Modulation of specific components of sleep disturbances by simultaneous subthalamic and nigral stimulation in Parkinson's disease.

OBJECTIVE: To compare the effect of simultaneous deep brain stimulation of the subthalamic nucleus and substantia nigra pars reticulata (STN+SNr-DBS) to conventional subthalamic stimulation (STN-DBS) on sleep quality in Parkinson's disease (PD) patients. METHODS: The study was a single-center, randomized, double-blind, cross-over clinical trial to compare the effect of STN-DBS vs. combined STN+SNr-DBS on subjective measures of sleep quality. Fifteen PD patients (2 female, age 62.5 ± 6.7 years) suffering from moderate idiopathic PD (disease duration: 12.0 ± 5.0 years, Hoehn & Yahr stage: 2.2 ± 0.4 in the MED-ON & STN-DBS-ON condition, Hoehn & Yahr stage: 2.6 ± 0.8 in the MED-OFF condition preoperatively) participated in the study. Sleep quality was evaluated in both stimulation conditions using the PDSS-2 score as a self-rating questionnaire covering several aspects of sleep disturbances. RESULTS: PD patients showed mild-moderate sleep disturbances (STN-DBS: PDSS-2 score 17.0 ± 11.0; STN+SNr-DBS: 14.7 ± 9.5) with slight but not significant differences between both stimulation conditions. Considering the different subitems of the PDSS-2, combined STN+SNr stimulation was superior to conventional STN stimulation in improving restless legs symptoms (RLS) at night (STN-DBS = 1.9 ± 2.7 STN+SNr-DBS = 1.0 ± 1.8; W = -2.06, p = 0.039) and immobility at night (STN-DBS = 1.5 ± 1.4 STN+SNr-DBS = 0.6 ± 0.8; W = -2.041, p = 0.041). CONCLUSION: This study demonstrates the safety of STN+SNr-DBS compared to conventional STN-DBS on sleep in general with potential beneficial input on RLS symptoms and akinesia at night.

Deep brain stimulation in the subthalamic area is more effective than nucleus ventralis intermedius stimulation for bilateral intention tremor.

BACKGROUND: The ventro-lateral thalamus is the stereotactic target of choice for severe intention tremor. Nevertheless, the optimal target area has remained controversial, and targeting of the subthalamic area has been suggested to be superior. PATIENTS AND METHODS: Eleven patients with disabling intention tremor of different etiology (essential tremor (n = 8), multiple sclerosis (n = 2) and one with, spinocerebellar ataxia) were implanted bilaterally with DBS electrodes targeted to the ventro-lateral thalamus using micro-recording and micro-stimulation. Among five tracks explored in parallel optimal tracks were chosen for permanent electrode implantation. Postoperative tremor suppression elicited by individual electrode contacts was quantified using a lateralised tremor rating scale at least 3 months (in most patients >1 year) after implantation. The position of electrode contacts was determined retrospectively from stereotactic X-ray exams and by correlation of pre- and postoperative MRI. RESULTS: In all patients, DBS suppressed intention tremor markedly. On average, tremor on the left and right side of the body was improved by 68% (+/-19; standard deviation) and 73% (+/-21), respectively. In most patients, distal electrode contacts located in the subthalamic area proved to be more effective than proximal contacts in the ventro-lateral thalamus. In stereotactic coordinates, the optimal site was located 12.7 mm (+/-1.4; mean +/- standard deviation) lateral, 7.0 (+/-1.6) mm posterior, and 1.5 (+/-2.0) mm ventral to the mid-commissural point. In general, the best contacts could be selected for permanent stimulation. Nevertheless, in some instances, more proximal contacts had to be chosen because of adverse effects (paraesthesiae, dysarthria, gait ataxia) which were more pronounced with bilateral stimulation resulting in slightly less tremor suppression on the left and right side of body (63 +/- 18 and 68 +/- 19%, respectively). CONCLUSION: Direct comparison of different stimulation sites in individual patients revealed that DBS in the subthalamic area is more effective in suppressing pharmacoresistant intention tremor than the ventro-lateral thalamus proper. Anatomical structures possibly involved in tremor suppression include cerebello-thalamic projections, the prelemniscal radiation, and the zona incerta.

