Subthalamic nucleus-language network connectivity predicts dopaminergic modulation of speech function in Parkinson's disease.

Speech impediments are a prominent yet understudied symptom of Parkinson's disease (PD). While the subthalamic nucleus (STN) is an established clinical target for treating motor symptoms, these interventions can lead to further worsening of speech. The interplay between dopaminergic medication, STN circuitry, and their downstream effects on speech in PD is not yet fully understood. Here, we investigate the effect of dopaminergic medication on STN circuitry and probe its association with speech and cognitive functions in PD patients. We found that changes in intrinsic functional connectivity of the STN were associated with alterations in speech functions in PD. Interestingly, this relationship was characterized by altered functional connectivity of the dorsolateral and ventromedial subdivisions of the STN with the language network. Crucially, medication-induced changes in functional connectivity between the STN's dorsolateral subdivision and key regions in the language network, including the left inferior frontal cortex and the left superior temporal gyrus, correlated with alterations on a standardized neuropsychological test requiring oral responses. This relation was not observed in the written version of the same test. Furthermore, changes in functional connectivity between STN and language regions predicted the medication's downstream effects on speech-related cognitive performance. These findings reveal a previously unidentified brain mechanism through which dopaminergic medication influences speech function in PD. Our study sheds light into the subcortical-cortical circuit mechanisms underlying impaired speech control in PD. The insights gained here could inform treatment strategies aimed at mitigating speech deficits in PD and enhancing the quality of life for affected individuals.

Illusory Responses across the Lewy Body Disease Spectrum.

OBJECTIVE: This study was undertaken to study pareidolias, or perceived meaningful objects in a meaningless stimulus, in patients across the Lewy body (LB) disease spectrum, where most do not report hallucinations or delusions. METHODS: We studied illusory responses on the Noise Pareidolia Task in 300 participants (38 cognitively impaired LB, 65 cognitively unimpaired LB, 51 Alzheimer disease spectrum [AD-s], 146 controls). Pairwise between-group comparisons examined how diagnosis impacts the number of illusory responses. Ordinal regression analysis compared the number of illusory responses across diagnosis groups, adjusting for age, sex, and education. Analyses were repeated after removing participants with reported hallucinations or delusions. RESULTS: Cognitively impaired LB participants were 12.3, 4.9, and 4.6 times more likely than control, cognitively unimpaired LB, and AD-s participants, respectively, to endorse illusory responses. After adjusting for age, sex, and education, the probability of endorsing 1 or more illusory responses was 61% in the cognitively impaired LB group, compared to 26% in AD-s, 25% in cognitively unimpaired LB, and 12% in control participants. All results were similar after repeated analysis only in participants without hallucinations or delusions. In LB without hallucinations or delusions, 52% with mild cognitive impairment and 66.7% with dementia endorsed at least 1 illusory response. INTERPRETATION: We found illusory responses are common in cognitively impaired LB patients, including those without any reported psychosis. Our data suggest that, prior to the onset of hallucinations and delusions, the Noise Pareidolia Task can easily be used to screen for unobtrusive pareidolias in all LB patients. ANN NEUROL 2023;93:702-714.

Dopaminergic medication normalizes aberrant cognitive control circuit signalling in Parkinson's disease.

Dopaminergic medication is widely used to alleviate motor symptoms of Parkinson's disease, but these medications also impact cognition with significant variability across patients. It is hypothesized that dopaminergic medication impacts cognition and working memory in Parkinson's disease by modulating frontoparietal-basal ganglia cognitive control circuits, but little is known about the underlying causal signalling mechanisms and their relation to individual differences in response to dopaminergic medication. Here we use a novel state-space computational model with ultra-fast (490 ms resolution) functional MRI to investigate dynamic causal signalling in frontoparietal-basal ganglia circuits associated with working memory in 44 Parkinson's disease patients ON and OFF dopaminergic medication, as well as matched 36 healthy controls. Our analysis revealed aberrant causal signalling in frontoparietal-basal ganglia circuits in Parkinson's disease patients OFF medication. Importantly, aberrant signalling was normalized by dopaminergic medication and a novel quantitative distance measure predicted individual differences in cognitive change associated with medication in Parkinson's disease patients. These findings were specific to causal signalling measures, as no such effects were detected with conventional non-causal connectivity measures. Our analysis also identified a specific frontoparietal causal signalling pathway from right middle frontal gyrus to right posterior parietal cortex that is impaired in Parkinson's disease. Unlike in healthy controls, the strength of causal interactions in this pathway did not increase with working memory load and the strength of load-dependent causal weights was not related to individual differences in working memory task performance in Parkinson's disease patients OFF medication. However, dopaminergic medication in Parkinson's disease patients reinstated the relation with working memory performance. Our findings provide new insights into aberrant causal brain circuit dynamics during working memory and identify mechanisms by which dopaminergic medication normalizes cognitive control circuits.

