Objectives: A significant minority of patients with Obsessive Compulsive Disorder (OCD) remain severely affected despite high quality standard treatment. We present the clinical results of a double-blind randomised crossover pilot trial of deep brain stimulation (DBS) for OCD.

Methods: Six patients with severe refractory OCD were recruited. Minimum inclusion criteria were: symptoms refractory to ≥2 selective serotonin reuptake inhibitors for ≥ 12 weeks at optimal doses, ≥2 trials of cognitive behavioural therapy (CBT) involving Exposure and Response Prevention (> 10 hours) plus intensive inpatient treatment within a specialist unit; ≥ 10 years’ illness duration; ≥ 2 years of unremitting symptoms; ≥ 32 on the Yale-Brown Obsessive Compulsive Scale (YBOCS).

Bilateral anteromedial subthalamic nucleus (amSTN) and bilateral ventral capsule/ventral striatum (VC/VS) DBS leads were implanted in each patient using an MRI-guided & MRI-verified approach. Patients were randomised to amSTN or VC/VS stimulation. After 3 months, the stimulation site was switched for a further 3 months, then both sites were stimulated for 3 months. Following this, patients received open label DBS optimisation and CBT. Patients and psychiatrists were blinded to stimulation site during the randomisation phase. YBOCS and global assessment of function (GAF) scores were performed at key time points.

Results: There were no surgical complications. YBOCS improved from baseline by a mean of 45% with amSTN DBS, 53% with VC/VS DBS and 61% with DBS at both sites. Following open label DBS plus CBT, mean YBOCS reduction was 74%, 3 patients were in remission (YBOCS < 8), all patients were “responders” (defined as YBOCS decrease of >35%). GAF scores improved from 22 to 72. Effective contacts at the VC/VS target were within the ventral aspect of the anterior limb of the internal capsule, above the nucleus accumbens. During the course of the trial, DBS was associated with a number of transient mood and behavioural changes that required close supervision and stimulation adjustment.

Conclusion: DBS was safe and efficient at both sites with improvement in OCD symptoms that was also accompanied by improvements in quality of life scores. In this patient group, the VC target provided greater benefit than the amSTN target. It must be emphasised that DBS is a labour-intensive and lifelong therapy that requires close surgical and psychiatric follow up. 

Background

Obsessive-compulsive disorder (OCD) affects 2-3% of the population, and approximately 20% of these patients are refractory to medical and behavioral therapy. These patients may be candidates for stereotactic radiosurgery capsulotomy (SRSC). In this study we identified SRSC lesion locations predicting favorable outcome, as well as lesion prefrontal connectivity.

Methods

SRSC Lesions were traced on T1 scans in 30 OCD patients, and transformed to standard imaging space. Yale-Brown Obsessive Compulsive Scale (Y-BOCS) reduction was regressed against a threshold-free cluster enhanced voxel-wise analysis of lesions. Tractography was performed on 40 patients from the Human Connectome Project, using the significant cluster center as a seed.

Results

24 of the 30 participants (80%) were full responders. A cluster (Fig1), centered in the right internal capsule, correlated with outcomes (corrected p < 0.05). Tractography showed that fibers through this cluster radiate to inferior medial prefrontal cortex (Fig2).

Conclusions

SRSC remains an effective treatment for refractory OCD. These results suggest a specific area in the right ventral capsule whose inclusion increases the likelihood of response. This region demonstrates connectivity to the orbitofrontal and ventromedial prefrontal cortex, highlighting the importance of these regions in OCD pathophysiology. Further analysis of individual variability and connectivity will be essential for improving outcomes.

Background: Treatment resistant depression (TRD) is a serious and debilitating disorder. Deep brain stimulation (DBS) to the superolateral branch of the medial forebrain bundle (MFB) has been reported by Schlaepfer et al. (2013) to lead to rapid anti-depressant effects. Here, we report the interim analysis of an ongoing pilot study investigating the efficacy of DBS- MFB in TRD. This report extends our recently published results (Fenoy et al., 2016).

Methods: We assessed the efficacy of MFB-DBS in a cohort of six TRD patients over a 52-week period using improvement on the Montgomery-Åsberg Depression Rating Scale (MADRS) as the primary outcome measure. Implanted patients entered a 4-week single-blinded sham stimulation period prior to stimulation initiation. Deterministic fiber tracking analysis was performed to compare modulated fiber tracts between patients.

Results: Upon stimulation at target intraoperatively, responders reported immediate increases in energy and motivation. During a 4 week sham stimulation phase, there was no significant mean change in mood. After initiating stimulation, 3 of 6 patients had a >50% decrease in MADRS scores relative to baseline at 7 days. The difference in MADRS score between baseline and week 1 of active stimulation was significant (mean change = 15 pts, 43% reduction, p = 0.005) as was the difference between baseline and week 2 (mean change = 17 pts, 49% reduction, p = 0.001). One patient withdrew from study participation for personal reasons. At 26 weeks, 4 of 5 patients have >75% decrease in MADRS scores relative to baseline. At 52 weeks, 2 of 3 remaining patients continue to have >80% decrease in MADRS scores; 2 patients have not yet completed their 52 week assessments. Evaluation of modulated fiber tracts reveals significant frontal connectivity to the target region in all 5 responder patients, but minimal connectivity in the non-responder at 26 weeks.

Conclusion: This study of MFB-DBS shows rapid anti-depressant effects within the first week of stimulation, as reported by Schlaepfer et al. (2013). The striking effects observed are very promising, but we await full completion of this pilot study before drawing further conclusions about efficacy. 

Objective: We investigated Volumes of Tissue activated (VTA) in dystonia subjects under effective bilateral pallidal DBS. We aimed to disentangle the sweet spot for dystonia suppression within the pallidal region.

Background: GPi-DBS is an established therapy for generalized and cervical dystonia. Average improvement of dystonia severity amounts to 50-60%, but outcomes are often variable and clinical studies report up to 25% non-responders. Variability in electrode placement may account for a large proportion of outcome variability. So far no study has been able to identify an “optimal efficacy volume” within the GPi.

Methods: 85 subjects with dystonia (41 cervical mean TWSTRS 20.3±3.6 points/44 generalized dystonia, mean BFMDRS 45.8±20.5 points) under chronic bilateral GPi-DBS from 8 European DBS centres were stratified for chronic motor improvement (median reduction of 46.7(±27.7)% after 12.0 months in cervical / median reduction of 52.3(±35.9)% after 34.8 months in generalised dystonia). We simulated VTAs for each lead in subject’s related MRI space based on chronic stimulation parameters obtained from a chart review and associated with BFMDRS/TWSTRS improvement. All patient images were registered to a common average MRI. Only VTAs with a motor improvement >50% were taken for the visualisation of three different areas, defined by allegorizing only voxels that were overlapped by >15(green); >30(orange) VTAs and the “sweetspot”, overlap volume of  >50(red) VTAs.

Results: Wide variability of lead location, stimulation parameters and chronic motor improvement was observed in this cohort of 85 subjects. VTA size did not exhibit a significant correlation with improvement in motor symptoms. Model-based analysis of 108 responding VTAs showed a core mean volume (=”sweetspot”) located within and below the ventroposterior GPi. Stereotactic coordinates of the center of gravity were lateral: 20.0, anterior: 2.3 and inferior 2.6 (based on AC-PC in mm).

Conclusions: In this study, we showed that the magnitude of current injection is not decisive for the therapeutic DBS effect. In fact, the outcome is highly correlated with the precise location of neuromodulation within the region of interest. The most beneficial (sweet-)spot hints to a relevant contribution of subpallidal white matter, which could indicate a possible modulation of the ansa lenticularis for the anti-dystonic effect of DBS in addition to stimulation of the presumed sensorimotor region of the GPi.

Objectives: Recently, magnetic resonance-guided focused ultrasound (MRgFUS) has emerged as an innovative treatment for numerous neurological disorders. This clinical trial was designed to identify the feasibility, effectiveness, and potential side effects of unilateral MRgFUS pallidotomy for the treatment of Parkinsonian dyskinesia.

Method: Ten patients with severe, medication-refractory Parkinson’s disease (PD) with motor fluctuation underwent unilateral MRgFUS pallidotomy using the Exablate 4000 device (Insightec, Israel) between December 2013 and May 2016. All patients provided written informed consent. Clinical assessments were conducted to evaluate the therapeutic effects after unilateral MRgFUS pallidotomy and according to our follow-up protocol. Technical failure and safety issues were also carefully assessed by monitoring all events during the study period.

Results: Seven of ten patients were followed-up for at least six months. Three patients were dropped from the study for various reasons. All patients who underwent MRgFUS pallidotomy experienced immediate and sustained improvements in dyskinesia, particularly in the treated hand. This reduction was accompanied by functional improvement in activities of daily living. However, thermal lesioning via MRgFUS also failed in several cases. In addition, several side effects were associated with MRgFUS, although no patient experienced persistent aftereffects.

