Core items to be included in a definition of moderate psoriatic arthritis: literature review and expert opinion.

Evidence-based treatment recommendations for psoriatic arthritis (PsA) suggest that treatment should be individualised but acknowledge the difficulty of correctly defining levels of activity (mild, moderate and severe). The aim of this study was to define the parameters or disease characteristics that should be included in a future definition of moderate PsA. Mixed. methods: (1) literature review to identify previous assessment tools used to classify patients into mild, moderate and severe forms, and (2) survey of rheumatologists, and experts in PsA, to obtain their opinion on the degree of validation and applicability of published definitions and tools, and on the parameters that should be included in a future definition of moderate PsA. We propose eight domains/items to be included in a definition of moderate PsA: number of active joints and inflamed entheses, physician global assessment (by visual analogue scale), dactylitis, body surface area (BSA) affected by psoriasis, psoriasis in special locations, and absence of hip involvement. The Disease Activity Index for Psoriatic Arthritis (DAPSA) score would be supported as part of this definition, as would the Psoriatic Arthritis Impact of Disease (PsAID) index. This study proposes a set of items/domains to be included in a definition of moderate PsA based on literature and expert opinion, which can be the starting point for further development and validation studies of the proposed items.

New, Fully Implantable Device for Selective Clearance of CSF-Target Molecules: Proof of Concept in a Murine Model of Alzheimer's Disease.

We have previously proposed a radical change in the current strategy to clear pathogenic proteins from the central nervous system (CNS) based on the cerebrospinal fluid (CSF)-sink therapeutic strategy, whereby pathogenic proteins can be removed directly from the CNS via CSF. To this aim, we designed and manufactured an implantable device for selective and continuous apheresis of CSF enabling, in combination with anti-amyloid-beta (Aß) monoclonal antibodies (mAb), the clearance of Aß from the CSF. Here, we provide the first proof of concept in the APP/PS1 mouse model of Alzheimer's disease (AD). Devices were implanted in twenty-four mice (seventeen APP/PS1 and seven Wt) with low rates of complications. We confirmed that the apheresis module is permeable to the Aß peptide and impermeable to mAb. Moreover, our results showed that continuous clearance of soluble Aß from the CSF for a few weeks decreases cortical Aß plaques. Thus, we conclude that this intervention is feasible and may provide important advantages in terms of safety and efficacy.

Long-term avian influenza virus epidemiology in a small Spanish wetland ecosystem is driven by the breeding Anseriformes community.

During 2007-2009 and 2012-2014, avian influenza virus (AIV) was studied in a wild avian community of a northern Spanish wetland using non-invasive sampling methods and host identification by COI barcoding. The aim of this longitudinal study was to evaluate AIV dynamics in a natural wetland ecosystem, taking into account both virological aspects and ecological traits of hosts. Global AIV prevalence decreased significantly during the second sampling period (0.3%) compared to the first (6.6%). Circulating subtype distributions were also different between periods, with a noteworthy H5 and H7 subtype richness during the first sampling period. Mallard Anas platyrhynchos was identified as the main AIV host, although not all positive samples could be ascribed to the host. We modelled AIV prevalence with regard to the avian host community composition and meteorological data from the wetland. Statistical analysis revealed seasonal differences in AIV detection, with higher prevalence during the breeding season compared to other phenological events. The model also shows that the lower AIV prevalence during the second study period was associated with a significant reduction of breeding Anseriformes in the wetland, revealing a long-term fluctuation of AIV prevalence driven by the breeding Anseriformes community. This longitudinal study on AIV epidemiology in a natural ecosystem reveals that although prevalence follows seasonal and annual patterns, long-term prevalence fluctuation is linked to the breeding community composition and size. These results are relevant to understanding the influence of host ecology on pathogen transmission for preventing and managing influenza emergence.

The role of contextual signal TGF-ß1 inducer of epithelial mesenchymal transition in metastatic lung adenocarcinoma patients with brain metastases: an update on its pathological significance and therapeutic potential.