Semantic fluency and processing speed are reduced in non-cognitively impaired participants with Parkinson's disease.

Introduction: Parkinson's disease (PD) is associated with a range of cognitive deficits. Few studies have carefully examined the subtle impacts of PD on cognition among patients who do not meet formal criteria for MCI or dementia. The aim of the current study was thus to describe the impact of PD on cognition in those without cognitive impairment in a well-characterized cohort.Methods: Non-cognitively impaired participants (122 with PD, 122 age- and sex-matched healthy volunteers) underwent extensive cognitive testing. Linear regression analyses compared diagnostic group performance across cognitive measures. For cognitive tasks that were significantly different between groups, additional analyses examined group differences restricting the group inclusion to PD participants with mild motor symptoms or disease duration less than 10 years.Results: Processing speed and semantic verbal fluency were significantly lower in the PD group (B = -3.77, 95% CIs [-5.76 to -1.77], p < .001, and B = -2.02, 95% CIs [-3.12, -0.92], p < .001, respectively), even after excluding those with moderate to severe motor symptoms (B = -2.73, 95% CIs [-4.94 to -0.53], p = .015 and B = -2.11, 95% CIs [-3.32 to -0.91], p < .001, respectively) or longer disease duration (B = -3.89, 95% CIs [-6.14 to -1.63], p < .001 and B = -1.58, 95% CIs [-2.78 to -0.37], p = .010, respectively). Semantic verbal fluency remained significantly negatively associated with PD diagnosis after controlling for processing speed (B = -1.66, 95% CIs [-2.79 to -0.53], p = .004).Conclusions: Subtle decline in specific cognitive domains may be present among people diagnosed with PD but without evidence to support a formal cognitive diagnosis. These results suggest the importance of early awareness of the potential for diminishing aspects of cognition in PD even among those without mild cognitive impairment or dementia.

Patient and Clinician Perspectives of New and Return Ambulatory Teleneurology Visits.

BACKGROUND AND OBJECTIVES: To evaluate the adoption and perceived utility of video visits for new and return patient encounters in ambulatory neurology subspecialties. METHODS: Video visits were launched in an academic, multi-subspecialty, ambulatory neurology clinic in March 2020. Adoption of video visits for new and return patient visits was assessed using clinician-level scheduling data from March 22 to May 16, 2020. Perceived utility of video visits was explored via a clinician survey and semistructured interviews with clinicians and patients/caregivers. Findings were compared across 5 subspecialties and 2 visit types (new vs return). RESULTS: Video visits were adopted rapidly; all clinicians (n = 65) integrated video visits into their workflow within the first 6 weeks, and 92% of visits were conducted via video, although this varied by subspecialty. Utility of video visits was higher for return than new patient visits, as indicated by surveyed (n = 48) and interviewed clinicians (n = 30), aligning with adoption patterns. Compared with in-person visits, clinicians believed that it was easier to achieve a similar physical examination, patient-clinician rapport, and perceived quality of care over video for return rather than new patient visits. Of the 25 patients/caregivers interviewed, most were satisfied with the care provided via video, regardless of visit type, with the main limitation being the physical examination. DISCUSSION: Teleneurology was robustly adopted for both new and return ambulatory neurology patients during the COVID-19 pandemic. Return patient visits were preferred over new patient visits, but both were feasible. These results provide a foundation for developing targeted guidelines for sustaining teleneurology in ambulatory care.