Conclusion: In the present study, which marks the first phase I pilot study of unilateral MRgFUS pallidotomy for advanced PD, we demonstrated the benefits of unilateral MRgFUS pallidotomy in PD, as well as certain limitations of this technique associated with incomplete thermal lesioning of the globus pallidus interna.

Objectives To describe and compare the clinical outcomes for two consecutive series of patients within our clinical service receiving either intensive psychological therapy (ITP) or bilateral anterior cingulotomy (ACING) for chronic severe OCD.

Method We reviewed data from the 8 most recent patients completing our intensive treatment programme and also the 5 most recent patients treated neurosurgically (ACING).  All ACING patients had previously failed to achieve a sustained improvement from an intensive treatment programme. In controlled treatment trials, a decrease of greater than or equal to 35% on the Yale Brown Obsessive Compulsive Rating Scale (Y-BOCS) is generally considered a clinically meaningful treatment response, with a reduction of greater than or equal to 25% a significant, but lesser improvement.  Outcomes were examined at the following time-points: baseline (pre-treatment); immediate post treatment (discharge); and 12-months after treatment.

Results Prior to treatment, ITP group Y-BOCS severity scores were in the moderate to extreme range (30.25±5.4) whilst the ACING patients were in the severe to extreme range (32.4±5.7). At discharge, 50% of the ITP group achieved a clinically meaningful response to treatment; 13% achieved a lesser, but significant response; whilst 37% failed to benefit from treatment.   Of the ACING patients 40% achieved a clinically meaningful response, whilst the remaining 60% showed no response.  This equates to the ITP group experiencing an average 30.5% improvement in symptom severity (20.21±8), compared to 22.4% improvement for the ACING group (19.75±9.8). However, at 12 months the ITP group showed no change in response rates and maintained a 30.3% overall improvement in Y-BOCS severity scores (20.25±8.8), but the ACING group continued to progress with 60% of patients now achieving either a significant or a clinically meaningful response; with remaining patients, although not achieving a significant response, gaining a 20% overall reduction in their Y-BOCS severity scores (25.5±3.5).  This gives the ACING group an overall improvement at 12 months of 48.5%

Conclusions Improvements made on discharge by ITP patients were maximal, with no additional improvements over the following 12 month period. ACING patients, however, continued to improve.  This suggests that the trajectory of response following surgery may differ from that of ITP.

Objective: To assess the feasibility of Gamma Knife   subthalamotomy in Parkinson's disease

Background:   Chronic STN stimulation   is an established treatment for complicated PD. Bilateral subthalamotomy may   induce significant and long-lasting results when DBS is not available.   However, which alternative can be proposed for patients with surgical contraindications   for electrodes implantation? Gamma Knife (GK) thalamotomy is an effective   therapy for treating disabling tremor. This technique encounters very few   contraindications. We report the results of a prospective trial on GK Subthalamotomy   for patients with absolute contraindications for DBS. The primary endpoint was tolerance.

Methods: 14 PD patients (10men, mean age 66.4) with   severe motor complications were included. STN DBS was contraindicated because   of vasculopathy or anticoagulant treatment.  Patients were assessed before and quarterly   for at least 24 months after GK subthalmotomy. A unilateral GK subthalamotomy   on the most affected side was proposed first followed by contralateral   subthalamotomy after M12 if necessary. STN lesioning was performed with   Leksell Gamma unit with a single exposure through a 4mm collimator. Radiosurgical   dose was 110Grays.

Results:  12 patients were   assessed at 2 years. 2 patients died before M6 (stroke, suicide). 7 patients   had bilateral GK subthalamotomy, 5 unilateral (2 previous contralateral STN   DBS, 2 refusals, 1 unilateral disease). UPDRS motor score was improved by   17.6% at M24,  motor fluctuations by   18% and dyskinesia were reduced by 66%. Cognitive score was stable except for   one patient. No significant decrease in LEDD was observed. MRI STN lesion   appeared 9 months after radiosurgery. One patient was a hyporesponder and 4   had an hyperresponse with clinical consequences: Severe transient dyskinesia   (2), transient hemiparesia and delirium (1), permanent hemiplegia.

Conclusions: Apart from a   significant decrease in dyskinesias, the patients did not improve following   STN GK and several experienced adverse effects. Although the cohort is small and with high comorbidities,   this study does not indicate that GK subthalamotomy may be a good alternative to   DBS for advanced PD.

Deep brain stimulation (DBS) of the subthalamic region is an established clinical therapy for the treatment of late stage Parkinson's disease. A fundamental biophysical effect of DBS is the generation of action potentials in axons surrounding the stimulating electrode. One axonal pathway of special interest is the corticofugal hyperdirect pathway to the subthalamic nucleus. Therefore, we developed a highly detailed patient-specific DBS model to study hyperdirect activation and action potential propagation. The DBS patient model was based on 7T MRI data. Subcortical nuclei were segmented from T1-weighted, T2-weighted, and susceptibility-weighted images. The hyperdirect pathway was reconstructed, as well as the internal capsule, with the assistance of tractography derived from diffusion-weighted images. Each of the 5000 axons reconstructed were modeled as a multi-compartment cable structure. The voltage distribution generated by the DBS electrode was calculated using a finite element method. This voltage distribution was then used to stimulate the model axons, and the response of the axons to DBS was quantified. We found that the hyperdirect pathway was robustly activated at the clinically effective stimulation parameters. In addition, we found that hyperdirect axons must be of especially large axon diameter (~10 um) to match the signal conduction velocity necessary to generate the cortical evoked potentials (~1 ms delay) recorded experimentally in DBS patients.

Objectives: Deep brain stimulation (DBS) of the anteromedial globus pallidus internus (amGPi) is emerging as a helpful method for severe cases of Tourette syndrome (TS) in adult patients but the optimal target is still under investigation.

Method: Patient-specific finite element method simulations of affected voxels were made in 15 patients in order to determine which are associated with symptom improvement at latest follow up (17-82 months from surgery). The equation for steady currents was solved with electric conductivities estimated from tissue classification into grey matter, white matter and cerebrospinal fluid in T1-weighted preoperative images. Voxels experiencing an electric field intensity sufficient to trigger axons with a diameter of 2 µm were assumed to be activated and were co-registered with the MNI 152 averaged T1-weighted brain space in which linear regression between each voxel and the DBS outcome scores were performed.

Results and conclusion: Tics (YGTSS: p < 0.0001) and mood (BDI: p = 0.012) improved significantly by DBS while obsessive-compulsive behavior (OCB) improved for some severe cases but the improvements did not reach statistical significance for the whole group. It was found that an area of the anterior pallidum encompassing the medial medullary lamina between GPi and GPe, and at the level of the AC-PC line, was significantly related to tic improvement. Improvements in mood or OCB could not be significantly associated with any specific area.

Introduction:The superolateral branch of the medial forebrain bundle (slMFB) is currently investigated as a putative DBS target for the treatment of major depression (MD) and OCD.  DTI FT- assisted targeting is necessary. A total of 24 patients have been bilaterally implanted and stimulated for MD at our institutions in two IITs. We present a first analysis focusing on the effectively stimulated fiber tracts and their connections using probabilistic DTI FT.

Methods: n=24, 9f, 47.3+/-10.5 years.  Imaging data consisted of high-resolution anatomical T1W and T2W MRI sequences (3T, Philips Intera, Best, Netherlands) and 32-direction diffusion tensor imaging. Postoperative (after DTI assisted DBS (1)) helical CT scans were used to delineate electrode positions. A complex pipeline of Probabilistic streamline tractography was performed with MRtrix 3 (http://www.mrtrix.org/).

Results: A total of 21 data sets had sufficient quality for further evaluation. In all cases only the slMFB and not the inferomedial branch of the medial forebrain bundle (imMFB) where included in the VAT, as expected. On the group level (not normalized), fibers that were affected by DBS connected bilaterally to the nucleus accumbens, the corpus callosum and the medial prefronal cortex (BA 24 and 32). The strongest connection was seen with the rostral prefrontal cortex (BA10) and BA46 (but only before normalizing data).

Conclusion: The presented data supports the modulation of a widespread network containing the rostral prefrontal cortex and parts of the forceps minor and the medial prefrontal cortex in slMFB DBS together with subcortical structures of the reward system. BA10 is a unique part of the human brain. Involvement of this region has also been described before with cg25 as target regions (2). BA10 might represent a common denominator for antidepressant efficacy. A combined modulation of cortical and subcortical structures might explain the short and long-term clinical effects (2).

References:

(1)  Schlaepfer, T. E., Bewernick, B., Kayser, S., Maedler, B., & Coenen, V. A. (2013). Rapid Effects of Deep Brain Stimulation for Treatment-Resistant Major Depression. Biological Psychiatry.

(2)  Riva-Posse, P., Choi, K. S., Holtzheimer, P. E., McIntyre, C. C., Gross, R. E., Chaturvedi, A., et al. (2014). Defining Critical White Matter Pathways Mediating Successful Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Depression. Biological Psychiatry, 76(12), 963–969.