Lung adenocarcinoma (LA) is the most common cause of cancer-related death worldwide. Despite the advances over last decade in new targeted therapies, cancer genetics, diagnostics, staging, and surgical techniques as well as new chemotherapy and radiotherapy protocols, the death rate from LA remains high. The tumour microenvironment is composed of several cytokines, one of which is transforming growth factor ß1 (TGF-ß1), which modulates and mediates the expression of epithelial-mesenchymal transition (EMT), correlated with invasive growth in LAs, and exhibits its pleiotropic effects through binding to transmembrane receptors TßR-1 (also termed activin receptor-like kinases - ALKs) and TßR-2. Accordingly, there is an urgent need to elucidate the molecular mechanisms associated with the tumoural spreading process and therapeutic resistance of this serious pathology. In this review, we briefly discuss the current role of contextual signal TGF-ß1 inducer of epithelial mesenchymal transition in metastatic lung adenocarcinoma patients with brain metastases, and give an overview of our current mechanistic understanding of the TGF-ß1-related pathways in brain metastases progression, TGF-ß1 pathway inhibitors that could be used for clinical treatment, and examination of models used to study these processes. Finally, we summarise the current progress in the therapeutic approaches targeting TGF-ß1.

Long-Term Results of Deep Brain Stimulation of the Mamillotegmental Fasciculus in Chronic Cluster Headache.

BACKGROUND: Deep brain stimulation (DBS) and the proper target for chronic cluster headache (CCH) are still subjects of controversy. OBJECTIVES: We present our long-term results of analysis of the target and its structural connectivity. METHODS: Fifteen patients with drug-resistant CCH underwent DBS in coordinates 4 mm lateral to the III ventricular wall and 2 mm behind and 5 mm below the intercommissural point. The clinical parameters recorded were the number of weekly attacks, pain intensity, and duration of the headache. Structural connectivity was studied using 3-T MR diffusion tensor imaging (DTI). RESULTS: All of our patients improved from a mean of 39 attacks/week to 2; pain intensity decreased from 9 to 3 out of 10, and the mean cephalalgia duration decreased from 53 to 8 min. The mean stereotactic coordinates of the effective contact location were 6.1 mm lateral to the midcommissural point and 1.2 mm behind and 4.0 mm below the intercommissural point. DTI analysis showed that this target was connected to tracts and nuclei of the posterior mesencephalic tegmentum, specifically the dorsal longitudinal and mamillotegmental fasciculi. CONCLUSIONS: Our data showed DBS to be a safe and useful procedure for the treatment of drug-resistant CCH; the rate of improvement was higher than those found in other series. Although these are promising results, larger series targeting those fasciculi with a longer follow-up are needed.

The EJES-3D tool for personalized prescription of exercise in axial spondyloarthritis through multimedia animations: pilot study.

To develop and evaluate a web application based on multimedia animations, combined with a training program, to improve the prescription of exercises in spondyloarthritis (SpA). After a review of exercises included in the main clinical trials and recommendations of international societies, a multidisciplinary team-rehabilitators, rheumatologists, physiotherapists, computer scientists and graphic designers-developed a web application for the prescription of exercises (EJES-3D). Once completed, this was presented to 12 pairs of rehabilitators-rheumatologists from the same hospital in a workshop. Knowledge about exercise was tested in rheumatologists before and 6 months after the workshop, when they also evaluated the application. The EJES-3D application includes 38 multimedia videos and allows prescribing predesigned programs or customizing them. A patient can consult the prescribed exercises at any time from a device with internet connection (mobile, tablet, or computer). The vast majority of the evaluators (89%) were satisfied or very satisfied and considered that their expectations regarding the usefulness of the web application had been met. They highlighted the ability to tailor exercises adapted to the different stages of the disease and the quality and variety of the videos. They also indicated some limitations of the application and operational problems. The EJES-3D tool was positively evaluated by experts in SpA, potentially the most demanding group of users with the most critical capacity. This allows a preliminary validation of the contents, usefulness, and ease of use. Analyzing and correcting the errors and limitations detected is allowing us to improve the EJES-3D tool.

Prognostic factors and survival study in high-grade glioma in the elderly.

