Supplementary Information
Method
MRI preprocessing methods
Hippocampal Manual Tracing: similar method details were presented elsewhere 1. To
minimize error, we firstly pitch-rotated a standard template so that the long axis of the
hippocampus was orientated horizontally on sagittal view. Each subject’s baseline and
follow-up T1 images were coregistered with each other, then coregistered to this new
template and coronally resliced at 1x1x1 mm3 resolution. The left hippocampus was
traced by a research assistant from these coronal images using ANALYZE (version
10, Mayo Clinic) using a previously published protocol 2. This assistant was blind to
information of the subjects’ temporal and grouping status for all measurements.
Hippocampal Longitudinal FSL-FIRST analysis: raw T1-weighted MRI scans were
firstly checked for obvious anatomical or positional abnormalities and extract the
brain. Next, bilateral hippocampi were segmented using Functional MRI of the Brian
(FMRIB)'s Integrated Registration and Segmentation Tool (FIRST, v5.0.0) in
FMRIB's Software Library (FSL, version v5.0). We used the vertex output of
hippocampi to assess the longitudinal morphometric change on the hippocampal
surface.
FreeSurfer (v5.1.0) to analyze the cortical structures: The longitudinal pipeline in
FreeSurfer was applied 3 to extract reliable longitudinal measures of cortical thickness.
It creates an unbiased within-subject template space and image 4 using robust, inverse
consistent registration 5. The surface map indicating the rate of thickness changes
were calculated between two time points for each subject. These maps were used to
test the longitudinal training effect on a vertex basis.
1
COGPACK Computerised Cognitive Training
Manual of Procedures
Rationale
The development of new intervention strategies in the prevention or delay of
Alzheimer’s disease onset are an international priority given the health burden
associated with the disease. Mental activity, or cognitive training, has recently been
identified as a means to provide stimulating brain exercises to optimize the potential
for neural plasticity: maintaining and potentially improving brain function.
The suite of cognitive training exercises are computer-based in keeping with recent
commercial and research programs (e.g. Mahncke et al 2006; Schreiber, 1999;
Hofman et al 2003) and according to the literature, multimodal, multi-domain and
task load-graded training in the areas of memory, executive function, attention and
speed of information processing.
Cogpack
The Cogpack package of exercises were developed by a German neuro-rehabilitation
centre and are largely based upon well established neuropsychological tests and
principles and, moreover, their effective use with psychiatric patients has been
reported (McGurk et al; 2005).
Fourteen exercises will be administered in the SMART study with multiple exercises
being used to target the one generic cognitive domain and encompassing both verbal
and visuo-spatial stimuli in order to maximize cognitive and neurological outcomes.
Within-domain multiplicity is also required to ensure participant engagement and
avoidance of ceiling effects during the long 6-month training phase.
Table 1: Cogpack exercise, cognitive domain, description.
Cogpack
exercise name
Reading
Memory:
Names
Memory:
Shopping List
Sequence:
Months
Memory:
Traffic
Memory:
Forms
Route
Reaction: 3x2
UFOs
Neuropsychological Description
Cognitive Domain
Verbal episodic memory
Verbal episodic
Verbal episodic
Verbal working memory
Visual episodic
Visual episodic
Visuospatial working
memory
Speed of processing
Speed of processing
Recognition multiple choice recall
format of structured verbal information
Recognition recall of verbal
information
Recall
Tracking and holding verbal
information
Recognition recall format visual
information
Recognition recall format visual
information
Free recall visuo-spatial information
Speed of comprehension.
Reaction time task to visual stimuli
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Anagrams
Executive
Logic: Blocks
Executive
Logic: And UK Executive
Search
Connect
Attention
Attention
Deductive word completion
Reasoning pattern completion.
Deductive reasoning and
comprehension task
Visual scan & search
Complex tracking and shift
Twelve of the 14 exercises require a simple touch-screen response with no mouse
operation and in this way will avoid training difficulties in the computer-naïve;
furthermore the touch-screen medium has been shown to be efficacious in cognitively
impaired elderly (Hofman et al 1996). Two exercises have been chosen to specifically
train mouse-based speed-dependent responses, and these will be completed before
commencement of the two additional exercises that require mouse skills. The
exercise set has been predetermined for each separate training session and will be
randomly delivered to each participant.
Procedure
Participants will begin their first session with an introductory session including the
provision of information regarding the training and obtaining their user code. A
maximum of ten participants will complete training within the same session. Each
session will involve the research assistant setting up the participant at their computer
station, entering the participant code and opening the specific session of exercises.
The RA will then provide computer support and positive feedback to maintain
motivation and compliance. At ten minute intervals the RA will ensure the
participant has started the next training exercise to guarantee that an exercise is
completed for each domain at every session.
