Enhancing Spatial Navigation Using Non-Invasive Brain Stimulation
Phase: NA
Conditions: Mild Cognitive Impairment, Alzheimer's Disease
Sponsor: VA Office of Research and Development

 
Title: Enhancing Spatial Navigation using Non-Invasive Brain Stimulation 
NCT01958437 
PI: Benjamin M. Hampstead, PhD, ABPP/CN 

Enhancing Spatial Navigation using Non-Invasive Brain Stimulation 
Hampstead 
 Cleaned 3-18 
2 
Objectives: Remembering how to travel from one location to another is critical in everyday life, yet this vital 
ability declines with normal aging and can be further affected by conditions that disproportionately affect older 
adults, such progressive dementia. Human and animal research has shown that two distinct memory systems 
interact during navigation. The first, referred to as allocentric navigation, is flexible and uses spatial knowledge 
of key features or landmarks to develop and use a mental map of the environment. This approach involves brain 
regions that are critical for new learning and memory but that decline with age. The second, referred to as 
egocentric navigation, is inflexible and relies on “habit” memories that link specific features with specific 
directions. This approach relies on brain regions that are critical for “automatic” responses and that are relatively 
unaffected by age.  
The main problem is that allocentric navigation declines with age and is accompanied increased 
dependence on egocentric navigation. This change increases the risk of becoming disoriented or “lost” when 
traveling in unfamiliar areas or even when traveling new routes in familiar areas. Therefore, the main goal of 
this project is to examine whether non-invasive brain stimulation, specifically transcranial direct current 
stimulation, can improve allocentric navigation in cognitively intact older adults and those who have been 
diagnosed with mild cognitive impairment (MCI) – a clinical precursor to Alzheimer’s type dementia.  
Specific Aims/Hypotheses: 
Specific Aim 1: Examine the effects of high definition tDCS (HD-tDCS) on both allocentric and egocentric 
memory test performance. We predict that participants will perform more accurately following active HD-tDCS 
when compared to sham HD-tDCS. 
Specific Aim 2: Examine the neurophysiologic response to HD-tDCS using fMRI. We predict that active 
HD-tDCS will increase BOLD signal in a behaviorally meaningful way regardless of diagnostic group (i.e., healthy 
control vs. MCI). Critical questions about the restorative vs. compensatory effects of tDCS in those with MCI will 
be examined by contrasting BOLD signal change between the groups  
Methodology 
Participants: We will enroll up to 60 older adults (age 50+), who are right handed and MRI compatible, 
from the VA Ann Arbor Healthcare System, the University of Michigan Alzheimer’s Disease Center (MADC), and 
the surrounding community. Enrollment is open to participants regardless of race, gender, or social status. 
Inclusion criteria: Patients will receive a diagnosis of MCI based on the Albert et al. (2011) criteria. 
Specifically, patients will 1) report a subjective decline in memory (report can also be provided by an informant), 
2) demonstrate objective impairment in memory (based on Neuropsychological testing), and 3) remain
independent in activities of daily living. All patients will be stable on nootropic medications for at least 1-2 months
prior to study initiation.
By definition, healthy controls (HC) will be free of objective memory test impairment (i.e., all scores within 
normal limits on the standardized testing protocol below). 
Exclusion criteria: A history of 1) contributory other neurological (e.g., epilepsy, moderate - severe 
traumatic brain injury) or medical conditions that are known to affect cognitive functioning; 2) significant 
psychiatric conditions (e.g., moderate - severe depression, bipolar disorder, schizophrenia); 3) sensory 
impairments that limit the ability to take part in the study; 4) a significant history or current use of alcohol or drug 
abuse/dependence. Participants will also be screened to ensure MRI compatibility (assessed using the 
guidelines set forth by the American College of Radiology); some of the criteria for which are also reasons for 
excluding someone from tDCS (e.g., metallic or electronic implants). Eligible participants who cannot undergo 
MRI will be enrolled in the study and will complete only the stimulation and behavioral portions of the study. We 
have successfully used this same approach in our previous RCTs.  
Recruitment: Participants will be recruited from both the VA Ann Arbor Healthcare system and the 
University of Michigan Alzheimer’s Disease Center. The primary recruitment source of MCI patients at the VA 
will be the Neuropsychology Clinic while HC will be recruited from the general VA community via postings/flyers 
in approved areas. The primary recruitment site for non-Veterans will be the University of Michigan Alzheimer’s 

Enhancing Spatial Navigation using Non-Invasive Brain Stimulation 
 
 
 
   
 
 
Hampstead 
 
 
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Disease Center (MADC). The MADC recruits participants from several sources including its memory disorders 
clinic, community screening events, and external referrals. Participants interested in research are maintained in 
an IRB-approved database, which is available to the PI and his study team. This database includes individuals 
who are cognitively intact (HC) and those with MCI. 
 