Background Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumour in adults. Due to the ageing of the population, diagnosis in the elderly is becoming more common. The aim of this study was to analyse different combinations of treatments and to identify preoperative factors, including O6-methylguanine-DNA methyltransferase status, that may be associated with decreased survival among patients older than 70 years. Methods and materials We retrospectively included all patients over 70 years of age, who underwent surgery at the Department of Neurosurgery (HUCA and HUMV) and were diagnosed of GBM by pathological criteria from January 2007 to September 2014. Results Eighty-one patients were analysed, whose mean age was 75 (SD 4) and 48 were male. Karnofsky performance status (KPS) was over 70 in 61 patients and 38.3% presented with motor deficit. Sixty-three patients underwent resection, and 18 had only a diagnostic biopsy. The complication rate was 17.28% and mortality rate was 7.4%. Survival was increased in patients who received radiotherapy (n = 41) or additional chemotherapy (n = 26) (p < 0.001). KPS < 70 was an independent factor associated with low-rate survival. Patients with optimal treatment had a median survival of 8 months compared to patients with suboptimal treatment who had a median survival of 4 months (p < 0.001). Conclusions This study suggests that KPS is the most important preoperative prognostic factor. Maximal safe resection followed by radical radiotherapy and temozolomide might be the optimal treatment of choice since glioblastoma-diagnosed patients over 70 years of age showed a statistically significant survival benefit.

Acid-sensing ion channels in healthy and degenerated human intervertebral disc.

Acid-sensing ion channels (ASICs) are a family of H(+)-gated voltage-insensitive ion channels that respond to extracellular acidification by regulating transmembrane Ca(2+) flux. Moreover, ASICs can also be gated by mechanical forces and may function as mechanosensors. The cells of the intervertebral disc (IVD) have an unusual acidic and hyperosmotic microenvironment. Changes in the pH and osmolarity determine the viability of IVD cells and the composition of the extracellular matrix, and both are the basis of IVD degeneration. In this study, the expression of ASICs (ASIC1, ASIC2, ASIC3 and ASIC4) mRNAs and proteins in human healthy and degenerated IVD was evaluated by quantitative reverse transcription-quantitative polymerase chain reaction and Western blot. The distribution of ASIC proteins was determined by immunohistochemistry. The mRNAs for all ASICs were detected in normal human IVD, and significantly increased levels were found in degenerated IVD. Western blots demonstrated the presence of proteins with estimated molecular weights of approximately 68-72 kDa. In both the annulus fibrosus (AF) and nucleus pulposus (NP) of normal IVD, ASIC2 is the most frequently expressed ASIC followed by ASIC3, ASIC1 and ASIC4. In the AF of degenerated IVD, there was a significant increase in the number of ASIC1 and ASIC4 positive cells, whereas in the NP, we found significant increase of expression of ASIC1, ASIC2 and ASIC3. These results describe the occurrence and localization of different ASICs in human healthy IVD, and their increased expression in degenerated IVD, thus suggesting that ASICs may be involved in IVD degeneration.

Involvement of autophagy in melatonin-induced cytotoxicity in glioma-initiating cells.

Glioblastoma-initiating cells (GICs) represent a stem cell-like subpopulation within malignant glioblastomas responsible for tumor development, progression, therapeutic resistance, and tumor relapse. Thus, eradication of this subpopulation is essential to achieve stable, long-lasting remission. We have previously reported that melatonin decreases cell proliferation of glioblastoma cells both in vitro and in vivo and synergistically increases effectiveness of drugs in glioblastoma cells and also in GICs. In this study, we evaluated the effect of the indolamine alone in GICs and found that melatonin treatment reduces GICs proliferation and induces a decrease in self-renewal and clonogenic ability accompanied by a reduction in the expression of stem cell markers. Moreover, our results also indicate that melatonin treatment, by modulating stem cell properties, induces cell death with ultrastructural features of autophagy. Thus, data reported here reinforce the therapeutic potential of melatonin as a treatment of malignant glioblastoma both by inhibiting tumor bulk proliferation or killing GICs, and simultaneously enhancing the effect of chemotherapy.

Surgical adverse events of deep brain stimulation in the subthalamic nucleus of patients with Parkinson's disease. The learning curve and the pitfalls.

