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Background: Deep brain stimulation (DBS) is a promising treatment option for treatment-refractory obsessive-compulsive disorder (OCD). Several stimulation targets have been used, mostly in and around the anterior limb of the internal capsule and ventral striatum. However, the precise target within this region remains a matter of debate., Methods: Here, we retrospectively studied a multicenter cohort of 82 patients with OCD who underwent DBS of the ventral capsule/ventral striatum and mapped optimal stimulation sites in this region., Results: DBS sweet-spot mapping performed on a discovery set of 58 patients revealed 2 optimal stimulation sites associated with improvements on the Yale-Brown Obsessive Compulsive Scale, one in the anterior limb of the internal capsule that overlapped with a previously identified OCD-DBS response tract and one in the region of the inferior thalamic peduncle and bed nucleus of the stria terminalis. Critically, the nucleus accumbens proper and anterior commissure were associated with beneficial but suboptimal clinical improvements. Moreover, overlap with the resulting sweet- and sour-spots significantly estimated variance in outcomes in an independent cohort of 22 patients from 2 additional DBS centers. Finally, beyond obsessive-compulsive symptoms, stimulation of the anterior site was associated with optimal outcomes for both depression and anxiety, while the posterior site was only associated with improvements in depression., Conclusions: Our results suggest how to refine targeting of DBS in OCD and may be helpful in guiding DBS programming in existing patients., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Rate control is the most commonly employed first-line management strategy for atrial fibrillation (AF) in patients with chronic kidney disease (CKD). Principal agents used to control heart rate (HR) include beta-blockers (BB) and nondihydropyridine calcium channel blockers (ND-CCB). However, there is a paucity of published studies of the differences between those drugs in CKD patients., Hypothesis: The present study aimed to investigate the differences, in terms of hospitalizations due to a poor HR control, in patients with AF under a rate-control strategy according to glomerular filtration rate (GFR)., Methods: The study cohort included 2804 AF patients under rate-control regime (BB or ND-CCB) between January 2014 and April 2020. The end point, determined by competing risk regression, was hospitalizations for AF with rapid ventricular response (RVR), slow ventricular response (SVR), and need for pacemaker., Results: On multivariate analysis, there were no statistical differences between ND-CCB and BB for subjects with GFR > 60 mL/min/1.73 m 2 (subdistribution heart rate [sHR] 0.850, 95% confidence interval [CI]: 0.61-1.19; p = .442) and GFR 30-59 mL/min/1.73 m 2 (sHR 1.242, 95% CI: 0.80-1.63; p = .333), while in patients with GFR < 30 mL/min/1.73 m 2 , ND-CCB therapy was associated with increased hospitalizations due to poor HR control (sHR 4.53, 95% CI: 1.19-17.18; p = .026)., Conclusion: In patients with GFR ≥ 30 mL/min/1.73 m 2 , the choice of ND-CCB or BB had no impact on hospitalizations due to poor HR control, while in GFR < 30 mL/min/1.73 m 2 , a possible association was detected. The effects of these drugs on GFR < 30 mL/min/1.73 m 2 would require further investigation., (© 2024 The Authors. Clinical Cardiology published by Wiley Periodicals, LLC.)

Background and Aims: Liver diseases play an important role in the development and progression of atrial fibrillation (AF). The Fibrosis-4 (FIB-4) index is a non-invasive score recommended for detecting liver fibrosis. Since the association between liver fibrosis and outcomes of AF patients is still not well defined, we aim to analyze prognosis impact of FIB-4 index in those patients., Methods: A retrospective population-based cohort study was performed with 12,870 unselected patients from a single health area in Spain with AF from 2014 to 2019. Cox regression models were used to estimate the association of FIB-4 index with mortality. The association with ischemic stroke (IS), major bleeding (MB), acute myocardial infarction (AMI), and heart failure (HF) was assessed by competing risk analysis., Results: A total of 61.1%, 22.0%, and 16.9% were classified as low, moderate and high risk of liver fibrosis according to FIB-4 index, respectively. During a mean follow-up of 4.5 ± 1.7 years, FIB-4 index was associated with mortality (adjusted HR 1.04; 95% CI 1.01-1.06; p = 0.002), MB and HF (adjusted sHR 1.03, 95% CI 1.01-1.04; p = 0.004), but not with IS or with AMI. The association between FIB-4 and MB was only found in patients treated with vitamin K antagonists, not in patients on direct oral anticoagulants., Conclusions: The FIB-4 index, a non-invasive scoring method for evaluating liver fibrosis, is independently associated with all-cause mortality, MB and HF in patients with AF, suggesting that it may be useful as a risk assessment tool to identify adverse outcomes in patients with AF., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: The predictive value of bleeding risk scores for atrial fibrillation in older patients is not as well known. The goal of this study was to evaluate the predictive value of HASBLED, ORBIT and ATRIA for major bleeding (MB) and intracranial hemorrhage (ICH) in patients ≥ 75 years with atrial fibrillation and oral anticoagulation (OAC)., Methods: A retrospective unicenter study including patients ≥ 75 years with atrial fibrillation (AF) and OAC. A total of 7613 patients ≥ 75 years with AF and OAC included between 2014 and 2018 (registry: NCT04364516). We analyzed the discriminative value of HASBLED, ATRIA and ORBIT scores for bleeding endpoints (major bleeding as primary endpoint and intracerebral hemorrhage as secondary). Cox regression was used to predict major bleeding with each scale and also for searching other variables potentially predictor of major bleeding. Model discrimination was assessed using Harrell's C-statistic. Calibration was assessed with goodness-of-fit test proposed by Gronnesby and Borgan., Results: During a mean follow up of 4.0 years (IQR: 2.4-5.7 years), 729 patients developed MB (2.61 per 100 patients/year) and 243 patients developed ICH (0.85 per 100 patients/year). Three scores showed a low discrimination for major bleeding, being ORBIT the best (HASBLED C statistic = 0.557; ATRIA C statistic = 0.568; ORBIT C statistic = 0.595) and also a low discrimination for ICH (HASBLED C statistic = 0.509; ATRIA C statistic = 0.522; ORBIT C statistic = 0.526). Among the variables that are part of the scores and other baseline characteristics, after multivariable adjustment only sex (male), dementia, prior admission for bleeding, anemia and liver disease were found as a predictors of MB., Conclusions: In older patients under oral anticoagulation with atrial fibrillation, the risk scores HASBLED, ATRIA and ORBIT showed a weak discrimination for major bleeding and intracranial hemorrhage. Therefore, other better alternatives should be evaluated for this purpose., Competing Interests: None., (© 2023 JGC All rights reserved; www.jgc301.com.)

