Objectives: Essential Voice Tremor (EVT) is the phonatory manifestation of Essential Tremor (ET). Several publications cite the prevalence of EVT in ET patients to be 10-25%. EVT is associated with significant social embarrassment, discontinuation of employment and hobbies, and an overall decrease in quality of life. In this study, we investigated whether unilateral (left / right) or bilateral thalamic Vim stimulation is necessary to treat EVT in a prospective, randomized, double-blinded fashion. Our goal was to determine hemispheric dominance in voice tremor as this may provide insight into speech motor neural control and treating medically-refractory isolated EVT.

Methods: All ET patients who were implanted at the Surgical Center for Movement Disorder, Vancouver, BC were screened for a pre-operative EVT. We identified n=8 right-handed patients. These patients underwent bilateral Vim DBS surgery. After several sessions of optimizing DBS parameters for limb tremor, patients were randomized to receive: none, left-only, right-only, or bilateral Vim stimulation for 15 minutes each to assess voice tremor. A five-minute washout period was used in between settings. With their limbs at rest, subjects read the ‘Rainbow Passage’, sustained vowels ‘a’ and ‘e’, and produced one minute of spontaneous speech. A speech-language pathologist blinded to these settings then evaluated voice recordings using the Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V) scale, a standard scale used in speech-language pathology and otolaryngology.

Results: CAPE-V results were examined in relation to hemispheric Vim DBS stimulation. Preliminary findings indicate that the left thalamic Vim plays a critical role in laryngeal speech motor control. This has not been reported before. This suggests that there is hemispheric dominance in speech production similar to language. A detailed analysis will be presented at the WSSFN meeting along with DBS kinetics of voice and limb tremor benefit/washout. 

Conclusions: This study adds to our knowledge of the effects of high-frequency left, right, and bilateral Vim thalamic stimulation on voice tremor in a prospective, randomized, double blinded, controlled manner. The results from this study should be taken into consideration for future endeavours using DBS for treatment of voice-related disorders and provides further information on the neurophysiology of speech motor control.

Background:  We present a new intra-operative MRI technique for evaluating placement of DBS electrodes in patients with movement disorders, using simultaneous electrical stimulation and fMRI, which elicits a strong BOLD effect whose pattern can reflect underlying networks. The strong spatial sensitivity of these maps suggests clinical utility in predicting clinical response and unwanted side-effects. DBS for patients with movement disorders is now FDA approved. While motor symptoms can improve, a drawback is non-motor side effects that overwhelm benefits. Implantation typically requires the patient awake, which deters many patients. This motivates this work to permitting functional implantation with patients under anesthesia. To address this we obtain functional information about DBS location in patients under GA, by using intra-operative fMRI while the DBS electrodes are electrically stimulated.

Method: Patients were scanned in a 1.5T intra-operative MRI, during DBS implantation while under GA. After anatomically guided implantation, a BOLD sensitive EPI sequence was acquired during stimulation of the electrodes in a block design of 30 seconds on/off. Stimulation parameters were 2,5,8 volts across bipolar contacts, at 130 Hz. A total of up to 4 DBS-fMRI sequences were obtained during the imaging session, each with variations of stimulation parameters such as voltages, contacts, and duration. Analysis was performed using AFNI.

Results: A total of 7 patients have been studied and there have been no adverse reactions. Various stimulation parameters explored parameter space, generally showing robust BOLD activation with voltages greater than 5 volts. BOLD activation was both proximal & distal to leads, with patterns reflecting motor circuits. Patterns were very sensitive to lead location. 

Conclusion: We present initial results from simultaneous stimulation of DBS electrodes and fMRI, performed in patients with movement disorders at 1.5T while under GA. Robust BOLD activation can be easily elicited at voltages greater than 4V, whose patterns are both proximal and distal, with high spatial sensitivity, and whose patterns reflect clinical efficacy. This technique offers a possible alternative for patients wishing DBS implantation while under GA, in which the functional location of electrodes is desired to maximize clinical response and minimize side effects. This technique could easily be generalized to any functional localization electrodes during implantation.

