Combining olfactory test and motion analysis sensors in Parkinson's disease preclinical diagnosis: a pilot study.

OBJECTIVES: Preclinical diagnosis of Parkinson's disease (PD) is nowadays a topic of interest as the neuropathological process could begin years before the appearance of motor symptoms. Several symptoms, among them hyposmia, could precede motor features in PD. In the preclinical phase of PD, a subclinical reduction in motor skills is highly likely. In this pilot study, we investigate a step-by-step method to achieve preclinical PD diagnosis. MATERIAL AND METHODS: We used the IOIT (Italian Olfactory Identification Test) to screen a population of healthy subjects. We identified 20 subjects with idiopathic hyposmia. Hyposmic subjects underwent an evaluation of motor skills, at baseline and after 1 year, using motion analysis sensors previously created by us. RESULTS: One subject showed significant worsening in motor measurements. In this subject, we further conducted a dopaminergic challenge test monitored with the same sensors and, finally, he underwent [123 I]-FP/CIT (DaTscan) SPECT brain imaging. The results show that he is probably affected by preclinical PD. CONCLUSIONS: Our pilot study suggests that the combined use of an olfactory test and motor sensors for motion analysis could be useful for a screening of healthy subjects to identify those at a high risk of developing PD.

After Effects of Cerebellar Continuous Theta Burst Stimulation on Reflexive Saccades and Smooth Pursuit in Humans.

The use of cerebellar repetitive transcranial magnetic stimulation has been attempted for perturbing reflexive and voluntary eye movements, but discrepancies are seen between the results of distinct studies possibly due to the different stimulation sites, intensities, and paradigms. We describe the after effects of 20 and 40 s continuous Theta Burst Stimulation (cTBS) as compared to sham stimulation, applied over the lateral cerebellar vermis and paravermis on Reflexive Saccades (RS) and Smooth Pursuit (SP) eye movements, recorded in the 30 min following stimulation. The experiments were carried out in eight healthy volunteers, and eye movements were recorded monocularly with video-oculography. The 40 s cTBS significantly increased the amplitude of ipsilateral RS and the acceleration of the ipsilateral SP, and this effect was detectable all over the 30-min recording period; 40 s cTBS did not modify the other parameters, namely the peak velocity, the duration and the latency of RS, and the latency and the velocity of SP. The 20 s cTBS was ineffective on all RS and SP parameters. Finally, we detected a significant quite-linear reduction of RS peak velocity over time, but this was independent from cTBS and was probably caused by fatigue. The effects of 40 s cTBS in our experiments mimic the disorder of ocular motility in Wallenberg's syndrome and could result from functional impairment of cerebellopontine pathways. This effect lasts 30 min at least, and can provide a useful framework for adaptive ocular motor studies.

Velocity storage contribution to vestibular self-motion perception in healthy human subjects.

Self-motion perception after a sudden stop from a sustained rotation in darkness lasts approximately as long as reflexive eye movements. We hypothesized that, after an angular velocity step, self-motion perception and reflexive eye movements are driven by the same vestibular pathways. In 16 healthy subjects (25-71 years of age), perceived rotational velocity (PRV) and the vestibulo-ocular reflex (rVOR) after sudden decelerations (90°/s(2)) from constant-velocity (90°/s) earth-vertical axis rotations were simultaneously measured (PRV reported by hand-lever turning; rVOR recorded by search coils). Subjects were upright (yaw) or 90° left-ear-down (pitch). After both yaw and pitch decelerations, PRV rose rapidly and showed a plateau before decaying. In contrast, slow-phase eye velocity (SPV) decayed immediately after the initial increase. SPV and PRV were fitted with the sum of two exponentials: one time constant accounting for the semicircular canal (SCC) dynamics and one time constant accounting for a central process, known as velocity storage mechanism (VSM). Parameters were constrained by requiring equal SCC time constant and VSM time constant for SPV and PRV. The gains weighting the two exponential functions were free to change. SPV were accurately fitted (variance-accounted-for: 0.85 ± 0.10) and PRV (variance-accounted-for: 0.86 ± 0.07), showing that SPV and PRV curve differences can be explained by a greater relative weight of VSM in PRV compared with SPV (twofold for yaw, threefold for pitch). These results support our hypothesis that self-motion perception after angular velocity steps is be driven by the same central vestibular processes as reflexive eye movements and that no additional mechanisms are required to explain the perceptual dynamics.