Background: Medical treatment in Heart Failure (HF) with reduced ejection fraction (HFrEF; LVEF ≤40%) has shifted towards quadruple therapy. Maximum tolerated dose is the goal, yet no hypotension's cut-off point has been specified. In this work, we analyze the impact of intensive drug titration in clinical events, focusing on low blood pressure (BP) patients at hospital discharge., Methods and Results: Retrospective analysis of 713 patients with HFrEF discharged after an acute HF event (mean LVEF 30 ± 5%). Mean SBP was 112.4 ± 16.5 mmHg and 50.6% were discharged on triple therapy. We considered hypotension as a Systolic blood pressure (SBP) <100 mmHg (21.7% of patients, mean SBP was 112.4 ± 16.5 mmHg) and codified the intensity of drug therapy in 5 stages from untreated to very high therapy intensity. The impact of the intensity of treatment was analysed with a propensity score and increasing the intensity was associated in the whole cohort with a reduction of the composite outcome of all-cause mortality and HF readmission, (HR 0.69; CI95% 0.57-0.85, p < 0.001) and benefit in mortality was maintained for SBP < 100 mmHg (HR 0.42; CI95% 0.22-0.82; p = 0.011). Moreover, therapy intensity was clearly associated with lower risk of HF-hospitalization and death after the additional regression, considering SBP as a covariate, in the whole cohort (HR 0.70; CI95% 0.57-0.85; p < 0.001)., Conclusions: In this retrospective cohort analysis, patients with HFrEF and an acute-HF admission, intensive drug dose titration was related to better outcomes, even in patients with low blood pressure at hospital discharge. Therefore, hypotension is not a contraindication for NHB uptitration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Clinical decision making on anticoagulation in patients with chronic kidney disease with atrial fibrillation (AF) is challenging. The current strategies are based on small observational studies with conflicting results. This study explores the impact of glomerular filtration rate (GFR) in the embolic-hemorrhagic balance among a large cohort of patients with AF. The study cohort included 15,457 patients diagnosed with AF between January 2014 and April 2020. The risk of ischemic stroke and major bleeding was determined by competing risk regression. During a mean follow-up of 4.29 ± 1.82 years, 3,678 patients (23.80%) died, 850 (5.50%) had an ischemic stroke, and 961 (6.22%) had a major bleeding. The incidence of stroke and bleeding increased as baseline GFR decreased. Interestingly, in GFR <30 ml/min/1.73 m 2 , the bleeding risk was clearly higher than the embolic risk. As GFR decreased, anticoagulation was associated with an increased bleeding risk (subdistribution hazard ratio 1.700, 95% confidence interval [CI] 1.13 to 2.54, p = 0.009 for patients with GFR 30 to 59 ml/min/1.73 m 2 and 2.00, 95% CI 0.77 to 5.21, p = 0.156 for subjects with <30 ml/min/1.73 m 2 compared with those with GFR >60 ml/min/1.73 m 2 , respectively), but it was not associated with a decrease in embolic risk in patients with GFR <30 ml/min/1.73 m 2 (subdistribution hazard ratio 1.91, 95% CI 0.73 to 5.04, p = 0.189) In GFR <30 ml/min/1.73 m 2 , the increase of major bleeding risk was higher than the increase of ischemic stroke risk, with a negative anticoagulation balance (greater increase in bleeding than reduction in embolism)., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2023. Published by Elsevier Inc.)

Background: Current guidelines recommend extending the use of dual antiplatelet therapy (DAPT) beyond 1 year in patients with an acute coronary syndrome (ACS) and a high risk of ischaemia and low risk of bleeding. No data exist about the implementation of this strategy in older adults from routine clinical practice., Methods: We conducted a Spanish multicentre, retrospective, observational registry-based study that included patients with ACS but no thrombotic or bleeding events during the first year of DAPT after discharge and no indication for oral anticoagulants. High bleeding risk was defined according to the Academic Research Consortium definition. We assessed the proportion of cases of extended DAPT among patients 65 ≥ years that went beyond 1 year after hospitalisation for ACS and the variables associated with the strategy., Results: We found that 48.1% (928/1,928) of patients were aged ≥ 65 years. DAPT was continued beyond 1 year in 32.1% (298/928) of patients ≥ 65; which was a similar proportion as with their younger counterparts. There was no significant correlation between a high bleeding risk and DAPT duration. Contrastingly, there was a strong correlation between the extent of coronary disease and DAPT duration (p < 0.001). Other variables associated with extended DAPT were a higher left ventricle ejection fraction, a history of heart failure and a prior stent thrombosis., Conclusion: There was no correlation between age and extended use of DAPT beyond 1 year in older patients with ACS. DAPT was extended in about one-third of patients ≥ 65 years. The severity of the coronary disease, prior heart failure, left ventricle ejection fraction and prior stent thrombosis all correlated with extended DAPT., (© 2023. The Author(s).)

Tricuspid regurgitation (TR) is one of the most common heart valve diseases, associated a with poor prognosis since significant TR is associated with an increased mortality risk compared to no TR or mild regurgitation. Surgery is the standard treatment for TR, although it is associated with high morbidity, mortality, and prolonged hospitalization, particularly in tricuspid reoperation after left-sided surgery. Thus, several innovative percutaneous transcatheter approaches for repair and replacement of the tricuspid valve have gathered significant momentum and have undergone extensive clinical development in recent years, with favorable clinical outcomes in terms of mortality and rehospitalization during the first year of follow-up. We present three clinical cases of transcatheter tricuspid valve replacement in an orthotopic position with two different innovative systems along with a review of the state-of-the-art of this emergent topic.