Objective: To assess the feasibility and tolerance of bilateral Gamma Knife thalamotomy (GKT) in Essential Tremor (ET).

Background: Unilateral GKT is an established treatment for severe tremors. However, essential tremor is usually bilateral. The persistence of contralateral tremor may induce an impairment in activities of daily living (ADL). Bilateral procedures with thermocoagulation were contraindicated because of the risk of balance, cognitive or speech problems. As the lesion induced by radiosurgery within the VIM is progressive and limited, we proposed a study on bilateral GKT. Here are the preliminary results.

Methods: 15 patients (8 women) with severe ET who had benefit from a first GKT and who had a severe permanent contralateral tremor were included. Patients were included if there was no impairment in their balance or speech and if the neuropsychological assessment was stable. The 2^nd GKT was performed at least 18 months after the first GKT. Patients were assessed before and quarterly for at least 12 months after GKT2, with tremor rating scale, neuropsychological and gait/balance assessments and MRI. VIM lesioning was performed with Leksell Gamma unit with a single exposure through a 4mm collimator. Radiosurgical dose was 130Grays.

Results:  here are the preliminary results for 9 patients who completed the study at 1 year. Tremor score on the treated hand was improved by 57%. The improvement of ADL was 95%. Cognitive score and gait assessment were stable. No patient had hypophonia or dysarthria. Two patients were not significantly improved. One patient had a side effect related to GKT2. She developed hemiataxia and dysarthria induced by a hyperresponse pattern 11months after GKT.

Conclusions: These preliminary results on bilateral GKT for severe ET in a selected cohort of patients shows that the procedure is feasible without a major risk of cognitive or balance problems. However, a longer follow-up is needed.

Background: Gait disturbances and freezing of gait (FoG) are common in late Parkinson’s disease (PD), often leading to loss of independence and increasing morbidity. A recent pilot study suggested positive effects of spinal cord stimulation (SCS) in PD patients previously treated with DBS. Despite the encouraging clinical results, no mechanistic approach was investigated at the initial trial. Anticipatory postural adjustment (APA) is an essential aspect of postural control required for starting any successful voluntary movement. APA combines motor and cognitive components of movement preparation involving the supplementary motor area (SMA) and prefrontal cortex. Aim: To evaluate the effects of SCS over the APA measurements in PD patients and its correlation to gait improvement.Methods: 4 PD patients with gait disorder and FoG, previously treated with STN DBS underwent evaluations in 3 conditions: SCS at 300 Hz, SCS at 60 Hz and SCS turned off. DBS was kept always on. We evaluated the SCS effects on APA and FoG. The assessment comprised: 1) Force plate analysis during step initiation (3 trials) measuring the amplitude and time of APA (time between onset of APA and the step); 2) Accelerometry spectral analysis during 10m-walk test (3 trials) providing the percentage of FoG occurrence and trunk acceleration. For each patient was calculated the average of 3 trials, so in each one the following calculations were made: 60-OFF/OFF*100 or 300-OFF/OFF*100, which is the gain of the condition (60Hz or 300Hz) in relation to OFF condition. For the group (N=4)a t-test was applied  and a simple t-test contrasting 60 and 300hz. Results:FoG index was reduced in SCS 300Hz in relation to SCS Off and 60Hz stimulation (p0.042), so patients had significantly less in freezing time while under SCS at 300Hz. APA time decreased in 300Hz condition comparing with OFF and 60 Hz conditions (p0,041), suggesting better coupling  between preparation and movement during step initiation. Conclusion: 300 Hz SCS seems to improve gait by decreasing FoG and increasing the efficiency of the preparation and movement coupling during step initiation.

