Parkinson's Disease Patients 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.

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.

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.

Pallidal beta bursts in Parkinson's disease and dystonia.

Exaggerated beta power has been discussed as a disease-specific biomarker for Parkinson's disease (PD) and has recently been suggested to rely on prolonged bursts of subthalamic beta synchronization. In this study, we test whether prolonged bursts are disease specific for beta activity in PD by comparison to oscillatory activity in dystonia. Pallidal local field potentials were recorded from 5 PD patients ON and OFF dopaminergic medication and 5 dystonia patients. Synchronization of beta and low-frequency oscillations in bursts was compared between groups with respect to their duration, amplitude, and rate. Pallidal beta bursts were longer in PD-OFF than PD-ON or dystonia (P < .05). PD-ON and dystonia displayed similar beta burst dynamics. Low-frequency burst features showed no differences across groups. Prolonged burst duration appears as a disease-specific feature for beta activity in PD across the basal ganglia. With dopaminergic medication, beta bursts in PD resemble those in dystonia, which supports the notion of short beta bursts as a physiological pattern. © 2018 International Parkinson and Movement Disorder Society.

Motor cognition in patients treated with subthalamic nucleus deep brain stimulation: Limits of compensatory overactivity in Parkinson's disease

Recent fMRI findings revealed that impairment in a serial prediction task in patients suffering from Parkinson's disease (PD) results from hypoactivity of the SMA. Furthermore, hyperactivity of the lateral premotor cortex sustained performance after withdrawal of medication. To further explore these findings, we here examined the impact of deep brain stimulation of the subthalamic nucleus on the activity of the putamen and premotor areas while performing the serial prediction task. To this end, we measured eight male PD patients ON and OFF deep brain stimulation and eight healthy age-matched male controls using [15O] water positron emission tomography to measure regional cerebral blood flow. As expected, PD patients showed poorer performance than healthy controls while performance did not differ between OFF and ON stimulation. Hypoactivity of the putamen and hyperactivity of the left lateral premotor cortex was found in patients compared to controls. Lateral premotor hyperactivity further increased OFF compared to ON stimulation and was positively related to task performance. These results confirm that the motor loop's dysfunction has impact on cognitive processes (here: prediction of serial stimuli) in PD. Extending prior data regarding the role of the lateral premotor cortex in cognitive compensation, our results indicate that lateral premotor cortex hyperactivity, while beneficial in moderate levels of impairment, might fail to preserve performance in more severe stages of the motor loop's degeneration.

Effects of feedback delay on learning from positive and negative feedback in patients with Parkinson's disease off medication

Phasic dopamine (DA) signals conveyed from the substantia nigra to the striatum and the prefrontal cortex crucially affect learning from feedback, with DA bursts facilitating learning from positive feedback and DA dips facilitating learning from negative feedback. Consequently, diminished nigro-striatal dopamine levels as in unmedicated patients suffering from Parkinson's Disease (PD) have been shown to lead to a negative learning bias. Recent studies suggested a diminished striatal contribution to feedback processing when the outcome of an action is temporally delayed. This study investigated whether the bias towards negative feedback learning induced by a lack of DA in PD patients OFF medication is modulated by feedback delay. To this end, PD patients OFF medication and healthy controls completed a probabilistic selection task, in which feedback was given immediately (after 800 ms) or delayed (after 6800 ms). PD patients were impaired in immediate but not delayed feedback learning. However, differences in the preference for positive/negative learning between patients and controls were seen for both learning from immediate and delayed feedback, with evidence of stronger negative learning in patients than controls. A Bayesian analysis of the data supports the conclusion that feedback timing did not affect the learning bias in the patients. These results hint at reduced, but still relevant nigro-striatal contribution to feedback learning, when feedback is delayed.

