Claudio Pollo

Electroencephalographic source imaging: a prospective study of 152 operated epileptic patients

Electroencephalography is mandatory to determine the epilepsy syndrome. However, for the precise localization of the irritative zone in patients with focal epilepsy, costly and sometimes cumbersome imaging techniques are used. Recent small studies using electric source imaging suggest that electroencephalography itself could be used to localize the focus. However, a large prospective validation study is missing. This study presents a cohort of 152 operated patients where electric source imaging was applied as part of the pre-surgical work-up allowing a comparison with the results from other methods. Patients (n = 152) with >1 year postoperative follow-up were studied prospectively. The sensitivity and specificity of each imaging method was defined by comparing the localization of the source maximum with the resected zone and surgical outcome. Electric source imaging had a sensitivity of 84% and a specificity of 88% if the electroencephalogram was recorded with a large number of electrodes (128–256 channels) and the individual magnetic resonance image was used as head model. These values compared favourably with those of structural magnetic resonance imaging (76% sensitivity, 53% specificity), positron emission tomography (69% sensitivity, 44% specificity) and ictal/interictal single-photon emission-computed tomography (58% sensitivity, 47% specificity). The sensitivity and specificity of electric source imaging decreased to 57% and 59%, respectively, with low number of electrodes (<32 channels) and a template head model. This study demonstrated the validity and clinical utility of electric source imaging in a large prospective study. Given the low cost and high flexibility of electroencephalographic systems even with high channel counts, we conclude that electric source imaging is a highly valuable tool in pre-surgical epilepsy evaluation.

Directional deep brain stimulation: an intraoperative double-blind pilot study

Deep brain stimulation of different targets has been shown to drastically improve symptoms of a variety of neurological conditions. However, the occurrence of disabling side effects may limit the ability to deliver adequate amounts of current necessary to reach the maximal benefit. Computed models have suggested that reduction in electrode size and the ability to provide directional stimulation could increase the efficacy of such therapies. This has never been demonstrated in humans. In the present study, we assess the effect of directional stimulation compared to omnidirectional stimulation. Three different directions of stimulation as well as omnidirectional stimulation were tested intraoperatively in the subthalamic nucleus of 11 patients with Parkinsons disease and in the nucleus ventralis intermedius of two other subjects with essential tremor. At the trajectory chosen for implantation of the definitive electrode, we assessed the current threshold window between positive and side effects, defined as the therapeutic window. A computed finite element model was used to compare the volume of tissue activated when one directional electrode was stimulated, or in case of omnidirectional stimulation. All but one patient showed a benefit of directional stimulation compared to omnidirectional. A best direction of stimulation was observed in all the patients. The therapeutic window in the best direction was wider than the second best direction (P = 0.003) and wider than the third best direction (P = 0.002). Compared to omnidirectional direction, the therapeutic window in the best direction was 41.3% wider (P = 0.037). The current threshold producing meaningful therapeutic effect in the best direction was 0.67 mA (0.3-1.0 mA) and was 43% lower than in omnidirectional stimulation (P = 0.002). No complication as a result of insertion of the directional electrode or during testing was encountered. The computed model revealed a volume of tissue activated of 10.5 mm(3) in omnidirectional mode, compared with 4.2 mm(3) when only one electrode was used. Directional deep brain stimulation with a reduced electrode size applied intraoperatively in the subthalamic nucleus as well as in the nucleus ventralis intermedius of the thalamus significantly widened the therapeutic window and lowered the current needed for beneficial effects, compared to omnidirectional stimulation. The observed side effects related to direction of stimulation were consistent with the anatomical location of surrounding structures. This new approach opens the door to an improved deep brain stimulation therapy. Chronic implantation is further needed to confirm these findings.

Structural and Resting State Functional Connectivity of the Subthalamic Nucleus: Identification of Motor STN Parts and the Hyperdirect Pathway

Deep brain stimulation (DBS) for Parkinson’s disease often alleviates the motor symptoms, but causes cognitive and emotional side effects in a substantial number of cases. Identification of the motor part of the subthalamic nucleus (STN) as part of the presurgical workup could minimize these adverse effects. In this study, we assessed the STN’s connectivity to motor, associative, and limbic brain areas, based on structural and functional connectivity analysis of volunteer data. For the structural connectivity, we used streamline counts derived from HARDI fiber tracking. The resulting tracks supported the existence of the so-called “hyperdirect” pathway in humans. Furthermore, we determined the connectivity of each STN voxel with the motor cortical areas. Functional connectivity was calculated based on functional MRI, as the correlation of the signal within a given brain voxel with the signal in the STN. Also, the signal per STN voxel was explained in terms of the correlation with motor or limbic brain seed ROI areas. Both right and left STN ROIs appeared to be structurally and functionally connected to brain areas that are part of the motor, associative, and limbic circuit. Furthermore, this study enabled us to assess the level of segregation of the STN motor part, which is relevant for the planning of STN DBS procedures.

