Background: Dentato-rubro-thalamic tract (DRT) deep brain stimulation  (DBS) suppresses tremor in essential tremor (ET) patients. However, DRT depiction through tractography can vary depending on the included brain regions. Moreover, it is unclear which section of the DRT is optimal for DBS.

Objective: Evaluating  deterministic DRT tractography and tremor control in DBS for ET.

Methods: After DBS surgery, DRT tractography was conducted in 37 trajectories (20 ET patients). Per trajectory, 5 different DRT depictions with various regions of interest (ROI) were constructed. Comparison resulted in an DRT depiction with highest correspondence to intraoperative tremor control. This DRT depiction was subsequently used for evaluation of short term postoperative adverse and beneficial effects.

Results: Postoperative optimized DRT tractography employing the ROIs motor cortex, posterior subthalamic area and ipsilateral superior cerebellar peduncle and dentate nucleus best corresponded with intraoperative trajectories (92%) and active DBS contacts (93%) showing optimal tremor control. DRT tractography employing a red nucleus or ventral intermediate nucleus of the thalamus ROI often resulted in a more medial course. Optimal stimulation was located in the section between VIM and PSA.

Conclusion: This optimized deterministic DRT tractography determination strongly correlates with optimal tremor control and shows limited side-effects. This technique is readily implementable for DBS target planning in ET. 

Figure legend

The panels A to G show the different possible depictions of DRTs which are used for comparison. The above panel shows an axial, the bottom a coronal view on a 3-Tesla T2 MRI of the thalamic and subthalamic area (commissural aligned imaging). The green DRT is depicted with ROIs in the ipsilateral motor area, ipsilateral PSA, ipsilateral cerebellar peduncle and dentate nucleus (DRT-PSA). The DRT-VIM (purple) is depicted after adding VIM (depicted by the software) as a ROI. The DRT-RN (orange) is depicted with ROIs in ipsilateral motor area, ipsilateral red nucleus, ipsilateral cerebellar peduncle and dentate nucleus (DRT-RN). The crossing DRT-RN (red) crosses the midline at the level of the red nucleus, and is depicted with ROIs in the ipsilateral motor area, and RN, contralateral cerebellar peduncle and dentate nucleus. The definite DBS electrode (yellow) is displayed. Panel A is located 2 mm above the commissural line, panel B at the commissural line, panel C is located 2 mm below the commissural line, panel D is located 4 mm below, panel E is located 6 mm below, panel F is located 8 mm below and panel G is located 10 mm below.

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective surgical treatment for patients with advanced Parkinson’s disease (PD). Combining 7.0-Tesla (7T)  T2 and diffusion weighted (DWI) sequences allows for segmenting the motor part of the STN and possible optimisation of DBS.

Methods: 7T T2 and DWI sequences were obtained and probabilistic segmentation of motor, associative and limbic STN subdivisions was performed. Left and right sided motor outcome (MDS-UPDRS) scores were used for evaluating the correspondence between segmented location of stimulation and DBS effect. The Bejjani line was reviewed for crossing of segments.

Results: A total of 50 STNs were segmented in 25 patients. Due to the high resolution of the sequences, segmentation was well feasible using 7T T2 and DWI. Although the highest density of motor connections was situated in the dorsolateral STN for all, exact partitioning of subdivisions differed considerably. For all the active electrode contacts situated within the predominantly motor-connected segment of the STN, the average hemi-body UPDRS motor improvement was 80%, outside this segment 52%. The Bejjani line was situated in the motor segment for 32 STNs.  

Conclusion: The implementation of 7T T2 and DWI for STN segmentation in DBS for PD is feasible and offers insight in location of the motor segment. Segment guided electrode placement, instead of classical targeting, is likely to further improve motor response in DBS for PD. However, for full exploitation commercially available DBS software would have to allow for post-processing imaging.  

Background: Subthalamic deep brain stimulation (DBS STN) became established as an effective treatment for advanced Parkinson's disease (PD). A new era in DBS appeared to be the introduction of segmented electrodes, which allow steering electric field in a certain direction horizontally. In view of ongoing discussion about the optimal stimulation spot within the STN in individual patients, directionality seems to be particularly relevant. Experimental modeling of directional stimulation suggests a possibility to increase the therapeutic window, reduce the appearance of stimulation-induced side effects, and enhance the efficiency of DBS. However, growing complexity of postoperative programming and patient management should be considered. There is still insufficient clinical data on eventual benefits of using segmented electrodes for outcome.

Objective: To assess efficacy and programming features of DBS STN using segmented directional electrodes compared to conventional omnidirectional leads in PD-patients with motor fluctuations.

Patients and methods: The study included 40 patients with advanced PD who underwent bilateral DBS STN surgery at our center in the last 3 years. In 20 patients (40 DBS-leads), segmented 8-contact electrodes were implanted (mean age at surgery 54.9±9.5 years, disease duration 13.2±4.3 years, Hoehn&Yahr stage 3.2±0.5). In the other 20 patients operated in the same timeframe (40 leads implanted), conventional 4-contact electrodes were used (mean age at surgery 57.4±9.0 years, disease duration 11.4±4.7 years, Hoehn&Yahr stage 3.2 ± 0.5). Groups did not differ significantly in baseline characteristics. All patients were operated by the same surgeon according to the uniform surgical technique including intraoperative microelectrode recording of neural activity (MER) and test stimulation. Neurological examination was standardized and performed preoperatively and at the 6-month follow-up in OFF- and ON-medication conditions (UPDRS, Schwab&England scale, PDQ39, levodopa equivalent daily doze/LEDD scoring). We analyzed intraoperative strategy, primary and following adjustments of the settings, and clinical outcome in each patient.

Results: Final trajectory of electrode implantation confirmed by MER and intraoperative stimulation coincided with central image-calculated trajectory in 67.5% of cases. In 32.5% of electrodes, correction of trajectory was performed (mainly in the medial direction). For MER, 1 to 3 microelectrodes were used (mean 1.5).

At the time of 6 months following continuous DBS STN, all patients experienced amelioration of parkinsonian symptoms and daily life activity in OFF-medication state with no significant difference between two groups. In patients with segmented leads implanted, mean OFF-state UPDRS-3 decreased from 51.3 to 16.7 points (66.3%) and UPDRS-2 from 23.0 to 8.7 (59.8%) compared to from 50.5 to 12.3 (73.9%) and from 22.9 to 9.8 (55.7%), respectively, in patients with conventional electrodes. In both groups, motor symptoms in ON-state also improved (mean UPDRS-3 changed from 13.0 to 7.9). Mean LEDD reduced from 1700 to 735 mg and from 1759 to 581 mg, respectively (p>0.05). Quality of life improvement comprised 19.3% for the whole group.

During initial setup, all leads were carefully screened for the best stimulation level, and then segmented ones were checked for the best direction of stimulation. Directional stimulation was preferentially used if better efficacy or minimization of DBS-induced side effects could be achieved. At the 3-month follow-up, in patients with segmented electrodes, directionality was employed in 9 patients (45%, 15 leads), To the 6-month follow-up, 14 leads were programmed directionally (9 patients). In 7 cases (17.5%), the most efficient electrode contact appeared to be outside the segmented level.

Conclusion: According to our data, efficacy of DBS STN via segmented electrodes is comparable to traditional omnipolar stimulation in short-term follow-up. Directional stimulation provides additional possibilities for programming and optimizing the clinical outcome of DBS STN. At the same time, high precision electrode placement is still required. Considering the increased complexity and time of selecting individual stimulation settings, systematic approach and development of new automated programming algorithms are desirable. We need studies in a larger patient population with long-term follow-up in order to evaluate potential benefits of directional DBS STN.

Objective: To characterize electrical features of long-term DBS settings for PD and ET patients, and how these features impact primary cell internal pulse generator (IPG) longevity derived from a global, multi-center registry.

Background: Several recent articles have been published on the impact of programmed settings and impedance on total electrical energy delivered (TEED) and consequently, battery longevity in DBS patients implanted with Activa PC have been compared with predecessor Kinetra IPGs.^1-2 However, Activa PC contains hardware and programming capabilities that expand features beyond those available with Kinetra to provide physicians with more choices and greater flexibility in managing patient symptoms. The difference in battery longevity between Activa PC and Kinetra may be due to a number of design improvements which include size reduction for patient comfort and additional device features valuable in therapy optimization. In addition, sample size, diagnosis and duration of disease, stimulation settings including longitudinal impedance changes, and length of follow-up vary widely in these studies. The effect of these electrical parameters is better understood when a standardized approach across diverse centers and patient populations is used, such as a global registry.

Methods: The Product Surveillance Registry (PSR) was established in 2009, as a prospective long-term, multi-center global registry to monitor the reliability and safety of DBS systems. The stimulation settings were analyzed for 612 patients at 35 centers in 11 countries; 452 were first-time implanted IPGs and 215 were replacement IPGs. Electrical parameters were noted after stable programmed settings were achieved (6 months in de novo patients, 1 month in replacement patients). IPG longevity was estimated as the time to replacement due to battery depletion.  TEED (µJ) per lead was estimated from the actual device reported stimulation parameters and impedances over the lifetime of the battery. Statistical analysis was completed using Cox Proportional Hazards regression and Kaplan-Meier methods. 

Results:  The median IPG longevity for first-time implanted devices was 4.7 and 4.5 years, in PD and ET patients, respectively and device longevity was significantly longer in the first-time implanted group compared to the IPG replacement group. The IPG replacement group had higher TEED per lead for both PD and ET patients resulting in reduced battery life (Table 1), likely due to higher stimulation settings. Therapy impedance was significantly higher in first-time IPG devices compared to replacement devices in PD patients (p<0.0001); but not in ET patients (p=0.174).  Also, monopolar stimulation was used more frequently (78 % in PD vs 70% in ET) and 82% of devices had lead placed in STN target site in PD patients. The analysis of different stimulation targets revealed significant reduction of TEED in STN-DBS compared to GPi-DBS in first-time implanted PD patients (p<0.0001).

TEED increased significantly over time in PD patients (p<0.0001 in first-time implanted IPGs, but change was not significant in ET patients (p=0.386). With respect to therapy impedance, there was  evidence of significant downward trend in first-time implanted  PD and ET patients (p<0.0001, Figure 1). Overall, a significant inverse correlation was observed between IPG longevity and TEED in both PD (HR=1.009, p<0.0001) and ET (HR=1.011, p<0.0001) patients. 

