Repeated Spiral Drawings in Essential Tremor: a Possible Limb-Based Measure of Motor Learning.

To investigate changes in tremor severity over repeated spiral drawings to assess whether learning deficits can be evaluated directly in a limb in essential tremor (ET). A motor learning deficit in ET, possibly mediated by cerebellar pathways, has been established in eye-blink conditioning studies, but not paradigms measuring from an affected, tremulous limb. Computerized spiral analysis captures multiple characteristics of Archimedean spirals and quantifies performance through calculated indices. Sequential spiral drawing has recently been suggested to demonstrate improvement across trials among ET subjects. One hundred and sixty-one ET and 80 age-matched control subjects drew 10 consecutive spirals on a digitizing tablet. Degree of severity (DoS), a weighted, computational score of spiral execution that takes into account spiral shape and line smoothness, previously validated against a clinical rating scale, was calculated in both groups. Tremor amplitude (Ampl), an independent index of tremor size, measured in centimeters, was also calculated. Changes in DoS and Ampl across trials were assessed using linear regression with slope evaluations. Both groups demonstrated improvement in DoS across trials, but with less improvement in the ET group compared to controls. Ampl demonstrated a tendency to worsen across trials in ET subjects. ET subjects demonstrated less improvement than controls when drawing sequential spirals, suggesting a possible motor learning deficit in ET, here captured in an affected limb. DoS improved independently of Ampl, showing that DoS and Ampl are separable motor physiologic components in ET that may be independently mediated.

Digitized spiral analysis may be a potential biomarker for brachial dystonia.

INTRODUCTION: Objective measures for detection and quantification of dystonic movements may guide both diagnosis and clinical monitoring. Digitized spiral analysis is a non-invasive method used to assess upper limb motor control in movement disorders and may have utility in dystonia. We aimed to determine if digitized spiral analysis can distinguish dystonia subjects from controls, and evaluated correlation with a validated clinical rating scale. METHODS: Kinematic, dynamic, and spatial attributes of Archimedean spirals drawn with an inking pen on a digitizing tablet were compared for participants with brachial dystonia and either Tor1A (DYT1) (n = 15) or THAP1 (DYT6) mutations (n = 12) and age and gender matched controls (n = 27) using Receiver Operator Characteristics (ROC) analysis. Spiral indices including an overall degree of severity (DoS) were also calculated and correlated with clinical severity ratings as measured by the Burke-Fahn-Marsden scale. RESULTS: Dystonia spirals had significantly higher severity scores as well as higher measures of spiral irregularity compared to controls. ROC analysis demonstrated that the DoS score had good discriminative ability to distinguish dystonia spirals from controls, with an Area Under the Curve (AUC) of 0.87. Measures of spiral irregularity correlated with validated clinical rates of dystonia severity in the analyzed arm, with one particular index, Residue of Theta vs R, showing the highest correlation (r = 0.55, p = 0.005). CONCLUSION: Digitized spiral analysis may be a promising non-invasive method to objectively quantify brachial dystonia. It may also be a useful way to monitor subtle changes in dystonia severity over time not captured with current clinical rating scales.

Computerized spiral analysis using the iPad.

BACKGROUND: Digital analysis of writing and drawing has become a valuable research and clinical tool for the study of upper limb motor dysfunction in patients with essential tremor, Parkinson's disease, dystonia, and related disorders. We developed a validated method of computerized spiral analysis of hand-drawn Archimedean spirals that provides insight into movement dynamics beyond subjective visual assessment using a Wacom graphics tablet. While the Wacom tablet method provides robust data, more widely available mobile technology platforms exist. NEW METHOD: We introduce a novel adaptation of the Wacom-based method for the collection of hand-drawn kinematic data using an Apple iPad. This iPad-based system is stand-alone, easy-to-use, can capture drawing data with either a finger or capacitive stylus, is precise, and potentially ubiquitous. RESULTS: The iPad-based system acquires position and time data that is fully compatible with our original spiral analysis program. All of the important indices including degree of severity, speed, presence of tremor, tremor amplitude, tremor frequency, variability of pressure, and tightness are calculated from the digital spiral data, which the application is able to transmit. COMPARISON WITH EXISTING METHOD: While the iPad method is limited by current touch screen technology, it does collect data with acceptable congruence compared to the current Wacom-based method while providing the advantages of accessibility and ease of use. CONCLUSIONS: The iPad is capable of capturing precise digital spiral data for analysis of motor dysfunction while also providing a convenient, easy-to-use modality in clinics and potentially at home.