Rapid Implementation of Video Visits in Neurology During COVID-19: Mixed Methods Evaluation.

BACKGROUND: Telemedicine has been used for decades. Despite its many advantages, its uptake and rigorous evaluation of feasibility across neurology's ambulatory subspecialties has been sparse. However, the COVID-19 pandemic prompted health care systems worldwide to reconsider traditional health care delivery. To safeguard health care workers and patients, many health care systems quickly transitioned to telemedicine, including across neurology subspecialties, providing a new opportunity to evaluate this modality of care. OBJECTIVE: To evaluate the accelerated implementation of video visits in ambulatory neurology during the COVID-19 pandemic, we used mixed methods to assess adoption, acceptability, appropriateness, and perceptions of potential sustainability. METHODS: Video visits were launched rapidly in ambulatory neurology clinics of a large academic medical center. To assess adoption, we analyzed clinician-level scheduling data collected between March 22 and May 16, 2020. We assessed acceptability, appropriateness, and sustainability via a clinician survey (n=48) and semistructured interviews with providers (n=30) completed between March and May 2020. RESULTS: Video visits were adopted rapidly; overall, 65 (98%) clinicians integrated video visits into their workflow within the first 6 implementation weeks and 92% of all visits were conducted via video. Video visits were largely considered acceptable by clinicians, although various technological issues impacted their satisfaction. Video visits were reported to be more convenient for patients, families, and caregivers than in-person visits; however, access to technology, the patient's technological capacity, and language difficulties were considered barriers. Many clinicians expressed optimism about future utilization of video visits in neurology. They believed that video visits promote continuity of care and can be incorporated into their practice long-term, although several insisted that they can never replace the in-person examination. CONCLUSIONS: Video visits are an important addition to clinical care in ambulatory neurology and are anticipated to remain a permanent supplement to in-person visits, promoting patient care continuity, and flexibility for patients and clinicians alike.

Hallucinations and Development of Dementia in Parkinson's Disease.

Neuropsychiatric symptoms are common in Parkinson's disease (PD). We investigated the relationship between neuropsychiatric symptoms and current and future diagnosis of PD dementia (PDD). Individuals with PD who had a study partner were enrolled (n = 696). Study partners were administered the Neuropsychiatric Inventory or Neuropsychiatric Inventory Questionnaire at baseline. Participants were assigned a cognitive diagnosis at baseline and follow up visits. Hallucinations were significantly associated with a diagnosis of PDD cross-sectionally (p < 0.001) and with shortened time to dementia longitudinally among initially nondemented participants (n = 444; p = 0.005). Screening for hallucinations may be useful for assessing risk of dementia in participants with PD.

Accelerated launch of video visits in ambulatory neurology during COVID-19: Key lessons from the Stanford experience.

The SARS-CoV-2 (COVID-19) pandemic has rapidly moved telemedicine from discretionary to necessary. Here, we describe how the Stanford Neurology Department (1) rapidly adapted to the COVID-19 pandemic, resulting in over 1,000 video visits within 4 weeks, and (2) accelerated an existing quality improvement plan of a tiered roll out of video visits for ambulatory neurology to a full-scale roll out. Key issues we encountered and addressed were related to equipment/software, provider engagement, workflow/triage, and training. On reflection, the key drivers of our success were provider engagement and dedicated support from a physician champion, who plays a critical role understanding stakeholder needs. Before COVID-19, physician interest in telemedicine was mixed. However, in response to county and state stay-at-home orders related to COVID-19, physician engagement changed completely; all providers wanted to convert a majority of visits to video visits as quickly as possible. Rapid deployment of neurology video visits across all its subspecialties is feasible. Our experience and lessons learned can facilitate broader utilization, acceptance, and normalization of video visits for neurology patients in the present as well as the much anticipated postpandemic era.

Cognitive associations with comprehensive gait and static balance measures in Parkinson's disease.