Figure 1 (A) shows the position of the accelerometer in lumbar region; (B) represents vertical curve acceleration; The dotted square shows a window to frequency analysis domain; (C) Spectral analysis of acceleration: band representing the locomotor period (0-3Hz) and the FoG band (3-8Hz). (D) FoG index showing the clinical threshold (>2=FoG).

Background: Essential tremor (ET), characterised by postural and/or action tremor, is the most common movement disorder. Several brain regions along the cerebello-thalamo-cortical network have been hypothesised to be involved in the generation of tremor oscillations, but the pathophysiology of ET is poorly understood.

ET can be disabling to the grade of necessitating invasive Deep Brain Stimulation (DBS). DBS in the caudal zona incerta (cZi) has shown a considerable reduction in tremor for patients with otherwise medically intractable tremor. However, the mechanisms underlying the effects of DBS remain unclear.

Objective: Investigating, by using blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI), whether regions within the cerebello-thalamo-cortical network are influenced by therapeutic DBS.

Method: Sixteen patients with cZi-DBS for ET underwent 1.5 T fMRI. During fMRI, the patients executed right-arm tremor-inducing postural holding movements as well as a baseline resting task. Tremor and hand movements were recorded by an MR-compatible single-axis accelerometer attached to the hand. The tasks were performed with the DBS turned on and off, with the initial stimulation setting (on/off) counterbalanced across patients. fMRI data were pre-processed and analysed using a general linear model implemented in SPM12.

Results: Clear therapeutic effects of cZi-DBS, in terms of tremor intensity reduction, were measured by the accelerometer. fMRI analysis showed effects of DBS in brain regions related to right-arm movement control: the contralateral motor cortex and ipsilateral cerebellum. However, different parts of this network showed different effects of the DBS depending on the motor task. Specifically, two circuits within these areas demonstrating different responses to DBS. Neural activity, expressed as BOLD, in the primary sensorimotor cortex and lobule VIII in the cerebellum decreased when performing postural holding while DBS was turned on. In contrast, neural activity in the supplementary motor area and lobule VI in the cerebellum increased during the resting condition when DBS was turned on.

Conclusions: Our results support the notion of DBS acting upon modulation of the cerebello-thalamo-cortical loop in ET. Furthermore, the study illustrates the complexity of DBS mechanisms by demonstrating different DBS actions depending on the motor state of the patient and in brain areas distant to the stimulated target.

Emerging innovations in deep brain stimulation (DBS) therapy are attempting to use local field potentials (LFPs) as biomarkers in the control of closed-loop algorithms. However, understanding of the biophysical origin of LFP signals remains elusive, and little is known about how the patient’s unique brain anatomy and electrode placement impact the recording of such signals. Therefore, we developed a computational framework to theoretically analyze LFP recordings from clinical DBS electrodes that can be customized to individual patients. To demonstrate our model system, we selected a subject with Parkinson’s disease implanted with a Medtronic Activa PC+S DBS system. First, we virtually reconstructed the subthalamic nucleus (STN) using MRI data. This virtual STN was then populated with ~250,000 realistic STN neuron models, each receiving time varying synaptic input. Finally, a finite element volume conductor model was used to represent the DBS electrode and tissue medium. We studied the role of subpopulations of highly synchronous neurons within the STN on the LFP recorded by DBS electrodes. We used three bipolar combinations of experimental LFP recordings to combinatorially determine the best fit model parameters. The results show that incorporating patient-specific STN anatomy impacted the LFP signal and varying the synchrony of spatially discrete subpopulations of neurons near the electrode had a strong effect on the LFP.  

OBJECTIVE: To test our hypothesis that targeting neural pathways underlying emotion and affective behavior could alleviate the suffering and disability associated with chronic pain, we conducted a first-in-humans study of deep brain stimulation (DBS) targeting the ventral striatum (VS) / anterior limb of the internal capsule (ALIC) in 10 patients with post-stroke pain syndrome.