Impact of Combined Subthalamic Nucleus and Substantia Nigra Stimulation on Neuropsychiatric Symptoms in Parkinson's Disease Patients.

The goal of the study was to compare the tolerability and the effects of conventional subthalamic nucleus (STN) and combined subthalamic nucleus and substantia nigra (STN+SNr) high-frequency stimulation in regard to neuropsychiatric symptoms in Parkinson's disease patients. In this single center, randomized, double-blind, cross-over clinical trial, twelve patients with advanced Parkinson's disease (1 female; age: 61.3 ± 7.3 years; disease duration: 12.3 ± 5.4 years; Hoehn and Yahr stage: 2.2 ± 0.39) were included. Apathy, fatigue, depression, and impulse control disorder were assessed using a comprehensive set of standardized rating scales and questionnaires such as the Lille Apathy Rating Scale (LARS), Modified Fatigue Impact Scale (MFIS), Becks Depression Inventory (BDI-I), Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease Rating Scale (QUIP-RS), and Parkinson's Disease Questionnaire (PDQ-39). Three patients that were initially assigned to the STN+SNr stimulation mode withdrew from the study within the first week due to discomfort. Statistical comparison of data retrieved from patients who completed the study revealed no significant differences between both stimulation conditions in terms of mean scores of scales measuring apathy, fatigue, depression, impulse control disorder, and quality of life. Individual cases showed an improvement of apathy under combined STN+SNr stimulation. In general, combined STN+SNr stimulation seems to be safe in terms of neuropsychiatric side effects, although careful patient selection and monitoring in the short-term period after changing stimulation settings are recommended.

Induction of immediate early gene expression by high-frequency stimulation of the subthalamic nucleus in rats.

Deep brain stimulation is associated with delayed improvement of parkinsonian symptoms, such as hypokinesia with subthalamic nucleus stimulation, or dystonia with globus pallidus internus stimulation. The latency observed is better explained by molecular alterations than immediate electrophysiological processes, and clinical improvement may involve adaptive gene expression. Here, we have studied immediate early gene expression as fast molecular response to subthalamic nucleus stimulation. Bipolar electrodes were implanted bilaterally into the subthalamic nucleus of anesthetized male Wistar rats. High-frequency stimulation (130 Hz or 80 Hz, 60 micros, 300 microA) or low-frequency stimulation (5 Hz, 60 micros, 300 microA) was performed with the right electrode for 15, 60, 120, and 240 min whereas the silent left electrode served as negative control. Brains were fixed by transcardial perfusion and frozen sections were stained with polyclonal antibodies directed against three immediate early gene-encoded proteins, c-Fos, c-Jun, and Krox-24 (NGFI-A, Egr-1, Zif268, Tis8, Zenk). After 120 and 240 h, c-Fos immunoreactivity was strongly upregulated in subthalamic nucleus neurons on the stimulated site. In contrast, no c-Fos immunoreactivity was detected on the non-stimulated site except for single positive cells located in close proximity to the electrode tracks. Furthermore, c-Fos immunoreactivity was induced in subthalamic nucleus projection areas, such as primary and secondary motor cortex, primary somatosensory and insular cortex, lateral and medial globus pallidus, suprageniculate thalamic nucleus, pontine nuclei, medial geniculate nucleus, and substantia nigra. Similarly, c-Jun and Krox-24 were induced at the site of stimulation and in projection areas following high-frequency subthalamic nucleus stimulation. Whereas high frequency stimulation with 80 Hz was similarly effective none of the three immediate early gene-encoded proteins was induced with low-frequency stimulation (5 Hz) for 4 h. This is in accordance with the therapeutic effects of deep brain stimulation which are only elicited with high frequency stimulation. Our data provide evidence that immediate early gene expression in the subthalamic nucleus is rapidly and substantially induced by high-frequency stimulation. The induction of immediate early genes in projection sites suggests ipsilateral transsynaptic modulation of neuronal activity.

Herpes simplex virus thymidine kinase/ganciclovir-mediated apoptotic death of bystander cells.

