Dopaminergic modulation of local non-oscillatory activity and global-network properties in Parkinson's disease: an EEG study

Dopaminergic medication for Parkinson's disease (PD) modulates neuronal oscillations and functional connectivity across the basal ganglia-thalamic-cortical circuit. However, the non-oscillatory component of the neuronal activity, potentially indicating a state of excitation/inhibition balance, has not yet been investigated and previous studies have shown inconsistent changes of cortico-cortical connectivity as a response to dopaminergic medication. To further elucidate changes of regional non-oscillatory component of the neuronal power spectra, functional connectivity, and to determine which aspects of network organization obtained with graph theory respond to dopaminergic medication, we analyzed a resting-state EEG (Electroencephalogram) dataset including 15 PD patients during OFF and ON medication conditions. We found that the spectral slope, typically used to quantify the broadband non-oscillatory component of power spectra, steepened particularly in the left central region in the ON compared to OFF condition. In addition, using lagged coherence as a functional connectivity measure, we found that the functional connectivity in the beta frequency range between centro-parietal and frontal regions was enhanced in the ON compared to the OFF condition. After applying graph theory analysis, we observed that at the lower level of topology the node degree was increased, particularly in the centro-parietal area. Yet, results showed no significant difference in global topological organization between the two conditions: either in global efficiency or clustering coefficient for measuring global and local integration, respectively. Interestingly, we found a close association between local/global spectral slope and functional network global efficiency in the OFF condition, suggesting a crucial role of local non-oscillatory dynamics in forming the functional global integration which characterizes PD. These results provide further evidence and a more complete picture for the engagement of multiple cortical regions at various levels in response to dopaminergic medication in PD.

Does Madopar Have a Role in the Treatment of Prolonged Disorders of Consciousness? A Call for Randomized Controlled Trials

It is suggested that dopaminergic treatment may contribute to accelerated improvement in patients with a disorder of consciousness (DoC). Dopamine is an important stimulatory neurotransmitter, which plays a key role in alertness, arousal, behavior, emotion, cognition, and motor function. We discuss our experience with Madopar in 2 patients with DoC and review the literature on dopaminergic medication in patients with DoC.

Neurophysiological Predictors of Response to Medication in Parkinson's Disease

Background: Although dopaminergic medication has been the foundation of Parkinson's disease (PD) therapy for decades, sensitive and specific therapeutic response biomarkers that allow for better treatment optimization are lacking.Objective: We tested whether the features of Transcranial Magnetic Stimulation-based neurophysiological measures taken off-medication are associated with dopaminergic medication-induced clinical effects.Method: Motor cortex excitability [short-latency intracortical inhibition (SICI), intracortical facilitation (ICF), short-latency afferent inhibition (SAI), and input-output (IO) curve], and plasticity [paired associative stimulation (PAS) protocol] neurophysiological measures were examined in 23 PD patients off-medication. Clinical features were quantified by the motor section of the Unified Parkinson's Disease Scale (total score and lateralized total, bradykinesia, and rigidity sub-scores), and the differences between measures off-medication and on-medication (following the usual morning dose), were determined. Total daily dopaminergic medication dose (expressed as levodopa equivalent daily dose-LEDD), was also determined.Results: SICI significantly correlated with changes in lateralized UPDRS motor and bradykinesia sub-scores, suggesting that patients with stronger basal intracortical inhibition benefit more from dopaminergic treatment than patients with weaker intracortical inhibition. Also, ICF significantly negatively correlated with LEDD, suggesting that patients with stronger intracortical facilitation require less dopaminergic medication to achieve optimal therapeutic benefit. Both associations were independent of disease severity and duration.Conclusions: The results suggest variability of (patho) physiological phenotypes related to intracortical inhibitory and facilitatory mechanisms determining clinical response to dopaminergic medication in PD. Measures of intracortical excitability may help predict patients' response to dopaminergic therapy, thus potentially providing a background for developing personalized therapy in PD.

Tit for tat: costly punishment in manifest Huntington’s disease

Objective: We aimed to investigate costly punishment in patients with HD. Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease with motor, cognitive, and psychiatric symptoms. As neuropsychiatric abnormalities often precede motor symptoms, we wanted to assess whether costly punishment is part of the neuropsychological profile of patients with HD. Methods: A total of 40 non demented subjects were prospectively enrolled in this study with a between-subject design comparing manifest HD patients (n=18) to healthy controls (HC; n=22). All participants performed eight rounds of a costly punishment task, in which money was shared unevenly in 5 rounds or in a fair manner in the remaining three rounds. Participants then had to decide whether they wanted to punish the trustee. Furthermore, all participants underwent neuropsychological background tasks. Results: HD patients performed worse in the neuropsychological background tests compared to HC (all p-values<0.05). Moreover, HD patients punished more often in fair (Wald x2=5.03, p=0.025) but not in unfair rounds (Wald x2=1.63, p=0.202). Conclusions: Our results demonstrate increased costly punishment during fair conditions in HD patients. Whether this behaviour is due to a lack of recognition of social norms, an impairment in top-down inhibition, or an effect of anti-dopaminergic medication remains unclear.

The Cost of Gait Slowness: Can Persons with Parkinson’s Disease Save Energy by Walking Faster?

Background: Gait slowing is a common feature of Parkinson’s disease (PD). Many therapies aim to improve gait speed in persons with PD, but goals are often imprecise. How fast should each patient walk? And how do persons with PD benefit from walking faster? There is an important need to understand how walking speed affects fundamental aspects of gait—including energy cost and stability—that could guide individualized therapy decisions in persons with PD. Objective: We investigated how changes in walking speed affected energy cost and spatiotemporal gait parameters in persons with PD. We compared these effects between dopaminergic medication states and to those observed in age-matched control participants. Methods: Twelve persons with PD and twelve control participants performed treadmill walking trials spanning at least five different speeds (seven speeds were desired, but not all participants could walk at the fastest speeds). Persons with PD participated in two walking sessions on separate days (once while optimally medicated, once after 12-hour withdrawal from dopaminergic medication). We measured kinematic and metabolic data across all trials. Results: Persons with PD significantly reduced energy cost by walking faster than their preferred speeds. This held true across medication conditions and was not observed in control participants. The patient-specific walking speeds that reduced energy cost did not significantly affect gait variability metrics (used as proxies for gait stability). Conclusion: The gait slowing that occurs with PD results in energetically suboptimal walking. Rehabilitation strategies that target patient-specific increases in walking speed could result in a less effortful gait.

Arm swing responsiveness to dopaminergic medication in Parkinson’s disease depends on task complexity

The evidence of the responsiveness of dopaminergic medication on gait in patients with Parkinson’s disease is contradicting. This could be due to differences in complexity of the context gait was in performed. This study analysed the effect of dopaminergic medication on arm swing, an important movement during walking, in different contexts. Forty-five patients with Parkinson’s disease were measured when walking at preferred speed, fast speed, and dual-tasking conditions in both OFF and ON medication states. At preferred, and even more at fast speed, arm swing improved with medication. However, during dual-tasking, there were only small or even negative effects of medication on arm swing. Assuming that dual-task walking most closely reflects real-life situations, the results suggest that the effect of dopaminergic medication on mobility-relevant movements, such as arm swing, might be small in everyday conditions. This should motivate further studies to look at medication effects on mobility in Parkinson’s disease, as it could have highly relevant implications for Parkinson’s disease treatment and counselling.

Defining Speech Subtypes in De Novo Parkinson Disease: Response to Long-term Levodopa Therapy

Background and Objectives:Patterns of speech disorder in Parkinson's disease (PD), that are highly variable across individual patients, were not systematically studied. Our aim was to identify speech subtypes in treatment-naïve PD patients and examine their response to long-term dopaminergic therapy.Methods:We recorded speech data from a total of 111 de-novo PD participants; 83 of the participants completed the 12-month follow-up (69 PD subjects on stable dopaminergic medication and 14 untreated PD controls). Unsupervised k-means cluster analysis was performed on eight distinctive parameters of hypokinetic dysarthria examined using quantitative acoustic analysis.Results:Three distinct speech subtypes with similar prevalence, symptom duration and motor severity were detected: 'prosodic', 'phonatory-prosodic' and 'articulatory-prosodic'. Beside monopitch and monoloudness that were common in each subtype, speech impairment was more severe in phonatory-prosodic subtype with predominant dysphonia and articulatory-prosodic subtype with predominant imprecise consonant articulation than in prosodic subtype. Clinically, the prosodic subtype was characterized by a prevalence of women and younger age while articulatory-prosodic subtype by the prevalence of men, older age, greater severity of axial gait symptoms and poorer cognitive performance. Phonatory-prosodic subtype clinically represented intermediate status in age with mostly men and preserved cognitive performance. While speech of untreated PD controls deteriorated over one year (p = 0.02), long-term dopaminergic medication maintained stable speech impairment severity in prosodic and articulatory-prosodic subtypes and improved speech performance in patients with phonatory-prosodic subtype (p = 0.002).Discussion:Distinct speech phenotypes in de-novo PD reflect divergent underlying mechanisms and allow to predict response of speech impairment to levodopa therapy.Classification of Evidence:This study provides Class II evidence that, in patients with newly diagnosed PD with speech impairment, speech phenotype is associated with levodopa responsiveness.

9 When the spark goes out: the neurology of apathy and motivation

Disorders of motivation are common across brain disorders. Clinicians frequently encounter pathological apathy across a range of conditions, including many neurodegenerative conditions such as small cerebrovascular disease, Parkinsons and Alzheimers disease. It is now becoming understood that apathy has a poor prognosis for long-term functional and cognitive outcome. Unfortunately, we understand very little about the mechanisms underlying the syndrome.In this talk, I shall put forward a conceptual framework with which we can begin to understand apathy by considering the processes that normally underlie motivated, goal- directed behavior. In particular Ill focus on the ability to generate options for behavior and effort-based decision making for rewards. Recent studies of the latter have been particularly revealing in both healthy people and neurological patient populations.Several lines of evidence suggest that when we make decisions about how much effort we might invest in actions, we weigh up the costs involved for the potential rewards to be obtained. Functional imaging in healthy people reveals both medial frontal and basal ganglia involvement when individuals make such decisions. In patients with apathy, this evaluation is altered. Apathetic patients show blunted sensitivity to rewards and less inclination to invest effort for low rewards than healthy individuals. Some evidence shows that these factors can be improved by dopaminergic medication. The findings support the view that it might be possible to provide a mechanistic account of the syndrome of apathy which might lead to treatments for the disorder.