Prediction of Electrode Contacts for Clinically Effective Deep Brain Stimulation in Essential Tremor.

BACKGROUND/AIM: Deep brain stimulation (DBS) is an established neurosurgical treatment that can be used to alleviate symptoms in essential tremor (ET) and other movement disorders. The aim was to develop a method and software tool for the prediction of effective DBS electrode contacts based on probabilistic stimulation maps (PSMs) in patients with ET treated with caudal zona incerta (cZi) DBS. METHODS: A total of 33 patients (37 leads) treated with DBS were evaluated with the Essential Tremor Rating Scale (ETRS) 12 months after surgery. In addition, hand tremor and hand function (ETRS items 5/6 and 11-14) were evaluated for every contact during stimulation with best possible outcome without inducing side effects. Prediction of effective DBS electrode contacts was carried out in a retrospective leave-one-out manner based on PSMs, simulated stimulation fields, and a scoring function. Electrode contacts were ranked according to their likelihood of being included in the clinical setting. Ranked electrode contacts were compared to actual clinical settings. RESULTS: Predictions made by the software tool showed that electrode contacts with rank 1 matched the clinically used contacts in 60% of the cases. Contacts with a rank of 1-2 and 1-3 matched the clinical contacts in 83 and 94% of the cases, respectively. Mean improvement of hand tremor and hand function was 79 ± 21% and 77 ± 22% for the clinically used and the predicted electrode contacts, respectively. CONCLUSIONS: Effective electrode contacts can be predicted based on PSMs in patients treated with cZi DBS for ET. Predictions may in the future be used to reduce the number of clinical assessments that are carried out before a satisfying stimulation setting is defined.

Optimization-Based Contact Fault Alleviation in Deep Brain Stimulation Leads.

Deep brain stimulation (DBS) is a neurosurgical treatment in, e.g., Parkinson's Disease. Electrical stimulation in DBS is delivered to a certain target through electrodes implanted into the brain. Recent developments aiming at better stimulation target coverage and lesser side effects have led to an increase in the number of contacts in a DBS lead as well as higher hardware complexity. This paper proposes an optimization-based approach to alleviation of the fault impact on the resulting therapeutical effect in field steering DBS. Faulty contacts could be an issue given recent trends of increasing number of contacts in DBS leads. Hence, a fault detection/alleviation scheme, such as the one proposed in this paper, is necessary ensure resilience in the chronic stimulation. Two alternatives are considered and compared with the stimulation prior to the fault: one using higher amplitudes on the remaining contacts and another with alleviating contacts in the neighborhood of the faulty one. Satisfactory compensation for a faulty contact can be achieved in both ways. However, to designate alleviating contacts, a model-based optimization procedure is necessary. Results suggest that stimulating with more contacts yields configurations that are more robust to contact faults, though with reduced selectivity.

Probabilistic mapping of deep brain stimulation effects in essential tremor.

OBJECTIVE: To create probabilistic stimulation maps (PSMs) of deep brain stimulation (DBS) effects on tremor suppression and stimulation-induced side-effects in patients with essential tremor (ET). METHOD: Monopolar reviews from 16 ET-patients which consisted of over 600 stimulation settings were used to create PSMs. A spherical model of the volume of neural activation was used to estimate the spatial extent of DBS for each setting. All data was pooled and voxel-wise statistical analysis as well as nonparametric permutation testing was used to confirm the validity of the PSMs. RESULTS: PSMs showed tremor suppression to be more pronounced by stimulation in the zona incerta (ZI) than in the ventral intermediate nucleus (VIM). Paresthesias and dizziness were most commonly associated with stimulation in the ZI and surrounding thalamic nuclei. DISCUSSION: Our results support the assumption, that the ZI might be a very effective target for tremor suppression. However stimulation inside the ZI and in its close vicinity was also related to the occurrence of stimulation-induced side-effects, so it remains unclear whether the VIM or the ZI is the overall better target. The study demonstrates the use of PSMs for target selection and evaluation. While their accuracy has to be carefully discussed, they can improve the understanding of DBS effects and can be of use for other DBS targets in the therapy of neurological or psychiatric disorders as well. Furthermore they provide a priori information about expected DBS effects in a certain region and might be helpful to clinicians in programming DBS devices in the future.