Velocity storage in the human vertical rotational vestibulo-ocular reflex.

Human horizontal rotational vestibulo-ocular reflex (rVOR) has been extensively investigated: the horizontal semicircular canals sense yaw rotations with high-pass filter dynamics and a time constant (TC) around 5 s, yet the rVOR response shows a longer TC due to a central processing stage, known as velocity storage mechanism (VSM). It is generally assumed that the vertical rVOR behaves similarly to the horizontal one; however, VSM processing of the human vertical rVOR is still to be proven. We investigated the vertical rVOR in eight healthy human subjects using three experimental paradigms: (1) per- and post-rotatory around an earth-vertical axis (ear down rotations, EDR), (2) post-rotatory around an earth-horizontal axis with different stopping positions (static otolith stimulation), (3) per-rotatory around an earth-horizontal axis (dynamic otolith stimulation). We found that the TC of vertical rVOR responses ranged 3-10 s, depending both on gravity and on the direction of rotation. The shortest TC were found in response to post-rotatory earth-horizontal stimulation averaging 3.6 s, while they were prolonged in EDR stimulation, i.e. when the head angular velocity vector is aligned with gravity, with a mean value of about 6.0 s. Overall, the longest TC were observed in per-rotatory earth-horizontal stimulation, averaging 7.8 s. The finding of longer TC in EDR than in post-rotatory earth-horizontal stimulation indicates a role for the VSM in the vertical rVOR, although its contribution appears to be weaker than on the horizontal rVOR and may be directionally asymmetric. The results from per-rotatory earth-horizontal stimulation, instead, imply a role for the otoliths in controlling the duration of the vertical rVOR response. We found no reorientation of the response toward earth horizontal, indicating a difference between human and monkey rVOR.

The Functional Head Impulse Test to Assess Oscillopsia in Bilateral Vestibulopathy.

Introduction: Bilateral vestibulopathy (BV) is a chronic condition in which vestibular function is severely impaired or absent on both ears. Oscillopsia is one of the main symptoms of BV. Oscillopsia can be quantified objectively by functional vestibular tests, and subjectively by questionnaires. Recently, a new technique for testing functionally effective gaze stabilization was developed: the functional Head Impulse Test (fHIT). This study compared the fHIT with the Dynamic Visual Acuity assessed on a treadmill (DVAtreadmill) and Oscillopsia Severity Questionnaire (OSQ) in the context of objectifying the experience of oscillopsia in patients with BV. Methods: Inclusion criteria comprised: (1) summated slow phase velocity of nystagmus of <20°/s during bithermal caloric tests, (2) torsion swing tests gain of <30% and/or phase <168°, and (3) complaints of oscillopsia and/or imbalance. During the fHIT (Beon Solutions srl, Italy) patients were seated in front of a computer screen. During a passive horizontal head impulse a Landolt C optotype was shortly displayed. Patients reported the seen optotype by pressing the corresponding button on a keyboard. The percentage correct answers was registered for leftwards and rightwards head impulses separately. During DVAtreadmill patients were positioned on a treadmill in front of a computer screen that showed Sloan optotypes. Patients were tested in static condition and in dynamic conditions (while walking on the treadmill at 2, 4, and 6 km/h). The decline in LogMAR between static and dynamic conditions was registered for each speed. Every patient completed the Oscillopsia Severity Questionnaire (OSQ). Results: In total 23 patients were included. This study showed a moderate correlation between OSQ outcomes and the fHIT [rightwards head rotations (r s = -0.559; p = 0.006) leftwards head rotations (r s = -0.396; p = 0.061)]. No correlation was found between OSQ outcomes and DVAtreadmill, or between DVAtreadmill and fHIT. All patients completed the fHIT, 52% of the patients completed the DVAtreadmill on all speeds. Conclusion: The fHIT seems to be a feasible test to quantify oscillopsia in BV since, unlike DVAtreadmill, it correlates with the experienced oscillopsia measured by the OSQ, and more BV patients are able to complete the fHIT than DVAtreadmill.

