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).

Up to 80% of patients with Parkinson's disease (PD) will suffer from cognitive symptoms, including impaired attention, planning, reasoning, and working memory as well as hallucinations, visuospatial dysfunction, and delusions. These impairments lead to mild cognitive impairment (PD-MCI) and dementia (PDD) in PD. Cognitive symptoms of PD are associated with enormous costs to society. There are no clear biomarkers and few effective treatments for PD-MCI/PDD. Because risk for PD increases dramatically with age, this problem will surge as the population grows older. The mechanisms contributing to PD-MCI/PDD are unknown. The investigators have found that low-frequency (1-8 Hz; or delta/theta bands) brain rhythms might be helpful in diagnosing cognitive dysfunction in PD. This delta/theta activity originates from areas of medial frontal cortex, such as the anterior cingulate, and is detectable by mid-frontal scalp EEG electrodes. We have found that mid-frontal delta/theta brain rhythms are engaged when healthy individuals detect novelty, errors, and conflict, or make decisions. These rhythms are attenuated in PD patients. The working model is that PD patients manifest diverse neuronal and network deficits that impair mid-frontal delta/theta activity, leading to failures in engaging cognitive control. These abnormalities contribute to PD-MCI and PDD.

In this proposal, we combine 'big-data' machine learning tools and new brain-stimulation paradigms to investigate the role of mid-frontal delta/theta rhythms in PD. We will test the overall hypothesis that mid-frontal delta/theta impairments are a mechanism of cognitive dysfunction in PD. We will determine if mid-frontal delta/theta activity predicts PD-MCI/PDD and if subthalamic nucleus deep-brain stimulation (DBS) at delta/theta frequencies improves cognitive control in PD patients. Because these experiments involve EEG recordings across several PD patient populations and brain stimulation, each of these aims will provide independent mechanistic insight into cognitive dysfunction in PD. PD is a complex disease, but if cortical EEG abnormalities are a consistent theme, it might inspire new diagnostic tools or new brain-stimulation therapies for cognitive dysfunction in PD. Results from this proposal could also be important for other neurodegenerative diseases such as dementia with Lewy bodies and Alzheimer's disease.

• We will perform the study on Parkinson's disease (PD) patients. PD patient takes anti-Parkinsonian medication (Levodopa) to improve motor symptoms. Medication can change their cognitive performances and neuronal activity; therefore, we will ask (on the phone) patients to withdraw medication (the night before) so that the next morning they will be off medication. For this study, it is crucial that the washout period is >12 hours. During OFF medication, PD patients will only be slow in walking and performing motor activities. There won't be worse effects since it's a motor disorder. We will stop the experiments if the subject worsens during the washout period, and we will provide him/her medications. At the same time, the subject will be examined by the expert neurologist.
• The purpose of the other experiments that are part of this study is to investigate the functions of the specific brain circuit underlying motor and cognitive tasks. Specifically, we are interested in investigating a well-known brain area that allows humans to interrupt ongoing neural representations interacts with active, ongoing motor processes (action initiation and execution) and cognitive processes within the context of simple laboratory tasks. The interaction between neural regions underlying controlling ongoing motor and cognitive processes allows the brain circuit to improve motor action and thought processes when necessary. Typically, patients with Parkinson's disease are slow to execute motor tasks and also show impairment in cognitive performance. We will combine electroencephalography (EEG) with transcranial magnetic stimulation (TMS) to study the effects of stimulation on neuronal activity.

The study will use TMS to temporarily and reversibly alter the activity of a specific node (brain area) of the wider brain network (specifically, the pre-supplementary motor, pre-motor area, and motor cortical regions), and measure the effects of this stimulation-related alteration on neural and behavioral measurements of motor and cognitive tasks. The brain stimulation methods use different protocols of TMS to evoke internally generated neural discharges through the use of focal magnetic fields.