Dopamine substitution alters effective connectivity of cortical prefrontal, premotor, and motor regions during complex bimanual finger movements in Parkinson's disease

Bimanual coordination is impaired in Parkinson's disease (PD), affecting patients' quality of life. Besides dysfunction of the basal ganglia network, alterations of cortical oscillatory coupling, particularly between prefrontal and (pre-)motoric areas, are thought to underlie this impairment. Here, we studied 16 PD patients OFF and ON medication and age-matched healthy controls recording high-resolution electroencephalography (EEG) during performance of spatially coupled and uncoupled bimanual finger movements. Dynamic causal modeling (DCM) for induced responses was used to infer task-induced effective connectivity within a network comprising bilateral prefrontal cortex (PFC), lateral premotor cortex (lPM), supplementary motor area (SMA), and primary motor cortex (M1). Performing spatially coupled movements, excitatory left-hemispheric PFC to lPM coupling was significantly stronger in controls compared to unmedicated PD patients. Levodopa-induced enhancement of this connection correlated with increased movement accuracy. During performance of spatially uncoupled movements, PD patients OFF medication exhibited inhibitory connectivity from left PFC to SMA. Levodopa intake diminished these inhibitory influences and restored excitatory PFC to lPM coupling. This restoration, however, did not improve motor function.Concluding, our results indicate that lateralization of prefrontal to premotor connectivity in PD can be augmented by levodopa substitution and is of compensatory nature up to a certain extent of complexity.

Subthalamic nucleus stimulation impairs emotional conflict adaptation in Parkinson's disease.

The subthalamic nucleus (STN) occupies a strategic position in the motor network, slowing down responses in situations with conflicting perceptual input. Recent evidence suggests a role of the STN in emotion processing through strong connections with emotion recognition structures. As deep brain stimulation (DBS) of the STN in patients with Parkinson’s disease (PD) inhibits monitoring of perceptual and value-based conflict, STN DBS may also interfere with emotional conflict processing. To assess a possible interference of STN DBS with emotional conflict processing, we used an emotional Stroop paradigm. Subjects categorized face stimuli according to their emotional expression while ignoring emotionally congruent or incongruent superimposed word labels. Eleven PD patients ON and OFF STN DBS and eleven age-matched healthy subjects conducted the task. We found conflict-induced response slowing in healthy controls and PD patients OFF DBS, but not ON DBS, suggesting STN DBS to decrease adaptation to within-trial conflict. OFF DBS, patients showed more conflict-induced slowing for negative conflict stimuli, which was diminished by STN DBS. Computational modelling of STN influence on conflict adaptation disclosed DBS to interfere via increased baseline activity.

Motor loop dysfunction causes impaired cognitive sequencing in patients suffering from Parkinson's disease

Cognitive impairment in Parkinson's disease (PD) is often attributed to dopamine deficiency in the prefrontal-basal ganglia–thalamo-cortical loops. Although recent studies point to a close interplay between motor and cognitive abilities in PD, the so-called “motor loop” connecting supplementary motor area (SMA) and putamen has been considered solely with regard to the patients' motor impairment. Our study challenges this view by testing patients with the serial prediction task (SPT), a cognitive task that requires participants to predict stimulus sequences and particularly engages premotor sites of the motor loop. We hypothesised that affection of the motor loop causes impaired SPT performance, especially when the internal sequence representation is challenged by suspension of external stimuli. As shown for motor tasks, we further expected this impairment to be compensated by hyperactivity of the lateral premotor cortex (PM).We tested 16 male PD patients ON and OFF dopaminergic medication and 16 male age-matched healthy controls in an functional Magnetic Resonance Imaging study. All subjects performed two versions of the SPT: one with on-going sequences (SPT0), and one with sequences containing non-informative wildcards (SPT+) increasing the demands on mnemonic sequence representation. Patients ON (compared to controls) revealed an impaired performance coming along with hypoactivity of SMA and putamen. Patients OFF compared to ON medication, while showing poorer performance, exhibited a significantly increased PM activity for SPT+ vs. SPT0. Furthermore, patients' performance positively co-varied with PM activity, corroborating a compensatory account. Our data reveal a contribution of the motor loop to cognitive impairment in PD, and suggest a close interplay of SMA and PM beyond motor control.

Elevated synchrony in Parkinson disease detected with electroencephalography.

