A longitudinal study of tremor frequencies in Parkinson's disease and essential tremor.

OBJECTIVE: There is evidence that the tremor frequency in essential tremor (ET) decreases with time. Longitudinal studies on the evolution of tremor frequencies in Parkinson's disease (PD) have so far not been published. Here, we present a longitudinal analysis of tremor frequencies in PD and ET. METHODS: We analyzed the standardized accelerometric and electromyographic tremor recordings of 53 patients with PD and 38 patients with ET who underwent repeated routine tremor recordings between 1991 and 2002. RESULTS: In an average follow-up period of 44.9 months in PD and 50.6 months in ET, the average number of tremor recordings was 3.3 in PD and 3.7 in ET. In both disorders, tremor frequencies tended to decrease with time. The average annual decrease of the tremor frequency was 0.09 Hz/year in Parkinsonian rest tremor, 0.08 Hz/year in Parkinsonian postural tremor and 0.12 Hz/year in ET. CONCLUSIONS: The tremor frequency decreases with time in both PD and ET. The similarity of this decrease in PD and ET may point to a common underlying pathophysiological mechanism. SIGNIFICANCE: Decreasing tremor frequencies with time may be functionally important by inducing larger tremor amplitudes due to the low-pass filtering properties of muscles and limbs.

On studentising and blocklength selection for the bootstrap on time series.

For independent data, non-parametric bootstrap is realised by resampling the data with replacement. This approach fails for dependent data such as time series. If the data generating process is at least stationary and mixing, the blockwise bootstrap by drawing subsamples or blocks of the data saves the concept. For the blockwise bootstrap a blocklength has to be selected. We propose a method for selecting the optimal blocklength. To improve the finite size properties of the blockwise bootstrap, studentised statistics is considered. If the statistic can be represented as a smooth function model this studentisation can be approximated efficiently. The studentised blockwise bootstrap method is applied for testing hypotheses on medical time series.

The effect of carpal tunnel release on median nerve flattening and nerve conduction.

Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy and extensive surveys have been given on the time course of electrophysiological findings pre- and postoperatively. In patients with clinical and electrophysiological confirmed diagnosis of CTS surgical decompression of the carpal tunnel is a first line treatment and has proven to be successfull in 70 to 90% of all cases. The objective of this work was to study the morphological changes of the median nerve after endoscopic release of the carpal tunnel. We used high resolution ultrasound to quantify flattening of the median nerve and to calculate a flattening ratio before endoscopic release as well as 2 weeks and 3 months postoperatively. Ten patients with clinical and electrophysiological confirmed CTS were included in the study. There was significant normalization of the calculated flattening ratio of the median nerve already 2 weeks after surgical release, whereas nerve conduction studies needed a longer period of time to normalize and thus were still abnormal 3 months postoperatively. We conclude that ultrasound is a simple and excellent objective method for visualizing the morphological recovery of the median nerve very early after decompression surgery. In complex cases with unsatisfactory outcome ultrasonography may prove useful in confirming successfull or failed decompression of the median nerve.

Tremor analysis in two normal cohorts.

OBJECTIVE: Quantitative tremor analyses using almost identical methods were compared between two independent large normal cohorts, to separate robust measures that may readily be used diagnostically from more critical ones needing lab-specific normalization. METHODS: Hand accelerometry and surface EMG from forearm flexors and extensors were recorded with (500 and 1000 g) and without weight loading under postural conditions in 117 and 67 normal volunteers in two different specialty centers for movement disorders in Germany. RESULTS: Tremor amplitude (total power) and frequency fell within a similar range but differed significantly. A significant reduction of tremor frequency under 1000 g weight load (>1 Hz), and a lack of rhythmic EMG activity at the tremor frequency in around 85-90% of the recordings were robust findings in both centers. CONCLUSIONS: The differences in frequency and total power indicate that these measures critically depend on the details of the recording conditions being slightly different between the two centers. Thus each lab needs to establish its own normative data. We estimate that at least 25 normal subjects have to be recorded to obtain normal values. The reduction of tremor frequency under load and lacking tremor-related EMG activity were well reproducible allowing a differentiation of physiological from low amplitude pathological tremor. SIGNIFICANCE: This study provides a framework for more standardized tremor analyses in clinical neurophysiology.

