Vivianne van Kranen-Mastenbroek

Double-blind clinical trial of thalamic stimulation in patients with Tourette syndrome

Deep brain stimulation of the thalamus has been proposed as a therapeutic option in patients with Tourette syndrome who are refractory to pharmacological and psychotherapeutic treatment. Patients with intractable Tourette syndrome were invited to take part in a double-blind randomized cross-over trial assessing the efficacy and safety of stimulation of the centromedian nucleus-substantia periventricularis-nucleus ventro-oralis internus crosspoint in the thalamus. After surgery, the patients were randomly assigned to 3 months stimulation followed by 3 months OFF stimulation (Group A) or vice versa (Group B). The cross-over period was followed by 6 months ON stimulation. Assessments were performed prior to surgery and at 3, 6 months and 1 year after surgery. The primary outcome was a change in tic severity as measured by the Yale Global Tic Severity Scale and the secondary outcome was a change in associated behavioural disorders and mood. Possible cognitive side effects were studied during stimulation ON at 1 year postoperatively. Interim analysis was performed on a sample of six male patients with only one patient randomized to Group B. Tic severity during ON stimulation was significantly lower than during OFF stimulation, with substantial improvement (37%) on the Yale Global Tic Severity Scale (mean 41.1 ± 5.4 versus 25.6 ± 12.8, P = 0.046). The effect of stimulation 1 year after surgery was sustained with significant improvement (49%) on the Yale Global Tic Severity Scale (mean 42.2 ± 3.1 versus 21.5 ± 11.1, P = 0.028) when compared with preoperative assessments. Secondary outcome measures did not show any effect at a group level, either between ON and OFF stimulation or between preoperative assessment and that at 1 year postoperatively. Cognitive re-assessment at 1 year after surgery showed that patients needed more time to complete the Stroop Colour Word Card test. This test measures selective attention and response inhibition. Serious adverse events included one small haemorrhage ventral to the tip of the electrode, one infection of the pulse generator, subjective gaze disturbances and reduction of energy levels in all patients. The present preliminary findings suggest that stimulation of the centromedian nucleus-substantia periventricularis-nucleus ventro-oralis internus crosspoint may reduce tic severity in refractory Tourette syndrome, but there is the risk of adverse effects related to oculomotor function and energy levels. Further randomized controlled trials on other targets are urgently needed since the search for the optimal one is still ongoing.

Somatosensory cortex responses to median nerve stimulation: fMRI effects of current amplitude and selective attention

OBJECTIVES The aim of this study was to localize and to investigate response properties of the primary (SI) and the secondary (SII) somatosensory cortex upon median nerve electrical stimulation. METHODS Functional magnetic resonance imaging (fMRI) was used to quantify brain activation under different paradigms using electrical median nerve stimulation in healthy right-handed volunteers. In total 11 subjects were studied using two different stimulus current values in the right hand: at motor threshold (I(max)) and at I(min) (1/2 I(max)). In 7 of these 11 subjects a parametric study was then conducted using 4 stimulus intensities (6/6, 5/6, 4/6 and 3/6 I(max)). Finally, in 10 subjects an attention paradigm in which they had to perform a counting task during stimulation with I(min) was done. RESULTS SI activation increased with current amplitude. SI did not show significant activation during stimulation at I(min). SII activation did not depend on current amplitude. Also the posterior parietal cortex appeared to be activated at I(min). The I(min) response in SII significantly increased by selective attention compared to I(min) without attention. At I(max) significant SI activity was observed only in the contralateral hemisphere, the ipsilateral cerebellum, while other areas possibly showed bilateral activation. CONCLUSIONS Distributed activation in the human somatosensory cortical system due to median nerve stimulation was observed using fMRI. SI, in contrast to SII, appears to be exclusively activated on the contralateral side of the stimulated hand at I(max), in agreement with the concept of SIs important role in processing of proprioceptive input. Only SII remains significantly activated in case of lower current values, which are likely to exclusively stimulate the sensible fibres mediating cutaneous receptor input. Selective attention only enhances SII activity, indicating a higher-order role for SII in the processing of somatosensory input.