Deep Brain Stimulation of the Caudal Zona Incerta: Tremor Control in Relation to the Location of Stimulation Fields.

BACKGROUND: The caudal zona incerta (cZi) and posterior subthalamic area (PSA) are an emerging deep brain stimulation (DBS) target for essential tremor (ET). OBJECTIVES: To evaluate the efficacy of tremor control in relation to the anatomical locations of stimulation fields in 50 patients with ET and DBS of the cZi. METHODS: A total of 240 contacts were evaluated separately with monopolar stimulation, and amplitudes were optimized for improvement of tremor and hand function. Stimulation fields, i.e., volumes of neural activation, were simulated for each optimized setting and assembled into probabilistic stimulation maps (PSMs). RESULTS: There were differences in the anatomical distribution of PSMs associated with good versus poor tremor control. The location of PSMs which achieved good and excellent tremor control corresponded well with the PSM for the clinically used settings, and they were located within the superior part of the PSA. CONCLUSIONS: PSMs may serve as a useful tool for defining the most efficacious anatomical location of stimulation. The best tremor control in this series of cZi DBS was achieved with stimulation of the superior part of the PSA, which corresponds to the final part of the cerebellothalamic projections before they reach the ventral lateral thalamus.

Progressive gait ataxia following deep brain stimulation for essential tremor: adverse effect or lack of efficacy?

Thalamic deep brain stimulation is a mainstay treatment for severe and drug-refractory essential tremor, but postoperative management may be complicated in some patients by a progressive cerebellar syndrome including gait ataxia, dysmetria, worsening of intention tremor and dysarthria. Typically, this syndrome manifests several months after an initially effective therapy and necessitates frequent adjustments in stimulation parameters. There is an ongoing debate as to whether progressive ataxia reflects a delayed therapeutic failure due to disease progression or an adverse effect related to repeated increases of stimulation intensity. In this study we used a multimodal approach comparing clinical stimulation responses, modelling of volume of tissue activated and metabolic brain maps in essential tremor patients with and without progressive ataxia to disentangle a disease-related from a stimulation-induced aetiology. Ten subjects with stable and effective bilateral thalamic stimulation were stratified according to the presence (five subjects) of severe chronic-progressive gait ataxia. We quantified stimulated brain areas and identified the stimulation-induced brain metabolic changes by multiple 18 F-fluorodeoxyglucose positron emission tomography performed with and without active neurostimulation. Three days after deactivating thalamic stimulation and following an initial rebound of symptom severity, gait ataxia had dramatically improved in all affected patients, while tremor had worsened to the presurgical severity, thus indicating a stimulation rather than disease-related phenomenon. Models of the volume of tissue activated revealed a more ventrocaudal stimulation in the (sub)thalamic area of patients with progressive gait ataxia. Metabolic maps of both patient groups differed by an increased glucose uptake in the cerebellar nodule of patients with gait ataxia. Our data suggest that chronic progressive gait ataxia in essential tremor is a reversible cerebellar syndrome caused by a maladaptive response to neurostimulation of the (sub)thalamic area. The metabolic signature of progressive gait ataxia is an activation of the cerebellar nodule, which may be caused by inadvertent current spread and antidromic stimulation of a cerebellar outflow pathway originating in the vermis. An anatomical candidate could be the ascending limb of the uncinate tract in the subthalamic area. Adjustments in programming and precise placement of the electrode may prevent this adverse effect and help fine-tuning deep brain stimulation to ameliorate tremor without negative cerebellar signs.

Deep brain stimulation of the pallidum internum for Gilles de la Tourette syndrome: a patient-specific model-based simulation study of the electric field.

