Cholinergic Functions and Modulation of the Cingulo-opercular Alertness Network in LBD
Phase: NA
Conditions: Lewy Body Disease, Lewy Body Variant of Alzheimer Disease, Lewy Body Dementia With Behavioral Disturbance
Sponsor: University of Michigan

Protocol version 05-05-22 
 
 
 
 
 
 
 
 
 
 
Cholinergic Functions and Modulation of the 
Cingulo-opercular Alertness Network in LBD  
 
NCT04817891 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol version 05-05-22 
 
 
 
 
 
SPECIFIC AIMS 
Fluctuating cognition is a characteristic core diagnostic feature of dementia with Lewy bodies (DLB) and is also 
a key clinical feature of Parkinson’s disease with dementia (PDD) (1, 2). Cognitive fluctuations are a major source 
of disability in these Alzheimer-related Lewy body dementias (LBD) (4). The central premise of this R21 
proposal is that cholinergic system changes in specific neural network regions underlie cognitive fluctuations in 
patients with LBD. Several independent lines of evidence implicate the cholinergic system in LBD. First, ex vivo 
post-mortem and in vivo acetylcholinesterase brain PET imaging studies have shown prominent cholinergic 
losses in LBD (5). In novel preliminary data using a vesicular acetylcholine transporter (VAChT) PET ligand, we 
extend these findings to show regionally distinct and prominent reductions in bilateral opercula and anterior-to-
mid cingulate cortices, bilateral insula, and other areas that are part of the cingulo-opercular task control (COTC) 
network (14) in patients with DLB. Therefore, the specific topography of cholinergic reductions in these 
DLB patients suggests preferential cholinergic involvement of the COTC network. The COTC neural 
network is believed to play a role in maintenance of alertness (15, 16) but this remains uncertain in LDB. This 
critical knowledge gap forms the basis of our first aim. We postulate that cholinergic losses in key COTC 
neural network hubs may underlie cognitive fluctuations in LBD. Second, there is clinical evidence that cognitive 
fluctuations in LBD are amenable to treatment with cholinesterase inhibitor drugs (19). However, the efficacy of 
current generation cholinesterase inhibitor drugs is typically limited due to poor brain penetrance (22). Novel 
approaches are needed to address this clinical unmet need. We propose to use transcranial direct current 
stimulation (tDCS) to “excite” critical cholinergic denervation components of the COTC as an adjunct to 
cholinergic pharmacotherapy in a target engagement study. tDCS is an emerging non-invasive neurostimulation 
technology that may improve a range of neurological symptoms, including cognition. There is also evidence that 
tDCS may modulate cholinergic activity modulation (25). Several small studies have employed tDCS in patients 
with LBD and revealed encouraging improvements in attention (26), though none have examined cognitive 
fluctuations to date. In the exploratory aim we will evaluate whether target engagement by tDCS excitation of 
cholinergic denervated COTC hubs may affect cognitive fluctuations in LBD subjects. 
 
Specific Aim 1: To perform detailed clinical evaluation, including measures of cognitive fluctuations, 18F-
fluoroethoxybenzovesamicol (18F-FEOBV) VAChT PET, and brain MR imaging, in patients with LBD (n=18 
enrolled; Net target completion rate = 12) in order to evaluate COTC integrity and the functional ramifications of 
dysfunction.  
 
Hypothesis 1: Severity of cognitive fluctuations associates with greater cholinergic deficits in COTC network 
regions in patients with LBD. We will evaluate subjective measures of fluctuations as well as objective measures 
of working memory and cognitive control that depend on the COTC and presumably underlie such fluctuations.  
 
 
Exploratory aim 2: To perform a target engagement study of 10 consecutive daily sessions of individualized 
tDCS to excite the bilateral opercular and anterior cingulum hubs of the COTC alertness network in patients with 
LBD. We will use a unique approach of creating MRI-based and VAChT PET-informed participant-specific 
computer models of electrical current flow through the brain in order to optimize stimulation effects and more 
precisely target the dysfunctional networks. tDCS dosing is traditionally defined by the amount of electrical 
current delivered at the scalp (e.g., 2mA); however, this neglects the individual differences in brain morphology 
that are known to affect the delivered dose (i.e., how much electricity reaches the brain). Thus, we will 
prospectively apply the MRI-based models to ensure a consistent dose is delivered to the targeted brain regions, 
selected from the VAChT PET scans, across participants. This approach substantially advances the field of tDCS 
and maximizes the probability of response at the individual level. 

Protocol version 05-05-22 
 
 
Exploratory hypothesis: tDCS excitation of key vulnerable cholinergic hubs of the cingulo-opercular alertness 
network will improve cognitive fluctuations in patients with LBD.  
 
Positive findings of this study will advance our scientific understanding of the role of key hubs of the COTC 
network in the etiology of cognitive fluctuations in LBD. Moreover, positive findings of the exploratory target 
engagement study may provide the impetus for clinical trials of cholinergic augmentation with adjunct tDCS 
therapy for cognitive fluctuations symptom relief to enhance everyday functioning in LBD patients.  

Protocol version 05-05-22 
 
RESEARCH STRATEGY 
 
Significance: Fluctuations in attention and alertness are a major source of disability for subjects with LBD. 
Current clinical treatment approaches are mainly based on pharmacotherapy but have limited clinical 
effectiveness. The COTC neural network is believed to play a key role in maintenance of alertness. Based on 
preliminary data of the topography of cholinergic denervation changes in persons with LBD we hypothesize that 
cholinergic denervation of this alertness network plays an important role in the pathophysiology of cognitive 
fluctuations in LBD. Our exploratory target engagement study proposes to examine the effects of non-invasive 
tDCS excitation of cholinergic denervation hubs in this network. Positive findings of this study could spur future 
clinical trials of targeted non-invasive neurostimulation using tDCS as adjunct to cholinergic pharmacotherapy 
as a novel way to manage fluctuations in alertness in people with LBD.  
 
Innovation: There is a high level of innovation in this proposal as we take advantage of recent neuro-imaging 
advances of cholinergic VAChT PET imaging and MR-based large-scale neural network identification in LBD. 
These include (i) the evaluation of novel regionally distinct cholinergic system changes associated with key hubs 
of the COTC neural network, implicated in maintenance of tonic alertness; (ii) the proposed research will develop 
a non-invasive neural network stimulation approach to boost and complement the limited brain penetrance of 
currently used cholinesterase inhibitor drugs in DLB; (iii) We will take the unique approach of creating VAChT 
PET-informed participant-specific computer models of electrical current flow through the brain in order to 
optimize tDCS effects and more precisely target the dysfunctional networks. This approach substantially 
advances the field of tDCS and maximizes the probability of response at the individual level. 
 