There is limited knowledge regarding the efficacy and safety of fixed-dose oral anticoagulants in overweight patients because of the possible increased risk of embolism and hemorrhage. This study aimed to evaluate embolic, hemorrhagic, and mortality events in anticoagulated patients, administered both antivitamin K and direct oral anticoagulants based on the body weight (<60 kg, 60 to 100 kg and >100 kg). A retrospective registry-based cohort study including all consecutive patients with a diagnosis of atrial fibrillation between January 2014 and January 2018 in the health area of Vigo (Galicia, Spain) was used (CardioCHUVI-AF registry; ClinicalTrials.gov identifier: NCT04364516). The final cohort comprised 11,821 AF patients. The cohort was classified into 3 categories: low body weight ([LBW], <60 kg, 924 patients); middle body weight (60 to 100 kg, 9,546 patients); and high body weight ([HBW], >100 kg, 958 patients). Outcomes were predicted using the Fine and Gray model and Cox proportional hazards model when appropriate. Middle body weight was the reference group. No association was found between the weight and major bleeding in the univariate analyses: LBW with a sub-distribution hazard ratio (sHR) of 1.13 (95% confidence interval [CI] 0.92 to 1.41), and HBW with an sHR of 1.02 (95% CI 0.83 to 1.26). Stroke/systemic embolism events occurred in 817 patients (6.6%). In the univariate analyses, we found an association between weight and risk of stroke/systemic embolism: LBW sHR 1.37 (95% CI 1.09 to 1.72), and HBW sHR 0.66 (95% CI 0.49 to 0.89) but no association was found in the multivariable model. The same situation was observed with all-cause death: in the univariable model, LBW presented a hazard ratio of 1.48 (95% CI 1.31 to 1.68) and the HBW group presented a hazard ratio of 0.53 (95%CI 0.44 to 0.63) whereas no significant association was found in the multivariable model. We conclude that in our registry, extreme weights were not related to more events during follow-up., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Clinical practice guidelines recommend extending dual antiplatelet therapy (DAPT) beyond 1 year after acute coronary syndrome (ACS) in patients with high ischemic risk and without high bleeding risk. The aim of this study was to identify variables associated with DAPT prolongation in a cohort of 1967 consecutive patients discharged after ACS without thrombotic or hemorrhagic events during the following year. The sample was stratified according to whether DAPT was extended beyond 1 year, and the factors associated with this strategy were analyzed. In 32.2% of the patients, DAPT was extended beyond 1 year. Overall, 770 patients (39.1%) were considered candidates for extended treatment based on PEGASUS criteria and absence of high bleeding risk, and DAPT was extended in 34.4% of them. The presence of a PEGASUS criterion was associated with extended DAPT in the univariate analysis, but not history of bleeding or a high bleeding risk. In the multivariate analysis, a history of percutaneous coronary intervention (odds ratio (OR) = 1.8, 95% confidence interval (CI) 1.4-2.4), stent thrombosis (OR = 3.8, 95% CI 1.7-8.9), coronary artery disease complexity (OR = 1.3, 95% CI 1.1-1.5), reinfarction (OR = 4.1, 95% CI 1.6-10.4), and clopidogrel use (OR = 1.3, 95% CI 1.1-1.6) were significantly associated with extended use. DAPT was extended in 32.2% of patients who survived ACS without thrombotic or hemorrhagic events. This percentage was 34.4% when the candidates were analyzed according to clinical guidelines. Neither the PEGASUS criteria nor the bleeding risk was independently associated with this strategy.

Background: Multiple deep brain stimulation (DBS) targets have been proposed for treating intractable obsessive-compulsive disorder (OCD). Here, we investigated whether stimulation effects of different target sites would be mediated by one common or several segregated functional brain networks., Methods: First, seeding from active electrodes of 4 OCD patient cohorts (N = 50) receiving DBS to anterior limb of the internal capsule or subthalamic nucleus zones, optimal functional connectivity profiles for maximal Yale-Brown Obsessive Compulsive Scale improvements were calculated and cross-validated in leave-one-cohort-out and leave-one-patient-out designs. Second, we derived optimal target-specific connectivity patterns to determine brain regions mutually predictive of clinical outcome for both targets and others predictive for either target alone. Functional connectivity was defined using resting-state functional magnetic resonance imaging data acquired in 1000 healthy participants., Results: While optimal functional connectivity profiles showed both commonalities and differences between target sites, robust cross-predictions of clinical improvements across OCD cohorts and targets suggested a shared network. Connectivity to the anterior cingulate cortex, insula, and precuneus, among other regions, was predictive regardless of stimulation target. Regions with maximal connectivity to these commonly predictive areas included the insula, superior frontal gyrus, anterior cingulate cortex, and anterior thalamus, as well as the original stereotactic targets., Conclusions: Pinpointing the network modulated by DBS for OCD from different target sites identified a set of brain regions to which DBS electrodes associated with optimal outcomes were functionally connected-regardless of target choice. On these grounds, we establish potential brain areas that could prospectively inform additional or alternative neuromodulation targets for obsessive-compulsive disorder., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Obsessive-compulsive disorder (OCD) has consistently been linked to abnormal frontostriatal activity. The electrophysiological disruption in this circuit, however, remains to be characterized., Objective/hypothesis: The primary goal of this study was to investigate the neuronal synchronization in OCD patients. We predicted aberrant oscillatory activity in frontal regions compared to healthy control subjects, which would be alleviated by deep brain stimulation (DBS) of the nucleus accumbens (NAc)., Methods: We compared scalp EEG recordings from nine patients with OCD treated with NAc-DBS with recordings from healthy controls, matched for age and gender. Within the patient group, EEG activity was compared with DBS turned off vs. stimulation at typical clinical settings (3.5 V, frequency of stimulation 130 Hz, pulse width 60 μs). In addition, intracranial EEG was recorded directly from depth macroelectrodes in the NAc in four OCD patients., Results: Cross-frequency coupling between the phase of alpha/low beta oscillations and amplitude of high gamma was significantly increased over midline frontal and parietal electrodes in patients when stimulation was turned off, compared to controls. Critically, in patients, beta (16-25 Hz) -gamma (110-166 Hz) phase amplitude coupling source localized to the ventromedial prefrontal cortex, and was reduced when NAc-DBS was active. In contrast, intracranial EEG recordings showed no beta-gamma phase amplitude coupling. The contribution of non-sinusoidal beta waveforms to this coupling are reported., Conclusion: We reveal an increased beta-gamma phase amplitude coupling in fronto-central scalp sensors in patients suffering from OCD, compared to healthy controls, which may derive from ventromedial prefrontal regions implicated in OCD and is normalized by DBS of the nucleus accumbens. This aberrant cross-frequency coupling could represent a biomarker of OCD, as well as a target for novel therapeutic approaches., Competing Interests: Declaration of competing interest JAB has received travel and speaker honoraria from Medtronic and Boston Scientific. The rest of authors declare no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Clinical trials of cell therapies that target stroke started at the beginning of this century and they have experienced a significant boost in recent years as a result of promising data from basic research studies. The increase in the information available has paved the way to carry out more innovative and varied human studies. Efforts have focused on the search for a safe and effective treatment to stimulate neuro-regeneration in the brain and to reduce the sequelae of stroke in patients. Therefore, this review aims to evaluate the clinical trials using cell therapy to treat stroke published to date and assess their limitations. From 2000 to date, most of the published clinical trials have focused on phases I or II, and the vast majority of them demonstrate that stem cells are essentially safe to use when administered by different routes, with transient and mild adverse events that do not generally have severe consequences for health. In general, there is considerable variation in the trials in terms of statistical design, sample size, the cells used, the routes of administration, and the functional assessments (both at baseline and follow-up), making it difficult to compare the studies. From this general description, possibly the experimental protocol is the main element to improve in future studies. Establishing an adequate experimental and statistical design will be essential to obtain favorable and reliable results when conducting phase III clinical trials. Thus, it is necessary to standardize the criteria used in these clinical trials in order to aid comparison. Shortly, cell therapy will be a key approach in the treatment of stroke if adequate and comprehensive levels of recovery are to be achieved., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rascón-Ramírez, Esteban-García, Barcia, Trondin, Nombela and Sánchez-Sánchez-Rojas.)