Conclusion: The present analyses represent battery longevity from a real-world global patient population and reflect standard practice patterns at most DBS centers without protocol constraints regarding the management of these patients.  IPG longevity was quite similar in PD and ET patients but shorter in replacement IPGs, likely due to  higher energy demand in replacement IPGs compared to first-time implanted systems. The increase in TEED over time and higher TEED in replacement IPG may reflect changes in stimulation settings, usage patterns, or local tissue impedance fluctuations. Overall this analysis demonstrated the expected performance of 3-5 years of primary cell battery longevity for DBS therapy from a multi-center global registry in PD and ET patients.

References

1.              Helmers AK, Lubbing I, Deuschl G, et al. Neuromodulation. 2018;21(6):593-596.

2.              Niemann M, Schneider GH, Kuhn A, Vajkoczy P, Faust K. Neuromodulation. 2018;21(6):597-603.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has demonstrated major improvement of motor and non-motor manifestations and quality of life in Parkinson"s disease (PD) despite various surgical approaches. This single-center study aims to compare clinical outcomes and electrode placement accuracy in patients who underwent robot-assisted versus conventional frame-based stereotactic STN DBS surgery for PD.

Methods

This retrospective study included 48 PD patients, enrolled between October 2016 and December 2018 in the University hospital of Neurology and Neurosurgery of Lyon. They underwent either robot-assisted surgery (RAS) (Neuromate®, Renishaw) (n=20) or conventional frame-based stereotactic surgery (FSS) (n=28) with the same principles of STN targeting on MRI. ES performed RAS surgery, while GP performed FSS. Patients were evaluated before and 1 year after surgery. Electrode contacts within the STN was determined using merge of post-operative CT- and pre-op MRI with Brainlab® GUIDE™ XT software (Fig1).

Results

Median age at surgery was the same (62.5 years old) in both groups. 1 year after surgery, with stimulation on and pharmaceutical treatment, there was no difference in the evolution of MDS-UPDRS III (p=0.29) and IV (p=0,80) between groups, the evolution of the quality of life (p=0.25), the evolution of levodopa treatment (p=0.94). The rate of complications was not different between both groups (p=0.99). Surgery duration was significantly longer in the RAS group (479 min, Q1-Q3: 460— 490) cmpared to the FSS group (351 min, Q1-Q3 317-392) (p=0.0001). There was no difference in electrode placement accuracy in both groups (table1).

Discussion

This is the first study comparing clinical outcomes between robot-assisted and conventional surgery for DBS in PD in the same surgical center. We showed no difference in motor results, quality of life improvement, evolution of Levodopa treatment, complications of the surgery or electrode placement accuracy. The duration of surgery was increased in the RAS group. Prospective randomized study including a larger sample is required to determine best surgical approach, keeping in mind that the most important remains surgeon’s experience with the technique used.

Fig.1 : electrode placement accuracy 

Table 1: Results 

Optimization of the stimulation parameters settings of directional leads with a patient-specific imaging software in implanted parkinsonian patients

Gustavo Touzet MD³, Anne-Sophie Rolland PhD ¹, Nicolas Carrière MD², Bastien Gouges³, Luc Defebvre MD PhD², David Devos MD PhD^1,2, Caroline Moreau MD PhD², Nicolas Reyns MD PhD³

¹Department of Medical Pharmacology, Lille University, INSERM UMRS_1171, University Hospital Center, LICEND COEN Center, Lille, France; ²Department of Neurology, Lille University, INSERM UMRS_1171, University Hospital Center, LICEND COEN Center, Lille, France; ³Department of Neurosurgery, CHU LILLE University Hospital, France

Objectives: Deep brain stimulation in the subthalamic nucleus (STN) is routinely proposed to parkinsonian patients. Introduction of directional leads offers more flexibility for programming but may also increase the complexity and duration of the procedure. Here we assess whether Guide XT^R, a new patient-specific imaging software, is helpful to refine stimulation parameters and to simplify the time consuming programming process.

Background: Clinical examination of the stimulation effect for each contact is the empirical method to set up stimulation parameters. Guide XT^R models the volume of activated tissue and provides semi-automatic lead localization and segmentation of deep brain structures in order to visualize leads position and anatomical structures relative to putative stimulation fields.

Methods: We evaluated all parkinsonian patients who were implanted with bilateral directional leads in the STN. After surgery, patients were programmed and followed by the neurological team while blinded from anatomical data. All parameters were reviewed (ring or directional mode) and optimized based on standard clinical evaluation. After surgery, Guide XT was used to analyze imaging data by the neurosurgical team to choose the best stimulation configuration and parameters blinded from clinical data. Clinically determined parameters were then compared to imaging-based parameters.

Results: Twenty-eight patients were included in the study (19 males, 9 females, 59.1 ± 5.5 years old, disease duration 12.3 ± 7.4 years). The stimulation depth was similar between imaging and clinical settings in 75% of cases. Stimulation direction was similar between imaging and clinical settings in 18.75% of cases. Ring mode was selected in 62.5% with the clinical procedure and in 25% with the imaging procedure.

Conclusion: Predicted depth of stimulation using imaging data and empirically determined stimulation using clinical effects showed good concordance. Clinician used mainly ring mode stimulation despite imaging data suggesting a potentially better stimulation configuration using directional mode, possibly due to the complexity of the clinical evaluation. Imaging-guided parameters settings refined with clinical evaluation could therefore help to optimize parameters and limit non-motor side effects and need to be further evaluated.

Keywords: Parkinson’s disease, stimulation parameters, directional leads

Trials based on individual parallel designs have demonstrated that deep brain stimulation (DBS) treatments targeting either the subthalamic nucleus (STN) or globus pallidus interna (GPi) are both effective for the motor symptoms of Parkinson’s disease. However, few studies have compared the motor effects of STN and GPi DBS in individual patients. We compared the acute effects of unilateral STN and unilateral GPi DBS on motor function in individual patients with Parkinson’s disease treated with continuous DBS of both unilateral targets.

This prospective, double-blind, randomized crossover study assessed eight patients with idiopathic Parkinson’s disease who had been treated with continuous DBS of the unilateral STN and contralateral GPi for 2 years. Motor symptom severity, quantified by the Movement Disorder Society-Unified Parkinson Disease Rating Scale part III (MDS UPDRS-III), was assessed preoperatively and at 2-year follow-up in four randomized, double-blinded conditions: 1) Med−STN+GPi−, 2) Med−STN−GPi+, 3) Med+STN+GPi−, and 4) Med+STN−GPi+. The MDS UPDRS-III total score and subscale scores, including scores for axial and bilateral limb symptoms, served as the dependent variables.

Of the eight participants, seven completed the assessments in all four conditions, while one missed two postsurgical Med+ conditions. At the 2-year follow-up, compared with the preoperative Med− state, in the Med−STN+GPi− condition, the cardinal symptoms in both limbs were all improved, although the axial symptoms had deteriorated, except in the context of arising from a chair. In the Med−STN−GPi+ state, symptoms of the GPi-stim limb were improved significantly, while only tremor was improved on the ipsilateral side. The axial symptoms in the Med−STN−GPi+ state significantly worsened, and all sub-scores showed aggravation. Compared with the preoperative Med+ state, in the Med+STN+GPi− state, cardinal symptoms were improved on both sides, except for the tremor on the STN-stim side. The axial symptoms were more serious and the only improved axial symptom was arising from a chair. In the Med+STN−GPi+ state, the overall motor symptoms were aggravated, and the treatment effect was only reflected in the symptoms of tremor and rigidity on the GPi-stim side. The axial symptoms of the Med+ states were all worsened, except in the context of arising from a chair.

In conclusion, improvement of motor symptoms was significantly increased in all sub-scores favoring STN, except for the worsening degree of gait, in which Med+STN−GPi+ was slightly lower than Med+STN+GPi−. We also noted the effects of STN+ acting on both limbs, in contrast to the effects of GPi+, which mainly acted on the contralateral side. 

Objective – To investigate the use of biphasic anode-first pulses on the therapeutic window in essential tremor (ET) patients treated with ventral intermediate nucleus deep brain stimulation (DBS). Figure 1.

Background – Since the inception of DBS, cathodic pulses have been used¹. Modelling studies suggest that biphasic pulses may influence the therapeutic window².

Methods – Stimulation was delivered on the most ventral contact, unless this elicited unbearable paresthesias. In that case, one level more dorsally was stimulated. The non-tested hemisphere was turned OFF. Three thresholds were acutely defined for both cathodic and biphasic anode-first pulses: lowest amplitude inducing tremor arrest while performing a finger-to-nose test contralaterally (LowerTW),  lowest amplitude inducing upper limb ataxia contralaterally (AtaxicTW) and lowest amplitude causing non-transient stimulation-induced side effects contralaterally, other than limb ataxia (UpperTW). The thresholds were defined twice in all hemispheres and average results per hemisphere were analyzed. Wilcoxon signed rank test was used to compare the thresholds.

Results – Four ET patients (8 hemispheres) participated in this study. LowerTW was not significantly different between cathode versus biphasic pulse (1.82 ± 0.69 mA versus 2.11 ± 0.62 mA, p = 0.25). The amplitude that elicited limb ataxia was however significantly higher in the biphasic anode-first pulse (2.74 ± 0.96 mA versus 3.75 ± 1.41 mA, p = 0.0078). Also, non-ataxic side effect was only evoked at higher stimulation amplitudes when compared to biphasic pulses (3.69 ± 1.84 mA versus 4.78 ± 1.97 mA, p = 0.0078). Figure 2.

Conclusions – Biphasic pulses elicit stimulation-induced side effects at higher amplitudes, therefore increasing the therapeutic window. Further work is needed to determine if these pulses can bring clinical benefit compared to standard cathodic pulses.