Irregularity distinguishes limb tremor in cervical dystonia from essential tremor.

INTRODUCTION: Patients with cervical dystonia (CD) often have limb tremor that is clinically indistinguishable from essential tremor (ET). Whether a common central mechanism underlies the tremor in these conditions is unknown. We addressed this issue by quantifying limb tremor in 19 patients with CD and 35 patients with ET. METHOD: Postural, resting and kinetic tremors were quantified (amplitude, mean frequency and regularity) using a three-axis accelerometer. RESULTS: The amplitude of limb tremor in ET was significantly higher than in CD, but the mean frequency was not significantly different between the groups. The cycle-to-cycle variability of the frequency (ie the tremor irregularity), however, was significantly greater (approximately 50%) in CD. Analysis of covariance excluded the possibility that the increased irregularity was related to the smaller amplitude of tremor in CD (ANCOVA: p = 0.007, F = 5.31). DISCUSSION: We propose that tremor in CD arises from oscillators with different dynamic characteristics, producing a more irregular output, whereas the tremor in ET arises from oscillators with similar dynamic characteristics, producing a more regular output. We suggest that variability of tremor is an important parameter for distinguishing tremor mechanisms. It is possible that changes in membrane kinetics based on the pattern of ion channel expression underlie the differences in tremor in some diseases.

Recognition of category-related visual stimuli in Parkinson's disease: before and after pharmacological treatment.

Visual-sensory dysfunctions and semantic processing impairments are widely reported in Parkinson's disease (PD) research. The present study investigated the category-specific deficit in object recognition as a function of both the semantic category and spatial frequency content of stimuli. In the first experiment, the role of dopamine in object-recognition processing was assessed by comparing PD drug naïve (PD-DN), PD receiving levodopa treatment (PD-LD), and control subjects. Experiment 2 consisted of a retest session for PD drug naïve subjects after a period of pharmacological treatment. All participants completed an identification task which displayed animals and tools at nine levels of filtering. Each object was revealed in a sequence of frames whereby the object was presented at increasingly less-filtered images up to a complete version of the image. Results indicate an impaired identification pattern for PD-DN subjects solely for animal category stimuli. This differential pharmacological therapy effect was also confirmed at retest (experiment 2). Thus, our data suggest that dopaminergic loss has a specific role in category-specific impairment. Two possible hypotheses are discussed that may account for the defective recognition of semantically different objects in PD.

A role for NMDAR-dependent cerebellar plasticity in adaptive control of saccades in humans.

BACKGROUND: Saccade pulse amplitude adaptation is mediated by the dorsal cerebellar vermis and fastigial nucleus. Long-term depression at the parallel fibre-Purkinjie cell synapses has been suggested to provide a cellular mechanism for the corresponding learning process. The mechanisms and sites of this plasticity, however, are still debated. OBJECTIVE: To test the role of cerebellar plasticity phenomena on adaptive saccade control. METHODS: We evaluated the effect of continuous theta burst stimulation (cTBS) over the posterior vermis on saccade amplitude adaptation and spontaneous recovery of the initial response. To further identify the substrate of synaptic plasticity responsible for the observed adaptation impairment, subjects were pre-treated with memantine, an N-methyl-d-aspartate receptor (NMDAR) antagonist. RESULTS: Amplitude adaptation was altered by cTBS, suggesting that cTBS interferes with cerebellar plasticity involved in saccade adaptation. Amplitude adaptation and spontaneous recovery were not affected by cTBS when recordings were preceded by memantine administration. CONCLUSION: The effects of cTBS are NMDAR-dependent and are likely to involve long-term potentiation or long-term depression at specific synaptic connections of the granular and molecular layer, which could effectively take part in cerebellar motor learning.