Differential effects of subthalamic nucleus stimulation in advanced Parkinson disease on reaction time performance

The aim of the present study was to assess the effect of bilateral subthalamic nucleus (STN) stimulation and dopaminergic medication on speed of mental processing and motor function. Thirty-nine patients suffering from advanced Parkinson disease (PD) were operated on. Motor function and reaction time (RT) performance [simple RT (SRT) and complex RT (CRT)] were evaluated under four experimental conditions with stimulation (stim) and medication (med) on and off: stim-on/med-on, stim-on/med-off, stim-off/med-off and stim-off/med-on. In the last condition, the patients received either low medication (usual dose) or high medication (suprathreshold dose). STN stimulation improved the motor performance in the SRT and CRT tasks. Furthermore, STN deep brain stimulation (DBS) also improved response preparation as shown by the significant improvement of the RT performance in the SRT task. This effect of STN DBS on the RT performance in the SRT task was greater as compared with the CRT task. This is due to the more complex information processing that is required in the CRT task as compared to the SRT task. These data suggest that treatment of STN hyperactivity by DBS improves motor function, confirming earlier reports, but has a differential effect on cognitive functions. The STN seems to be an important modulator of cognitive processing and STN DBS can differentially affect motor and associative circuits.

Safety and one-year efficacy of intrathecal baclofen therapy in children with intractable spastic cerebral palsy

BACKGROUND Prospective studies that address both efficacy and safety of continuous infusion of intrathecal baclofen (CITB) in children with spastic cerebral palsy (CP), and that use outcome measures beyond muscle tone are lacking. AIMS To study the efficacy at 12 months and safety up to 24 months after start of CITB in children with intractable spastic CP. METHODS Nine girls and eight boys, aged 13.7 years (SD 2.9), received a SynchroMed pump for CITB. We prospectively recorded effects and adverse events at regular follow-up visits up to 24 months. Outcome measures included the 0-10 visual analogue scale (VAS) for individual problems, Gross Motor Function Measure (GMFM) and health related quality of life as measured with the Child Health Questionnaire-PF50. RESULTS CITB for 12 months significantly improved the VAS for individual problems with 4.7 (SD 2.0; p=0.000), VAS for ease of care with 5.2 (SD 2.1; p=0.000), VAS for pain with 5.4 (SD 2.7; p=0.002); GMFM sitting dimension with 3.3 (range -4.0 to 22.0; p=0.022), GMFM goal dimension with 4.0 (range 0.0-26.0; p=0.007); and Child Health Questionnaire-PF50 domains of bodily pain/discomfort with 25.6 (SD 35.9; p=0.016) and mental health with 9.8 (SD 11.3; p=0.007). During a mean follow-up of 18.4 months (range 12-24), we recorded 80 adverse events. Eight adverse events were serious, but not life-threatening. CONCLUSIONS CITB was effective at 12 months and safe up to 24 months for carefully selected children with intractable spastic CP. CITB relieved pain, facilitated ease of care and improved mental health. The majority of children could extend their activities and participation.

40-Hz steady state response in Alzheimer's disease and mild cognitive impairment

The 40-Hz steady state response (SSR) reflects early sensory processing and can be measured with electroencephalography (EEG). The current study compared the 40-Hz SSR in groups consisting of mild Alzheimers disease patients (AD) (n=15), subjects with mild cognitive impairment (MCI) (n=20) and healthy elderly control subjects (n=20). All participants were naïve for psychoactive drugs. Auditory click trains at a frequency of 40-Hz evoked the 40-Hz SSR. To evaluate test-retest reliability (TRR), subjects underwent a similar assessment 1 week after the first. The results showed a high TRR and a significant increase of 40-Hz SSR power in the AD group compared to MCI and controls. Furthermore a moderate correlation between 40-Hz SSR power and cognitive performance as measured by ADAS-cog was shown. The results suggest that 40-Hz SSR might be an interesting candidate marker of disease progression.

Automatic burst detection for the EEG of the preterm infant

To aid with prognosis and stratification of clinical treatment for preterm infants, a method for automated detection of bursts, interburst-intervals (IBIs) and continuous patterns in the electroencephalogram (EEG) is developed. Results are evaluated for preterm infants with normal neurological follow-up at 2 years. The detection algorithm (MATLAB®) for burst, IBI and continuous pattern is based on selection by amplitude, time span, number of channels and numbers of active electrodes. Annotations of two neurophysiologists were used to determine threshold values. The training set consisted of EEG recordings of four preterm infants with postmenstrual age (PMA, gestational age + postnatal age) of 29-34 weeks. Optimal threshold values were based on overall highest sensitivity. For evaluation, both observers verified detections in an independent dataset of four EEG recordings with comparable PMA. Algorithm performance was assessed by calculation of sensitivity and positive predictive value. The results of algorithm evaluation are as follows: sensitivity values of 90% ± 6%, 80% ± 9% and 97% ± 5% for burst, IBI and continuous patterns, respectively. Corresponding positive predictive values were 88% ± 8%, 96% ± 3% and 85% ± 15%, respectively. In conclusion, the algorithm showed high sensitivity and positive predictive values for bursts, IBIs and continuous patterns in preterm EEG. Computer-assisted analysis of EEG may allow objective and reproducible analysis for clinical treatment.