Scientific premise 
Cognitive fluctuations in LDB: Fluctuations in cognition and alertness are key manifestations of DLB (19). 
Fluctuating cognition is not only a core diagnostic feature but also the most characteristic feature of DLB (1, 2, 
19). Fluctuating cognition is also a key clinical feature of PDD (27). Cognitive fluctuations consisting of 
pronounced variations in attention and alertness are a major source of disability of patients and caregivers alike 
(4). The exact underlying pathophysiological processes underlying cognitive fluctuations remain unclear. 
However, neuroimaging and neurophysiological techniques have recently provided insight into potential drivers 
of the phenomenon (4). Several mechanistic theories have been posited to explain the etiology of cognitive 
fluctuations. Most authorities hold that cognitive fluctuations are attributable to a separate pathophysiological 
process to that driving progressive cognitive decline, as fluctuations by nature are transient and reversible. 
Putative pathophysiological models include fluctuations in cognition as an attentional disorder, as a consequence 
of loss of cholinergic drive, as a manifestation of failure in neuronal efficiency and synchrony, or as a disorder of 
sleep/arousal (4). Evidence for a hypocholinergic etiology is further provided by a highly selective animal lesion 
model, which demonstrated a correlate of fluctuating cognition with variable response latencies on an attention 
task in rats subjected to cholinergic denervation of the pedunculopontine tegmental nucleus, which is functionally 
linked to the cholinergic forebrain (28). The argument is further buttressed by data from both mechanistic (29) 
and clinical studies (30, 31) identifying improvements - albeit modest - in fluctuating cognition in patients treated 
with cholinesterase inhibitors. 
 
Large-scale neural networks and cognitive fluctuations: Graph theory analysis of functional connectivity resting 
state MRI has identified two distinct top-down task-control networks involved in attention (14, 32). The 
dorsolateral prefrontal cortex and intraparietal sulcus are hubs within the frontoparietal task control (FPTC) 
network. The FPTC network is important for start-cue and error-related activity and may initiate and adapt control 
on a more rapid and trial-by-trial basis. The COTC network encompasses medial superior frontal cortex, dorsal 
anterior cingulate, frontal operculum, anterior insula and thalamic regions (14). Effectively, the COTC graph may 
include parts of both the large-scale distributed network of the cingulo-opercular and salience networks (14, 32, 
33). The COTC network has been implicated in important cognitive functions, including sustaining alertness, task 
set maintenance and salience detection of stimuli (14, 16, 34). Hence, the COTC network controls goal-directed 
behavior more on a set maintenance mode using a longer duration time scale, such as needed for maintenance 
of alertness (15). Clinically, this may be reflected in a lack of maintenance of a functional operative state and 
difficulties staying on task in DLB persons in their daily life functions resulting in cognitive fluctuations. 
Morphometric studies have shown atrophy in the right anterior cingulate cortex and bilateral insular regions in 

Protocol version 05-05-22 
 
patients with prodromal DLB, 93% of who exhibited fluctuating cognition (35, 36). A prior resting state fMRI 
network study found evidence that cognitive fluctuations in patients with DLB correlated with widespread brain 
regions, including opercular/insular and anterior cingulum regions (37). These regions are implicated in the 
integrity of attentional circuits, and therefore provide supportive evidence for attentional impairments in cognitive 
fluctuations (38).  
 
tDCS in LBD is in a nascent stage. Briefly, tDCS modulates neuronal excitability (i.e., the probability of neuronal 
firing) by passing a low intensity electric current between electrodes that are typically placed on the scalp 
according to the international 10-20 (or 10-10) system. This same measurement system is used with EEG and 
provides a standardized, accepted, and clinically friendly placement method. tDCS electrodes are either 
characterized as an anode that “introduces” the electrical current or a cathode that “collects” the current. 
Evidence suggests that neuronal soma under the anode(s) consistently become depolarized (“excited”) (39, 40). 
Single session effects can last 60-90 minutes (41) and can be extended by consecutive daily sessions (see (42). 
Only a single tDCS study in those with DLB focused on arousal/attention. That study reported improved attention 
following a single session of tDCS (2.8mA) when the anode was placed over the left dorsolateral prefrontal cortex 
and the cathode over the right deltoid (26). Evidence from related alpha-synucleinopathies (-Syns), particularly 
Parkinson disease (PD), have been favorable as reflected by enhanced working memory after 2mA over the 
prefrontal cortex (43, 44) as well as by enhanced phonemic fluency and functional connectivity of brain regions 
mediating such cognitive abilities (45).  
 
Impact: This project builds on novel FEOBV findings, ongoing work with tDCS, and a unique patient cohort at 
the University of Michigan MADRC and the Ann Arbor VAMC. Promising findings in the study may augur novel 
neurostimulation targets to enhance cholinergic network maintenance of arousal and alertness in LBD. 
 
Preliminary data: Topography of cholinergic vulnerability in patients with DLB using VAChT PET:  Five DLB 
subjects and 21 normal control elderly underwent clinical assessment and 18F-FEOBV PET imaging. Compared 
to the control group, reduced VAChT binding in DLB patients demonstrated non-diffuse but regionally distinct 
and prominent reductions in bilateral opercula and anterior-to-mid cingulate cortices, bilateral insula, right more 
than left lateral geniculate nuclei, pulvinar, right proximal optic radiation, bilateral anterior and superior thalami, 
and posterior hippocampal fimbria and fornices (Fig. 1). With respect to the extent of these topographic changes 
major hubs of the COTC network predominate the observed cholinergic denervation changes in the DLB 
patients.  
 
Figure 1: Reduced cholinergic binding in 
key 
areas 
associated 
with 
alertness 
(cingulo-opercular) 
networks, 
saliency 
(insula), visual attention (visual thalamus), 
spatial navigation (fimbria/fornix). Spatial 
extent of changes is most prominent for the 
COTC network hubs. 
Figure 2: Data-driven cholinergic 
sub-networks in PD. The sub-network 
shown in green color has striking 
topographic overlap with the COTC. 
Figure 3: Pyramid of cognitive 
functions 
(modified 
after 
Scott, 
2011). 

Protocol version 05-05-22 
 
 
 
 
Data-driven cholinergic sub-networks defined by VAChT PET in PD. We performed a principal component 
analysis of whole brain VOIs from FEOBV PET scans in 86 patients with PD. Different factors are shown in 
different colors (Fig. 2). The green colored factor (third row) has striking topographic overlap with the COTC 
alertness network. Importantly, analysis of cognitive test performance showed significant cognitive correlates of 
the cholinergic binding in the COTC hubs across all cognitive domains (attention, language, visuospatial, 
memory and execution). Notably, the VAChT binding topography of significant voxel based correlations with the 
different cognitive domains showed overlapping areas that included key hubs of the COTC alertness network 
including the anterior cingulum and bilateral opercular regions. We hypothesize that the shared topography of 
cholinergic correlates of various cognitive domains correlates with findings of functional neuroimaging studies 
showing a core co-activation pattern as a result of cognitive task engagement independent of the specific task 
(34, 46). The term 'task-positive' has been reserved for this type of co-activation of different brain regions during 
cognitive tasks (47). Hence, the general task activation pattern suggests an involvement of foundational 
capacities such attentional control common to cognitive performance in general (15), see also a simplified model 
of shared 'sub-serving' cognitive functions in Figure 3 (48). 
 