INTRODUCTION: Gait and balance impairments are cardinal features of Parkinson's disease (PD) that require cognitive input. However, the extent to which specific gait and balance characteristics relate to cognition in PD is unclear. In addition, independent models of gait and balance have not been developed from the same cohort. We aimed to i) develop models of gait and balance in a large PD cohort and ii) determine which gait and balance characteristics best related to cognition. METHODS: One hundred and ninety-eight people with PD were recruited to the Pacific Udall Center. Using six inertial sensors (APDM, Inc.), comprehensive gait measurements were collected over a 2-min continuous walk and comprehensive static balance measures were collected during a 60-second standing task. Six domains of cognition were assessed: global cognition, attention, executive function, language, memory, and visuospatial function. Correlations and hierarchical linear regression determined independent associations. RESULTS: Principal components analysis identified a gait model containing four domains accounting for 80.1% of total variance: pace/turning, rhythm, variability, and trunk. The balance model contained four independent domains accounting for 84.5% of total variance: sway area/jerkiness, sway velocity, sway frequency anteroposterior, and sway frequency mediolateral. Gait domains of pace/turning and variability were strongly associated with attention and executive function. Sway area and jerkiness of balance associated with attention and visuospatial function. CONCLUSIONS: Gait and balance characteristics were associated with specific types of cognition. The specific relationships between gait or balance with cognitive functions suggests shared cerebral cortical circuitry for mobility and cognitive functions.

Feature visualization and classification for the discrimination between individuals with Parkinson's disease under levodopa and DBS treatments.

BACKGROUND: Over the years, a number of distinct treatments have been adopted for the management of the motor symptoms of Parkinson's disease (PD), including pharmacologic therapies and deep brain stimulation (DBS). Efficacy is most often evaluated by subjective assessments, which are prone to error and dependent on the experience of the examiner. Our goal was to identify an objective means of assessing response to therapy. METHODS: In this study, we employed objective analyses in order to visualize and identify differences between three groups: healthy control (N = 10), subjects with PD treated with DBS (N = 12), and subjects with PD treated with levodopa (N = 16). Subjects were assessed during execution of three dynamic tasks (finger taps, finger to nose, supination and pronation) and a static task (extended arm with no active movement). Measurements were acquired with two pairs of inertial and electromyographic sensors. Feature extraction was applied to estimate the relevant information from the data after which the high-dimensional feature space was reduced to a two-dimensional space using the nonlinear Sammon's map. Non-parametric analysis of variance was employed for the verification of relevant statistical differences among the groups (p < 0.05). In addition, K-fold cross-validation for discriminant analysis based on Gaussian Finite Mixture Modeling was employed for data classification. RESULTS: The results showed visual and statistical differences for all groups and conditions (i.e., static and dynamic tasks). The employed methods were successful for the discrimination of the groups. Classification accuracy was 81 ± 6% (mean ± standard deviation) and 71 ± 8%, for training and test groups respectively. CONCLUSIONS: This research showed the discrimination between healthy and diseased groups conditions. The methods were also able to discriminate individuals with PD treated with DBS and levodopa. These methods enable objective characterization and visualization of features extracted from inertial and electromyographic sensors for different groups.

Platelet mitochondrial activity and pesticide exposure in early Parkinson's disease.

BACKGROUND: Mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson's disease (PD), but the cause of this dysfunction is unclear. METHODS: Platelet mitochondrial complex I and I/III (nicotinamide adenine dinucleotide cytochrome c reductase, NCCR) activities were measured in early PD patients and matched controls enrolled in a population-based case-control study. Ambient agricultural pesticide exposures were assessed with a geographic information system and California Pesticide Use Registry. RESULTS: In contrast to some previous reports, we found no differences in complex I and I/III activities in subjects with PD and controls. We did find that NCCR activity correlated with subjects' exposure to pesticides known to inhibit mitochondrial activity regardless of their diagnosis. CONCLUSIONS: Electron transport chain (ETC) activity is not altered in PD in this well-characterized cohort when compared with community-matched controls but appears to be affected by environmental toxins, such as mitochondria-inhibiting pesticides.