An emerging strategy for cancer gene therapy involves the transfer of the herpes simplex virus thymidine kinase (HSV-tk) gene into tumor cells, rendering them susceptible to the cytotoxic effects of ganciclovir. The observation that HSV-tk-expressing cells can also induce cell death in neighboring cells, which do not express HSV-tk, has been called the bystander effect. Gap junction-mediated transfer of cytotoxic molecules to bystander cells may be an important mechanism of bystander cell death, although others have suggested a role for phagocytosis. In this study, we evaluated the mode of cell death in bystander cells. We detected apoptosis in bystander cells and found that bystander cell death could be inhibited by BCL2 expression. We determined that ganciclovir incubations for 10 h were sufficient to induce cell death in most bystander cells cocultured with HSV-tk-expressing cells. During this period, no phagocytosis was detected, although it was obvious at later stages.

Deep brain stimulation for idiopathic or secondary movement disorders.

Deep brain stimulation has gained increasing interest in the treatment of movement disorders. Presenting our clinical series of 179 patients operated upon since 1999, the indications, risks and benefits for the patients are discussed in order to further improve the techniques and their applications.

Subthalamic deep brain stimulation improves auditory sensory gating deficit in Parkinson's disease.

OBJECTIVE: While motor effects of dopaminergic medication and subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) patients are well explored, their effects on sensory processing are less well understood. Here, we studied the impact of levodopa and STN-DBS on auditory processing. METHODS: Rhythmic auditory stimulation (RAS) was presented at frequencies between 1 and 6Hz in a passive listening paradigm. High-density EEG-recordings were obtained before (levodopa ON/OFF) and 5months following STN-surgery (ON/OFF STN-DBS). We compared auditory evoked potentials (AEPs) elicited by RAS in 12 PD patients to those in age-matched controls. Tempo-dependent amplitude suppression of the auditory P1/N1-complex was used as an indicator of auditory gating. RESULTS: Parkinsonian patients showed significantly larger AEP-amplitudes (P1, N1) and longer AEP-latencies (N1) compared to controls. Neither interruption of dopaminergic medication nor of STN-DBS had an immediate effect on these AEPs. However, chronic STN-DBS had a significant effect on abnormal auditory gating characteristics of parkinsonian patients and restored a physiological P1/N1-amplitude attenuation profile in response to RAS with increasing stimulus rates. CONCLUSIONS: This differential treatment effect suggests a divergent mode of action of levodopa and STN-DBS on auditory processing. SIGNIFICANCE: STN-DBS may improve early attentive filtering processes of redundant auditory stimuli, possibly at the level of the frontal cortex.

Predictive timing functions of cortical beta oscillations are impaired in Parkinson's disease and influenced by L-DOPA and deep brain stimulation of the subthalamic nucleus.

Cortex-basal ganglia circuits participate in motor timing and temporal perception, and are important for the dynamic configuration of sensorimotor networks in response to exogenous demands. In Parkinson's disease (PD) patients, rhythmic auditory stimulation (RAS) induces motor performance benefits. Hitherto, little is known concerning contributions of the basal ganglia to sensory facilitation and cortical responses to RAS in PD. Therefore, we conducted an EEG study in 12 PD patients before and after surgery for subthalamic nucleus deep brain stimulation (STN-DBS) and in 12 age-matched controls. Here we investigated the effects of levodopa and STN-DBS on resting-state EEG and on the cortical-response profile to slow and fast RAS in a passive-listening paradigm focusing on beta-band oscillations, which are important for auditory-motor coupling. The beta-modulation profile to RAS in healthy participants was characterized by local peaks preceding and following auditory stimuli. In PD patients RAS failed to induce pre-stimulus beta increases. The absence of pre-stimulus beta-band modulation may contribute to impaired rhythm perception in PD. Moreover, post-stimulus beta-band responses were highly abnormal during fast RAS in PD patients. Treatment with levodopa and STN-DBS reinstated a post-stimulus beta-modulation profile similar to controls, while STN-DBS reduced beta-band power in the resting-state. The treatment-sensitivity of beta oscillations suggests that STN-DBS may specifically improve timekeeping functions of cortical beta oscillations during fast auditory pacing.

(E)-5-(2-bromovinyl)-2'-deoxyuridine potentiates ganciclovir-mediated cytotoxicity on herpes simplex virus-thymidine kinase--expressing cells.