Traditional tDCS dosing methods apply a pre-specified amount of electrical current to each participant via the 
scalp-based electrodes with the assumption that this yields comparable current delivery to the brain. However, 
this fails to account for individual morphological differences in “normal” brains as well as additional disease 
related changes, as would be expected in our LBD cohort. Our preliminary data are from 12 cognitively intact 
older adults who underwent high definition (HD) tDCS over the right parietal cortex (2mA for 20 minutes). In two 
separate sessions (randomized to active or sham), each participant completed an fMRI task (spatial navigation) 
and subsequent memory test after HD-tDCS. We then created individualized MRI-based finite element models 
of electrical current flow for each participant.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol version 05-05-22 
 
Figure 4: Individualized models for 12 cognitively intact 
older adults showing the functional significance of E-fields 
where 
there 
were 
strong 
relationships 
with 
neurophysiologic (BOLD signal change in 2B) and 
cognitive (memory test performance in 2C) effects. 
Figure 5: Individualized finite element model (left) targeting 
the hypo-metabolic region identified via 18F-FDG PET. This 
resulted in increased functional connectivity and meaningful 
speech improvement over the course of the tDCS 
intervention. 
 
 
Figure 4a reveals 100% variability in the amount of electrical field (E-field) reaching a targeted brain region 
(intraparietal sulcus). Thus, the reference participant (represented by “100”) would have required 4mA of current 
delivered at the scalp to achieve the same amount as the “optimal” patient received at 2mA (represented by 
“200”). Figures 4B and 2C show the functional significance of these E-fields as there were strong relationships 
with neurophysiologic (BOLD signal change in 4B) and cognitive (memory test performance in 4C) effects. 
Interestingly, those receiving more electrical current showed less BOLD signal; an effect typically interpreted as 
evidence of increased processing efficiency. This interpretation is strengthened by the cognitive data showing a 
positive relationship between E-field and improved memory test performance. Together, findings indicate higher 
E-fields enhance both processing efficiency and memory performance. We build on these results by being the 
first, to our knowledge, to establish dosing using individualized finite element models; an approach that should 
yield far more consistent results across participants as well as more replicable procedures across future studies. 
As an example of this approach (Fig. 5), we developed an MRI-based model for a 57-year-old individual with 
logopenic variant primary progressive aphasia and identified a 9-electrode montage that delivered ~1V/m to the 
18F-FDG hypometabolic left temporoparietal junction. The participant demonstrated notable increases in 
functional connectivity as well as a 10-25% increase in the number of words spoken.    
 
Overall strategy 
 
Overview  
The overarching goal of this proposal is to perform 
brain 18F-FEOBV VAChT PET and MRI and 
detailed clinical and cognitive characterization in at least 12 (n=18 enrolled; Net target completion rate = 12) 
patients with LBD who are on stable doses of cholinesterase inhibitors, i.e., at least 4 weeks. In exploratory Aim 
2, we will use MRI-guided finite element models that are informed by FEOBV PET imaging to create participant-
specific computer models of electrical current flow through the brain in order to optimize stimulation effects and 
more precisely target COTC hubs via tDCS in a target engagement study. Assessment of cognitive fluctuations 
will be measured by the Dementia Cognitive Fluctuation Scale (49). Details on the baseline (pre-) and post tDCS 
testing protocol are listed in the General Methods. 
 
Design & subjects and consideration of relevant biological variables, such as gender and age: Cross-sectional 
neuroimaging-clinical correlation study with exploratory non-invasive neurostimulation target engagement study. 
Although LBD affects men more than women, we will place special emphasis on equal recruitment of women. 
We have no a priori rationale to expect the findings to differ as a result of sex but will directly evaluate sex 
differences. Effects of age will also be taken into account. 
 
Timeline and milestones: Gross recruitment for the project will be 18 persons with probable DLB while 
anticipating 12-18% attrition (net recruitment target n=12). We will recruit and test 8-9 persons per year 
(approximately one every 2 months). Subject recruitment and testing will be completed within the first 10 months 

Protocol version 05-05-22 
 
of year 2 to allow statistical analysis and write-up of the study findings. Milestones of success are net completion 
of 6 persons for year 1 by 12 months and a total of 12 by 10 months in year 2.  
 
Statistical analysis: The primary objective of this proposal is to establish VAChT PET COTC neural network 
correlates of cognitive fluctuations. We will employ generalized linear mixed models (GLMM) to accommodate 
correlation via fixed and random predictor effects. GLMM has the advantage that it also allows for modeling of 
non-normal distributions and nonlinear models. The main predictors will be bilaterally averaged opercular, insular 
and anterior cingulum VAChT PET binding and the summed score of the 17-item Dementia Cognitive Fluctuation 
Scale (49). As LBD affect men more than women, gender will be included as a key biological variable in all 
analyses. Other co-variates will include measures of (motor) disease severity such as modified Hoehn and Yahr 
stage or MDS-UPDRS part III score, global cognition (MoCA), age, and levodopa equivalent dose and use of 
cholinergic drugs. Analysis of exploratory Aim 2 will use GLMM to evaluate the overall tDCS effects and 
regression analysis of the relationship between bilaterally averaged opercular, insular and anterior cingulum 
VAChT PET and tDCS changes in the Dementia Cognitive Fluctuations Scale. To avoid Type II error inflation 
correction for multiple testing will be performed. Statistical analysis will be performed by the Department of 
Radiology statistician Dr. Johnson. 
Expected results: For aim 1, we predict that severity of cognitive fluctuations as measured by the Dementia 
Cognitive Fluctuation Scale (49) associate with greater cholinergic deficits in COTC network regions in patients 
with DLB. For our exploratory aim 2, we predict that tDCS targeting key hubs of the COTC neural network using 
VAChT PET-derived stimulation volumes will improve subjective and objective cognitive fluctuations in the LBD 
patients and as a function of the degree of cholinergic losses in the targeted regions.  
Sample size considerations: Our main hypothesis will be tested using GLMM analysis. We have preliminary data 
obtained in persons with PD showing a correlation coefficient of R=0.59 (P<0.001) between COTC VAChT 
binding and attention/working memory functions yielding a power of >.95 to find a significant correlation (P<0.05). 
Exploratory aim 2 is a target engagement study to provide go/no go feasibility for future clinical trials. 
 
Pitfalls and alternative strategies: Effects of neural networks other than the COTC: It is possible that large-scale 
neural networks other than the COTC may be more robust drivers of an association between cholinergic system 
changes and cognitive fluctuations than the COTC hubs per se. For this purpose, we will compute VAChT binding 
changes in hubs of networks, such as the dorsal attention, ventral attention or central executive networks for 
alternative analyses. The MRI based computational model (CM) for each participant allow us to determine the 
extent to which any such network effects were affected by tDCS, thereby parsing direct effects of stimulation 
(i.e., the electrical field – EF) delivered to the associated brain regions) from those arising from between-network 
connectivity changes. Given the nature of the R21 mechanism, our goal is to evaluate the feasibility of the 
proposed methods and detect any evidence of change in the outcome measures so we will not include a sham 
control group at this preliminary stage. Positive findings in this study will allow a subsequent R01 application to 
include an appropriate control group as in Co-PI Hampstead’s ongoing studies. 
Target engagement study: We will perform an exploratory open-label tDCS target engagement study to provide 
causative evidence of cingulo-opercular alertness network involvement in the pathophysiology of cognitive 
fluctuations. Positive results will provide guidance for future clinical dose-finding trials. We propose 10 tDCS 
sessions based on Co-PI Hampstead’s experience with ongoing clinical trials and evidence of cumulative and 
persistent improvements following multiple sessions (typically ~5+) in other populations (see (42). As an initial 
step, this design balances feasibility (i.e., participant burden) by providing a sufficient and known (via the EF 
maps) dosage for each participant. 
Effect of acetylcholinesterase inhibitor drugs on FEOBV binding: We have selected the 18F-FEOBV PET 
radioligand because of its high affinity and selectivity binding to the VAChT based on stereospecificity of 
biological effects, pharmacologic blocking studies and in vivo brain autoradiography and metabolites studies 
(50). FEOBV PET studies appear to be not significantly affected by cholinesterase inhibitor drugs based on 
preliminary rodent data (Dr. Kirk A. Frey, University of Michigan). 
 