Parkinson disease (PD) can be difficult to diagnose and treat. Development of a biomarker for PD would reduce these challenges by providing an objective measure of disease. Emerging theories suggest PD is characterized by excessive synchronization in the beta frequency band (∼20Hz) throughout basal ganglia-thalamocortical loops. Recently we showed with invasive electrocorticography that one robust measure of this synchronization is the coupling of beta phase to broadband gamma amplitude (ie, phase-amplitude coupling [PAC]). Other recent work suggests that high-frequency activity is detectable at the scalp using electroencephalography (EEG). Motivated by these findings, we tested whether beta-gamma PAC over sensorimotor cortex, recorded noninvasively with EEG, differs between PD patients off and on medications, and healthy control subjects. Resting EEG was compared from 15 PD patients and 16 healthy control subjects. PD patients were tested on and off medications on different days, in a counterbalanced order. For each data set we calculated PAC and compared results across groups. PAC was elevated in the patients off medications compared to on medications (p = 0.008) and for patients off medications compared to controls (p = 0.009). Elevated PAC is detectable using scalp EEG in PD patients off medications compared to on medications, and compared to healthy controls. This suggests that EEG PAC may provide a noninvasive biomarker of the parkinsonian state. This biomarker could be used as a control signal for closed-loop control of deep brain stimulation devices, for adjustment of dopaminergic treatment, and also has the potential to aid in diagnosis.

Different effects of dopaminergic medication on perceptual decision-making in Parkinson's disease as a function of task difficulty and speed–accuracy instructions

When choosing between two options, sufficient accumulation of information is required to favor one of the options over the other, before a decision is finally reached. To establish the effect of dopaminergic medication on the rate of accumulation of information, decision thresholds and speed–accuracy trade-offs, we tested 14 patients with Parkinson's disease (PD) on and off dopaminergic medication and 14 age-matched healthy controls on two versions of the moving-dots task. One version manipulated the level of task difficulty and hence effort required for decision-making and the other the urgency, requiring decision-making under speed vs. accuracy instructions. The drift diffusion model was fitted to the behavioral data.As expected, the reaction time data revealed an effect of task difficulty, such that the easier the perceptual decision-making task was, the faster the participants responded. PD patients not only made significantly more errors compared to healthy controls, but interestingly they also made significantly more errors ON than OFF medication. The drift diffusion model indicated that PD patients had lower drift rates when tested ON compared to OFF medication, indicating that dopamine levels influenced the quality of information derived from sensory information.On the speed–accuracy task, dopaminergic medication did not directly influence reaction times or error rates. PD patients OFF medication had slower RTs and made more errors with speed than accuracy instructions compared to the controls, whereas such differences were not observed ON medication. PD patients had lower drift rates and higher response thresholds than the healthy controls both with speed and accuracy instructions and ON and OFF medication. For the patients, only non-decision time was higher OFF than ON medication and higher with accuracy than speed instructions.The present results demonstrate that when task difficulty is manipulated, dopaminergic medication impairs perceptual decision-making and renders it more errorful in PD relative to when patients are tested OFF medication. In contrast, for the speed/accuracy task, being ON medication improved performance by eliminating the significantly higher errors and slower RTs observed for patients OFF medication compared to the HC group. There was no evidence of dopaminergic medication inducing impulsive decisions when patients were acting under speed pressure. For the speed–accuracy instructions, the sole effect of dopaminergic medication was on non-decision time, which suggests that medication primarily affected processes tightly coupled with the motor symptoms of PD. Interestingly, the current results suggest opposite effects of dopaminergic medication on the levels of difficulty and speed–accuracy versions of the moving dots task, possibly reflecting the differential effect of dopamine on modulating drift rate (levels of difficulty task) and non-decision time (speed–accuracy task) in the process of perceptual decision making.

Does the cerebellum intervene in the abnormal somatosensory temporal discrimination in Parkinson's disease?

somatosensory temporal discrimination threshold (STDT) measures the ability to perceive two stimuli as being sequential. Altered STDT has been reported in Parkinson's disease (PD). The cerebellum seems to play a role in the pathophysiology of PD, and may consequently be involved in the pathophysiology of STDT abnormalities. STDT was investigated in fifteen PD patients who underwent real and sham cerebellar continuous theta burst stimulation (cTBS) in the OFF condition. Eight patients underwent a further real cTBS session in ON condition. STDT was measured on both hands before, 5 and 25min after real and sham cTBS delivered over the cerebellar hemisphere ipsilateral to the more affected side. We controlled the efficacy of our protocol by monitoring primary motor cortex (M1) excitability. Ten healthy subjects acted as control group. STDT values were increased in PD patients in the OFF condition compared with healthy subjects and PD patients in the ON condition. In PD patients OFF condition, real but not sham cerebellar cTBS, significantly reduced STDT values only in the hand ipsilateral to the stimulated cerebellar hemisphere. Cerebellar cTBS also decreased motor evoked potentials (MEP) size in the contralateral M1. When PD patients were tested in the ON condition, cerebellar cTBS failed to modify STDT values. cerebellar cTBS improved STDT values in PD patients exclusively in OFF condition. We hypothesize that cerebellar stimulation partially compensates for increased STDT values only when patients are OFF dopaminergic therapy. This suggests that the cerebellum may act as compensatory system in PD.