BACKGROUND: The subgenual cingulate (SGC) is an investigational target for DBS in treatment-resistant depresion (TRD). Case series have reported 40-60% response rates, however a large industry sponsored randomized sham controlled trial failed futility analysis and closed accrual prematurely. In 2013, we developed an open label study to examine the safety and efficacy of SGC DBS using two types of stimulation (long pulse width or high amplitude) and targeted the confluence of uncinate, frontothalamic, cingulate and forceps minor using 3T MR tractography.

METHODS: In this pilot study of bilateral SGC-DBS we enrolled 23 patients with TRD (12M: 11F, mean age 47, range 23-69) into two different DBS protocols: ‘short pw’, where we increased amplitude (from 4-8 V, keeping pulse width at 90 μs, 130 Hz); ‘long pw’, where we increased pulse width (from 210-450 μs, keeping 3 V, 130 Hz) monthly based on response. Non-responders at 6 months were crossed over to the other stimulation protocol for another 6 months. Study psychiatrist and patients were blinded to stimulation type. Primary outcome was the Hamilton Depression Rating Scale (HDRS-17) and 50% reduction from baseline was considered response. Several other scales, imaging (PET, MRI), electrophysiological (EEG), and chemical biomarkers were also obtained.

RESULTS: Among the 23 patients enrolled one did not receive an implant and another committed suicide shortly after surgery. Six month outcomes are available in 18 patients, at present. HDRS-17 scores improved from a baseline of 23.2±3.9 (mean±SD) to 12.7±6.0 at 6 months (paired t-test, t=5.9, p<0.001), with 9 of 18 patients fulfilling response criteria. Responders were younger than non-responders (37.6±11.9 vs. 54.0±13.2, p=0.014). Four responders were on long pulse duration DBS. Aside from the 1 suicide and 3 intra-op seizures, no complications were encountered at the 6 month time point.

CONCLUSIONS: Our preliminary results support ≈50% efficacy of SGC DBS for TRD. The surgery is overall safe and phenytoin prophylaxis has eliminated the seizure complications. There is no obvious advantage of one type of stimulation over the other, which may suggest that optimization of stimulation over time is more important than type of stimulation. We are examining possible predictive biomarkers of response, however these data suggest that younger patients do better.

FUNDING: Alberta Innovates Health Solutions

Introduction

Although most patients with obsessive-compulsive disorder (OCD) are well controlled with pharmacological and cognitive behavioral therapy, 10-20% remain severe and refractory. Stereotactic lesions in the anterior limb of the internal capsule (ALIC) have been used for decades to treat these patients. However, there is controversy about optimal sites for lesions within the ALIC as different locations appear to have variable efficacy in alleviating symptoms. Using diffusion tensor imaging (DTI), we segmented the ALIC based on frontal connectivity and used the resulting segmentation to evaluate capsulotomy targeting in OCD.

Methods

A segmentation of the ALIC based on frontal structural connectivity was generated using connectivity-based seed classification on 40 control subjects from the Human Connectome Project (HCP) (Figure 1a). Literature review revealed five differentially defined stereotactic radiosurgical (SRS) and radiofrequency (RF) targets for capsulotomy for OCD performed between 2003 and 2014. Capsulotomy lesions were modeled as 5mm-spheres centered on these targets (Figure 1b) and were evaluated for overlap with the created ALIC segmentation and with surrounding gray matter structures (Figure 1c). Modeled lesions were used as seed regions for deterministic tractography on an 842-subject diffusion data template from HCP in order to identify involved connectomic networks.

Results

Across the five targets, a mean of 25.4% of modeled lesions overlapped with the ALIC by volume. Means of 16.2%, 12.7%, and 36.8% of modeled lesions coincided with nucleus accumbens, caudate, and putamen, respectively. According to the ALIC segmentation, a mean of 63.9% of the volume of modeled lesions within the ALIC intersected with the subregion connecting primarily to Brodmann area 11 (orbitofrontal cortex, OFC). All five modeled lesions exhibited connectivity to OFC as per the 842-subject HCP template (Figure 2).

Conclusion

These results indicate that anterior capsulotomies for OCD have generated lesions extending outside of the ALIC. The overlap between lesions and gray matter structures surrounding the ALIC could represent incidental effects of capsulotomy or it could possibly represent alternate therapeutic mechanisms. These findings also suggest that capsulotomy for OCD may involve the modulation of frontal-subcortical tracts connecting to the OFC, which bears relevance to the cortico-striato-thalamo-cortical (CSTC) model of OCD pathophysiology.

Objective: OCD is a sometimes debilitating psychiatric disease with a 2% lifetime prevalence. Up to 10% of patients do not respond to conservative treatment. For severe cases, DBS targeting the Nacc/ALIC is a viable option, receiving CE-mark in 2009. However, because of variable success rates and side effects, 8 different targets have been proposed for OCD in the last 18 years - the search for a hotspot continues.

In this study, using a novel visualization software, we correlated lead position and resulting volume of tissue activated (VTA) with clinical outcome and side effects in order to narrow down the optimal target area.

 Methods: We analyzed data for 16 consecutive patients treated at our center over a period of 3 years with DBS of the Nacc/ALIC, following a routine targeting procedure. Based on improvement on the Yale-Brown obsessive compulsive scale (YBOCS) and clinical profit at 12 months follow up, four outcome groups were defined. Subgroups were also designated for unexpected side effects.

Individual ROIs from all patient hemispheres were stacked to create a median intensity image, and then registered to the resulting intermediate to create a common anatomical space (Patient average MRI, PAM). Using the Suretune Expert Tuning Tool software (Medtronic), the location of the individual contacts used and the resulting VTA were aggregated into the PAM and probabilistic stimulation maps (PSM) were calculated. The adapting Yelnik-Bardinet atlas was aligned to the PAM as an anatomical reference.

 Results: The graphical analysis indicates anatomical localization to be correlating with both clinical outcome as well as side-effects. PSM of non- and fair responders were revealed to be distinct from - but nearby to - the PSM of good and excellent responders. All patients reporting unwanted weight-gain had their active contacts clustered in a circumscript area, independent of their improvement in OCD. These patients are followed up with a multidisciplinary approach to further elucidate the underlying mechanism.

 Conclusion: While data and analysis is preliminary, this novel tool shows promise for correlation of lead location and clinical effect in the way that PSM suggest an area of best profit. The results also open the way for further research into the insufficiently understood side effect of weight gain through DBS in OCD.

Obsessive-compulsive disorder (OCD) affects 2-3% of the American population. Patients suffering from severe, refractory OCD have limited therapeutic options. Neurosurgical interventions (e.g. deep brain stimulation (DBS) and stereotactic lesions (cingulotomy, capsulotomy)) are currently employed in treating OCD, but are limited in their applications owing to the complexity of potential targets and involved circuitry. Therefore, it is essential to delineate imaging correlates of pathological circuits in OCD. The objective of this study is to use multimodal imaging (simultaneous EEG-fMRI) to identify specific brain regions that are implicated in OCD.

We used multimodal imaging to identify correlates of cognitive control impairment that correspond to OCD by comparing results from healthy controls (n=6) and patients with severe, refractory OCD preparing to undergo neurosurgical intervention (n=5). We simultaneously acquired fMRI and EEG data while subjects engaged in the Multi-Source Interference Task (MSIT), a Stroop-like cognitive interference task that is known to engage the dorsal anterior cingulate cortex (dACC). Cue-locked midline frontal theta power (4-8Hz) from EEG was used in the general linear model as a modulator of fMRI regressors. Implicated regions were determined by thresholding the images at a corrected cluster significance of p = 0.05.

Results from the EEG analyses confirm that midline frontal theta power, as measured at electrode Fz, is modulated during the MSIT. Additionally, we observed increased task-relevant BOLD activations in the dorsolateral prefrontal cortex (dlPFC) in the control group and in the dlPFC, supplementary motor area (SMA) and the insula for the OCD group. Compared to controls, OCD subjects exhibited increased BOLD activations in the OFC, insula, and the dlPFC in high conflict versus low conflict trials (Figure 1). These results are specific to the cue-locked analysis using an EEG-informed fMRI model and were not observed in the fMRI-only model.

We used simultaneous EEG and fMRI in this study to overcome their respective limitations in spatial and temporal resolution. The fMRI model incorporated behavioral task (trial type and reaction times) and EEG data, thereby optimizing the information obtained from the neural signals. The results of this study are a step towards precisely understanding the dysfunction of cognitive control in OCD and delineating specific regions in the brain that are implicated in OCD. 

Background: Essential tremor (ET) is the most common adult movement disorder and is usually confined to the upper extremities. However, head and voice tremor is also common, with reports indicating the prevalence of head tremor to be around 50%.

Aim: The aim of this study was to analyse the short- and long-term results in a patient cohort with essential head tremor treated with DBS in the caudal Zona incerta(cZi).

Method: Retrospective analysis of patients fulfilling the following criteria: Essential tremor (ET); Unilateral or bilateral cZi-DBS without previous DBS or lesional surgery on either side; Completed evaluation with Essential Tremor Rating Scale (ETRS) at baseline before surgery and on/off stimulation at short-term follow-up 12 months after surgery, and at long-term follow-up, at least 24 months after surgery.