Involvement of oxidative stress in protocatechuic acid-mediated bacterial lethality.

The involvement of oxidative stress in protocatechuic acid-mediated bacterial lethality was investigated. Minimum inhibitory concentrations (MIC) and minimum bactericidal concentration (MBC) of protocatechuic acid against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus are 600 and 700 µg/ml, 600 and 800 µg/ml, and 600 and 800 µg/ml, respectively. The optical densities and colony-forming units of protocatechuic acid-treated bacteria decreased in time-dependent manner. Protocatechuic acid (4× MIC) significantly increased the superoxide anion content of E. coli, P. aeruginosa, and S. aureus compared to dimethyl sulfoxide (DMSO). Superoxide dismutase, catalase, and NAD+ /NADH in protocatechuic acid-treated E. coli, P. aeruginosa, and S. aureus increased significantly when compared to DMSO. Conversely, level of reduced glutathione decreased in protocatechuic acid-treated E. coli, P. aeruginosa, and S. aureus, while glutathione disulfide increased when compared to DMSO. Furthermore, malondialdehyde and fragmented DNA increased significantly following exposure to protocatechuic acid. Protocatechuic acid inhibited the activity of complexes I and II. From the above findings, protocatechuic acid enhanced the generation of reactive oxygen species (superoxide anion radical and hydroxyl radical) in E. coli, P. aeruginosa, and S. aureus, possibly by autoxidation, fenton chemistry, and inhibiting electron transport chain resulting in lipid peroxidation and DNA fragmentation and consequentially bacterial cell death.

Extraction of traditional COP-based features from COM sway in postural stability evaluation.

Postural control during quiet standing is evaluated by analyzing CoP sway, easily measured using a force platform. However, recent proliferation of motion tracking systems made easily available an estimate of the CoM location. Traditional CoP-based measures presented in literature provide information about age-related changes in postural stability and fall risk. We investigated, on an age-matched group of subjects, the relationship between classical CoP-based measures computed on sway path and statistical mechanics parameters on diffusion plot, with those extracted from CoM time-series. Our purpose is to understand which of these parameters, computed on CoM sway, can discriminate postural abnormalities, in order to use a video tracking system to evaluate balance in addition to motor capabilities.

Conjugate ocular oscillations during shifts of the direction and depth of visual fixation.

PURPOSE: To characterize dynamic properties of combined saccade-vergence eye movements that occur as the point of visual fixation is shifted between objects lying in different directions and at different depths. METHODS: Using the scleral search-coil technique, eye movements were measured in 10 normal subjects as they made voluntary, disjunctive gaze shifts comprising a range of saccades and vergence movements. RESULTS: By analyzing eye acceleration records, the authors identified small-amplitude (0.2-0.7 degrees), high-frequency (23-33 Hz), conjugate horizontal oscillations of the eyes during the vergence movement that followed the initial saccade. When the shift of the fixation point required a large vergence component (17 degrees , every subject showed these oscillations; they were present in approximately a third of responses. Approximately 5% of responses showed oscillations that had horizontal and vertical components. Oscillations were less prominent with shifts that had smaller vergence components and were absent after saccades made between targets located at optical infinity. CONCLUSIONS: These findings suggest that a common mechanism gates both the saccadic and vergence components of disjunctive gaze shifts, a likely candidate being the pontine omnipause neurons. When a saccade is immediately followed by a prolonged vergence movement, the omnipause neurons remain silent, leading to small-amplitude saccadic oscillations. Shifts in the point of visual fixation that require a large vergence movement may be a useful experimental strategy to induce saccadic oscillations.

Translational vestibulo-ocular reflex evoked by a "head heave" stimulus.