A Cross Validation Study of Deep Brain Stimulation Targeting: From Experts to Atlas-Based, Segmentation-Based and Automatic Registration Algorithms

Validation of image registration algorithms is a difficult task and open-ended problem, usually application-dependent. In this paper, we focus on deep brain stimulation (DBS) targeting for the treatment of movement disorders like Parkinsons disease and essential tremor. DBS involves implantation of an electrode deep inside the brain to electrically stimulate specific areas shutting down the diseases symptoms. The subthalamic nucleus (STN) has turned out to be the optimal target for this kind of surgery. Unfortunately, the STN is in general not clearly distinguishable in common medical imaging modalities. Usual techniques to infer its location are the use of anatomical atlases and visible surrounding landmarks. Surgeons have to adjust the electrode intraoperatively using electrophysiological recordings and macrostimulation tests. We constructed a ground truth derived from specific patients whose STNs are clearly visible on magnetic resonance (MR) T2-weighted images. A patient is chosen as atlas both for the right and left sides. Then, by registering each patient with the atlas using different methods, several estimations of the STN location are obtained. Two studies are driven using our proposed validation scheme. First, a comparison between different atlas-based and nonrigid registration algorithms with a evaluation of their performance and usability to locate the STN automatically. Second, a study of which visible surrounding structures influence the STN location. The two studies are cross validated between them and against experts variability. Using this scheme, we evaluated the experts ability against the estimation error provided by the tested algorithms and we demonstrated that automatic STN targeting is possible and as accurate as the expert-driven techniques currently used. We also show which structures have to be taken into account to accurately estimate the STN location

Chronic deep brain stimulation in mesial temporal lobe epilepsy

The objective of this study was to evaluate the efficiency and the effects of changes in parameters of chronic amygdala-hippocampal deep brain stimulation (AH-DBS) in mesial temporal lobe epilepsy (TLE). Eight pharmacoresistant patients, not candidates for ablative surgery, received chronic AH-DBS (130 Hz, follow-up 12-24 months): two patients with hippocampal sclerosis (HS) and six patients with non-lesional mesial TLE (NLES). The effects of stepwise increases in intensity (0-Off to 2 V) and stimulation configuration (quadripolar and bipolar), on seizure frequency and neuropsychological performance were studied. The two HS patients obtained a significant decrease (65-75%) in seizure frequency with high voltage bipolar DBS (≥1 V) or with quadripolar stimulation. Two out of six NLES patients became seizure-free, one of them without stimulation, suggesting a microlesional effect. Two NLES patients experienced reductions of seizure frequency (65-70%), whereas the remaining two showed no significant seizure reduction. Neuropsychological evaluations showed reversible memory impairments in two patients under strong stimulation only. AH-DBS showed long-term efficiency in most of the TLE patients. It is a valuable treatment option for patients who suffer from drug resistant epilepsy and who are not candidates for resective surgery. The effects of changes in the stimulation parameters suggest that a large zone of stimulation would be required in HS patients, while a limited zone of stimulation or even a microlesional effect could be sufficient in NLES patients, for whom the importance of the proximity of the electrode to the epileptogenic zone remains to be studied. Further studies are required to ascertain these latter observations.

Electrical source imaging for presurgical focus localization in epilepsy patients with normal MRI.

Purpose:  Patients with magnetic resonance (MR)–negative focal epilepsy (MRN‐E) have less favorable surgical outcomes (between 40% and 70%) compared to those in whom an MRI lesion guides the site of surgical intervention (60–90%). Patients with extratemporal MRN‐E have the worst outcome (around 50% chance of seizure freedom). We studied whether electroencephalography (EEG) source imaging (ESI) of interictal epileptic activity can contribute to the identification of the epileptic focus in patients with normal MRI.

A level set method for segmentation of the thalamus and its nuclei in DT-MRI

We present a method for segmenting white matter as well as the gray matter structures from diffusion tensor magnetic resonance images (DT-MRI). The segmentation is done evolving a set of coupled level set functions. The zero level set of each level set function forms a surface in 3D that is driven by the region-based force including all tensors belonging to a certain region. The region-based force is defined by using a very sensitive similarity measure between DT. We apply our method for segmenting the thalamus and its nuclei. This technical paper proposes several new strategies for level set methods to segment efficiently complex objects as present in DT-MRI. First of all, we present a very sensitive similarity measure that distinguishes very subtle differences between regions within, for example, the thalamus. Secondly, we present a new way of selecting the most representative tensor for group of tensors for these kinds of applications. We argue for the importance to use the tensor minimizing the variation within the group of tensors instead of the mean tensor as suggested in other papers on tensor segmentation. The third important point is the necessity of using several coupled level sets to define the background. Methods differentiating only between foreground and background will fail when applied to complex structures such as the brain. It is crucial for a region-based approach to consider all the surrounding structures for a correct definition of the forces driving the segmentation.