15 patients with unilateral and 2 with bilateral DBS, thus in total 19 leads were identified and included in the present study. The two bilaterally implanted patients were evaluated separately for each side and analysed as two unilateral procedures. Friedman test with Wilcoxon as a post hoc analysis was used for ordinal values. One-way ANOVA with repeated measurements with Bonferroni correction was used for continuous variables. A p-value<0.05 was considered significant.

Results: Of 36 unilateral and 12 bilateral DBS procedures fulfilling the inclusion criteria, 15 and 2, respectively, had head tremor. Nine were women and 12 men with a mean age at surgery of 70.4±9.3 years. Evaluations were done at a mean of 12 months and 35 months after surgery.

Total ETRS before surgery at baseline was 55.5±10.3 points. This was improved by 55% and 54% with unilateral stimulation at short-term and long-term follow-up, respectively(p≤0.00001). Contralateral tremor of the hand (item 5/6) was improved by 94% with stimulation at short-term and by 83% at long-term follow-up(p≤0.00001).

The mean head tremor score was reduced from 1.7 at baseline to 0.2 with stimulation at both short- and long-term follow-up (88%, p≤0.0001).

The mean coordinates of contacts used for stimulation was 11.7 mm lateral to the AC-PC-line, 6.8mm posterior to the mid-commissural point (MCP) and 2.1 mm inferior to the MCP. The mean coordinates did not change over time. 

Conclusion: Unilateral stimulation in the cZi was effective in alleviating essential head tremor and the effect did not diminish over time.

Background: High field MRI is expected to increase visibility of STN contour representation and considered an advantage for direct planning in STN DBS. Whether this results in significant alterations of target coordinates in comparison to lower field strengths is currently unknown.     

Objective: Evaluating possible influence of different field strength T2-weighted MRI on STN target planning.

Design/methods: STN target planning was performed by three DBS surgeons on 1.5, 3.0 and 7.0-Tesla MRI in order to evaluate if higher field strength leads to significant alterations of STN target coordinates. For all sequences X, Y and Z coordinates were compared.

Results: Direct planning of the target point based on STN representation on 1.5 Tesla, 3.0 Tesla and 7.0 Tesla showed high correspondence for X, Y and Z coordinates between the three field strengths (intra-rater) and between surgeons (inter-rater).

Conclusion: STN targeted coordinates were comparable on 1.5, 3.0 and 7.0-Tesla T2-weighted MRI. This could be explained by the fact that visibility of anatomical references used for target planning as red nucleus and medial STN border were comparable on the different sequences. 

figure: Axial midbrain section showing STN at maximal diameter of RN on three different MRI sequences. The horziontal red dotted line coincides with the Bejjani line, the cross section of the lines coincides with the medial STN border, identification of both references is readily done on all field strenghts.

Background: 7-Tesla T2-weighted Magnetic Resonance Imaging (MRI) offers improved visibility of the dorsolateral subthalamic nucleus (STN), which is considered the optimal location for deep brain stimulation (DBS) in Parkinson’s Disease (PD). However, it is unknown whether the dorsolateral STN on 7-Tesla T2 corresponds to the neurophysiological location.

Objective: To compare dorsolateral STN border identified on 7.0-Tesla T2-weighted MRI with the border obtained during microelectrode recordings (MER) in patients undergoing DBS for PD.

Design/methods: Dorsolateral border identification was done using axial and coronal orientated 7.0-Tesla T2-weigthed MRI. This was compared to dorsolateral border identified by MER.

Results: A total of 108 microelectrode tracks were evaluated in 19 patients. For the central and anterior microelectrode channel, the dorsolateral STN border on MRI was located more superior in 74% of trajectories compared to MER. Average distance from MRI to MER border was 1.0 millimeter.

Conclusion: 7-Tesla T2 MRI offers the possibility of dorsolateral STN identification. In the vast majority of cases this border was located more superior compared to MER. For STN DBS, the optimal location on 7-Tesla MRI is located just below the dorsolateral border. 

figure: Axial and coronal midbrain sections showing optimal DBS location within the STN on three different MRI field-strenghts. The cross section of the two dotted red lines coincides with the defined optimal DBS location.

Background:  Previous retrospective studies of DBS lead revision and removal rates conducted at single sites have reported a percentage between 4.7-12.4%.  However, patient follow-up time in these analyses had wide variation.  A recent retrospective report evaluating United States Medicare data, as well as from a smaller patient cohort where data was collected at two sites, reported a revision and removal rate of 15.2% and 34.0%, respectively.  In order to characterize the rates and types of events that result in lead revisions or removals in a prospective study, information was analyzed from the Product Surveillance Registry (PSR). The PSR tracks data across a large practice population beyond Medicare or single payor systems. It provides insights in how the therapy is utilized at DBS implanting and managing centers while collecting product and safety information on DBS systems and patients. 

Methods: Data was analyzed on 2109 DBS patients registered from July 2009-2016 from 36 centers located in three continents.  Lead survival was the primary endpoint, and analyses were performed to quantify the duration of time until a lead revision or removal occurs while adjusting for varying lengths of post-implant follow-up time. 

Results: Of the 2109 DBS patients, 67.1% were implanted for Parkinson’s disease (n=1416), 21.3% for Essential Tremor (n=449), 7.1% for Dystonia (n=150), and 4.5% for other indications (n=94).  Based upon survival analyses for all indications, lead revision and removal rates were 2.7% at 6 months and 7.9% at 57 months.  There were no observed differences by indication; however the study was not powered for that endpoint. The technical reasons for lead revision and removal were unacceptable lead impedance issues (6/16), lead fracture (5/16), and lead migration (5/16). Whereas, the reasons for lead revision and removal due to non-technical reasons were device-related infections (39/57), other infections (6/57), implant site erosion (4/57), wound dehiscence (4/57), subdural hygroma (2/57), and other reasons (2/57).

Conclusions: Results from this large, prospective global registry demonstrated lead revision and removal rates of 7.9% at approximately five years post-implant.  Lead revision and removals were predominately due to non-technical issues such as infection versus technical issues.  Further analyses of this registry over time will enable comparison across anatomical lead locations or other variables of interest.

Introduction: Deep Brain Stimulation is an established treatment modality in various movement disorders. Targets are
usually located within the basal ganglia. Due to the proximity of the target points to critical functional structures as the
internal capsule, therapeutic yield might be limited by side effects. Furthermore energy consumption is potentially
higher in conventional monopolar stimulation. Recently, segmented DBS leads have been made available. This
technique comes with the promise of increased efficacy and side effect reduction. We therefore compared our
preliminary data with segmented leads with the data from the Libra study conducted 4 years ago.
Materials/Methods: The purpose of the Libra study was to evaluate the effects of a new Deep Brain Stimulation
System for reducing symptoms of advanced, Parkinson’s disease Also the Activities of Daily Living, UPDRS scores,
Quality of life of subject, device parameters including active contact in relation to efficacy, frequency, type and severity
of therapy related AE’s events were evaluated. 3 months data from patients with segmented leads (Infinity) 6 patients
will be compared to the Libra data (6 patients).
Results: DBS Targeting was guided by three micro electrode recording tracts and a directional lead system (Infinity
DBS, SJM) was implanted in an all-in-one GA setting in 6 patients. The segmented contacts were intensively tested at
90μs and 130 Hz in the postoperative course. Distinct effect/side-effect patterns for each contact were observed.
Comparison of Parkinson’s symptoms as demonstrated by the UPDRS motor scores in the medication “off” state at
Baseline compared to the medication “off” with stimulation “on” 3 months after device implantation. No differences in
efficacy where seen between Libra and Infinity data among those 6 patients. However compared to the Libra data, no
stimulation dependent side effects occurred in the Infinity group. Amplitude and frequency did not differ, however
lower pulse width was used in 2 patients.
Discussion: Segmented leads allowing current steering offer new perspectives for DBS and will likely result in
increased treatment efficacy while reducing side effect at the same time. 
Conclusions: Since the threshold for side effects is higher in segmented leads, they are more adaptable to the
individual patients’ needs and potentially resulting in a longer battery life

Introduction: The mechanisms of the anti-epileptic action of vagal nerve stimulation (VNS) are still poorly understood.In this study, we investigated the impact of VNS on functional connectivity (Fc) using direct intracerebral recordings of several cortical areas (SEEG) by comparing the “on” versus “off’ stimulation periods.

Material & Methods:Six patients with drug resistant epilepsy who underwent SEEG recordings during ongoing VNS therapy were investigated. Five patients were regarded as non responders to VNS whereas one was deemed responder (> 50% seizure-frequency decrease). SEEG signal was acquired during resting periods without sleep at a distance from seizures. The functional connectivity was computed from co-occurrence of signal estimated by nonlinear regression analysis based of h² coefficient between pairs of selected bipolar SEEG channels from all sampled cortical areas of the patients. Comparisons were performed during ‘on’ and ‘off’ periods of stimulation. The parameters were similar to those chronically used for the patients. For four patients, different stimulation amplitude were also tested and in one patient different stimulation frequencies and pulse widths.Levels for significance were adjusted according to Bonferroni’s method.

