Parkinson's Disease Off Research Articles

Plasticity-Induced Effects of Theta Burst Transcranial Ultrasound Stimulation in Parkinson's Disease.

Low-intensity transcranial ultrasound stimulation (TUS) is a noninvasive brain stimulation (NIBS) technique with high spatial specificity. Previous studies showed that TUS delivered in a theta burst pattern (tbTUS) increased motor cortex (MI) excitability up to 30 minutes due to long-term potentiation (LTP)-like plasticity. Studies using other forms of NIBS suggested that cortical plasticity may be impaired in patients with Parkinson's disease (PD). The aim was to investigate the neurophysiological effects of tbTUS in PD patients off and on dopaminergic medications compared to healthy controls. We studied 20 moderately affected PD patients in on and off dopaminergic medication states (7 with and 13 without dyskinesia) and 17 age-matched healthy controls in a case-controlled study. tbTUS was applied for 80 seconds to the MI. Motor-evoked potentials (MEP), short-interval intracortical inhibition (SICI), and short-interval intracortical facilitation (SICF) were recorded at baseline, and at 5 minutes (T5), T30, and T60 after tbTUS. Motor Unified Parkinson's Disease Rating Scale (mUPDRS) was measured at baseline and T60. tbTUS significantly increased MEP amplitude at T30 compared to baseline in controls and in PD patients on but not in PD patients off medications. SICI was reduced in PD off medications compared to controls. tbTUS did not change in SICI or SICF. The bradykinesia subscore of mUPDRS was reduced at T60 compared to baseline in PD on but not in the off medication state. The presence of dyskinesia did not affect tbTUS-induced plasticity. tbTUS-induced LTP plasticity is impaired in PD patients off medications and is restored by dopaminergic medications. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cortico-cortical connectivity is influenced by levodopa in tremor-dominant Parkinson's disease

Resting tremor is the most common presenting motor symptom in Parkinson's disease (PD). The supplementary motor area (SMA) is a main target of the basal-ganglia-thalamo-cortical circuit and has direct, facilitatory connections with the primary motor cortex (M1), which is important for the execution of voluntary movement. Dopamine potentially modulates SMA and M1 activity, and both regions have been implicated in resting tremor. This study investigated SMA-M1 connectivity in individuals with PD ON and OFF dopamine medication, and whether SMA-M1 connectivity is implicated in resting tremor. Dual-site transcranial magnetic stimulation was used to measure SMA-M1 connectivity in PD participants ON and OFF levodopa. Resting tremor was measured using electromyography and accelerometry. Stimulating SMA inhibited M1 excitability OFF levodopa, and facilitated M1 excitability ON levodopa. ON medication, SMA-M1 facilitation was significantly associated with smaller tremor than SMA-M1 inhibition. The current findings contribute to our understanding of the neural networks involved in PD which are altered by levodopa medication and provide a neurophysiological basis for the development of interventions to treat resting tremor.

Real-World Experiences of Parkinson's Disease OFF Time and Role of Demographics.

