Mid-frontal Delta/Theta and Cognitive Control

NCT06984757 | Enrolling By Invitation FDA Device

• 2 other identifiers: 2017078282R01NS100849-06A1
• Study Type: interventional
• Target: 635
• Locations: 1 country
• Sites: 1

Brief Summary

Abstract Cognitive symptoms of Parkinson's disease (PD) include deficits in attention, working memory, and reasoning. These deficits affect up to 80% of PD patients and lead to mild cognitive impairment (PD-MCI) and dementia in PD (PDD). There is a critical need to better understand cognitive impairment in PD to develop new targeted treatments. The long-term goal is to define the mechanisms of PD-related cognitive impairment. PD involves diverse processes such as dopamine and acetylcholine dysfunction, synuclein aggregation, and genetic factors. During the past funding period, the investigators linked PD-related cognitive impairment to dysfunction in frontal midline delta (1-4 Hz) and theta (5-7 Hz) rhythms, which the work has established as a marker of cognitive control. However, it is unknown why PD patients have deficits in these low-frequency brain rhythms. The preliminary magnetic resonance imaging (MEG) and magnetoencephalography (MRI) implicate the anterior midcingulate cortex (aMCC) as a potential source of frontal midline delta/theta rhythms. In the next funding period, the objective is to determine the mechanisms and predictive power of delta/theta rhythms in PD, which will help to better understand the pathophysiology of PD-related cognitive impairment. Collaboration between the University of New Mexico (UNM) and University of Iowa (UI) that will bring together MEG, MRI, longitudinal EEG, and adaptive subthalamic (STN) deep-brain stimulation (DBS). The investigators will test the overall hypothesis that frontal midline delta/theta dysfunction contributes to cognitive impairments in PD. In Aim 1, the investigators will determine the structural basis for delta/theta rhythm deficits in PD. In Aim 2, the investigators will determine the predictive power of delta/theta rhythm deficits in PD. In Aim 3, the investigators will determine how tuned low-frequency STN DBS impacts cortical activity and cognition. The results will have relevance for basic-science knowledge of the fundamental pathophysiology of cognitive impairment in PD and related dementias. Because this proposal will study patients with PDD, the findings are directly relevant to Alzheimer's-related dementias (ADRD).

Conditions

Parkinson&Amp;Amp;#39;s Disease (PD)

Keywords

Parkinson's disease; deep-brain stimulation; mild cognitive impairment; dementia

Outcome Measures

Primary Outcomes (1)

• Changes to EEG physiological parameters (mid-frontal delta/theta activity) due to Parkinson's disease (PD) at Day 1

  The investigators use a conventional repeated-measures ANOVA where the independent variable is PD/PD-MCI/PDD and the dependent variable is mid-frontal delta/theta activity (EEG physiological parameter).

  From enrollment to the end of treatment at Day 1

Secondary Outcomes (1)

• Changes to EEG physiological parameters (mid-frontal delta/theta activity) due to the Deep Brain Stimulation (DBS) stimulation setting at Day 1

  From enrollment to the end of treatment at Day 1

Study Arms (4)

Deep-brain Stimulation (DBS)

EXPERIMENTAL

Device: Deep-brain Stimulation

Transcranial Magnetic Stimulation (TMS)

EXPERIMENTAL

Device: Transcranial Magnetic Stimulation

Transcranial Alternating Current Stimulation (tACS)

EXPERIMENTAL

Device: Transcranial Alternating Current Stimulation

Observational

NO INTERVENTION

Interventions

Deep-brain Stimulation DEVICE

a neurosurgical procedure that uses implanted electrodes and electrical stimulation to treat movement disorders and certain neuropsychiatric conditions when medications are ineffective or cause significant side effects.

Deep-brain Stimulation (DBS)

Transcranial Magnetic Stimulation DEVICE

Transcranial magnetic stimulation (TMS) is a non-invasive treatment that uses magnetic fields to stimulate specific areas of the brain.

Transcranial Magnetic Stimulation (TMS)

Transcranial Alternating Current Stimulation DEVICE

Transcranial Alternating Current Stimulation (tACS) is a non-invasive brain stimulation technique that uses weak, alternating electrical currents applied to the scalp to modulate brain activity and potentially influence cognitive processes by entraining brain oscillations.