Cognitive training feedback
During any small group or individual training, discussion and motivational support
and advice will naturally occur. In order to standardize this feedback throughout the
SMART trial a series of ‘strategies’ (internal cognitive strategies based upon well
established rehabilitation techniques) have been developed for each exercise. This
feedback is to be provided to all participants.
Administration
First training session
1. Participant File codes
Each participant of the SMART cognitive training exercises needs to be entered into
the Cogpack system- a person file code. There are three stages to identifying the
person- 1- ID codes which can only contain numbers. Then name, and last is Your
code which can be numbers, letters or symbols. Keep same as ID code for tracking.
1.
2.
3.
4.
5.
6.
Open Cogpack
Open [person] from menu
go to [input]
complete all fields with information from participant file
Enter participant ID code- must be numbers only
Enter first name
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7.
8.
click [both of the above] okay
Enter participant ‘Your code’ can be anything
2. Welcome
Welcome each participant to the mental exercise training program.
“This is the beginning of your mental activity program. The program will last for 52
sessions over 26 weeks, three sessions each week. Every session will consist of 5
different computer exercises for memory, problem solving, speed, and attention, and
will take about 50 minutes to complete”.
“Each exercise has been selected to be challenging so you are having trouble don’t
worry, just continue to complete the task. Everyone will complete the same program
but in a different sequence, so don’t be concerned if other people are completing
different exercises to you”.
“I will be here during your exercise session to start you off and to help you, so if you
are having any concerns just ask. Let us begin your first session”.
3. Start training
Cogpack commands:
1.
open Cogpack
2.
click on [person]
3.
go to [code], and enter participant’s ID code
4.
click on [training]
5.
click on [series]
4
6.
7.
click on session # for that participant
[start] the exercise session will proceed automatically
Using Equipment
Participants can use the mouse, touch screen or keyboard. Please identify with each
participant which method/s suit them best. Get participant to practice on touch
screen. They must hit screen in single movement with finger pad NOT nail, and hit
on or above icons.
Progress through the exercises
Every ten minutes insure that the participant has moved on to the next exercise so that
they can complete 5 exercises within each session.
At the end of each exercise participants can review their progress by clicking on
[compare your scores]. Only participant codes will be evident with their performance
being the last entry.
Exercise feedback
Memory
Reading (session 1; 4; 7; 10; 14; 16; 19; 22; 25)
A passage is provided to read followed by multiple choice questions.
Participants will complete 2 trials of each passage per session. After completing the
first reading trail, click the [complete trial again] option. See below
Strategy: While reading the passage repeat the important information in your headthis is a rehearsal strategy to increase your learning.
5
Memory: Names (session: 2; 5; 8; 11; 13; 17; 20; 23; 26)
A set of 4 names are to be learnt and then recognized from a set of 12. 10 trials.
Strategy: Repeat the names in your mind as you read them, a rehearsal strategy. You
could shorten the names to the first 3 letters and make a new ‘word’ – chunking the
information together.
Sequence (session: 3; 6; 9; 12; 14; 18; 21; 24)
Months of the year are displayed and the user has to determine if in order with the
preceding item.
Strategy: Repeat the items in your mind in order to ‘hold’ them between each
display.
Memory: traffic (session: 1; 4; 7; 12; 15; 19; 22; 26)
A set of 6 road traffic signs are displayed to be learnt, and then a set of 12. 10 trials.
Strategy: Link the signs together between the images eg. Stop sign and train sign
could become stop for a train- make associations between the information to assist
your memory. Another strategy is to verbally describe the visual image in order to
give you a visual and verbal memory of the information.
Memory: forms (session: 2; 5; 9; 10; 13; 16; 18; 20; 24)
A set of 3 geometric shapes are displayed followed by a set of 12 items for
recognition.
Strategy: Link the signs together between the images eg. Stop sign and train sign
could become stop for a train- make associations between the information to assist
your memory. Another strategy is to verbally describe the visual image in order to
give you a visual and verbal memory of the information.
Memory: route (session: 3; 6; 8; 11; 15; 21; 23; 25)
A journey through a map is displayed and user has to recall trail.
Strategy: Describe the trial in verbal commands to yourself- go left 3 down 2 left 2,
and repeat.
Memory: shopping (session: 3; 6; 8; 11; 15; 21; 23; 25)
List of shopping items to recall.
Strategy: Chunking items, and repeat.
Speed of processing
Reaction: 3x2 mouse (session: 4; 7; 11; 14; 18; 25)
Follow command.
Visuomotor: raft (session: 5; 8; 10; 13; 16; 19; 24)
Move target through screen.
UFO’s: permanently adaptive (session: 1; 3; 6; 17; 20; 23; 26)
Hit targets as soon as they appear on screen.
Falling Stars (session: 2; 9; 13; 19; 22; 26)
Catch items.
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Strategy: Keep finger or mouse in centre of screen and move it in a calm systematic
manner to increase accuracy.
Executive
Anagrams (session: 1; 9; 13; 19; 22; 26)
Re-ordering letters to spell known words.
Strategy: Start with a single consonant and generate options, then progress to another
letter
Guess-words (session: 2; 5; 12; 16; 21)
Following clues to deduce the target word.
Strategy: Use your general knowledge, systematically try letter options- eg start with
vowels.
Labyrinths (session: 3; 8; 11; 18; 23)
Maze completion
Strategy: Take your time and plan your route
Logic: blocks (session: 4; 7; 14; 17; 24)
Complete patterns
Strategy: Recognise what the pattern is by systematically thinking about how / why
the items are in that pattern.
Logic: And UK (session: 6; 10; 15; 20; 25)
Comprehending a statement and applying the rule to an array of pictures.
Strategy: Read the statement carefully so you understand what it means. Apply the
rule and check your work.
Attention
Search (session: 1; 3; 5; 7; 9; 11; 13; 15; 17; 19; 210; 22; 24)
Visually scanning to locate a target item
Strategy: Look along each row or section in a systematic left right motion.
Connect: I A @ B (session: 2; 4; 6; 8; 10; 12; 14; 16; 18; 21; 23; 25; 26)
Linking numbers and letters
Strategy: Recite items to help keep track of your progress
End Session
Thank participant for coming to the session and remind them when you will see them
next.
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Functional MRI results
Posterior Cingulate (PC) seed/ Default Mode Network (DMN)
The sole RES x time effect was to decrease FC between PC and left inferior temporal
lobe (ITL_L, df=67, F=14.8, p<0.001, Figure S1A) as well as ACC†1 (df=67, F=23.3,
p<0.001, Figure S1A).
The COG x time interaction also decreased the FCs of PC and right ACC (ACC_R†,
df=67, F=13.9, p<0.001, Figure S1B) and left superior frontal lobe (SFL_L†, df=67,
F=31.7, p<0.001, Figure S1B).
The RES x COG x time interaction indicated that the combination of the two types of
training significantly reduced the FC between PC and two regions, ventral ACC †
(df=65, F=5.3, p=0.017, Figure S1C) and within the PC† itself (df=65, F=6.1,
p<0.001, Figure S1C).
In general, training has a global effect on decreasing the FCs of the PC (Figure S1).
† Where marked (†) in text or figures indicates statistical results after additional control for baseline FC,
because of significant differences on baseline FC between groups.
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Figure S1. Longitudinal training effects on the Posterior Cingulate (PC) seed FCs. PC
seed is shown at the right top corner. Regions with whole brain cluster level pFDRcorrected<0.05
were considered significant. RES x time had a longitudinal effect on
decreasing FC network to the left ITL as well as ACC. COG by time also decreased
the PC FCs to right ACC (ACC_R) and left superior frontal lobe (SFL_L). RES x
COG x time indicated that the combination of the two types training significantly
reduce the FC between PC and two regions, ACC and PC itself. Several results
further remained significant after controlling for baseline connectivity (due to
significant baseline group difference on FC), indicated by † at p-value
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Hippocampal (HP) Seed
For the RES x Time interaction, functional connectivity between HP and right inferior
temporal lobe (ITL_R†2 df=67, F=18, p<0.001, Figure S2A) was significantly
decreased. By contrast, the PRT x time interaction was also significant, but in the
opposite direction when examining FC between HP and right middle frontal cortex
(MFC_R, df=67, F=13.0, p=0.001, Figure S2A).
The CT x time interaction produced positive changes on the hippocampal FCs of right
inferior temporal lobe (ITL_R†, df=67, F=10.6, p=0.006, Figure S2B) as well as left
superior frontal gyrus (SFG_L, df=67, F=6.1, p=0.012, Figure S2B).
The three-way interaction found significant areas at the right superior frontal gyrus
(SFG_R†, df=65, F=7.0, p<0.001) and dorsal ACC (df=66, F=4.6, p=0.005). Post-hoc
analysis showed that the combination of CT and PRT increased the FCs between HP
and these two regions more than the stand alone interaction (Figure S2C).
Where marked (†) in text or figures indicates statistical results after additional control for baseline FC, because of
significant differences on baseline FC between groups.
2
10
Figure S2. Longitudinal training effect on hippocampal (HP) FCs. Bilateral
hippocampal seed is shown at top right corner. Regions with whole brain cluster level
pFDR-corrected<0.05 were considered significant. RES x time decreased FC between HP
and right inferior temporal lobe (ITL) but increased the FC between HP and right
middle frontal cortex (MFC). COG x time elevated hippocampal FCs to the right ITL
and left superior frontal gyrus (SFG_L). RES x COG x time indicated that the
combination of the two types of training significantly increased the FC between HP
and two regions, right SFG and ACC. Several results further remained significant
after controlling for baseline connectivity (due to significant differences between
groups on baseline FC), indicated by † at p-value.
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