Dynamic synchronisation of central oscillators in essential tremor.

OBJECTIVE: Coherence analysis of electromyography (EMG) signals in essential tremor (ET) suggests that tremor in the right and left arm is induced by independent central oscillators. The sensorimotor cortex seems to be part of the tremor-generating neuronal network in ET. Here, we investigated using electroencephalography (EEG) whether the independence of central oscillators in ET is supported by the analysis of cortical activity. METHODS: In 8 patients with ET, bilateral hand tremor was activated by wrist extension. EMGs from the wrist flexors and extensors were recorded simultaneously with an EEG. EEG-EMG coherence was estimated for 74 epochs of 60 s duration. RESULTS: In 42.6% of the cases, EEG-EMG coherence at the tremor frequency existed only with the contralateral sensorimotor cortex. However, 21.6% of the tremor-EMGs were coherent with EEG activity over both the contralateral and ipsilateral sensorimotor cortex. Bilateral and exclusively contralateral EEG-EMG coherence could alternate within the same recording. Bilateral EEG-EMG coherence was associated with increased right-left EEG-EEG coherence, increased right-left EMG-EMG coherence as well as with increased tremor strength. CONCLUSIONS: In ET, central oscillators in the right and left brain are not entirely independent of each other. They may dynamically synchronise, presumably by interhemispheric coupling via the corpus callosum.

Effect of chronic bilateral subthalamic nucleus (STN) stimulation on postural control in Parkinson's disease.

Postural instability is one of the most incapacitating factors in Parkinson's disease (PD). The underlying deficits and the effects of treatment are still not well understood. The aims of the present study were: (i) to identify abnormalities of postural control in PD patients during unperturbed stance and externally perturbed stance (anterior-posterior tilts of the support surface and of the visual scene); (ii) to assess the effects of L-dopa medication and subthalamic nucleus (STN) stimulation on posture control; and (iii) to characterize potential differential or additive effects of both treatments. Eight PD patients under chronic STN stimulation were investigated and compared with 10 normal controls. The assessment was performed in a crossover design (+/- STN stimulation, +/- L-dopa). During unperturbed stance, we recorded measures of spontaneous sway in terms of displacement, velocity and frequency of the centre of pressure (COP), lower body (LB) and upper body (UB) excursions. In addition, inter-segmental UB-LB coupling was investigated as a measure of axial stiffness. All these measures were abnormally large in patients OFF treatment. Under L-dopa treatment, the velocity, frequency and coupling measures were reduced, whereas sway amplitude increased. Very similar effects were obtained under STN stimulation, and these effects became more pronounced in the combined treatment condition. In these data, reduction of inter-segmental coupling correlated with increase in sway amplitude. The finding suggests that axial stiffness reduction under treatment revealed a treatment- resistant deficit in the sensorimotor postural control loop. However, these two effects did not correlate with the motor subscores of the unified Parkinson's disease rating scale (UPDRS), which indicates that they are of minor functional relevance for posture control. A frequency peak in the COP excursions at 0.7-1.1 Hz, which we take to indicate a resonance behaviour of the postural control loop, became reduced under therapy. The reduction of this peak did correlate with most improvements in the UPDRS under therapy. Support surface tilt revealed that an UB righting on the LB segment, which is present in normal controls, is missing in the patients. The postural responses to visual tilt were abnormally large in patients, independent of whether the support was stable or slightly moving, while the control subjects clearly profited from a stable support. This finding suggests that PD patients lack the ability of normal subjects to use sensory or cognitive information when suppressing the destabilizing effect of visual tilt. These abnormal tilt reactions of the patients were resistant to treatment with L-dopa, STN stimulation and a combination of the two. Overall, the effects of STN stimulation on posture control essentially paralleled those of L-dopa during both unperturbed and externally perturbed stance.

Estimation of delay times in biological systems.

