementia, including
decreases in agitation (Cohen-Mansfield, 2007; Detweiler, Murphy, Kim, Myers, & Ashai, 2009; La Garce, 2002;
Mather, Nemecek, & Oliver, 1997; Mooney & Nicell, 1992;
11
Burgener et al.
Riemersma-van der Lek et al., 2008; Whall et al., 1997); decreased psychotropic drug use and falls (Detweiler, Murphy, 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 therapies as having benefits for cognitive functioning for older
adults, including individuals with dementia. The mechanism 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 multidimensional activities; therefore, identifying the precise mechanisms 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 participating in social activities, and a feeling of being socially
supported (Cacioppo & Hawkley, 2009). It is generally accepted that individuals with higher social engagement 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 social 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 isolated 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 subsequently 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 = <3
months) caged in groups, providing social engagement.
However, this same effect was not found in adult mice,
suggesting the benefit of social engagement on associative
12
learning and related hippocampal neurogenesis is more

pronounced at younger ages (Madroal et al., 2010).
The benefit of social engagement on brain functioning
has been further supported by evidence generated from
multiple large-scale human studies (Amieva et al., 2010;
Bennett, Schneider, Tang, Arnold, & Wilson, 2006). An
early longitudinal, 12-year study of 2,812 home-dwelling
older adults revealed that individuals with more social ties
had a lower incidence of cognitive decline compared to
their less socially connected counterparts (Bassuk, Glass,
& Berkman, 1999). Similarly, another longitudinal study
found that older adults with poor social connections, lower participation in social activities, and social disengagement were at high risk for cognitive decline (Zunzunegui,
Alvarado, Del Ser, & Otero, 2003). Moreover, Bennett et
al. (2006) reported that social network size can modify the
association between dementia pathology and cognitive
function; individuals with a larger network size showed
higher cognitive function despite having more severe
dementia pathology. This effect was especially pronounced
for semantic and working memory, controlling for relevant mediating factors (e.g., depression). In a later crosssectional study, Krueger et al. (2009) examined 838 institutionalized older adults without dementia and found that
a higher frequency of social activity and perceived social
support were significantly associated with higher global
cognitive function, including memory, perception speed,
and visuospatial ability.
Taken together, evidence (from animal and human
studies) supports that social engagement is associated with
higher cognitive function (including learning, executive
function, and hippocampus-related memory), as well as
improved neurogenesis and synaptic plasticity in the hippocampus (animal studies only). Moreover, the possibility
exists that decreased cognitive functioning resulting from
isolation may be reversed through later social interaction.
These collective findings are promising; however, there is
a lack of intervention trials testing social engagement as
therapy for individuals with dementia (Flicker, 2009).
DISCUSSION
Although not exhaustive, the current review includes
a variety of nonpharmacological therapies with evidence
of the underlying mechanism of action on cognitive functioning from cellular, animal, and human studies (Table 2).
A conceptual view of the various mechanisms of action on
cognitive functioning is included (Figure), providing an
overview of the mechanisms of action identified from the
reviewed research. From this conceptual model, it is clear
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.
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 social engagement, whereas neurotrophic factors, including
increased BDNF, were found to be modulated following
physical exercise and music therapies. Changes (i.e., increases) in cerebral blood flow have also been found following cognitive therapies. Impaired HPA axis function
was also positively affected by a number of therapies, including 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 cognitive function, many of which have been identified as being associated with aging and cognitive decline (Arking,
2006; Burke & Barnes, 2006; Mora et al., 2007). These findings underscore the understanding that many nonpharmacological 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 functioning. Although medication therapies have been available 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 select treatment options that fit with the individuals preferences 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 preferences, 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 therapies are also considered pleasant activities (e.g., music,
social engagement, interacting with the natural environment).
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
13
Burgener et al.
Physical 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 movement, 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
to the growing body of research identifying protective or preventive factors

and therapies that may be
beneficial prior to the onset of memory loss or dementia. Findings may also
point to the importance of
future research testing nonpharmacological therapies
to ameliorate pathology
and potentially improve
cognitive functioning in
individuals with dementia.
Environmental/recreational
therapies
May include: social engagement, interacting with the natural

environment, music therapy
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TABLE 3
Treatment Plan for Nonpharmacological Therapies

Therapy
Treatment Plan
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MCI or early-stage dementia. Research that includes
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randomized trials testing these two therapies. Studies
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the mechanisms of action identified for cognitive therapies
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The current analysis and overview provides a beginning understanding of the potential positive effects of a
variety of nonpharmacological interventions on neuropathology 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
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Mechanism of Action For Nonpharmacological Therapies For Individuals With Dementiaalio

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State of the Science

Mechanism of Action for Nonpharmacological Therapies

cological interventions designed to assist individuals with

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

to effectively treat dementia (Foster, Rosenblatt, & Kuljis,

AGING- AND DEMENTIA-RELATED

THEORIES OF NEUROLOGICAL REGENERATION

Copyright SLACK Incorporated

Nonpharmacological Therapies for Individuals With Dementia

zation, termed brain plasticity. Plasticity is described as

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

have shown that individuals with dementia can learn

Scheme for Grading the Strength

Evidence from well-designed meta-analysis or

Evidence from high-quality, evidence-based

Evidence from one or more quasi-experimental

Evidence from observational studies with

Inconsistent evidence from observational studies

Evidence from expert opinion, multiple case

Note. A1 and A2 = strong evidence; B1 and B2 = moderate evidence; C1, C2,

mental stimuli (Yevchak, Loeb, & Fick, 2008). It is suggested

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Increased neurogenesis, specifically in the dentate gyrus and hippocampus

sol, and IGF-1 levels;

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

Salivary cortisol and

MRI and fMRI scans;

Increased BDNF secretion

Serum BDNF, corti-

Increased alpha-band activity in the frontoparietal lobes

Increased immune function leading to reduction in neuroendocrine stress responses

Buffers the hyper-secretion of the corticosteroid associated with

3. Activates neurotransmitter secretion

2. Buffers the hyper-secretion of the corticosteroid associated with

1. Modulated immune response

Increased synaptic connectivity

Increased hippocampal volume

Diminished stress responses; decreased cortisol secretion

Increased clearance and delayed accumulation of brain amyloid

Adults with mild to

Adults with mild to

Increased connectivity (white matter)

Increased blood flow to specific brain regions

basal ganglia, and prefrontal cortex

occipito-parietal, frontal, and temporal lobes, and the cerebellum,

Increased activation to brain regions, including the parietal,

MRI, fMRI, PET, and

Improved mood and cognitive scores (MOCA; AMMSE),

Improved short-term recall

Increased verbal fluency and

Improved word recall, face

Nonpharmacological Therapies for Individuals With Dementia

Brain autopsy; MRI

Increased synaptic plasticity in the hippocampus

Non-impaired adults and

Increased hippocampal neurogenesis

Restored attention capacity

Faster recovery from sympathetic activation

Decreased cortisol levels

Activation of specific neural regions including: superior and middle

Increased alpha activation indicating relaxation; decreased autonomic arousal

Reduced urinary cortisol in TM practitioners

Increased antibody titers