METHOD: Patients presenting with persistent and medically-refractory post-stroke hemibody pain and anesthesia dolorosa due to contralateral lesion(s) of thalamic areas and somatosensory pathways were enrolled in a prospective, double-blind, randomized, placebo-controlled, double-arm crossover trial over 24 months. The figure summarizes the trial design. Patients had had severe pain for more than six months and had failed treatment with at least one antidepressant, one anticonvulsant and one opioid. A quadripolar lead was implanted along the ALIC into the VS bilaterally, with the tip ~3-5 mm ventral to the junction between the ALIC and the anterior commissure.

RESULTS: A total of 10 patients were enrolled in the trial and primary and secondary clinical outcome measures were prospectively acquired in each study phase. Active DBS versus sham stimulation was associated with an increased probability of response (i.e. ≥ 50% improvement) in the Montgomery-Åsberg Depression Rating Scale (44% DBS ON v. 19% DBS OFF, p=0.02), Beck's Depression Inventory (45% DBS ON v. 27% DBS OFF, p=0.004), and the Affective Pain Rating Index (39% DBS ON v. 18% DBS OFF, p=0.002) and Present Pain Intensity (10% DBS ON v. 3% DBS OFF, p=0.002) in the Short-form McGill Pain Questionnaire. Individual patients showed changes in the following measures but we did not observe significant group effects: Visual Analog Scale, Pain Disability Index and the Sensory Pain Rating Index in the Short-form McGill Pain Questionnaire.

CONCLUSION: Our results suggest that DBS of the ventral capsule and ventral striatal area is safe and can effectively modulate the affective sphere of chronic pain, benefiting select patients. 

The aim of this study was to compare the results of chronic stimulation and bilateral radiofrequency lesions of anterior thalamic nuclei in patients with pharmacoresistant epilepsy. The selection of the anterior nucleus of thalamus (ANT) as a potential target for treatment of pharmacoresistant epilepsy was based on data suggesting its crucial role in seizure propagation. This article describes the results of bilateral ANT lesions and chronic stimulation in 31 patients with refractory epilepsy. 19 patients underwent the stereotactic radiofrequency lesions of ANT (I group) and 12 have the ANT-DBS (II group).  Targeting was based on stereotactic atlas information with correction of the final coordinates according to location of clearly visible structures and microelectrode recording. Both groups were quite similar in age, gender, seizures frequency and duration of disease. The median x, y, and z coordinates of ANT were found to be 2.9, 5, and 11 mm anterior, lateral, and superior to the midcommissural point, respectively. Mean seizures reduction reached 80,3% in I group with 2 non-responders and 91,2% in II group. 3 patients form I group and 4 patients from II group are seizure-free now. The morbidity rate was low in both groups. The stereotactic lesion and chronic stimulation of ANT both effective for seizure control in epilepsy originated from frontal and temporal lobes. Secondary generalized seizures more demonstrated more sensitivity to ANT lesions and stimulation comparatively to simple partial seizures. Microelectrode recording allows to identify the physiological borders of ANT and improves the surgical outcomes. 

Introduction: Chronic stimulation of visual cortices could potentially be used to restore some vision in individuals with blindness. However, the feasibility, utility, and consistency of response to chronic epicortical stimulation of the medial occipital lobe remains uncharacterized. Our goal was to evaluate the nature, stimulation thresholds, retinotopic localization, and reproducibility over time, of cortical stimulation-evoked phosphenes in a blind volunteer over 6 months. 

Methods: A 30 year old with an 8 year history of bare light perception blindness due to Voght-Koaynagi-Harada Syndrome underwent implantation of a Neuropace responsive neurostimulation device with 2 parallel 4-contact leads implanted over the right medial occipital lobe via a posterior interhemispheric approach. Postoperatively, the subject’s perception of cortically-stimulated phosphenes was assessed with systematic manipulations of stimulation intensity, pulse width, frequency, and site of stimulation over a period of 6 months.