References

1.          Benabid AL, Pollak P, Hoffmann D, et al. Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet. 1991;337(8738):403-406. doi:10.1016/0140-6736(91)91175-T

2.          Wongsarnpigoon A, Grill W. Energy-efficient waveform shapes for neural stimulation revealed with a genetic algorithm. J Neural Eng. 2010;7(4):1-20. doi:10.1088/1741-2560/7/4/046009.Energy-efficient

Directional subthalamic nucleus deep brain stimulation in Parkinson’s disease allows for a better therapeutic window, with increased motor effects and less stimulation side effects. In our study, we aimed to determine the preferred type of stimulation (omnidirectional or directional) on last-follow-up in patients who were all implanted with directional leads. We then correlated the results of choice of type of stimulation with the anatomical electrode position in the subthalamic nucleus.

From April 2018 to August 2020, 17 patients received directional leads (Boston Scientific) for severe Parkinson’s disease implanted bilaterally into the subthalamic nucleus. The neurologists of the team had all freedom to change the mode of stimulation, but were at that time blinded to the exact lead position of the contacts as revealed by the guide XT software. DBS stimulation status (omnidirectional vs directional) and its evolution was compared post-operatively (when the patient was discharged) and at last follow-up with at least 1 year of follow up.  This mode of stimulation was then correlated to the evolution of the MDS UPDRS scores, to the side effects and to the anatomical position of the implanted electrodes. 1 patient was followed in another centre and data were not available.

6 and 10 patients were stimulated with directional (37%) or omnidirectional mode (63%) respectively at discharge. At last follow up, 11 out of 16 (69%) had a directional mode of stimulation, 7 switching from omnidirectional to directional mode, and 2 switching from directional to omnidirectional mode. Reasons for change included better efficacy and the need to reduce the side-effects. Anatomical correlations will be discussed according to those findings.

In conclusion, there was a great tendency to stimulate preferentially a majority of patients using directional mode for different reasons discussed in the paper.

Doparesistant Freezing of gait (FOG) and falls represent the dominant motor disabilities in advanced  Parkinson’s disease (PD). Their pathophysiology is poorly understood, but imaging and post-mortem studies suggest a causal role of cholinergic dysfunction within the pedunculopontine nucleus (PPN), located in the mesencephalic locomotor region (MLR), also including the cuneiform nucleus (CuN) dorsally. We herein investigate the effects of deep brain stimulation (DBS) of the PPN and CuN nuclei, for treating gait and balance disorders in Parkinson’s disease (PD) patients in a randomized double-blind cross-over clinical trial. Six PD patients with dopa-resistant freezing of gait (FOG) and/or falls were included and operated for bilateral MLR-DBS. Patients each received three DBS conditions, PPN, CuN or sham, in a randomized order for 2-months each, followed by an open-label phase. The primary outcome was the change in anteroposterior anticipatory postural adjustments (APAs) during gait initiation on a force platform at the end of each DBS condition. Secondary outcomes included safety and differences in gait kinetics, and clinical gait, cognitive and quality of life scales between DBS conditions. During the randomized period, we found that the anteroposterior APA were not significantly different between the DBS conditions (median displacement [1^st_3^rd quartile] of 3.07 [3.12_4.62] mm with sham-DBS, 1.95 [2.29_3.85] mm with PPN-DBS and 2.78 [1.66_4.04] mm with CuN-DBS; p=0.25). Step length and velocity were significantly higher with CuN-DBS vs both sham-DBS and PPN-DBS. Conversely, step length and velocity were lower with PPN-DBS vs sham-DBS, with greater double stance and gait initiation durations. One year after surgery, step length was significantly lower with PPN-DBS vs inclusion. We also found no significant differences in the clinical scales including  the parkinsonian disability, gait and balance scales, and assessment of cognition or psychiatric troubles. Lastly, we observed 3 serious adverse events with one electrode displacement in one patient, one patient had a subdural hematoma following recurrent falls that did not necessitated surgery. Our study suggests a better effect of CuN-DBS relative to PPN-DBS on walking ability in advanced PD patients. However, the absence of significant clinical benefit with 2 months of DBS with no aggravation in FOG or falls one year after surgery would suggest that optimized DBS and for longer period might be beneficial. Further research is needed to better understand the role of the MLR in gait and balance control in humans using new imaging or neurophysiological approaches.

Objetive:

Deep brain stimulation (DBS) has been shown to be effective and safe for treating the cardinal symptoms of Parkinson's disease.

Some aspects of the disease, such as gait disorders, respond worse to DBS. Various publications suggest the efficacy of combined DBS in the subthalamic nucleus (STN) and the substantia nigra (SN) for refractory gait disorder in PD. The objectives of our study are to confirm these previous findings. Material and methods:We present data from our randomized, crossover, double-blind, single-center study conducted in 10 patients with advanced PD.
Octopolar deep brain stimulation electrodes were placed bilaterally at STN, leaving the most distal contacts at SN. To perform the quantitative gait analysis, the Step 32 system was used. Clinical and neurophysiological parameters were compared after 4 weeks of STN stimulation versus 4 weeks of combined STN and SN stimulation. Side effects and patient preferences were reported. Results:
There were no complications associated with surgery Postoperative improvement was observed in the cardinal symptoms of PD and in gait parameters. The number of normal gait cycles increased significantly after surgery in both forms of stimulation.
The greatest increase in normal gait cycles occurred in combined STN and SN stimulation (0.57 preoperative, 0.71 STN, 0.79 STN + SN). Coclusion: The combined STN and SN DBS is a safe and effective technique to improve the axial motor disorders of PD, such as gait blocks and postural instability. Studies with a larger number of patients and long-term follow-up would be very useful to confirm the evidence of our work.

Background: Both the FDA, under 21 CFR 1271.15(b), and the EU, under Art 2§2(a) and Preamble 8 of Dir. 2004/23/EC, allow for a Same Surgical Procedure Exemption for the grafting of autologous tissue during a same surgical procedure. With a goal of providing support to sick or dying cells, we have previously used this Exemption to deliver autologous injury-activated peripheral nerve graft tissue (APNG) to the substantia nigra in patients with Parkinson’s disease who are undergoing deep brain stimulation (DBS) surgery (van Horne et al. 2018). Following injury, the peripheral nervous system, activates a reparative response that generates a host of neurotrophic and cell-survival factors.

Objective: As part of an open-label Phase I clinical trial (NCT02369003) to expand the utility of this approach and examine dose escalation, we unilaterally implanted APNG to the substantia nigra under two different dosing regimens: a single deployment of APNG or two deployments of APNG.

Methods: As part of the standard of care, participants underwent a two-staged DBS procedure. At the time of stage I, the sural nerve was transected and the incision was closed. Later (3 to 14 days later) at stage II, the injured sural nerve was identified, and an about 1 cm section was excised. The fascicles were identified, diced, and deposited in the substantia nigra with one deployment or a deployment both to the anterior and to the posterior substantia nigra. Participants were followed for 12 months and the motor component of the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) was used to assess for changes in Parkinson’s disease severity.

Results: Across our previous trial (van Horne et al. 2018) and this one, a total of 37 participants have received only unilateral grafts to the substantia nigra with a mean age of 62 years (95% Confidence Interval: 60 to 65 years). Adverse event profiles were comparable to standard DBS with the most common study-related events being paresthesias of the lateral foot distal to the sural nerve tissue harvest site.  For the single deployment, off-state motor MDS-UPDRS mean scores were 45.3 points (40.2 to 50.5; n=28) at screening and 36.6 points (30.5 to 42.7; n=24) at 12 months. For participants receiving two deployments: 42.8 points (30.7 to 54.9; n=9) at screening and 35.8 points (21.5 to 50.0; n=8) at 12 months. Overall for unilateral APNG delivery, pooling both groups, the mean decrease in scores at 12 months was -8.4 points (-4.1 to -12.6; n=32). When we analyzed the lateral components of the MDS-UPDRS, the mean difference in scores at 12 months for the body side contralateral to the APNG deployment was -4.6 points (-2.8 to -6.6) and for the side ipsilateral to the APNG deployment it was -0.8 (-2.0 to + 0.5).

Conclusions: Further examination of the approach is merited to further establish the safety profile for this procedure and to investigate the potential for this strategy for disease modification.

Introduction

Essential tremor (ET) is one of the most common neurological disorders with a prevalence of 4.6% in people aged 65 years or older. Medical management is generally initiated when the tremor begins to interfere with the patient’s ability to undertake daily activities, but the effectiveness of drugs for this disorder is limited.

Stereotactic radiofrequency (RF) thalamotomy and deep brain stimulation (DBS), targeted to the ventralis intermedius nucleus of the thalamus (Vim), have proven effective for treating ET and other tremors. These interventions, although highly effective, have risks associated with an open neurosurgical operation.  Radiosurgical Vim thalamotomy with Gamma Knife has been used as a non-invasive alternative treatment. However, the lack of immediate clinical improvement and the possibility of extension of the lesion beyond the initially targeted region over time inducing permanent neurological deficits have limited the use of this technique.1

For the last decade, MRgFUS has been raising a lot of interest, as an incisionless and low-risk therapeutic option. This type of treatment creates a coagulation lesion via high-intensity ultrasound beams that converge in a selected target, with great accuracy and with neither need of incising the skin nor opening the skull. Vim-MRgFUS has been used to treat tremor associated with Parkinson´s disease, Essential Tremor, Multiple Sclerosis and Fragile X-associated ataxia.

In the present study, the durability of tremor relief in patients followed for 6 months after MRgFUS thalamotomy was evaluated to confirm the durability of efficacy and safety of MRgFUS thalamotomy for the treatment of medically refractory ET.

Methods

One hundred twenty-three ET patients treated with unilateral MRgFUS VIM between 2018 and 2021 were evaluated using the Clinical Rating Scale for Tremor (CRST) score at month, three months, and 6 months. Lesion characteristics were assessed on routine MRI sequences at 6 months in 44 patients. Relationships between imaging appearance in Brainlab Sotware (BrainLAB AG, Munich, Alemania), details of thalamotomy procedure (Insightec Inc, Tirat Carmel, Israel) and clinical outcome were investigated.

Results

Mean hand tremor score section A and B at baseline (20.77 ± 5.81; 123 patients) improved by 83.33% ± 22.10% (Section A), 73.51% ± 28.40% (Section B) and 75.74% ± 33.53% (Section C;) at 6 months. This improvements difference was significant (p= 0.05). Paresthesias and gait disturbances were the most common adverse effects at 1 months and at 6 months only 28% patients presented soft adverse effects.