OFF periods are episodes when Parkinson's disease (PD) medications work suboptimally, with symptoms returning and impacting quality of life. We aimed to characterize OFF periods using patient-reported frequency, severity, and duration, as well as determine these characteristics' associations with demographics. A retrospective cohort study using Fox Insight Data Exploration Network (Fox DEN) database was conducted. Eligible patients had PD and were >18 years. The experience of OFF periods was characterized by frequency (number of episodes/day), duration (duration/episode), and severity (impact on activities). Significance level was Bonferroni-corrected for multivariate analyses. From a population of 6,757 persons with PD, 88% were non-Hispanic Whites (mean age: 66 ± 8.8 years); 52.7% were males versus 47.3% females; mean PD duration was 5.7 ± 5.2; and 51% experienced OFF periods. Subsequent analyses were limited to non-Hispanic Whites, as they constituted a large majority of the participants and were the subgroup that had the sample size to derive reliable inferences. The analyses showed that 67% experienced 1-2 episodes/day, 90% experienced >15-minute episodes, and 55% reported slight-mild severity/episode. Lower age was associated with a higher frequency (incidence rate ratio [IRR]: 0.992; P<0.001) and severity (odds ratio [OR]: 0.985; P=0.001) of OFF episodes. Income of <$35,000 was associated with 15.1% more episodes/day (IRR: 1.15, p<0.001) and 66.5% higher odds of a severe episode (OR: 1.66; P<0.001). Females experienced 7.5% more episodes compared to males (IRR: 1.075; P=0.003). Longer PD duration was associated with 1.3% more episodes/day (IRR: 1.013; P<0.001) and 10% higher odds of a severe episode (OR: 1.10; P<0.001). Lower age, income <$35,000, longer PD duration, female gender, and being unemployed are associated with a higher frequency and severity of OFF periods with no associations for duration/episode among non-Hispanic Whites with PD. In time-constrained clinic environments, clinicians should tailor OFF periods management counseling to vulnerable demographic groups to enhance care delivery.(J Patient Cent Res Rev. 2024;11:8-17.).

Ensemble classifiers fed by functional connectivity during cognitive processing differentiate Parkinson’s disease even being under medication

Brain–computer interface technologies, as a type of human-computer interaction, provide a control ability on machines and intelligent systems via human brain functions without needing physical contact. Moreover, it has a considerable contribution to the detection of cognitive state changes, which gives a clue for neurodegenerative diseases, including Parkinson’s disease (PD), in recent years. Although various studies implemented different machine learning models with several EEG features to detect PD and receive remarkable performances, there is a lack of knowledge on how brain connectivity during a cognitive task contributes to the differentiation of PD, even being under medication. To fill this gap, this study used three ensemble classifiers, which were fed by functional connectivity through cognitive response coherence (CRC) with varying selected features in different frequency bands upon application of the 3-Stimulation auditory oddball paradigm to differentiate PD medication ON and OFF and healthy controls (HC). The results revealed that the most remarkable performances were exhibited in slow frequency bands (delta and theta) in comparison to high frequency and wide range bands, especially in terms of target sounds. Moreover, in the delta band, target CRC distinguishes all groups from each other with accuracy rates of 80% for HC vs PD-OFF, 80% for HC vs PD-ON, and 81% for PD-ON vs PD-OFF. In the theta band, again target sounds were the most distinctive stimuli to classify HCxPD-OFF (80% accuracy), HCxPD-ON (80.5% accuracy) with quite good performances, and PD-ONxPD-OFF (76% accuracy) with acceptable performance. Besides, this study achieved a state-of-the-art performance with an accuracy of 87.5% in classifying PD-ONxPD-OFF via CRC of standard sounds in the delta band. Overall, the findings revealed that brain connectivity contributes to identifying PD and HC as well as the medication state of PD, especially in the slow frequency bands.

Abnormally low sensorimotor α band nonlinearity serves as an effective EEG biomarker of Parkinson's disease.

Biomarkers obtained from the neurophysiological signals of patients with Parkinson's disease (PD) have objective value in assessing their motor condition for effective diagnosis, monitoring, and clinical intervention. Prominent cortical biomarkers of PD have typically been derived from various β band wave features. This study approached the topic from an alternative perspective and attempted to estimate a recently suggested measure representing α band nonlinear autocorrelative memory from a publicly available EEG dataset that involves 15 patients with earlier-stage PD (dopaminergic medication OFF and ON states) and 16 age-matched healthy controls. The cortical nonlinearity was elevated for the PD ON state compared with the OFF state for bilateral sensorimotor channels C3 and C4 (n = 26; P = 0.003). A similar statistical difference was also identified between PD OFF state and healthy subjects (n = 26; P = 0.049). Analysis over all channels revealed that the α band nonlinearity induced upon medication was constrained to sensorimotor regions. The α nonlinearity measure was compared with a well-accepted cortical biomarker of β-γ phase-amplitude coupling (PAC). They were in moderate negative correlation (r = -0.412; P = 0.036) for only healthy subjects, but not for the patients. The nonlinearity measure was found to be insusceptible to the nonstationary variations within the particular data. Our study provides further evidence that the α band nonlinearity measure can serve as a promising cortical biomarker of PD. The suggested measure can be estimated from a noninvasive low-resolution single scalp EEG channel of patients with relatively early-stage PD, who did not yet need to undergo deep brain stimulation operation.NEW & NOTEWORTHY This study suggests a nonlinearity measure that differentiates Parkinson's disease (PD) dopamine OFF-state scalp EEG data from those of dopamine ON-state patients and healthy subjects. Unlike typical PD cortical biomarkers based on β band activity, this metric shows elevation upon dopaminergic medication in the α band. We provide evidence supporting its potential as an early-stage promising PD biomarker that can be estimated from noninvasive EEG recordings with low resolution and SNR.