Tumor cells expressing the thymidine kinase gene of the herpes simplex virus (HSV-tk) are rendered highly susceptible to the cytotoxic effects of different antiherpes drugs. In an attempt to enhance cytotoxicity of this therapeutic approach in glioma and other tumor cell lines transduced with the HSV-tk gene, we evaluated tumor cell killing following co-administration of two different prodrugs metabolized by HSV-tk, (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), and ganciclovir (GCV). In 8 of 12 cell lines investigated, addition of BVDU in concentrations showing no cytotoxic effect or only limited cytotoxicity could enhance GCV-mediated cell killing by as much as one order of magnitude. In co-cultures consisting of HSV-tk(+) (9L STK) and HSV-tk(-) (9L wild-type) cells, we also observed potentiation of GCV-mediated cytotoxicity in the presence of BVDU, suggesting strongly enhanced bystander cell killing. BVDU is thought to exert its cytotoxic effect through inhibition of thymidylate synthase activity or by incorporation into replicating DNA. Both effects could be observed in all HSV-tk--expressing cells investigated, including cell lines which did not exhibit cytotoxicity after incubation with BVDU. These findings argue against current concepts of BVDU-mediated cytotoxicity in HSV-tk--expressing cells. Taken together, our data suggest that gene therapy utilizing prodrug activating enzymes may be rendered more effective by simultaneous treatment with two different prodrugs metabolized by the same enzyme.

Effects of bilateral subthalamic nucleus stimulation on parkinsonian gait.

Gait analysis was carried out to assess the effects of L-dopa and bilateral subthalamic nucleus stimulation on gait velocity, cadence, stride length, and gait kinematics in nine patients with PD. Substantial effects of bilateral subthalamic nucleus stimulation on gait, with an increase in gait velocity and stride length comparable to that of a suprathreshold L-dopa dose, were found. Interestingly, stride length was more improved by L-dopa and cadence more by subthalamic nucleus stimulation. In two patients with freezing during the "on" period, subthalamic nucleus stimulation failed to reduce this symptom effectively.

Protooncogene expression in human glioma derived cell-lines.

Growth factor/ligand interactions have been shown to play an important role in various malignancies. Expression of two differentially spliced forms of SCF was detected in 20 of 24 glioma cell lines by RT-PCR. Northern blot analysis revealed expression of the corresponding receptor, c-kit (11/24), as well as PDGF alpha-receptor (22/25 glioma cell lines), PDGF beta-receptor (22/25), TGF-alpha (13/24 ) and PDGF B/c-sis (7/16) expression. As determined by FACS analysis, expression of EGFR and p185HER2 was detected in 21 of 21 and 15 of 21 glioma cell lines, respectively. Four cell lines showed moderate EGFR overexpression (>90,000 receptors/cell) and in one cell line p 185HER2 expression exceeded EGFR levels. Loss of EGFR gene amplification during in vitro culturing was observed in 3 of 18 investigated cell lines by differential PCR. In summary, our work suggests the simultaneous activation of several different growth factor/receptor systems in human glioma cell lines.

Expression of retinoblastoma gene in human intracranial neoplasms.

The retinoblastoma gene (RB) is a tumour suppressor gene, of which mutations are associated with carcinogenesis in a broad spectrum of human malignacies. To evaluate its putative role in tumorigenesis in intracranial tumours, we investigated cell lines derived from human gliomas and 91 fresh surgical specimens derived from a broad spectrum of intracranial tumours. We found 7 out of 24 cell lines with markedly reduced levels of the retinoblastoma gene protein (pRB) by Western blot and its mRNA by Northern blot analysis. Such a decrease of RB expression appeared not to be clonal, as none of these lines showed subpopulations with nuclear staining in immunocytochemistry. Loss or decreased expression of pRB, however, could only be detected in a small proportion of the glioma tissues. None of the informative lines or the 21 glioma specimens presented any mutation by Southern blot. Furthermore only in 2 out of 28 pituitary adenomas pRB was undetectable, which is interesting, as heterozygous RB-knockout mice are known to develop pituitary tumours. We conclude that alterations of the RB gene seem to be relevant in only a small subset of gliomas. Our findings also suggest, that not only loss, but also ineffectively low levels of pRB, which are not necessarily caused by mutations might play a role in the pathophysiology of tumours.

Gene therapy of gliomas.