Finger dexterity deficits in Parkinson's disease and somatosensory cortical dysfunction.

The patho-physiological basis for finger dexterity deficits in Parkinson's disease (PD) is controversial. Previously, bradykinesia was regarded as the major mechanism. However, recent research suggested limb-kinetic apraxia as an important component of impaired fine motor skills in PD. In contrast to bradykinesia, limb-kinetic apraxia only marginally responds to dopaminergic treatment. Here we investigate the novel hypothesis that the dexterity deficits are related to an intrinsic dysfunction of primary somatosensory cortex (S1), which is not reversible by dopaminergic medication. Applying a standard and approved dexterity task (coin rotation), brain activation networks were investigated using functional magnetic resonance imaging in PD patients both ON and OFF medication and matched healthy controls. PD patients both ON and OFF medication showed impaired S1 activation relative to controls (p < 0.05; region of interest based analysis). The impaired S1 activation remained unchanged by dopaminergic medication. Despite the considerable clinical deficit, no other brain area showed impaired activation. In contrast, structures of the basal ganglia--motor cortex loop responded to dopaminergic medication. Behaviorally, dexterity performance both ON and OFF was significantly (p < 0.05) reduced relative to controls. Our results provide first evidence that dexterity deficits in PD are related to an S1 dysfunction which is insensitive to dopaminergic treatment.

Effects of Stochastic Vestibular Galvanic Stimulation and LDOPA on Balance and Motor Symptoms in Patients With Parkinson's Disease.

Balance problems contribute to reduced quality of life in Parkinson's disease (PD) and available treatments are often insufficient for treating axial and postural motor symptoms. To investigate the safety of use and possible effects of stochastic vestibular stimulation (SVS) alone and combined with LDOPA in patients with PD. SVS or sham stimulation was administered to 10 PD patients in a double-blind placebo controlled cross-over pilot study. Motor symptoms and balance were evaluated in a defined off-medication state and after a 200 mg test dose of LDOPA, using UPDRS-III, Posturo-Locomotor-Manual (PLM) movement times (MT), static posturography and force plate measurements of the correcting response to a balance perturbation. Patients did not detect when SVS was active, but SVS increased nausea after LDOPA in two patients. Mixed model analysis demonstrated that SVS improved balance corrections after a backward perturbation and shortened the postural response time. In static posturography there was significant interaction between effects of SVS, medication and proprioceptive input (standing on foam vs. on hard support) and SVS decreased the total sway-path with eyes closed and off medication. As expected, LDOPA improved the UPDRS-III scores and MT. There was an interaction between the effect of SVS and LDOPA on UPDRS-III partly because of reduced UPDRS-III scores with SVS in the off-medication state. Short term use of SVS is safe, improves corrective postural responses and may have a small positive effect on motor symptoms in PD patients off treatment.

Pathomechanisms and compensatory efforts related to Parkinsonian speech.

Voice and speech in Parkinson's disease (PD) patients are classically affected by a hypophonia, dysprosody, and dysarthria. The underlying pathomechanisms of these disabling symptoms are not well understood. To identify functional anomalies related to pathophysiology and compensation we compared speech-related brain activity and effective connectivity in early PD patients who did not yet develop voice or speech symptoms and matched controls. During fMRI 20 PD patients ON and OFF levodopa and 20 control participants read 75 sentences covertly, overtly with neutral, or with happy intonation. A cue-target reading paradigm allowed for dissociating task preparation from execution. We found pathologically reduced striato-prefrontal preparatory effective connectivity in early PD patients associated with subcortical (OFF state) or cortical (ON state) compensatory networks. While speaking, PD patients showed signs of diminished monitoring of external auditory feedback. During generation of affective prosody, a reduced functional coupling between the ventral and dorsal striatum was observed. Our results suggest three pathomechanisms affecting speech in PD: While diminished energization on the basis of striato-prefrontal hypo-connectivity together with dysfunctional self-monitoring mechanisms could underlie hypophonia, dysarthria may result from fading speech motor representations given that they are not sufficiently well updated by external auditory feedback. A pathological interplay between the limbic and sensorimotor striatum could interfere with affective modulation of speech routines, which affects emotional prosody generation. However, early PD patients show compensatory mechanisms that could help improve future speech therapies.

