Effects of Six-Month Interventions on White Matter Integrity of Aging Adults: Randomized Control...

Effects of Six-Month Interventions on White Matter Integrity of

Aging Adults: Randomized Control Trial on Healthy Older Adults

By

Tammy L. Chen

Thesis for the

Degree of Bachelor of Science

In Psychology

College of Liberal Arts and Sciences

University of Illinois

Urbana-Champaign, Illinois

2015

Advisors:

Agnieszka Z. Burzynska, PhD & Arthur F. Kramer, PhD

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Table of ContentsAbstract 2Introduction 3Methods 9Participants 9Participation Criteria and Eligibility 10Cardiorespiratory Fitness (CRF) 11

Interventions 11Magnetic Resonance Imaging (MRI) 13DTI preprocessing 14DTI ROI analysis 14

Statistical Analysis 15Ethic Statement 18

Results 19Between-Group Homogeneity Test of Pre Intervention FA Values

19General Decline of FA over Time across All Groups 19Dance Intervention had positive Effect on FA of the Fornix 19

Discussion 22Dance Is Related to Increase in Fornix’s WM Integrity 22FA Decrease Over Six Months across Multiple ROIs 25Corpus Callosum Displays Anterior-Posterior Gradient in FA Decline 27Nutrient Supplement Beta-Alanine Displayed No Significant Effect on FA 29

Directions for Future Studies 29

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Neural Correlates and Statistical Methods 29TBSS 30Suggestions for Further Analysis 30

Acknowledgements 31Appendix 32References 45

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Abstract

The normal aging process of humans involves decline in cognitive

functions, and one of the major related neural mechanisms is the

degeneration of cerebral white matter (WM). Past studies have

demonstrated beneficial effects of lifestyle factors such as

increased cardiorespiratory fitness, physical activity, cognitive

training, social engagement, education, and nutrition on

cognitive functioning and brain in aging. This study is a 6-month

randomized control trial on older (60–80 years) low-active adults

with four different lifestyle interventions: dance, walking,

walking + nutrition, and active control of stretching and toning.

The aim of this study is to 1) compare the effects of the four

interventions on WM integrity, 2) investigate the regional

specificity of these changes by analyzing integrity of 21 major

WM tracts, an analysis not performed before in such detail. Our

results show that 1) the dance intervention is related to

increase in fornix’s WM integrity, 2) multiple regions showed

decline in WM integrity over the study’s six-month span, and 3)

corpus callosum displayed anterior-posterior gradient in FA

decline. Our findings suggest that physical and cognitive

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engagement through socially interactive exercises such as dancing

can help maintain healthy WM integrity in older age, particularly

in the limbic/memory system. These findings support the public

health recommendations that emphasize the importance of a

physically active and socially engaging lifestyle among aging

adults.

Keywords: diffusion tensor imaging; white matter; aging;

factional anisotropy; longitudinal study; exercise; cognition;

dance; neurodevelopment; fornix; corpus callosum; association

fibers

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Introduction

The world population of the twenty-first century, owing to

medical progression and rising health awareness, is aging at a

historically unprecedented pace, according to reports from the

United Nation Population Division (2013). United Nation projects

that the world population of older adults over 60 is expected to

double within the next four decades, culminating to new depths of

the aging trend, with the population of elders over 60

outnumbering children by 2047 (2013). Growing numbers in older

population has amassed public health concerns in the aging

process within the recent years.

Advanced age is most notably associated with decline in

cognitive functioning and brain health, even in the absence of

dementia (Bartzokis et al., 2003; Madden & Bennett & Song, 2009;

Gunning‐Dixon et al., 2009; Bennett et al., 2010). Therefore,

improving cognitive functioning and brain health of older adults

have recently become a major interest in the field of cognitive

neuroscience of aging (Hertzog, Kramer, Wilson, & Lindenberger,

2008). Non-invasive neuroimaging studies in the last two decades

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have demonstrated that loss of white matter (WM) integrity is one

of the key factors underlying poor performance in certain age-

related cognitive abilities, including executive skills, working

memory, processing speed, and episodic memory (Gunning-Dixon et

al, 2009; Madden et al., 2012). Hence, maintaining WM structural

connectivity may be crucial to preserving brain functionality and

high cognitive performance, both of which aid in leading an

independent life in old age.

WM is a fundamental component of brain that is composed of

mostly of glial cells and myelin-coated axons (Fields, 2008). It

is responsible for transmitting signals between anatomically

distinct cerebral regions and, as such, it is crucial to

information processing and communication between distinct

functional brain networks (Teipel et al, 2010; Wakana et al.,

2004). Age-related deterioration of WM’s structure is reflected

by changes in both its volume as well as microstructure

(Pfefferbaum, 2003; Olesen et al., 200; Salat et al., 2005;

Sullivan et al., 2001). Our study focuses on WM microstructure in

aging.

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In the human brain, majority of axons are surrounded by a

multi-layer lipid-rich cellular membrane produced by glial cells

called myelin (Daniel, 2008). Myelin acts as an electrical

insulator and plays an important role in fostering the speed of

nerve signaling (Calabresi, 2011; Griggs, 2011). Myelin acts as

the key player in the saltatory conduction of electrical

signaling along the axons, in which the electric signal, also

known as action potential, is propagated along the axons from the

node of Ranviers, which are the low-resistance sections of axonal

membrane in-between the myelin warps (Hsu et al, 1975; Norton,

1984). Thus, myelinated axons have higher conducting velocity

(Saladin, 1998).

Structural integrity of myelin sheaths deteriorates during

normal aging, especially in regions requiring intense

myelination, such as the frontal lobes (Kochunov, 2007; Gunning‐

Dixon et al., 2009). Decline in WM integrity is also found to be

predominantly related to loss of myelinated axons (Meier-Ruge et

al., 1992; Pakkenberg and Gundersen, 1997; Marner et al., 2003;

Bartzokis, 2004), and myelin (Peters, 2002). In addition, it is

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possible to study WM integrity in aging with non-invasive

Magnetic Resonance Imaging (MRI) methods (Bennet, 2010;

Burzynska, 2010). Diffusion tensor imaging (DTI) allows

inferences about WM microstructure in vivo by quantifying the

magnitude and directionality of diffusion of water within a

tissue (Beaulieu, 2002). DTI quantifies magnitude and

directionality of diffusion of water molecules within tissues

(Alexander, 2007; Huisman, 2010). The most common measure

extracted from DTI measurements is fractional anisotropy (FA). FA

describes the extent of directionality of water diffusion in a

voxel, thus making it a quantitative measure that refers to the

alignment of axons within fiber tracts as well as their

structural integrity (Basser, 1995). FA values ranges between 0 –

1, with higher FA values indicating more myelinated WM tract

(Kochunov, 2009). FA reflects WM health by describing with the

index how well the structure of myelin sheath helps inhibit the

diffusion of water molecules in directions other than the one

along the fiber tracts (Pierpaoli and Basser, 1996). More random

than unidirectional movements of water molecules will yield a

more isotropic diffusion, which produces a smaller FA closer to

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zero. Given that FA is commonly referred to as an index of WM

health, a decline in FA often serves as a reliable indicator of

decline in microstructural integrity of WM (Beaulieu, 2002;

Kochunov, 2009). Age-related FA decline offers insight to axon

density, degree of myelination, and microstructural integrity of

WM (Burzynska et al., 2010; Bennett, 2010).