The problem of delay time estimation in biological systems is addressed with the focus on practical applicability of methods. Four delay time estimators are described: a cross correlation method and three increasingly sophisticated interpretations of the phase spectrum, ranging from a pointwise interpretation of the phase spectrum in terms of a delay to a Hilbert transform method. The four methods are compared through simulation studies showing that, in general, the Hilbert transform method performs best. The methods are then used to estimate delay times in three physiological systems: vestibular stimulation, cerebral autoregulation, and human orthostatic tremor. In all three cases, the Hilbert transform method yields the best results, leading in some cases to physiologically more sensible interpretations of experiments than the other methods.

Essential tremor and cerebellar dysfunction: abnormal ballistic movements.

BACKGROUND: Clinical characteristics reminiscent of cerebellar tremor occur in patients with advanced essential tremor. Ballistic movements are known to be abnormal in cerebellar disease. The hypothesis was proposed that ballistic movements are abnormal in essential tremor, reflecting cerebellar dysfunction. OBJECTIVE: To elucidate the role of the cerebellum in the pathophysiology of essential tremor. METHODS: Kinematic parameters and the triphasic electromyographic (EMG) components of ballistic flexion elbow movements were analysed in patients assigned to the following groups: healthy controls (n = 14), pure essential postural tremor (ET(PT); n = 17), and essential tremor with an additional intention tremor component (ET(IT); n = 15). RESULTS: The main findings were a delayed second agonist burst (AG(2)) and a relatively shortened deceleration phase compared with acceleration in both the essential tremor groups. These abnormalities were most pronounced in the ET(IT) group, which had additional prolongation of the first agonist burst (AG(1)) and a delayed antagonist burst (ANT). CONCLUSIONS: Abnormalities of the triphasic pattern and kinematic parameters are consistent with a disturbed cerebellar timing function in essential tremor. These abnormalities were most pronounced in the ET(IT) group. The cerebellar dysfunction in essential tremor could indicate a basic pathophysiological mechanism underlying this disorder. ET(PT) and ET(IT) may represent two expressions within a continuous spectrum of cerebellar dysfunction in relation to the timing of muscle activation during voluntary movements.

Hyperglycemia in patients with focal cerebral ischemia after intravenous thrombolysis: influence on clinical outcome and infarct size.

The aim of the present prospective study was to investigate whether hyperglycemia influences the clinical outcome or the infarct size after intravenous thrombolysis of focal cerebral ischemia. A consecutive series of hyperglycemic (n = 14) and normoglycemic patients (n = 17) with acute focal cerebral ischemia (<3 h) in the middle cerebral artery (MCA) territory received rtPA (0.9 mg/kg body weight) intravenously. Clinical outcome was measured using the NIH Stroke Score on admission and was followed up until day 28. Infarct volume was measured by diffusion-weighted MR imaging on admission, on days 3 and 7. There was a significantly better neurological outcome on day 28 in the normoglycemic patients than in the hyperglycemic group (NIH SS 4.0 versus 7.4; p < 0.05). The infarction volume increased significantly in the hyperglycemic patients Delta = 39.9 plus minus 17.4% compared to normoglycemic patients Delta = 27.1 plus minus 14.1% (p < 0.05). The present study suggests that hyperglycemia in patients with a focal MCA ischemia can cause a worse clinical outcome despite recanalization of the occluded vessel by thrombolysis therapy. This correlates with a markedly larger increase of the infarction volume in the hyperglycemic group. These results may be explained by an accentuated lactate accumulation and pH decrease by elevated energy levels which cannot be compensated by restoration of blood flow alone.

Up-regulation of D3 dopaminergic receptor mRNA in the core of the nucleus accumbens accompanies the development of seizures in a genetic model of absence-epilepsy in the rat.