Transcranial Alternating Current Stimulation (tACS)

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• GROUP 1: Parkinson's disease without cognitive impairment
• Parkinson's disease, with MOCA \> 26
• under stable PD medication
• able to walk independently, make their own decisions
• age range = 18 - 89 years old
• GROUP 2: Parkinson's disease with mild cognitive impairment
• Parkinson's disease, with MOCA 23-26
• under stable PD medication
• able to walk independently, make their own decisions
• age range = 18 - 89 years old
• GROUP 3: Parkinson's disease with dementia
• Parkinson's disease, with MOCA \< 23
• under stable PD medication
• Make their own decisions
• age range = 18 - 89 years old

You may not qualify if:

• Patients with dementia with Lewy Bodies and Alzheimer's disease, drug-induced parkinsonism, Parkinson's-plus, on investigational drugs, with hearing loss will be excluded, or with color-blindness will be excluded. Subjects with a history of neuropsychiatric disorders, like Schizophrenia or Depression will be also be excluded.
• For the TMS sub-study, PD patients with DBS leads will be excluded and any subject with a seizure disorder will also be excluded. For the HD-tACS sub-study, PD patients with DBS leads will be excluded and any subject with a seizure disorder will also be excluded.
• Control Group: patients with Alzheimer's Disease (AD) and dementia with Lewy Bodies (DLB) A group of patients with AD and DLB will be recruited for the cognitive tasks to compare data with PD. Since AD is non-dopamine deficiency disease so they can serve as another control group for the study.
• \) age range = 18 - 89 years old (will have to match with the age of subjects with Parkinson's Disease)
• \) with any neurological disorders, including epilepsy
• Control Group: patients with mTBI A group of patients with mTBI will be recruited for the cognitive tasks to compare data with PD.
• \) age range = 18 - 89 years old (will have to match with the age of subjects with Parkinson's Disease)
• Control Group: patients with 16pDel Autism A group of patients with 16pDel Autism will be recruited for the cognitive tasks to compare data with PD.
• \) age range = 18 - 89 years old (will have to match with the age of subjects with Parkinson's Disease)
• Control Group: patients with Brain Lesions A group of patients with Brain Lesions will be recruited for the cognitive tasks to compare data with PD.
• \) age range = 18 - 89 years old (will have to match with the age of subjects with Parkinson's Disease)
• Control Group: Older Normal Subjects A group of older healthy individuals will be matched with subjects with Parkinson's disease in terms of age, sex, and years of education. We will also recruit a small group of older healthy individuals specifically to pilot new behavioral tasks.
• \) age range = 35 - 99 years old (most of this group will have to match with the age of subjects with Parkinson's Disease. One subset from this group (N = 40) will be independent from the demographics of the subjects with Parkinson's Disease, so they can have a wider age range).
• \) with any neurological disorders, including epilepsy
• Control Group: Older Subjects with Mood Disorders A group of older individuals with Mood Disorders will be recruited to perform cognitive tasks to compare data with both PD with Mood Disorders and PD without Mood Disorders.

Sponsors & Collaborators

• Nandakumar Narayanan: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator

Study Sites (1)

University of Iowa

Iowa City, Iowa, 52242, United States

Location

Related Publications (25)

• Anjum MF, Espinoza AI, Cole RC, Singh A, May P, Uc EY, Dasgupta S, Narayanan NS. Resting-state EEG measures cognitive impairment in Parkinson's disease. NPJ Parkinsons Dis. 2024 Jan 3;10(1):6. doi: 10.1038/s41531-023-00602-0.

  PMID: 38172519 BACKGROUND

• Narayanan NS, Jourahmad Z, Cole RC, Cavanagh JF. Cognition falters at ~4 Hz in Parkinson's disease. Trends Cogn Sci. 2024 Sep;28(9):789-791. doi: 10.1016/j.tics.2024.06.002. Epub 2024 Jul 12.

  PMID: 39003229 BACKGROUND

• Yeager BE, Twedt HP, Bruss J, Schultz J, Narayanan NS. Salience network and cognitive impairment in Parkinson's disease. medRxiv [Preprint]. 2023 Oct 14:2023.10.13.23296825. doi: 10.1101/2023.10.13.23296825.

  PMID: 37873396 BACKGROUND

• Bosch TJ, Cole RC, Bezchlibnyk Y, Flouty O, Singh A. Effects of Very Low- and High-Frequency Subthalamic Stimulation on Motor Cortical Oscillations During Rhythmic Lower-Limb Movements in Parkinson's Disease Patients. J Parkinsons Dis. 2023;13(4):549-561. doi: 10.3233/JPD-225113.

