Kinematic evaluation in Parkinson's disease using a hand-held position transducer and computerized signal analysis.

BACKGROUND: The objective of this work was to develop a device for quantification of akinesia in Parkinson's disease, for the use in home monitoring of PD patients, as a part of home telecare programs. For this purpose a simple movement task is to be preferred, and the measurement devices must be small, lightweight, and easy to use, so patients may perform the measurements unattended. Another intended application was optimisation of the electrode position during implantations of neuromodulation systems for treatment of Parkinson. METHOD: A hand held transducer was used to measure the position of the thumb while the patient repeatedly flexed and extended the thumb. The position data was sampled and stored on a personal computer with a plug in converter card and software. Measurements were performed on 15 PD patients and 6 age-matched controls. Signal analysis procedures were developed in order to automatically derive numerical parameters that quantify the movement performance. In order to select the most relevant parameters, they were correlated to Unified Parkinson Disease Rating Scale (UPDRS) motor scores (Spearman's rank, single sided, p < 0.05). FINDINGS: In reviews of the raw position signals the amplitude and frequency was found to be lower in patients than in controls. In patients the movement was frequently interrupted by short periods of hesitation. The calculated parameters of covered distance (correlation coefficient r = -0.63), hesitation (r = 0.64) and frequency (r = -0.6) were found to be most relevant, as they correlated best to the UPDRS hand pronation/supination score. DISCUSSION: The equipment proved to be fast to setup and easy to use. The signal analysis methods provided meaningful numerical parameters for quantification of akinesia, represented in hand pronation/supination. These results suggest that the described methods may be useful for telemedicine and intraoperative use.

Mirtazapine increases cortical excitability in healthy controls and epilepsy patients with major depression.

BACKGROUND: Epilepsy is often complicated by depression requiring antidepressant treatment. Such treatment might be proconvulsive. OBJECTIVE: To examine the effects of the noradrenergic and specific serotonergic antidepressant mirtazapine on motor cortex excitability in epilepsy patients with depression and in healthy controls, using transcranial magnetic stimulation (TMS). METHODS: Seven clinically depressed epilepsy patients treated with anticonvulsant drugs and six healthy volunteers were studied. Before intake of mirtazapine and 24 hours afterwards (and also three weeks afterwards in the patients), the active and resting motor threshold (AMT, RMT), the size of the motor evoked potential (MEP), the cortical silent period (SP), and intracortical inhibition/facilitation and intracortical facilitatory I wave interactions were determined using single and paired pulse TMS. RESULTS: At baseline, AMT and RMT were higher (p = 0.049 and p = 0.04, respectively) and the ratio SP duration/MEP area greater in patients (p = 0.041). In patients but not in healthy subjects AMT was lower 24 hours after intake of mirtazapine (p = 0.028). Mirtazapine had no significant effect on the MEP size, duration of the SP, or the ratio of SP duration to MEP size in patients. The duration of the SP was longer (p = 0.037) but the ratio of SP duration to MEP size remained similar in healthy subjects after mirtazapine. There were no significant differences in paired pulse measures between the two groups either at baseline or after mirtazapine. CONCLUSIONS: Mirtazapine increased neuronal excitability of pyramidal tract axons in an activated state in both healthy controls and epilepsy patients with major depression.

Quality of life in patients with orthostatic tremor.

We assessed health-related quality of life (QoL) and depression, using the SF-36 and the Beck Depression Inventory (BDI), in 20 orthostatic tremor (OT) patients. All dimensions of the SF-36 were markedly reduced in OT and depression was found in 11 patients. The BDI score correlated significantly with several SF-36 subscores. We conclude that OT strongly impacts on QoL. The results highlight the importance of recognizing and treating depression in patients with OT.

rTMS over the cerebellum can increase corticospinal excitability through a spinal mechanism involving activation of peripheral nerve fibres.