Visual velocity perception dysfunction in Parkinson’s disease

ObjectiveCompared with motor deficits, sensory information processing in Parkinson’s disease (PD) is relatively unexplored. While there is increasing interest in understanding the sensory manifestations of PD, the extent of sensory abnormality in PD has remained relatively unexplored. Furthermore, most investigations on the sensory aspects of PD involve motor aspects, causing confounding results. As sensory deficits often arise in early PD development stages, they present a potential technological target for diagnosis and disease monitoring that is affordable and accessible. Considering this, the current study’s aim is to assess visual spatiotemporal perception independent of goal directed movements in PD by designing and using a scalable computational tool. MethodsA flexible 2-D virtual reality environment was created to evaluate various cases of visual perception. Using the tool, an experimental task quantifying the visual perception of velocity was tested on 37 individuals with PD and 17 age-matched control participants. Results: PD patients, both ON and OFF PD therapy, displayed perceptual impairments (p = 0.001 and p = 0.008, respectively) at slower tested velocity magnitudes. These impairments were even observed in early stages of PD (p = 0.015). ConclusionVisual velocity perception is impaired in PD patients, which suggests impairments in visual spatiotemporal processing occur in PD and provides a promising modality to be used with disease monitoring software. SignificanceVisual velocity perception shows high sensitivity to PD at all stages of the disease. Dysfunction in visual velocity perception may contribute to observed motor dysfunction in PD.

Cannabinoid Receptor Type 1 in Parkinson's Disease: A Positron Emission Tomography Study with [18 F]FMPEP-d2.

ABSTRACTBackgroundThe endocannabinoid system is a widespread neuromodulatory system affecting several biological functions and processes. High densities of type 1 cannabinoid (CB1) receptors and endocannabinoids are found in basal ganglia, which makes them an interesting target group for drug development in basal ganglia disorders such as Parkinson's disease (PD).ObjectiveThe aim of this study was to investigate CB1 receptors in PD with [18F]FMPEP‐d 2 positron emission tomography (PET) and the effect of dopaminergic medication on the [18F]FMPEP‐d 2 binding.MethodsThe data consisted of 16 subjects with PD and 10 healthy control subjects (HCs). All participants underwent a [18F]FMPEP‐d 2 high‐resolution research tomograph PET examination for the quantitative assessment of cerebral binding to CB1 receptors. To investigate the effect of dopaminergic medication on the [18F]FMPEP‐d 2 binding, 15 subjects with PD underwent [18F]FMPEP‐d 2 PET twice, both on and off antiparkinsonian medication.Results[18F]FMPEP‐d 2 distribution volume was significantly lower in the off scan compared with the on scan in basal ganglia, thalamus, hippocampus, and amygdala (P < 0.05). Distribution volume was lower in subjects with PD off than in HCs globally (P < 0.05), but not higher than in HCs in any brain region.ConclusionsSubjects with PD have lower CB1 receptor availability compared with HCs. PD medication increases CB1 receptor toward normal levels. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Dopamine depletion and subcortical dysfunction disrupt cortical synchronization and metastability affecting cognitive function in Parkinson's disease.