Results: In comparison with ‘off’ periods, the ‘on’ periods disclosed significantly higher values (increased Fc) for five patients (P1, P3, P4, P5, P6) and lower values for one patient (P2). In P6, we observed a significant but nonlinear effect of stimulation parameters on Fc (Fc increased by setting the frequency from 20 to 25 Hz, the amplitude from 1 to 1.25 mA or the pulse-width from 250 to 500μs but without additional effect of setting the parameters to higher values (plateau effect).Finally, the only decreased Fc occurring during VNS corresponded to the responder patient suggesting that the therapeutic benefit might be related to this mechanism.

Conclusion: Our study suggests that VNS alters brain functional connectivity but in a complex and variable way according to the brain areas and parameters settings. The only patient in whom the functional connectivity was decreased was the only patient deriving a true benefit from VNS. The study is too preliminary to draw any solid conclusion but the mechanisms of action may involve a decrease in Fc. These results are consistent with the existing literature (decreased Fc of interictal activity during VNS in responders).

Objective: Magnetoencephalography (MEG) is a functional neuroimaging technique for mapping brain activity by recording magnetic fields produced by electrical currents occurring naturally in the brain. The clinical uses of MEG are in detecting and localizing pathological activity in patients with epilepsy. Single dipole method is an established procedure for analyzing single or spatially and temporally limited activities such as interictal epileptiform activities; however, it has limitations for analyzing spatially propagated and temporally prolonged rhythmic magnetological activity including ictal data during the secondary generalization. Thus, a reliable confirmatory method for analyzing ictal MEG is needed. We analyzed MEG using time-frequency method. It estimated the time frequency component of the signal and it could show the spectral distribution of signal. In such spectral distributions, the gamma oscillation (GOs) is known as useful indicator of epileptogenic focus. In the present study, we investigated GOs of pre-and post-operative MEG to define it had value of prognostic factor.

Methods: From July 2012 to July 2016, a total of 31 patients received the pre- and post-operative MEG test. Among them, we selected ten patients which composed of 5 patients with seizure free and 5 with symptoms after surgery. We find to the epileptic spike on pre-operative electroencephalography (EEG), and then we estimate epileptogenic zone on the brain. Then, based on the EEG, we designate a region of interest location (ROI). Then, we did time frequency analysis of MEG for ROI.

Results: In seizure free group, all patients showed spike wave and GOs on pre-operative EEG and MEG. However, despite the absence of symptoms, spike wave and GOs were seen in one patient on post-operative tests. In the group with seizure after surgery, all patients showed spike wave and GOs on pre-operative tests. However, on post-operative tests, while three patients showed spike wave on EEG, a total of five patients showed GOs still on MEG. We evaluated the relationship between surgical outcome and epileptogenic sign. There was statistical significance between GOs and surgical outcome (p=0.048).

Conclusion: MEG could provide valuable information for post-surgical evaluations to define epileptic focus for patients with persistent symptom after surgery and GOs on MEG is correlated with epileptic focus. Ascertaining the presence of GOs on MEG after epilepsy surgery could predict the prognosis of seizures.

Objectives: To investigate the clinical outcome and location of active contacts in chronic centromedian nucleus (CM) deep brain stimulation (DBS) for refractory epilepsy.

Methods: The outcome of CM stimulation was evaluated with percent (%) seizure reduction compared to the baseline three months. To determine the location of active contacts, 27 leads in 14 patients with refractory epilepsy were studied. An analysis was conducted to determine whether any coordinates of the center of the active contacts predicted percent seizure reduction. (Fig. 1)

Results: With an average follow-up of 18.2 ± 5.6 months, the mean percent seizure reduction (n=14) was 68 ± 22.4% (25-100%). Eleven of 14 patients (78.6%) could achieve >50% improvement in the frequency of seizure. Specifically, all four patients (100%) with generalized epilepsy (Lennox-Gastaut syndrome) and seven out of 10 patients (70%) with multilobar epilepsy showed >50% reduction in seizure frequency. (Fig. 2)

The mean coordinates of center of the active contact were located in the superior part of anterior ventrolateral CM. The calculated coordinates of laterality from midline (x), anterior-posterior (y) and height (z) from posterior commissure (PC) did not correlate with seizure outcome measured by percent seizure reduction. However, the locations of active contacts used during chronic CM stimulation in multilobar epilepsy were identified more dorsal to those used in generalized epilepsy. (Fig. 3).

Conclusions: Chronic CM stimulation is a safe and effective means in the treatment of refractory epilepsy. 

OBJECTIVES: Stereotactic laser amygdalohippocampotomy (SLAH) is a less invasive alternative to anterior temporal lobectomy (ATL) for medically intractable mesial temporal lobe epilepsy (MTLE). To properly compare SLAH to ATL, a large series with 12-month seizure outcomes is required. Here we present 12-month outcomes on 50 SLAH MTLE patients, the largest single center series. We hypothesized that ATL was superior to SLAH.

METHODS: Outcomes 12-months following SLAH were retrospectively analyzed and the proportion of patients who were seizure free was compared to that following ATL, as demonstrated by the Wiebe et al. 2001 randomized controlled trial (64%). The outcome of patients who had recurrent seizures and underwent repeat SLAH (N=9) was re-categorized only if they were seizure free at 12-months. A performance goal of 43% seizure free was also set, the threshold at which SLAH is predicted to achieve higher quality adjusted life years than ATL (Attiah et al. 2015). A select subgroup of MTLE patients with mesial temporal sclerosis (MTS) and without evidence of dual pathology or previous epilepsy surgery was similarly analyzed as an “ideal MTS” subgroup (N=29).

RESULTS: 56.0% (95% CI ±14.3%) of all patients, and 65.5% (95% CI ±18.4%) of the ideal MTS subgroup were seizure free for ≥12 months following all SLAH procedures. These outcomes were not significantly different from the ATL historical comparator group (all: p=0.24; ideal: p=0.87). Further, the ideal MTS subgroup’s seizure free rate was superior to the 43% performance goal. Four of the 9 patients who underwent repeat SLAH became seizure free for ≥12 months, which was included in the above analysis. Four patients not seizure free following SLAH underwent ATL, only 1 of whom became seizure free. Complications were minimal, including 4 postoperative visual field deficits (1 transient; 1 disabling), 2 hemorrhages without persistent deficit and 3 transient cranial nerve palsies.

CONCLUSION: These results fail to reject the null hypothesis that there is no statistically significant difference between ATL and SLAH with respect to 12-month seizure freedom, supporting SLAH as a minimally invasive alternative to open resection for patients with MTLE. Additionally, consistent with ATL outcomes, a higher seizure free rate was achieved in the ideal MTS subgroup. Furthermore, in the minority of patients where seizure freedom remains elusive following SLAH, this procedure does not preclude subsequent open resection.

Relevant behavioral events may be signaled by the Centromedian-Parafascicular Complex

Anne-Kathrin Beck¹, Kerstin Schwabe¹, Mahmoud Abdallat¹, Pascale Sandmann², Joachim K. Krauss¹

¹ Department of Neurosurgery, Hannover Medical School, Hanover, Germany

² Department of Otorhinolaryngology, University of Cologne, Cologne, Germany

Objective: The centromedian-parafascicular complex (CM-Pf) of the intralaminar thalamus was shown to be activated during attentional orienting and processing of behaviorally relevant stimuli. Therefore, the CM-Pf was suggested to be a part of a subcortical cognitive control loop. Here, we investigated the human CM-Pf and its involvement in processing of task relevant information during an auditory three-class oddball paradigm with simultaneous cortical recordings.

Methods: Simultaneous intracranial local field potentials (LFPs) and scalp electroencephalographic (EEG) recordings were obtained in 6 patients (2 woman; mean age=48±12 years) who received deep brain stimulation (DBS) electrodes in the CM-Pf for the treatment of their pain syndromes. Within 2 days after surgery, they performed an auditory three-class oddball paradigm with externalized DBS electrodes. Subcortical and cortical event-related potentials (ERPs) were analyzed upon presentation of one frequent standard stimulus (900Hz; 72%) and two infrequent stimuli (600Hz and 1200Hz; 14%), either being a relevant or a distractor stimulus.

Results: Analysis revealed high accuracy (>70%) for all participants. As expected, the rare relevant stimuli elicited a P3 response over parietal regions in the EEG. The P3 component of an ERP is known to reflect attentional processes in tasks requiring stimulus detection and discrimination. Recordings in the CM-Pf revealed highest amplitudes to the relevant stimuli as well. Interestingly, peak latencies of the CM-Pf precede the cortical P3 response.   

Conclusion: The CM-Pf seems to be involved in goal-oriented action selection and attentional mechanisms. Importantly, subcortical responses in the CM-Pf precede cortical responses, suggesting that auditory information is labelled as behavioral relevant from subcortical circuits and is then distributed to cortical areas; possibly via thalamo-striatal loop mechanisms.