OBJECTIVES: Single-pulse transcranial magnetic stimulation (TMS) over the cerebellum affects corticospinal excitability by a cerebellar and a peripheral mechanism. We have investigated whether any of the long-lasting effects of repetitive TMS (rTMS) over cerebellum can also be attributed to peripheral effects. METHODS: Five hundred conditioning stimuli at 1 Hz were given over either the right cerebellum using a double-cone coil, or over the right posterior neck using a figure-8-coil. Corticospinal excitability was assessed by measuring the amplitude of motor evoked potentials (MEPs) evoked in the right and left hand and forearm muscles. Hoffman reflexes (H-reflex) were also obtained in the right flexor carpi radialis muscle. RESULTS: rTMS over either the right cerebellum or the right posterior neck significantly facilitated MEPs in hand and forearm muscles in the right but not in the left arm (n=8) for up to 30 min after the end of the train. rTMS (1 Hz) of the right neck area increased the amplitude of the H-reflex (n=5). CONCLUSIONS: Much of the persisting effects of rTMS over the cerebellum on corticospinal excitability appear to be mediated through stimulation of peripheral rather than central structures. Moreover, the results show that rTMS over peripheral areas can cause long-lasting changes in spinal reflexes.

Are the after-effects of low-frequency rTMS on motor cortex excitability due to changes in the efficacy of cortical synapses?

OBJECTIVES: To investigate the mechanisms responsible for suppressing the amplitude of electromyogram (EMG) responses to a standard transcranial magnetic stimulus (TMS) after prior conditioning of the motor cortex with repetitive subthreshold TMS (rTMS) at a frequency of 1 Hz. METHODS: EMG responses from the first dorsal interosseous, abductor pollicis brevis and flexor carpi radialis (FCR) muscles were recorded after suprathreshold TMS of the motor cortex. In some experiments, H-reflexes were also obtained in the FCR. The amplitude of these responses was compared before and after applying from 150 to 1500 rTMS pulses to motor cortex at an intensity of 95% resting motor threshold through the same figure-of-8 coil. RESULTS: When tested with subjects relaxed, rTMS conditioning reduced the amplitude of motor evoked potentials (MEPs) to approximately 60% of pre-conditioning values for 2-10 min after the end of the conditioning train, depending on the number of pulses in the train. There was more suppression with 1500 rTMS pulses than with 150 pulses. There was no effect on H-reflexes. There was no effect on MEPs if the test stimuli were given during active contraction of the target muscle. CONCLUSIONS: The findings confirm previous observations that low-frequency, low-intensity rTMS to motor cortex can produce transient depression of MEP excitability. Since there was no effect on spinal H-reflexes, this is consistent with the idea that some of the suppression occurs because of an effect on the motor cortex itself. The lack of any conditioning effect on MEPs evoked in actively contracting muscle is not readily consistent with the idea that rTMS depresses transmission in synaptic connections to pyramidal cells activated by the test TMS pulse. An alternative explanation is that rTMS reduces the excitability of cortical neurones in relaxed subjects, so that responses to a given input are smaller than before conditioning. Voluntary contraction normalises excitability levels so that the effect is no longer seen.

Decreased corticospinal excitability after subthreshold 1 Hz rTMS over lateral premotor cortex.

OBJECTIVE: To study whether trains of subthreshold 1 Hz repetitive transcranial magnetic stimulation (rTMS) over premotor, prefrontal, or parietal cortex can produce changes in excitability of motor cortex that outlast the application of the train. BACKGROUND: Prolonged 1 Hz rTMS over the motor cortex can suppress the amplitude of motor-evoked potentials (MEP) for several minutes after the end of the train. Because TMS can produce effects not only at the site of stimulation but also at distant sites to which it projects, the authors asked whether prolonged stimulation of sites distant but connected to motor cortex can also lead to lasting changes in MEP. METHODS: Eight subjects received 1500 magnetic stimuli given at 1 Hz over the left lateral frontal cortex, the left lateral premotor cortex, the hand area of the left motor cortex, and the left anterior parietal cortex on four separate days. Stimulus intensity was set at 90% active motor threshold. Corticospinal excitability was probed by measuring the amplitude of MEP evoked in the right first dorsal interosseous muscle by single suprathreshold stimuli over the left motor hand area before, during, and after the conditioning trains. RESULTS: rTMS over the left premotor cortex suppressed the amplitude of MEP in the right first dorsal interosseous muscle. The effect was maximized (approximately 50% suppression) after 900 pulses and outlasted the full train of 1500 stimuli for at least 15 minutes. Conditioning rTMS over the other sites did not modify the size of MEP. A control experiment showed that left premotor cortex conditioning had no effect on MEP evoked in the left first dorsal interosseous muscle. CONCLUSIONS: Subthreshold 1 Hz rTMS of the left premotor cortex induces a short-lasting inhibition of corticospinal excitability in the hand area of the ipsilateral motor cortex. This may provide a model for studying the functional interaction between premotor and motor cortex in healthy subjects and patients with movement disorders.