 
Screening & Cognitive Assessment: After providing informed, written consent, participants will undergo 
a brief neuropsychological protocol to ensure they continue meeting MCI criteria as outlined above (for patients) 
or that they are, in fact, cognitively intact (for the HC). This protocol includes standardized measures that are 
shown in the table below. Other measures may be added to the protocol to characterize the nature of the patient’s 
cognitive functioning as necessary. Participants will be given breaks as necessary to ensure their comfort and 
are allowed to discontinue at any point for any reason. 
 
 
 
 
Eligible participants move forward into the study, details of which are provided below.  
 
  
Study Procedures:  
Eligible participants will undergo 2 sessions within a 2-week period of time. Some degree of flexibility is 
necessary with these visits in order to accommodate both patient and MRI availability. 
Once determined to be eligible, participants will be randomized to one of two groups within their 
respective diagnostic groups. The first group will receive active HD-tDCS during session 1 and then sham HD-
tDCS during session 2. The second group will receive the opposite order.  
Participants will first receive 20 minutes of HD-tDCS at 2mA or sham as appropriate to the assigned 
condition. Participant specific codes are entered into the Soterix Medical Inc Clinical Trial unit thereby ensuring 
participants and study staff are blinded to stimulation condition. Stimulation will be performed using a Soterix 
Medical Inc. tDCS unit (Clinical Trial system with attached 4x1 HD stimulation unit) within a quiet room. The unit 
automatically discontinues stimulation after the specified time has elapsed (here 20 minutes). The patient will 

Enhancing Spatial Navigation using Non-Invasive Brain Stimulation 
 
 
 
   
 
 
Hampstead 
 
 
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complete a brief questionnaire about the nature and severity of any side effects (see tDCS Safety below) as well 
as whether they believe they received active or sham stimulation.  
The active tDCS protocol will provide an initial ramp-up period in which the electrical current is gradually 
increased, followed by 20 minutes of stimulation at 2mA, and finally a ramp down period during which the 
electrical current is gradually removed.  
The sham tDCS group will receive a ramp-up period to 2mA followed immediately by ramp down period. 
This is repeated at the end of the session.   
 
fMRI Scanning: After completing HD-tDCS, participants will be escorted to the MRI machine where they first 
undergo a resting-state fMRI scan and then complete the spatial navigation task. Structural imaging data were 
collected through a GE MR750 3T magnetic resonance system (GE, Milwaukee, WI) with a 32-channel phased 
array head coil. Sequence parameters for acquisition were: Field of view (FOV) = 256, Matrix = 256 × 256, 156 
slices per volume, 1 mm3 voxel size, TR = 12 ms, TE = 5 ms, TI = 500 ms, flip angle = 15°. For resting state 
fMRI, participants were instructed to focus their gaze on the fixation cross on the screen and to not fall asleep. 
Resting state data was acquired through an echo planar imaging (EPI) multi-band sequence and parameters 
were: FOV = 240, Matrix = 74 × 74, 45 slices per volume, 3.4 × 3.4 × 3 mm voxel size, TR = 900 ms, TE = 30 
ms, flip angle = 70°. For the functional task portion, participants were instructed to view the spacial navigation 
videos and remember key landmarks or series of turns depending whether it was allocentric or egocentric task. 
Functional task data was also acquired through an echo planar imaging (EPI) multi-band sequence with the 
following parameters: FOV = 220, Matrix = 88 × 88, 51 slices per volume, 2.5 × 2.5 × 2.5 mm voxel size, TR = 
1200 ms, TE = 30 ms, flip angle = 70°. 
 
 
Memory Testing:  After scanning, participants perform a spatial navigation memory test that uses a 
touchscreen monitor to evaluate responding. Allocentric accuracy is measured as the distance (in CM) between 
the actual and selected location (lower values indicate greater accuracy) of a given landmark within a given map. 
Egocentric memory accuracy is evaluated by showing participants an image of a given environment after which 
they recall the sequence of turns through the environment. The dependent variable is the number of turns 
correctly recalled.    
 
Statistical Design: 
The primary analytic technique for the behavioral measures will be a repeated measures ANOVA (via 
the current version of SPSS). The effects of HD-tDCS for allocentric and egocentric performance will be 
examined separately.  These analyses may include potential confounding factors as covariates. 
 
fMRI data analysis MRI images were preprocessed and analyzed through SPM8 (SPM8; Wellcome Trust 
Centre for Neuroimaging). Slice timing correction was performed for functional volumes. Functional volumes 
were realigned to the first volume in the experiment to correct for head motion, co-registered with the high-
resolution sagittal images. The structural images were spatially normalized to a standard MNI template using 
the voxel-based morphometry toolbox (VBM8 http://dbm.neuro.uni-jena.de/vbm) and DARTEL high-
dimensional warping and resampled to a 3x3x3 mm voxel size. Estimated deformation fields from warping 
were applied to normalize images to MNI space, and smoothed using an 5-mm FWHM Gaussian kernel. 
Motion scrubbing (removal of volumes) was performed based on a framewise displacement threshold of 0.3. 
The time course data for each voxel was band-pass filtered (0.01 to 0.10 Hz band) to capture the low-
frequency spontaneous BOLD oscillations in resting state signals. 
 