Parkinson's disease (PD) is primarily characterized by the loss of dopaminergic cells and atrophy in subcortical regions. However, the impact of these pathological changes on large‐scale dynamic integration and segregation of the cortex are not well understood. In this study, we investigated the effect of subcortical dysfunction on cortical dynamics and cognition in PD. Spatiotemporal dynamics of the phase interactions of resting‐state blood‐oxygen‐level‐dependent signals in 159 PD patients and 152 normal control (NC) individuals were estimated. The relationships between subcortical atrophy, subcortical–cortical fiber connectivity impairment, cortical synchronization/metastability, and cognitive performance were then assessed. We found that cortical synchronization and metastability in PD patients were significantly decreased. To examine whether this is an effect of dopamine depletion, we investigated 45 PD patients both ON and OFF dopamine replacement therapy, and found that cortical synchronization and metastability are significantly increased in the ON state. The extent of cortical synchronization and metastability in the OFF state reflected cognitive performance and mediates the difference in cognitive performance between the PD and NC groups. Furthermore, both the thalamic volume and thalamocortical fiber connectivity had positive relationships with cortical synchronization and metastability in the dopaminergic OFF state, and mediate the difference in cortical synchronization between the PD and NC groups. In addition, thalamic volume also reflected cognitive performance, and cortical synchronization/metastability mediated the relationship between thalamic volume and cognitive performance in PD patients. Together, these results highlight that subcortical dysfunction and reduced dopamine levels are responsible for decreased cortical synchronization and metastability, further affecting cognitive performance in PD. This might lead to biomarkers being identified that can predict if a patient is at risk of developing dementia.

Effects of Levodopa Therapy on Cerebral Arteries and Perfusion in Parkinson's Disease Patients.

Levodopa is the most-commonly used therapy for Parkinson's Disease (PD). Imaging findings show increased cerebral blood flow (CBF) response to levodopa, but the artery morphological change is less studied. To investigate the effect of levodopa on cerebral arteries and CBF. Prospective. 57 PD patients (56 ± 10 years, 26 males) and 17 age-matched healthy controls (AMC, 57 ± 9 years, 9 males) were scanned at baseline (OFF). Patients were rescanned 50 minutes after taking levodopa (ON). 3 T; Simultaneous noncontrast angiography intraplaque imaging (SNAP) based on turbo field echo; Pseudo-continuous arterial spin labeling (PCASL) based on echo-planner imaging. The Unified Parkinson's Disease Rating Scale (UPDRS-III) was used to assess the disease severity. Length and radius of arteries were measured from SNAP images. CBF was calculated from PCASL images globally and regionally. Mann Whitney U tests were conducted in comparing PD vs. AMC. Wilcoxon matched-pairs signed rank tests were used in comparing OFF vs. ON, and the more-affected vs. the less-affected hemisphere in PD. Linear regressions were performed to test the correlations of neuroimaging findings with behavioral changes. Significance threshold was P < 0.05 with Bonferroni correction. PD patients were identified with significantly lower CBF (PD OFF Mean=40.15 ± 5.99, AMC Mean= 43.48 ± 6.21 mL/100 g/min) and shortened total artery length (PD OFF Mean=5851.07 ± 1393.45, AMC Mean= 7479.16 ± 1335.93 mm). Levodopa elevated CBF of PD brains (PD ON Mean=41.48 ± 6.32 mL/100 g/min) and expanded radius of proximal arteries. Artery radius change significantly correlated with CBF change in corresponding territories (r=0.559 for Internal Carotid Arteries, r=0.448 for Basilar Artery, and r=0.464 for Middle Cerebral Artery M1). Global CBF significantly related to UPDRS-III (r=-0.391) post-levodopa. Levodopa can increase CBF by dilating proximal arteries. 1 TECHNICAL EFFICACY STAGE: 4.