Results: Phosphenes were elicited with stimulation of every contact; percepts elicited at each electrode varied in brightness, shape, color, and spatial location. Phosphene characteristics were related to charge density and could be elicited with as little as a single stimulation pulse. The perceived quality and spatial localization of elicited phosphenes varied with eye position but was stable over time. The perception of simultaneous stimulation of two contacts as distinct phosphenes varied depending on distance between contacts. Percepts did not change over 6 months. There were no significant adverse events.

Conclusion: This is the first demonstration of chronic epicortical stimulation of visual cortices (primary and secondary) demonstrating feasibility and safety of chronic stimulation in providing reproducible phosphenes. Based on these results, further studies exploring using epicortical visual cortex stimulation, including biobehavioral studies, are warranted to evaluate the utility of this approach to restore some form of useful vision to blind individuals who were previously sighted. 

Object. Chronic neuropathic pain is estimated to affect 3%-4,5% of the worldwide population. Deep Brain Stimulation (DBS) is established for movement disorders but, for the treatment of chronic, drug refractory, neuropathic pain, DBS has shown variable outcomes, in the few studies performed in the past. Thus, this procedure has consensus approval in parts of Europe but not in the USA. This study prospectively evaluated the efficacy at 3 years of DBS for neuropathic pain.

Methods. Sixteen consecutive patients received 36 months post-surgical follow-up in a single-center. Five had phantom limb pain after amputation and eleven deafferentation pain after brachial plexus avulsion (BPA), all due to trauma. To evaluate the efficacy of DBS, patient-reported outcome measures were collated before and after surgery, using a visual analogue scale (VAS) score, University of Washington Neuropathic Pain Score (UWNPS), Brief Pain Inventory (BPI), and 36-Item Short-Form Health Survey (SF-36).

Results. Contralateral ventroposterolateral sensory thalamic DBS was performed in sixteen patients with chronic neuropathic pain over 29 months. A postoperative trial of externalized DBS failed in one patient with BPA. Fifteen patients proceeded to implantation. One patient with phantom limb pain after amputation was lost for follow-up after 12 months. No surgical complications or stimulation side effects were noted. After 36 months, mean pain relief was sustained, and the median (and interquartile range) of the improvement of VAS score was 52.8% (45.4%) (p=0,00021), UWNPS was 30.7% (49.2%) (p=0,0590), BPI was 55.0 % (32.0%) (p=0,00737) and SF-36 was 16.3% (30.3%) (p=0,4754). Among the BPA patients, VAS score improved by 40% (31,9%) (p=0.01298), UWNPS by 22.7% (37.1%) (p=0.4632), BPI by 47.8% (62.8%) (p=0.189) and SF-36 by 16.0% (42.7%) (p=0.9953). In the amputation group, after 36 months median VAS score improved by 66.7% (51.7%) (p=0.0494), UWNPS by 50.8% (62.9%) (p=0.3225), BPI by 65.2% (31.6%) (p=0.1623) and SF-36 by 16.7% (140,2%) (p=0.2406). Initial mean parameters were 2.1V, 23Hz and 187 µs and after 36 months both amplitude and pulse width were increased with parameters of 4.1V, 15 Hz and 196 µs.

Conclusions. DBS demonstrated efficacy at 3 years for chronic neuropathic pain after traumatic amputation and BPA, with benefits sustained across all pain outcome measures and slightly greater improvement in phantom limb pain.

Objective: To assess long-term efficacy of deep brain stimulation (DBS) for chronic neuropathic pain in consecutive patient.

Methods: Patients with chronic neuropathic pain which were refractory to medication underwent bifocal thalamic implantation of DBS electrodes. Targets were the centromedian parafascicular nucleus (CM-Pf) and somatosensory thalamus (either nucleus ventralis postereolateralis, VPL, or ventralis postereomedialis, VPM) Elektrodes were implanted by CT-stereotactic surgery and externalized for 4-14 days to assess the effect of the two targets and to decide whether chronic stimulation could be administrated. Therefore DBS electrodes were either removed or a pulse generator was implanted. Assesment of pain included VAS scores and patient self rating. Patients were follow-up regularly at annual visits on longterm.