BACKGROUND: Several surgical adverse events (SAEs) have been associated with Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's Disease (PD) patients, leading to certain confusion about the risk/benefit ratio of this technique, and giving rise to the need of more and more extensive control studies over longer periods. The aim of this article is to identify and quantify the factors associated with the most frequent AEs from STN DBS in PD-diagnosed patients. METHODS: The following variables were studied: aborted procedure, misplaced leads, intracranial haemorrhage, and seizures. This study was carried out in 233 patients diagnosed with PD, with 455 STN electrodes implanted and follow-up after 7 (8-14) years follow up. RESULTS: A total amount of 56 SAEs occurred in 49 patients (11.76 % of total procedures, 12.31 % of implanted leads, 21.03 % of patients). SAEs were: five aborted procedures, 26 misplaced leads, ten intracranial haemorrhages, and 15 seizures. Of all the SAEs, long-term effects only happened in two cases of hemiparesis caused by intracranial haemorrhage; the other SAEs were reversible and didn't leave any long-term clinical consequences (0.42 % of procedures, 0.44 % of leads, and 0.86 % of patients). CONCLUSIONS: STN DBS in PD patients is a safe surgical procedure, with good risk/benefit ratios: procedure reliability/correct lead implantation in 95.59 %, 0 mortality/implanted lead, 0.12 morbidity/implanted lead, and 0.0043 neurological sequelae/implanted lead.

Medicinal plant extracts interfere in gastric cancer stem cells fluorescence-based assays.

Fluorescence is used in various biological assays due to its high sensitivity, versatility, and precision. In recent years, studies using medicinal plant extracts have increased. However, fluorescence-based assays could be biased by plant metabolites autofluorescence. To address this issue, this study investigated the interference caused by methanolic extracts and chloroform fractions of three medicinal plants in three fluorescence-based assays on gastric cancer stem cells(CSC): resazurin reduction, confocal microscopy, and flow cytometry. CSC were isolated based on CD44 surface marker, incubated with methanolic extracts and chloroform fractions of Buddleja incana, Dracontium spruceanum, Piper aduncum. Resazurin assay evidenced that CSC exposed to extracts and fractions from the three plants showed significant differences in relative fluorescence units (RFU) levels (p < 0.001) compared to the unexposed groups after a 3-hour incubation. In addition, DMSO-treated CSC exposed to extracts and fractions had significantly lower fluorescence levels than living ones, but higher than extracts and fractions without cells. In confocal microscopy, cancer stem cells exposed to extracts and fractions of B. incana and P. aduncum were observed in the same emission spectra of the CSC markers. In flow cytometry, CSC exposed to extracts and fractions without any fluorescent dyes were detected in the double positive quadrants for CSC markers (CD44+/CD133 + ). Among the three plants, D. spruceanum exhibited the least interference. These results show that methanolic extracts and chloroform fractions contain autofluorescent metabolites that interfere with fluorescence-based assays. These results highlight the importance of a prior evaluation for possible fluorescence interference to avoid interpretation biases in fluorescence assays.

Real-world apremilast use in biologic-naïve psoriatic arthritis patients. Data from Spanish clinical practice.

INTRODUCTION: Apremilast is approved for treatment of psoriasis and psoriatic arthritis (PsA). Real-world evidence on apremilast effectiveness in clinical practice is limited. METHODS: Observational study enrolling adult patients, across 21 Spanish centres, who had initiated apremilast in the prior 6 (±1) months and were biologic naive. Data were collected at routine follow-up visits 6 and 12 months after apremilast initiation. Primary outcome was 6 and 12-month persistence to apremilast. Secondary outcomes included Disease Activity for PsA (DAPSA), joint erosions, enthesitis, dactylitis, and patient-reported quality of life (QoL, measured using the PsA impact of disease [PsAID] questionnaire). RESULTS: We included 59 patients. Most had oligoarticular PsA, moderate disease activity, and high comorbidity burden. Three-quarters were continuing apremilast at 6 months and two-thirds at 12 months; mean (SD) apremilast treatment duration was 9.43 (1.75) months. DAPSA scores showed improved disease activity: one-third of patients in remission or low activity at apremilast initiation versus 62% and 78% at 6 and 12 months, respectively. Eleven of 46 patients with radiographic assessments had joint erosions at apremilast initiation and none at month 12. Median (Q1, Q3) number of swollen joints was 4.0 (2.0, 6.0) at apremilast initiation versus 0.0 (0.0, 2.0) at 12 months. Incidence of dactylitis and enthesitis decreased between apremilast initiation (35.6% and 28.8%, respectively) and month 12 (11.6% and 2.4%, respectively). Over two-thirds of patients had a PSAID-9 score <4 (cut-off for patient-acceptable symptom state) at month 12. CONCLUSIONS: In Spanish clinical practice, two-thirds of PsA patients continued apremilast at 12 months, with clinical benefits at the joint level, no radiographic progression of erosions, and a positive impact on patient-reported QoL. Trial registration number Clinicaltrials.gov: NCT03828045.