General methods  
 
Clinical characterization: All subjects will undergo a general clinical assessment. Severity of motor parkinsonism 
will be assessed using the Movement Disorder Society-revised Unified Parkinson's Disease Rating Scale (MDS-

Protocol version 05-05-22 
 
UPDRS) (51). Neuropsychological testing measures are presented in Table 1. Neurobehavioral and sleep 
assessment will consist of Epworth Sleepiness Scale for daytime somnolence (52); The Mayo Sleep 
Questionnaire for sleep quality and disturbances (53); The Spielberger State Trait Anxiety scale for trait anxiety 
levels (54). The Brief Psychiatric Rating Scale will be used for the assessment of hallucinations (55). We will use 
the Geriatric Depression Scale for the assessment of depression (56). The Apathy Evaluation Scale (AES) 
clinician version will be used to assess apathy severity (57). Patient on dopaminergic medications will be testing 
in the medication 'on' state. The test battery will be repeated after the target engagement tDCS study.  
 
Outcome measures:  
Primary outcome measures. The subjective report of fluctuations will be evaluated using the 17-item Dementia 
Cognitive Fluctuations scale (49), which was developed to address limitations in prior scales, e.g., (58, 59) and 
has good test-retest and inter-rater reliability.  
 
Secondary outcome measures include: 1) Neuroimaging  (see below). 2) Objective measures of working memory 
(n-back test) and 3) cognitive control (Stroop Color Word Interference Test) will serve as outcome variables for 
secondary analyses given the known deficits in those with LBD (60-63), relationship to the COTC (15), and 
positive benefits after tDCS (26, 64). 
 
Exploratory 
outcome 
measures 
include: 
1) 
Attention dependent mobility functions: Dopamine 
medication refractory postural instability and gait 
difficulties (PIGD) motor features are common in 
LBD. These mobility impairments are highly 
dependent on allocation of attentional resources 
(65). Expectedly, fluctuations in cognition may be 
a cause for falls or freezing of gait in LDB. For this 
reason, we may also perform a sensor-based gait 
and postural control test battery in the study to 
explore tDCS target engagement of cognitive 
fluctuations mediated mobility parameters. This 
test battery will include postural sway using tests 
such as the iSWAY and instrumented Timed Up 
and Go test  (iTUG) Mobility Lab modules (APDM, 
Inc., Portland, OR) (66-68), dynamic balance 
using the Mini-BESTest (69) with sensored 
subtests, and electronic gait mat assessment 
using 
the 
Protokinetics 
Zeno™ 
Walkway 
(Protokinetics LLC, Havertown, PA) for spatiotemporal gait measurements.  Our team has special expertise in 
the assessment of PIGD motor features (70). These mobility assessments will be used for a post hoc analysis. 
2) Additional exploratory measures include objective measures such as WAIS-III Digit Span and 3) Digit Symbol 
Coding (12) to measure attention and cognitive control, 4) PD-Cognitive Rating Scale (6-11) as an objective 
measure of overall mental status, 5) Colorado Assessment Tests Reaction Time to objectively measure 
information processing speed, and 6) Clock drawing (21) as an objective measure of visuospatial construction.  
 
tDCS stimulation sessions: Our preliminary data highlight the need for individualized approaches to stimulation 
that assure sufficient electric field delivery to the bilaterally targeted brain region based on significant cholinergic 
denervation (defined as binding below the 5th percentile of age and gender matched controls) of the COTC 
opercular, insula and anterior cingulate hubs. Additionally, we overcome the weaknesses associated with 
traditional large electrodes (e.g., 35 cm2) by integrating multi-electrode HD tDCS since this approach allows for 
greater flexibility in montage configuration. The protocol provides a 30-second ramp-up period in which the 
electrical current is gradually increased, followed by 20 minutes of stimulation at the amplitude specified by the 
model (this will vary by participant), and finally a 30-second ramp down period during which the electrical current 
is gradually removed (71). A computational model (CM) will be created for each participant using a resolution 
structural MR scan in order to move beyond the “one size fits all” dosing approach that is currently the “gold 
Table 1: Typical Neuropsychological tests (comparable measures 
may be used as necessary to accomplish study aims) 
Overall mental status 
Montreal Cognitive Assessment Scale (3) 
PD-Cognitive Rating Scale (6-11) 
Intelligence 
WAIS-III: Information(12) (OPTIONAL) 
Attention & Cognitive 
Control 
n-back test (13), Stroop Color Word Interference 
Test (17) 
WAIS-III: Digit Span, Digit Symbol-Coding (12) 
Language 
Boston Naming Test (30 item) (18) (OPTIONAL) 
D-KEFS verbal fluency test 
Learning & Memory 
Hopkins Verbal Learning Test—Revised (20) 
Brief Visuospatial Memory Test—Revised (90) 
Visuospatial/Construction 
Clock drawing (21) 
Benton Judgment of Line Orientation (23) 
Executive/Working 
Memory 
Stroop Color Word interference Test, D-KEFS 
Verbal Fluency Test, Trail Making Test, Sorting 
Test (24) (OPTIONAL) 
WAIS-III: Matrix Reasoning (OPTIONAL), Digit 
Backwards (12) 
Information processing 
speed 
D-KEFS: Trail Making Test (24) 
WAIS-III: Digit Symbol-Coding (12) (OPTIONAL) 
Reaction time (Colorado Assessment Tests) 
 

Protocol version 05-05-22 
 
standard”. The CMs provide quantitative values about the electrical field (E-field) in the targeted COTC neural 
network brain region(s) of each participant (note that values will be available for all brain regions but our primary 
analyses will focus on those involved in the COTC). Full details of CMs are available in the literature (72-75) and 
we will employ the most common approach, which involves finite element models (FEM) using the newly 
available ROAST pipeline (76). Once calculated, the E-fields can be visualized and values extracted for the 
desired regions of interest (COTC in our study). An example of this approach is shown above in Figure 5 and 
these models have been validated against intracranial recordings, e.g., (77). Given our prior review of the 
literature (78), we will develop montages that provide a minimum of 1 V/m to the key regions of each participant’s 
COTC. This approach overcomes known limitations in the standard administration of tDCS and increases the 
probability of positive results. We aim for 10 sessions split as 3-5 per week (71), with 4-5 sessions during the 
first week. Doses of cholinesterase inhibitor drugs will be kept the same throughout the duration of the study. 
 