Various lifestyle factors can alleviate WM and cognitive

deterioration throughout the aging process. Specifically,

engaging in aerobic exercise, higher cardiorespiratory fitness

(CRF), cognitive training, social engagement, education,

expertise, fitness training, and nutrition can have beneficial

effects on brain structure and function and may prevent age-

related cognitive decline (Kramer et al., 1999; Hillman, Erickson

& Kramer, 2008; Voss et al, 2013; Hertzog et al, 2008). Hence,

this study aims to expand upon several recent studies on the

effects of CRF and physical activity on WM integrity of older

adults (Burzynska et al., 2014; Voss et al, 2013; Colcombe et

al., 2006).

Results from studies by Colcombe et al. and Voss et al.

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provide grounds for the rationales behind this study (2006,

2013). Study by Colcombe et al. found that increase in CRF

resulting from a six-month walking exercises coincided with

increases in brain volumes of both grey and WM, particularly in

the anterior WM and regions connecting the anterior and posterior

parietal lobes (2006). Study by Voss et al. further expanded upon

the previous study by demonstrating in a study on older adults of

55 – 80 years old (n=70), that increase in CRF in the context of

a one-year walking intervention program is associated with

regional increase in WM integrity in the frontal and temporal

lobes and enhanced short term memory, particularly, improved

backward digit span performance (2013). However, they found no

overall interaction between the changes in WM integrity and the

interventions groups (no time × group interaction). Namely, there

was no difference between the walking and the active control

(stretching & toning) groups in their changes of WM integrity,

executive function, or short-term memory.

This study aims to investigate and build upon the findings

and shortcomings of these two studies by providing the following

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two improvements. First, the previous studies investigated either

voxel-wise macrostructural or lobar properties of brain

integrity. Our study, in contrast, aims to take a more region-

specific approach by examining WM integrity in the 21 main WM

tracts. Second, the previous studies compared only walking

intervention aimed to increase CRF to the active stretching-

toning control group. Our study adds two additional intervention

groups: walking combined with nutritional supplement, and the

cognitively challenging exercise of dance.

The nutritional supplement beta-alanine used in this study

is an amino acid supplement that has been found to increase the

integrity and build-up of muscle fibers (Sale et al, 2010).

Research by Spradley et al. indicates that dietary interventions

with beta-alanine may postpone exercise-related fatigue by

improving CRF (2012). It is included in this study and combined

with the walking intervention to observe whether increased muscle

mass will enhance CRF, which in turn help increase brain

functions (Zoeller, 2007). This intervention is thus considered

as further enhancing the health benefits of walking through

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nutritional supplement.

The design of the dancing condition provides an amalgamation

of improvements in CRF as well as specific cognitive functioning

tasks by integrating aerobic dance movement and the cognitive

challenges from learning sequential dance steps and routines. The

process of learning to dance for non-dancers heavily involves

incorporation of social cognition, executive cognitive functions

(ie. control processes such as planning, coordination,

inhibition), and different types of memory, particularly working

memory. The Ballroom dance that will be taught in this group

particularly achieves the goal of combining fitness training with

cognitive training, particularly memory and executive control.

Furthermore, past research has shown that dancing has been

associated with being protective against dementia in older adults

and reduced depression among older adults with depression

(Verghese et al., 2003; Haboush et al., 2006). Compared with

activities aimed to specifically increase CRF, such as walking,

dancing is not only more versatile, engaging, and enjoyable, but

also provides and fosters companionship and social bonding among

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the elderly population of the community (Jonas, 1998; Palo-

Bengtsson, 1998). The social involvement, dedication,

recreational effects, and complexity of dance trainings motivate

participants to persist through the duration of the six-month

intervention, resulting in lower attrition rate.

The active control group with activities consisting of

stretching and toning provides a non-aerobic comparison against

the effects of other intervention groups on neurocognitive,

physical and psychosocial functions. Each of the aforementioned

intervention treatment lasted six months. We recruited 247

neurologically healthy, non-active older adults (60 to 80 years

of age) from the local community. Following completion of

baseline testing and meeting the eligibility criteria,

participants were randomly assigned to one of the four groups

with double-blind precautions. Out of 247 participants we

successfully collected 174 complete DTI datasets, namely, those

with satisfactory pre and post intervention quality according to

our DTI quality control guideline. In addition, to ensure

randomization between the groups, we acquired the CRF measures

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and demographic information from the participants in the

screening process. In order to investigate the changes of WM

integrity over the time span of the intervention, we examined the

changes in diffusivity, measured in fractional anisotropy (FA).

The design of this study aims to test the three main

hypotheses: 1) participation in a six-month intervention that

aims to increase CRF (walking and walking + nutrition) should

result in beneficial effects in the WM, such as increase in FA or

lack of a typical age-related decline, as compared to the control

condition; 2) dance intervention should result in a similar

effects on WM integrity as aerobic exercise through walking, but

its additional motor learning and socializing aspects could aid

in producing stronger improvements in WM integrity than walking

alone, or these affects could relate to different WM regions than

walking interventions; 3) WM integrity would likely deteriorates

across the duration of the study’s six-month intervention in the

control group, 4) Combining nutritional supplement with walking

intervention to stimulate lean muscle mass growth could enhance

the effects of walking on CRF, resulting in more pronounced

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effects on WM integrity than participating in walking alone.

These effects are of great interest both for what they

impart about the nature of cognitive and brain aging and also for

their implications in public health and active lifestyle of the

aging population.

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Methods

Participants

Sample and Recruitment

The sample of this study was drawn and recruited from the

population of healthy, sedentary older adults (N=1119) dwelling

in the Champaign county area through a variety of advertising

methods. Older, sedentary adults were recruited to participate in

a series of neuroimaging, psychosocial and cardiorespiratory

testing, followed by a six-month program of physical activity. Of

the 1119 participant recruited, 247 met inclusion criteria and

agreed to enroll in the study. Stratified sampling strategies has

been employed to ensure equal numbers of males and females and

five year age (from 60 to 75) cohorts in each of the intervention

groups. Minority participants were recruited proportionately to

the Champaign county census figures (11.4% black, 4% Hispanic, 8%

Asian). Further details on recruitment and attrition rate can be

found in Figure 1.