Falls in the elderly. I. Identification of risk factors.

Falls severely threaten the health of elderly persons and pose high costs to the public health service. Unfortunately, falls are often regarded as unavoidable and untreatable features of aging. Therefore, many clinicians merely treat the physical injuries of a fall. However, falls and gait limitations are markers of underlying (sometimes otherwise subclinical) diseases that can be amenable to treatment. Moreover, falls and gait limitations herald the onset of repeated falls, physical decline, serious psychosocial consequences and a reduced survival. We review how clinically relevant risk factors can be traced by reviewing the medical notes, by careful history taking and by physical examination. The identified risk factors can serve as a template for the design of prevention strategies, which are discussed in the companion article.

Falls in the elderly. II. Strategies for prevention.

In the companion paper, we have outlined how relevant risk factors for falls can be identified using a systematic approach. Once identified, the underlying diseases and pattern of (usually multiple) risk factors guides the design of an individually tailored intervention program. Such intervention programs follow one or more of the following goals: (a) to treat the underlying disease; (b) to reduce or even eliminate the number of falls; (c) to prevent or minimise the associated injuries; and (d) tertiary prevention of fall-related disability, including immobilisation, muscle weakness, reduced fitness, osteoporosis, fear of falling and mortality. The successful results of various intervention studies underscores that falls should be regarded as a potentially treatable disorder in elderly persons. Such knowledge is important for clinicians, which could apply prevention strategies to individual patients with risk factors that are strongly associated with falls. In addition, prevention is important for health policy makers who aim to reduce falls in the general population by reducing or eliminating commonly present risk factors (even if they are only weakly associated with falls).

Bilateral subthalamic nucleus stimulation does not improve prolonged P300 latencies in Parkinson's disease.

Bilateral deep brain stimulation is an effective treatment for most motor signs of Parkinson's disease (PD), but the effects on cognitive functions are less clear. We therefore examined the effects of bilateral deep brain stimulation on central information processing, using the event-related auditory P300 potential as an electrophysiological index of mental chronometry. Eight PD patients with bilateral stimulators within the subthalamic nuclei (STN) and eight age-matched controls participated. Patients were examined after overnight withdrawal of antiparkinson medication, both "on" and "off" stimulation (in random sequence). The P300 and reaction times were recorded using an auditory oddball paradigm. P300 latencies were prolonged in PD patients off stimulation (440 +/- 45 ms) compared to controls (397 +/- 16 ms; P < 0.05). STN stimulation significantly reduced clinical disease severity (as indexed by the Unified Parkinson's Disease Rating Scale) and markedly improved reaction times, but did not improve the prolonged P300 latencies in PD patients (429 +/- 36 ms). These results confirm that P300 latencies are prolonged in PD. Significantly, bilateral STN stimulation did not improve this electrophysiological measure of cognitive impairment, even though motor disability was markedly reduced. This suggests that some dopa-responsive features are resistant to STN stimulation, possibly due to involvement of dopaminergic deficits outside the nigrostriatal pathway, which are not influenced by outflow from the STN.

[123I]beta-CIT SPECT in multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration.

Differentiation between Parkinson's disease (PD) and other neurodegenerative disorders with parkinsonian features, such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), is difficult on clinical grounds. We studied the pattern of dopaminergic degeneration in 18 patients with probable MSA, 8 patients with PSP, 4 patients with CBD, 48 patients with PD and a similar degree of disability, and 14 control subjects performing single photon emission computed tomography (SPECT) 20 hours after injection of [123I]beta-CIT. Overall striatal binding was significantly reduced in MSA (-51% of normal mean), PSP (-60%), CBD (-35%), and PD (-58%), without overlap with control values. Asymmetry of striatal beta-CIT binding was significantly increased in patients with CBD and PD, as compared with control subjects. Although asymmetry seemed to be less pronounced in MSA and PSP than in PD, this was not statistically significant. Putamen-caudate nucleus ratios in patients with PD, MSA, and PSP, but not with CBD, were significantly reduced, as compared with control subjects. In conclusion, [123I]beta-CIT SPECT reliably enables the visualization of the presynaptic dopaminergic lesion in patients with MSA, PSP, and CBD. In most patients, however, it does not seem to be possible to differentiate these disorders from PD with this method.