Inhibitory control is considered a compromised cognitive function in obsessive-compulsive (OCD) patients and likely linked to corticostriatal circuitry disturbances. Here, 9 refractory OCD patients treated with deep brain stimulation (DBS) were evaluated to address the dynamic modulations of large-scale cortical network activity involved in inhibitory control after nucleus accumbens (NAc) stimulation and their relationship with cortical thickness. A comparison of DBS "On/Off" states showed that patients committed fewer errors and exhibited increased intraindividual reaction time variability, resulting in improved goal maintenance abilities and proactive inhibitory control. Visual P3 event-related potentials showed increased amplitudes during Go/NoGo performance. Go and NoGo responses increased cortical activation mainly over the right inferior frontal gyrus and medial frontal gyrus, respectively. Moreover, increased cortical activation in these areas was equally associated with a higher cortical thickness within the prefrontal cortex. These results highlight the critical role of NAc DBS for preferentially modulating the neuronal activity underlying sustained speed responses and inhibitory control in OCD patients and show that it is triggered by reorganizing brain functions to the right prefrontal regions, which may depend on the underlying cortical thinning. Our findings provide updated structural and functional evidence that supports critical dopaminergic-mediated frontal-striatal network interactions in OCD., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

A consensus has yet to emerge whether deep brain stimulation (DBS) for treatment-refractory obsessive-compulsive disorder (OCD) can be considered an established therapy. In 2014, the World Society for Stereotactic and Functional Neurosurgery (WSSFN) published consensus guidelines stating that a therapy becomes established when "at least two blinded randomized controlled clinical trials from two different groups of researchers are published, both reporting an acceptable risk-benefit ratio, at least comparable with other existing therapies. The clinical trials should be on the same brain area for the same psychiatric indication." The authors have now compiled the available evidence to make a clear statement on whether DBS for OCD is established therapy. Two blinded randomized controlled trials have been published, one with level I evidence (Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score improved 37% during stimulation on), the other with level II evidence (25% improvement). A clinical cohort study (N = 70) showed 40% Y-BOCS score improvement during DBS, and a prospective international multi-center study 42% improvement (N = 30). The WSSFN states that electrical stimulation for otherwise treatment refractory OCD using a multipolar electrode implanted in the ventral anterior capsule region (including bed nucleus of stria terminalis and nucleus accumbens) remains investigational. It represents an emerging, but not yet established therapy. A multidisciplinary team involving psychiatrists and neurosurgeons is a prerequisite for such therapy, and the future of surgical treatment of psychiatric patients remains in the realm of the psychiatrist.

Introduction: Alexander disease is a rare disorder caused by mutations in the gene coding for glial fibrillary acidic protein (GFAP). In a previous study, differentiation of neurospheres transfected with these mutations resulted in a cell type that expresses both GFAP and NG2., Objective: To determine the effect of molecular marker mutations in comparison to undifferentiated glioma cells simultaneously expressing GFAP and NG2., Methods: We used samples of human glioblastoma (GBM) and rat neurospheres transfected with GFAP mutations to analyse GFAP and NG2 expression after differentiation. We also performed an immunocytochemical analysis of neuronal differentiation for both cell types and detection of GFAP, NG2, vimentin, Olig2, and caspase-3 at 3 and 7 days from differentiation., Results: Both the cells transfected with GFAP mutations and GBM cells showed increased NG2 and GFAP expression. However, expression of caspase-3-positive cells was found to be considerably higher in transfected cells than in GBM cells., Conclusions: Our results suggest that GFAP expression is not the only factor associated with cell death in Alexander disease. Caspase-3 expression and the potential role of NG2 in increasing resistance to apoptosis in cells co-expressing GFAP and NG2 should be considered in the search for new therapeutic strategies for the disease., (Copyright © 2017 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

The repair of demyelinated lesions is a key objective in multiple sclerosis research. Remyelination fundamentally depends on oligodendrocyte progenitor cells (OPC) reaching the lesion; this is influenced by numerous factors including age, disease progression time, inflammatory activity, and the pool of OPCs available, whether they be NG2 cells or cells derived from neural stem cells. Administering OPCs has been proposed as a potential cell therapy; however, these cells can only be administered directly. This article discusses the potential administration of OPCs encapsulated within hydrogel particles composed of biocompatible biomaterials, via the nose-to-brain pathway. We also discuss conditions for the indication of this therapy, and such related issues as the influence on endogenous remyelination, migration of OPCs to demyelinated areas, and the immune response, given the autoimmune nature of multiple sclerosis. Chitosan and derivatives constitute the most promising biomaterial for this purpose, although these issues must be addressed. In conclusion, this line of research may yield an alternative to the remyelinating drugs currently being studied., (Copyright © 2020 Matías-Guiu, Matías-Guiu, Montero-Escribano, Barcia, Canales-Aguirre, Mateos-Diaz and Gómez-Pinedo.)

Multiple surgical targets for treating obsessive-compulsive disorder with deep brain stimulation (DBS) have been proposed. However, different targets may modulate the same neural network responsible for clinical improvement. We analyzed data from four cohorts of patients (N = 50) that underwent DBS to the anterior limb of the internal capsule (ALIC), the nucleus accumbens or the subthalamic nucleus (STN). The same fiber bundle was associated with optimal clinical response in cohorts targeting either structure. This bundle connected frontal regions to the STN. When informing the tract target based on the first cohort, clinical improvements in the second could be significantly predicted, and vice versa. To further confirm results, clinical improvements in eight patients from a third center and six patients from a fourth center were significantly predicted based on their stimulation overlap with this tract. Our results show that connectivity-derived models may inform clinical improvements across DBS targets, surgeons and centers. The identified tract target is openly available in atlas form.

Ischemic stroke (IS) is the leading cause of disability in the western world, assuming a high socio-economic cost. One of the most used strategies in the last decade has been biomaterials, which have been initially used with a structural support function. They have been perfected, different compounds have been combined, and they have been used together with cell therapy or controlled release chemical compounds. This double function has driven them as potential candidates for the chronic treatment of IS. In fact, the most developed are in different phases of clinical trial. In this review, we will show the ischemic scenario and address the most important criteria to achieve a successful neuroreparation from the point of view of biomaterials. The spontaneous processes that are activated and how to enhance them is one of the keys that contribute to the success of the therapeutic approach. In addition, the different routes of administration and how they affect the design of biomaterials are analyzed. Future perspectives show where this broad scientific field is heading, which advances every day with the help of technology and advanced therapies., (Copyright © 2020 Esteban-Garcia, Nombela, Garrosa, Rascón-Ramirez, Barcia and Sánchez-Sánchez-Rojas.)