RESULTS :Over a period of 16 years, a total of forty patients (20 women, 20 men; mean age of surgery 53.8 years, range 24-73 years) underwent bifocal implantation of thalamic DBS electrodes. Etiologies included central pain after stroke or hemorrhage (11 patients), complex regional pain syndrome (10 patients), a typical facial pain (5 patients), post Zoster pain (4 patients), post-amputation pain (2 patients), myelon injury (2 patients), and others. There were no surgical complications. Impulse generator were implanted in 33/40 patients for chronic stimulation, while 7 patients did not a chieve adequate benefit during test stimulation. Three patients were lost to follow-up in longterm followup, and in five patients the neurostimulation system was explanted due to infection. On longterm 20/33 had chronic CM-Pf stimulation and 13/33 had VPL/VPM stimulation. The properties of marked/ excellent vs moderate/ minor vs no improvement was similar with both targets in longterm follow-up according to patient self-rating.

Conclusion: Thalamic DBS is a useful treatment option in selected patients with severe and medically refractory neuropathic pain. While some patients achieve greater benefit with CM-Pf stimulation (which is thought to represent the paleospinothalamic projection associated with the sensation of unpleasant of pain), others prefer somatosensory thalamic stimulation (which relates to the neospinothalamic pathway transferring the most immediate pain experience. Bifocal implantation is helpful to select the optimal stimulation target in the individual patient.

Background

Stereotactic anterior cingulotomy has been reported to be effective in the treatment of patients suffering from refractory oncological pain by influencing pain perception. However, the optimal target as well as suitable candidates have not been well defined. We have established a specialized palliative service consisting of palliative care specialists, pain specialists and a neurosurgeon to aid in the patients’ selection process and outcome assessment. We report our initial experience in the ablation of two cingulotomies targets on each side and the use of brief pain inventory (BPI) as a perioperative assessment tool. 

Methods

This is a retrospective review of all patients who underwent stereotactic anterior cingulotomy in our department between November 2015 and February 2017. All patients had advanced metastatic cancer with limited prognosis and suffered from intractable oncological pain.

Results

Thirteen patients (10 females) underwent 14 cingulotomy procedures. Mean age was 56±13.5, and median KPS was 50. Median pain duration was 12 months (range 1-48). All patients reported significant pain relief immediately after the operation and out of the 6 pre-operatively bedridden patients, 3 started ambulating shortly after. Eight patients were discharged home, 3 were referred for rehabilitation and 2 for hospice care. Median pre-operative and post-operative VAS scores were 9/10 (range 8-10) and 3/10 (range 0-5), respectively. Mean pre-operative BPI pain severity and interference scores were 30±12 and 59±11, respectively, as compared with post-operative values of 14±9 and 32± 13, respectively. During the 1-month and 3-months follow-up visits, 10/11 patients (90%) and 5/7 patients (71%) available for follow-up, reported significant pain relief. No patient reported worsening of the pain.

Adverse events included transient confusion or mild apathy in 5 patients (38%) lasting 1-4 weeks. Two of these patients developed transient urinary incontinence that resolved after 1 week.

Neuropsychological analyses of 5 patients showed mild deficits in focused attention and visual memory, while the rest of cognitive functions were relatively stable. There was a significant improvement in depression symptoms.

Conclusions

Two-target stereotactic cingulotomy is safe and effective in alleviating refractory pain of cancer patients. BPI score may add to VAS for the evaluation of response to cingulotomy. No substantial cognitive changes were detected.