Extent and Patterns of MGMT Promoter Methylation in Glioblastoma- and Respective Glioblastoma-Derived Spheres

Purpose: Quantitative methylation-specific tests suggest that not all cells in a glioblastoma with detectable promoter methylation of the O6-methylguanine DNA methyltransferase (MGMT) gene carry a methylated MGMT allele. This observation may indicate cell subpopulations with distinct MGMT status, raising the question of the clinically relevant cutoff of MGMT methylation therapy. Epigenetic silencing of the MGMT gene by promoter methylation blunts repair of O6-methyl guanine and has been shown to be a predictive factor for benefit from alkylating agent therapy in glioblastoma. Experimental Design: Ten paired samples of glioblastoma and respective glioblastoma-derived spheres (GS), cultured under stem cell conditions, were analyzed for the degree and pattern of MGMT promoter methylation by methylation-specific clone sequencing, MGMT gene dosage, chromatin status, and respective effects on MGMT expression and MGMT activity. Results: In glioblastoma, MGMT-methylated alleles ranged from 10% to 90%. In contrast, methylated alleles were highly enriched (100% of clones) in respective GS, even when 2 MGMT alleles were present, with 1 exception (<50%). The CpG methylation patterns were characteristic for each glioblastoma exhibiting 25% to 90% methylated CpGs of 28 sites interrogated. Furthermore, MGMT promoter methylation was associated with a nonpermissive chromatin status in accordance with very low MGMT transcript levels and undetectable MGMT activity. Conclusions: In MGMT-methylated glioblastoma, MGMT promoter methylation is highly enriched in GS that supposedly comprise glioma-initiating cells. Thus, even a low percentage of MGMT methylation measured in a glioblastoma sample may be relevant and predict benefit from an alkylating agent therapy. Clin Cancer Res; 17(2); 255–66. ©2010 AACR.

Magnetic resonance artifact induced by the electrode Activa 3389: an in vitro and in vivo study

SummaryBackground. The electrode Activa 3389 is widely implanted for deep brain stimulation (DBS) and MRI is often used to control the position of the electrode. However, induced distorsion artifacts may result in imprecise localization and may lead to misinterpretations of the clinical effects and mechanisms of DBS. Methods. In vitro 3D MR study: the proximal and distal contacts of one electrode were spotted by two localizers. The maximal artifact height (MAH) and width (MAW: measured on distal contact), and the distances between the artifact and the localizers (proximal, distal and lateral) were measured on 2 transverse and sagittal MR sequences with 90 degrees rotation of frequency-encoded gradient and phase direction.In vivo 3D MR study: coronal and sagittal reconstructions along the main axis of the electrode were performed on 10 postoperative MR (20 electrodes) to measure MAH and MAW.A Student t test was used to compare in vitro and in vivo measurements. Findings. In vitro study: A MAH of 10.35 mm (±0.23) and MAW of 3.6 mm (±0.2) were found. We measured symmetrical extensions of the artifact over the distal contact.In vivo study: A MAH of 10.36 mm (±0.44) and MAW of 3.56 mm (±0.30) were obtained. No significant different artifact dimensions were measured between in vitro and in vivo studies (p<0.0001). Interpretation. Precise 3D localization of the electrode in implanted patients is provided by MR identification of the limits of the distal contact artifact. The position of the other contacts is deduced given the size of the contacts and the intercontact distance.

Rapid resolution of dopamine dysregulation syndrome (DDS) after subthalamic DBS for Parkinson disease (PD): a case report.

ObjectiveTo describe how subthalamic deep brain stimulation (STN-DBS) and reduction in dopamine replacement therapy (DRT) allowed rapid resolution of dopamine dysregulation syndrome (DDS) with severe behavioral disorder in a patient with late stage Parkinson disease (PD). BackgroundDDS was recently defined as compulsive use of dopaminergic drugs, associated with severe behavioral symptoms, and impaired social functioning, occurring in about 4% of PD patients under DRT. STN-DBS is an effective treatment for late stage PD with treatment resistant motor fluctuations, which frequently allows also to reduce DRT. MethodsA late stage PD patient referred to our center for STN-DBS, suffering from severe DDS necessitating in-ward psychiatric management, was comprehensively assessed preoperatively and postoperatively for motor, cognitive, and psychiatric status. ResultsFollowing subthalamic DBS procedure and medication reduction, we observed a rapid and dramatic resolution of DDS and associated psychiatric symptoms, allowing discharge from a 2-year stay in a psychiatric institution. ConclusionsDDS occurring in late stage PD patients may be dramatically improved by STN-DBS, possibly in relation with the reduction of dopaminergic medication. In contrast to other psychiatric symptoms, DDS should not be considered as an obstacle to DBS procedure in late stage PD patients.