Digitized Spiral Drawing: A Possible Biomarker for Early Parkinson's Disease.

INTRODUCTION: Pre-clinical markers of Parkinson's Disease (PD) are needed, and to be relevant in pre-clinical disease, they should be quantifiably abnormal in early disease as well. Handwriting is impaired early in PD and can be evaluated using computerized analysis of drawn spirals, capturing kinematic, dynamic, and spatial abnormalities and calculating indices that quantify motor performance and disability. Digitized spiral drawing correlates with motor scores and may be more sensitive in detecting early changes than subjective ratings. However, whether changes in spiral drawing are abnormal compared with controls and whether changes are detected in early PD are unknown. METHODS: 138 PD subjects (50 with early PD) and 150 controls drew spirals on a digitizing tablet, generating x, y, z (pressure) data-coordinates and time. Derived indices corresponded to overall spiral execution (severity), shape and kinematic irregularity (second order smoothness, first order zero-crossing), tightness, mean speed and variability of spiral width. Linear mixed effect adjusted models comparing these indices and cross-validation were performed. Receiver operating characteristic analysis was applied to examine discriminative validity of combined indices. RESULTS: All indices were significantly different between PD cases and controls, except for zero-crossing. A model using all indices had high discriminative validity (sensitivity = 0.86, specificity = 0.81). Discriminative validity was maintained in patients with early PD. CONCLUSION: Spiral analysis accurately discriminates subjects with PD and early PD from controls supporting a role as a promising quantitative biomarker. Further assessment is needed to determine whether spiral changes are PD specific compared with other disorders and if present in pre-clinical PD.

Intention Tremor of the Legs in Essential Tremor: Prevalence and Clinical Correlates.

OBJECTIVE: To estimate the prevalence and assess the clinical correlates of intention tremor in the legs in essential tremor (ET) patients. BACKGROUND: The cerebellar features of ET are of growing interest to clinical neurologists. Arm tremor has an intentional component in many ET patients. Intention tremor in the legs, however, has never been systematically evaluated. METHODS: One-hundred-twenty-eight ET patients were enrolled in a clinical-epidemiological study at Columbia University. A videotaped neurological examination included 10 toe-to-target movements with each foot. Videotapes were independently reviewed by two movement disorder neurologists who noted the presence vs. absence of intentional leg tremor. Two patients underwent quantitative computerized tremor analysis to study the physiological characteristics of the tremor. RESULTS: Thirty-five patients (27.3%) had intentional leg tremor; in 21, tremor was unilateral and in 14 it was bilateral. The 35 patients with intentional leg tremor did not differ from the remaining 93 patients in their clinical characteristics. Analyses comparing the 14 patients with bilateral intentional leg tremor to the 93 patients with no intentional leg tremor showed trends towards longer disease duration and more severe intentional arm tremor in the former. Tremor analysis showed a 3-fold increase in average tremor amplitude from movement onset to the point just prior to touching the target. CONCLUSIONS: Our data suggest that intentional leg tremor, another cerebellar feature, is common in ET patients. The tremor may be associated with longer disease duration and more severe intentional arm tremor, but these preliminary trends need to be assessed in larger study samples.

Increased variability in spiral drawing in patients with functional (psychogenic) tremor.