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The 247 participants that met participation criteria are

assigned to one of following four conditions: stretching and

toning control, dance, walking, and walking + nutrition. 213

participants completed the intervention (58 in the control group,

59 in dance group, 48 in walking group, and 48 in walking +

nutrient group). After the DTI images were processed for quality

control, we end up with the final sample of 174 participants

(120 females, 54 males; 43 in control, 49 in dance, 40 in

walking, and 42 in walking + nutrition) with the average age 66±4

years , average level of education 3.94 (out of a 1-6 scale), the

average body mass index (BMI) M=30.5, average VO2 max M=20.2

mL/kg/min, and average resting heart rate M=73.09 (refer to Table

1.1 – 1.5 for further details in sample descriptions). The sample

contains more females (120) because fewer males (54) from the

aging population met the eligibility criteria or demonstrated

willingness to participate in the study.

Participation Criteria and Eligibility

All participants were required to satisfy a number of entry

criteria before any testing begins. Eligible participants met the

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following criteria: (1) were between the ages of 60 and 80 years

old, (2) were free from psychiatric and neurological illness and

had no history of stroke or transient ischemic attack, (3) scored

<10 on the geriatric depression scale (GDS-15), (4) scored ≥75%

right-handedness on the Edinburgh Handedness Questionnaire, (5)

demonstrated normal or corrected-to-normal vision of at least

20/40 and no color blindness, (6) cleared for suitability in the

MRI environment; that is, no metallic implants that could

interfere with the magnetic field or cause injury, no

claustrophobia, and no history of head trauma.

All participants met the study’s sample criteria for low-fit

and low-active, albeit capable of performing exercise (i.e. no

physical disability that prohibits mobility) given that none of

them reported participation in regular physical activity (maximum

of two moderate bouts per week) within the past six months.

Medication use was also screened for, in particular

pharmacological therapies for cardiovascular disease (ie. beta

blockers, diuretics, etc.,) and psychological/emotional problems

(ie. neuroleptic, antidepressant, and anxiolytic agents) which

can respectively influence cardiorespiratory responses and 19

cognitive function. This information was used to minimize

differences among conditions by using a modification of the

baseline-adaptive randomization scheme of Begg & Iglewicz

(1980). Finally, standard procedures were enforced to secure

medical clearance from participants’ personal physician for

participation in all testing and interventions and to screen for

the presence of any cognitive deficits which would preclude

participation in cognitive tasks.

Cardiorespiratory Fitness (CRF)

CRF was assessed on a motor-driven treadmill by employing a

modified Balke protocol (graded exercise test). The protocol

involves walking at a self-selected pace with incremental grades

of 2-3% every 2 minutes. Measurements of oxygen uptake, heart

rate and blood pressure were constantly monitored. Oxygen uptake

(VO2) were measured from expired air samples taken at 30-second

intervals until a peak VO2 (the highest VO2) is attained; test

termination was determined by symptom limitation, volitional

exhaustion, and/or attainment of VO2 peak as per ACSM guidelines.

Interventions

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Following completion of the aforementioned baseline testing

and meeting the eligibility criteria, participants participated

in a six-month intervention program. All interventions met three

times per week. All four conditions were controlled and monitored

for the same level of social interaction. Each condition is

described in the following.

The walking condition is a regular exercise program of brisk

walking. Frequent assessment of heart rate (both by palpation and

Polar Heart Rate Monitors) and rating of perceived exertion

ensured that the exercise intensities were performed at the

prescribed level. Exercise logs were completed after each

exercise session noting frequency, intensity and enjoyment levels

associated with that session.

Walking with regular nutritional supplement condition is

comprised of brisk walking and regular administration of

supplement. The supplement was similar to Ensure®, developed for

this project by Abbott Nutrition. The supplement was delivered in

liquid, milk-based carrier (similar to protein shakes) and the

active ingredient was beta-alanine, which promotes lean muscle

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growth. The aim of this intervention was to test whether

promoting muscle mass growth would enhance CRF, and thus further

enhance the beneficial effects of walking on the brain (Zoeller,

2007). All participants in this group were requested to ingest

the provided supplement on a daily basis and complete an

evaluation of the supplement at the end of the intervention.

The stretching and toning control condition consisted of an

organized curriculum of stretching, toning, and balance activity

for the whole body and is specially designed for individuals 60

years of age and older. This group met on the same basis as the

walking exercise group and was led by an experienced exercise

leader, and therefore received the same amount of attention as

other intervention groups. Participants used resistance bands,

activity balls, balance disks, and exercise mats to engage in a

variety of non-cardiorespiratory activities. Each stretch was

constant, controlled and smooth, gradual and steady progressions

that were held to the point of slight tension but not pain. Each

stretch was held for approximately 20-30 seconds. Stretches and

simple strength exercises for all large muscle groups and

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functional balancing exercises were also included in the

intervention program. Each stretching and toning session lasted

for approximately 30-45 minutes and met 3 times per week. Each

session were preceded and followed by 10-15 minutes of warm-up

and cool-down exercises. Activities were made incrementally more

difficult over the first three months and then maintained for the

final 3 months. This program was designed not to result in

significant increases in CRF (Colcombe et al., 2004).

The dance condition involved learning a combination of dance

varieties including ballroom, Latin square-dancing, polka, line-

dancing, swing, folk, etc., including both partnered and non-

partnered choreography. Since the participants were non-active at

the beginning of the program, the curriculum started with easier

choreographed dance combinations and advanced to more challenging

combinations over the course of the six month program. Given that

the recruited participants had an uneven gender representation,

all participants were required to learn the choreography of both

gender roles in order to maximize the cognitive challenge

involved during the partnered dancing.

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Magnetic Resonance Imaging (MRI)

MRI sessions were scheduled within two to three weeks before

and after the intervention. The MRI appointments were ensured to

not occur on the same day in which the participants have

exercised.

DTI images to probe miscrostructural properties of WM

integrity were collected from all included participants of this

study (Basser et al., 1994; Pierpaoli & Basser, 1996; Pfefferbaum

et al, 2000) on a 3T Siemens Trio Tim system with 45 mT/m

gradients and 200 T/m/sec slew rates (Siemens, Erlangen,

Germany). All images were obtained parallel to the anterior-

posterior commissure plane with no inter-slice gap. DTI images

were acquired with a twice-refocused spin echo single-shot Echo

Planar Imaging sequence (Reese et al, 2003) to minimize Eddy

current-induced image distortions. The protocol consisted of a

set of 30 non-collinear diffusion-weighted acquisitions with b-

value =1000 s/mm2 and two T2-weighted b-value =0

s/mm2 acquisitions, repeated two times (TR/TE =5500/98 ms,

128×128 matrix, 1.7×1.7 mm2 in-plane resolution, FA =90, GRAPPA

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acceleration factor 2, and bandwidth of 1698 Hz/Px, comprising 40

3-mm-thick slices).

DTI preprocessing

Visual checks were performed on every volume of the raw data

of every participant (for general exclusion criteria of brain

volumes, refer to Table 5). In case a DTI scan contained more

than two volumes with artifacts, these volumes as well as the

corresponding b-vectors and b-values were removed before

processing. If artifacts were found in more than two volumes,

such datasets were excluded from analyses, resulting in 174 good

quality pre-post datasets.

