Parkinson Disease: Gross J

Bergert FW, Conrad D, Ehrenthal K, Fessler J, Gross J, Gundermann K, Kluthe B, Lang Heinrich W, Liesenfeld A, Loew PG, Luther E, Pchalek R, Seffrin J, Sterzing A, Wolfring HJ, Zimmermann U. · General practitioners, Association of Statuatory Health Insurance Physicians in Hesse (Kassenärztliche Vereinigung in Hessen (KVH) Frankfurt (Main)), Germany. · Int J Clin Pharmacol Ther. · Pubmed #19281722 No free full text.

Abstract: The part "Special pharmacology of the aged" of this guideline contains recommendations for typical conditions in the family doctors practice: in the January issue 2009 dementia and Morbus Parkinson, in this issue osteoporosis and urinary incontinence and in the next issue rectal incontinence and obstipation. This issue of the IJCPT contains the third part of the Pharmacotherapy guidelines for the aged by family doctors for family doctors. Part 3: Osteoporosis and urinary incontinence. Osteoporosis is a systematic disease characterized by low bone mass and declining bone structure. Exercise, adequate diet, nicotine abstinence as well as reduction of alcohol consumption may counteract the progression of the disease. Osteoporosis manifests in bone fractures with minimal trauma. Attention must be given to the risk of falling, e.g., by avoiding drugs that increase the risk of falling: e.g., psychotropic agents, analgesic drugs and antiarrhythmic agents. Specific osteoporosis medication e.g. calcium, vitamin D, biphosphonates and SERM (selective estrogen receptor modulators) is evaluated by family doctors according to indication, dosage, contraindications, long-term therapy and nature of any fracture. Duration of therapy is at least 3 - max. 5 years followed by reassessment of indication. There are 3 types of urine incontinence (urge-, stress-, and overflow-incontinence). Another standardization of urinary incontinence follows dysfunctions of the pelvic floor: detrusor muscle-dependent, due to sphincter spasm, prostate gland dependent. Urge incontinence with a dysfunction of the detrusor muscle is the most common type. Mixed types are frequent. Non-drug measures (e.g. pelvic muscle training, bladder training, toilet training are first choice treatments. Drug therapy (estrogen, imipramine) are without proven effect.

Schnitzler A, Timmermann L, Gross J. · Department of Neurology, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany. · J Physiol Paris. · Pubmed #16054347 No free full text.

Abstract: Human brain functions are heavily contingent on neural interactions both at the single neuron and the neural population or system level. Accumulating evidence from neurophysiological studies strongly suggests that coupling of oscillatory neural activity provides an important mechanism to establish neural interactions. With the availability of whole-head magnetoencephalography (MEG) macroscopic oscillatory activity can be measured non-invasively from the human brain with high temporal and spatial resolution. To localise, quantify and map oscillatory activity and interactions onto individual brain anatomy we have developed the 'dynamic imaging of coherent sources' (DICS) method which allows to identify and analyse cerebral oscillatory networks from MEG recordings. Using this approach we have characterized physiological and pathological oscillatory networks in the human sensorimotor system. Coherent 8 Hz oscillations emerge from a cerebello-thalamo-premotor-motor cortical network and exert an 8 Hz oscillatory drive on the spinal motor neurons which can be observed as a physiological tremulousness of the movement termed movement discontinuities. This network represents the neurophysiological substrate of a discrete mode of motor control. In parkinsonian resting tremor we have identified an extensive cerebral network consisting of primary motor and lateral premotor cortex, supplementary motor cortex, thalamus/basal ganglia, posterior parietal cortex and secondary somatosensory cortex, which are entrained in the tremor or twice the tremor rhythm. This low frequency entrapment of motor areas likely plays an important role in the pathophysiology of parkinsonian motor symptoms. Finally, studies on patients with postural tremor in hepatic encephalopathy revealed that this type of tremor results from a pathologically slow thalamocortical and cortico-muscular coupling during isometric hold tasks. In conclusion, the analysis of oscillatory cerebral networks provides new insights into physiological mechanisms of motor control and pathophysiological mechanisms of tremor disorders.