Impaired motor cortical facilitatory-inhibitory circuit interaction in Parkinson’s disease

ObjectiveMotor cortical (M1) inhibition and facilitation can be studied with short-interval intracortical inhibition (SICI) and short-interval intracortical facilitation (SICF). These circuits are altered in Parkinson’s disease (PD). The sensorimotor measure short latency afferent inhibition (SAI) is possibly altered in PD. The aim was to determine if the manner in which these circuits interact with each other is abnormal in PD. MethodsFifteen PD patients were studied at rest in ON and OFF medication states, and were compared to 16 age-matched controls. A triple-stimulus transcranial magnetic stimulation paradigm was used to elicit a circuit of interest in the presence of another circuit. ResultsSICF was increased in PD OFF and PD ON conditions compared to controls. SICI facilitated SICF in controls and PD ON, but not in PD OFF. SICF in the presence of SICI negatively correlated with UPDRS-III scores in OFF and ON medication conditions. SAI showed similar inhibition of SICI in controls, PD OFF and PD ON conditions. ConclusionsThe facilitatory effect of SICI on SICF is absent in PD OFF, but is restored with dopaminergic medication. SignificanceImpaired interaction between M1 circuits is a pathophysiological feature of PD.

Altered Inhibitory Mechanisms in Parkinson's Disease: Evidence From Lexical Decision and Simple Reaction Time Tasks.

IntroductionAlthough the motor signs of Parkinson’s disease (PD) are well defined, nonmotor symptoms, including higher-level language deficits, have also been shown to be frequent in patients with PD. In the present study, we used a lexical decision task (LDT) to find out whether access to the mental lexicon is impaired in patients with PD, and whether task performance is affected by bradykinesia.Materials and MethodsParticipants were 34 nondemented patients with PD, either without (off) medication (n = 16) or under optimum (on) medication (n = 18). A total of 19 age-matched control volunteers were also recruited. We recorded reaction times (RTs) to the LDT and a simple RT (control) task. In each task, stimuli were either visual or auditory. Statistical analyses consisted of repeated-measures analyses of variance and Tukey’s HSD post hoc tests.ResultsIn the LDT, participants with PD both off and on medication exhibited intact access to the mental lexicon in both modalities. In the visual modality, patients off medication were just as fast as controls when identifying real words, but slower when identifying pseudowords. In the visual modality of the control task, RTs for pseudowords were significantly longer for PD patients off medication than for controls, revealing an unexpected but significant lexicality effect in patients that was not observed in the auditory modality. Performances of patients on medication did not differ from those of age-matched controls.DiscussionMotor execution was not slowed in patients with PD either off or on medication, in comparison with controls. Regarding lexical access, patients off medication seemed to (1) have difficulty inhibiting a cognitive-linguistic process (i.e., reading) when it was not required (simple reaction time task), and (2) exhibit a specific pseudoword processing deficit in the LDT, which may have been related to impaired lateral word inhibition within the mental lexicon. These deficits seemed to be compensated by medication.

Detection of Parkinson’s disease using automated tunable Q wavelet transform technique with EEG signals

Deep brain simulations play an important role to study physiological and neuronal behavior during Parkinson’s disease (PD). Electroencephalogram (EEG) signals may faithfully represent the changes that occur during PD in the brain. But manual analysis of EEG signals is tedious, and time consuming as these signals are complex, non-linear, and non-stationary nature. Therefore EEG signals are required to decompose into multiple subbands (SBs) to get detailed and representative information from it. Experimental selection of basis function for the decomposition may cause system degradation due to information loss and an increased number of misclassification. To address this, an automated tunable Q wavelet transform (A-TQWT) is proposed for automatic decomposition. A-TQWT extracts representative SBs for analysis and provides better reconstruction for the synthesis of EEG signals by automatically selecting the tuning parameters. Five features are extracted from the SBs and classified different machine learning techniques. EEG dataset of 16 healthy controls (HC) and 15 PD (ON and OFF medication) subjects obtained from ”openneuro” is used to develop the automated model. We have aimed to develop an automated model that effectively classify HC subjects from PD patients with and without medication. The proposed method yielded an accuracy of 96.13% and 97.65% while the area under the curve of 97% and 98.56% for the classification of HC vs PD OFF medication and HC vs PD ON medication using least square support vector machine, respectively.