DTI data were processed using the FSL Diffusion Toolbox

v.3.0 in a standard multistep procedure, including: a) motion and

Eddy current correction of the images and corresponding b-

vectors, b) removal of the skull and non-brain tissue using the

Brain Extraction Tool (Smith, 2002), and c) voxel-by-voxel

calculation of the diffusion tensors. Next, FA maps were computed

using DTIFit within the FDT. All motion and Eddy current outputs,

25

as well as FA images were visually inspected and controlled for

quality.

DTI ROI analysis

Among all other DTI indices of WM integrity, only FA is

considered for this study. We used Tract-Based Spatial Statistics

(TBSS, a toolbox within FSL v5.0.1), to create a representation

of main WM tracts common to all subjects (also commonly known as

the WM “skeleton”) (Tract-Based Spatial Statistics, Smith et al.,

2004, 2006, 2007). This included: (1) nonlinear alignment of each

participant's FA volume to the 1×1×1 mm3 standard Montreal

Neurological Institute (MNI152) space via the FMRIB58_FA template

using the FMRIB's Nonlinear Registration Tool (FNIRT; Rueckert,

1999), (2) calculation of the mean of all aligned FA images, (3)

creation of the WM “skeleton” by perpendicular non-maximum-

suppression of the mean FA image and setting the FA threshold to

0.25, and (4) perpendicular projection of the highest FA value

(local center of the tract) onto the skeleton, separately for

each subject.

Next, we selected regions of interest (ROIs) on the TBSS

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skeleton with the use of the DTI WM atlas to probe FA in the core

parts of the selected tracts (Burzynska et al., 2013). The

following entails the included 21 brain regions and their

respective acronyms : Superior corona radiata (SCR), superior

longitudinal fasciculus (SLF), anterior and posterior limb of the

internal capsule (ALIC and PLIC), external capsule (EC), fornix

(FX), 5 regions of the corpus callosum [reg1, 2, 3, 4, 5 (Hofer

and Frahm, 2006)], forceps major (fMAJ), forceps minor (fMIN),

anterior cingulum (ACC), and posterior cingulum (PCC), WM

containing occipital portion of inferior longitudinal fasciculi

and inferior frontal-occipital fasciculi (IFOF_ILF_occ), WM of

gyrus rectus (gyrRect), parahippocampal WM (HIPP_st), ventral

prefrontal part of uncinated (UNC_pfc),WM containing uncinate and

inferior frontal-occipital fasciculi (IFOF_UNC), and WM of the

temporal pole related to inferior longitudinal fasciculus

(ILF_temp).

Statistical Analysis

One-way ANOVA with Levene’s test of homogeneity was

conducted on the five variables from participants’ demography

27

(age, education, BMI, VO2 man in mL/kg/min, and resting heart

rate) and pre intervention FA values of the 21 ROIs to ensure

that the participants were randomly assigned into groups also

with respect to these variables. The verification of between-

group homogeneity of variance assumption allows for further

comparisons of changes in FA values between different

intervention groups with minimum interference from the

distribution differences between the groups before intervention

(Winer et al., 1971; Tabachnick & Fidell, 2001).

In order to quantify the change in FA during the six-month

intervention period, we calculated percent change (%Δ) for the FA

of all 21 ROIs. The calculation of FA %Δ is based on the

following method devised by Voss et al. in their study on aerobic

exercise (2013). FA %Δ for each ROI was calculated by subtracting

the pre intervention FA value from the post intervention FA

value, and dividing the result by pre-intervention value [i.e.

(FApost – FApre)/FApre] (Voss et al., 2013). Next, we carried out

one-way ANOVA on each ROI to compare the differences in FA%Δ

between intervention groups, with the four interventions as the

28

between-subjects factor.

Repeated measures ANOVA was then performed on raw FA values

from pre and post intervention for each ROI separately. In this

analysis, the within-person factor was the two levels of time

points (pre and post intervention), while the between-person

factor was the four intervention groups. This analysis aimed to

verify for each ROI, 1) whether there is an effect of time (i.e.,

change in FA over the period of intervention) and 2) whether

there is an interaction between time and group (i.e., difference

in FA change between the intervention groups).

The ROI(s) that exhibited significant FA variation from

interventions is further processed in two types of post hoc

analyses to 1) determine which intervention(s) exerts the

strongest effect on the FA change of the ROI(s) and 2) assess the

strength of the observed relationship. First, independent t-tests

were conducted to compare the between-group difference of FA%Δ

for each group pair. A total of six possible pairwise

combinations can be generated from the four intervention groups

of this study, based on the mathematical calculation of

29

combinations (4C2 = 6), which include dance vs. control, walking

vs. control, walking + nutrition vs. control, dance vs. walking,

dance vs. walking + nutrition, and walking vs. walking +

nutrition group respectively (Allen, 2014). If the t-test results

were significant, effect size would be further calculated to

measure the strength of the observed relationships. Effect size

helps interpret the magnitude of the effect observed from the

significance level and assess whether the observed effect is

strong enough to be statistically meaningful (Kotrlik & Williams,

2003). In the context of this study, it interprets how much of FA

variability can be accounted by the interventions. Strength of

effect size for the t –tests results were assessed with Cohen’s

guidelines for Cohen’s d (small = 0.2; medium = 0.5; large = 0.8)

(1988). Second, another pairwise comparison of the intervention

groups was performed with Tukey’s HSD (honest significant

difference) as a post hoc follow-up to one-way ANOVA of FA %Δ.

Tukey’s HSD test was conducted to 1) confirm results from one-way

ANOVA on the ROI(s) that display significant between-group

difference in FA %Δ and 2) distinguish which intervention

group(s) differ significantly in FA %Δ from others (Field, 2009).

30

Finally, in order to determine the nature of influence

exerted by the intervention(s) on the FA of the ROI(s) (i.e.,

improved or deteriorated), we referred to the results of the

repeated measures ANOVA on pre and post FA values to examine the

graph(s) of the ROI(s) demonstrating significant FA change. We

also referred to the graph results of one-way ANOVA on FA %Δ of

21 ROIs to confirm the trend by looking at whether FA%Δ of the

intervention(s) within the ROI(s) displayed a positive or

negative trend.

All the aforementioned statistical tests and analyses were

performed with the statistical software tool SPSS Statistics

(v.22, SPSS Inc., Chicago, IL, USA). Refer to Table 6 for

flowchart delineating the detailed process of statistical

analysis.

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Ethic Statement

A University of Illinois Institutional Review Board approved

the study, and written informed consent was obtained from all

participants and the study was performed in accordance with the

1964 Declaration of Helsinki. Participants received financial

reimbursement.