On T2-weighted images the most lesion was hyperintense, the mean relative volume at 6 months was 0,037 ± 0.026cm3 (IQR 0.31– 0.058cm3), some lesions were no longer discernable in T2-weighted images. Mean AC-PC line length was 25.98 ± 1.87 mm (IQR 24.63– 27.45mm). Clinically determined centers of Vim lesion placement differed from the assumed position of the nucleus as suggested in the literature. On the right-left axis, mean lesion position was 14.33 ± 1.95 mm (range 13.37 – 14.93mm) from third wall and 6.75 ± 1.19mm (IQR 5.76 ± 7.45mm) distance from the posterior commissure on the AC-PC line, what represents 26.01 ± 4.21% (IQR 23.55- 27.76%) of AC-PC line. On the dorso- ventral axis, mean lesion position was 3.01 ± 1.21mm (IQR 2.13-3.75). The mean of III ventricle measured on T2-weighted images was 6.81 ± 2.02 mm (IQR 5.63 – 8.35mm). The median patient SDR was 0.52 (IQR 0.44 -0.57). MRgFUS thalamotomies were performed using a median of 3.4 ± 1.4 sonications over maximal mean temperature of 55°C (IQR 2-4), delivering a median of 16243 ± 8640 joules (IQR 8655- 24154). The median of seconds over 55° was 29.85 ± 12.5 seconds (IQR 21 -37.5 seconds). The median median maximal mean temperature of 58 ± 2.14°C (IQR 57-60°C). There was no significant correlation between lesion volume at 6 months and clinical improvement (p =0.13) for tremor reduction on the treated side. The technical parameters were no significant correlation with clinical improvement, nevertheless, III ventricle size was significant correlation with tremor reduction (p=0,046), the greater ventricular size the clinical improvement decrease. 

Conclusion

MRgFUS thalamotomy for ET is an effective and safe procedure that provides long-term tremor relief and improvement in quality of life even in patients with medication-resistant disabling tremor.

Introduction

Management of drug-resistant essential tremor (ET) is a challenge for clinicians. Thalamic deep brain stimulation (DBS) has proven to be effective in ET patients with drug-resistant tremor. However, for various reasons some patients are not eligible or refuse these DBS procedures. For these reasons, less invasive neurosurgical procedures have emerged in these second-line indications to create thalamic lesions using radiation or MRI-guided focused ultrasound. Recently a new technology has emerged allowing realization of brain lesion by laser with real-time guided MRI imaging: MRI-guided Laser Interstitial Thermal Therapy (MRIg-LITT). MRIg-LITT is increasingly used in neurosurgery thanks to its promising clinical results in treatment of epilepsy and tumors. Here, we report early data of MRIg-LITT thalamotomy in drug-resistant ET patients.

Methods

Briefly, MRIg-LITT thalamotomy consisted of stereotaxically placing a laser probe (Medtronic) in the ventral intermediate (VIM) nucleus of the thalamus using the ROSA robot system (Zimmer Biomet) under general anesthesia. Targeting and trajectory planning were established on the dedicated ROSANA planning software (Zimmer Biomet) separate from the robotic platform, allowing automatic image fusion between preoperative MRI and CT scan images. Intraoperative guidance by CT scans obtained with the O-Arm system (Medtronic) and microelectrode recording (FHC) allowed assisted laser probe placement. Once the probe was in place, patient was transported to MRI still under general anesthesia. A single MRIg-LITT thalamotomy in a 1.5T MRI (GE Optima MR 450w) was performed using the Visualase system (Medtronic) equipped with a diode laser (max power of 15W and 985 nm wavelength). MRIg-LITT protocol was carried out in stepwise, increasing deliveries of 10%, 15%, 20%, and 25% laser power sessions. The overall heating time was 9 min 50 s, alternating with rest periods of 1-2 min (laser power range of 1-2.5W). Then, the laser probe was removed and patient was awakened.

Improvement of upper limb tremor contralateral to the thalamotomy on Fahn-Tolosa-Marin (FTM) scale was evaluated at 3 months postoperative blindly by video by an external expert neurologist. Quality of life was assessed on the Quality of Life in Essential Tremor Questionnaire (QUEST) at 3 months postoperative. All patients gave their consent for the study

Quantitative variables are presented with their mean and standard deviation, qualitative variables with their percentages and numbers. Comparisons of quantitative variables are made using a Wilcoxon test.

Results

Unilateral MRIg-LITT thalamotomy was performed in 5 patients with ET drug-resistant tremor. Mean age was 73.00 (7.07) years, 3/5 were male, 4/5 were right handed and mean duration of the tremor was 441.60 (263.24) months. Preoperative mean FTM score of upper limb contralateral to the thalamotomy was 14.60 (0.89) (rest tremor 0.40 (0.55), postural tremor 3.00 (0.71), action tremor 2.20 (1.09), drawings and writing 9.00 (2.00)). Preoperative mean QUEST Summary Index was 49.55 (11.68). Postoperative mean FTM score of upper limb contralateral to the thalamotomy was 3.80 (1.09) (rest tremor 0 (0), postural tremor 0.20 (0.45), action tremor 0 (0), drawings and writing 3.60 (0.89)). Postoperative mean QUEST Summary Index was 21.77 (11.86). Postoperative mean FTM score of upper limb contralateral to the thalamotomy was improved by 73.98% (p=0.098) and QUEST Summary Index by 56.07% (p=0.043). No serious adverse events have been reported. 5/5 patients report only transient motor weakness and proprioceptive disorders on the upper limb contralateral to the thalamotomy during 1 to 2 weeks post procedure. Persistence of long-term efficacy is currently being assessed, as is cognitive security.

Discussion

Unilateral MRIg-LITT thalamotomy seems to be an effective and safe technique to treat upper limb drug-resistant ET when thalamic DBS is impossible or refused by the patient. It could be an alternative to radiosurgery or MRI-guided focused ultrasound to perform stereotaxic VIM thalamotomy. However, other studies with a larger number of patients and a longer follow-up period are necessary to validate the use of this technique in current practice. To our knowledge, only one study involving 13 patients reports use of MRIg-LITT thalamotomy for drug-resistant tremors in the literature.

Ipsilateral effects of unilateral Deep Brain Stimulation for Essential Tremor

Background: Essential tremor (ET) is the most common adult movement disorder. For the relatively large group of patients which do not respond adequately to pharmacological therapy, deep brain stimulation (DBS) might constitute an alternative. Most ET patients will have bilateral symptoms and many of them receive bilateral DBS. Even so, unilateral DBS is still the most common procedure and some papers suggest an ipsilateral effect in these patients. 

Objectives: To analyze if we could find an ipsilateral effect of DBS for essential tremor.

Method: We retrospectively analyzed our patient cohort with DBS surgery from 1996 to 2017, selecting patients with ET that underwent surgery with unilateral DBS without previous DBS or lesional surgery. A total number of 68 patients (39 males, 29 females) were identified. The patients were evaluated at a mean time of 12 and 49 months after surgery using Essential tremor rating scale (ETRS).

Results: Total ETRS score was reduced from 49.5 points at baseline before surgery to 20.2 (p<0.001) at short term and 28.3 (p<0.001) at long term follow up. Contralateral tremor was reduced from 6.1 to 0.4 (p<0.001) and 1.2 (p<0.001) respectively. Contralateral hand function was reduced from 11.5 to 2.6 (p<0.001) and 4.6 (p<0.001), respectively. Ipsilateral hand function was reduced from 9 to 8.3 (p<0.05) but this was not maintained at long term follow up (9.4. p>0.05). Ipsilateral tremor was reduced from 4.0 at baseline to 3.7 (p<0.05) but not maintained at long term follow up (4.3. p>0.05).

Discussion:
In this study, we found a small but significant improvement on ipsilateral hand function (items 11-14 on the ETRS) and hand tremor (item 5/6) on short term follow up. But the effect was lost on long term follow up. Although we could see a larger improvement in a few of our study objects, on the group level this improvement was very modest (8% improvement). Furthermore, the effect was not maintained on the long-term evaluation.The situation is similar in the literature. Often a minor reduction is seen regarding hand tremor (item 5/6) which sometimes reaches significance. However, at the group level the improvement is always modest. It has been suggested that ipsilateral effects are caused by ipsilateral connections in this are . However, it is possible that other factors might contribute.

Conclusions:

We observed a significant improvement on ipsilateral hand function and tremor in our material, but the effect was small and transient. Hence, we consider this question to merit limited consideration regarding decision making or patient counseling on DBS for ET.

INTRODUCTION: Individual improvement in motor symptoms can vary considerably after subthalamic deep brain stimulation (STN DBS). Through evaluating this, we have been able to define an optimal theoretic location for STN DBS by introducing a patient-specific reference point: the medial STN border. We aimed to evaluate the implementation of the medial STN border as a patient-specific reference point and its consistency for correlation with lateralized motor improvement using a larger and more recent cohort of PD patients who underwent STN DBS surgery at our institution. METHODS: Patients were selected from a single-center randomized controlled trial comparing bilateral STN DBS surgery under general versus local anesthesia, that included PD patients between May 2016 and November 2018. Body-sides were categorized into three groups, based on percentual MDS-UPDRS-III improvement: (1) non-responding (<30%), (2) responding (between 30% and 70%) and (3) optimally responding (>70%). A theoretic ‘hotspot’ was calculated by averaging X, Y, and Z coordinates of the ‘optimally responding’ group, relative to the medial STN border as well as to the MCP. The Euclidean distance from each active contact to both defined hotspots were calculated separately. RESULTS: 218 DBS electrodes were implanted in 109 patients with PD. Thirty-seven corresponding body-sides were categorized as non-responding body-sides (18%), whereas 108 as responding body-sides (51%) and 67 as optimally responding body-sides (32%). Average percentual UPDRS change of the non-responding body-side group were significantly higher in the current study population compared to the previous population (Bot et al. 2018; independent T(52) = 2.14, P = 0.037), whereas the responding body-side group had less average percentual UPDRS change in the current population (independent T(136) = 2.74, P = 0.007). Using the medial STN border as a patient-specific reference point, difference in mean Euclidean distances between non-responders and responders were statistically significant (independent t(143) = 2.25, P = 0.026), as well as between non-responders and optimal responders (independent t(102) = 3.22, P = 0.002). We found a significant negative correlation (Pearson’s correlation -0.23; P = 0.001) between percentage MDS-UPDRS-III Lateralized scores change and Euclidean distance from active contact to the refined ‘hotspot’ defined relative to the medial STN border. CONCLUSION: We evaluated the implementation of the medial STN border as a patient-specific reference point and its consistency for correlation with lateralized motor improvement using a larger and more recent cohort of PD patients who underwent STN DBS surgery at our institution. We reaffirmed the significance of the medial STN border as patient-specific reference point for DBS location and motor improvement in patients with PD in a larger and highly recent cohort. This refined optimal location for DBS in PD can be used for optimizing lateralized motor outcome scores and was defined at 2.8 mm lateral, 1.1 mm anterior, and 2.2 mm superior to the medial STN border.