Increased variability is a characteristic clinical and physiologic feature of functional (psychogenic) tremor. In this study, we use computerized spiral analysis to show that the variability of a motor task is a quantifiable characteristic of functional tremor. We compare functional tremor patients to phenomenologically similar dystonic tremor patients and to normal controls. We used the spiral severity score, a measure that does not incorporate spiral tightness, as a marker of spiral drawing performance, and inter-spiral tightness variability (based on the 25-75%(ile) range in tightness across ten spirals) to evaluate the effects of functional tremor on drawing spirals. The spirals of 74 participants: 22 functional tremor, 21 dystonic tremor, and 31 normal controls were analyzed. Spiral severity was higher in both tremor groups compared to controls, but did not differentiate them. Inter-spiral variability, however, was higher in the functional tremor group compared to both other groups. Thus, spiral analysis captures variability of a motor task and may be used as an objective test for functional tremor. The effect of functional tremor in other motor tasks should be investigated.

Features and timing of the response of single neurons to novelty in the substantia nigra.

Substantia nigra neurons are known to play a key role in normal cognitive processes and disease states. While animal models and neuroimaging studies link dopamine neurons to novelty detection, this has not been demonstrated electrophysiologically in humans. We used single neuron extracellular recordings in awake human subjects undergoing surgery for Parkinson disease to characterize the features and timing of this response in the substantia nigra. We recorded 49 neurons in the substantia nigra. Using an auditory oddball task, we showed that they fired more rapidly following novel sounds than repetitive tones. The response was biphasic with peaks at approximately 250 ms, comparable to that described in primate studies, and a second peak at 500 ms. This response was primarily driven by slower firing neurons as firing rate was inversely correlated to novelty response. Our data provide human validation of the purported role of dopamine neurons in novelty detection and suggest modifications to proposed models of novelty detection circuitry.

Hypotensive effects induced by herbal fomentation at Yongquan point.

OBJECTIVE: This study aimed at assessing the adequacy of blood pressure (BP) control with the Chinese herbal fomentation at Yongquan point (K1). METHOD: A total of 51 participants as a group were enrolled. In 10 participants as the subgroup, BP data were compared with those simultaneously recorded from the radial artery of the same side. After the baseline examination, each enrolled patient participated in one session lasting 24 hours, during which Yongquan point (K1) of both sides were fomented with a mixture of Chinese herbs. The technique of 24-hour Ambulatory BP monitoring (ABPM) was repeated at baseline and on the day after the therapy. RESULTS: The systolic and diastolic BP measured intra-arterially during the test were, on average, similar to those measured noninvasively. Patients obtained a 6.0mmHg reduction for systolic BP and a 4.8mmHg reduction for diastolic BP during daytime. The rate of adverse events was 2.0% in the group. CONCLUSION: Our data demonstrated that BP recording by the ABPM method in our study provided a relatively accurate estimate of the average radial BP of the population. So the conclusion, "Chinese herbal fomentation at Yongquan point (K1) of both sides has some hypotensive potentials" was more reliable.

Chinese herbal fomentation at the Yongquan point (K1): a potential hypotensive regimen.

OBJECTIVE: The goal of this research was to assess the adequacy of blood pressure (BP) control by applying Chinese herbal fomentation (a type of thermotherapy) at the Yongquan point (K1). METHODS: A total of 102 patients with hypertension, ages 39-55, were included in this study. After a baseline examination, each enrolled patient participated in one session per day lasting 24 hours for 3 continuous days, during which the Yongquan point (K1) on both sides of the body were fomented (given thermotherapy) with a mixture of Chinese herbs. In addition, 24-hour ambulatory BP (ABP) monitoring (ABPM) was repeated at baseline and on the day after the therapy. RESULTS: Patients had significantly lower daytime systolic and diastolic BP post-treatment. There were no significant changes in 24-hour, or night-time systolic BP (SBP), diastolic BP (DBP), or mean arterial BP, and in pulse pressure after therapy. The rate of adverse events was 0.98% in these patients. CONCLUSIONS: The regimen sustained SBP and DBP control during the day for the majority of patients. This study suggested that a Chinese herbal fomentated at the Yongquan point (K1) of both sides of the body has some hypotensive potential.