32

Results

Between-Group Homogeneity Test of Pre Intervention FA Values

The outcome of both Levene’s test of variance homogeneity

and one-way ANOVA conducted on the five variables from demography

(age, education, BMI, VO2 man in mL/kg/min, and resting heart

rate) displayed no significant (p<0.05) between-group differences

for all demographic variables. However, Levene’s test on pre

intervention FA values did show that two ROIs, Hipp_st (p=0.030)

and Reg3cc (p=0.031), displayed significant between-group

difference in variances (p<0.05) before the interventions were

administered. Nevertheless, results from one-way ANOVA on pre

intervention FA values show no significant between-group

differences on all 21 ROIs. Given that only two out of the 21

ROIs violated the homogeneity of variance assumption for the pre

intervention FA and none displayed significant one-way ANOVA

result, concerns on the two ROIs with significant Levene’s test

result were disregarded and the 21 ROIs were thus further

processed for pre vs. post intervention and between-group

comparisons.

General Decline of FA over Time across All Groups

33

Time had a significant effect (p<0.05) on the FA values of

multiple ROIs, regardless of group. Results from repeated

measures ANOVA showed a significant trend of FA decline over time

in ten out of the 21 ROIs (refer to Table 2). These ten ROIs

displayed declining trend in FA over time, but their within-

subject FA decline over time showed no significant time × group

interaction.

Dance Intervention had positive Effect on FA of the Fornix

Of all 21 ROIs, fornix (FX) was the only brain region that

displayed time × group interaction. This interaction of fornix is

manifested in both the one-way ANOVA on FA %Δ of 21 ROIs and the

repeated measures ANOVA on pre and post intervention raw FA

values.

Independent t-tests comparing the between-group difference

of FA%Δ for each group pair shows that none of the intervention

group pairs differ significantly in their FA%Δ. Hence, effect

size was not calculated for any of the pairs. Note that FA%Δs of

the two walking intervention groups also do not differ

significantly from each other.

34

The result from Tukey’s HSD test, conducted as a post hoc

for one-way ANOVA on FA %Δ of all 21 ROIs featured fornix as the

only ROI displaying significant between-group difference in FA

%Δ, and singled out dance as the group that differs significantly

from other groups in FA %Δ. Tukey’s pairwise comparisons of the

four interventions in Table 3a show that only the pairs involving

the dance group demonstrated significant difference. Homogenous

Subsets from Tukey’s test result further reify this observation

by providing groupings for the mean of FA %Δ (refer to column 1

and 2 in Table 3b). Means of active control, walking, and walking

+ nutrition groups are all within the same subset (column 1),

indicating that they are not significantly different from each

other, and hence the 0.894 significance value at the bottom of

column 1. As shown in Table 3b, dance is the only group with its

mean of FA %Δ (0.0233) grouped in a different subset (column 2).

Table 3b on homogenous subsets summarizes Table 3a on Tukey’s

pairwise comparisons between intervention groups and isolates

dance as the only intervention group that exerted significant

influence on fornix’s FA.

35

The two graphs generated from repeated measures ANOVA

(Figure 2) and one-way ANOVA (Figure 3) tests reveal that FA in

the dance group increased over the six months. The graph of

fornix FA generated from repeated measures ANOVA on pre and post

FA values shows that dance is the only intervention exhibiting an

increasing trend over time, while all other groups decreased in

FA means (Figure 2). The graph generated by one-way ANOVA on FA

%Δ also shows that of all the ROIs, fornix is the only ROI that

manifested significant between-group variation in FA %Δ, and of

all the interventions within fornix, only dance displayed

positive FA %Δ (Figure 3).

36

Discussion

Dance Is Related to Increase in Fornix’s WM Integrity

Fornix was the only region that displayed a significant time

× group effect. FA values in the fornix increased after the six–

month dance intervention, which is a trend that was neither

observed in the active control nor the walking groups. This

unique finding on fornix encourages a closer look at its

structure, functions, and its possible role in dance learning,

and age-related cognitive decline.

The structure of fornix is comprised of a bundle of C-shaped

fibers of the limbic system that is wrapped closely around the

hippocampus. It projects from the posterior hippocampus and

reaches to the septal area and hypothalamus. The major role of

fornix is to carry incoming (afferent) and exiting (efferent)

information in its bundle fibers to and from the hippocampi and

it also serves as the major efferent pathway from hippocampus to

various other regions such as anterior thalamic nuclei,

mammillary bodies, striata, and prefrontal cortices. It is,

therefore, a part of the limbic system, which plays a major role

37

in the behavioral processes of learning, memory, emotion, and

socializing (King et al., 2013). For instance, fornix holds a

crucial role in assisting the hippocampus to retain working

memory and maintain episodic memory, based on previous animal

studies (Packard et al, 1989). Studies on brain diseases that

involve impairments or underdevelopments of fornix also found

significant deterioration in cognitive performances, especially

episodic memory (Douet & Chang, 2015).

These cognitive processes that fornix is responsible for are

essential components in every aspect of learning to dance. Thus,

FA changes in fornix in the dancing group can be related to its

role in maintaining the executive cognitive functions and

episodic memories, both of which may play a role in learning new

dance moves and choreographies (Nestor, 2007; Douet & Chang,

2015). The incremental difficulty of choreography serves to

actively engage the learning and memory processes, which are

mainly accounted by the limbic system. In addition to the memory

load, the dancing program exerts the most intensive training upon

the limbic system out of all four treatment groups by heavily

engaging the processes of learning, memory, emotion, and 38

socializing. The dance varieties such as ballroom, Latin square

dancing, polka, line dancing, swing, and folk are all aimed at

engaging partners and directed at social facilitations, not to

mention that all these social stimulations and physical

challenges will definitely elicit certain level of emotional

engagements among older adults. Since fornix is the major bundle

of fibers responsible for communication within and beyond the

limbic network, the significant increase of its WM integrity

after dance intervention suggest that the activities in the

dancing program helped fostering the communication within limbic

network, possibly through mechanisms of myelination (Calabresi,

2011; Griggs, 2011).

Fornix is a particularly pertinent and appealing region to

the study of aging processes in the brain due to its suggested

plasticity in lifelong neurodevelopment by several literatures

(Berger, 1978; Hofstetter, 2013; Douet & Chang, 2015). Of all WM

tracts in the brain, fornix is one of the earliest tracts to

mature. The maturation of fornix peaks around late adolescence.

After its maturation peak, fornix then declines in its integrity

throughout the later adulthood (Douet & Chang, 2015). Douet & 39

Chang suggested in their meta-analysis that the typical age-

related WM decline in fornix is perhaps more aptly described by

the process of “pruning” rather than neuro-degeneration (2015).

Therefore, the increases in FA through cognitively enhanced

exercise interventions like dancing, as demonstrated in the

results of this study, supports possibility of persistence of

fornix’s plasticity into the older age. However, it is important

to note that the extent to which the results of this study on

fornix is valid should be taken with caution, given that only the

body of fornix, instead of the entire portion, was covered in

the analysis.

The possibility of improving fornix microstructure could

have a great impact on improving cognitive abilities in aging.