P 76. Cerebellar sensory processing alterations impact motor cortical plasticity in Parkinson’s disease: Clues from dyskinetic patients

Introduction The plasticity of primary motor cortex (M1) in patients with Parkinson's disease (PD) and levodopa-induced dyskinesias (LIDs) is severely impaired (Morgante, 2006; Kishore, 2012). We reported that inhibitory cerebellar stimulation with continuous theta burst stimulation (cTBS) enhanced the sensori-motor plasticity of M1 induced by paired associative stimulation (PAS) in healthy subjects (Popa, 2012). Koch (2009) demonstrated a beneficial effect on LIDs of repeated sessions of cTBS to the cerebellum. Objectives To find out (1) if cerebellar inhibitory stimulation is able to enhance the deficient plasticity of M1 associated with LIDs in PD and (2) whether this could be the mechanism underlying the reduction of LIDs after repeated sessions of cerebellar stimulation reported earlier. Materials and methods Study 1: 16 PD patients with LIDs made 3 visits: (1) patients were OFF drug and received PAS to M1 opposite to the side with the worst dyskinesias; (2) in ON patients received cTBS to the cerebellum followed by PAS to the opposite M1; (3) in ON patients received sham stimulation to the cerebellum and PAS to M1. Responsiveness of M1 to PAS was tested before and after stimulations. Study 2: 20 PD patients with LIDs received 10days of bilateral cTBS stimulation of the cerebellum. Dyskinesias were scored blindly on videos before stimulations started and at 2nd ( n =20), 4th ( n =10) and 8th week ( n =10) after the end of the stimulations. Responsiveness of M1 to PAS was tested at each visit. Results Study 1. PAS-induced response of PD patients OFF and ON was weak (rANOVA P =0.5, 0.7 respectively). After real and not sham, cerebellar stimulation M1 gained responsiveness to PAS ( P Study 2. Repeated real and not sham cerebellar stimulation, led to a decrease of the total ( P P Correlation. The larger the additional plasticity generated by a single session of cTBS to the cerebellum, the greater was the decrease in the worst dyskinesia score after 10days of bilateral cerebellar stimulation ( P Conclusion The abnormal signaling within the striato-thalamo-cortical circuit, possibly due to non physiological, excessive release of striatal synaptic dopamine in dyskinetic patients, could impinge on the cerebello-thalamo-cortical circuit. Alterations in the cerebellar sensory processing function in advanced PD could lead to an inappropriate filtering of the relevant sensory volley that is responsible for a maladaptive state of cortical plasticity. Such a maladaptive state could predispose to the selection of abnormal motor programs generating abnormal movements. Cerebellar inhibition, by increasing the gain of the sensory afferent volley to M1, permits better sensori-motor integration, thereby reducing involuntary movements.

Spatial extent of beta oscillatory activity in and between the subthalamic nucleus and substantia nigra pars reticulata of Parkinson's disease patients

Parkinson's disease (PD) is accompanied by a significant amount of β-band (11Hz–30Hz) neuronal and local field potential (LFP) oscillatory activity in the subthalamic nucleus (STN). Previous studies have shown significant coherence between neuronal firing and LFPs at β frequencies at sites separated by ~1mm and that the magnitude of β oscillatory LFP activity and coherence are greatly reduced following levodopa administration. However, these data have been collected from large DBS contact electrodes or pairs of microelectrodes in proximity to each other and so it is not clear whether all regions of STN are synchronized. It is also not known whether the LFP and neuronal activity in the substantia nigra pars reticulata (SNr) shows β activity and whether it is coherent with STN activity. Therefore, the aim of this study was to measure the spatial extent of β coherent activity in the STN and coherence between STN and SNr in PD patients OFF levodopa by systematically varying the distance between the dual microelectrodes. A total of 170 pairs of recordings were collected from 20 patients at rest undergoing DBS-STN implantation surgery. Trajectories passed dorsoventrally through STN and into SNr using two microelectrodes initially ~1mm apart. Once the microelectrodes entered the dorsal STN, one of the two was held stationary, while the other one was advanced into SNr over a distance of ~4–6mm. Pairs of recordings were obtained from STN/STN (n=111), STN/SNr (n=42), and SNr/SNr (n=17). We confirmed previous reports of a progressive attenuation in β power as electrodes were driven from dorsal to ventral STN and into SNr. Furthermore, we found significant β-LFP coherence across the dorsoventral extent of STN. Detailed analysis suggested that at least some of the ventral STN and SNr beta activity was locally generated rather than arising from volume conduction from dorsal STN and thus suggests that β oscillations synchronize both the input and output nuclei of the basal ganglia.