  PMID: 37092236 BACKGROUND

• Singh A, Cole RC, Espinoza AI, Wessel JR, Cavanagh JF, Narayanan NS. Evoked mid-frontal activity predicts cognitive dysfunction in Parkinson's disease. J Neurol Neurosurg Psychiatry. 2023 Nov;94(11):945-953. doi: 10.1136/jnnp-2022-330154. Epub 2023 Jun 1.

  PMID: 37263767 BACKGROUND

• Lin LC, Cole RC, Greenlee JDW, Narayanan NS. A Pilot Study of Ex Vivo Human Prefrontal RNA Transcriptomics in Parkinson's Disease. Cell Mol Neurobiol. 2023 Aug;43(6):3037-3046. doi: 10.1007/s10571-023-01334-8. Epub 2023 Mar 23.

  PMID: 36952070 BACKGROUND

• Anjum MF, Espinoza A, Cole R, Singh A, May P, Uc E, Dasgupta S, Narayanan N. Resting-state EEG measures cognitive impairment in Parkinson's disease. Res Sq [Preprint]. 2023 Mar 20:rs.3.rs-2666578. doi: 10.21203/rs.3.rs-2666578/v1.

  PMID: 36993450 BACKGROUND

• Simmering JE, Welsh MJ, Schultz J, Narayanan NS. Use of Glycolysis-Enhancing Drugs and Risk of Parkinson's Disease. Mov Disord. 2022 Nov;37(11):2210-2216. doi: 10.1002/mds.29184. Epub 2022 Aug 22.

  PMID: 36054705 BACKGROUND

• Cole RC, Okine DN, Yeager BE, Narayanan NS. Neuromodulation of cognition in Parkinson's disease. Prog Brain Res. 2022;269(1):435-455. doi: 10.1016/bs.pbr.2022.01.016. Epub 2022 Feb 11.

  PMID: 35248205 BACKGROUND

• Cole RC, Espinoza AI, Singh A, Berger JI, Cavanagh JF, Wessel JR, Greenlee JD, Narayanan NS. Novelty-induced frontal-STN networks in Parkinson's disease. Cereb Cortex. 2022 Dec 20;33(2):469-485. doi: 10.1093/cercor/bhac078.

  PMID: 35297483 BACKGROUND

• Espinoza AI, May P, Anjum MF, Singh A, Cole RC, Trapp N, Dasgupta S, Narayanan NS. A pilot study of machine learning of resting-state EEG and depression in Parkinson's disease. Clin Park Relat Disord. 2022 Sep 27;7:100166. doi: 10.1016/j.prdoa.2022.100166. eCollection 2022.

  PMID: 36203748 BACKGROUND

• Zhang Q, Schultz JL, Aldridge GM, Simmering JE, Kim Y, Ogilvie AC, Narayanan NS. COVID-19 Case Fatality and Alzheimer's Disease. J Alzheimers Dis. 2021;84(4):1447-1452. doi: 10.3233/JAD-215161.

  PMID: 34690147 BACKGROUND

• Singh A, Cole RC, Espinoza AI, Evans A, Cao S, Cavanagh JF, Narayanan NS. Timing variability and midfrontal ~4 Hz rhythms correlate with cognition in Parkinson's disease. NPJ Parkinsons Dis. 2021 Feb 15;7(1):14. doi: 10.1038/s41531-021-00158-x.

  PMID: 33589640 BACKGROUND

• Groth CL, Singh A, Zhang Q, Berman BD, Narayanan NS. GABAergic Modulation in Movement Related Oscillatory Activity: A Review of the Effect Pharmacologically and with Aging. Tremor Other Hyperkinet Mov (N Y). 2021 Nov 10;11:48. doi: 10.5334/tohm.655. eCollection 2021.

  PMID: 34824891 BACKGROUND

• Simmering JE, Welsh MJ, Liu L, Narayanan NS, Pottegard A. Association of Glycolysis-Enhancing alpha-1 Blockers With Risk of Developing Parkinson Disease. JAMA Neurol. 2021 Apr 1;78(4):407-413. doi: 10.1001/jamaneurol.2020.5157.

  PMID: 33523098 BACKGROUND

• Zhang Q, Abdelmotilib H, Larson T, Keomanivong C, Conlon M, Aldridge GM, Narayanan NS. Cortical alpha-synuclein preformed fibrils do not affect interval timing in mice. Neurosci Lett. 2021 Nov 20;765:136273. doi: 10.1016/j.neulet.2021.136273. Epub 2021 Sep 30.

  PMID: 34601038 BACKGROUND

• Anjum MF, Haug J, Alberico SL, Dasgupta S, Mudumbai R, Kennedy MA, Narayanan NS. Linear Predictive Approaches Separate Field Potentials in Animal Model of Parkinson's Disease. Front Neurosci. 2020 Apr 24;14:394. doi: 10.3389/fnins.2020.00394. eCollection 2020.