Impaired Touchscreen Skills in Parkinson's Disease and Effects of Medication.

Deficits in fine motor skills may impair device manipulation including touchscreens in people with Parkinson's disease (PD). To investigate the impact of PD and anti-parkinsonian medication on the ability to use touchscreens. Twelve PD patients (H&Y II-III), OFF and ON medication, and 12 healthy controls (HC) performed tapping, single and multi-direction sliding tasks on a touchscreen and a mobile phone task (MPT). Task performance was compared between patients (PD-OFF, PD-ON) and HC and between medication conditions. Significant differences were found in touchscreen timing parameters, while accuracy was comparable between groups. PD-OFF needed more time than HC to perform single (P = 0.048) and multi-direction (P = 0.004) sliding tasks and to grab the dot before sliding (i.e., transition times) (P = 0.040; P = 0.004). For tapping, dopaminergic medication significantly increased performance times (P = 0.046) to comparable levels as those of HC. However, for the more complex multi-direction sliding, movement times remained slower in PD than HC irrespective of medication intake (P < 0.050 during ON and OFF). The transition times for the multi-direction sliding task was also higher in PD-ON than HC (P = 0.048). Touchscreen parameters significantly correlated with MPT performance, supporting the ecological validity of the touchscreen tool. PD patients show motor problems when manipulating touchscreens, even when optimally medicated. This hinders using mobile technology in daily life and has implications for developing adequate E-health applications for this group. Future work needs to establish whether touchscreen training is effective in PD.

Proprioceptive recalibration following implicit visuomotor adaptation is preserved in Parkinson's disease.

Individuals with Parkinson's disease (PD) and healthy adults demonstrate similar levels of visuomotor adaptation provided that the distortion is small or introduced gradually, and hence, implicit processes are engaged. Recently, implicit processes underlying visuomotor adaptation in healthy individuals have been proposed to include proprioceptive recalibration (i.e., shifts in one's proprioceptive sense of felt hand position to match the visual estimate of their hand experienced during reaches with altered visual feedback of the hand). In the current study, we asked if proprioceptive recalibration is preserved in PD patients. PD patients tested during their "off" and "on" medication states and age-matched healthy controls reached to visual targets, while visual feedback of their unseen hand was gradually rotated 30° clockwise or translated 4cm rightwards of their actual hand trajectory. As expected, PD patients and controls produced significant reach aftereffects, indicating visuomotor adaptation after reaching with the gradually introduced visuomotor distortions. More importantly, following visuomotor adaptation, both patients and controls showed recalibration in hand position estimates, and the magnitude of this recalibration was comparable between PD patients and controls. No differences for any measures assessed were observed across medication status (i.e., PD off vs PD on). Results reveal that patients are able to adjust their sensorimotor mappings and recalibrate proprioception following adaptation to a gradually introduced visuomotor distortion, and that dopaminergic intervention does not affect this proprioceptive recalibration. These results suggest that proprioceptive recalibration does not involve striatal dopaminergic pathways and may contribute to the preserved visuomotor adaptation that arises implicitly in PD patients.

Ventilatory Impairments Associated with Parkinson’s Disease: A Systematic Review and Meta-Analysis