Introduction: In vivo spinal cord fiber tracts have never been described precisely in humans. Current knowledge corresponds to the results of animal dissections, cyto-histological findings and electrophysiological approaches. Advances in brain MRI have recently made it possible, via Diffusion Tensor Imaging (DTI), to highlight the tracts of the brain's white matter. To date, no study has been able to differentiate clearly spinal cord tracts using tractography.

Methods: 1) Using the MEDLINE database, a systematic review was carried out to try to define the optimal DTI parameters used until now for spinal cord tractography studies. 2) From MRI of the EMISEP (healthy subject cohort database), starting with the parameters previously defined, evaluate the effect of patient geometry (sagittal balance) and acquisition geometry on the quality of the tractography rendering, before and after distortion correction (with DSIStudio software). 3) From previous data, develop an original DTI protocol to distinguish different spinal tracts.

Results :

1)      Best DTI parameters coming from literature have been defined.

2)      Distortion corrections had a direct impact on the tractography according to the patient's sagittal balance. Moreover, the geometry of the acquisition had a direct impact on the quality of the tractography rendering, since adaptations had to be performed at each vertebral level.

3)      Performing a stitching process between encephalic and spinal cord DTI data, and a meticulous placement of region of interest are both keys to distinguish different fiber tracts inside the spinal cord. By performing these post-processing distorsions, the corticospinal tract, can be distinguish from the spinal cord disease (tumor for example) and allows new advances neuro-anatomy, and spinal cord neurosurgery.

Conclusion: The differentiation of spinal tracts with tractography seems to be possible. This imaging would be useful to improve human neuroanatomical and physiological knowledges. When will become usable in routine, spinal DTI will allow to analyze the consequences of intraspinal deseases on fiber tracts and could help the neurosurgeon to define their surgical approaches to intraspinal lesions.

Objective: The analysis and visualization of brain's white matter structures by diffusion magnetic resonance imaging (dMRI) is becoming an important prerequisite during planning of neurosurgical interventions (1). In this work, we propose a rather simple approach to visualize structural connectivity information in certain target regions (Spectre - Subject sPEcific brain Connectivity display in Target REgion). Our idea is closely related to track-weighted imaging (2), where dMRI streamlines are used to aggregate distal information, however we use normative geometric information as the underlying contrast for aggregation. For example, if we want to know whether a voxel in the brain is rather connected to the frontal or to the posterior region, we could just compute the mean of the y-coordinate (in MNI space) along each fiber emitted in this voxel. To realize this concept in a way, which is more suitable for visualization, we assigned cortical regions certain colors in a continuous fashion.

Methods: The concept is demonstrated on a group of subjects from the human connectome project (HCP). The used coloring scheme and target area is shown in Figure A. The rationale of the coloring scheme was developed in appreciation of deep brain stimulation (DBS) planning especially for the subthalamic nucleus (STN). STN anatomy typically is interpreted as follows: Medial and anterior parts of the nucleus are regarded as “limbic” and connect to prefrontal and frontopolar parts of the cortex. Adjacent and more posterior regions are the prefrontal association regions followed on the  posterior and lateral by motor parts (3). With this idea in mind the STN was color-coded in a ‘fronto-polar to motor’ gradient (green to blue) by its mere connectivity pattern.  For warping the coloring scheme to native space of the subject, SPM’s CAT12 is applied on the provided T1 images and the corresponding warping fields are used for warping.  For tract/fiber orientation distributions (FODs) were determined by (4). Then, ordinary probabilistic streamline tractography similar to FSL’s probtrax is used to generate the SPECTRE contrast. Seeds were placed in the area to be colored (here the midbrain) and during propagation of the streamlines the underlying coloring is accumulated. In every voxel (we use a supersolution of 0.5mm isotropic), 500 streamline were seeded to get a robust color value in each voxel.  We applied this procedure on 200 HCP subjects, normalized to group space (MNI) and averaged the SPECTRE maps. 

Results: In Figure B a transversal slice for an example subject together with outlines of deep nuclei is given, while in Figure C several transversal slices of the group average in MNI space are displayed. SPECTRE shows how the fronto-parietal-occipital cortical gradient experiences a twist by 90° while proceeding ventrally towards the midbrain, where the gradient becomes mostly medial-lateral with an interruption at the interface between RN and SNR. The interpretation of the fronto-parietal gradient as limbic-associative-sensori/motor is quite intuitive, in particular when focusing on the STN. In the tripartite descriptions (5) medial/anterior and inferior parts are regarded as limbic and connect prefrontally, especially to frontopolar and orbitofrontal regions. More posterior regions are the prefrontal association regions of the dorsolateral and prefrontal cortex followed laterally by motor parts (3). This agrees mostly with the segmentation used by Ewert et al (6). In Figure D Ewert’s STN subsegmentation is shown, in E the STN overlaid by the group SPECTRE maps. 

Discussion: With the aim of giving neuroscientists a comprehensive view of structural connectivity patterns we have proposed a novel imaging principle, which joins individual tractographic information with normative anatomical information.  SPECTRE allows us to appreciate the fronto-occipital connectivity gradient on the individual level and thereby helps to understand the amount of frontopolar contribution of connectivity to the STN and the region just adjacent to it. Preliminary experiments (not shown) suggest that robust and repeatable SPECTRE maps can be computed, even on clinically feasible dMRI data.

References: (1) Essayed et al. NeuroImage Clin. 2017;15:659–672.  (2) Calamante et al. Neuroimage. 2010;53(4):1233–1243. (3) Haynes et al. J Neurosci. 2013;33(11):4804–4814. (4) Alkemade et al. Brain Struct Funct. 2015;220(6):3075–3086. (5) Ewert et al. Neuroimage. 2018;170:271–282.

ABSTRACT

Introduction and Aims

Ensuring a safe and accurate approach is fundamental in stereotactic functional neurosurgery. Reliance on anatomical targeting and dispensing with awake surgery is growing in popularity but can be vulnerable to suboptimal targeting. Despite the use of traditional techniques such as microelectrode recording (MER), suboptimal lead placement is currently one of the commonest indications for revision DBS procedures. This can be avoided by confirming lead placement in relation to the visible anatomical target with dedicated imaging during the procedure. Here, the accuracy, precision and safety of using intraoperative-MRI (iMRI) to both guide and verify lead placement during frame-based stereotactic surgery is examined.

Materials and methods

A 1.5 T MRI machine was installed in our surgical theatre in August 2011. Retrospective analysis of 1201 DBS leads implanted in 650 consecutive procedures over an 8-year period (Aug 2011 to Aug 2019) was performed for targeting accuracy, precision and perioperative complications. All patients underwent frame-based lead placement adjacent to the MRI machine with image verification before removing the stereotactic frame, allowing immediate lead re-implantation when necessary and systematic analysis of the targeting error. Fisher Exact test was used for statistical significance when relevant (p value set at 0.01)

Results

Verification with stereotactic MRI was performed in 643 procedures and with stereotactic CT in 7.  The mean final targeting error was 0.85 mm, +/- 0.29 mm SD (range 0.05-2.29). Accuracy was submillimetre in 68 %, within the diameter of the implanted lead (1.27mm) in 80 % and within 1.5 mm in 92 % of analysed leads. Anatomically acceptable lead placement was achieved with a single brain-pass in 97% (n = 1164) of leads; immediate intraoperative relocation was performed in 37 of 1201 leads (3 %) to obtain satisfactory anatomical placement. General Anaesthesia was used in 91% (n=593) of procedures.

Four patients suffered a haemorrhage (0.6%), three presenting with transient neurological symptoms (0.4%), one associated with delayed cognitive decline [Figure]. We do not think that any of the haemorrhages led directly to long term deficits. Two of the bleeds coincided with immediate retargeting (2 of 37 leads, 5.4%). This contrasts with haemorrhage in 2 of 1164 leads implanted on first-pass. (0.17%) (p-value 0.0053)

Transient behavioural changes were noted in 27 patients (4.2%), while 2 suffered from moderate cognitive decline following surgery despite no radiological evidence of haemorrhage. Three patients had transient seizures in the postoperative period, two of which coincided with haemorrhage and one with immediate lead retargeting.

There were 21 infections leading to hardware removal (3.2% of patients), seven of which commenced cranially. Fourteen patients presenting with infection around the neurostimulator were initially treated by removal of the neurostimulator and cables plus appropriate antibiotic therapy; however, 12 of these ultimately progressed to total removal of hardware.

Delayed (>3 months) retargeting of 6 leads (0.5% of 1201) in four patients (0.6%) was performed following suboptimal stimulation benefit. Delayed distal maintenance procedures were performed in 20 patients (3.1%) due to hardware failure (n=10), discomfort or erosion (n=10). There were no MRI related hardware issues, no motor deficits and mortality was zero.

Conclusion

To our knowledge, this is the largest series reporting on the use of iMRI as a tool to both guide and verify lead location during DBS surgery. It demonstrates a high level of accuracy, precision and safety across targets, patients and surgeons. Although numbers are small, a significantly higher rate of haemorrhage was encountered when multiple brain passes were required for lead implantation. Thankfully, all of the haemorrhages were small and did not lead to permanent deficit. Nevertheless, this emphasises the importance of meticulous accuracy, perpetual audit and calibration to improve precision and maximise the safety of stereotactic functional neurosurgery.