Background: The application of pharmacological therapeutics in neurological disorders is limited by
the ability of these agents to penetrate the blood-brain barrier (BBB). We examined
several FUS conditions in order to optimize FUS sonication for BBB opening in small animals.

Methods: Changes in BBB permeability were observed during transcranial sonication with contrast
agent microbubbles (MB) using low-intensity focused ultrasound (FUS) in rats (N = 20). We examined the
effects of FUS sonication with different sonication parameters, varying acoustic pressure, center
frequency, burst duration, MB type, MB dose, pulse repetition frequency (PRF), and total exposure time.
The focal region of BBB opening was identified Evans blue dye extravasation. Additionally,
hematoxylin and eosin staining was used to identify tissue damage in the sonicated region.

Results: Acoustic pressure amplitude, burst duration, and total exposure time were associated with
increased damage in the sonicated region of the brain when parameter values were increased. In contrast,
variations in MB type, MB dose, and PRF had little effect on the degree of tissue damage after FUS
sonication. 

Conclusions: The clinical application of FUS sonication for drug delivery across the BBB requires the
guarantee of both safety and efficacy and thus the careful optimization of relevant sonication conditions.
Our study aimed to identify these influential conditions and provide optimized values for further studies.

Objective: MR-guided focused ultrasound (MRgFUS) is increasingly used as a lesioning tool in functional neurosurgery. While the generated lesion can be visualized using traditional MR imaging, these do not provide detailed information about tissue microstructure or direct visualization of affected tracts. To study this, we used a neonatal swine model to investigate in-vivo acute changes in water diffusion and fiber tracts after MRgFUS treatment of the fornix.

Methods: Four piglets (5-6.7kg) were treated with MRgFUS system (Sonalleve, Philips Medical Systems, Finland). Treatment cells were positioned along the anterior body of the fornix with a cross-sectional diameter of 4mm and a length of 10mm (volume= 83.78mm³). 3-4 sonications from 40W to 80W, frequency 1.2MHz were performed to generate the ablation with a peak temperature above 60°C. Between each sonication, there was a 5-minute cool-down interval. Pre- and post-treatment T1, Diffusion weighted images (DWI), and histological data were collected. DWI metrics (FA, AD, RD, MD, and ADC) were calculated for the lesion core, inner and outer boundaries of the lesion determined on the hyper-intensity signal in the mean DWI image. Paired t-test was performed for DWI metrics from each region of interest. One-way ANOVA followed by post-hoc Tukey’s HSD was applied for each DWI metric across the three regions of interest for pre- and post-treatment separately. Fornix fiber tracts were generated before and after the treatment for qualitative assessment.

Results: In all treatments, final peak temperature reached a range between 60.8°C and 68.8°C. The volume of treatment was comparable (correlation= 0.88) between values measured through mean DWI (347.5±58.12 mm³) and histological data (342.35±44.69mm³), however this was significantly larger than the treatment cell volume. MRgFUS resulted in a significant decrease in diffusion metrics in the treatment region (Ps<0.05 FDR-corrected). The fiber disruption was most pronounced as the lesion core was approached.

Conclusions: Diffusion metrics and tractography can accurately assess treatment location, volume and necrotic core after MRgFUS treatment. DWI can successfully advance MRgFUS targeting. In our case, ablated tissue volume was much larger than the planned cell likely due to the set peak temperature. Further comparative tract alterations based on peak temperature should help determine the relationship between temperature and final lesion volume more accurately. 

Introduction

The anterior limb of internal capsule (ALIC) is a promising target for neuromodulatory interventions for severe, treatment refractory psychiatric disorders, including deep brain stimulation (DBS) and capsulotomy, for obsessive-compulsive disorder (OCD) and depression. These disorders are heterogeneous phenomena and there is controversy about optimal targets within the ALIC. Using diffusion tensor imaging (DTI), we parcellated the ALIC based on structural connectivity. We then compared the ALIC segmentations between individuals to evaluate regional patterns of consistency.

Methods

ALIC segmentations were generated for 40 subjects from the Human Connectome Project (HCP) using connectivity-based seed classification in FSL v5.0. Voxels within the ALIC were treated as seed regions and frontal Brodmann areas (BAs) as independent targets. We combined patient-specific segmentations by assigning each ALIC voxel to the most frequently associated frontal BA in the 40 individual segmentations. We compared this combined individual-based parcellation to one similarly created using a template from HCP that averaged diffusion data from 842 subjects. Segmentations were compared to one another using the Sørensen-Dice Index of similarity (SDI).

Results

All 40 segmentations exhibited a posterior-superior to anterior-inferior axis of organization (Figure 1). On average, the frontal BA assignments of voxels in the group analysis were consistent with 66.2% of individuals’ segmentations. In this analysis, the region assigned to BA11 (orbitofrontal cortex, OFC), exhibited the highest degree of consistency across individuals, with 12.1% of this region being assigned to BA11 in all 40 subjects. The mean SDI between the individual-based combined segmentation and the template-based segmentation regions was 0.283. The mean SDI between individual segmentation regions was 0.455. Regions assigned to BA11 were the most similar across individual segmentations, with a mean SDI of 0.714.

Conclusion

These results clarify the organization of the ALIC in humans. They also demonstrate the high variability in ALIC organization between individuals, albeit with some loci of focal consistency. This variability suggests that patients may benefit from tractography prior to neuromodulation in order to facilitate patient-specific targeting. Interestingly, the most consistent regions of the ALIC, those connecting to OFC, are the regions most frequently targeted by neuromodulatory procedures.

Intro:

While pharmacological therapy for essential tremor is the first line of treatment, some patients may only experience partial benefits.  For these patients, surgical lesion or deep brain stimulation (DBS) of the ventral intermediate (VIM) nucleus of the thalamus has been shown to ameliorate tremor symptoms. Precise targeting of the VIM has been correlated with superior outcomes, but targeting of this structure based on MRI may be challenging.  Diffusion tensor imaging (DTI) has been used to approximate the VIM indirectly by calculating the pyramidal tracts (PT) and medial lemniscus (ML) trajectories as anatomical reference.  Here we show that the primary diffusion vector map can be used to directly delineate VIM without the need for post processing tractography calculation.

Methods:

DTI from 40 subjects in the Human Connectome Project was used to compare methodologies.  Free surfer library’s FDT toolkit was used to calculate the primary diffusion vector map, PT, and ML. Using the vector map we identified the VIM internal capsule boundary and sensory boundary, and compared the location to the indirect DTI localization (Fig1).  The average Euclidian distance between both methods was compared.

Results:

By comparing methods, the Euclidian distance in the VIM internal capsule boundary in the ACPC plane was found to differ by 0.53mm(+/- 0.70mm), and the VIM sensory boundary was found to differ by 0.96mm(+/- 0.99mm).

Conclusion:

Our localization method allows delineation of VIM thalamus utilizing a primary vector map. The method is able to produce a direct VIM delineation similar to tractography calculated methods within a millimeter on average.  This map can be produced using most current surgical navigation software packages, making this technique easy to use and readily accessible.  Future directions include comparing the localized area to both efficacy and side effects resulting from DBS implantation and radio surgery lesions.

Caudate Is Involved in Human Associative Learning

Introduction

Disorders of learning and memory account for an increasing disease burden in our aging population with significant social and financial consequences. Unfortunately, existing treatments have limited utility. Research in humans and primates supports an important role for the caudate in learning. Our objective was to further characterize the role of the caudate in human learning and to determine whether caudate stimulation could alter performance on a learning task.

Methods

Five subjects who underwent depth electrode placement for seizure localization for medically refractory epilepsy participated in our study. Local field potentials were recorded from intracranial electrodes while subjects participated in study tasks. A learning task required subjects to learn an association between a series of presented images and a button press. A gambling task required subjects to place a wager on the outcome of a simulated card game. We computed power in caudate electrodes and compared power during the feedback epoch of the task between correct and incorrect trials for the learning task and between winning and losing trials for the gambling task. Three subjects additionally played a stimulated block of the learning task during which half of the images received bilateral caudate stimulation at 200Hz and 2mA for 1 second during the feedback epoch after correct responses.

Results

There was a significant increase in caudate beta (15-30Hz) power during the feedback period of the learning task. There was a significant difference between beta power following correct versus incorrect trials. There was no difference in beta power following winning versus losing trials in the gambling task. Of the three subjects who underwent caudate stimulation during the feedback epoch of the learning task, 2 had a significant improvement in learning for stimulated versus unstimulated images.

Conclusion

Changes in caudate beta power during feedback differed between correct and incorrect trials in the learning task. Stimulation during feedback following correct trials enhanced learning. These findings suggest that the caudate plays an important role in updating response associations in human associative learning, 

Objective

A DBS device that enables current fractionalization using a multiple-source mode of delivery can permit the application of a well-defined, shaped electrical field. Thus, we postulated that a multiple-source, constant-current device that permits a well-defined distribution of current would lead to motor improvement in patients with Parkinson’s disease (PD). Previously, results from the VANTAGE clinical study demonstrated highly significant improved motor function (p < 0.0001) as assessed by UPDRS III "meds off" at 6 months post-first lead implant as compared with Baseline "meds off," thereby successfully achieving the study primary endpoint. Here we present the four year, long-term follow up results of patients in the VANTAGE clinical study that employed multiple independent current control (MICC) Deep Brain Stimulation (DBS) in the management of motor symptoms of Parkinson's disease.

