Stimulation of Cingulo-opercular Alertness Network (SCAN)

Cholinergic Functions and Modulation of the Cingulo-opercular Alertness Network in LBD

Fluctuations in alertness are very common in persons with Lewy body dementias and are a major source of disability. Changes in a chemical messenger molecule called acetylcholine within certain brain regions may play a role in these fluctuations. We propose to test this hypothesis and also determine whether a non-invasive way of stimulating affected brain regions may be of relevance for future management of these fluctuations.

Study Overview

• Status: Completed
• Conditions: Lewy Body Dementia With Behavioral Disturbance; Lewy Body Disease; Lewy Body Variant of Alzheimer Disease
• Intervention / Treatment: Device: HD-tDCS

Detailed Description

The central premise of the research study was that cholinergic system changes in specific neural network regions underlie cognitive fluctuations in patients with LBD. The cingulo-opercular task control (COTC) neural network is believed to play a role in maintenance of alertness but this remains uncertain in LDB. This critical knowledge gap formed the basis of the study's first aim. The study proposed 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. The study evaluated whether target engagement by tDCS excitation of cholinergic denervated COTC hubs may affect cognitive fluctuations in LBD subjects.

While the cingulo-opercular network was expected to be the primary site of cholinergic denervation based on preliminary evidence, and thus the focus of the stimulation intervention, the typical pattern of cholinergic denervation in our sample occurred at a temporal lobe region that is classified as a node of the ventral attention network in the Gordon atlas. Additional results from examining different networks have been added to reflect the unanticipated relocation of stimulation location.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • 4250 Plymouth Road (University of Michigan)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• LBD patients (DLB or PDD) 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.
• 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.
• PDD patients will meet the criteria by Emre et al. (Cognitive deficits in at least two of four of the following cognitive domains: Impaired attention, impaired executive functions, impairment in visuo-spatial functions, impaired free recall memory typically improved with cuing. Must also meet criteria for at least one behavioral symptom: apathy, depressed or anxious mood, hallucinations, delusions, excessive daytime sleepiness). Lack of behavioral symptoms does not exclude the diagnosis. Must also have none of Group III features present: (1) Co-existence of any other abnormality which might cause impairment, but judged not to be the cause of dementia. (2) Time interval between development of motor and cognitive symptoms not known. Must also have none of Group IV symptoms present: (1) Cognitive and behavioral symptoms appear solely in the context of other conditions such as acute confusion caused by systemic diseases or abnormalities, drug intoxication, or major depression according to DSM IV. (2) Features compatible with Probable Vascular Dementia criteria accordingly to NINDS-AIREN.

Exclusion Criteria:

• Subjects with contra-indications to MR imaging and/or tDCS, including pacemakers or claustrophobia
• Evidence of large vessel stroke or mass lesion on MRI
• Use of anti-cholinergic or neuroleptic drugs
• Evidence of atypical parkinsonism on neurological exam
• Major psychiatric illness, such as bipolar disorder
• Neurological conditions such as epilepsy, stroke, multiple sclerosis, or moderate to severe brain injury
• Sensory impairments that significantly limit one's ability to see or hear
• A significant history of recent alcohol or drug dependence
• Previous major radiation exposure
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental: HD-tDCS; Maximum 4 milliAmp (mA) per channel of HD-tDCS treatment for 20 minutes, for 10 sessions. Total mA dose determined by individualized computational models.	Device: HD-tDCS; Participants will receive HD-tDCS at up to 4 mA per channel for 20 minutes for 10 sessions. Dose determined through individualized computational models.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dementia Cognitive Fluctuations Scale	Score on a 4-item subscale of the 17-item Dementia Cognitive Fluctuation Scale (DCFS), developed to address limitations in prior scales and has good test-retest and inter-rater reliability; this subscale highly discriminates between dementia with Lewy bodies (DLB) and other dementia groups. The DCFS is a subjective report of cognitive fluctuation, the spontaneous change in cognitive ability which is a core diagnostic feature of DLB. Total subscale scores range from 4 to 20, with higher scores indicating greater cognitive fluctuations. A decrease in score between Baseline and Post-Testing indicates an improvement in cognitive fluctuation.	Baseline and Post-Testing (3-4 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Resting State fMRI	Functional connectivity measures whether activity in different brain regions show similar patterns of change over time. Graph theory metrics of resting-state fMRI can characterize functional connectivity among nodes (regions) of a brain network, and well as between nodes of different brain networks. Network segregation is the difference of within-network and between-network connectivity as a proportion of within-network connectivity, such that higher numbers reflect more segregation. Given that network segregation typically decreases with normal and pathological aging, higher network segregation is generally considered cognitively beneficial. Network segregation was examined for the ventral attention network (the actual focus of stimulation based on observed cholinergic denervation) and the original cingulo-opercular network, which was predicted at the time of grant proposal (but not supported by the observed cholinergic denervation).	Baseline and Post-Testing (3-4 weeks)
Stroop Color Word Interference Test - Cognitive Control Performance	Outcome Measure Description: Interference score in time to complete the Color Word Interference Test version of the Stroop task from the Delis-Kaplan Executive Function System. Participants 1) identify a series of colors, 2) read color words (e.g. blue) all written in black ink, and 3) name the ink color of color words printed in incongruous colored inks (e.g. for the word "green" written in red ink, the correct response is "red"). Tasks are performed as quickly as possible. Time to complete each task is recorded. Interference score is calculated as the time to complete the color-word (interference) test (CWT), less the average of the time to complete the color task (CT) and word-reading task (WT): CWT - ((CT + WT)/2). The score has a theoretical valid range of 0 - 300; a lower score suggests better cognitive control. A negative change (decrease) in score between Baseline and Post-Testing indicates improvement in cognitive control performance.	Baseline, 3-4 weeks
Objective Measures of Working Memory (N-back Test)	The n-back test is a working memory task where a participant identify a stimulus that matches the stimulus experienced "n" steps back. Participants performed a 2-back test, in which they were asked to remember and press a button when presented with a stimulus that appeared two steps before the current one (e.g. square, circle, square). The number of correct and incorrect identifications are normalized (z-score). Total score is the z-score of correct button presses minus the z-score of incorrect button presses. Possible scores range from -4.85 to 4.85. A higher score (d') reflects better discrimination between target and non-target stimuli, and therefore better working memory performance. A positive change (increase) in 2-back score (d') between Baseline and Post-Testing indicates an improvement in working memory performance.	Baseline, 3-4 weeks

Collaborators and Investigators

• Sponsor: University of Michigan
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Benjamin Hampstead, PhD, University of Michigan

Study record dates

Study Major Dates

• Study Start (Actual): May 3, 2021
• Primary Completion (Actual): August 26, 2024
• Study Completion (Actual): August 26, 2024

Study Registration Dates

• First Submitted: March 23, 2021
• First Submitted That Met QC Criteria: March 23, 2021
• First Posted (Actual): March 26, 2021

Study Record Updates

• Last Update Posted (Estimated): October 22, 2025
• Last Update Submitted That Met QC Criteria: October 7, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: Imaging; Dementia; Cognition; Cognitive Rehabilitation; Brain Stimulation; Cognitive; Lewy Body Dementia; Thinking; Lewy Body
• Additional Relevant MeSH Terms: Synucleinopathies; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Neurodegenerative Diseases; Movement Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Dementia; Lewy Body Disease; Lewy Body Variant of Alzheimer Disease
• Other Study ID Numbers: HUM00184296; R21AG069387 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes