Drug-induced dyskinesia in Parkinson's disease. Should success in clinical management be a function of improvement of motor repertoire rather than amplitude of dyskinesia?

BACKGROUND: Dyskinesia, a major complication in the treatment of Parkinson's disease (PD), can require prolonged monitoring and complex medical management. DISCUSSION: The current paper proposes a new way to view the management of dyskinesia in an integrated fashion. We suggest that dyskinesia be considered as a factor in a signal-to-noise ratio (SNR) equation where the signal is the voluntary movement and the noise is PD symptomatology, including dyskinesia. The goal of clinicians should be to ensure a high SNR in order to maintain or enhance the motor repertoire of patients. To understand why such an approach would be beneficial, we first review mechanisms of dyskinesia, as well as their impact on the quality of life of patients and on the health-care system. Theoretical and practical bases for the SNR approach are then discussed. SUMMARY: Clinicians should not only consider the level of motor symptomatology when assessing the efficacy of their treatment strategy, but also breadth of the motor repertoire available to patients.

The organization of upper limb physiological tremor.

The objectives of this study are (1) to assess the relationship between tremor displacement of different segments of the upper limb, (2) to assess whether an attempt to voluntarily reduce tremor amplitude affects this relationship. Twenty-five young healthy participants were tested. Tremor of the finger, hand, arm and shoulder was assessed using laser displacement sensors while the upper limb was in a postural position. Results show strong correlations (r > 0.90), high coherence (>0.9) and in-phase movement between tremor displacement oscillations of different segments. The majority of finger tremor amplitude can be predicted by angular movement generated at the shoulder joint (r(2) > 0.86). Participants were able to voluntarily reduce tremor amplitude, but no change in the relationship between segments was observed. Tremor of all segments of the upper limb was mechanically driven by the angular movement generated at the shoulder joint. This study provides evidence that there is no compensatory organization of physiological tremor. This lays the groundwork to evaluate whether pathological tremors also lack this organization.

Quantifying the importance of high frequency components on the amplitude of physiological tremor.

The objective of this study was to determine the importance of every frequency component on total physiological tremor (PT) amplitude. We suspect that since high frequencies of PT are of lower amplitude in displacement, removing them will have little to no impact on PT amplitude. PT of the index finger was measured with a laser displacement sensor while the finger was held horizontally. Amplitude of tremor was calculated in displacement, velocity and acceleration. PT amplitude was also calculated within five frequency bands. Although displacement amplitude of oscillations within the 7.5-12.5 and 16.5-30 Hz frequency bands represent 24 and 10% of total PT oscillation amplitude, respectively, their removal reduced PT amplitude by less than 3%. Conversely, the removal of the oscillations within 1-3.5 Hz band from the PT signal reduced the amplitude of the original PT signal by 56% in displacement. This suggests that when a task to be studied involves the measurement of a reduction in tremor, focus should be on the oscillations in the 1-3.5 Hz band.

The amplitude of physiological tremor can be voluntarily modulated.

The objective of this study was to determine whether it was possible to voluntarily modulate physiological tremor (PT), i.e., reduce its amplitude. We recorded the postural index finger tremor of 30 healthy participants with a laser in four conditions: (A) eyes closed, without any attempt to modulate PT amplitude, (B) no visual feedback, trying to reduce PT amplitude, (C) visual feedback, trying to reduce PT amplitude. For conditions B and C, subjects were asked to avoid using muscle contraction as a means to stabilize the finger. Finally, (D) subjects were asked to reduce PT amplitude using voluntary muscle contraction to stabilize the finger. We used electromyography to monitor the extensor digitorum communis and flexor digitorum superficialis. Total amplitude of PT did not change significantly between conditions A and B. In condition C, a significant decrease of PT amplitude was observed. A significant increase in tremor amplitude was observed in D compared with other conditions, confirming that co-contraction was not used to modulate the amplitude of PT in other conditions. Subsequently, we formed three subgroups based on their ability to modulate PT: Most Improved (n = 7), Least Improved (n = 16) and Not Improved (n = 7). Although oscillations within the low frequency bands increased only in the Not Improved group, oscillations within the 8-12 and 16-30 Hz bands either remained stable or decreased for all participants, supporting a disassociation between mechanical-reflex and central components of PT. Our results show that it is possible to voluntarily modulate PT. Therefore, a cortical influence is being exerted on tremor.