Scientific rigor: All tests and neuroimaging procedures used in this proposal have been validated and protocols 
have been published. Both PET and MR neuroimaging assessments will follow established and published 
acquisition protocols. Neuroimaging analysis will include well-validated and widely used software packages and 
processing pipelines such as SPM12, FreeSurfer, FSL, and AFNI. All equipment for mobility testing is 
commercially available and vendor-provided (validated) outcome parameters will be used. The 
neuropsychological test battery includes tailored components for use in LBD patients (63). We will rigorously 
guard against Type I and Type II errors and correct all our statistical inferences with family-wise error and false 
discovery rate corrections where appropriate. This reproducible and rigorous methodological and analysis 
approach will ensure results and conclusions that can be replicated by other investigations.   
 
Magnetic resonance imaging (MRI) will be performed on a 3 Tesla Philips Achieva system (Philips, Best, The 
Netherlands) or comparable MRI system (e.g., GE 3T system). Some MRI scans/parameters may change to 
accomplish study goals; though typical parameters are included below. A 3D inversion recovery-prepared turbo-
field-echo was performed in the sagittal plane using TR/TE/TI=9.8/4.6/1041ms; turbo factor=200; single average; 
FOV=240x200x160mm; acquired Matrix = 240x200x160 slices and reconstructed to 1mm isotropic resolution. 
Resting-state fMRI scans will serve as a secondary outcome measure and be acquired using a 32-channel head 
coil and multi-band sequence (79), with nominal parameters: (TR/TE/FA = 720/34/52, 2mm isotropic resolution, 
72 slices). Data are collected with eyes fixated on a cross for 10 minutes (80), though we may ultimately 
implement a continuous stimulus presentation framework (e.g., children’s movie) since this is replacing the 
typical resting-state paradigm in the literature. Pre-processing follows our standard pipeline that includes 
physiologic noise reduction and thorough motion correction (81, 82).  Graph theory analysis or comparable 
methods will be used to identify the most highly connected nodes following published methods. Briefly, ROIs will 
be represented as nodes and pairwise correlations, based upon the mean time series for each ROI, will serve 
as weights over corresponding edges, thresholded by FDR correction, p<0.05 or appropriate correction methods 
(81, 82). Change from baseline will serve as the primary measure of interest. 
 
PET imaging will be performed in 3D imaging mode on a Biograph 6 TruPoint PET/CT scanner (Siemens 
Molecular Imaging, Inc., Knoxville, TN), which acquire 63 transaxial slices (slice thickness: 2.4 mm) over a 15.2 
cm axial field-of-view. Images were corrected for scatter and motion. Subjects will be scanned in the 
dopaminergic medication 'on' state. 18F-FEOBV will be prepared as described previously (83, 84). 18F-FEOBV 
delayed dynamic imaging will be performed over 30 minutes (in six 5-minute frames) starting 3 hours after an 
intravenous bolus dose injection of 8 mCi [18F]-FEOBV (85). A white matter reference tissue approach will be 
used to determine VAChT binding as previously reported (86). The PET imaging frames will be spatially 
coregistered within subjects with a rigid-body transformation to reduce the effects of subject motion during the 
imaging session (87). Statistical parametric mapping (SPM) software (SPM12; Wellcome Trust Centre for 
Neuroimaging, University College, London, England [https://www.fil.ion.ucl.ac.uk/spm/software/spm12/] will be 
used for PET-MRI registration using the cropped T1-weighted MR volumetric scan. Freesurfer software 
(http://surfer.nmr.mgh.harvard.edu) will be used to define cortical and subcortical volumes-of-interest (VOI).  
 
Functional Near Infrared Spectroscopy (fNIRS): enables the evaluation of brain functioning via scalp optodes 
that use LED or lasers to emit/detect changes in cerebral blood oxygenation. In contrast to information derived 
from the fMRI BOLD signal that can identify portions of the hemodynamic response, the fNIRS signal offers 

Protocol version 05-05-22 
 
added information regarding the coupling between tissue metabolic activity and its blood supply.  Supporting 
direct measures of both oxy- and deoxyhemoglobin, with deep tissue penetration, the NIRS signal supports real-
time evaluation of related biometrics that are known to influence brain function. While fNIRS has lower spatial 
resolution than fMRI, it has superior temporal resolution and is highly user friendly since it can be performed in 
an office setting. Using this technology will grant us another valuable tool through which to measure changes 
induced by the tDCS.  
 
PI Hampstead has purchased two NIRSport2 units (NIRx.com), which will enable up to 64 channels and whole 
head coverage. fNIRS is safe and accepted as a measure of neurophysiology. Data can be acquired during 
“rest” (e.g., eyes open staring at fixation cross) or task (e.g., during a memory task). The NIRSport2 units can 
also be worn as a “backpack” which enables measurement of brain functioning during ecologically-relevant tasks 
(e.g., making a pot of coffee, moving through one’s environment). This lightweight, wearable brain imaging 
system will allow us to study cerebral blood oxygenation during activities. A typical fNIRS “session” is anticipated 
to be 60-120 minutes. The typical session will include 1) placing the cap/headgear that contain fNIRS optodes 
on the participant’s scalp, 2) ensuring optimal contact with the scalp (e.g., moving hair to ensure the sensors are 
not blocked from the scalp), 3) performing the task and/or “resting-state”, 4) removing the fNIRS optodes. The 
user-friendly nature of fNIRS enables multiple measurement sessions, which will be determined based on 
participant/study needs.  
When participants have an MRI in this study, there are structural and functional sequences. For participants who 
require sedatives or for other reasons are unable to tolerate the fMRI, we will continue to obtain the structural 
portion of the MRI at the first imaging visit (visit 2).  This is necessary to determine dosing. We will do fNRIS in 
place of the functional portion of the fMRI prior to the start of tDCS.  At the second imaging session (visit 12), 
the participants who had fNIRS at visit 2 will have fNIRS repeated in place of the MRI 
 
 
Protection of Human Subjects 
 
i) Human Subjects 
 
Description of subject populations: LBD patients (n=18; M/F; 50-90 years) who have cognitive fluctuations and 
who are on stable doses of cholinesterase inhibitors (i.e., at least 4 weeks) will be recruited to participate in this 
study. DLB patients will meet the Fourth consensus report of the DLB Consortium inclusion criteria for probable 
DLB (2). Subjects will be identified according to the following recognized DLB features: spontaneous 
parkinsonian motor signs, fluctuating attention and concentration, recurrent well-formed visual hallucinations, 
presence of REM behavioral sleep disturbance, anosmia/hyposmia, or autonomic dysfunction (2). PDD patients 
will meet the criteria by Emre et al. (88).  
 