The basal ganglia system is thought to play a key role in the control of absence-seizures and there is ample evidence that epileptic seizures modify brain dopamine function. We recently reported that local injections of dopamine D1 or D2 agonists in the core of the nucleus accumbens suppressed absence-seizures in a spontaneous, genetic rodent model of absence-epilepsy whereas injections of D1 or D2 antagonists had aggravating effects. These findings raised the possibility that the dopaminergic system may be altered in absence-epilepsy prone rats. Therefore, we studied by in situ hybridization histochemistry the expression of pre- and postsynaptic components of the dopaminergic system in this strain of rats. When compared to non-epileptic control rats, epileptic rats displayed no change in the expression of mRNAs coding for the neuronal dopaminergic markers (tyrosine hydroxylase, membraneous and vesicular dopamine transporters). In addition, there was no difference between the two strains concerning the expression of the dopamine receptor transcripts D1, D2 and D5. In adult absence-epilepsy prone rat with an overt epileptic phenotype, however, an elevated level of D3 mRNA expression was observed in neurons of the core of the nucleus accumbens (+23% increase in silver grain density compared to non-epileptic control rats). D3 transcripts were not increased in juvenile epileptic rats without seizures. These findings suggests that up-regulation of D3 receptor mRNA is part of the epileptic phenotype in absence-epilepsy prone rats. Its localization in the core of the nucleus accumbens bears close resemblance to the dopamine-sensitive antiepileptic sites in ventral striatum and further support the involvement of ventral structures of the basal ganglia system in the control of absence-seizures.

Valproic acid triggers acute rhabdomyolysis in a patient with carnitine palmitoyltransferase type II deficiency.

A 47-year-old man suffering from a bipolar disorder and intermittent myoglobinuria presented with acute rhabdomyolysis with renal failure after starting therapy with valproic acid. On morphological examination, skeletal muscle revealed increased lipid storage. Biochemically, decreased enzyme activity of carnitine palmitoyltransferase (CPT) type II with carnitine levels in the lower limit was found. Genetic analysis detected the common Ser113Leu substitution on one allele of the CPT2 gene. We conclude that valproic acid should be avoided in patients with CPT type II deficiency.

Variability of frequency and phase between antagonistic muscle pairs in pathological human tremors.

We investigated the electromyographic activity (EMG) of flexor and extensor muscles with different hand positions in patients with essential (ET) and parkinsonian (PD) tremor. Using a previously developed bootstrap method and standard cross-spectral analysis, we performed statistical tests to assess the effect of hand position on: (1) the frequency of the EMG; and (2) the phase between the EMGs recorded from antagonistic muscle pairs. Frequency as well as phases changed significantly with different positions of the hands but not during the recordings when the position was left unchanged. Besides confirmation that frequency and phase are stationary and reliable parameters during short-term recordings under controlled laboratory conditions, these results are of particular interest for ambulatory long-term tremor measurements. A higher variability of the estimated parameters reported in long-term recordings may perhaps reflect a patient's mobility only. Our study shows that long-term recording systems should have the means to monitor the patient's movements to provide reliable results.

Cortical current density reconstruction of interictal epileptiform activity in temporal lobe epilepsy.

OBJECTIVE: To investigate the value of cortical current density (CCD) reconstruction in localizing intracranial generators of interictal epileptiform activity in mesial and lateral temporal lobe epilepsy (TLE). METHODS: Non-linear minimum L(1)-norm CCD reconstruction (with current sources restricted to the individual cortical surface and a realistic boundary element method (BEM) head model) was used to localize and to study the propagation of interictal epileptiform EEG activity in 13 pre-surgical patients with TLE. RESULTS: In all but one patient with mesial temporal lesions, an initial activation maximum corresponding to the ascending part of averaged sharp waves was found in the ipsilateral anterior basolateral temporal lobe, mostly extending up to the affected mesial structures whose resection rendered the patients seizure-free. In all 3 patients with lateral temporal lesions, the activation was initially confined to temporal neocortex immediately adjacent to the epileptogenic lesion. Towards the peak of sharp waves, two patients showed a propagation of interictal activity to anterior and posterior and partly contralateral temporal regions. A conventional EEG analysis based on amplitude maxima or phase reversal would have missed the initial onset zone. CONCLUSIONS: The findings demonstrate that CCD reconstruction can be a valuable additional non-invasive component in the multimodal pre-surgical evaluation of epilepsy patients.