Subthalamic deep brain stimulation and dopaminergic medication in Parkinson's disease: Impact on inter-limb coupling.

Patients with Parkinson's disease (PD) often present with bimanual coordination deficits whose exact origins remain unclear. One aspect of bimanual coordination is inter-limb coupling. This is characterized by the harmonization of movement parameters between limbs. We assessed different aspects of bimanual coordination in patients with PD, including inter-limb coupling, and determined whether they are altered by subthalamic (STN) deep brain stimulation (DBS) or dopaminergic medication. Twenty PD patients were tested before STN DBS surgery; with and without medication. Post- surgery, patients were tested with their stimulators on and off as well as with and without medication. Patients were asked to perform a unimanual and bimanual rapid repetitive diadochokinesis task. The difference in mean amplitude and mean duration of cycles between hands was computed in order to assess inter-limb coupling. Also, mean angular velocity of both hands and structural coupling were computed for the bimanual task. There was a positive effect of medication and stimulation on mean angular velocity, which relates to clinical improvement. PD patients exhibited temporal inter-limb coupling that was not altered by either medication or STN stimulation. However, PD patients did not exhibit spatial inter-limb coupling. Again, this was not altered by medication or stimulation. Collectively, the results suggest that structures independent of the dopaminergic system and basal ganglia may mediate temporal and spatial inter-limb coupling.

Measuring tremor with a smartphone.

Tremor is the most common movement disorder. However; characterizing it in large populations is not easily accomplished since current methodologies are not adapted to large-scale field studies. To overcome this challenge, a smartphone application was developed as a stand-alone platform to assess tremor. The current book chapter details the steps taken to validate this mobile application. Data recorded with the smartphone was analyzed online and offline as well as compared to laboratory equipment and a clinical scale. This allowed for the identification of the tremor properties that could reliably be characterized with the smartphone as well as the limits of the hardware. It also allowed for the identification of tasks that could be performed with the smartphone when tremor was being assessed. Finally, we confirmed the clinical relevance of the results provided by the smartphone application.

Inter-limb coupling during diadochokinesis in Parkinson's and Huntington's disease.

Patients with neurodegenerative diseases often exhibit deficits in bimanual coordination. One characteristic of bimanual movements is inter-limb coupling. It is the property of motor performance harmonization between hands during a bimanual task. The objective of this study was to identify whether spatial and temporal inter-limb coupling occurred in Parkinson's disease (PD) and Huntington's disease (HD) patients. Twenty-three PD patients and 15 healthy controls were tested. Data from 12 choreic HD patients were also taken from a databank. Participants were asked to perform a unimanual and bimanual rapid repetitive diadochokinesis task. The difference between hands in mean amplitude and mean duration of cycles was computed in the unimanual and bimanual tasks for each group. Results show that healthy controls exhibited temporal and spatial inter-limb coupling during the bimanual diadochokinesis task. Conversely, PD and HD patients exhibited temporal inter-limb coupling; but failed to exhibit spatial inter-limb coupling during the bimanual diadochokinesis task. Furthermore, HD patients exhibited reduced levels of structural coupling compared to controls and PD patients. These results suggest that alterations in basal ganglia-thalamo-cortical networks due to PD and HD do not affect temporal inter-limb coupling. However, common pathophysiological changes related to PD and HD may cause altered spatial inter-limb coupling during a rapid repetitive bimanual diadochokinesis task.

Are quantitative and clinical measures of bradykinesia related in advanced Parkinson's disease?