Introduction

Arm pain following brachial plexus avulsion injury is known to be refractory to any conventional method for pain relief. Dorsal root entry zone (DREZ)-lesioning has been the most effective surgical treatment for the relief of pain this kind. However, residual pain and a decrease in pain relief in the follow-up period have been reported in 23-70% of patients. Based on the most recent studies on neuropathic pain, we modified the conventional DREZ lesioning procedure to improve clinical outcomes.

Methods

Both the original DREZ-lesioning, employing electrode insertion and coagulation technique by Nashold and microsurgical technique by Sindou, intended destruction of the dorsal horn cells at Rexed layer I & II. We extended area of microsurgical destruction deep into Rexed layer V.

Fourteen patients underwent surgery between 2011 and 2017.

Results

All patients achieved excellent (n=10, pain relief without medication) or good (n=4, pain relief with medication) pain relief post-operatively, and the recurrence was not reported in any patients (median of 28 months after surgery,6-84 months).

Twelve patients (88%) achieved total pain relief (0 or 1 on the VAS) with or without medication.

Although, intraoperative MEP amplitude attenuation down to 10% of the original level were observed in 1/3 of the cases, no motor deficit was observed.

A sensory deficit was observed in 2 patients and disappeared within one month in 1 patient. New pain at the adjacent level of DREZ lesioning was observed in 3 patients and disappeared within one month in 2 patients. In the other patient, new pain persisted and required analgesics.

The most prominent gliotic change were observed at the gray matter of the spinal segment which was compatible with the most painful area.

Conclusion

Our preliminary results demonstrated that total and persistent global pain relief was achieved with the modified DREZ lesioning procedure in 90% of patients without major neurological deficits. Our results clearly suggested that the wide dynamic range neuron in Rexed layer V played a cardinal role in pain formation in case of brachial plexus avulsion injury.

OBJECTIVE: To review our initial experience with a first-in-human FDA-approved trial of deep cerebellar nucleus deep brain stimulation (DBS) for post-stroke recovery, including intraoperative physiological data and observations as well as the effects of acute stimulation titration on behavior and on cortical excitability indexed by transcranial magnetic stimulation (TMS).

BACKGROUND: Over the past decade, our group has demonstrated that chronic electrical stimulation of the lateral cerebellar nucleus (LCN) can enhance motor recovery following cortical ischemia in preclinical rodent models. Those motor rehabilitative findings were accompanied by enhanced synaptogenesis and increased expression of markers of long-term potentiation in perilesional cortex as well as modulation of cortical excitability and motor representation.

METHODS: All data are being collected as part of a first-in-man, single-center, prospective, open-label, single-arm, safety and feasibility trial for patients with persistent (>12 months post-stroke), moderate-to-severe upper extremity hemiparesis secondary to middle cerebral artery ischemic stroke.

RESULTS: Two participants have been enrolled to date. In addition to safety and feasibility indices we will present measures of therapeutic efficacy as well as modulation of perilesional cortical excitability and changes in motor representations measured by TMS. Intraoperative electrophysiological data including EEG and local field potential data acquired during lead implantation will also be presented. Finally, we will review our development of patient-specific biophysical models of DBS of the dentatothalamocortical network based upon pre- and post-operative imaging data.

CONCLUSION: This study and its data represent the initial steps in the translation of more than a decade worth of preclinical work towards the development of deep brain stimulation of the dentatothalamocortical pathway as a therapy for post-stroke motor rehabilitation. Its review will provide an interactive forum concerning the process and timing of translating neurostimulation-based research for neurorehabilitation.

Objective: To assess for the first time structural brain changes, by voxel-based morphometry (VBM), before and after unilateral Gamma Knife thalamotomy (GKT) for drug-resistant tremor. To identify differences between clinical responders and non-responders to GKT.

Methods: Thirty-eight patients (mean age 71.8 years) with severe refractory right essential tremor (ET) were treated with unilateral left GKT. Targeting of ventro-intermediate nucleus (Vim) was performed with Leksell Gamma Knife using a single 4-mm collimator and 130 Gy.  Neurological, neuropsychological and neuroimaging (3 Tesla, including 3D T1 weighted) assessment had been done at baseline and 1 year after GKT. Clinical responders were considered those improved in tremor score (Fahn-Tolosa-Marin) with at least 45%.