Introduction

Patients in an intensive care unit (ICU) often require neuroimaging to rule out a wide variety of intracranial problems. Computed tomography (CT) may be available in the ICU itself, but magnetic resonance imaging (MRI) has greater sensitivity for many conditions that affect the brain. However, transporting patients who are on ventilators and other life-sustaining devices is a labor intensive process and involves placing the patient at risk for adverse events. This is the first report of portable MRI in a clinical setting. 

Methods  

This is a prospective, non-randomized, observational study at one institution utilizing portable MRI in patients with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients selected for imaging had any of the following: 1) unexplained encephalopathy or coma, 2) seizures, 3) focal neurologic deficit, 4) abnormal head CT. Imaging was performed in each patient’s ICU room with a portable, self-shielding, 0.064 Tesla (T) MRI.  

Results  

Among 19 patients, a total of 20 MRI scans in seven ICUs were acquired between April 20 and May 1, 2020. No adverse events to patients or staff from MRI acquisition were reported. In 12 patients, abnormal findings were seen, which included increased fluid attenuated inversion recovery (FLAIR) signal (n=12), hemorrhage (n=3), and diffusion-weighted imaging (DWI) positivity (n=3). Imaging led to a change in clinical management in 5 patients. 

Conclusion

Portable MRI is safe, feasible, and leads to changes in clinical management. This technique can be applied to any ICU patient whose care requires imaging of the brain. This novel technology offers a path towards new modalities for bedside stereotaxis and intraoperative imaging.

Background: Parkinson's disease (PD), is a neurodegenerative disease characterized by, the loss of dopaminergic neurons in substantia nigra.

Objective: To contribute to the pathogenesis of the disease by comparing Diffusion tensor (DTI) and contrast perfusion MRI (PWI) findings in medical treatment resistant PD cases.

Material and Methods: 19 control and 18 medical treatment-resistant PD cases, who are candidates for deep brain stimulation, were included in our study. DTI and PWI examination were performed on all cases. Cerebral blood flow (rCBF), mean transit time (MTT) and fractional anisotropy (FA) values were measured in both hemispheres; on primary motor cortex (M1), supplementary motor cortex (SMA), putamen (P), external and internal globus pallidus (GPe / GPi), ventrolateral nucleus (T) of the thalamus, substantia nigra(SN).

Results: The average age of our control group cases was 59.2 ± 13.2 (31-79) and the median was 60 years. The average age of PD patient group was 56.7 ± 16 (42-77) and the median was 60.5 years. The duration of the disease was 12.4 ± 7.1 (5-30) years on average. In PD group, FA values were significantly lower (p ˂ 0.05) than the control group, in all regions. In the case group, rCBF-SMA values on both sides were significantly higher than the control group (p˂ 0.05). In the case group, MTT-GPi value on the left and MTT-M1, MTT-SMA, MTT-GPe and MTT-T values on both sides were significantly higher than the control group (p ˂ 0.05).

Conclusion: It is thought that decrease in FA compared to the control group in all regions except the motor cortex may be secondary to cell loss. In PWI, on the other hand, in medical treatment resistant PD cases, rCBF, increases in the supplementary motor and motor cortex. MTT, moreover, is prolonged in all regions, evident in left GPi. Perfusion differences may be due to increased blood brain barrier permeability, endothelial degeneration, and abnormal angiogenesis, and may contribute to dopa-resistant symptoms in PD cases. More research is needed to improve measurement techniques and standardize research protocols, not only to improve diagnostic accuracy, but also to monitor treatment effectiveness in clinical trials.

Introduction

Deep brain stimulation (DBS) relies on precise electrode targeting and stimulation of small, deep structures within the brain to effectively treat various movement disorders. Target accuracy is contingent upon an assumed rigid alignment between the preoperative imaging data and intraoperative patient anatomy. However, this assumption can be compromised by intraoperative brain shift. Although gold-standard microelectrode recording (MER) effectively accounts for brain shift, it requires patients to remain unmedicated and awake in addition to potentially introducing intracranial bleeding due to multiple lead passes. Intraoperative magnetic resonance (MR) imaging is an effective alternative, but the associated image distortion from the implant as well as encumbrance and cost hinder widespread adoption. Considering that shift only occurs in approximately 10-20% of implants, we propose the use of low-cost burr hole ultrasound (US) during DBS to better visualize brain subsurface structures, and to potentially account for deleterious instances of brain shift during surgery. In this work, we aim to demonstrate initial feasibility of using burr hole US registered to preop MR as an additional intraoperative guidance tool for DBS.

Methods

A BK5000 ultrasound system and N11C5 burr hole transducer were used to acquire coronal and sagittal ultrasound images during N=6 DBS procedures. Ultrasound images were acquired prior to the placing of the stereotactic frame and implanting of electrodes for each case. The probe was sterilized prior to the start of each procedure. Corresponding MR slice views were selected using CRAVE-registered pre-op MR and post-op CT scans with lead placement confirmation. Regions of interest (ROIs) corresponding to the ventricles were manually generated on the US and MR slices using MATLAB. An iterative closest point (ICP) algorithm was used to map the US ROI to the MR ROI, and the corresponding transformation matrix was used to register the US image to the MR image. The percent of overlap between the US and MR ROIs was computed for each case and slice view. Additionally, a root mean square error (RMSE) was computed on the areas of the ROIs for each slice view.

Results

The coronal and sagittal US ventricle ROIs resulted in 89.3% and 83.0% overlap, respectively, with the MR ventricle ROIs. The RMSE between the US and MR areas of the coronal and sagittal ROIs were 0.42cm² and 1.77cm², respectively. Fig. 1 shows example coronal US and MR ventricle ROIs before and after ICP registration.

Conclusion

The results in this work demonstrate that burr hole US can be used intraoperatively to better visualize deep brain structures that align well with preoperative imaging data. Although intraoperative US by itself can be difficult to interpret, we have demonstrated in this work that it has the potential to be an invaluable real-time guidance tool when registered to preoperative MR. Moreover, we hypothesize that, once optical tracking is incorporated, burr hole US can be used to drive biomechanical models of brain shift that normally rely on sparse intraoperative surface data, which is otherwise difficult to obtain within a small burr hole.

Introduction: Essential tremor (ET) is a debilitating disease affecting millions. DBS targeting the ventral intermediate (Vim) nucleus of the thalamus has been an effective treatment modality for years. Yet, it is unclear which functional connections in the brain are most modulated by DBS to effect tremor control, and in fact, are most influential in tremor production.

Objective: We studied ET patients undergoing DBS of a major input/output tract of the Vim, the dentato-rubro-thalamic tract (DRTt), using resting state functional MRI (rsfMRI). By collecting rsfMRI scans with DBS ON at parameters for optimal tremor control, and then again with DBS OFF, our goal was to evaluate functional connectivity differences between the two states in the hopes of elucidating which regions connected to the motor cortex might be most involved in tremor regulation.

Methods: We enrolled five ET patients who had previously undergone DBS of the DRTt. Tremor severity using The Essential Tremor Rating and Assessment Scale (TETRAS) was scored with DBS ON at optimal stimulation parameters and with DBS OFF. Anatomical (gradient echo FFE 3D T1 sequence sagittal acquisition; voxel size = 1.2x0.94x0.94 mm³; TR 8.5 ms; TE 4.0 ms; Flip Angle 8) and functional (fMRI BOLD EPI sequence axial acquisition; voxel size 2x2x2 mm³; TR 3113 ms; TE 30 ms; 450 dynamics) 1.5T MRIs were acquired and replicated for the two DBS states; (scan time 24 minutes for each DBS state). Anatomical 3D T1 segmentation was performed using Freesurfer. Regions of interest (ROI) were pre-defined as the bilateral pre-central gyrus, superior and inferior parietal lobules (SPL/IPL), dentate nucleus (DN), and cerebellar nodule. fMRI data was preprocessed (slice timing, motion correction, despiking, linear detrending, nuisance regression, bandpass filtering (0.01-0.08 Hz) and smoothing were all performed). After the T1 data was registered with the fMRI data using FSL, these ROIs were transformed to fMRI space. All patients had their electrode-extension connections placed on the left parietal location; the EPI distortion and susceptibility artifact from these implants resulted in signal loss, to which a mask was applied to exclude from analysis. Timeseries for each ROI was extracted from the fMRI data; the Pearson correlation coefficient for each timeseries pair was calculated. A connectivity matrix was generated with threshold criteria to include only p-value < 0.05 and R-value > 0.40 for each DBS state. Comparison of DBS ON/OFF was then performed for each patient and a connectivity rank difference matrix was calculated with the following values for each cell: 1 = ON>OFF, 0 = ON=OFF, -1 = ON<OFF. Group analysis was performed by adding up the connectivity rank matrix per cell for all 5 patients.

Results: Of the five patients, 2 were male and 3 female; all were RH. Mean age was 74 years and disease duration was 28 years. Mean bilateral appendicular TETRAS with DBS ON was 1.3; DBS OFF was 6.5. Difference in tremor severity with DBS ON/OFF was highly significant (TETRAS p<0.001). The regions where most decreases in connectivity were seen between DBS OFF and ON  were the left and right IPL, right pre-central gyrus and right SPL, right pre-central gyrus and left SPL, and left and right SPL. Left and right SPL had the greatest connectivity differences relative to other regions, namely the left and right pre-central gyri, with decreased connectivity in the DBS ON state vs. DBS OFF. Group analysis revealed that overall, all ROIs except the left precentral gyrus had less connectivity with other ROIs when DBS was ON relative to OFF.  The cerebellar nodule had no significant connectivity. Please review Figure 1.

Conclusion: Stimulation of the DRTt and concordant improvement of tremor resulted in connectivity decreases seen in multiple regions thought to be involved with tremor pathology. The SPL and IPL were the ROIs displaying the greatest connectivity changes between DBS states. Parallel structural and electrophysiological connectivity analyses performed confirm that the SPL and IPL are critical regions that are involved in tremor modulation. Further work to characterize the correlation of clinical response to stimulation evoked functional changes could improve DBS for tremor. 

Background: The dentato-rubro-thalamic tract (DRT) is currently considered as a potential target in Deep Brain Stimulation (DBS) for various types of tremor. However, tractography depiction can vary depending on the included brain regions. The Fast Gray Matter Acquisition T1 Inversion Recovery (FGATIR) sequence, with excellent delineation of grey and white matter, possibly provides anatomical identification of rubro-thalamic DRT fibers.