The gain and symmetry of vestibulo-ocular reflexes for high-frequency, high-acceleration movements of the head are altered following unilateral vestibular lesions. These changes have been well characterized for rotational head movements (thrusts), and provide reliable markers of dysfunction in individual semicircular canals. Alterations in the vestibulo-ocular reflex (VOR) evoked by lateral, whole-body translations have also been observed. In an approach directed at the development of a bedside test of otolith function, we have recorded (scleral search coil) the VOR evoked by brief, high-acceleration lateral translations (heaves). We delivered these stimuli manually and also developed a "head sled" device that minimizes any rotational contaminating component of the stimulus. Our geometrical analysis of the stimuli enables us to take into account the translational and rotational components of the movement, and to calculate an ideal response required for stabilization of images on the fovea at different fixation distances. We observed a tracking response (visually assisted VOR) that was close to ideal for image stabilization when these methods were used to analyze responses to slow, low-amplitude lateral translations of the head. When applied to rapid, high-acceleration (0.5 g) translations, the VOR was found to be less than compensatory in subjects with normal vestibular function. In a patient with unilateral vestibular hypofunction following intratympanic gentamicin injections, both the rotational and the translational VOR were asymmetric. Responses for translations toward the treated side had lower gain than those for translations toward the normal side. These findings provide a basis for further development of this technique as a clinical test and as a method for quantitative evaluation of otolith function.

Evaluation of upper limb sense of position in healthy individuals and patients after stroke.

The aims of this study were to develop and evaluate reliability of a quantitative assessment tool for upper limb sense of position on the horizontal plane. We evaluated 15 healthy individuals (controls) and 9 stroke patients. A robotic device passively moved one arm of the blindfolded participant who had to actively move his/her opposite hand to the mirror location in the workspace. Upper-limb's position was evaluated by a digital camera. The position of the passive hand was compared with the active hand's 'mirror' position. Performance metrics were then computed to measure the mean absolute errors, error variability, spatial contraction/expansion, and systematic shifts. No significant differences were observed between dominant and non-dominant active arms of controls. All performance parameters of the post-stroke group differed significantly from those of controls. This tool can provide a quantitative measure of upper limb sense of position, therefore allowing detection of changes due to rehabilitation.

A wearable system for measuring limb movements and balance control abilities based on a modular and low-cost inertial unit.

Monitoring balance and movement has proven useful in many applications ranging from fall risk assessment, to quantifying exercise, studying people habits and monitoring the elderly. Here we present a versatile, wearable instrument capable of providing objective measurements of limb movements for the assessment of motor and balance control abilities. The proposed device allows measuring linear accelerations, angular velocities and heading either online, through wireless connection to a computer, or for long-term monitoring, thanks to its local storage abilities. One or more body parts may be simultaneously monitored in a single or multiple sensors configuration.

Affordable, automatic quantitative fall risk assessment based on clinical balance scales and Kinect data.

The problem of a correct fall risk assessment is becoming more and more critical with the ageing of the population. In spite of the available approaches allowing a quantitative analysis of the human movement control system's performance, the clinical assessment and diagnostic approach to fall risk assessment still relies mostly on non-quantitative exams, such as clinical scales. This work documents our current effort to develop a novel method to assess balance control abilities through a system implementing an automatic evaluation of exercises drawn from balance assessment scales. Our aim is to overcome the classical limits characterizing these scales i.e. limited granularity and inter-/intra-examiner reliability, to obtain objective scores and more detailed information allowing to predict fall risk. We used Microsoft Kinect to record subjects' movements while performing challenging exercises drawn from clinical balance scales. We then computed a set of parameters quantifying the execution of the exercises and fed them to a supervised classifier to perform a classification based on the clinical score. We obtained a good accuracy (~82%) and especially a high sensitivity (~83%).

Alternative normalization methods demonstrate widespread cortical hypometabolism in untreated de novo Parkinson's disease.