Background: Although deep brain stimulation (DBS) of the dorsolateral subthalamic nucleus (STN) is a well-established surgical treatment for patients with Parkinson disease (PD), there is still controversy about the relationship between the functional segregation of the STN and clinical outcomes., Objective: To correlate motor and neuropsychological (NPS) outcomes with the overlap between the volume of activated tissue (VAT) and the tractography-defined regions within the STN., Methods: Retrospective study evaluating 13 patients with PD treated with STN-DBS. With the aid of tractography, the STN was segmented into 4 regions: smaSTN (supplementary motor area STN), m1STN (primary motor area STN), mSTN (the sum of the m1STN and the smaSTN segments), and nmSTN (non-motor STN). We computed the overlap coefficients between these STN regions and the patient-specific VAT. The VAT outside of the STN was also calculated. These coefficients were then correlated with motor (Unified Parkinson's Disease Rating Scale, UPDRS III) and NPS outcomes., Results: Stimulation of the mSTN segment was significantly correlated with UPDRS III and bradykinesia improvement. Stimulation of the smaSTN segment, but not the m1STN one, had a positive correlation with bradykinesia improvement. Stimulation of the nmSTN segment was negatively correlated with the improvement in rigidity. Stimulation outside of the STN was correlated with some beneficial NPS effects., Conclusion: Stimulation of the tractography-defined motor STN, mainly the smaSTN segment, is positively correlated with motor outcomes, whereas stimulation of the nmSTN is correlated with poor motor outcomes. Further validation of these results might help individualize and optimize targets prior to STN-DBS., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Endogenous neurogenesis in stroke is insufficient to replace the lost brain tissue, largely due to the lack of a proper biological structure to let new cells dwell in the damaged area. We hypothesized that scaffolds made of hyaluronic acid (HA) biomaterials (BM) could provide a suitable environment to home not only new neurons, but also vessels, glia and neurofilaments. Further, the addition of exogenous cells, such as adipose stem cells (ASC) could increase this effect. Athymic mice were randomly assigned to a one of four group: stroke alone, stroke and implantation of BM, stroke and implantation of BM with ASC, and sham operated animals. Stroke model consisted of middle cerebral artery thrombosis with FeCl 3 . After 30 days, animals underwent magnetic resonance imaging (MRI) and were sacrificed. Proliferation and neurogenesis increased at the subventricular zone ipsilateral to the ventricle and neuroblasts, glial, and endothelial cells forming capillaries were seen inside the BM. Those effects increased when ASC were added, while there was less inflammatory reaction. Three-dimensional scaffolds made of HA are able to home newly formed neurons, glia, and endothelial cells permitting the growth neurofilaments inside them. The addition of ASC increase these effects and decrease the inflammatory reaction to the implant. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1598-1606, 2019., (© 2018 Wiley Periodicals, Inc.)

Radiotherapy is a highly effective tool for the treatment of brain cancer. However, radiation also causes detrimental effects in the healthy tissue, leading to neurocognitive sequelae that compromise the quality of life of brain cancer patients. Despite the recognition of this serious complication, no satisfactory solutions exist at present. Here we investigated the effects of intranasal administration of human mesenchymal stem cells (hMSCs) as a neuroprotective strategy for cranial radiation in mice. Our results demonstrated that intranasally delivered hMSCs promote radiation-induced brain injury repair, improving neurological function. This intervention confers protection against inflammation, oxidative stress, and neuronal loss. hMSC administration reduces persistent activation of damage-induced c-AMP response element-binding signaling in irradiated brains. Furthermore, hMSC treatment did not compromise the survival of glioma-bearing mice. Our findings encourage the therapeutic use of hMSCs as a non-invasive approach to prevent neurological complications of radiotherapy, improving the quality of life of brain tumor patients.

Background: Psychiatric conditions currently treated with deep brain stimulation (DBS), such as obsessive-compulsive disorder (OCD), are heterogeneous diseases with different symptomatic dimensions, indicating that fixed neuroanatomical DBS targets for all OCD cases may not be efficacious., Objective/hypothesis: We tested whether the optimal DBS target for OCD is fixed for all patients or whether it is individualized and related to each patient's symptomatic content. Further, we explored if the optimal target can be predicted by combining functional neuroimaging and structural connectivity., Methods: In a prospective, randomized, double-blinded study in 7 OCD patients, symptomatic content was characterized pre-operatively by clinical interview and OCD symptom-provocation during functional MRI. DBS electrode implantation followed a trajectory placing 4 contacts along a striatal axis (nucleus accumbens to caudate). Patients underwent three-month stimulation periods for each contact (and sham), followed by clinical evaluation. Probabilistic tractography, applied to diffusion-weighted images acquired pre-operatively, was used to study the overlap between projections from the prefrontal areas activated during symptom provocation and the volume of activated tissue of each electrode contact., Results: Six patients were classified responders, with median symptomatic reduction of 50% achieved from each patient's best contact. This was located at the caudate in 4 cases and at the accumbens in 2. Critically, the anatomical locus of the best contact (accumbens or caudate) was related to an index derived by combining functional MRI responses to prevailing symptom provocation and prefronto-cortico-striatal projections defined by probabilistic tractography., Conclusion: Our results therefore represent a step towards personalized, content-specific DBS targets for OCD., (Copyright © 2018. Published by Elsevier Inc.)

The original version of this article, published on 15 October 2018, unfortunately contained a mistake. The following correction has therefore been made in the original: The name of Mariano Amo-Salas and the affiliation of Ismael Herruzo were presented incorrectly.

Background and Purpose: Multifocal glioblastomas (ie, glioblastomas with multiple foci, unconnected in postcontrast pretreatment T1-weighted images) represent a challenge in clinical practice due to their poor prognosis. We wished to obtain imaging biomarkers with prognostic value that have not been found previously., Materials and Methods: A retrospective review of 1155 patients with glioblastomas from 10 local institutions during 2006-2017 provided 97 patients satisfying the inclusion criteria of the study and classified as having multifocal glioblastomas. Tumors were segmented and morphologic features were computed using different methodologies: 1) measured on the largest focus, 2) aggregating the different foci as a whole, and 3) recording the extreme value obtained for each focus. Kaplan-Meier, Cox proportional hazards, correlations, and Harrell concordance indices (c-indices) were used for the statistical analysis., Results: Age ( P < .001, hazard ratio = 2.11, c-index = 0.705), surgery ( P < .001, hazard ratio = 2.04, c-index = 0.712), contrast-enhancing rim width ( P < .001, hazard ratio = 2.15, c-index = 0.704), and surface regularity ( P = .021, hazard ratio = 1.66, c-index = 0.639) measured on the largest focus were significant independent predictors of survival. Maximum contrast-enhancing rim width ( P = .002, hazard ratio = 2.05, c-index = 0.668) and minimal surface regularity ( P = .036, hazard ratio = 1.64, c-index = 0.600) were also significant. A multivariate model using age, surgery, and contrast-enhancing rim width measured on the largest foci classified multifocal glioblastomas into groups with different outcomes ( P < .001, hazard ratio = 3.00, c-index = 0.853, median survival difference = 10.55 months). Moreover, quartiles with the highest and lowest individual prognostic scores based on the focus with the largest volume and surgery were identified as extreme groups in terms of survival ( P < .001, hazard ratio = 18.67, c-index = 0.967)., Conclusions: A prognostic model incorporating imaging findings on pretreatment postcontrast T1-weighted MRI classified patients with glioblastoma into different prognostic groups., (© 2019 by American Journal of Neuroradiology.)