Objective: Evaluating the FGATIR sequence by comparison to DRT depiction, electrode localisation and effectiveness of DBS therapy. 

Methods: In patients with DBS therapy due to medication-refractory tremor, the FGATIR sequence was evaluated for depiction of thalamus, red nucleus (RN) and rubro-thalamic connections. Deterministic tractography of the DRT, electrode localisation and tremor control were compared. The Fahn-Tolosa-Marin Clinical Rating Scale for Tremor was used to assess (hand) tremor. Tremor control was considered successful when complete tremor suppression (grade 0) or almost complete suppression (grade 1) was observed. Stimulation-induced side effects, including dysarthria and gait ataxia, were categorized into moderate or severe.

Results: We retrospectively evaluated 14 patients; 12 essential tremor (ET), 1 tremor-dominant Parkinson's disease (PD), 1 multiple sclerosis (MS); representing 24 trajectories. Mean follow-up was 11.3 months (range 6-19 months). Two patients (PD and ET) were operated under general anesthesia. In all twelve awake electrode placements, a single trajectory was needed for complete intraoperative tremor control. The FGATIR sequence provided a clear delineation of the hyperintense thalamus in the hypointense surrounding internal capsule. A hypointense white matter tract within the thalamus, generally visible from the level of the posterior commissure, was distinguishable in both axial and coronal projections. In coronal plane this tract was most readily recognizable as a 'rubral wing', with the round RN as base and lateral triangular convergence. The deterministic DRT depiction was consistently situated within the rubral wing as visualized by the FGATIR sequence. The number of active contacts located within the DRT (and rubral wing) was 22 (92%), of which 16 (73%) showed successful tremor control. The two active contact points outside the DRT depiction were closely located at 0.5 (within rubral wing) and 2.0 (outside rubral wing) millimeters, and both showed good tremor control. The 6 active contact points located within the DRT with suboptimal tremor response represent 4 patients (1 MS, and 3 ET). Three patients (21%) experienced gait disturbances. Two patients (14%) experienced stimulation-induced dysarthria. 

Conclusion: The FGATIR sequence offers visualisation of rubro-thalamic connections which form the DRT, most readily recognizable as a 'rubral wing' in coronal plane. This sequence contributes to tractographic depiction of DRT and provides a direct anatomical DBS target area for tremor control. 

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective surgical treatment for patients with advanced Parkinson’s disease (PD). Combining 7.0-Tesla (7T) T2 and diffusion weighted (DWI) MRI sequences allows for segmenting the motor part of the STN. It is unclear whether STN microelectrode recordings (MER) differ in signal power depending on the location relative to the segmented motor part.

Methods: 7T T2 and DWI MRI sequences were obtained and probabilistic segmentation of motor STN subdivisions was performed in the postoperative phase in a total of 50 STNs in 25 PD patients, using FSL. A voxel connectivity threshold of 20% was applied, enabling visualising an area within 7T T2 STN representation with the highest density of connections to the motor cortices (motor and supplementary motor area). Intraoperative CT was used for DBS electrode localization and the coordinates of the center of the active electrode contact used for stimulation were determined. The active electrode contacts and corresponding MER were evaluated for being located inside (motor STN group) or outside (STN group) the segmented part with the highest density of motor connections. Subsequently, mean power and mean sigma (standard deviation) of the MER were compared between the two groups.

Results: There were no significant differences between motor STN and STN MER for mean signal power (p = 0.72) and mean signal variation (p = 0.72).

Conclusions: No differences between MER signal power inside or outside the segmented part with the highest density of motor connections were found. The MER signal power could not be used for distinguishing the motor part of the STN.

Introduction: We report the case of a now 49-year old woman who had an ischemic stroke in 2000. This caused right-sided low-frequency action tremor in the proximal upper limb, rigidity in the right shoulder and slight paresthesia and dysesthesia in the right hand. Cerebral imaging showed a thalamic cavity with a volume of approximately 154mm³.  Medication (Propranolol, Primidone, Gabapentin) did not alleviate the symptoms. Therefore, she requested deep brain stimulation (DBS).

Methods: To implant the DBS lead at an optimal target, an fMRI was performed comparing the resting state (upper arm supported; In this position there was no tremor) to a tremorous state, where the patient was asked to hold the right arm in a wing-beating position. Secondly, a fluorodeoxyglucose (F18) position emission tomography (FDG-PET) was acquired to investigate the metabolic state of the thalamic cavity. To evaluate the clinical effectiveness of DBS on the tremor, A Fahn-Tolosa-Marin (FTM) tremor rating scale (part A and B of the right upper extremity) was performed prior to surgery as a baseline, as well as one month after surgery with DBS off and on. Next, a randomized, double-blinded monopolar review was performed, where the therapeutic window (TW) of every individual DBS-contact was defined, as well as from the two directional levels as omnidirectional contact. Bottom of TW was defined as the lowest amplitude at which tremor arrest occurred in the right arm when performing a finger-to-nose test. Top of TW was defined as the lowest amplitude where non-transient stimulation-induced side effects appeared. To investigate a possible relationship between the distance from each DBS-contact to the fMRI activity to the TW, we first calculated the Euclidian distances between the center of each DBS-contact and the elevated fMRI signal. Thereafter, we correlated these distances to the TW calculated from each DBS-contact.

Results: Imaging (Fig. 1A) showed the cavity just anterior to the indirectly targeted ventral intermediate nucleus of the thalamus (VIM; targeted at 75% to posterior of the AC-PC line, at 14.26mm to lateral left, at the height of the AC-PC line), an increased fMRI signal during tremor anterior to the cavity and intersecting the dentatorubrothalamic (DRT) tract. Furthermore, the DRT on the affected side showed a decreased fiber density. Lastly, FDG-PET showed decreased tracer uptake at the left thalamus. Taken all of the above together, surgical planning proceeded with the hypothesis that the areas with increased fMRI signal on fMRI are expected to be most effective in reducing the tremor when electrically stimulated. For surgery, a directional lead was chosen. Fusion of the preoperative MRI scan to the postoperative CT scan showed that the lead was positioned immediately anterior to the cavity, where the most dorsal DBS-contacts were closest to the elevated fMRI signal and the largest part of the DBS lead intersected the DRT tract. When comparing the clinical measures, the FTM tremor rating scale indicated an 84.6% decrease in tremor before versus after surgery with DBS-on.

Conclusion: We report the case of a 49-year old woman in whom DBS was implanted due to a post-stroke low-frequency action tremor in her upper right arm. A single directional lead was implanted based on information gathered via diffusion MRI, fMRI and FDG-PET immediately anterior from the cavity, thereby intersecting the elevated BOLD signal and the DRT tract. After surgery, the tremor had disappeared, with only a minor tremorous trend when drawing a spiral. We propose that, in rare cases such as the one described here, additional imaging may provide the necessary information to guide the surgery, which could optimize the patients’ chances for a successful implantation.

Background

Neurosurgical practice still relies heavily on pre-operatively acquired images to guide intra-operative decision-making during procedures such as tumor resection and DBS electrode placement. This practice comes with inherent pitfalls such as registration inaccuracy due to brain shift, and lack of real-time functional or morphological feedback. Exploiting the opportunity for real-time imaging of the exposed brain can improve intra-operative decision-making, neurosurgical safety and patient outcomes. Previously, we described functional Ultrasound (fUS) as a high-resolution, depth-resolved imaging technique able to detect functional regions and vascular morphology during awake tumor resections [1]. Here, we describe our recent progress towards fUS as a fully integrated, MRI/CT-registered imaging modality in the Operating Room (OR) (Figure 1A).

Materials and Methods

fUS relies on high-frame-rate (HFR) ultrasound, making the technique sensitive to very small motions caused by vascular dynamics (µDoppler) and allowing measurements of changes in cerebral blood volume (CBV) with micrometer-millisecond precision. This opens up the possibility to 1) detect functional response, as CBV-changes reflect changes in metabolism of activated neurons through neurovascular coupling, and 2) visualize in-vivo vascular morphology of pathological and healthy tissue with high resolution at unprecedented depths. During a range of anesthetized and awake neurosurgical procedures we acquired images of brain and spinal cord using conventional linear ultrasound probes connected to a research acquisition system. The ultrasound probes were either handheld for dynamic scans of tissue volumes (Figure 1B) or stabilized over regions of interest using an intra-operative arm developed in-house (Figure 1C). During conventional awake craniotomy procedures, we asked patients to perform functional tasks to elicit cortical responses following the Electrocortical Stimulation Mapping (ESM)-procedure. During all procedures, our research system recorded real-time vital signs data of the patient (arterial pressure and EKG), which can be used to improve image quality in post-processing. Building on Brainlab’s Cranial Navigation and Intra-Operative Ultrasound modules, we co-registered our intra-operative Power Doppler Images (PDIs) to patient-registered MRI/CT-data in real-time. Using the IGTLink research interface, we were able to access and store real-time tracking data for informed volume reconstructions in post-processing.

Results

Intra-operative fUS was registered to MRI/CT-images in real-time within the Brainlab interface, showing overlays of PDIs over the conventional neuro-navigation volume including pre-operatively drawn regions of interest and tumor borders (Brainlab Elements Smartbrush) (Figure 1D). During meningioma and glioma resections, these co-registered PDIs revealed fUS’ ability to visualize the tumor’s feeding vessels and surrounding vasculature, with a level of detail unprecedented by conventional MRI-sequences (Figure 1E-F). Using the intra-operatively recorded tracking data facilitated through the IGTLink, we made MRI-registered 3D-reconstructions of the 2D-PDIs post-operatively, which revealed unique vascular details such as the presumed middle cerebral artery originating from the circle of Willis (white arrow, Figure 1G). Imaging of deep brain nuclei (Figure 1H) reveals potential for vascular-guided DBS electrode placements, both in terms of improving morphological delineation as well as increasing safety by avoiding vital vascular structures during electrode implantation. During awake resections, fUS was able to detect distinct, ESM-confirmed functional areas as activated during conventional motor and language tasks (Figure 1I). In all cases, images were acquired with micrometer-millisecond (300 µm, 1.5-2.0 ms) precision at imaging depths exceeding 5 cm.