  PMID: 32390797 BACKGROUND

• Singh A, Cole RC, Espinoza AI, Brown D, Cavanagh JF, Narayanan NS. Frontal theta and beta oscillations during lower-limb movement in Parkinson's disease. Clin Neurophysiol. 2020 Mar;131(3):694-702. doi: 10.1016/j.clinph.2019.12.399. Epub 2020 Jan 13.

  PMID: 31991312 BACKGROUND

• Zhang Q, Schultz JL, Aldridge GM, Simmering JE, Narayanan NS. Coronavirus Disease 2019 Case Fatality and Parkinson's Disease. Mov Disord. 2020 Nov;35(11):1914-1915. doi: 10.1002/mds.28325. Epub 2020 Oct 15. No abstract available.

  PMID: 32954522 BACKGROUND

• Zhang Q, Aldridge GM, Narayanan NS, Anderson SW, Uc EY. Approach to Cognitive Impairment in Parkinson's Disease. Neurotherapeutics. 2020 Oct;17(4):1495-1510. doi: 10.1007/s13311-020-00963-x. Epub 2020 Nov 17.

  PMID: 33205381 BACKGROUND

• Anjum MF, Dasgupta S, Mudumbai R, Singh A, Cavanagh JF, Narayanan NS. Linear predictive coding distinguishes spectral EEG features of Parkinson's disease. Parkinsonism Relat Disord. 2020 Oct;79:79-85. doi: 10.1016/j.parkreldis.2020.08.001. Epub 2020 Aug 23.

  PMID: 32891924 BACKGROUND

• Narayanan NS, Wessel JR, Greenlee JDW. The Fastest Way to Stop: Inhibitory Control and IFG-STN Hyperdirect Connectivity. Neuron. 2020 May 20;106(4):549-551. doi: 10.1016/j.neuron.2020.04.017.

  PMID: 32437650 BACKGROUND

• Aldridge GM, Birnschein A, Denburg NL, Narayanan NS. Parkinson's Disease Dementia and Dementia with Lewy Bodies Have Similar Neuropsychological Profiles. Front Neurol. 2018 Mar 12;9:123. doi: 10.3389/fneur.2018.00123. eCollection 2018.

  PMID: 29593630 BACKGROUND

• Singh A, Richardson SP, Narayanan N, Cavanagh JF. Mid-frontal theta activity is diminished during cognitive control in Parkinson's disease. Neuropsychologia. 2018 Aug;117:113-122. doi: 10.1016/j.neuropsychologia.2018.05.020. Epub 2018 May 23.

  PMID: 29802866 BACKGROUND

• Kelley R, Flouty O, Emmons EB, Kim Y, Kingyon J, Wessel JR, Oya H, Greenlee JD, Narayanan NS. A human prefrontal-subthalamic circuit for cognitive control. Brain. 2018 Jan 1;141(1):205-216. doi: 10.1093/brain/awx300.

  PMID: 29190362 BACKGROUND

Related Links

• Please send any questions about data to nandakumar-narayanan@uiowa.edu

MeSH Terms

Conditions

Cognitive Dysfunction; Dementia

Interventions

Deep Brain Stimulation; Transcranial Magnetic Stimulation; Transcranial Direct Current Stimulation

Condition Hierarchy (Ancestors)

Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Electric Stimulation Therapy; Therapeutics; Surgical Procedures, Operative; Magnetic Field Therapy; Convulsive Therapy; Psychiatric Somatic Therapies; Behavioral Disciplines and Activities; Electroshock; Psychological Techniques

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Neurology

Study Record Dates

• First Submitted: April 16, 2025
• First Posted: May 22, 2025
• Study Start: September 25, 2017
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2029
• Last Updated: May 22, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: 25 Sept 2017 to 31 Dec 2029
• Access Criteria: We keep participation in this research study confidential to the extent permitted by law. However, it is possible that other people such as those indicated below may become aware of participation in the study and may inspect and copy records pertaining to this research. Some of these records could contain information that personally identifies the participant. * federal government regulatory agencies, * auditing departments of the University of Iowa, and * the University of Iowa Institutional Review Board (a committee that reviews and approves research studies) To help protect confidentiality, we store all information in a locked, password encrypted secure research drive that is stored in a locked room. If we write a report or article about this study or share the study data set with others, we will do so in such a way that you cannot be directly identified.

Locations

US (1)