INTRODUCTION: Bradykinesia is usually assessed using clinical rating scales. In some circumstances, a laboratory assessment of bradykinesia using tools of higher resolution is required. One task often used for the evaluation of bradykinesia is a rapid alternating movement (RAM) of the hand. However, the relationship between clinical scores of bradykinesia and the properties of a RAM task assessed quantitatively has yet to be determined. OBJECTIVE: Identify which of the commonly used properties of a RAM task are related to a clinical score of bradykinesia and assess the strength of this relationship. METHODS: Nineteen patients with idiopathic Parkinson's disease were tested ON and OFF medication. They performed three trials of the RAM task and were assessed clinically using the Unified Parkinson's disease rating scale in each condition and with each hand. RESULTS: A statistically significant correlation was observed between the clinical score of bradykinesia and two of the properties of the RAM task; namely mean and maximal velocity. COMPARISON WITH EXISTING METHODS: These results indicate that a RAM task does provide a measure of bradykinesia but it is only moderately correlated to a clinical rating of this motor symptom. CONCLUSION: We propose that the results from the RAM task represent a measure of "core bradykinesia" while a clinical evaluation represents a composite score of bradykinesia, movement amplitude and motor coordination.

The effect of changes in joint angle on the characteristics of physiological tremor.

INTRODUCTION: Physiological tremor, as a whole, can be influenced by changes in muscle activity. However, the origin of low-frequency physiological tremor oscillations has yet to be conclusively determined. It is possible that by experimentally manipulating muscular activity, a better determination of the origin of those low-frequency oscillations can be achieved. It was demonstrated that changes in joint angle modify characteristics of muscular activity. As such, we hypothesize that changes in wrist-joint angle will alter the characteristics of low-frequency physiological tremor oscillations. OBJECTIVE: Assess the influence of changes in joint angle of the wrist on characteristics of physiological finger tremor. METHODS: Physiological finger tremor was recorded (n = 25) using a laser displacement system while the arm and hand were supported. The relative angle between the dorsum of the hand and the forearm was altered between conditions (135°, 180°, 225° and 270°), while the hand and the finger remained parallel to the ground. EMG of the extensors and flexors were also recorded. RESULTS: Tremor amplitude was significantly altered by changes in wrist-joint angle. This was especially the case for lower frequency oscillations. In addition, electromyography properties of forearm muscles were also significantly modified by changes in wrist-joint angles. CONCLUSIONS: This study demonstrates that changes in wrist-joint angle modify the characteristics of physiological finger tremor. This should be taken into account when interpreting tremor data as well as when developing tools to minimize tremor.

Using a smart phone as a standalone platform for detection and monitoring of pathological tremors.

INTRODUCTION: Smart phones are becoming ubiquitous and their computing capabilities are ever increasing. Consequently, more attention is geared toward their potential use in research and medical settings. For instance, their built-in hardware can provide quantitative data for different movements. Therefore, the goal of the current study was to evaluate the capabilities of a standalone smart phone platform to characterize tremor. RESULTS: Algorithms for tremor recording and online analysis can be implemented within a smart phone. The smart phone provides reliable time- and frequency-domain tremor characteristics. The smart phone can also provide medically relevant tremor assessments. DISCUSSION: Smart phones have the potential to provide researchers and clinicians with quantitative short- and long-term tremor assessments that are currently not easily available. METHODS: A smart phone application for tremor quantification and online analysis was developed. Then, smart phone results were compared to those obtained simultaneously with a laboratory accelerometer. Finally, results from the smart phone were compared to clinical tremor assessments.

Changes in physiological tremor associated with an epileptic seizure: a case report.