High width variability during spiral drawing: further evidence of cerebellar dysfunction in essential tremor.

Essential tremor (ET) is among the most prevalent neurological diseases, yet the location of the primary disease substrate continues to be a matter of debate. The presence of intention tremor and mild gait ataxia suggests an underlying abnormality of the cerebellum and/or cerebellar pathways. Uncovering additional signs of cerebellar dysfunction would further substantiate the proposition that ET is a disease of the cerebellar system. We evaluated 145 ET cases and 34 normal controls clinically and by computerized spiral analysis. Spiral analysis is a program that objectively characterizes kinematic and physiologic features of hand-drawn spirals using specific calculated spiral indices that correlate with spiral shape and motor execution. We used the spiral width variability index (SWVI), a measure of loop-to-loop spiral width variation with the influence of tremor removed, as a metric of drawing ataxia. The SWVI was higher in cases than controls (0.91 ± 1.94, median=0.46 vs. 0.40 ± 0.29, median=0.30, p<0.001). Cases with higher SWVI also had greater intention tremor during the finger-nose-finger maneuver, r=0.27, p=0.001), and cases with intention tremor of the head had the highest SWVI (1.57 ± 3.44, median=0.51, p<0.001). There was a modest association between SWVI and number of missteps during tandem gait (r=0.16, p=0.06). The primary anatomical substrate for ET continues to be a matter of speculation, yet these and other clinical data lend support to the notion that there is an underlying abnormality of the cerebellum and/or its pathways.

Clinical and neurophysiological improvement of SGCE myoclonus-dystonia with GPi deep brain stimulation.

Myoclonus-dystonia (M-D) is characterized by early onset myoclonus and dystonia. It is thought to be subcortical in origin. Response to oral medications may be incomplete, such that deep brain stimulation (DBS) surgery to the globus pallidum interna (GPi) or ventral intermediate thalamic nucleus (VIM) may be considered. The optimal site is not known. The physiology and surgical response for a 63-year-old woman who underwent GPi DBS for M-D with onset at age 2 and related to a mutation in the epsilon-sarcoglycan gene (SGCE) is described. She showed excellent clinical and neurophysiological improvement of both myoclonus and dystonia, suggesting that modulation by DBS is effective even after long disease duration and only partial response to oral medications.

HPLC Method for the Simultaneous Determination of Ten Annonaceous Acetogenins after Supercritical Fluid CO2 Extraction.

Annonaceous acetogenins (ACGs) isolated from Annonaceae plants exhibited a broad range of biological bioactivities such as cytotoxic, antitumoral, antiparasitic, pesticidal and immunosuppresive activities. However, their structures were liable to change at more than 60°C and their extraction yields were low using traditional organic solvent extraction. In the present study, all samples from Annona genus plant seeds were extracted by supercritical carbon dioxide under optimized conditions and a high-performance liquid chromatography (HPLC) method was established for simultaneously determining ten ACGs. All of the ten compounds were simultaneously separated on reversed-phase C18 column (250 mm × 4.6 mm, 5 µm) with the column temperature at 30°C. The mobile phase was composed of (A) methanol and (B) distilled water, the flow rate was 1.0 ml/min and the detection wavelength was set at 220 nm. All calibration curves showed good linear regression (γ>0.9995) within the test range. The established method showed good precision and accuracy with overall intra-day and inter-day variations of 0.99-2.56% and 1.93-3.65%, respectively, and overall recoveries of 95.16-105.01% for the ten compounds analyzed. The established method can be applied to evaluate the intrinsic quality of Annonaceae plant seeds. The determination results recover the content-variation regularities of various ACGs in different species, which are helpful to choose the good-quality Annonaceae plant seeds for anticancer lead compound discovery.