Melatonin-induced methylation of the ABCG2/BCRP promoter as a novel mechanism to overcome multidrug resistance in brain tumour stem cells.

BACKGROUND: Current evidence indicates that a stem cell-like sub-population within malignant glioblastomas, that overexpress members of the adenosine triphosphate-binding cassette (ABC) family transporters, is responsible for multidrug resistance and tumour relapse. Eradication of the brain tumour stem cell (BTSC) compartment is therefore essential to achieve a stable and long-lasting remission. METHODS: Melatonin actions were analysed by viability cell assays, flow cytometry, quantitative PCR for mRNA expression, western blot for protein expression and quantitative and qualitative promoter methylation methods. RESULTS: Combinations of melatonin and chemotherapeutic drugs (including temozolomide, current treatment for malignant gliomas) have a synergistic toxic effect on BTSCs and A172 malignant glioma cells. This effect is correlated with a downregulation of the expression and function of the ABC transporter ABCG2/BCRP. Melatonin increased the methylation levels of the ABCG2/BCRP promoter and the effects on ABCG2/BCRP expression and function were prevented by preincubation with a DNA methyltransferase inhibitor. CONCLUSION: Our results point out a possible relationship between the downregulation of ABCG2/BCRP function and the synergistic toxic effect of melatonin and chemotherapeutic drugs. Melatonin could be a promising candidate to overcome multidrug resistance in the treatment of glioblastomas, and thus improve the efficiency of current therapies.

Refining Stereotaxic Neurosurgery Techniques and Welfare Assessment for Long-Term Intracerebroventricular Device Implantation in Rodents.

Stereotaxic surgeries enable precise access to specific brain regions, being of particular interest for chronic intracerebroventricular drug delivery. However, the challenge of long-term studies at this level is to allow the implantation of drug storage devices and their correct intrathecal connection while guaranteeing animal welfare during the entire study period. In this study, we propose an optimized method for safe intrathecal device implantation, focusing on preoperative, intraoperative, and postoperative procedures, following the 3Rs principle and animal welfare regulations. Our optimized protocol introduces three main refinements. Firstly, we modify the dimensions of the implantable devices, notably diminishing the device-to-mouse weight ratio. Secondly, we use a combination of cyanoacrylate tissue adhesive and UV light-curing resin, which decreases surgery time, improves healing, and notably minimizes cannula detachment or adverse effects. Thirdly, we develop a customized welfare assessment scoresheet to accurately monitor animal well-being during long-term implantations. Taken together, these refinements positively impacted animal welfare by minimizing the negative effects on body weight, surgery-related complications, and anxiety-like behaviors. Overall, the proposed refinements have the potential to reduce animal use, enhance experimental data quality, and improve reproducibility. Additionally, these improvements can be extended to other neurosurgical techniques, thereby advancing neuroscience research, and benefiting the scientific community.

Down-regulation of spinophilin in lung tumours contributes to tumourigenesis.

The scaffold protein spinophilin (Spn, PPP1R9B) is one of the regulatory subunits of phosphatase-1a (PP1), targeting it to distinct subcellular locations and to its target. Loss of Spn reduces PPP1CA levels, thereby maintaining higher levels of phosphorylated pRb. This effect contributes to an increase in p53 activity. However, in the absence of p53, reduced levels of Spn increase the tumourigenic properties of cells. In addition, Spn knockout mice have a reduced lifespan, an increased number of tumours and increased cellular proliferation in some tissues, such as the mammary ducts. In addition, the combined loss of Spn and p53 activity leads to an increase in mammary carcinomas, confirming the functional relationship between p53 and Spn. In this paper, we report that Spn is absent in 20% and reduced in another 37% of human lung tumours. Spn reduction correlates with malignant grade. Furthermore, the loss of Spn also correlates with p53 mutations. Analysis of miRNAs in a series of lung tumours showed that miRNA106a* targeting Spn is over-expressed in some patients, correlating with decreased Spn levels. Proof-of-concept experiments over-expressing miRNA106a* or Spn shRNA in lung tumour cells showed increased tumourigenicity. In conclusion, our data showed that miRNA106a* over-expression found in lung tumours might contribute to tumourigenesis through Spn down-regulation in the absence of p53.