Subthalamic Nucleus High-Frequency Stimulation for Advanced Parkinson's Disease: Motor and Neuropsychological Outcome after 10 Years

Background: Since the introduction of subthalamic nucleus deep brain stimulation (STN DBS), many clinical studies have shown that this therapy is safe and effective in the short and medium term. Only little is known about long-term results. Objectives: To provide an analysis of motor and cognitive outcome 10 years after STN DBS. Methods: In this observational cohort study, we report on the motor and cognitive outcome in a cohort of 26 Parkinsons disease patients who were prospectively followed up for 10 years after STN DBS surgery. Results: In the early post-operative phase, improvement in the Unified Parkinsons Disease Rating Scale (UPDRS) III (10.6, p < 0.01) and IV (2.5, p < 0.01) was seen as well as a 32% reduction in levodopa equivalent dose (p < 0.01). After 5 years, a worsening of the motor performance was observed. The worsening of motor performance was mainly due to a deterioration in bradykinesia (12.4 ± 4.6, p < 0.05) and axial symptoms (6.9 ± 2.8, p < 0.01). Memory function seemed to improve in the short term, but there was a significant decline between 1 and 5 years after surgery (p < 0.01). Mood remained relatively stable during follow-up, and one third of the patients showed impulsive behaviour after surgery. Conclusions: The motor performance of patients showed deterioration over time, due to an increase in bradykinesia and axial symptoms.

Subthalamic neuronal responses to cortical stimulation

Deep brain stimulation of the subthalamic nucleus alleviates motor symptoms in Parkinsons disease patients. However, some patients suffer from cognitive and emotional changes. These side effects are most likely caused by current spread to the cognitive and limbic territories in the subthalamic nucleus. The aim of this study was to identify the motor part of the subthalamic nucleus to reduce stimulation‐induced behavioral side effects, by using motor cortex stimulation.

Placebo controlled utility and feasibility study of the H-reflex and flexor reflex in spastic children treated with intrathecal baclofen

OBJECTIVE To evaluate feasibility and utility of the soleus H-reflex and tibialis anterior flexor reflex (FR) in identifying spinal cord neuronal response to intrathecal baclofen (ITB) in children with severe spastic cerebral palsy. METHODS During a randomized, double-blind, placebo-controlled dose-escalation test treatment, maximum H amplitude/maximum M amplitude (H/M ratio) and FR parameters were bilaterally recorded at baseline and 2-3 h after intrathecal bolus administration of placebo and increasing doses of baclofen until both an improvement in the individual treatment goal(s) and a one-point reduction on the Ashworth scale were observed. RESULTS Electrophysiological data of 14 children were studied. The H-reflex was feasible in 13 children, the FR threshold area in 9 and the FR, elicited with supramaximal stimulation, in only one child. After ITB, the H/M ratio significantly decreased (left: 0.67+/-0.47 to 0.15+/-0.18, P=0.005; right: 0.55+/-0.32 to 0.14+/-0.19, P=0.002) without placebo effect. FR threshold area after ITB, only decreased significantly in children not taking oral baclofen (left: 146+/-53 to 41+/-54 mV ms, P=0.000; right: 156+/-80 to 66+/-48 mV ms, P=0.002). CONCLUSIONS This is the first randomized, double-blind, placebo-controlled dose-escalation study in spastic children demonstrating the soleus H-reflex to be a feasible and objective measure to quantify the decreasing motoneuron excitability in response to ITB bolus administration. Only in children not taking oral baclofen, FR threshold area can also be used as an objective outcome measure, yet feasibility is limited. SIGNIFICANCE We suggest introducing the H-reflex as the electrophysiological gold standard for the evaluation of the effect of ITB in spastic children.

EEG Feature Pre-processing for Neonatal Epileptic Seizure Detection

Aim of our project is to further optimize neonatal seizure detection using support vector machine (SVM). First, a Kalman filter (KF) was used to filter both feature and classifier output time series in order to increase temporal precision. Second, EEG baseline feature correction (FBC) was introduced to reduce inter patient variability in feature distributions. The performance of the detection methods is evaluated on 54 multi channel routine EEG recordings from 39 both term and pre-term newborns. The area under the receiver operating characteristics curve (AUC) as well as sensitivity and specificity are used to evaluate the performance of the classification method. SVM without KF and FBC achieves an AUC of 0.767 (sensitivity 0.679, specificity 0.707). The highest AUC of 0.902 (sensitivity 0.801, specificity 0.831) is achieved on baseline corrected features with a Kalman smoother used for training data pre-processing and a KF used to filter the classifier output. Both FBC and KF significantly improve neonatal epileptic seizure detection. This paper introduces significant improvements for the state of the art SVM based neonatal epileptic seizure detection.