• All subjects will perform questionnaires related to the cognitive and motor impairments.
• Afterwards, we will record EEG and respiratory data during elementary cognitive tasks such as interval timing, oddball detection, stop-signal, and Simon choice reaction-time tasks and upper- and lower limb motor tasks (flexion and extension (such as key board pressing and pedaling), gait imagery, and observation)and at resting state (during sitting (eyes open and close) and standing on soft pad) from PD patients without PD-MCI/PDD, patients with PD-MCI, patients with PDD, and demographically-matched healthy controls. We will also include patients with Alzheimer's disease (AD) and Lewy body dementia (DLB) as control subjects since they don't have dopamine deficiency. We will also include healthy young and middle age adults as comparison groups to compare neural mechanisms of cognitive control across age groups.
• For another aim, we will record EEG with 4 Hz STN DBS during above tasks (rest, cognitive, and motor tasks ) in PD patients.
• For another study, We will record EEG with TMS during simple upper and lower limb flexion-extension motor task (such as key board pressing and pedaling), cognitive tasks (as above) and resting state (as above) in different group of PD subjects. We will not include PD subjects with DBS in TMS experiments. We will recruit PD subjects on different day only for EEG-TMS experiment.
• We will also be piloting the behavioral tasks with a small group of control subjects and PD patients. This will allow us to optimize the tasks to be used in all other aims.
• We would like to use patients with DBS in VIM thalamus for essential tremor as a control.
• For another study, we will record EEG during tasks in healthy young and middle-aged adults. We will be examining brain circuitry and activity involved with cognitive tasks. We will also be acquiring information from the control young adults' mothers about stress experienced while they were pregnant with their child (the control subjects). The purpose of this study is to examine the relationship between prenatal and early life stress and brain function during adulthood.
• For another study, we will record patient quality of life using questionnaires and interviews after EEG recordings have been completed. This information will then be correlated with prior collected EEGs to assess the relationship between EEG and quality of life in PD patients. We will be recruiting approximately 100 parkinson's patients who have already completed EEG recordings and cognitive tasks for the study for the quality of life project. The prior projects indicate that this amount is enough to discern differences in EEG activity in the regions of concern to establish a relationship between this signal and quality of life surveys.
• For another study, we will study the effects of transcranial Alternating Current Stimulation (HD-tACS) on EEG and behavioral responses. We will do EEG recordings in PD patients during cognitive tasks (the flanker task and the N-back task) and resting condition (as above) during and after tACS. We will be recruiting 24 Parkinson's disease patients.

We will study individuals with idiopathic mild-moderate Parkinson's Disease. Diagnosis will be confirmed by Dr. Narayanan - a neurologist.

Inclusion criteria:

GROUP 1: Parkinson's disease without cognitive impairment

1. Parkinson's disease, with MOCA > 26
2. under stable PD medication
3. able to walk independently, make their own decisions
4. age range = 18 - 89 years old

GROUP 2: Parkinson's disease with mild cognitive impairment

1. Parkinson's disease, with MOCA 23-26
2. under stable PD medication
3. able to walk independently, make their own decisions
4. age range = 18 - 89 years old

GROUP 3: Parkinson's disease with dementia

1. Parkinson's disease, with MOCA < 23
2. under stable PD medication
3. Make their own decisions
4. age range = 18 - 89 years old

GROUP 4: Parkinson's disease with STN-DBS 1) Parkinson's disease with functioning bilateral STN-DBS electrodes 2) under stable PD medication 3) able to walk independently, make their own decisions 4) age range = 18 - 89 years old 5) THIS GROUP WILL NOT UNDERGO TMS

GROUP 5: Parkinson's disease without DBS and with no seizure history for EEG-TMS study

1. Parkinson's disease with MOCA 23-30
2. under stable PD medication
3. able to walk independently, make their own decisions
4. age range = 18 - 89 years old

GROUP 6: Essential tremor with VIM-DBS

1) Essential tremor with functioning bilateral VIM-DBS electrodes 2) able to walk independently, make their own decisions 3) age range = 18 - 89 years old 4) THIS GROUP WILL NOT UNDERGO TMS

GROUP 7: Parkinson's disease without DBS and with no seizure history for EEG-HD-tACS study 1) Parkinson's disease with MOCA 23-30 2) under stable PD medication 3) able to walk independently, make their own decisions 4) age range = 18 - 89 years old

Exclusion criteria:

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.

Inclusion criteria:

1) age range = 18 - 89 years old (will have to match with the age of subjects with Parkinson's Disease)

Exclusion criteria:

1) 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.

Inclusion criteria:

1) age range = 18 - 89 years old (will have to match with the age of subjects with Parkinson's Disease)

Exclusion criteria:

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.

Inclusion criteria:

1) age range = 18 - 89 years old (will have to match with the age of subjects with Parkinson's Disease)

Exclusion criteria:

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.

Inclusion criteria:

1) age range = 18 - 89 years old (will have to match with the age of subjects with Parkinson's Disease)

Exclusion criteria:

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.

Inclusion criteria:

1) 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).

Exclusion criteria:

1) 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.

Inclusion criteria:

1) age range = 18 - 89 years old (will have to match with the age of subjects with Parkinson's Disease)

Exclusion criteria:

1) with any neurological disorders, including epilepsy

Control group: Healthy young and middle-aged adults

• A group of healthy young and middle-aged adults without Parkinson's disease or other neurological issues.
• 1) age range = 18-60 years old
• Exclusion criteria: 1) any neurological disorders, including epilepsy

Control subjects' mothers

- The group of mothers of the healthy young adult control subjects.

We may share health information related to this study with other parties including federal government regulatory agencies, the University of Iowa Institutional Review Boards and support staff.

25 Sept 2017 to 31 Dec 2029

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.