Objectives: We wished to determine whether tumor morphology descriptors obtained from pretreatment magnetic resonance images and clinical variables could predict survival for glioblastoma patients., Methods: A cohort of 404 glioblastoma patients (311 discoveries and 93 validations) was used in the study. Pretreatment volumetric postcontrast T1-weighted magnetic resonance images were segmented to obtain the relevant morphological measures. Kaplan-Meier, Cox proportional hazards, correlations, and Harrell's concordance indexes (c-indexes) were used for the statistical analysis., Results: A linear prognostic model based on the outstanding variables (age, contrast-enhanced (CE) rim width, and surface regularity) identified a group of patients with significantly better survival (p < 0.001, HR = 2.57) with high accuracy (discovery c-index = 0.74; validation c-index = 0.77). A similar model applied to totally resected patients was also able to predict survival (p < 0.001, HR = 3.43) with high predictive value (discovery c-index = 0.81; validation c-index = 0.92). Biopsied patients with better survival were well identified (p < 0.001, HR = 7.25) by a model including age and CE volume (c-index = 0.87)., Conclusions: Simple linear models based on small sets of meaningful MRI-based pretreatment morphological features and age predicted survival of glioblastoma patients to a high degree of accuracy. The partition of the population using the extent of resection improved the prognostic value of those measures., Key Points: • A combination of two MRI-based morphological features (CE rim width and surface regularity) and patients' age outperformed previous prognosis scores for glioblastoma. • Prognosis models for homogeneous surgical procedure groups led to even more accurate survival prediction based on Kaplan-Meier analysis and concordance indexes.

Background/aim: The prevalence of cognitive symptoms in recently diagnosed Parkinson's disease (PD) patients may be as high as 60%. We report a novel deep brain stimulation (DBS) strategy targeting both motor and cognitive symptoms., Methods: A PD patient diagnosed with mild cognitive impairment underwent DBS surgery targeting the globus pallidus interna (GPi; to treat motor symptoms) and the nucleus basalis of Meynert (NBM; to treat cognitive symptoms) using a single electrode per hemisphere., Results: Compared to baseline, 2-month follow-up after GPi stimulation was associated with motor improvements, whereas partial improvements in cognitive functions were observed 3 months after the addition of NBM stimulation to GPi stimulation., Conclusion: This case explores an available alternative for complete DBS treatment in PD, stimulating 2 targets at different frequencies with a single electrode lead., (© 2019 S. Karger AG, Basel.)

Repair of central nervous system (CNS) lesions is difficulted by the lack of ability of central axons to regrow, and the blocking by the brain astrocytes to axonal entry. We hypothesized that by using bridges made of porous biomaterial and permissive olfactory ensheathing glia (OEG), we could provide a scaffold to permit restoration of white matter tracts. We implanted porous polycaprolactone (PCL) bridges between the substantia nigra and the striatum in rats, both with and without OEG. We compared the number of tyrosine-hydroxylase positive (TH+) fibers crossing the striatal-graft interface, and the astrocytic and microglial reaction around the grafts, between animals grafted with and without OEG. Although TH+ fibers were found inside the grafts made of PCL alone, there was a greater fiber density inside the graft and at the striatal-graft interface when OEG was cografted. Also, there was less astrocytic and microglial reaction in those animals. These results show that these PCL grafts are able to promote axonal growth along the nigrostriatal pathway, and that cografting of OEG markedly enhances axonal entry inside the grafts, growth within them, and re-entry of axons into the CNS. These results may have implications in the treatment of diseases such as Parkinson's and others associated with lesions of central white matter tracts. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 107B: 190-196, 2019., (© 2018 Wiley Periodicals, Inc.)

Introduction: Stroke represents an attractive target for cell therapy. Although different types of cells have been employed in animal models with variable results, the human adipose-derived stem cells (hASCs) have demonstrated favorable characteristics in the treatment of diseases with inflammatory substrate, but experience in their intracerebral administration is lacking. The purpose of this study is to evaluate the effect and safety of the intracerebral application of hASCs in a stroke model., Methods: A first group of Athymic Nude mice after stroke received a stereotactic injection of hASCs at a concentration of 4 × 10 4 /µL at the penumbra area, a second group without stroke received the same cell concentration, and a third group had only stroke and no cells. After 7, 15, and 30 days, the animals underwent fluorodeoxyglucose-positron emission tomography and magnetic resonance imaging; subsequently, they were sacrificed for histological evaluation (HuNu, GFAP, IBA-1, Ki67, DCX) of the penumbra area and ipsilateral subventricular zone (iSVZ)., Results: The in vitro studies found no alterations in the molecular karyotype, clonogenic capacity, and expression of 62 kDa transcription factor and telomerase. Animals implanted with cells showed no adverse events. The implanted cells showed no evidence of proliferation or differentiation. However, there was an increase of capillaries, less astrocytes and microglia, and increased bromodeoxyuridine and doublecortin-positive cells in the iSVZ and in the vicinity of ischemic injury., Conclusions: These results suggest that hASCs in the implanted dose modulate inflammation, promote endogenous neurogenesis, and do not proliferate or migrate in the brain. These data confirm the safety of cell therapy with hASCs., (Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Purpose To evaluate the prognostic and predictive value of surface-derived imaging biomarkers obtained from contrast material-enhanced volumetric T1-weighted pretreatment magnetic resonance (MR) imaging sequences in patients with glioblastoma multiforme. Materials and Methods A discovery cohort from five local institutions (165 patients; mean age, 62 years ± 12 [standard deviation]; 43% women and 57% men) and an independent validation cohort (51 patients; mean age, 60 years ± 12; 39% women and 61% men) from The Cancer Imaging Archive with volumetric T1-weighted pretreatment contrast-enhanced MR imaging sequences were included in the study. Clinical variables such as age, treatment, and survival were collected. After tumor segmentation and image processing, tumor surface regularity, measuring how much the tumor surface deviates from a sphere of the same volume, was obtained. Kaplan-Meier, Cox proportional hazards, correlations, and concordance indexes were used to compare variables and patient subgroups. Results Surface regularity was a powerful predictor of survival in the discovery (P = .005, hazard ratio [HR] = 1.61) and validation groups (P = .05, HR = 1.84). Multivariate analysis selected age and surface regularity as significant variables in a combined prognostic model (P < .001, HR = 3.05). The model achieved concordance indexes of 0.76 and 0.74 for the discovery and validation cohorts, respectively. Tumor surface regularity was a predictor of survival for patients who underwent complete resection (P = .01, HR = 1.90). Tumors with irregular surfaces did not benefit from total over subtotal resections (P = .57, HR = 1.17), but those with regular surfaces did (P = .004, HR = 2.07). Conclusion The surface regularity obtained from high-resolution contrast-enhanced pretreatment volumetric T1-weighted MR images is a predictor of survival in patients with glioblastoma. It may help in classifying patients for surgery., (© RSNA, 2018 Online supplemental material is available for this article.)