AIM: Previous positron emission tomography (PET) [18F]fluorodeoxyglucose ([18F]FDG) studies in Parkinson's disease (PD) demonstrated that moderate to late stage patients display widespread cortical hypometabolism, whereas early stage PD patients exhibit little or no cortical changes. However, recent studies suggested that conventional data normalization procedures may not always be valid, and demonstrated that alternative normalization strategies better allow detection of low magnitude changes. We hypothesized that these alternative normalization procedures would disclose more widespread metabolic alterations in de novo PD. METHODS: [18F]FDG PET scans of 26 untreated de novo PD patients (Hoehn & Yahr stage I-II) and 21 age-matched controls were compared using voxel-based analysis. Normalization was performed using gray matter (GM), white matter (WM) reference regions and Yakushev normalization. RESULTS: Compared to GM normalization, WM and Yakushev normalization procedures disclosed much larger cortical regions of relative hypometabolism in the PD group with extensive involvement of frontal and parieto-temporal-occipital cortices, and several subcortical structures. Furthermore, in the WM and Yakushev normalized analyses, stage II patients displayed more prominent cortical hypometabolism than did stage I patients. CONCLUSION: The use of alternative normalization procedures, other than GM, suggests that much more extensive cortical hypometabolism is present in untreated de novo PD patients than hitherto reported. The finding may have implications for our understanding of the basic pathophysiology of early-stage PD.

The relationship between cerebral vascular disease and parkinsonism: The VADO study.

BACKGROUND: The observation of gait abnormalities, parkinsonism and vascular lesions in elderly patients is often reported as vascular parkinsonism (VP). However the status of striatal dopamine transporter (DAT) and the effects of brain vascular lesions on motor features and levodopa responsiveness are poorly defined. METHODS: We recorded clinical features, chronic response to levodopa and vascular risk factors in a cross-sectional cohort of consecutive elderly patients with possible Parkinson's disease (PD) or VP recruited in 20 centers in Italy. RESULTS: We included a total of 158 patients. Onset of motor symptoms was asymmetric in 93 (59%) and symmetric in 65 patients (41%). Symmetric motor onset was associated with greater disease severity. Chronic levodopa response was positive in 75 (47.8%) and negative in 82 patients (52.2%). A negative response to levodopa was associated with greater frequency of symmetric onset of motor symptoms, worst disease severity, absence of dyskinesia and greater number of vascular risk factors. Frontal lobe showed largest vascular load. Striatal DAT was normal in 48 (30.4%) and abnormal in 110 (69.6%) patients. Patients with normal DAT binding showed higher vascular load at MRI. Significant predictive factors of worst disease severity and negative response to levodopa were hypertension, vascular lesions in basal ganglia/periventricular regions, and normal DAT uptake. CONCLUSIONS: Multiple cerebral vascular lesions modify clinical presentation and severity in patients with parkinsonism and this is underlined by specific risk factors primarily hypertension. Striatal DAT assessment is helpful in identifying patients where therapy benefit is less likely.

A software program for the head impulse testing device (HITD).

The vestibulo-ocular reflex (VOR) uses head angular acceleration information transduced by the semicircular canals in the inner ear in order to drive eye movements that compensate for head rotations, and thus stabilize the visual scene on the retina. Peripheral and central vestibular pathologies may impair the function of the VOR, so that compensation becomes incomplete, making clear vision during head movement impossible. Powerful adaptive mechanisms quickly allow the central nervous system to use residual vestibular information or information provided through other senses to supplement the deficient VOR. Such recovery makes the clinical diagnosis difficult to classical testing techniques, yet the head impulse test allows to reveal vestibular deficits even in adapted patients. A compensatory saccade at the end of the head movement is the clinical sign of a vestibular deficit, and may be spotted by the experienced clinician. Here we describe the rationale and the software program driving a new computerized technique for reliably assessing vestibular function at different head angular accelerations, based on evaluating the ability of the patient in reading a character on the screen while the head is being rotated.