Exclusion criteria: 
1. Exclusion criteria include: (a) Subjects with contra-indications to MR imaging and/or tDCS, including 
pacemakers or claustrophobia, brain aneurysms; (b) Evidence of large vessel stroke or mass lesion on MRI; (c) 
Use of anti-cholinergic or neuroleptic drugs, (d) Evidence of atypical parkinsonism on neurological exam, (e) 
Major untreated psychiatric illness, such as bipolar disorder, (f) pregnancy (determined at the first study visit, (g) 
other neurological conditions such as epilepsy, stroke, multiple sclerosis, or moderate to severe brain injury 
deemed to be the primary cause of impairment (h) Sensory impairments that significantly limit one’s ability to 
see or hear, (i) significant history of recent alcohol or drug dependence, (j) Previous major radiation exposure. 
 
Recruitment: Participants will be recruited from the NIA P30-funded MADRC where Dr. Hampstead is the Clinical 
Core leader. The Carl Rinne Lewy Body Dementia Initiative within the MADRC provides longitudinal monitoring 
and multiple supportive activities for those with DLB. Most participants have expressed an interest in intervention 
related studies and, given Dr. Hampstead’s ties to the MADRC, all participants will be available for screening 
and potential enrollment. Other potential recruitment avenues include UM DataDirect, the UM Health Research 
Recruitment Registry (umhealthresearch.org), and community outreach activities. Potential participants may also 
be recruited from UM Lewy Body Dementia Biomarkers study (HUM00120024). 
 

Protocol version 05-05-22 
 
ii) Sources of Materials: 
 
Information gathered specifically for this research project includes test results from clinical test scales, 
psychometric cognitive measures, neurobehavioral rating scales, clinical motor data, questionnaires, and data 
derived from the PET that reflect the amount of vesicular cholinergic transporters and from brain MRI and/or 
fNIRS. 
 
iii) Potential Risks: 
 
Confidentiality of Research Information:  The research data to be collected from subjects will consist of 
confidential information relating to clinical, motor, cognitive, neurobehavioral and neuro-imaging functions.  
These research data are not intended for entry into the subjects’ clinical medical records.  However, the data 
remain potentially discoverable. This may lead to violation of privacy and embarrassment of the subject. 
 
Clinical Testing: Risks in regard to the clinical assessment are limited to fatigue, frustration and momentary 
embarrassment that may occur when one experiences difficulty performing a task or learning a new skill.  
 
MRI scan: There is a substantial risk to persons who have metallic objects inside their bodies, as the magnet in 
the MR scanner can cause these to move. Consequently, participants with pacemakers or metallic objects 
located in the eye, ear, brain or blood vessel walls will be excluded. There is a potential risk of heart rhythm 
disturbances in patients who have previous heart rhythm abnormalities or in patients who have certain types of 
heart pacemakers. If an X-ray study is required to rule out the presence of metallic fragments, the maximum 
radiation dose to the involved body area will be 0.3 rems (a unit of radiation dosage), with minimum exposure of 
the other areas of the body. Participants who developed claustrophobic anxiety during scanning found that this 
fear dissipated within 15 min while remaining in the scanner, or as necessary, after exiting the scanner. There 
also is the potential that imaging could reveal a previously unrecognized but pre-existing abnormality. Many such 
abnormalities are not clinically significant, but they may cause anxiety or require further investigation by a 
personal physician. If one of the investigators identifies such an abnormality, they will contact the personal 
physician, who will arrange for appropriate care. 
 
PET scans & venipuncture:  Insertion of a catheter for intravenous injection of the PET radiopharmaceutical may 
be commonly associated with slight pain or bruising at the puncture site and rare chance of infection. Participation 
in this research study will involve exposure to radiation associated with the PET transmission scans and the 
administration of the radioactive drugs. The exposure for a single 18F-FEOBV PET and the CT scan is 6.9 mSv. 
The total study exposure for the DLB subjects will be 13.8% of the annually allowed exposure limit for radiation 
workers. These exposure levels are considered low with acceptable risk by the University of Michigan RDRC. 
Participants will be instructed to void two hours post injection to minimize bladder exposure.  This radiation dose 
is not expected to produce any harmful effects, although there is no known minimum level of radiation exposure 
for non-radiation workers considered to be totally free of the risk of causing genetic defects or cancer.  The risk 
associated with the amount of radiation exposure participants receive in this study is considered low and 
comparable to everyday risks.  No PET studies will be performed on pregnant or potentially pregnant women, 
as confirmed by pregnancy testing.  The use of 18F-FEOBV is considered to be generally safe and effective as 
approved by the University of Michigan Radioactive Drug Research Committee in accordance with Food and 
Drug Administration regulations (21 CFR 361.1).  Adverse reactions to FEOBV used in this study have not been 
reported.  However, the possibility exists for a rare reaction to any of the drugs or procedures to which the 
participant will be exposed. Certified staff will be in attendance at all times during the study and an emergency 
cart will be in close proximity. Other physical risks involve possible muscle aches from lying still. 
 
Risks Associated with fNIRS: As the name implies, fNIRS uses near infrared light to measure cerebral 
oxygenation using LED and/or lasers. The only known risks are associated with damage to the eye or skin 
following prolonged exposure to bright lights. NIRx, the manufacturer of NIRSport2, has obtained safety test 
certifications for all their products. We have obtained the Optical Safety R3 document, which covers eye/retinal 
and skin exposure and revealed that the LED are within safety limits when at least four time steps are employed. 
The NIRSport2 units provide an eye safe intensity of 25mWmax per wavelength, with a time-switched; selectable 

Protocol version 05-05-22 
 
between 70 and 160Hz rate. The Aurora software that controls the NIRSport2 unit has imposed limits on the 
maximum allowable intensity in order to mitigate risk. Thus, there is little possibility of injury when following these 
safety guidelines. Participants will be informed of such potential risk and the unit will be turned off should 
participants report discomfort or significant feeling of heating/burning. 
 
 
Risks Associated with tDCS: The general consensus is that tDCS is safe. In a meta-analysis of over 200 tDCS 
studies conducted from 1998 to 2010, 56% of studies mentioned some type of adverse effect (see Table 1, which 
was taken directly from Brunoni et al., 2011). The effects were generally minor, including itching, tingling, 
headache, burning sensation and discomfort limited to the scalp site where the tDCS electrodes were applied. 
To date, there have been no reports of seizures or other severe events induced by tDCS (Brunoni et al., 2011; 
Nitsche & Paulus, 2011; Bikson et al., 2016). Importantly this is the case in both healthy volunteers and in 
different populations of patients, including patients with disorders where there might be an increased risk of 
seizures (e.g., dementia, recent stroke, epilepsy). In one study applying tDCS transcranially to the frontal cortex 
in rats, Liebetanz et al found that cathodal tDCS increased the threshold for localized seizure activity (i.e., 
lowered the risk of seizure occurrence), while anodal tDCS had no effect on the seizure threshold.  
 