Spiral analysis in Niemann-Pick disease type C.

Spiral analysis is a computerized method of analyzing upper limb motor physiology through the quantification of spiral drawing. The objective of this study was to determine whether spirals drawn by patients with Niemann-Pick disease type C (NPC) could be distinguished from those of controls, and to physiologically characterize movement abnormalities in NPC. Spiral data consisting of position, pressure, and time were collected from 14 NPC patients and 14 age-matched controls, and were analyzed by the Mann-Whitney U test. NPC spirals were characterized by: lower speed (2.67 vs. 9.56 cm/s, P < 0.001) and acceleration (0.10 vs. 2.04 cm/s(2), P < 0.001), higher loop width variability (0.88 vs. 0.28, P < 0.001), tremor (5/10 vs. 0/10 trials in the dominant hand, P < 0.001), and poor overall spiral rating (2.53 vs. 0.70, P < 0.005). NPC spirals also exhibited sustained drawing pressure profiles that were abnormally invariant with time. Other features, such as the tightness of loop widths, were normal. Our findings reveal that differing aspects of tremor, Parkinsonism, ataxia, and dystonia are quantifiable in NPC patients.

Typical variations of subthalamic electrode location do not predict limb motor function improvement in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for patients with medically refractory Parkinson's disease (PD). The degree to which the anatomic location of the DBS electrode tip determines the improvement of contralateral limb movement function has not been defined. This retrospective study was performed to address this issue. Forty-two DBS electrode tips in 21 bilaterally implanted patients were localized on postoperative MRI. The postoperative and preoperative planning MRIs were merged with the Stealth FrameLink 4.0 stereotactic planning workstation (Medtronic Inc., Minneapolis, MN, USA) to determine the DBS tip coordinates. Stimulation settings were postoperatively optimized for maximal clinical effect. Patients were videotaped 1 year postoperatively and assessed by a movement disorder neurologist blinded to electrode tip locations. The nine limb-related components of the Unified PD Rating Scale Part III were tabulated to obtain a limb score, and the electrode tip locations associated with the 15 least and 15 greatest limb scores were evaluated. Two-tailed t-tests revealed no significant difference in electrode tip location between the two groups in three-dimensional distance (p=0.759), lateral-medial (x) axis (p=0.983), anterior-posterior (y) axis (p=0.949) or superior-inferior (z) axis (p=0.894) from the intended anatomical target. The range of difference in tip location and limb scores was extensive. Our results suggest that anatomic targeting alone may provide the same clinical efficacy as is achieved by "fine-tuning" DBS placement with microelectrode recording to a specific target.

Spiral analysis-improved clinical utility with center detection.

Spiral analysis is a computerized method that measures human motor performance from handwritten Archimedean spirals. It quantifies normal motor activity, and detects early disease as well as dysfunction in patients with movement disorders. The clinical utility of spiral analysis is based on kinematic and dynamic indices derived from the original spiral trace, which must be detected and transformed into mathematical expressions with great precision. Accurately determining the center of the spiral and reducing spurious low frequency noise caused by center selection error is important to the analysis. Handwritten spirals do not all start at the same point, even when marked on paper, and drawing artifacts are not easily filtered without distortion of the spiral data and corruption of the performance indices. In this report, we describe a method for detecting the optimal spiral center and reducing the unwanted drawing artifacts. To demonstrate overall improvement to spiral analysis, we study the impact of the optimal spiral center detection in different frequency domains separately and find that it notably improves the clinical spiral measurement accuracy in low frequency domains.

Validity of spiral analysis in early Parkinson's disease.