Namely, recent studies on fornix in patients with mild cognitive

impairments and dementia demonstrated that changes in the

integrity of fornix serves as a reliable neural correlate to

predict hippocampal functions and lifelong memory capabilities

(Aggleton et al., 2000; Rudebeck et al., 2009; Fletcher et al.,

2013; Pelletier et al., 2013). Building upon this result,

40

Fletcher et al. argues that deterioration in fornix’s integrity

may precede hippocampal dysfunction, and serves as a better

predictor for the onset of cognitive impairment than hippocampal

atrophy (2013). This finding could also be extended to the

decline of cognitive functions generally observed in aging

adults. Our study further adds to this finding by demonstrating

the selective malleability of WM integrity in fornix. This

malleability was only induced by the dance intervention, which

requires the concurrent coordination of memory and limbic systems

with other higher cognitive networks through exercise.

In confirmation with the results in the study by Voss et

al., the results in this study also did not find significant time

× group effect in FA for the two walking groups (2013). However,

we did not conduct any further correlations of FA with CRF, as in

the study by Voss et al., which will be further tested in future

investigations. The lack of time × group interaction among the

walking groups of this study in particular shows that the

supplementary nutrition beta-alanine did not manifest a

significant between-group difference on any of the ROIs, even

41

when the group is compared pairwise with the other walking group.

The lack of effect displayed by beta-alanine might be due to the

variation of health conditions and physiques among the

participants of this group, or that its effect simply could not

be manifested within the six-month time frame of the

intervention. Further testing is required in order to verify the

factors behind beta-alanine’s lack of effect.

In addition, the significant time × group effect of fornix

in this study corroborates and extends upon the previous study by

Voss et al. on the relationship between lifestyle changes and WM

integrity in older adults (2013). First, Voss et al. analyzed WM

by broader ROIs of lobes, while the ROI analysis of this study is

more regional and specific. Fornix was not considered as an

individual structure in the analysis of the study by Voss et al.,

which accounts for the lack of this finding in their study.

Second, this study incorporated the dance intervention, which was

not included their study. As explained previously, the process of

learning to dance involves a specific set of tasks that requires

the memory and limbic systems, which may help explain why the

42

observed time × group effect is only manifested in the dance

group, but not for any of the walking groups in both this study

and the study by Voss et al.

FA Decrease Over Six Months across Multiple ROIs

Multiple ROIs showed decrease in FA during the six months,

regardless of the type of intervention. This included the

following ten ROIs: anterior cingulum, anterior limb of the

internal capsule, external capsule, parahippocampal WM,

occipital portion of inferior longitudinal fasciculi and

inferior frontal-occipital fasciculi, uncinate and inferior

frontal-occipital fasciculi, posterior limb of the internal

capsule, genu of the corpus callosum, superior corona radiata,

and ventral prefrontal part of uncinate fasciculi. These ROIs

did not display statistically significant interaction between

time and intervention group, indicating that their FA declined

over the span of six months in the same way for all intervention

groups. In other words, the WM tracts of these ROIs underwent

age-related decline in microstructural integrity over six

43

months, regardless of the lifestyle changes induced by

interventions.

Our finding of FA decline over several months in healthy older

adults is in line with numerous publications on decrease in WM

integrity of the aging adults (Guttman, 1998; Christiansen et al,

1994; Pfefferbaum, 2000, 2003; Kennedy, 2003; Kochunov, 2007;

Marks, 2007). However, the study designs of these findings are

usually cross-sectional instead of longitudinal, indicating that

evidences on loss of WM over time has been usually derived from

comparisons between WM integrity of younger adults and that of

the older adults (Pfefferbaum, 2003; Madden et al, 2004; Kennedy

& Raz, 2009). While cross-sectional comparisons allow

investigators to draw age-related associations on the WM

deterioration of certain brain regions, the pace at which WM

integrity declines over time can only be confirmed by

longitudinal studies. Given that this study has the longitudinal

design of six-month interventions between the pre and post-

treatment MRI assessments, the result of multiple ROIs displaying

statistically significant change in FA over the relatively short

time span implies that the WM integrity of these ROIs were 44

declining at a fairly rapid pace among the 60~79 years old sample

of this study.

The majority of the ten ROIs (except for internal capsule,

corpus callosum, and superior corona radiata) where we observed

significant FA decline over time are classified as association

fibers (Table 4). The association fibers consist of two types:

short association fibers connecting the adjacent gyri and long

association fibers connecting more distant grey matter regions

(Mori et al., 2002; Wiegell et al., 2000). Association fibers

continue to develop their myelin sheaths well into the middle

adulthood and are known to be sensitive to age-related changes

that involve demyelination and axonal loss. These two age-related

cognitive impairments reduce network connectivity (Bartzokis et

al, 2003; Kochunov et al, 2006). Thus, the general trend that

describes the relationship between age and association fibers’

myelination pattern follows a quadratic trajectory resembling an

inverted “U” (Yakovlev and Lecours, 1967; Miller et al., 1980;

Benes et al., 1994; Bartzokis et al., 2001, 2003, 2004; Ge et

al., 2002; Sowell et al., 2003; Bartzokis, 2004a,b; Allen et al.,

2005; Jelsing et al., 2005; Walhovd et al., 2005). Given that the45

age range of our data sample is between 60 – 79 years, these

participants were well into their descending phase of the

inverted-U trajectory of changes in myelin when participating in

our study. Previous longitudinal study by Voss et al. (2012) on

improving WM integrity and short-term memory of older adults

through CRF interventions also demonstrated that the WM integrity

in the 55 – 80 years old sample in their study can be improved by

acquiring increased CRF from intervention. This result from their

study implies that the 55 – 80 years old sample, with a similar

age range to the sample of this study, still demonstrated certain

level of WM plasticity for improvement even though her

participants are already in the age of descending phase of

myelination according to inverted-U trajectory. Overall, our

study provides an important evidence of longitudinal change in FA

over 6 months, which affected mostly association fibers. Future

analyses will investigate whether 1) the slope of the decline in

FA was uniform in the seventh and eighth decade of life or

accelerated the most dramatically in the oldest participants, 2)

whether the initial CRF levels predicted the amount of FA decline

over the 6 months.

46

Corpus Callosum Displays Anterior-Posterior Gradient in FA

Decline

Among the five segments of the corpus callosum, FA of the

most anterior segment (the genu, Reg1cc in Figure 4) is the only

segment among the five that displayed significant decrease in FA

(Table 2.3).