We recently published a manuscript (Reckow et al., 
2018, Brain Stimulation, 11, 991-997) describing the 
safety, tolerability, and blinding of HD-tDCS using data 
from 101 older adults who took part in our prior and 
ongoing studies. All participants received HD-tDCS for 
20-30 minutes at 2 mA (n=66, 31 active) or 3 mA (n=35, 
20 active). Participants completed the standardized side 
effect questionnaire (included below) and were asked 
whether they received active or sham stimulation at the 
end of each session.  Results revealed that there were 
no serious adverse effects/events, supporting the safety 
of HD-tDCS. No participants withdrew. Tolerability was 
comparable between active and sham HD-tDCS 
regardless of intensity (2 mA and 3 mA) in first session 
(see Tables 2 & 3 below – taken from the manuscript). 
There were no significant group differences between individuals correctly stating their stimulation condition 
indicating adequate blinding. These findings persisted when multiple session data (i.e., 190 additional sessions) 
were considered.  Our conclusions were that HD-tDCS appears well tolerated and safe with effective sham-
control in older adults. Our ongoing studies consistently administer at least 3-4 mA per electrode with comparable 
results.  
Table 2. Frequency of adverse effects in 117 (active 
group) and 82 (sham group) experiments. Side 
effects were reported per study and counted as 
positive if even 1 patient within the study reported 
experiencing the symptom. Data taken directly from 
Brunoni et al., 2011. 

Protocol version 05-05-22 
 
 
  
 
 
 
Additionally, 
several 
important safety/tolerability 
points should be made: 1) 
prior research with pad-
based tDCS has revealed 
the possibility of skin lesions 
or burns. While this typically 
has occurred when best 
practices 
were 
violated 
(e.g., using water instead of 
saline), the data above 
demonstrate 
that 
skin 
redness (i.e., a precursor for 
burns that reflects increased 
skin 
temperature) 
was 
virtually non-existent in our 
HD-tDCS data. In fact, the 
only redness occurred in 
those randomized to the 
sham group. We believe this 
reflects the difference in 
electrode 
preparation 
as 
HD-tDCS uses a known 
quantity of gel (~10ml) that 
is housed within tailor made 
holders – this results in 
reliable 
and 
standard 
preparation 
across 
participants. In contrast, pad-based tDCS is prone to saline drip due to over saturation or pressure from the 
head-strap as well as heating due to inadequate sponge saturation. 2) the absence of differences between active 
and sham HD-tDCS at either 2 or 3 mA supports the proposed study methods. 3) We implemented a 10-minute 
“saturation” phase that significantly reduces impedance levels (baseline mean = 1.16 (SD=.97); 10-minute mean 
= 0.82 (SD=.80), t(232)=18.25, p<.001) and presumably increases comfort. We are in the process of completing 
a manuscript describing these data. 4) We follow best practices in monitoring safety data with tDCS and will 
specifically use the questionnaire provided by Brunoni and colleagues (2011), which is included below. 
 
Animal work has revealed that a standard dose, including those used in the current study, are substantially below 
that necessary to cause brain lesions in animal models ((89); see 
figure to right – taken directly from Liebetanz’s study). In fact, 
consultant Bikson recently completed a comprehensive review of 
over 32,000 tDCS sessions and found no unexpected adverse events 
or severe adverse events (PI Hampstead is a co-author on this study, 
which was published in 2016 in Brain Stimulation). In this same 
review, a variety of data and simulation approaches determined that 
a constant current of 67mA to 173mA would be needed to cause a 
parenchymal lesion. Thus, our intended dose is far below the 
estimated lesion threshold.  
 
Consistent with these data, a multiple consensus statements on the 
state-of-the-art of tDCS concluded that tDCS is safe, with minimal 
adverse effects and risks, even in patient populations, if appropriate 
Figure 6: From Liebetanz et al., 2009 
 

Protocol version 05-05-22 
 
guidelines are followed (39, 42). We intend to follow safety guidelines in regards to dosing and will use a current 
strength of 4mA (or less) per channel and duration of 20 minutes per session. 
  
We will use a Soterix Medical Inc. multichannel clinical trial HD-tDCS stimulation unit with double blinding 
capability, which is considered an investigational device by the FDA. Based on the safety information provided 
above, review of the scientific literature, and consultation with colleagues, we believe this device is of non-
significant risk (NSR). The University of Michigan IRBMED has accepted this designation in our ongoing work. 
This stimulator has a number of built-in safety features that limit the maximum possible current. It operates off of 
9v batteries, which limits the available power and prevents possible surges. This system gradually adds and 
subtracts current in order to avoid a sudden discharge that may be aversive (but not “damaging”) to the 
participant. There are automatic shut offs built in the event of excessive resistance or other factors that could 
affect stimulation.  
 
Risks associated with clinical, neuropsychological and behavioral testing: This study involves cognitive tests and 
questionnaires. The cognitive tests are not harmful but some people find them frustrating and concerning. Risks 
in regard to the neuropsychological and behavioral assessment are limited to fatigue, frustration and momentary 
embarrassment that may occur when one experiences difficulty performing a task or learning a new skill. Some 
people may be uncomfortable/embarrassed disclosing personal information or become a little nervous about 
memory testing, and may experience discomfort or become tired. Trained research assistants, however, are all 
under the direct supervision of the study MPI who is a Board Certified Clinical Neuropsychologist. Study team 
members are very well experienced in the assessment of older individuals and persons with dementia, 
understanding the need for breaks, gentle reassurance, or reinforcement. All assessments will be stopped if 
requested by the participant.   
 
iv) Adequacy of protection against risks: 
 
Recruitment and Informed Consent:  
 
Subjects will be recruited from the MADRC. Individuals willing to participate will be scheduled for the research 
procedures at which time the nature and risks of the procedures will again be reviewed with the subjects and an 
informed consent form will be obtained by one of the study investigators or their designee. Electronic informed 
consent may be utilized via HIPAA and FDA approved SignNow at a date prior to the initial study visit. One copy 
of the signed consent form will be given to the subject, one will be placed in the patient’s medical record and a 
third will be kept in the patient’s study binder. Study visits will take place at the UM Functional Neuroimaging, 
Cognitive & Mobility Laboratory where Dr. Bohnen has his office and the MADRC where Dr. Hampstead has his 
office. Imaging procedures will be performed at the University of Michigan Medical Center.  
 
Protection Against Risk: 
 
Confidentiality of Research Information:  The possibility of unintended disclosure of medical or research data is 
minimal, but not entirely impossible. We will employ stringent safeguards against unintended and inappropriate 
discovery and dissemination of personal medical and research data in our subjects by a multi-layered approach.  
All data bearing potential subject identifiers will reside solely in locked files in the offices of the study investigator.  
Original data collection documents will be maintained in secure files under the control of the investigators.  
Entries regarding details of the research project and its results will not be submitted to clinical medical databases.  
Electronic databases in the project will employ subject codes that cannot be linked directly to participants without 
a “key”, possessed only by the study investigators in a secure location, and maintained separately from the 
databases.  Databases will not be housed on systems with internet access, preventing unauthorized intrusions. 
Personal information that would directly identify study subjects will not be used in any publications or 
presentations resulting from this research study, unless separate written permission is given by the subject (or 
proxy).  Any superfluous records will be shredded. 
 
Clinical, cognitive and behavioral Testing: Great care will be taken to minimize distress.  