Spiral analysis is an objective, easy to administer noninvasive test that has been proposed to measure motor dysfunction in Parkinson disease (PD). We compared overall Unified Parkinson Disease Rating Scale Part III scores to selected indices derived from spiral analysis in seventy-four patients with early PD (mean duration of disease 2.4 +/- 1.7 years, mean age 61.5 +/- 9.7 years). Of the spiral indices, degree of severity, first order zero crossing, second order smoothness, and mean speed were best correlated with total motor Unified Parkinson's Disease Rating Scale (UPDRS) score (all P < 0.01), and these indices showed a gradient across worsening tertiles of UPDRS (P < 0.05). Spiral indices also correlated with UPDRS ratings for the worst side and worst arm scores as well. The domains of bradykinesia, rigidity, and action tremor were correlated with first order crossing, second order smoothness, and mean speed, where as rest tremor was most highly correlated with degree of severity. This suggests that the spiral analysis may supplement motor assessment in PD, although further analysis of spiral metrics, a larger sample and longitudinal data should be evaluated.

A technique for minimally altering anatomically based subthalamic electrode targeting by microelectrode recording.

OBJECT: Implantation of a subthalamic nucleus (STN) deep brain stimulation (DBS) electrode is increasingly recognized as an effective treatment for advanced Parkinson disease (PD). Despite widespread use of microelectrode recording (MER) to delineate the boundaries of the STN prior to stimulator implantation, it remains unclear to what extent MER improves the clinical efficacy of this procedure. In this report, the authors analyze a series of patients who were treated at one surgical center to determine to what degree final electrode placement was altered, based on readings obtained with MER, from the calculated anatomical target. METHODS: Subthalamic DBS devices were placed bilaterally in nine patients with advanced PD. Frame-based volumetric magnetic resonance images were acquired and then transferred to a stereotactic workstation to determine the anterior and posterior commissure coordinates and plane. The initial anatomical target was 4 mm anterior, 4 mm deep, and 12 mm lateral to the midcommissural point. The MERs defined the STN boundaries along one or more parallel tracks, refining the final electrode placement by comparison of results with illustrations in a stereotactic atlas. In eight of 18 electrodes, the MER results did not prompt an alteration in the anatomically derived target. In another eight placements, MER altered the target by less than 1 mm and two of 18 electrode positions differed by less than 2 mm. The anterior-posterior difference was 0.53 +/- 0.65 mm, whereas the medial-lateral direction differed by 0.25 +/- 0.43 mm. The ventral boundary of the STN defined by MER was 2 +/- 0.72 mm below the calculated target (all values are the means +/- standard deviation). All patients attained clinical improvement, similar to previous reports. CONCLUSIONS: In this series of patients, microelectrode mapping of the STN altered the anatomically based target only slightly. Because it is not clear whether such minor adjustments improve clinical efficacy, a prospective clinical comparison of MER-refined and anatomical targeting may be warranted.

Psychogenic tremor disorders identified using tree-based statistical algorithms and quantitative tremor analysis.

Detecting psychogenic tremors (PsychT) is often challenging. As there are no laboratory investigations or imaging techniques that can confirm the diagnosis, PsychT is identified on a clinical basis. We present a tree-based statistical algorithm derived from quantitative computerized tremor recordings as a novel method to help in the recognition of PsychT. The goal of this study was to show that objective data from computerized tremor recordings, when processed through a tree-based statistical algorithm, can be used to determine whether a patient can be classified as having PsychT.

Clinical and neurophysiologic spectrum of orthostatic tremor: case series of 26 subjects.

Orthostatic tremor (OT) is a condition described as high-frequency tremors predominantly in the legs and trunk, which are present not only in the standing position but also during isometric contraction of the limb muscles. This report is one of the largest OT series describing clinical and neurophysiologic findings in 26 subjects with OT. The main findings included 13.0 to 18.6 Hz leg tremors while standing with varied patterns of phase relationships between the antagonists of the ipsilateral leg and between the homologous muscles of the contralateral leg, short latency tremor onset upon standing with abrupt cessation after sitting, coexistence of tremors in the cranial structures and the arms, and sense of unsteadiness without actual falls. Although the oscillator of OT is most likely located in the brainstem, cerebral cortex, basal ganglia, and cerebellum may also be involved in its pathogenesis.