OBJECTIVES: The aim of this study was to investigate the deep brain stimulation (DBS) electric field distribution in proton-density MRI scans visualizing the globus pallidus internus (GPi) of patients with Gilles de la Tourette syndrome (GTS), along with its relation to the anatomy. METHODS: Patient-specific brain tissue models (n = 7) with bilateral DBS electrodes in the GPi were set up using the finite element method in five patients who had undergone stereotactic proton-density MRI-guided surgery and showed variable improvement with DBS. Simulations (n = 27) of the electric field were performed and the results visualized on the respective preoperative stereotactic MRI scans. The mean electric field volumes (n = 81) within the 0.1, 0.15, and 0.2 V/mm isosurfaces were calculated and compared with the anatomy. RESULTS: Visualization of the simulated electric field confirmed that the anteromedial limbic GPi was the main stimulated target for four of the patients and the posteromedial sensorimotor GPi for one. Larger volumes extended asymmetrically, with parts of fields stretching into the lamina between GPi and globus pallidus externus and into the internal capsule. There was a high correlation (r = 0.994, n = 54) between volumes and brain sides, but with a systematic shift toward the right side, especially for the larger volumes. Simulations with homogeneous tissue models showed no differences. CONCLUSIONS: Patient-specific DBS electric field simulations in the GPi as visualized on proton-density MR scans can be implemented in patients with GTS. Visualization of electric fields together with stereotactic thin-slice MRI can provide further support when predicting anatomical structures possibly influenced by DBS in this complex disorder.

Relationship between neural activation and electric field distribution during deep brain stimulation.

Models and simulations are commonly used to study deep brain stimulation (DBS). Simulated stimulation fields are often defined and visualized by electric field isolevels or volumes of tissue activated (VTA). The aim of the present study was to evaluate the relationship between stimulation field strength as defined by the electric potential V, the electric field E, and the divergence of the electric field ∇(2) V, and neural activation. Axon cable models were developed and coupled to finite-element DBS models in three-dimensional (3-D). Field thresholds ( VT , ET, and ∇(2) VT ) were derived at the location of activation for various stimulation amplitudes (1 to 5 V), pulse widths (30 to 120 µs), and axon diameters (2.0 to 7.5 µm). Results showed that thresholds for VT and ∇(2) VT were highly dependent on the stimulation amplitude while ET were approximately independent of the amplitude for large axons. The activation field strength thresholds presented in this study may be used in future studies to approximate the VTA during model-based investigations of DBS without the need of computational axon models.

Target coverage and selectivity in field steering brain stimulation.

Deep Brain Stimulation (DBS) is an established treatment in Parkinson's Disease. The target area is defined based on the state and brain anatomy of the patient. The stimulation delivered via state-of-the-art DBS leads that are currently in clinical use is difficult to individualize to the patient particularities. Furthermore, the electric field generated by such a lead has a limited selectivity, resulting in stimulation of areas adjacent to the target and thus causing undesirable side effects. The goal of this study is, using actual clinical data, to compare in silico the stimulation performance of a symmetrical generic lead to a more versatile and adaptable one allowing, in particular, for asymmetric stimulation. The fraction of the volume of activated tissue in the target area and the fraction of the stimulation field that spreads beyond it are computed for a clinical data set of patients in order to quantify the lead performance. The obtained results suggest that using more versatile DBS leads might reduce the stimulation area beyond the target and thus lessen side effects for the same achieved therapeutical effect.

Effects of deep brain stimulation in the caudal zona incerta on verbal fluency.

