Deep brain stimulation for refractory obsessive-compulsive disorder (OCD): emerging or established therapy?

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.

Nucleus Accumbens Stimulation Modulates Inhibitory Control by Right Prefrontal Cortex Activation in Obsessive-Compulsive Disorder.

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.

Morphological MRI-based features provide pretreatment survival prediction in glioblastoma.

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.

Correction to: Morphological MRI-based features provide pretreatment survival prediction in glioblastoma.

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.

Simultaneous Stimulation of the Globus Pallidus Interna and the Nucleus Basalis of Meynert in the Parkinson-Dementia Syndrome.

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.

Tumor Surface Regularity at MR Imaging Predicts Survival and Response to Surgery in Patients with Glioblastoma.

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.

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.

Evaluation of the Safety and Efficacy of the Therapeutic Potential of Adipose-Derived Stem Cells Injected in the Cerebral Ischemic Penumbra.

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 × 104/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.

Glioblastoma: does the pre-treatment geometry matter? A postcontrast T1 MRI-based study.

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.

Dynamic risk control by human nucleus accumbens.

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.

Tractographical model of the cortico-basal ganglia and corticothalamic connections: Improving Our Understanding of Deep Brain Stimulation.

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.

Assessment of a method to determine deep brain stimulation targets using deterministic tractography in a navigation system.

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.

In vivo porcine training model for cranial neurosurgery.

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.

Occipital cortex activation by long-term repetitive tactile stimulation is necessary for object recognition in blinds: a case report.

Tactile vision has been approached from a variety of angles using different techniques. So far, a certain kind of object (and text) recognition has been shown, though seeing as such has not been achieved yet, and it remains unclear. Trough repetitive passive tactile stimulation perceptual processing is transferred from temporo-parietal to occipital areas, which affects object recognition. We report the results of passive tactile stimulation, as well as rTMS, applied to a 50 year old left handed blind male with over 97% loss of vision, who suffers from Peter's anomaly and microphthalmia. After 15 weeks of passive tactile stimulation, the subject showed increased activity in occipital areas associated with the development of visual-like perception which remained unchanged after three months without passive tactile stimulation. Inhibitory rTMS over the visual cortex led to noticeable reduction of spatial recognition performance and visual sensations in this subject. Stable changes in occipital cortical activity can be associated with subjective sensations of seeing. Once occipital activation has been achieved, it is necessary for spatial object recognition. Both facts highlight the implication of occipital areas in tactile vision and the cortical plasticity of passive tactile long-term stimulation in people with blindness.

Deep brain stimulation for obsessive-compulsive disorder: is the side relevant?

BACKGROUND: Deep brain stimulation for obsessive-compulsive disorder (OCD) has targeted several subcortical nuclei, including the subthalamic nucleus (STN) and the nucleus accumbens. While the most appropriate target is still being looked for, little attention has been given to the side of the stimulated hemisphere in relationship to outcome. METHODS: We report 2 patients diagnosed with OCD, one having symmetry obsessions and the other one with sexual-religious obsessive thoughts. They were implanted bilaterally with deep electrodes located at both STN and nuclei accumbens. The effectiveness of the stimulation was tested for every possible paired combination of electrodes guided by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score reduction. RESULTS: In both cases, the combination of electrodes which best relieved the OCD symptoms was both the left STN and left accumbens. In case 1, the preoperative Y-BOCS score was 33, and 1 month after stimulation it was 16. In case 2, the Y-BOCS scores were 33 and 3, respectively, with the patient being free of obsessions. CONCLUSION: Some reports suggest that lesion stimulation or stimulation of only the right side relieves OCD symptoms. However, anatomical and functional studies are not conclusive as to which side is most affected in OCD. Possibly, each OCD patient has an individualized optimal side to stimulate.

Deep Brain Stimulation for Obsessive-Compulsive Disorder: Optimal Stimulation Sites.

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.

[Recommendations on the use of 5-amino-levulinic acid in surgery of malignant gliomas. Consensus document. The Neuro-oncology Working Group of the Spanish Neurosurgical Society (SENEC)]. / Recomendaciones sobre el uso de ácido 5-aminolevulínico en la cirugía de los gliomas malignos. Documento de consenso.

Among the prognostic factors when it comes to patients with high-grade gliomas, we find the radicality of the surgery performed. The limitations of this factor are caused by either the extension of the tumour or its location in an eloquent area. To achieve this goal, in the last few years we have developed several methods that allow us to maximise tumour resection, while always trying to cause the least possible co-morbidity. One of these methods includes the use of 5-amino-levulinic acid (5-ALA) and the development of fluorescence guided surgery. However, optimal performance requires knowledge of the product employed, the mode of administration and precautions to consider. Members of the neuro-oncology work group of the Spanish Neurosurgical Society (SENEC) have prepared this guideline or consensus document for anyone who wishes to become familiar with the use of 5-ALA fluorescence-guided surgery in the management of high-grade gliomas. For those who already utilise this technique, this document can be useful for consultation purposes.