Deep brain stimulation electrodes used for staged lesion within the basal ganglia: experimental studies for parameter validation. Laboratory investigation.

OBJECT: Deep brain stimulation (DBS) has been shown to be an effective treatment for various types of movement disorders. High-frequency stimulation is applied to specific brain targets through an implanted quadripolar lead connected to a pulse generator. These leads can be used for creating lesions in the brain. The experimental study reported here was designed to examine the electrical parameters that could be used to create reproducible therapeutic lesions in the brain. METHODS: Egg whites were used to measure the relationship between the electrical parameters (current and voltage) applied through the DBS electrode and the size of coagulum. The authors measured current spread from the electrode contact used for lesioning to the adjacent contact. Similar studies were performed in the pallidum or the thalamus of human cadavers. Modeling of the lesion size was performed with simulation of current density and temperature. The ultrastructure of the electrodes after lesioning was verified by electron microscopy. RESULTS: Coagulation size increased with time but reached a plateau after 30 seconds. For a given set of electrical parameters, reproducibility of the size of lesions was high. Using constant voltage, lesions were larger in egg whites than in cadaveric brains with a mean length of 5 +/- 0.6 mm in egg whites at 40 V, 125 mA, impedance 233 Omega; and 4.0 +/- 0.8 mm in cadavers at 40 V, 38 mA, impedance 1333 Omega. Computer modeling indicated negligible current flow to the adjacent, unused electrodes. The electrodes showed no structural alterations on scanning electron microscopy after more than 200 lesions. CONCLUSIONS: Results of this study demonstrate that DBS electrodes can be used to generate lesions reproducibly in the brain. The choice of lesioning parameters must take into account differences in impedance between the test medium (egg whites) and the human brain parenchyma.

Fear recognition is impaired by subthalamic nucleus stimulation in Parkinson's disease.

Behavioural disturbances such as disorders of mood, apathy or indifference are often observed in Parkinson's disease (PD) patients with chronic high frequency deep brain stimulation of subthalamic nucleus (STN DBS). Neuropsychological modifications causing these adverse events induced by STN DBS remain unknown, even if limbic disturbances are hypothesised. The limbic system supports neural circuits processing emotional information. The aim of this work is to evaluate changes of emotional recognition in PD patients induced by STN DBS. Thirty PD patients were assessed using a computerised paradigm of recognition of emotional facial expressions [Ekman, P., & Friesen, W. V. (1976). Pictures of facial affect. Palo Alto, CA: Consulting Psychologists Press], 15 before STN DBS and 15 after. The two patients groups were compared to a group of 15 healthy control subjects. One series of 55 pictures of emotional facial expressions was presented to each patient. Patients had to classify the pictures according to seven basic emotions (happiness, sadness, fear, surprise, disgust, anger and no emotion). The intact ability to percept faces was firstly assured using the Benton Recognition Test. Recognition of fear expressions was significantly and selectively reduced in the post-operative group in comparison to both pre-operative and control groups. Our results demonstrate for the first time a selective reduction of recognition of facial expressions of fear by STN DBS. This impairment could be the first neuropsychological marker of a more general limbic dysfunction, thought to be responsible for the behavioural disorders reported after STN DBS.

Motor and non motor effects during intraoperative subthalamic stimulation for Parkinson's disease.

Spatial distribution of the clinical effects induced by deep brain stimulation during the intraoperative investigation of the subthalamic nucleus (STN) for Parkinson's disease (PD) was analysed in 17 patients under local anesthesia. The stimulation parameters were 130 hertz, 100 micros, and voltage ranged from 0.05 to 5 volts. Optimal motor response was assessed as the total and lasting disappearance of wrist rigidity on the side opposite to stimulation. Among the adverse effects induced by stimulation, special attention was given to frequently observed autonomic effects (AE). Full motor response was achieved in 49.2% of the 301 points evaluated,with a mean voltage (MV) of 0.94 volts; paresthesiae occurred in 6.6% (MV: 2 volts), dystonia in 10.6% (MV: 3.4 volts), autonomic effects in 19.6% (MV: 3.1 volts) and oculomotor effects in 31.6% (MV: 3 volts). The motor target was located in the posterodorsal part of the nucleus and the optimal point for motor response was close to the superior limit of the nucleus. Whereas other adverse effects occurred relatively far from the motor target, AE occurred with statistic significance near this point. Their neural substrates, such as limbic system and their relationship with postoperative behavioral disorders, are discussed.

[Ventriculo-ureteric shunt without associated nephrectomy for the treatment of hydrocephalus]. / Dérivation ventriculo-urétérale sans néphrectomie associée pour hydrocéphalie.