Protocol version 05-05-22 
 
In addition to a lunch and afternoon rest break, subjects are given multiple short breaks during the clinical testing 
day when needed. Subjects will be addressed in a courteous manner that does not infringe the patient’s dignity. 
Physicians and trained personnel with considerable experience working with older individuals and patients with 
PD or dementia will perform all evaluations and administer tests. These individuals are prepared to respond to 
patient anxiety, concern and other behavioral changes as appropriate to the situation. Offering breaks and 
reassuring subjects will further minimize risks when necessary. If needed for some subjects, the clinical testing 
protocol can be split over 2 days. The UM functional neuroimaging, cognitive and mobility laboratory has facilities 
to allow rest breaks when needed. The PI has several studies with 1-day clinical testing and 1-day imaging 
protocols in similar patient populations. Except when subjects are severely demented, our PD participants who 
are typical septuagenarians or octogenarians have no difficulties completing these protocols. There is a risk of 
falling with the gait and balance tests. During clinical examination and testing, the subject will be constantly 
supervised by the research staff and guard against falls when the patient is standing. During over ground walking 
subjects will be closely guarded, with “spotters” at gait initiation and turning.  
MRI Scan:  Additional safety is built into standard protocols of the Functional MRI Laboratory at the University 
of Michigan, where the MRI will be performed. These require the senior MRI technologist and study staff to 
also screen each participant prior to beginning the MRI. These individuals are independent of our study staff 
and have complete institutional authority to cancel scans should any potential safety issues arise.  
Pads and blankets are provided to make the scan as comfortable as possible and subjects are asked to wear 
foam earplugs to reduce the loud noises made by the MRI scanner. Individuals scanned are able to talk to the 
technologist throughout the study and can indicate right away if they wish to stop the study and get out of the 
scanner. To prevent the risks associated during the MRI scan with implanted devices or metal imbedded in the 
body, the study staff and the radiology staff review the subject’s medical history and medical records. 
Specifically, we will seek evidence of neurosurgical procedures, cardiac procedures including pacemaker 
placement, and orthopedic surgery. In addition, individuals are strongly urged to identify any and all surgeries 
they have had to assess the chance that any metal in the body. Also subjects will be asked if they have had 
any occupation (for example, being a metal worker) or other experience that might have left metal fragments in 
the body. Subjects with a history of metal work (e.g., welding) or injury related to metallic foreign matter, will 
undergo a radiograph of the affected area to ensure the safety of proceeding with MR scanning. The potential 
risks related to MR scanning will be further minimized in the following manner: 1) Claustrophobia from MR 
imaging will be reduced by thoroughly explaining the procedure and nature of the scanner to subjects in 
advance of scanning. Subjects who have a significant history of claustrophobia will not be entered in the study. 
Furthermore, the study will be terminated at the subject's request. The UM fMRI Lab has a mock MRI scanner 
that we use as necessary to ensure participants are comfortable in the MRI environment (e.g., in those with 
possible claustrophobia).  
2) Subjects with contraindications to MR scanning, including but not limited to aneurysm clip, pacemaker, 
intraocular metal, and cochlear implant, will be excluded from the study. 
 
PET Scan & venipuncture: A nuclear medicine technologist will perform the PET studies under the supervision 
of a physician who is a specialist in nuclear medicine. A physician or nurse will be available at all times during 
the study, and any adverse reactions will be treated immediately. A fully equipped medical cart is located in the 
Nuclear Medicine suite. We will use aseptic techniques and highly trained personnel to minimize the risks 
associated with venipuncture. No PET studies will be performed on pregnant or potentially pregnant women, as 
confirmed by pregnancy testing within 48 hours prior to each PET imaging session. In order to lessen the pain 
and fatigue of lying still, the subject will be given a break outside of the scanner midway through the procedure.  
 
Observational Study Monitoring Plan: (please see below). 
 
Potential Benefits of the Proposed Research to the Subjects and Others:  
 
In the course of this study patients will receive clinical evaluations including cognitive testing and, imaging 
studies. No direct immediate benefit of these studies is anticipated. Although generally the results of these 
examinations will not be made available to their treating physician, if a significant, unexpected abnormality is 
detected this will be reported to the patient and his/her physician.  

Protocol version 05-05-22 
 
 
Importance of the Knowledge to be Gained:   
 
Data obtained from this research will become important for the development of improved understanding of 
mechanisms underlying impaired turning functions and mobility impairments in patients with PD. Such 
mechanisms would provide a rational basis for targeted intervention in PD patients with decreased turning 
functions putting them at risk of falls and freezing of gait. 
 
Observational Study Monitoring Plan: 
 
The independent safety monitor, Dr. Shawn McClintock, who has been approved by the NIA as a safety 
monitor will review the tDCS side effect/safety data twice in the first recruitment year (6 months after the first 
participant is enrolled and at 12 months). Biannual reviews will continue if any safety concerns emerge during 
this first year. Annual reviews will be conducted (at the time of the IRBMED continuing review/renewal) if no 
safety concerns are evident.  
The co-PIs will be responsible for monitoring any break in confidentiality and for reporting any adverse events 
following IRB guidelines. For purposes of this study, an adverse event (AE) is defined as any unfavorable or 
unintended change in structure, function, signs, or symptoms temporally associated with participation in this 
study, whether or not a causal relationship with the study has been established. Clinically significant 
abnormalities may be considered an AE if deemed appropriate by the co-PIs.  Unexpected worsening of a pre-
existing condition is also considered an AE, as is the discovery of an abnormal finding during physical exam that 
was not included in the medical history. Breaches of confidentiality will be considered related to the research 
whenever they occur and will be reported. Withdrawals from the study and the reason for these withdrawals will 
also be reported. 
 
The co-PIs are in daily contact with the Project research staff who will test the participants, score and enter the 
data and will monitor their procedures to ensure that confidentiality is maintained. The co-PIs will ensure that the 
IRB is notified of any adverse event following the IRB guidelines. Expected and unexpected serious (including 
fatal) adverse reactions and major unresolved disputes between the research investigator(s) and the research 
participant or between research investigator(s) will be expeditiously reported to the IRB. At the time of renewal, 
the IRB will be provided with a summary indicating the frequency of the monitoring, cumulative adverse event 
data, information regarding participant safety or ethics changes, confidentiality issues, benefit-to-risk changes 
and recommendations on continuing, changing or terminating the study. 
 
Inclusion of Women and Minorities: 
 
Inclusion of Women: 
 
Women will be included in this research project.  Males and females will be given equal priority in recruitment.  
However, because DLB affects males more than women we expect to recruit a higher percentage of males. The 
PI will monitor recruitment of women to this project throughout the study, and institute procedures to enhance 
the enrollment of women, if numbers are not adequate. 
 
Inclusion of Minorities: 
 
Enrollment targets are based on population estimates of the 2010 US census for the state of Michigan.  Estimates 
are < 1-2% (or N <1) for American Indian/Alaska natives, Native Hawaiian or Other Pacific Islander, and Asian 
Americans for Michigan. 
 
Inclusion of Children 
 
Justification for Exclusion of Children: 
 

Protocol version 05-05-22 
 
No children will be included. LBD occurs predominantly in late-life and, indeed, the risk of developing PD 
increases with increasing age. In rare cases with clear familial inheritance, the onset of the disease may occur 
in the 30’s and 40’s, but there is no evidence of clinical LBD in children. Therefore, the research topic to be 
studied is not relevant to children. 
 
 
 
 
 
 

Protocol version 05-05-22 
 
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