Malignant glioma formation is associated with characteristic genetic alterations, although epigenetic mechanisms may contribute in tumorigenesis. Until recently, our knowledge has mainly been based on chromosomal and molecular studies performed in the last two decades. This has increased tremendously with the advent of new technologies, in particular expression arrays for simultaneous analysis of thousands of genes. Consequently, gene therapy of gliomas may aim at molecular interference with 'gain of function' genes (oncogenes) or replacement of 'loss of function' genes (tumor suppressor genes). Such approaches require transgene expression in whole tumor cell populations (if not other mechanisms come into play) which cannot be achieved with current vector systems. Hence other strategies have been pursued which may be independent of genes actually involved in tumorigenesis. Microbial genes (e.g. herpes simplex virus thymidine kinase) may be transferred into the tumors allowing for prodrug activation (e.g. ganciclovir). Furthermore, cytokines or other immunomodulatory genes may be used for vaccination purposes which frequently involves ex vivo transfection of autologous tumor cells with such genes. These approaches proved promising in preclinical studies performed in cell culture and different inbred rodent models. A considerable number of clinical trials have been initiated based on these approaches. Although most therapeutic strategies proved safe, clinical responses fell short of expectations raised by preclinical results. This, to a large extent, has to be attributed to a lag in the development of efficient vector systems. Although much effort has been put into this area of research, neuro-oncologists are still in await of a vector system allowing for selective and efficient tumor cell transduction. This has led to increased interest in distinct but related strategies, e.g. oncolytic viruses or direct intra-tumoral delivery of anti-sense oligonucleotides.

The effects of music intervention on anxiety in the patient waiting for cardiac catheterization.

BACKGROUND: Hospitalization causes anxiety for many patients. It increases when patients anticipate their turn for cardiac catheterization. Music therapy reduces the psychophysiologic effects of anxiety and stress through the relaxation response. AIM: To determine the effects of music therapy an anxiety, heart rate and arterial blood pressure in patients waiting for their scheduled cardiac catheterization. METHODS: In a quasi-experimental, pretest-posttest design, 101 subjects were randomly assigned to either the test group: those who listened to 20 minutes of preselected music, or the control group: those who received treatment as usual. Subject anxiety levels and physiological values were measured while waiting their turn for cardiac catheterization and just prior to departure to the cardiac lab. RESULTS: 63 males and 38 females participated in the study. There was a statistically significant reduction in anxiety in the test group alone (P = 0.003) and in comparing the test to the control group (P = 0.004). In comparing the initial and departure physiologic values, it was noted that both heart rate and systolic blood pressure dropped in the test group, but increased in the control group. Within gender groups, there were no statistically significant differences in hemodynamics or STAI scores, but between gender groups there were significantly higher diastolic blood pressure in males and STAI initial and departure scores for females. DISCUSSION: Patients waiting for their cardiac catheterization benefit from music therapy. Anxiety and the heightened physiological values elicited by the stress response are reduced. Results also suggest that women waiting for cardiac catheterization experience a higher level of anxiety than males.

Suppose a Perclose.

The development of coronary interventional strategies and devices has provided an alternative to surgery for coronary artery disease. The femoral artery is the most common access site for therapeutic cardiac interventions. The methods to achieve hemostasis post procedure vary from conventional, where the arterial puncture site is externally compressed, to novel, where the femoral artery is sealed with a device. One such device is a suture mediated percutaneous vascular closure system developed by Perclose, Incorporated. It provides a safe, effective method to achieve immediate hemostasis of the femoral artery. The vascular complication rate is only 0.78%, time to hemostasis is within 1.3 minutes, and time to ambulation in within 5.5 minutes. These advantages provide improved patient comfort and have a positive economic impact.

Surgical treatment of a basilar perforator aneurysm not accessible to endovascular treatment.

Aneurysms originating from perforatoring branches of the midbasilar artery are extremely rare. Rupture of such an aneurysm resulted in a subarachnoid hemorrhage with a prepontine clot in a 44 year old male who presented with an acute confusional state. After coil embolization had failed, the partially thrombosed aneurysm was wrapped and coagulated via a combined supra-/infratentorial subtemporal presigmoid approach in prone position. The postoperative course was complicated by a tension pneumatocephalus and liquorrhea. Additional aneurysms of the anterior communicating artery and right middle cerebral artery were clipped several months later. The patient recovered well, and except for slight gait ataxia no other deficit remained.