Task analysis 
For the spatial navigation task, preprocessed MRI data were analyzed with the general linear model framework 
in SPM8. Two block regressors were modeled: allocentric and egocentric. The onsets and durations of blocks 
were convolved with a canonical hemodynamic response function (HRF) to create the block regressors, in 
addition to covariates of six image realignment parameters to reduce movement induced artifacts. In the first-
level analysis for each participant, the parameter estimates of block regressors were computed at each voxel. 
Appropriate linear contrasts were applied to the parameter estimates to produce contrast images and statistical 
parametric maps (SPM t map). To evaluate activations associated with task, session, and group effects, we’ve 

Enhancing Spatial Navigation using Non-Invasive Brain Stimulation 
 
 
 
   
 
 
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constructed a mixed ANOVA model to test the influence of the aforementioned variables. Second-level maps 
were initially thresholded at whole-brain p < .01 to .001, uncorrected (extent threshold, k = 10). In addition to 
whole brain analysis, we also created a mask from activations seen in the whole brain analysis of task main 
effects (voxel-wise FWE p < .05) for use in group analyses of session effects. Specific regions of interests 
(ROIs) were also utilized, selected based on prior work (Hampstead et al., 2014) in regards to spatial 
navigation and derived from the Anatomical Automatic Labeling software (Tzourio-Mazoyer et al, 2002). These 
ROIs included hippocampus, superior parietal lobule, and caudate (all small volume corrected at voxel-wise 
FWE p < .05). Beta values of surviving brain activations were extracted and analyzed with ANOVA with 
significance threshold set at p <.05. 
 
Resting state analysis 
Resting state functional connectivity was first examined using a region of interest (ROI) “seed” at the 
stimulation site, right superior parietal lobule (rSPL), using a 10 mm radius spheres centered at MNI: (24, -60, 
60). Pearson product–moment correlation coefficients were calculated between the average BOLD time course 
in the seed region and all other voxels in the brain. Each correlation resulted in a 3D correlation coefficient 
image (r-image). R-images were then transformed to z scores using a Fisher r to z transformation. Z score 
images from the individual functional connectivity analyses were entered into second-level random effects 
analyses (factorial ANOVA and t-tests) implemented in SPM8. 
We have further applied a 'data-driven' approach based on Graph Theory to analyze the functional 
connectivity network before and after the intervention. We've used Power's 264 anatomical coordinates to 
segment the brain into 264 ROIs. We included additional medial temporal and subcortical ROIs. Each ROI was 
defined as a 5 mm sphere centered around these coordinates. A binary grey matter mask was created through 
the segmentation procedure in VBM8 and the threshold probability of 0.6 (as suggested by Zalesky et. al.) was 
used to overlay on the normalized resting state images. The average time course signal of the grey matter 
voxels in each ROI was measured. Pearson's correlation between the signal time course of all possible pairs of 
ROIs was conducted. Correlation weights that failed the false discovery rate (FDR) threshold at p < 0.05 were 
discarded. Graph parameters, including total functional connections, network strength, and network cost were 
calculated. 
Within each group (HC and MCI), we will use the active > sham contrast to identify regions that differ as 
a result of HD-tDCS. Correlations between behavioral performance (e.g., accuracy in CM) and BOLD signal will 
also be calculated to determine whether the altered BOLD signal is behaviorally meaningful. Because we expect 
functional reorganization throughout the brain within both groups as a result of HD-tDCS, we intend to use 
connectivity analyses to examine changes in the connectivity between the parietal cortex and the remainder of 
the brain.  
 
Exploratory between group analysis will use two primary contrasts. 1) HC sham > MCI sham – which will 
identify disease-related differences in activation between the groups; 2) HC active > MCI active – which will 
examine whether the tDCS-related changes are greater in one group than the other. Taken together, these 
contrasts will also clarify whether tDCS restores functioning in brain regions involved in “normal” (i.e., age 
appropriate) navigation or whether it allows MCI patients to recruit alternative brain regions in a compensatory 
manner.   
Additional analyses will be performed as necessary in order to fully characterize the nature of tDCS-
related changes.  
 
tDCS Safety: tDCS has been used with literally thousands of patients world-wide. Brunonni et al., (2011) 
demonstrated that the rate of side effects is comparable between those receiving active and sham stimulation. 
We will follow current safety guidelines for dosing and will use a current strength of up to 2mA and duration of 
20 minutes per session. Few, if any, side effects are reported with these parameters and those that are reported 
are mild in nature (e.g., tingling, itching, burning sensation, (Nitsche & Paulus, 2011). Importantly, we will collect 
data on tDCS-related adverse effects using the questionnaire provided by Brunoni and colleagues (2011). This 
questionnaire is provided below. 
   
 

Enhancing Spatial Navigation using Non-Invasive Brain Stimulation 
 
 
 
   
 
 
Hampstead 
 
 
 Cleaned 3-18 
6