INTRODUCTION: Epileptic seizures are associated with motor, sensory, somatosensory or autonomic symptoms that have all been described in varying detail over the years. Of interest in the present report is a case of normal physiological tremor, which to date has never been evaluated prior to and during an epileptic seizure. In fact, there is only anecdotal mention of pre-ictal and ictal changes in clinically noticeable tremor in the literature. CASE PRESENTATION: Our patient was a left-handed, 27-year-old Caucasian woman diagnosed seven years previously with partial epileptic seizures, secondarily generalized. Physiological tremor was measured simultaneously on the index finger of both hands of our patient. Electromyography as well as heart rate and respiration were also monitored. A previously performed electroencephalography examination revealed abnormal oscillations focalized to the left primary somatosensory cortex. She was also diagnosed with left frontal neuronal heterotopias. We detected subclinical changes in tremor characteristics, such as amplitude, median power frequency and power dispersion, contralateral to the localization of epileptic activity. Tremor characteristics remained relatively steady ipsilateral to the localization of the epileptic activity. CONCLUSIONS: Changes in physiological tremor characteristics should be considered as another possible pre-ictal or ictal manifestation. We propose that the network associated with physiological tremor might be more sensitive to abnormal oscillations generated within the central nervous system by epileptic activity from certain structures.

Finger tremor can be voluntarily reduced during a tracking task.

INTRODUCTION: IT is a well-known fact that physiological tremor has a deleterious effect on small and precise movements. We recently showed that the amplitude of postural physiological tremor can be voluntarily reduced. Whether this is also applicable to tremor during small movements has not been explored. OBJECTIVE: This study aims to characterize tremor during movement, assess whether it is possible to reduce tremor amplitude during voluntary movements, and quantify any changes in accuracy that may result from this modulation. METHODS: Finger tremor was measured in 12 healthy volunteers using a laser displacement sensor and recorded during (A) a postural physiological tremor condition, (B) a slow target tracking task, and (C) the same tracking task while trying to reduce tremor amplitude. RESULTS: The tremor characteristics such as distribution of power within the power spectrum remained similar during movement when compared to the static postural condition. Tremor amplitude was significantly reduced when participants attempted to do so. However, this reduction was accompanied with a systematic increase in error. Finally, mean error was significantly higher when the target line moved at higher velocity. DISCUSSION: Our results demonstrate that tremor remains present during movement and that its amplitude can be voluntarily modulated. However, attempting to voluntarily reduce the amplitude of that tremor during movement is not an efficient way to improve tracking performance.

Assessing drug-induced dyskinesia in the clinic, the laboratory and the natural environment of patients.

The assessment of drug-induced dyskinesia (DID) in Parkinson's disease represents a formidable challenge for clinicians and researchers alike. The present review describes the current assessment tools used in the clinic, where different scales have been developed for monitoring levels of DID in patients. We also review laboratory tools used to assess the quantity and characteristics of DID. Finally, we review assessment methods currently in development for monitoring DID and voluntary mobility in the natural living environment of patients. Here, we discuss the strengths and weaknesses of these tools as it pertains to their efficacy in assessing the quantity of DID, its characteristics, as well as its impact on the quality of life of patients. Finally, we discuss ongoing challenges and research questions that may guide future development of assessment methods aimed at monitoring DID and its impact on daily lives of patients.

Bilateral effect of a unilateral voluntary modulation of physiological tremor.

OBJECTIVE: Verify whether a unilateral physiological tremor modulation attempt has a bilateral effect on central oscillators responsible for physiological tremor. METHODS: Bilateral finger physiological tremor was recorded in 35 right-handed participants with laser displacement sensors in: (A) control condition, (B) modulation attempt of physiological tremor of the right index finger, (C) modulation attempt of physiological tremor of the right index finger by using co-contraction as a means to stabilize the finger. RESULTS: Physiological tremor amplitude was significantly reduced between the control and modulation conditions for the right index finger. Physiological tremor amplitude was also significantly reduced for the left index finger. Regression analysis of oscillation amplitudes showed little relationship between both fingers, even during modulation attempts. The lack of relationship between fingers is also evident by low coherence values obtained in the control and modulation conditions. The coherence in the co-activation condition was significantly higher, albeit still low, in each frequency band. CONCLUSION: Our results confirm that physiological tremor can be voluntarily reduced, and this reduction is bilateral. The modulation attempt did not however increase the frequency relationship between both sides. SIGNIFICANCE: A central command aiming at modulating tremor amplitude will not increase the synchronization between oscillators responsible for the central components of physiological tremor.