Timmermann L, Braun M, Groiss S, Wojtecki L, Ostrowski S, Krause H, Pollok B, Südmeyer M, Ploner M, Gross J, Maarouf M, Voges J, Sturm V, Schnitzler A. · Department of Neurology, University of Cologne, Cologne, Germany. · Mov Disord. · Pubmed #18044706 No free full text.

Abstract: Cardinal symptoms of Parkinson's disease (PD) respond well to treatment with levodopa and deep brain stimulation (DBS) of the subthalamic nucleus (STN). However, it has remained unclear whether levodopa and STN-DBS have differential effects on bradykinesia. We investigated 8 PD-patients with STN-electrodes in four conditions: STN-DBS and levodopa (ON(MED)/ON(STIM)), STN-DBS only (OFF(MED)/ON(STIM)), levodopa only (ON(MED)/OFF(STIM)), without STN-DBS/levodopa (OFF(MED)/OFF(STIM)). Fourteen volunteers served as controls. Subjects performed fastest possible (1) pronation/supination of the forearm (diadochokinesia) and (2) flexion and extension of the index finger (finger movements). Movements were recorded using a 3D-ultrasound-system. Maximum frequency, amplitude, and smoothness of movements were determined. During OFF(MED)/OFF(STIM), all parameters were worser than in all other conditions. In proximal diadochokinesia, OFF(MED)/ON(STIM) significantly improved the amplitude and frequency, whereas ON(MED)/OFF(STIM) had no significant effect. In contrast, we found a stronger effect of levodopa (ON(MED)/OFF(STIM)) on amplitudes of distal finger movement than on amplitudes of diadochokinesia. Combination of treatments during ON(MED)/ON(STIM) further improved both movements. However, maximum frequency remained lower in PD-patients during ON(MED)/ON(STIM) compared with controls. This study demonstrates a better effect of levodopa on distal finger movements and STN-DBS on proximal diadochokinesia. Furthermore, a complementary effect of both therapies on brain areas involved in bradykinesia can be assumed.

Wojtecki L, Timmermann L, Jörgens S, Südmeyer M, Maarouf M, Treuer H, Gross J, Lehrke R, Koulousakis A, Voges J, Sturm V, Schnitzler A. · Department of Neurology, Heinrich Heine University, Moorenstrasse 5, 40225 Düsseldorf, Germany. · Arch Neurol. · Pubmed #16966504 links to  free full text

Abstract: BACKGROUND: High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor functions in those with Parkinson disease but may worsen frontal functions such as verbal fluency (VF). In contrast, low-frequency DBS leads to deterioration of motor functions. It is not known whether low-frequency STN DBS also has an effect on frontal functions. OBJECTIVE: To examine whether low-frequency STN DBS in contrast to high-frequency STN DBS has a positive effect on frontal functions on the basis of VF test results. DESIGN: A double-blind randomized crossover experiment to compare performance in 4 VF subtests and motor performance at 10 Hz, 130 Hz, and no stimulation. SETTING: University hospitals in Düsseldorf and Cologne, Germany. PATIENTS: Twelve patients with Parkinson disease 3 months or more after bilateral electrode implantation into the STN. MAIN OUTCOME MEASURE: Mean number of words in VF at different stimulation frequencies. RESULTS: The VF was significantly better at 10 Hz (48.3 words) compared with 130 Hz and showed a nonsignificant trend toward worsening at 130 Hz (42.3 words) compared with no stimulation (43.8 words). These results were consistent across all subtests. CONCLUSIONS: The study provides evidence of a beneficial effect of low-frequency (10 Hz) STN DBS on VF, which may be caused by activating neural pathways projecting to the frontal cortex. In addition, the study reproduces the negative effect of therapeutic high-frequency STN DBS on VF. The study results provide evidence for a frequency-dependent modulation of cognitive circuits involving the STN.

Florin E, Reck C, Burghaus L, Lehrke R, Gross J, Sturm V, Fink GR, Timmermann L. · Department of Neurology, University Hospital Cologne, Kerpener Str. 62, 50937 Köln, Cologne, Germany. · Clin Neurophysiol. · Pubmed #18632305 No free full text.