Effect of bilateral subthalamic nucleus stimulation on gait in Parkinson's disease.

The fundamental disturbance of the parkinsonian gait is the reduction in walking velocity. This is mainly due to reduction in stride length, while cadence (steps/min) is slightly enhanced. Treatment with L-dopa increases stride length while cadence is unchanged. Chronic stimulation of the thalamus has no effect on Parkinsonian gait. The efficacy of electrical stimulation of the subthalamic nucleus (STN) on gait in advanced Parkinson's disease has been clearly demonstrated clinically. The aim of the present study was to quantify the changes in gait measures induced by STN stimulation and L-dopa and to assess possible differential or additive effects. Eight Parkinson's disease patients (mean +/- SD age 48.1 +/- 7.3 years) with chronic bilateral STN stimulation (mean duration of disease 13.3 +/- 2.4 years, mean stimulation time 15.4 +/- 10.6 months) and 12 age-matched controls were investigated. Subjects walked on a special treadmill with a closed-loop ultrasound control system that used the subject's position to adjust treadmill speed continuously for the actual walking velocity. In an appropriate crossover design, spatiotemporal gait measures and leg joint angle movements were assessed for at least 120 stride cycles in four treatment conditions: with and without stimulation and with and without a suprathreshold dose of L-dopa. With STN stimulation, there were increases of almost threefold in mean walking velocity (from 0.35 to 0.96 m/s) and stride length (from 0.34 to 0.99 m). Cadence remained constant. The range of motion of the major leg joints also increased. L-Dopa alone had a slightly weaker effect, with an increase in walking velocity to 0.94 m/s and in stride length to 0.92 m at a similar cadence. These increased values were in the range of those for healthy age-matched subjects performing the same task. The combination of both treatments further increased the mean walking velocity to 1.19 m/s and stride length to 1.20 m at an unchanged cadence. However, not all patients receiving STN stimulation improved further when they also received L-dopa. These results demonstrate that chronic bilateral STN stimulation, like treatment with L-dopa, improves walking velocity by increasing stride length without changing cadence. STN stimulation almost exclusively affects mechanisms involved in the control of spatial gait measures rather than rhythmicity. The gait measures obtained with STN stimulation alone are in the range of control subjects.

[3H]acetycholine release in rat striatal slices is not subject to dopamine heteroreceptor supersensitivity 30 months after 6-hydroxydopamine lesion of the substantia nigra.

Using the rat model of Parkinson's disease described by Ungerstedt the release of [3H]acetylcholine ([3H]ACh) in the caudatoputamen was investigated to assess possible long-term effects of unilateral dopaminergic denervation on the modulation of cholinergic interneurons. This seemed of interest since rats with 6-hydroxydopamine (6-OHDA) lesions of the left substantia nigra showed an increase in the behavioural susceptibility to small doses of dopamine (DA) D2 receptor agonists 30 months after the lesion. Electrical field stimulation with 3 Hz elicited release of [3H]ACh in slices of both the lesioned and the intact striatum. The DA reuptake blocker nomifensine was ineffective on the lesioned side but diminished the release of [3H]ACh in the intact striatum. This inhibition was reversed by the D2 receptor antagonist domperidone and hence probably due to the effect of endogenously released DA. Single electrical pulses at 0.05 Hz, which neither induced autoinhibition of [3H]ACh release nor heteroinhibition by endogenous DA, elicited a higher release of [3H]ACh on the intact side. Under this stimulation paradigm activation of the D2 heteroreceptor with quinpirole depressed the release of [3H]ACh to a similar extent on both sides, irrespective of the absence or presence of the competitive NMDA receptor antagonist D-CPPene. Also blockade of the NMDA receptor channel by dizocilpine, or of AMPA receptors by NBQX, was ineffective on either side. The NMDA-evoked release of [3H]ACh was higher on the lesioned side. It was equally depressed by quinpirole and by ethanol on both sides. Thus, single electrical pulses and NMDA stimulation per se had opposite effects on the lesioned and the intact side, whereas the modulation of release was similar. Since the lesioned striata were considerably smaller, measurements of mRNA levels of choline acetyltransferase (ChAT) were used to assess the density of cholinergic interneurons and their content of ChAT mRNA. This analysis did not reveal any side difference. In conclusion, the function of D2 heteroreceptors on, and the density and ChAT mRNA content of, cholinergic interneurons are not or no longer altered after long-term DA denervation. Most probably, cholinergic interneurons are not involved in the increased behavioural susceptibility of 6-OHDA-lesioned rats to DA agonists.