Methods

VANTAGE is a prospective, multi-center, non-randomized, open-label study sponsored by Boston Scientific Corporation. Forty subjects with idiopathic PD were implanted bilaterally with a DBS system (Vercise, Boston Scientific) targeting the subthalamic nucleus and followed up to three years post-lead placement. Assessments measured up to 3 years post-lead placement included the following: Levodopa Equivalent Dose (LED), Parkinson's Disease Questionnaire (PDQ-39), Global Impression of Change (GIC), and Modified Schwab and England (SE) scores.

Results

Data from three years post-lead placement has been collected and analyzed.  Anti-parkinsonian medications were found to have remained stable (average of 1399 mg at baseline versus average of 699 mg at 3 years follow up). PDQ-39 summary index scores demonstrate continued improvement (versus baseline values) in quality of life based on assessments of bodily discomfort, activity of daily living, mobility, emotional well-being, and stability of cognition.  Further, a high proportion of GIC responses were characterized as "improved" (Clinician: 88.2% ; Subject: 82.4%), and modified Schwab and England scores remained stable. Results from 4 years post-lead placement to be presented.

Conclusion

The collected outcomes from the VANTAGE clinical study will inform clinicians on the use of this system, and its flexibility to manage the motor symptoms of idiopathic PD.

Purpose.

It is well known that deep brain stimulation (DBS) of the subthalamic nucleus (STN) alleviates motor symptoms of Parkinson’s disease (PD). However, the effects of STN-DBS on presynaptic dopaminergic systems are still unclear. The nigrostriatal neuronal degeneration usually continues to progress in PD patients without DBS. Positron emission tomography (PET) with ¹¹C-Labeled 2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane ([¹¹C]CFT) is a marker for loss of presynaptic dopamine transporters in the striatum in PD. Here we used  [¹¹C]CFT PET in order to evaluate binding to the dopamine transporter in PD patients before and after neurosurgical treatment with STN-DBS.

Methods.

10 patients with PD were examined with [¹¹C]CFT-PET pre-operatively (within one month before surgery), and 12 months after surgery. [¹¹C]CFT  binding was evaluated using the region-of interest (ROI) method. ROIs were set bilaterally over the head of the caudate (divided into ventral and dorsal segments at its midpoint), nucleus accumbens, and putamen (divided into anterior-ventral, anterior-dorsal, posterior-ventral, and posterior-dorsal segments at its midpoint).

Results.

There was a significant reduction in postoperative [¹¹C]CFT uptake in the posterior-dorsal putamen contralateral to the clinically more affected side (to 7.4% of the preoperative mean, p<0.05). However, there was significant increase in [¹¹C]CFT uptake in the contralateral anterior-ventral putamen and ipsilateral ventral caudate (to 4.9% and 10.1% of the preoperative mean, respectively, p<0.05). [¹¹C]CFT uptake was also increased in the bilateral nucleus accumbens although it did not reach statistical significance.

Conclusions.

Our result showed that STN-DBS increases dopamine transporters in the ventral striatum, which is different from natural course of PD. This result may indicate the compensative and neuroprotective effect of STN-DBS on the presynaptic dopaminergic systems of PD.

Before the advent of levodopa, pallidotomy was the most effective treatment for Parkinson's disease but was soon superseded by thalamotomy. It is widely unknown that, apart from Lars Leksell in Sweden, two neurologists from Göttingen, Hans Orthner and Fritz Roeder, held on to pallidotomy. Using a unique and sophisticated stereotactic technique lesions were individually tailored, and lesion volume was reduced over time. Post-mortem studies demonstrated that eventually true posterior and ventral pallidoansotomy sparing the overwhelming mass of the pallidum was accomplished. During surgery complete alleviation of rigidity was observed as well as associated pain. In 1962, the long-term effects (3 years follow-up on average) of the first 18 out of 36 patients (largest published cohort) with staged bilateral pallidotomies were reported in great detail. In detailed descriptions of each case, long-term improvements of parkinsonian posture, gait, and akinesia (e.g. improved repetitive movements and arm swinging) were reported. Alleviation of tremor was found to require larger lesions than needed for suppression of rigidity. No improvement of speech, drooling or seborrhea was observed. By 1962 the team had operated 13 patients with postencephalitic oculogyric crises with remarkable results (mean follow-up 5 years). They also described alleviation of hyperkinetic disorders (e.g. hemiballism, chorea) with pallidotomy. Surgical mortality and complications (e.g. hemorrhages; inadvertant lesioning of the corticospinal or optic tract; cognitive and behavioural abnormalities) had been remarkably low. In the mid-1980ies, unilateral posteroventral pallidotomy was re-introduced by Laitinen after that long-term complications of levodopa treatment had become evident, but none of the contemporary approaches did reach the same technical sophistication as the Göttingen technique. The intricate history of pallidotomy is incomplete without the appreciation of the achievements of these pioneers who perpetuated pallidotomy against the mainstream of that time, and mastered bilateral and safe pallidal lesioning in an era long before modern imaging was available.

Background:  DBS for Parkinson’s Disease, has traditionally been performed awake using microelectrode recording to confirm accurate placement of electrodes.  Newer technologies have allowed DBS to be performed asleep, using intraoperative image guidance to confirm electrode placement without the need of multiple passes into the brain.  

Methods:  DBS candidates with PD referred to Oregon Health & Science University underwent asleep DBS using image guidance.  Patients underwent awake DBS by the same surgeon at the same center. Assessments at preoperative baseline and 6-month follow-up included an OFF-levodopa motor UPDRS part II, the PD Questionnaire quality of life scale, motor diaries, the dementia rating scale and speech fluency with the controlled oral word association category fluency and F-A-S  phonemic fluency tests. 

Results:  62 subjects underwent asleep DBS using iCT and 39 subjects underwent awake DBS using MER guidance.  No significant difference was observed in the change of motor UPDRS (14.5±9.9 point improvement in asleep DBS, 17.6±12.3 point improvement in awake DBS, t=1.24, p=0.222) or UPDRS II score (9.3±2.7 point improvement in asleep DBS, 7.4±5.8 point improvement in awake DBS, t=1.75).  Improvement in ON time without dyskinesia was superior in the asleep DBS group (+6.4 hours/day versus +1.7 hours/day, p=0.04).  Quality of life scores significantly improved in both the asleep and awake groups (17.7±15.7 and 8.9 ±11.5 points respectively), with improvement in the total score (p=0.004) and subscores for cognition (p=0.002), communication (p<0.001) and emotional well-being (p=0.03) being superior in asleep DBS.  Speech fluency outcomes were superior in asleep DBS  (category fluency 3.66±11.9 point improvement versus 6.31±9.7 point decline, p<0.001; phonemic fluency 0.18 ±10.6 point improvement versus 5.5 ±9.6 point decline, p=0.023).  The dementia rating scale remained stable without significant change in both the asleep and awake cohorts (p=0.44).  One subject in the awake DBS cohort and two subjects in the asleep DBS cohort had treatment-related adverse events.  

Conclusions:  Asleep DBS for PD with intraoperative imaging guidance improved motor outcomes over 6 months that were on par with or better than awake DBS at our center, and superior with regard to speech fluency and quality of life.   Serious adverse events were uncommon in both groups.  

STN-DBS is a well-established treatment for motor complications in PD. However, there is a significant individual outcome variability. This includes patient/disease related factors and differences in lead placement/DBS programming. It’s important to identify patients with suboptimal outcome after DBS for an intensified reevaluation of programming or lead revision. The levodopa response correlates significantly with the DBS stimulation response and is therefore used as a DBS eligibility criterion. Here we propose to use a ratio between best levodopa and DBS response as a benchmark for individual DBS outcome quality and show that surgical revision can rescue suboptimal outcome, when re-programming is inefficient.

Methods

We investigated 9 PD patients with STN DBS (Øage 63,7 years, ØUPDRS III(off): 54) 6-60 months after implantation. Motor symptoms control (in UPDRS III) by STN-DBS (after median reprogramming time of 60 hours) and Levodopa challenge were assessed after an overnight medication (+1h stim off) washout. The DBS response ratio (DBSrr) was defined as stimulation effect / levodopa response. Surgical revision was considered if the primary electrodes were placed outside the dorsolateral part of the STN (>2mm) in MRI-CT fusion analysis and the DBSrr was <0,7. Surgical techniques included explantation and reimplantation in two or one sessions.

 Results

15 electrodes were revised (6 bilateral, 3 unilateral), six were initially located in the anterio-medial part of STN, one lateral to the STN and four slightly medial (red cylinders, Figure 1). Median vector distance between active contact pre/postrevision was 4.08mm (range 1.6mm–8.42mm). Mean UPDRS III under DBS was significantly improved after revision (38.2±6.6 to 15.5±7.9 points, p<0.001), being even superior to the levodopa effect (15.5±7.9 vs. 27.1±9.7 points, p=0.014). Therefore, the DBSrr was significantly increased from 57% to 132% after revision.