Abstract: OBJECTIVE: In patients with Parkinson's disease (PD) the effect of thalamic stimulation on tremor pathophysiology remains largely unclear. By recording local field potentials (LFPs) in the subthalamic nucleus (STN) while stimulating the nucleus ventralis intermedius thalami (VIM), information of the stimulation effects should be gained. METHODS: We had the unique opportunity to intraoperatively record LFPs of the STN in a patient with PD while stimulating the VIM. VIM electrodes had been implanted 9 years previously because of tremor. Due to worsening of clinical symptoms an implantation of STN electrodes had become necessary. RESULTS: High frequency stimulation in the VIM lowered the power of the tremor frequency band (4-7Hz) in the STN. In contrast, 10Hz VIM stimulation elevated the power of the tremor frequency band as well as STN-EMG coupling. CONCLUSIONS: The effect of high frequency stimulation may explain the improvement of tremor in patients who are treated with VIM deep brain stimulation. The power elevation during 10Hz stimulation suggests that the pathological cerebral and cerebral-muscular communication in PD is mainly driven at 10Hz. SIGNIFICANCE: The direct cerebral recordings support the view that a 10Hz network is a pathophysiological key mechanism in the generation of motor deficits in PD.

Timmermann L, Gross J, Butz M, Kircheis G, Haussinger D, Schnitzler A. · Department of Neurology and Gastroenterology, University Hospital Düsseldorf, Germany. · Neurol Clin Neurophysiol. · Pubmed #16012624 No free full text.

Abstract: Whole-head MEG-systems and modern spatial-filter-based analysis tools recently provided new possibilities to analyze non-invasively cerebral networks of human tremor syndromes. We compared tremor syndromes in Parkinsonian patients with a typical resting tremor as well as in patients with hepatic encephalopathy (HE) with a postural tremor called "mini-asterixis". In 6 patients with idiopathic Parkinson's disease (PD) we found strong coherence between the electromyography (EMG) of forearm muscles and activity in the contralateral primary motor cortex (M1) at tremor frequency but also at double tremor frequency. Furthermore, significant coherences were observed between M1 and medial wall areas (CMA/SMA), lateral premotor cortex, diencephalon, SII cortex, posterior parietal cortex and the contralateral cerebellum at tremor and, stronger, at double tremor frequency. In contrast, in 6 patients with "mini-asterixis" and HE due to chronic liver cirrhosis excessive corticomuscular coherence occurred at the individual tremor frequency between EMG and M1 activity. Interestingly, thalamus-M1 coupling was significantly altered towards lower frequencies matching the individual frequency of the mini-asterixis. Cerebro-muscular or cerebro-cerebral coupling at double tremor frequency was not observed. Therefore, "mini-asterixis" reflects most likely a pathologically decelerated and augmented synchronized rhythmical motor cortical output. This could be due to functional alterations in the M1-basal-ganglia-thalamo-cortical loops in severe HE. In summary, tremor syndromes in PD as well as in patients with HE and "mini-asterixis" are characterized by pathological oscillatory activity within cerebral networks of motor areas. However, the present study shows different mechanisms of tremor generation in PD and HE patients.

Timmermann L, Wojtecki L, Gross J, Lehrke R, Voges J, Maarouf M, Treuer H, Sturm V, Schnitzler A. · Department of Neurology, Heinrich-Heine-University, Düsseldorf, Germany. · Mov Disord. · Pubmed #15389990 No free full text.

Abstract: Recently, a pathological oscillatory network at 10 Hz including several motor areas was described in patients with idiopathic Parkinson's disease (PD). In 7 PD patients, we tested the clinical effect of subthalamic nucleus (STN) stimulation at varying frequencies 1 to 3 years after implantation of electrodes. STN stimulation at 10 Hz induced significant worsening of motor symptoms, especially akinesia, compared with no stimulation and therapeutic stimulation (> or =130 Hz). This finding indicates the clinical relevance of pathological 10 Hz synchronization in PD.

Timmermann L, Gross J, Dirks M, Volkmann J, Freund HJ, Schnitzler A. · Department of Neurology, Heinrich-Heine University, Duesseldorf, Germany. · Brain. · Pubmed #12477707 No free full text.