Electrophysiological, neuropsychological and clinical findings in multiple sclerosis patients receiving interferon beta-1b: a 1-year follow-up.

We assessed serial event-related potentials (ERPs) as well as neuropsychological and clinical test findings in a group of multiple sclerosis (MS) patients (n = 14) treated with interferon beta-1b (INF-beta-1b) compared to normal controls (n = 14). All investigations were done within 1 week before INF-beta-1b therapy was started and 12 months later. An auditory oddball paradigm was employed. No significant differences in the N100, P200, N200 or P300 latencies between patients and control group were found, but 3 out of 14 MS patients developed abnormal P300 latencies (more than 2 standard errors from the mean) after 1 year of INF-beta-1b therapy. This was not reflected by the respective neurological impairment as assessed by the Expanded Disability Status Scale score. ERPs might be a useful tool in clinical studies in order to evaluate drug effects on cognition, but for a final statement, the analysis of ERPs in a larger group of patients is required.

Bilateral subthalamic nucleus stimulation improves frontal cortex function in Parkinson's disease. An electrophysiological study of the contingent negative variation.

Parkinson's disease involves impaired activation of frontal cortical areas, including the supplementary motor area and prefrontal cortex, resulting from impaired thalamocortical output of the basal ganglia. Electrophysiologically, such impaired cortical activation may be seen as a reduced amplitude of the contingent negative variation (CNV), a slow negative potential shift reflecting cognitive processes associated with the preparation and/or anticipation of a response. Surgical interventions aimed at increasing basal ganglia-thalamic outflow to the cortex, such as electrical stimulation of the subthalamic nucleus with chronically implanted electrodes, have been shown to be effective in improving the clinical symptoms of Parkinson's disease. This study examined changes in cortical activity, as reflected in the CNV, associated with bilateral subthalamic nucleus stimulation in Parkinson's disease. The CNV was recorded from 10 patients with Parkinson's disease when on and off bilateral subthalamic nucleus stimulation, and was compared with the CNV of 10 healthy control subjects. Without subthalamic nucleus stimulation, Parkinson's disease patients showed reduced CNV amplitudes over the frontal and frontocentral regions compared with control subjects. With bilateral subthalamic nucleus stimulation, however, CNV amplitudes over the frontal and frontocentral regions were significantly increased. Results therefore suggest that impaired cortical functioning in Parkinson's disease, particularly within the frontal and premotor areas, is improved by subthalamic nucleus stimulation.

Language-related hemispheric asymmetry in healthy subjects and patients with temporal lobe epilepsy as studied by event-related brain potentials and intracarotid amobarbital test.

There are current attempts to replace the WADA test for pre-surgical evaluation of hemispheric language capabilities by one of the methods of functional brain imaging. Recent PET and fMRI studies using verbal cognitive tasks like verb generation, semantic monitoring or semantic ('deep') encoding of words showed asymmetries of activation in the fronto-lateral cortex. In a previous ERP study subjects were required to indicate whether pronounceable non-words and abstract geometric figures were presented for the first time ('new item') or whether they had been shown before ('old item'). Group analyses of this study showed significant material-specific hemispheric asymmetries with ERPs being more negative-going in recordings of the posterior part of the left hemisphere with verbal material (CP5/6) but more negative-going in recordings of the right hemisphere with the spatial material (P7/8). The aim of the present study was to test statistically ERP lateralization effects in individual healthy subjects as well as WADA-tested patients suffering from seizures of the mesio-temporal lobe (MTL). In all subjects ERP lateralization with verbal material was tested in the electrode pair CP5/6, and ERP lateralization with figures in the electrode pair P7/8. Statistical analyses of single trials showed that in 20 out of 24 subjects ERPs with verbal material started to be more negative-going in CP5 as compared to CP6 in the period between 100 and 200 ms after stimulus onset or the subsequent time epoch (200-300 ms). In one subject not CP5/6 but the closely adjacent electrode pair P7/P8 showed this verbal material-related hemispheric effect. In patients language dominance as indicated by ERPs was not always consistent with the data of the WADA test. In one patient with left MTL seizures ERPs with verbal material and figures were found to be significantly lateralized to the right hemisphere although the WADA test assigned this patient to have a language-dominant left hemisphere.

Event-related potentials in patients with temporal lobe epilepsy reveal topography specific lateralization in relation to the side of the epileptic focus.