Background: The peripheral and central repercussions of Parkinson’s disease (PD) affect the neuromuscular system producing a loss of muscle strength that can influence the respiratory system. Although several studies have examined various respiratory aspects of PD, to the best of our knowledge no study to date has systematically reviewed the existing data. Objectives: To examine the available literature related to the respiratory impairment in PD patients. Methods: We used PRISMA guidelines when reporting this review. We searched Pubmed, Cinhal, SciELO, and Cochrane Library, from inception until August 2018. Main variables assessed were forced vital capacity percent predicted (FVC%) and forced expiratory volume in 1 s percent predicted (FEV₁%) for PD patients. Results: Six studies were included in this systematic review and meta-analysis. The obtained results concluded that PD patients present poorer pulmonary function when compared to healthy controls. When PD patients were compared between ON and OFF states, the results reviewed are in favour of the ON state. In the meta-analysis performed for FVC% and FEV₁%, the results fail to find significant differences between PD patients and controls (p = 0.336 and p = 0.281, respectively), and between PD ON and OFF states (p = 0.109 and p = 0.059, respectively). Conclusions: We conclude that PD patients have impaired respiratory capacities that are related to the PD severity, time since diagnosis, and OFF state. Adequate follow-up of the respiratory function and studies focused on PD phenotypes have to be considered in future studies.

Cognitive effects of theta frequency bilateral subthalamic nucleus stimulation in Parkinson’s disease: A pilot study

BackgroundThere is significant evidence for cognitive decline following deep brain stimulation (DBS). Current stimulation paradigms utilize gamma frequency stimulation for optimal motor benefits; however, little has been done to optimize stimulation parameters for cognition. Recent evidence implicates subthalamic nucleus (STN) theta oscillations in executive function, and theta oscillations are well-known to relate to episodic memory, suggesting that theta frequency stimulation could potentially improve cognition in Parkinson’s disease (PD). ObjectiveTo evaluate the acute effects of theta frequency bilateral STN stimulation on executive function in PD versus gamma frequency and off, as well as investigate the differential effects on episodic versus nonepisodic verbal fluency. MethodsTwelve patients (all males, mean age 60.8) with bilateral STN DBS for PD underwent a double-blinded, randomized cognitive testing during stimulation at (1) 130–135 Hz (gamma), (2) 10 Hz (theta) and (3) off. Executive functions and processing speed were evaluated using verbal fluency tasks (letter, episodic category, nonepisodic category, and category switching), color-word interference task, and random number generation task. Performance at each stimulation frequency was compared within subjects. ResultsTheta frequency significantly improved episodic category fluency compared to gamma, but not compared to off. There were no significant differences between stimulation frequencies in other tests. ConclusionIn this pilot trial, our results corroborate the role of theta oscillations in episodic retrieval, although it is unclear whether this reflects direct modulation of the medial temporal lobe and whether similar effects can be found with more canonical memory paradigms. Further work is necessary to corroborate our findings and investigate the possibility of interleaving theta and gamma frequency stimulation for concomitant motor and cognitive effects.

Dopamine effects on memory load and distraction during visuospatial working memory in cognitively normal Parkinson’s disease

ABSTRACT Visuospatial working memory (WM) impairments in Parkinson’s disease (PD) are more prominent and evolve earlier than verbal WM deficits, suggesting some differences in underlying pathology. WM is regulated by dopaminergic neurotransmission in the prefrontal cortex, but the effect of dopamine on specific processes supporting visuospatial WM are not well understood. Dopamine therapeutic effects on different WM processes may also differ given the heterogeneity of cognitive changes in PD. The present study examined the effect of dopamine therapy on memory load and distraction during visuospatial WM. Exploratory analyses evaluated whether individual differences in medication effects were associated with a gene, catechol-O-methyltransferase (COMT), which regulates prefrontal cortex dopamine levels. Cognitively normal PD participants (n = 28) and controls (n = 25) performed a visuospatial WM task, which manipulated memory load and the presence/absence of distractors. PD participants performed the task on and off medication. PD COMT groups were comprised of Met homozygote (lower COMT activity) and heterozygote and Val homozygote carriers (higher COMT activity, Het/Val). The results showed that handling higher memory loads and suppressing distraction were impaired in PD off, but not on medication. Medication improved distraction resistance in Met, but not Het/Val group. COMT did not modulate medication effects on memory load. These findings demonstrate that dopaminergic therapy restores visuospatial WM processes in patients without cognitive impairment and suggest that COMT variants may partly explain the mixed effects of medication on specific processes governed by distinct brain systems. Future investigations into gene-modulated effects of medication could lead to individualized strategies for treating cognitive decline.