Abstract: Data from experiments in MPTP monkeys as well as from invasive and non-invasive recordings in patients with Parkinson's disease suggest an abnormal synchronization of neuronal activity in the generation of resting tremor in Parkinson's disease. In six patients with tremor-dominant idiopathic Parkinson's disease, we recorded simultaneously surface electromyograms (EMGs) of hand muscles, and brain activity with a whole-head magnetoencephalography (MEG) system. Using a recently developed analysis tool (Dynamic Imaging of Coherent Sources; DICS), we determined cerebro-muscular and cerebro-cerebral coherence as well as the partial coherence between cerebral areas and muscle, and localized coherent sources within the individual MRI scans. The phase lag between the EMG and cerebral activity was determined by means of a Hilbert transform of both signals. After overnight withdrawal from medication, patients showed typical Parkinson's disease resting tremor (4-6 Hz). This tremor was associated with strong coherence between the EMG of forearm muscles and activity in the contralateral primary motor cortex (M1) at tremor frequency but also at double tremor frequency. Phase lags between M1 activity and EMG were between 15 and 25 ms (M1 activity leading) at single, but also at double tremor frequency, corresponding well to the corticomuscular conduction time. Furthermore, significant coherence was observed between M1 and medial wall areas (cingulate/supplementary motor area; CMA/SMA), lateral premotor cortex (PM), diencephalon, secondary somatosensory cortex (SII), posterior parietal cortex (PPC) and the contralateral cerebellum at single tremor and, even stronger at double tremor frequency. Spectra of coherence between thalamic activity and cerebellum as well as several brain areas revealed additional broad peaks around 20 Hz. Power spectral analysis of activity in all central areas indicated the strongest frequency components at double tremor frequency. Partial coherence analysis and the calculation of phase shifts revealed a strong bidirectional coupling between the EMG and diencephalic activity and a direct afferent coupling between the EMG and SII and the PPC. In contrast, the cerebellum, SMA/CMA and PM show little evidence for direct coupling with the peripheral EMG but seem to be connected with the periphery via other cerebral areas (e.g. M1). In summary, our results demonstrate tremor-related oscillatory activity within a cerebral network, with abnormal coupling in a cerebello-diencephalic-cortical loop and cortical motor (M1, SMA/CMA, PM) and sensory (SII, PPC) areas contralateral to the tremor hand. The main frequency of cerebro-cerebral coupling corresponds to double the tremor frequency.

Gross J, Kujala J, Hamalainen M, Timmermann L, Schnitzler A, Salmelin R. · Department of Neurology, Heinrich-Heine-University, Moorenstrasse 5, D-40225 Duesseldorf, Germany. · Proc Natl Acad Sci U S A. · Pubmed #11209067 links to  free full text

Abstract: Functional connectivity between cortical areas may appear as correlated time behavior of neural activity. It has been suggested that merging of separate features into a single percept ("binding") is associated with coherent gamma band activity across the cortical areas involved. Therefore, it would be of utmost interest to image cortico-cortical coherence in the working human brain. The frequency specificity and transient nature of these interactions requires time-sensitive tools such as magneto- or electroencephalography (MEG/EEG). Coherence between signals of sensors covering different scalp areas is commonly taken as a measure of functional coupling. However, this approach provides vague information on the actual cortical areas involved, owing to the complex relation between the active brain areas and the sensor recordings. We propose a solution to the crucial issue of proceeding beyond the MEG sensor level to estimate coherences between cortical areas. Dynamic imaging of coherent sources (DICS) uses a spatial filter to localize coherent brain regions and provides the time courses of their activity. Reference points for the computation of neural coupling may be based on brain areas of maximum power or other physiologically meaningful information, or they may be estimated starting from sensor coherences. The performance of DICS is evaluated with simulated data and illustrated with recordings of spontaneous activity in a healthy subject and a parkinsonian patient. Methods for estimating functional connectivities between brain areas will facilitate characterization of cortical networks involved in sensory, motor, or cognitive tasks and will allow investigation of pathological connectivities in neurological disorders.