Impaired executive function signals in motor brain regions in Parkinson's disease

Recent evidence has shown that patients with Parkinson's disease (PD) often display deficits in executive functions, such as planning for future behavior, and these deficits may stem from pathologies in prefrontal cortex and basal ganglia circuits that are critical to executive control. Using the antisaccade task (look away from a visual stimulus), we show that when the preparatory 'readiness' to perform a given action is dissociated from the actual execution of that action, PD patients off and on dopamine medication display behavioral impairments and reduced cortical brain activation that cannot be explained by a pathology related to dysfunction in movement execution. Rather, they show that the appropriate task set signals were not in place in motor regions prior to execution, resulting in impairments in the control of subsequent voluntary movement. This is the first fMRI study of antisaccade deficits in Parkinson's disease, and importantly, the findings point to a critical role of the basal ganglia in translating signals related to rule representation (executive) into those governing voluntary motor behavior.

L-DOPA changes spontaneous low-frequency BOLD signal oscillations in Parkinson's disease: a resting state fMRI study

Analysis of the amplitude of low frequency BOLD signal fluctuations (ALFF) in the resting state has recently been used to study the dynamics of intrinsic neural activity. Several studies have also suggested its potential as a biomarker for neuropsychiatric disease. In the current study, we quantified ALFF to determine changes in intrinsic neural oscillations in patients with Parkinson's disease (PD) on and off L-DOPA. Twenty-four PD patients and 24 healthy age-matched controls participated in the study. PD patients underwent two resting state fMRI sessions, either ON a controlled dose of L-DOPA or following a placebo pill (OFF). Control participants underwent one test session. We found that there was increased amplitude of low frequency BOLD signal oscillations for PD patients OFF L-DOPA in the primary and secondary motor areas, and in the middle and medial prefrontal cortices. L-DOPA significantly reduced the amplitude of low frequency oscillations within these regions. The degree of ALFF in the premotor cortex predicted patients' motor performance as measured by the Grooved Pegboard task, such that greater ALFF was associated with poorer performance. These results are in line with the pathophysiology of PD, which shows changes in neural oscillations. Thus, frequency domain analyses of resting state BOLD fMRI signals may provide a useful means to study the pathophysiology of PD and the physiology of the brain's dopaminergic pathways.

Dopamine Alters Tactile Perception in Parkinson's Disease

Abnormal somatosensory processing may contribute to motor impairments observed in Parkinson's disease (PD). Dopaminergic medications have been shown to alter somatosensory processing such that tactile perception is improved. In PD, it remains unclear whether the temporal sequencing of tactile stimuli is altered and if dopaminergic medications alter this perception. Somatosensory tactile perception was investigated using temporal order judgment in patients with Parkinson's disease on and off dopaminergic medications and in aged-matched healthy controls. Measures of temporal order judgment were acquired using computer controlled stimulation to digits 2 and 3 on the right hand and subjects were required to determine which stimuli occurred first. Two experimental tasks were compared, temporal order judgment without and with synchronization whereby digits 2 and 3 were vibrated synchronously in advance of the temporal order judgment sequence of stimuli. Temporal order judgment in PD patients of and on medications were similar to controls. Temporal order judgment preceded by synchronous vibration impaired tactical acuity in controls and in PD patients off medications to similar degrees, but this perceptual impairment by synchronous vibration was not present in PD patients on medications. These findings suggest that dopamine in PD reduces cortico-cortical connectivity with SI and this leads to changes in tactical sensitivity.