Long-Duration Response to Levodopa in Parkinson Disease

The natural progression of Parkinson disease OFF levodopa is unknown. Now, investigators have conducted a prospective, naturalistic, 2-year study to

Levodopa Changes Functional Connectivity Patterns in Subregions of the Primary Motor Cortex in Patients With Parkinson’s Disease

BackgroundThe primary motor cortex (M1) is a critical node in Parkinson’s disease (PD)-related motor circuitry; however, the functional roles of its subregions are poorly understood. In this study, we investigated changes in the functional connectivity patterns of M1 subregions and their relationships to improved clinical symptoms following levodopa administration.MethodsThirty-six PD patients and 37 healthy controls (HCs) were enrolled. A formal levodopa challenge test was conducted in the PD group, and the Unified Parkinson’s Disease Rating Scale motor section (UPDRS-III) was assessed before (off state) and 1 h after administration of levodopa (on state). The PD group underwent resting-state functional magnetic resonance imaging in both off and on states, whereas the HC group was scanned once. We used the Human Brainnetome Atlas template to subdivide M1 into twelve regions of interest (ROIs). Functional connectivity (FC) was compared between PD on and off states [paired t-test, voxel-level p < 0.001, cluster-level p < 0.05, Gaussian random field (GRF) correction] and between patients and HC (two-sample t-test voxel-level p < 0.001, cluster-level p < 0.05). Correlations between ΔFC (differences in FC between PD off and on states) and clinical symptom improvements were examined.ResultsThere was decreased FC between the right caudal dorsolateral area 6 and the anterior cingulate gyrus (ACC), the right upper limb region and the left medial dorsal thalamus (mdTHA), as well as increased FC between the left tongue and larynx region and the left medial frontal gyrus. ΔFC between the right caudal dorsolateral area 6 and ACC was positively correlated with improvements in UPDRS-III total scores as well as the rigidity (item 22) and bradykinesia (items 23–26 and 31) subscores. ΔFC between the right upper limb region and left thalamus was positively correlated with improvements in the left upper limb tremor (items 20c and 21b) and postural tremor (item 21b) subscores.ConclusionsOur results reveal novel information regarding the underlying mechanisms in the motor circuits in the M1 and a promising way to explore the internal function of the M1 in PD patients. Notably, M1 is a potential therapeutic target in PD, and the exploration of its subregions provides a basis and a source of new insights for clinical intervention and precise drug treatment.

Arterial spin labeling detects perfusion patterns related to motor symptoms in Parkinson's disease

IntroductionImaging neurovascular disturbances in Parkinson's disease (PD) is an excellent measure of disease severity. Indeed, a disease-specific regional pattern of abnormal metabolism has been identified using positron emission tomography. Only a handful of studies, however, have applied perfusion MRI to detect this disease pattern. Our goal was to replicate the evaluation of a PD-related perfusion pattern using scaled subprofile modeling/principal component analysis (SSM-PCA). Methods. We applied arterial spin labeling (ASL) MRI for this purpose. Uniquely, we assessed this pattern separately in PD individuals ON and OFF dopamine medications. We further compared the existence of these patterns and their strength in each individual with their Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor (MDS-UPDRS) scores, cholinergic tone as indexed by short-term afferent inhibition (SAI), and other neuropsychiatric tests. Results. We observed a PD-related perfusion pattern that was similar to previous studies. The patterns were observed in both ON and OFF states but only the pattern in the OFF condition could significantly (AUC=0.72) differentiate between PD and healthy subjects. In the ON condition, PD subjects were similar to controls from a CBF standpoint (AUC=0.45). The OFF pattern prominently included the posterior cingulate, precentral region, precuneus, and the subcallosal cortex. Individual principal components from the ON and OFF states were strongly associated with MDS-UPDRS scores, SAI amplitude and latency. Conclusion. Using ASL, our study identified patterns of abnormal perfusion in PD and were associated with disease symptoms.