Event-related potentials (ERPs) were recorded during a continuous recognition memory paradigm in patients with left-sided (LTLE; n = 8) or right-sided temporal lobe epilepsy (RTLE; n = 6), and in healthy control subjects (n = 24). Control subjects and both patient groups exhibited consistent OLD/NEW ERP-differences from 200-600 ms after stimulus onset. ERPs did not differ significantly between LTLE and RTLE patients, with respect to OLD/NEW distinction or the type of presented material (verbal vs. non-verbal). However, ERP topography showed significant differences between LTLE and RTLE patients: in lateral fronto-temporal recordings, patients showed larger negativities contralateral to the seizure focus, whereas we found larger negativities ipsilateral to the seizure focus in parietal recordings. Differences between the groups were significant from 300 to 600 ms post-stimulus. As a consequence, the amplitude gradient from fronto-temporal to parietal recordings was higher on the right side in LTLE patients and on the left side in RTLE patients. Again, differences between LTLE and RTLE patients were highly significant. We assume that ERPs reflect disturbances of a cortico-cortical network dependent on the side of the seizure focus in temporal lobe epilepsy. Furthermore, scalp-recorded ERPs might be a useful tool in the prediction of the side of the seizure focus in patients with temporal lobe epilepsy.

Long-term follow-up in cerebral Whipple's disease.

OBJECTIVE: To evaluate the long-term outcome in patients with cerebral Whipple's disease. PATIENTS: We reviewed the literature and contacted authors who had reported on cerebral Whipple's disease within the last 10 years. Fifteen patients were evaluated, including one patient treated at our hospital and the one presented in this paper. The mean observation period was 41 +/- 37 months (minimum 1 month, maximum 120 months). RESULTS: Four patients had improved and were able to pursue an independent lifestyle, three patients had improved but are still dependent on help with simple activities of daily life, one patient was unchanged, and seven patients had died. Patients with initial penicillin alone had a worse prognosis than patients with initial penicillin plus streptomycin. CONCLUSION: Third generation cephalosporins have been shown to be beneficial in cerebral Whipple's disease, therefore initial antibiotic treatment of Whipple's disease should consist of ceftriaxone (instead of penicillin) combined with streptomycin. Since five of 12 patients (40%) treated with co-trimoxazole (trimethoprim plus sulphamethoxazole) did not respond, we conclude that the combination of trimethoprim and sulphamethoxazole does not prevent or cure central nervous system (CNS) involvement in all patients with Whipple's disease. If CNS relapse occurs during treatment with trimethoprim and sulphamethoxazole, oral third generation cephalosporins might be a useful alternative.

Electric and magnetic fields of the brain accompanying internal simulation of movement.

Methods of functional brain imaging have been used to identify brain structures which are active during internal simulation of movements (ISM). Between 1977 and 1993 it was consistently reported that the primary motor cortex (MI) is not active during ISM whereas other cortical areas, in particular the supplementary motor area (SMA) are active. ISM was assumed to be a situation of "internal programming'. Brain systems involved in ISM or 'programming' were hypothesized to be superior to and separable from 'executive system' including MI. We have studied electric and magnetic fields of the brain when subjects internally simulated either a single movement or a sequence of movements. Results of the studies are consistent with the assumption that MI is active with ISM. Internally subjects experienced effort which was required to inhibit overt movements during ISM. A recent EEG study showed different patterns of cortical activity with ISM and with movement inhibition suggesting that different brain structures may be active during ISM and movement inhibition [23].

Effects of neuropeptide Y and vasoactive intestinal peptide on human venous smooth muscle in vivo.

The direct and noradrenaline-modulating effects of neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP) on venous smooth muscle were studied in healthy volunteers employing the dorsal hand vein compliance technique. Local infusions of NPY had no measurable effect on venous tone, but coinfusion of a constant high dose of NPY (242 pmol/min) with noradrenaline caused a 2.9-fold increase in the mean ED50 for noradrenaline. The dilating effect of VIP on preconstricted hand veins was weak, maximal venodilation could not be achieved, because systemic side effects occurred at submaximally venodilating doses. Coinfusion of noradrenaline with a weakly venodilating, constant dose of VIP (93.2 pmol/min) caused a 0.5-fold decrease in the sensitivity for noradrenaline. Although functional interactions between NPY or VIP and noradrenaline could be demonstrated, the dosages of the peptides required were high. Thus our results indicate that neither NPY nor VIP exert a major direct or noradrenaline-modulating effect on human veins.