This result is in line with several past studies. These

studies reported that, in comparison with posterior regions, age-

related FA deteriorations are more prominent in the anterior

regions (O’Sullivan et al, 2001), especially in the ventromedial

prefrontal and deep frontal lobes (Salat et al, 2005). Further

investigations on this topic also corroborated the overall

pattern of anterior –posterior gradient in age-related FA decline

across the brain (Pfefferbaum & Sullivan, 2003; Salat et al.,

2005; Grieve et al., 2007). Importantly, past studies focusing on

age-related decline of corpus callosum predominantly observed

more significant age-related annual FA decline in the genu,

negative association between age and FA in genu, or the largest

FA difference between younger and older adults (Frederiksen,

2013; Hou & Pakkenberg, 2012; Salat et al., 2004, Burzynska et 47

al., 2011; Kochunov et al., 2007; Sullivan et al., 2001). Our

result, which shows that only genu out of all corpus callosum

regions have significant FA decline, supports and builds on

previous studies by proposing the “anterior-posterior” gradient

of age-related WM deterioration in the corpus callsoum (Head et

al..., 2004; Salat et al..., 2005; Sullivan et al..., 2001).

The decline in microstructural integrity of the genu can be

attributed to its fibers’ susceptibility to the build-up of

metabolic damage. The factors contributing to this vulnerability

are: oligodendrocyte-to-axon ratio (Lamantia & Rakic, 1990; Wood

P & Bunger RP, 1984), reduced rate of myelin turnover and repair

(Hof, Cox, & Morrison, 1990; Wakana, Jiang, Nagae-Poetscher, van

Zijl, & Mori, 2004), and high percentage of unmyelinated or

thinly myelinated axons (Aboitiz, Scheibel, Fisher, & Zaidel,

1992; Aboitiz, 1992).

It is also interesting to note that there was no time ×

group interaction in the genu, which contradicts with past

research findings. It has been shown that continuous cognitive

and physical trainings can help improve FA of anterior corpus

callosum (Burzynska et al., submitted, Lovden et al., 2010). 48

Lovden et al. have demonstrated in their study that 100 days of

multi-facet cognitive trainings helped increase the FA of

anterior corpus callosum (2010). Although not a longitudinal

study, a recent study showed an exceptionally high FA in the genu

of a female, nonagenarian, professional track-and-field athlete

Olga Kotelko (Burzynska et al., submitted), possibly related to

her physically and cognitively active lifestyle after retirement.

Although we observed the decline in FA in the genu but not in the

more posterior sections, this finding has still to be directly

tested. However, it should be noted that this finding cannot be

confirmed in this study, as we did not conduct direct statistical

testing to determine whether the anterior corpus callosum

displayed significantly greater decline than posterior section,

nor did we investigate how this gradient effect in corpus

callosum differs among the intervention groups, or how it may

differ between the youngest and oldest participants in this

study.

Nutrient Supplement Beta-Alanine Displayed No Significant Effect

on FA

49

Pairwise comparisons of the interventions with t-tests show

that FA%Δs of the two walking intervention groups (walking vs.

walking + nutrient) do not differ significantly from each other.

This indicates that the nutrient supplement beta-alanine did not

produce the projected enhancing effects on FA of the older adults

in this study.

Directions for Future Studies

Neural Correlates and Statistical Methods

Due to the time constraints of this project, FA was the only

DTI measure we managed to analyze. It is suggested that other

parameters such as MD, AD, RD can provide a more dimensional

approach to WM integrity and its change over time.

Given the convoluted factorial structure, multi-level, and

multivariable design of this study, we suggest using more

sophisticated statistical methods for data analysis (ie.

generalized linear mixed model, GLMM) and post hoc assessments

(Scheffe’s, Pillai’s, or Least Significant Difference test) in

the future investigations.

50

TBSS

It is important to note that the TBSS analysis used here

inherently focuses on normal appearing WM and the center of the

tracts, as the highest FA values perpendicular to the tract are

being projected to the WM skeleton for further analysis (Tract-

Based Spatial Statistics, Smith et al., 2004, 2006, 2007). This

means that there may be some bias for excluding voxels affected

by white matter hyperintensities (WMH) from FA analyses and that

the parts of the tract that are not in its center are not

included in the analyses, but may be most susceptible to change

as a result of intervention. In the future investigations we will

consider more voxel-wise approaches, not restricted to the WM

skeleton, such as https://www.nitrc.org/projects/dtitk. So far,

however, we consider TBSS approach most suitable for the current

study as it maximizes the independence of FA in addition to

circumventing the inter-subject anatomy (NITRC, v2.1.23-1).

Suggestions for Further Analysis

The current data at hand for this study is not enough to

determine whether the effects on FA are meaningful indicators of

51

https://www.nitrc.org/projects/dtitk

cognitive functions. In the future analyses, we plan on relating

our DTI results to the participants’ performance on mini–mental

state examination (MMSE) and a battery of cognitive tasks

(including episodic memory, working memory, processing speed,

vocabulary knowledge, and fluid intelligence), both of which have

been collected from the participants of this study. Finally, the

lack of effect in the two walking groups can be further

investigated by assessing individual differences in CRF and level

of physical activity, since fitness gains vary between

individuals.

Acknowledgements

This work was supported by the National Institute on Aging

(NIA) grant (R37-AG025667) and a grant from Abbott Nutrition

through the Center of Nutrition, Learning and Memory at the

University of Illinois, granted to Arthur F Kramer and Edward

McAuley. I thank Holly Tracy and Nancy Dodge for MRI data

collection, the Department of Kinesiology and Community Health

for CRF data collection, and Anya Knecht and Susan H. Herrel for

project coordination. I express special thanks to Vineet Agarwal

52

for providing the python script that removes the unwanted images

and the corresponding bvec and bvals, Agnieszka Z. Burzynska and

Anamarta Lamoutte for conducting visual checks on DTI images,

Katie Kramer for guidance on draft formatting, and Agnieszka Z.

Burzynska and Arthur F. Kramer for guidance on draft

proofreading.

53

Appendix

Figure 1. Participants

54

Figure 2. Variations of Fornix’s FA Mean over Six Months

*Vertical axis: “FA Means of Participants” is the aggregated regional FA of all participants, segregated by groups and time points.

*Horizontal axis: Each number corresponds to the pre and post intervention time points as follows: 1 = pre intervention; 2 = post intervention

*ROI 6, fornix, manifested as the only ROI with distinct FA difference between groups

*Among the four interventions of fornix; only dance increased in FA over time, while all other interventions declined in FA over time.

55

FA Means of Participants

Figure 3. FA %Δ Mean of 21 ROIs

*Vertical axis: “FA %Δ of Participants” is the aggregated regional FA %Δ of all participants, segregated by intervention groups.

*Horizontal axis: Each number corresponds to one of the 21 ROIs as follows:

56

FA %Δ Means of Participants

1 = ACC; 2 = ALIC; 3 = EC; 4 = fMAJ; 5 = fMIN; 6 = FX; 7 = gyrRect; 8 = HIPP_st; 9 = IFOF_ILF_occ; 10 = IFOF_UNC; 11 = ILF_temp; 12 = PCC; 13 = PLIC; 14 = reg1cc; 15 = reg2cc; 16 = reg3cc; 17 = reg4cc; 18 = reg5cc; 19 = SCR; 20 = SLF; 21= UNC_pfc

*ROI 6, fornix, manifested as the only ROI with distinct FA difference between groups

*Among the four interventions of fornix; only dance demonstrated positive FA %Δ, while all other interventions demonstrated negative FA %Δ.