Hypermetabolism in the ventrolateral thalamus in unilateral Parkinsonian resting tremor: a positron emission tomography study.

Tremorogenesis in Parkinson's disease (PD) is assumed to involve a cerebral network including the thalamus. An imaging study was performed on eight PD patients with strictly unilateral resting tremor using fluorodeoxyglucose positron emission tomography coregistered to 3-dimensional magnetic resonance imaging. Increased metabolic activity of high statistical significance (P<0.001) was found in the anterior ventrolateral nuclear group of the thalamus located contralateral to the tremor side. The metabolic changes significantly covaried with tremor amplitudes. For the first time, it could be demonstrated that thalamic metabolic changes associated with tremor in PD are localized in the ventral lateral anterior nucleus (VLa). The results are discussed with respect to previous studies on tremor generation.

Evaluation of impaired dynamic cerebral autoregulation by the Mueller manoeuvre.

Arterial blood pressure (ABP) shows polyphasic changes during the Mueller manoeuvre (voluntary negative intrathoracic pressure). The aim of the present study was to investigate (1) whether these changes could be applied to detect impaired dynamic cerebral autoregulation (dCA) in carotid stenosis and (2) whether the degree of indicated impairment correlates with transfer function phase as another current measure for dCA (deep breathing method) and CO2-reactivity. We examined 13 patients with severe unilateral carotid artery stenosis and 16 age-matched controls during 15-s Mueller manoeuvres (MM) at -30 mmHg using bilateral transcranial Doppler sonography and non-invasive ABP recordings (Finapres, 2300, Ohmeda, Englewood, CO, USA). After an initial biphasic oscillation, cerebral blood flow velocity (CBFV) and ABP decreased to below baseline. CBFV reincreased in controls and on contralateral sides in patients 6.0 s (3.8-9.5 s, median and range) after the onset of the decrease, despite a further fall in ABP. CBFV over the affected side revealed a significantly delayed reincrease (8.0 (5.6-10.3) s; P<0.01) combined with a relatively flat and inertial amplitude behaviour. An applied autoregulation index derived from the MM (mROR), phase shift and CO2-reactivity were severely reduced on the affected side in patients (P<0.01). Reduction of the mROR correlated significantly with reduction of phase shift (r=0.69; P=0.002) and CO2-reactivity (r=0.78; P=0.002). In conclusion, the different cerebral haemodynamic pattern during the MM in patients is likely to reflect impaired dCA. The degree of indicated impairment correlates with that of transfer function phase and CO2-reactivity. Therefore, the MM represents a convenient method for grading of compromised cerebral haemodynamics in patients with carotid artery stenosis.

[Posttraumatic dystonia. Review and legal aspects]. / Die posttraumatische Dystonie. Ein Uberblick und gutachterliche Aspekte.

More attention should be paid to dystonia as a consequence of trauma, particularly with regard to legal aspects. The underlying pathophysiological mechanisms of dystonia following central or peripheral trauma are largely unknown. Hemidystonia after severe head trauma is regarded to be due to contralateral basal ganglia lesions, particularly of the putamen. Focal and segmental dystonias follow various kinds of peripheral trauma. Central synaptic reorganisation due to altered peripheral input may play a role in its genesis. Clinically, post-traumatic dystonia differs from the idiopathic disease by the presence of accompanying pain or causalgia, limitation of the range of movement up to fixed posture, and poor response to conventional pharmacotherapy. If an expert opinion is requested, it is important to ascertain the diagnosis clinically and by EMG. To establish the cause-and-effect relationship between trauma and movement disorder, the severity of the injury, time course, and anatomical relationship must be taken into consideration.