Introduction: Cerebrospinal fluid (CSF) from amyotrophic lateral sclerosis (ALS) patients induces cytotoxic effects in in vitro cultured motor neurons., Material and Methods: We selected CSF with previously reported cytotoxic effects from 32 ALS patients. Twenty-eight adult male rats were intracerebroventricularly implanted with osmotic mini-pumps and divided into 3 groups: 9 rats injected with CSF from non-ALS patients, 15 rats injected with cytotoxic ALS-CSF, and 4 rats injected with a physiological saline solution. CSF was intracerebroventricularly and continuously infused for periods of 20 or 43days after implantation. We conducted clinical assessments and electromyographic examinations, and histological analyses were conducted in rats euthanised 20, 45, and 82days after surgery., Results: Immunohistochemical studies revealed tissue damage with similar characteristics to those found in the sporadic forms of ALS, such as overexpression of cystatinC, transferrin, and TDP-43 protein in the cytoplasm. The earliest changes observed seemed to play a protective role due to the overexpression of peripherin, AKTpan, AKTphospho, and metallothioneins; this expression had diminished by the time we analysed rats euthanised on day 82, when an increase in apoptosis was observed. The first cellular changes identified were activated microglia followed by astrogliosis and overexpression of GFAP and S100B proteins., Conclusion: Our data suggest that ALS could spread through CSF and that intracerebroventricular administration of cytotoxic ALS-CSF provokes changes similar to those found in sporadic forms of the disease., (Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

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., (© 2018 S. Karger AG, Basel.)

OBJECTIVE The extent of resection is the most important prognostic factor following brain glioma surgery. However, eloquent areas within tumors limit the extent of resection and, thus, critically affect outcomes. The authors hypothesized that presurgical suppression of the eloquent areas within a tumor by continuous cortical electrical stimulation, coupled with appropriate behavioral training ("prehabilitation"), would induce plastic reorganization and enable a more extensive resection. METHODS The authors report on 5 patients harboring gliomas involving eloquent brain areas within tumors as identified on intraoperative stimulation mapping. A grid of electrodes was placed over the residual tumor, and continuous cortical electrical stimulation was targeted to the functional areas. The stimulation intensity was adjusted daily to provoke a mild functional impairment while the function was intensively trained. RESULTS The stimulation intensity required to impair function increased progressively in all patients, and all underwent another operation a mean of 33.6 days later (range 27-37 days), when the maximal stimulation voltage in all active contacts induced no functional deficit. In all cases, a substantially more extensive resection of the tumor was possible. Intraoperative mapping and functional MRI demonstrated a plastic reorganization, and most previously demonstrated eloquent areas within the tumor were silent, while there was new functional activation of brain areas in the same region or toward the contralateral hemisphere. CONCLUSIONS Prehabilitation with continuous cortical electrical stimulation and appropriate behavioral training prior to surgery in patients with WHO Grade II and III gliomas affecting eloquent areas accelerate plastic changes. This can help maximize tumor resection and, thus, improve survival while maintaining function.

Background: Deep brain stimulation within or adjacent to the subthalamic nucleus (STN) represents the most common stereotactic procedure performed for Parkinson disease. Better STN imaging is often regarded as a requirement for improving stereotactic targeting. However, it is unclear whether there is consensus about the optimal target., Methods: To obtain an expert opinion on the site regarded optimal for "STN stimulation," movement disorder specialists were asked to indicate their preferred position for an active contact on hard copies of the Schaltenbrand and Wahren atlas depicting the STN in all 3 planes. This represented an idealized setting, and it mimicked optimal imaging for direct target definition in a perfectly delineated STN., Results: The suggested targets were heterogeneous, although some clustering was observed in the dorsolateral STN and subthalamic area. In particular, in the anteroposterior direction, the intended targets differed to a great extent. Most of the indicated targets are thought to also result in concomitant stimulation of structures adjacent to the STN, including the zona incerta, fields of Forel, and internal capsule., Conclusions: This survey illustrates that most sites regarded as optimal for STN stimulation are close to each other, but there appears to be no uniform perception of the optimal anatomic target, possibly influencing surgical results. The anatomic sweet zone for STN stimulation needs further specification, as this information is likely to make magnetic resonance imaging-based target definition less variable when applied to individual patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The potential of a tumour's volumetric measures obtained from pretreatment MRI sequences of glioblastoma (GBM) patients as predictors of clinical outcome has been controversial. Mathematical models of GBM growth have suggested a relation between a tumour's geometry and its aggressiveness., Methods: A multicenter retrospective clinical study was designed to study volumetric and geometrical measures on pretreatment postcontrast T1 MRIs of 117 GBM patients. Clinical variables were collected, tumours segmented, and measures computed including: contrast enhancing (CE), necrotic, and total volumes; maximal tumour diameter; equivalent spherical CE width and several geometric measures of the CE "rim". The significance of the measures was studied using proportional hazards analysis and Kaplan-Meier curves., Results: Kaplan-Meier and univariate Cox survival analysis showed that total volume [p = 0.034, Hazard ratio (HR) = 1.574], CE volume (p = 0.017, HR = 1.659), spherical rim width (p = 0.007, HR = 1.749), and geometric heterogeneity (p = 0.015, HR = 1.646) were significant parameters in terms of overall survival (OS). Multivariable Cox analysis for OS provided the later two parameters as age-adjusted predictors of OS (p = 0.043, HR = 1.536 and p = 0.032, HR = 1.570, respectively)., Conclusion: Patients with tumours having small geometric heterogeneity and/or spherical rim widths had significantly better prognosis. These novel imaging biomarkers have a strong individual and combined prognostic value for GBM patients., Key Points: • Three-dimensional segmentation on magnetic resonance images allows the study of geometric measures. • Patients with small width of contrast enhancing areas have better prognosis. • The irregularity of contrast enhancing areas predicts survival in glioblastoma patients.

The cortico-basal ganglia and corticothalamic projections have been extensively studied in the context of neurological and psychiatric disorders. Deep brain stimulation (DBS) is known to modulate many of these pathways to produce the desired clinical effect. The aim of this work is to describe the anatomy of the main circuits of the basal ganglia using tractography in a surgical planning station. We used imaging studies of 20 patients who underwent DBS for movement and psychiatric disorders. We segmented the putamen, caudate nucleus (CN), thalamus, and subthalamic nucleus (STN), and we also segmented the cortical areas connected with these subcortical areas. We used tractography to define the subdivisions of the basal ganglia and thalamus through the generation of fibers from the cortical areas to the subcortical structures. We were able to generate the corticostriatal and corticothalamic connections involved in the motor, associative and limbic circuits. Furthermore, we were able to reconstruct the hyperdirect pathway through the corticosubthalamic connections and we found subregions in the STN. Finally, we reconstructed the cortico-subcortical connections of the ventral intermediate nucleus, the nucleus accumbens and the CN. We identified a feasible delineation of the basal ganglia and thalamus connections using tractography. These results could be potentially useful in DBS if the parcellations are used as targets during surgery., (© 2016 Wiley Periodicals, Inc.)