Meningeal Melanomatosis with a Spinal Meningeal Melanocytoma Trigger by an in vitro Fertilization.

Meningeal melanomatosis is an infrequent tumor originating from the melanocytes in the leptomeninges and one of the recognized primary melanocytic tumors of the central nervous system. The average survival has known to be about 5 months. It can be associated with solid tumors, such as meningeal melanocytomas. The patient we present was diagnosed of a meningeal melanomatosis that developed two solid tumors related to an in vitro fertilization. The clinical course was rapidly fatal. Although the use of comprehensive diagnostic procedures, usually the final diagnosis of primary diffuse meningeal melanomatosis is postmortem, it would be advisable for the appropriate management of the patient to make a differential diagnosis and to be aware of the behavior of the tumor.

Risk Factors Associated With Inadequate Brain Relaxation in Craniotomy for Surgery of Supratentorial Tumors.

INTRODUCTION: Cerebral swelling often occurs during craniotomy for cerebral tumors. Poor brain relaxation can increase the risk of cerebral ischemia, possibly worsening the outcome. The surgical team should identify any risk factors that could cause perioperative brain swelling and decide which therapies are indicated for improving it. The present investigation aimed to elucidate the risk factors associated with brain swelling during elective craniotomy for supratentorial brain tumors. METHODS: This prospective, nonrandomized, observational study included 52 patients scheduled for elective supratentorial tumor surgery. The degree of brain relaxation was classified upon the opening of the dura according to a four-point scale (brain relaxation score: 1, perfectly relaxed; 2, satisfactorily relaxed; 3, firm brain; and 4, bulging brain). Moreover, hemodynamic and respiratory parameters, arterial blood gas, and plasma osmolality were recorded after the removal of the bone flap. RESULTS: This study showed that the use of preoperative dexamethasone was associated with a brain relaxation score of ≤2 (p = 0.005). The median midline shift of 6 (3-0) mm and median hemoglobin level of >13 g/dL were associated with a brain relaxation score of ≥3 (p = 0.02 and p = 0.01, respectively). The dosage of mannitol (0.25 g/kg versus 0.5 g/kg), physical status, intraoperative position, tumor diameter and volume, peritumoral edema and mass effect, World Health Organization (WHO) grading, mean arterial pressure, PaCO2, osmolality, and core temperature were not identified as risk factors associated with poor relaxation. CONCLUSION: The use of preoperative dexamethasone was associated with improved brain relaxation, whereas the presence of a preoperative midline shift and a higher level of hemoglobin were associated with poor brain relaxation.

Neuromodulation of the posterolateral hypothalamus for the treatment of chronic refractory cluster headache: Experience in five patients with a modified anatomical target.

INTRODUCTION: Deep brain stimulation (DBS) of the posterior hypothalamus has been found to be effective in the treatment of refractory chronic cluster headache (CCH). METHODS: We report the long-term outcomes of five patients with refractory CCH on whom stimulation of a modified target of approximately 3 mm in radius, which included the posterolateral hypothalamus, the fasciculus mammillotegmentalis, the fasciculus mammillothalamicus and the fasciculus medialis telencephali, was performed. The stereotaxic coordinates were 4 mm from the third ventricle wall, 2 mm from behind the mid-intercommissural point and 5 mm from under the intercommissural line. RESULTS: All patients became pain-free for 1-2 weeks after the procedure, but then needed an average of 54 days to optimize stimulation parameters. After a mean follow-up of 33 months, two remain pain-free, two have an excellent response (>90% decrease in attack frequency) and in one the attacks have been reduced by half. There were no serious adverse events. Permanent myosis and euphoria/well-being feeling were seen in three patients. Other adverse events, such as diplopia, dizziness, global headache of cervical dystonia, were seen transiently related to an increase in stimulation parameters. Attacks reappeared transiently in two patients as a result of cable rupture and when the stimulator was disconnected. CONCLUSIONS: Our results supports the efficacy of DBS in very refractory CCH with a slightly modified hypothalamic target conceived to avoid the lateral ventricle wall so as to extend the stimulated brain area and to decrease the morbidity of potential haemorrhagic complications.