Conclusions

STN-DBS has proved to be a very effective treatment for PD on a group level, but there is an increasing concern about DBS “failures”, in whom postoperative outcomes do not match the preoperative expectations. Our study suggests this patients, can be rescued with surgical replacement to a response similar to the levodopa-induced one, even years after surgery. The computation of the ratio of STN-DBS and levodopa motor improvement might support clinicians managing DBS “failure” cases, anticipating the benchmark of possible improvement after revision.

Objectives:

    Despite available pharmacological and psychotherapeutic treatments about 10% of obsessive-compulsive disorder (OCD) patients remain severe, treatment-refractory. For some of these patients deep brain stimulation (DBS) offers an appropriate treatment method. In hopes of identifying better treatment options such as DBS, many attempts have been made to clarify pathological brain mechanisms, but neurophysiological measures have not been systematically examined yet. To address this question, the aim of the present study was to search for specific functional correlates cross brain region/frequency interactions in OCD patients.

Methods:

    Routine scalp-EEG (19 electrodes) was recorded in ten OCD patients and ten healthy controls matched for age, while they were at rest with eyes closed. The investigation compares current source density measures of patients with OCD to the control group by using the techniques of low-resolution brain electromagnetic tomography (LORETA; Pascual-Marqui, et al, 1994). We also used the functional independent component analysis (fICA) to examine the interaction patterns of brain activity across region and frequency in the resting state networks by comparing between OCD patients and control subjects (Pascual-Marqui, et al, 2011).

Results:

    The findings of the current source density measure indicated that OCD patients were characterized by significantly higher activities in the following three regions, compared to control subjects. 1) In the delta, theta and alpha bands in the fronto-temporal region, 2) in the alpha and beta bands in the cingulate and 3) in the theta, alpha and beta bands in the nucleus accumbens and the bed nucleus of the stria terminalis (BNST).

    Although both groups of brain utilized the common resting networks, the fICA study showed how the OCD brain used following two resting state networks differently from the healthy control brain. OCD patients have 1) excess left prefrontal (PFC) delta and reduced right PFC delta, and 2) excess left frontal alpha and reduced parieto-occipital alpha.   

Conclusions:

    The nucleus accumbens as well as adjacent nucleus BNST are suggested as feasible targets for DBS in OCD from LORETA current density measures. Although most resting state networks were common to both groups of subjects, two resting state networks (between PFC hemispheres for delta activity, between left frontal and parieto-occipital area for alpha activity) differently used in OCD brain.

Background: Deep brain stimulation (DBS) is under investigation for severe obsessive-compulsive disorder (OCD) resistant to other therapies. OCD is a chronic disorder affecting approximately 2 % of the population. The disorder is characterized by persistent obsessive, intrusive thoughts generating anxiety, and related compulsions (tasks or "rituals") with the aim of neutralizing the distress. Up to 10 % of patients with OCD continue to demonstrate severe therapy-refractory symptoms despite trying multiple available treatments. We present here the 12-month follow-up data from 6 patient with severe therapy resistant OCD treated with DBS in the bed nucleus of the stria terminalis (BNST).

Methods: 6 patients with severe OCD who had tried psychotherapy and several different pharmacological treatments with little effect were included in an ongoing study of DBS for OCD. The patients underwent bilateral electrode implantation in the BNST and the stimulation was started immediately after surgery. The patients were evaluated at baseline and at 6 and 12 months after surgery with the Yale-Brown Obsessive-Compulsive Scale (YBOCS) as the primary outcome measure.

Results: Twelve months after surgery the mean YBOCS had improved from 33 to 18 points (46%). Thus, the severity of the OCD had decreased from severe to moderate on average. Similar effects were seen in secondary outcome measures for depression and anxiety. Minor signs of hypomania, reversed with a change of stimulation parameters, were seen in one patient. No serious adverse events occurred. 

Conclusions: The preliminary results from this study of BNST DBS in severe therapy-refractory OCD are promising and in line with previous publications. Nevertheless, DBS for OCD is still an investigational therapy and should therefore be performed in clinical studies driven by multidisciplinary teams.

【objectives】 Neuropsychiatric disorders can be caused by dysfunction in specific brain circuits. Accordingly, the stereotactic neurosurgical techniques for intractable mental disorders, such as deep brain stimulation, might have effect through modulation of the aberrant circuit and the interest of this field has been rapidly increasing. Although prefrontal lobotomy was performed to treat psychiatric disorders such as severe schizophrenia in the past, such procedure became an obsolete remedy in 1970s. Therefore, the neuroimaging and neuropathological studies in the lobotomized brains have not been systematically made until now. 【methods】 We identified fiber connectivities in the lobotomiized brains using diffusion tensor imaging (DTI). Voxelwise statistical analysis of the fractional anisotropy (FA) data in white matter tracts were carried out to compare between non lobotomized schizophrenic group (n=4), lobotomized schizophrenic group (n=4) and healthy control subject group (n=4). Furthermore, in two lobotomized schizophrenic brains, the sections were stained with hematoxylin-eosin and Kluver-Barrera stains. Immunohistochemistry was performed with the antibodies specific to tau protein. This study was approved by the local ethical committee and ethical aspects have been fully considered. 【results】 In the DTI study, lobotomized schizophrenia group had lower FA in the bilateral white matter of ventromedial prefrontal lobe, forceps minor, forceps major, corpus callosum, nucleus accumbens, cingulate bundle, the medial nucleus of thalamus, the anterior and a part of posterior limb of internal capsule and brainstem. As for histological study, gliosis and neural cell loss were found not only in prefrontal ablated lesion but also in the medial nucleus of thalamus, cingulate gyrus and nucleus accumbens, all of which connect to prefrontal related areas. Tau accumulation was detected in lobotomized prefrontal area and in thalamus or striatum which connect to prefrontal areas, similar to the pattern found in the DTI study. These findings may support the idea that abnormal tau aggregation reflects the afflicted pathways with the secondary degeneration by the surgical impact. 【conclusion】 This study demonstrated that the connectivity sacrificed by lobotomy is largely divergent, which was confirmed by the secondary neurodegeneration in the pathological study. Abnormal tau aggregation may propagate along the pathways with the secondary degeneration in lobotomized brains.

Objective:

Deep brain stimulation (DBS) of the accumbens nucleus (AN), ventral striatum and ventral capsule (VC/VS) region has shown a 50% response in adults with severe treatment-refractory obsessive-compulsive disorder (OCD), no matter which target is used. We sought to improve the effectiveness of DBS, by inserting the electrode along the three targets, so we might change the stimulation site depending on the patient's response.

Materials and Methods: A multicentric prospective study was conducted on eight patients, four from the University Hospital La Princesa,  two from the University Hospital Central de Asturias, and two from University Hospital Fundación Jiménez Díaz. All patients were operated on under the same protocol. Qualitative and quantitative data were collected.

Results:  Out of the 8 patients (mean age 42±9), 7 had a reduction in OCD symptoms, as objectified in an improvement in their YBOCS rates (preoperatory and 6 months follow-up means were 31±7 y 13±9, respectively). Six of them responded with stimulation at the AN (the first area we set for stimulation), while in one patient, stimulation needed to be switched to the ventral capsule to be effective.

Discussion:  These data indicate that DBS was safe and conferred a benefit in reduction in Y-BOCS scores in our series of patients with obsessive-compulsive symptoms. The insertion of the electrode through the three stimulation sites might improve effectiveness to the therapy, although this results need to be confirmed with further studies.

Introduction: An effective treatment of patients in a minimally conscious state (MCS) or vegetative state (VS), caused by hypoxic encephalopathy (HE) or traumatic brain injury (TBI), is not yet available. Deep brain stimulation (DBS) of the thalamic reticular nuclei, as a therapeutic procedure, has been attempted mainly in patients with TBI. 
Methods: Fourteen out of 49 patients were included in this study (4 patients had TBI and 10 patients had HE, 4 being in MCS and 10 patients in VS). The selection criteria for DBS, evaluating status of cerebral cortex and thalamocortical reticular formation, included: neurological evaluation, electrophysiological evaluation and the use of imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI). The target for DBS was the centromedian-parafascicular nucleus (CM-pf) complex. Patient follow-up was between 38 and 60 months. 
Results: Two MCS patients regained consciousness and regained their ability to walk, to speak fluently and live independently. One MCS patient reached the level of consciousness, but currently is still in a wheelchair. One VS patient (after cerebral ischemic lesion) improved to the level of consciousness and currently responds to simple commands. Three VS patients died from respiratory infection, sepsis or cerebrovascular insult, respectively. Other patients remained without substantial improvement of consciousness. 
Conclusion: The spontaneous recovery of MCS/ VS to the level of consciousness with no or minimal need for assistance in everyday life is very rare, therefore if a patient is a candidate according to the above mentioned criteria, DBS could be a treatment option.