BACKGROUND: Deep brain stimulation (DBS) of the caudal zona incerta (cZi) is a relatively unexplored and promising treatment in patients with severe essential tremor (ET). Preliminary data further indicate that the ability to produce language may be slightly affected by the treatment. OBJECTIVE: To evaluate the effects on verbal fluency following cZi DBS in patients with ET. METHOD: Seventeen consecutive patients who had undergone DBS of the cZi for ET were tested regarding verbal fluency before surgery, 3 days after surgery and after 1 year. Ten patients were also evaluated by comparing performance on versus off stimulation after 1 year. RESULTS: The total verbal fluency score decreased slightly, but significantly, from 22.7 (SD = 10.9) before surgery to 18.1 (SD = 7.5) 3 days after surgery (p = 0.036). After 1 year the score was nonsignificantly decreased to 20.1 (SD = 9.7, p = 0.2678). There was no detectable difference between stimulation on and off after 1 year. CONCLUSION: There was a tendency of an immediate and mostly transient postoperative decline in verbal fluency following cZi DBS for ET. In some of the patients this reduction was, however, more pronounced and also sustained over time.

Unilateral caudal zona incerta deep brain stimulation for Parkinsonian tremor.

BACKGROUND: The subthalamic nucleus is currently the target of choice in deep brain stimulation (DBS) for Parkinson's disease (PD), while thalamic DBS is used in some cases of tremor-dominant PD. Recently, a number of studies have presented promising results from DBS in the posterior subthalamic area, including the caudal zona incerta (cZi). The aim of the current study was to evaluate cZi DBS in tremor-dominant Parkinson's disease. METHODS: 14 patients with predominately unilateral tremor-dominant PD and insufficient relief from pharmacologic therapy were included and evaluated according to the motor part of the Unified Parkinson Disease Rating Scale (UPDRS). The mean age was 65 ± 6.1 years and the disease duration 7 ± 5.7 years. Thirteen patients were operated on with unilateral cZi DBS and 1 patient with a bilateral staged procedure. Five patients had non-L-dopa responsive symptoms. The patients were evaluated on/off medication before surgery and on/off medication and stimulation after a minimum of 12 months after surgery. RESULTS: At the follow-up after a mean of 18.1 months stimulation in the off-medication state improved the contralateral UPDRS III score by 47.7%. Contralateral tremor, rigidity, and bradykinesia were improved by 82.2%, 34.3%, and 26.7%, respectively. Stimulation alone abolished tremor at rest in 10 (66.7%) and action tremor in 8 (53.3%) of the patients. CONCLUSION: Unilateral cZi DBS seems to be safe and effective for patients with severe Parkinsonian tremor. The effects on rigidity and bradykinesia were, however, not as profound as in previous reports of DBS in this area.

Influence of heterogeneous and anisotropic tissue conductivity on electric field distribution in deep brain stimulation.

The aim was to quantify the influence of heterogeneous isotropic and heterogeneous anisotropic tissue on the spatial distribution of the electric field during deep brain stimulation (DBS). Three finite element tissue models were created of one patient treated with DBS. Tissue conductivity was modelled as (I) homogeneous isotropic, (II) heterogeneous isotropic based on MRI, and (III) heterogeneous anisotropic based on diffusion tensor MRI. Modelled DBS electrodes were positioned in the subthalamic area, the pallidum, and the internal capsule in each tissue model. Electric fields generated during DBS were simulated for each model and target-combination and visualized with isolevels at 0.20 (inner), and 0.05 V mm(-1) (outer). Statistical and vector analysis was used for evaluation of the distribution of the electric field. Heterogeneous isotropic tissue altered the spatial distribution of the electric field by up to 4% at inner, and up to 10% at outer isolevel. Heterogeneous anisotropic tissue influenced the distribution of the electric field by up to 18 and 15% at each isolevel, respectively. The influence of heterogeneous and anisotropic tissue on the electric field may be clinically relevant in anatomic regions that are functionally subdivided and surrounded by multiple fibres of passage.

Long term follow-up of deep brain stimulation of the caudal zona incerta for essential tremor.