Conclusion

fUS is a new real-time, high-resolution and depth-resolved imaging technique, combining favorable imaging specifications with characteristics such as mobility and ease of use which are uniquely beneficial for a potential image-guided neurosurgical tool. The successful integration of fUS in the neurosurgical OR demonstrated by our team is an essential step towards clinical integration of fUS, as well as the technique’s validation against modalities such as MRI and CT.

References

[1] Soloukey, S. et al. Functional Ultrasound (fUS) During Awake Brain Surgery. Front. Neurosci. (2020)

Aims: Disorders of consciousness (DOC) are one of the major consequences after anoxic or traumatic brain injury. So far, several studies have described the regaining of consciousness in DOC patients using

deep brain stimulation (DBS). However, these studies often lack detailed data on the structural and functional cerebral changes after such treatment. The aim of this study was to conduct a volumetric analysis of specific cortical and subcortical structures to determine the impact of DBS after functional recovery of DOC patients.

Methods: Five DOC patients underwent unilateral DBS electrode implantation into the centromedian parafascicular complex of the thalamic intralaminar nuclei. Consciousness recovery was confirmed using the Rappaport Disability Rating and the Coma/Near Coma scale. Brain MRI volumetric measurements were done prior to the procedure, then approximately a year after, and finally 7 years after the implementation of the electrode. The volumetric analysis included changes in regional cortical volumes and thickness, as well as in subcortical structures.

Results: Limbic cortices (parahippocampal and cingulate gyrus) and paralimbic cortices (insula) regions showed a significant volume increase and presented a trend of regional cortical thickness increase 1 and 7 years after DBS. The volumes of related subcortical structures, namely the caudate, the hippocampus as well as the amygdala, were significantly increased 1 and 7 years after DBS, while the putamen and nucleus accumbens presented with volume increase.

Conclusion: Volume increase after DBS could be a result of direct DBS effects, or a result of functional recovery. Our findings are in accordance with the results of very few human studies connecting DBS and brain volume increase. Which mechanisms are behind the observed brain changes and whether structural changes are caused by consciousness recovery or DBS in patients with DOC is still a matter of debate.

Introduction: The two middle contacts of directional leads for deep brain stimulation are split into three segments, allowing current steering toward desired axial directions. To facilitate programming, their final orientation needs to be reliably determined. Moreover, the rotational stability of directional leads is a major prerequisite for sustained clinical effects. Thus, it is of major importance to determine if and for how long directional leads rotate after their implantation. We here aimed to evaluate the short- and long-term rotational stability of directional leads.

Methods: We retrospectively evaluated the orientation of directional leads in a consecutive series of 33 patients implanted with a total of 63 directional electrodes at different time points. In all cases a postoperative CT scan on the day of surgery (T1) and CT or rotational fluoroscopy at a second time point (T2) were available. In 32 directional leads, which had been implanted with an anterior intention (=0°) their intraoperative X-rays (T0) were evaluated.

Results: Sixty-three leads were evaluated. The mean follow-up between T1 and T2 was 409 (4–1171) days. The difference in rotation between T1 and T2 was 2.4° (0°-9.0°) indicating stable orientation. The difference between T0 and T1 was 155 minutes (108-189 minutes). In nine of the 32 d-leads with intraoperative X-ray, an iron-sight ( ISi; indicating 0° +/- 6° orientation) was visible at T0. In these electrodes median orientation was 1.5° (range 0.5-6.0°) at T1, confirming anterior orientation. In directional leads without ISi or where ISi was not evaluable, the median rotation was 15.5° (9.5–35.0°) and 26.5° (5.5-62.0°), respectively.

Conclusion: Directional lead orientation remains stable both in the short- or long-term. Postoperative images can thus be used at any postoperative time point to reliably determine their orientation. Intraoperative determination of lead orientation using marker-based X-ray alone is too imprecise, which explains the large deviations from the intended anterior (=0°) orientation at implantation in most leads; adding the ISi method can increase the accuracy and permits to define the orientation of directional leads intraoperatively.

Introduction

Targeted treatment for lesions presenting with a brainstem location requires above all a precise histopathological diagnosis. In the current technological era, robot-assisted stereotactic biopsies represent an accurate and safe procedure for tissue diagnosis. We present our center’s experience in performing frameless robot-assisted biopsies for lesions of the brainstem. 

Material and methods

We performed a retrospective analysis of all patients benefitting from a frameless robot-guided stereotactic biopsy at the University Hospital in Lille (France), from 2001 to 2018. The NeuroMate robot (Renishaw, UK) was used in all cases. We report on lesion location, trajectory choice, histopathological diagnosis and follow-up. 

Results

Our series encompasses 106 patients treated during an 18 years period, presenting with various anatomopathological diagnoses. Mean age at biopsy was 35.4 years (range 1-78). Most common location was pontine region (71.4%). A transcerebellar approach was used in 66 patients (62.2%). Various diagnoses are described, most commonly being diffuse glioma (65.7%), metastases (7.6%) and lymphoma (4.8%). Non conclusive diagnosis was found in 13 cases (12.6%). After second biopsy this decreased to 6 cases (5.8%). Transitory complications were recorded in 16% of cases (17 patients). The most common was oculomotor transitory disorder (5 patients). Permanent disability was seen in 5.6% (6 patients). Adjuvant targeted treatment was performed in 71% of patients. Surgery for debulking was possible in only 5 patients (after adjuvant therapy in two cases). Mean postoperative follow-up in the Neurosurgery Department was 2.2 years. 

Conclusion

Frameless robot-assisted stereotactic biopsies can provide the initial platform towards a safe and accurate management for brainstem lesions. To our best knowledge, we report on the largest case series for frameless robot-assisted stereotactic biopsies, with high diagnostic precision and low morbidity.    

Objective: Rapid and accurate diagnostic confirmation of brain tumor tissue during stereotactic biopsies is of major importance. Frozen section analysis is the gold standard, nevertheless in cases of multiple samples analysis it may be time consuming. Intraoperative flow cytometry is a novel technique that permits differentiation of low from high-grade tumors, brain tumor margins assessment and diagnosis of central nervous system lymphoma within 6 minutes. The technique is based on the evaluation of tumor’s cell cycle phases, ploidy status and cluster differentiation (CD) markers.  Major advantages of flow cytometry are the evaluation of multiple samples, minimal tissue requirements and there is no need to administer any substance to the patient.  In the present pilot study we assessed the value of intraoperative flow cytometry during brain tumor biopsies.

Material-Method: Four patients (3 males, 1 female, mean age 63.2 years) that underwent a stereotactic biopsy for a suspected neoplastic lesion were included in the study. Upon sample receipt fast flow cytometric analysis (Ioannina Protocol) was performed  and the results were compared to standard pathology.

Results: The final diagnosis were three glioblastoma cases and one case of metastatic cancer. Presence of neoplastic tissue was readily identified in all cases based on ploidy status, decreased G0/G1 and increased S and G2/M phase fractions. The exclusion of central nervous system lymphoma was performed within 6 minutes of sample receipt based on CD markers analysis. Histopathology verified the results in all cases.  

Conclusions: Intraoperative flow cytometry might be a novel promising technique for the rapid identification of neoplastic tissue during stereotactic brain lesion biopsies.

Tourette syndrome (TS) is a neuropsychological disorder characterized by vocal and motoric tics, mainly affecting children and young adults. The pathophysiology of this disorder is not yet completely understood. Nevertheless, studies have shown a delayed neurodevelopment with abnormal connectivity patterns in the cortico-striatal-thalamic-cortical (CSTC) loops. While in most patients, symptoms either cease or considerably diminish in early adulthood, about 20% of the patients continue having symptoms their whole life, with the same or increased intensity. For adult patients with severe treatment-refractory TS, deep brain stimulation (DBS) is a safe and effective therapy option. So far numerous anatomical structures have been researched as DBS targets along the CSTC loops, including the centromedian nucleus- ventrooralis internus (CM-Voi), the CM-parafascicular complex (CM-Pf), the anteromedial (amGPi) and posteroventral globus pallidus internus (pvGPi), the globus pallidus externus (GPe) and the nucleus accumbens (Nacc). According to a recent review, the average improvement for all targets in the Yale Global Tic Severity Scale was about 47%, with none of them showing a greater benefit than the others. Studies on small cohorts showed that some patients responded better to stimulation of amGPi than CM-Pf while in others there was no significant difference. Furthermore, patients with additional obsessive-compulsive disorder seem to profit more from amGPi or Nacc DBS. The aim of this study is to correlate cortical connectivity patterns of patients stimulated in CM-Voi with clinical results, and to compare connectivity patterns of DBS targets for TS in order to elucidate if specific targets are better suited for patients with specific clinical phenotypes.

To establish relevant cortical areas in TS, we investigated diffusion tensor imaging (DTI) in seven Tourette patients who underwent CM-Voi DBS at our clinic. We analyzed the connectivity between the tissue activated by the electrodes and individual cortical areas. Connectivity profiles more specific to the motor cortex (M1, SMA, preSMA) were associated with a reduction of motor and vocal tics.  In poor responders the cortical connectivity was more widespread, mainly projecting to the prefrontal cortex.

Based on these results, we examined the connectivity profile of all DBS targets for TS namely CM, Voi, Pf, amGPi, pvGPi, GPe and Nacc, using a normative connectome. We compared the connectivity of each structure to the motor cortex (M1, SMA, preSMA), the primary sensory cortex, the amygdala and the hippocampus.

The connectivity profile of these targets was remarkably different. While pvGPi and GPe showed the strongest connection to the motor cortex, most fibers from Voi, CM, amGPi and Nacc connected to the prefrontal cortex, and Pf mainly to the amygdala. The connectivity profiles of the thalamic structures, Nacc and amGpi were more specific to single areas, while fiber tracts from pvGPi and GPe were more scattered.  Notably, neither CM nor Voi showed a particularly strong connection to the motor cortex, other than the individual tractography of our patients might have suggested.

In summary, we found that a better clinical outcome after TS DBS targeting CM-Voi correlated with a more specific connectivity of the tissue activated by the electrodes to the motor cortex based on individual tractography. Furthermore, the connectivity profiles of different TS DBS targets were highly variable based on the normative connectome. Further research is necessary to assess whether clinical outcome in TS patients with other DBS targets is also correlated with similar connectivity patterns.