57

a.

b.

Figure 4. Corpus Callosum Anatomy and Subdivisions Used in Current Analyses

(images from Hofer & Frahm 2006)

*Region I: prefrontal; region II: premotor and supplementary motor; region III: motor; region IV: sensory; region V: parietal,temporal, and occipital.

58

*A, anterior (genu); P, posterior (splenium).

59

Variables N Range Minimum Maximum MeanStd.

Deviation

Age 174 19.00 60.00 79.00 65.6552 4.43404

Highest Level of Education 174 5.00 1.00 6.00 3.9425 1.15660

Resting Heart Rate 174 57.00 50.00 107.00 73.086

2 10.33981

Body Mass Index 174 34.27 14.95 49.22 30.4723 5.46853

VO2 max (mL/kg/min) 172 23.40 10.80 34.20 20.207

6 4.44996

Valid N (listwise) 172

Table 1.1 Overall Descriptive Statistics of Participants

Table 1.2 Control (Stretching and Toning) Group Descriptive Statistics


Deviation

Age 43 19.00 60.00 79.00 66.7209 4.65130


Resting Heart Rate 43 37.00 55.00 92.00 72.5814 9.77907

Body Mass Index 43 28.52 20.69 49.22 30.3431 6.03593

VO2 max (mL/kg/min) 41 19.80 11.00 30.80 19.7610 4.45067

60


Table 1.3 Dance Group Descriptive Statistics


Deviation

Age 49 19.00 60.00 79.00 65.8776 4.70209



Body Mass Index 49 25.71 14.95 40.66 30.5797 5.93565

VO2 max (mL/kg/min) 49 16.40 13.90 30.30 20.1408 4.34098



Deviation

Age 40 15.00 60.00 75.00 64.9750 4.00312

61



Body Mass Index 40 20.38 23.10 43.49 31.1750 4.93237

VO2 max (mL/kg/min) 40 21.70 12.50 34.20 20.6725 4.83009


Table 1.4 Walking Group Descriptive Statistics

62

Table 1.5 Walking + Nutrition Group Descriptive Statistics


Deviation

Age 42 17.00 60.00 77.00 64.9524 4.17865



Body Mass Index 42 20.54 19.40 39.94 29.8098 4.84888

VO2 max (mL/kg/min) 42 18.50 10.80 29.30 20.2786 4.31161


63

Table 2 Repeated Measures ANOVA on Pre and Post Intervention FA

ROIs Sig. (p) oftime effect

Sig. (p) oftime * group effect

Observed Trends in pre/post FA Variations from graph

ACC 0.008 0.201 Dance group remains stableacross time. All other groups declined.

ALIC 0.008 0.560 All groups declined. Control group declined most. Dance group declinedleast.

EC 0.000 0.434 All groups declined.fMAJ 0.185 0.891 All groups increase. Dance

group increase the most.fMIN 0.297 0.156 Only control group

decreased. All other groups increased.

FX 0.003 0.001 Dance group increased. Allother group decreased, with control group decreased the most.

gyrRect 0.775 0.782 Walking group increased. All other groups decreased.

HIPP_st 0.037 0.526 All groups decreased. Walking group decreased the most. Dance group least decreased.

IFOF_ILF_occ

0.014 0.410 All groups decreased. Dance group least

64

decreased.IFOF_UNC 0.033 0.569 Walking + nutrition group

remained same. All other group decreased.

ILF_temp 0.163 0.810 Walking + nutrition group remained same. All other group decreased.

PCC 0.674 0.907 Walking + nutrition group increased. All other groupdecreased. Walking group decreased the most.

PLIC 0.000 0.553 All groups decreased. Control group decreased the most.

reg1cc 0.008 0.910 All groups decreased. Walking group decreased the least.

reg2cc 0.232 0.306 Walking group increased. All other groups decreased.

reg3cc 0.869 0.969 All groups remained same.reg4cc 0.344 0.747 Control group decreased.

All other group increased.Walking and walking + nutrition group increased the most.

reg5cc 0.241 0.548 Dance and walking + nutrition groups increased. Other groups remain same.

SCR 0.009 0.491 All groups decreased. Dance and walking group

65

decrease less than the other two groups.

SLF 0.094 0.530 Walking + nutrition group slight increase. All othergroups decreased.

UNC_pfc 0.001 0.861 All groups decreased.*Significance value(s) of ROI(s) with only time effect: underscored.

*Significance value(s) of ROI(s) with time × group effect: underscored and bolded.

*Fornix is the only ROI that displayed time × group effect.

*α level = 0.05

66

Table 3a. Tukey’s HSD Post Hoc Result of Fornix

Dependent Variable Groups Sig.Fornix FA %Δ Dance SSS .002

Aerobic .018Aerobic+ .021

SSS DanceAerobic .931Aerobic+ .896

Aerobic DanceSSSAerobic+ 1.000

Aerobic+ DanceSSSAerobic

*Significant: underscored

*Significant values of repeated group pairs are identical, therefore left blank to avoid confusion.

*Only pairs involving the dance group show effect.

Table 3b. Tukey’s HSD Homogenous Subsets

*Means for groups in homogeneous subsets are displayed.

67

Treatment Group

N Subset for alpha= 0.05

1 2SSS 4

3-.0357

Aerobic 40

-.0254

Aerobic+ 42

-.0239

Dance 49

.0233

Sig. .894 1.000

*The group sizes are unequal so harmonic mean sample size (43.256) is used.

*Mean of dance group is the only group mean singled out in a different subset.

68

Table 4. Classification of WM Tracts with Significant Time Effect(FA decrease over 6 months)

Fiber Type ROIsAssociation Anterior cingulum (ACC)

Ventral prefrontal part of uncinate fasciculi (UNC_pfc)External capsule (EC)Parahippocampal WM (HIPP_st)Occipital portion of inferior longitudinalfasciculi and inferior frontal-occipital fasciculi (IFOF_ILF_occ)Uncinate and inferior frontal-occipital fasciculi (IFOF_UNC)

Projection Posterior limb of the internal capsule (PLIC)Anterior limb of the internal capsule (ALIC)Superior corona radiata (SCR)

Commissural Region 1 (genu) of corpus callosum (reg1cc)

69

Table 5. General Types of Brain Artifacts of Removed Volumes in DTI Visual Checks

Artifact Types Image ExampleStriped lines on the image that do not seem to indicate gyri or other anatomical structures

Significant portions of the brain is cut off

Dark spots or “holes” that do notseem to indicate ventricles or otheranatomical structures Blurry images

70

Table 6. Statistical Analysis Flowchart

*Labels at bottom of the chart indicate what factor the section aims to investigate

*The final product of this flow chart, or the ultimate goal of statistical analysis in this study, is to find the nature (ie. increase or decline) that certain intervention(s) changes the FA of certain ROI(s).

71

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