Real-world decisions about reward often involve a complex counterbalance of risk and value. Although the nucleus accumbens has been implicated in the underlying neural substrate, its criticality to human behaviour remains an open question, best addressed with interventional methodology that probes the behavioural consequences of focal neural modulation. Combining a psychometric index of risky decision-making with transient electrical modulation of the nucleus accumbens, here we reveal profound, highly dynamic alteration of the relation between probability of reward and choice during therapeutic deep brain stimulation in four patients with treatment-resistant psychiatric disease. Short-lived phasic electrical stimulation of the region of the nucleus accumbens dynamically altered risk behaviour, transiently shifting the psychometric function towards more risky decisions only for the duration of stimulation. A critical, on-line role of human nucleus accumbens in dynamic risk control is thereby established., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Recent advances in imaging permit radiologic identification of target structures for deep brain stimulation (DBS) for movement disorders. However, these methods cannot detect the internal subdivision and thus cannot determine the appropriate DBS target located within those subdivisions. The aim of this study is to provide a straightforward method to obtain an optimized target (OT) within DBS target nuclei using a widely available navigation system. We used T1- and T2-weighted images, fluid-attenuated inversion recovery (FLAIR) sequence, and diffusion tensor imaging (DTI) of nine patients operated for DBS in our center. Using the StealthViz® software, we segmented the targeted deep structures (subcortical targets) and the anatomically identifiable areas to which these target nuclei were connected (projection areas). We generated fiber tracts from the projection areas. By identifying their intersections with the subcortical targets, we obtained an OT within the DBS target nuclei. We computed the distances from the clinically effective electrode contacts (CEEC) to the OT obtained by our method and the targets provided by the atlas. These distances were compared using a Wilcoxon signed-rank test, with p < 0.05 considered statistically significant. We were able to identify OT coincident with the motor part of the subthalamic nucleus and the ventral intermediate nucleus. We clinically tested the results and found that the CEEC were significantly more closely related to the OT than with the targets obtained by the atlas. Our present results show that this novel method permits optimization of the stimulation site within the internal subdivisions of target nuclei for DBS.

Objective: Scalp metastases of meningiomas seldom have been reported. Here, we report a series of 4 cases of this rare event and discuss the relevant potential risk factors., Methods: We performed a retrospective review of patients treated for scalp metastases of meningiomas at our institution. A literature review was performed for the terms "scalp meningioma," "cutaneous meningioma," "skin meningioma," "extracranial meningioma," and "subcutaneous meningioma.", Results: Four patients showed scalp metastases of recurrent meningiomas with the following associated clinical features: multiple reoperations (n = 4), immunosuppression (n = 2), radiation therapy (n = 3), surgical wound complications with cerebrospinal fluid fistula (n = 2), and histologic grade progression (n = 2). The timescale for development of scalp metastasis was between 5 months and 13 years after intracranial meningioma surgery. In all cases, the metastases were located close to the surgical scalp incision for the craniotomy. Previously, 11 cases of meningioma with scalp metastasis, with similar features to those described here, were reported in the literature., Conclusions: Spreading of meningioma cells during surgery is a possible mechanism for scalp metastases of recurrent meningiomas. Factors associated with scalp metastases include reoperations, immunosuppression, radiation therapy, torpid course of the surgical wound with cerebrospinal fluid fistula, and histologic progression. Awareness of these features is advisable for neurosurgeons involved in the care of patients with similar profiles., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The objective of the present study was to evaluate the biocompatibility and cell hosting ability of a copolymer scaffold based on ethyl acrylate (EA) and hydroxyl ethyl acrylate (HEA) in vivo after an experimental brain injury. Wistar rats were subjected to cryogenic traumatic brain injury. We evaluated the tissue response to the implanted materials after 8 weeks. The materials were implanted devoid of cells; they provoked a minimal scar response by the host tissue and permitted the invasion of neurons and glia inside them. We also found new blood vessels surrounding and inside the implant. Thus, the copolymer scaffold proves to offer a suitable environment producing a cellular network potentially useful in brain repair after brain injury., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Supplemental education is desirable for neurosurgical training, and the use of human cadaver specimen and virtual reality models is routine. An in vivo porcine training model for cranial neurosurgery was introduced in 2005, and our recent experience with this unique model is outlined here. For the first time, porcine anatomy is illustrated with particular respect to neurosurgical procedures. The pros and cons of this model are described. The aim of the course was to set up a laboratory scenery imitating an almost realistic operating room in which anatomy of the brain and neurosurgical techniques in a mentored environment free from time constraints could be trained. Learning objectives of the course were to learn about the microsurgical techniques in cranial neurosurgery and the management of complications. Participants were asked to evaluate the quality and utility of the programme via standardized questionnaires by a grading scale from A (best) to E (worst). In total, 154 residents have been trained on the porcine model to date. None of the participants regarded his own residency programme as structured. The bleeding and complication management (97%), the realistic laboratory set-up (89%) and the working environment (94%) were favoured by the vast majority of trainees and confirmed our previous findings. After finishing the course, the participants graded that their skills in bone drilling, dissecting the brain and preserving cerebral vessels under microscopic magnification had improved to level A and B. In vivo hands-on courses, fully equipped with microsurgical instruments, offer an outstanding training opportunity in which bleeding management on a pulsating, vital brain represents a unique training approach. Our results have shown that education programmes still lack practical training facilities in which in vivo models may act as a complementary approach in surgical training.

Background and Objective: Occluding a ruptured intracranial aneurysm as early as possible may entail certain periprocedural conditions that compromise the outcome. The aim of the present study was to evaluate the effectiveness, safety, and clinical outcome of endovascular coiling procedures performed on an emergency basis under potentially suboptimal conditions, and to compare results with those from scheduled procedures under potentially optimal conditions., Methods: Interventions performed on 66 SAH patients were retrospectively analysed by classifying them into two groups: under emergency (within three hours from diagnosis or during non-standard working hours) or scheduled conditions. A binary logistic regression analysis was also performed to identify characteristics associated with poor outcomes., Results: No differences in effectiveness, periprocedural complications, or clinical outcomes were found between the two groups. Rebleeding was detected in 4.8 % of the emergency interventions and 2.2 % of the scheduled interventions. Multivariate analysis identified age and Hunt and Hess grade, but no conditions of treatment, as the factors associated to poor outcome., Conclusion: Suboptimal interventional conditions for occluding ruptured intracranial aneurysms, such as performing procedures outside of standard working hours or within three hours of diagnosis, do not result in increased periprocedural complications and poor clinical outcomes compared with scheduled procedures under potentially optimal conditions. These results suggest the need for treatment to be provided as soon as possible.