The authors report the case of a 51-year-old patient with hydrocephalus following posterior fossa surgery (cerebellar astrocytoma) treated by ventriculo-peritoneal shunt, then ventriculo-atrial shunt. After repeated valve revisions (diffuse peritoneal loculation, intracardiac thrombus responsible for dyspnoea and recurrent pulmonary embolism, shunt infections), another mode of shunting was required. The authors opted for ventriculo-ureteric shunt comprising ureteric reimplantation into a psoas bladder, without associated nephrectomy, which appears to constitute an alternative in the case of difficult surgical management of hydrocephalus or after failure of other modes of ventricular shunting.

Staged lesions through implanted deep brain stimulating electrodes: a new surgical procedure for treating tremor or dyskinesias.

Thalamotomy and pallidotomy have been shown to have some efficacy for treating some movement disorders such as disabling tremor or parkinsonian levodopa-induced dyskinesias (LID). Compared to continuous deep brain stimulation (DBS), this surgical procedure has the disadvantage of irreversibility and a lack of adaptability. Making a lesion involves a risk of inducing permanent side effects, especially if the lesion is large, or of observing a resurgence of the symptoms if the lesion is too small. We performed unilateral pallidotomy in one patient suffering from LID and unilateral thalamotomy in two patients suffering from tremor through the lead classically used for DBS. The technique of lead implantation was similar to that used for DBS treatment but, instead of connecting the lead to a pulse generator, it was left in place and used to make a radiofrequency lesion. This technique allowed the lesion to be kept as small as possible, thereby minimizing the risk of permanent side effects and made possible to extend the lesion if the symptoms reappeared. One lesioning session was enough to relieve tremor in the two patients treated by thalamotomy; three lesioning sessions over a 7-month period were required to relieve drug-induced dyskinesias in the patient treated by pallidotomy. In all 3 patients, disabling symptoms were still relieved without any permanent side effects 6 months after the last lesion was performed.

Indirect detection of photosensitizer ex vivo.

Photodynamic therapy induces the production of reactive oxygen species (ROS) within tissues exposed to laser light after administration of a sensitizer. In the context of continuing clinical and commercial development of chemicals with sensitizing properties, a minimally invasive assay is needed to determine the tissue kinetics of fluorescent or non-fluorescent photoreactive drugs. The level of ROS was determined ex vivo from 1 mm3 biopsy samples using 2'-7' dichlorofluorescin diacetate (DCFH-DA), a fluorescent probe which was converted into highly fluorescent dichlorofluorescein (DCF) in the presence of ROS. This assay was tested on meta(tetrahydroxyphenyl)chlorin (m-THPC, FOSCAN), a powerful and fluorescent sensitizer, and bacteriochlorophyll derivative WST09 (TOOKAD), a near-infrared absorbing sensitizer that is only slightly fluorescent. In conjunction with the ROS assay, the tissue accumulation of m-THPC was determined on biopsy samples using an optic fibre spectrofluorometer (OFS). DCF fluorescence was proportional to the level of oxidation induced by horseradish peroxidase used as a control and to the concentration (range: 0-5 microg x ml(-1)) of both selected photosensitizers irradiated in a tube together with DCFH. Regardless of the organ studied, an excellent correlation was found between fluorescence measurement by OFS and ROS determination for m-THPC. m-THPC (2 mg x kg(-1) iv) accumulation in tumour tissues was best after 48 h, and the best signal was obtained in liver. With non-fluorescent WST09 (2 mg x kg(-1)), ROS determination showed the best tumour uptake 48 h after injection, with a tumour/muscle ratio of 5.4. The ROS assay appears to be feasible for determining sensitizer concentration in regular grip biopsy tissue samples.

Potential efficacy of a delta 5-aminolevulinic acid thermosetting gel formulation for use in photodynamic therapy of lesions of the gastrointestinal tract.

Photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX may play a role in the treatment of dysplastic Barrett's oesophagus. An ALA thermosetting gel Pluronic F-127) was developed and evaluated in an in vivo mouse model for potential use in PDT of Barrett's mucosa. In vitro studies of the influence of Pluronic F-127 percentage on thermosetting gel temperature, followed by the influence of ALA concentration on thermosetting temperature and ALA-gel stability as a function of time or temperature were studied. In vivo relationships between ALA doses and fluorescence were studied to determine the optimal concentration. Fluorescence measurement in vivo showed that ALA concentration and time had a nonlinear influence on protoporphyrin IX synthesis. For ALA-gel applications longer than 30 min a plateau fluorescence was reached, the maximum fluorescence being obtained after 4 h whatever the time of contact. The maximum intensity (2824 counts s(-1)) was found with 40 mg mL(-1) ALA-gel, and fluorescence intensities differed with time, reaching a maximum after 3-4 h. ALA-Pluronic F-127 is a suitable formulation for treatment of Barrett's oesophagus, allowing easy application in liquid form at 4 degrees C and good adhesion in the oesophagus in gel form, with efficient diffusion of ALA into treated mucosa.