PURPOSE: The ventral intermediate nucleus of thalamus is the standard target for deep brain stimulation (DBS) in essential tremor (ET). However, favourable data have recently highlighted the caudal zona incerta (cZi) as an alternative target. Reports concerning the long-term results are however lacking, and we have therefore evaluated the long-term effects in our patients with ET and cZi DBS. METHODS: 18 patients were evaluated using the Essential Tremor Rating Scale (ETRS) before and on-/off-stimulation at 1 and 3-5 years after surgery (mean 48.5±10.6 months). Two patients were operated on bilaterally but all electrodes were evaluated separately. The stimulation parameters were recorded and the stimulation strength calculated. RESULTS: A baseline total ETRS mean score of 46.0 decreased to 21.9 (52.4%) at the final evaluation. On the treated side, tremor of the upper extremity (item 5 or 6) improved from 6.1 to 0.5 (91.8%) and hand function (items 11-14) improved from 9.3 to 2.0 (78.0%). Activities of daily living improved by 65.8%. There was no increase in stimulation strength over time. CONCLUSION: cZi DBS is a safe and effective treatment for the long term suppression of ET.

Patient-specific model-based investigation of speech intelligibility and movement during deep brain stimulation.

BACKGROUND/AIMS: Deep brain stimulation (DBS) is widely used to treat motor symptoms in patients with advanced Parkinson's disease. The aim of this study was to investigate the anatomical aspects of the electric field in relation to effects on speech and movement during DBS in the subthalamic nucleus. METHODS: Patient-specific finite element models of DBS were developed for simulation of the electric field in 10 patients. In each patient, speech intelligibility and movement were assessed during 2 electrical settings, i.e. 4 V (high) and 2 V (low). The electric field was simulated for each electrical setting. RESULTS: Movement was improved in all patients for both high and low electrical settings. In general, high-amplitude stimulation was more consistent in improving the motor scores than low-amplitude stimulation. In 6 cases, speech intelligibility was impaired during high-amplitude electrical settings. Stimulation of part of the fasciculus cerebellothalamicus from electrodes positioned medial and/or posterior to the center of the subthalamic nucleus was recognized as a possible cause of the stimulation-induced dysarthria. CONCLUSION: Special attention to stimulation-induced speech impairments should be taken in cases when active electrodes are positioned medial and/or posterior to the center of the subthalamic nucleus.

Method for patient-specific finite element modeling and simulation of deep brain stimulation.

Deep brain stimulation (DBS) is an established treatment for Parkinson's disease. Success of DBS is highly dependent on electrode location and electrical parameter settings. The aim of this study was to develop a general method for setting up patient-specific 3D computer models of DBS, based on magnetic resonance images, and to demonstrate the use of such models for assessing the position of the electrode contacts and the distribution of the electric field in relation to individual patient anatomy. A software tool was developed for creating finite element DBS-models. The electric field generated by DBS was simulated in one patient and the result was visualized with isolevels and glyphs. The result was evaluated and it corresponded well with reported effects and side effects of stimulation. It was demonstrated that patient-specific finite element models and simulations of DBS can be useful for increasing the understanding of the clinical outcome of DBS.

The effect of cystic cavities on deep brain stimulation in the basal ganglia: a simulation-based study.

Although the therapeutic effect of deep brain stimulation (DBS) is well recognized, a fundamental understanding of the mechanisms responsible is still not known. In this study finite element method (FEM) modelling and simulation was used in order to study relative changes of the electrical field extension surrounding a monopolar DBS electrode positioned in grey matter. Due to the frequently appearing cystic cavities in the DBS-target globus pallidus internus, a nucleus of grey matter with and without a cerebrospinal fluid filled cystic cavity was modelled. The position, size and shape of the cyst were altered in relation to the electrode. The simulations demonstrated an electrical field around the active element with decreasing values in the radial direction. A stepwise change was present at the edge between grey and white matters. The cyst increased the radial extension and changed the shape of the electrical field substantially. The position, size and shape of the cyst were the main influencing factors. We suggest that cystic cavities in the DBS-target may result in closely related unexpected structures or neural fibre bundles being stimulated and could be one of the reasons for suboptimal clinical effects or stimulation-induced side effects.