Results: Thirty-one (81.6%) patients were responders (R) and 7 (18.4%) non-responders (NR). With regard to GM changes after GKT, independently of clinical answer, atrophy was present in extensive areas (right globus pallidus, left putamen, left thalamus, right anterior and medio-dorsal thalamus, cerebellar, right premotor and supplementary motor area, left and right visual association cortex, right ventral temporal, left parahippocampal and posterior cingulate gyrus). The interaction between R - NR with time showed brain plasticity in R remote areas, within left temporal pole (BA 38) and cluster including left occipital cortex (BA 19), visual areas V4 and V5, parahippocampal place area (p_unc<0.005, k>120).

Conclusions: Our results show brain plasticity after unilateral left GKT. Responders present changes in areas involved in motion, mainly locomotor monitoring towards the local and distant environment, suggesting the requirement to recruit in the targeting specific visuomotor networks. 

Objective: DBS and RF lesions of Raprl may induce different degree of improvement on tremor, rigidity, bradykinesia, posture and gait in PD patients, which indicates that different symptoms are mediated by different fiber tracts. The goal was to determine the fiber tract lesion related of individual symptom improvement.

Material and Methods. Eleven PD patients had stereotactic ally placed unilateral RF lesions in Raprl to treat contralateral prominent symptoms. Prior surgery, symptoms’ severity was evaluated through specific items of UPDRS part III in off medication condition and a 3T-MRI-DTI high resolution was performed. Two lesions were made using bipolar 1.3 mm diameter electrode introduced by a frontal parasagittal approach, with temp 80°C, 60 seconds, 3 mm apart in dorsal-caudal direction. MRI were repeated 6 months post-operatively and co-registered with preoperative MRI, to determine the place and size of lesions as well as the degree of different tract components involved.  UPDRS-III was applied 2 years after surgery in off medication condition to determine the percent improvement of different symptoms. Spearman correlation was performed between the tract lesions and symptom improvement.

Results. Three main tracts were composing Raprl in all cases: cerebellar-thalamic-cortical, Globus pallidum (Gp)-peduncle pontine (PPN) and orbital and prefrontal-mesencephalic. Patients with optimum improvement (>75% decrease in global score) had lesions impinging the 3 fiber tracts. Patients with suboptimum results had lesions in one or 2 tracts. Positive correlation was obtained between improvement of tremor and rigidity with lesion in cerebellar-thalamic fibers, while negative correlation was obtained between posture and gait and fibers connecting with pre frontal cortex. In one case with improvement mainly in tremor and poor for rigidity and bradykinesia a lesion was placed over zona incerta caudalis; another patient with improvement only in gait and posture lesion was placed in Gp-PPN component; a third case with prominent tremor completely controlled without decrease in muscular tone, the lesion involved only fibers ending in Vim.

Conclusions. Cerebellar-thalamic cortical fibers seem related to the physiopathology of tremor and rigidity. Gp-PPN fibers related to gait and posture. Orbitofrontal-mesencephalic component might be related to bradykinesia as part of the medial forebrain bundle. Surgery directed to individual symptoms is feasible.

Objective: This study aims at reporting the correlation between the clinical results and the one-year postoperative MR neuro-imaging characteristics of the thalamic lesion after Gammaknife radiosurgery for  tremor.
Methods: Between April 2004 and March 2015, a Vim Gammaknife thalamotomy was performed in 319 patients for essential or Parkinsonian tremor in Marseille University hospital with a very stereotyped procedure. A neuro-imaging and clinical assessment was performed at one year FU for 253 patients. The volume of the lesion defined as the whole area of post-contrast enhancement was calculated for each patient in mm³, the pattern of lesion determined and the amount of edema evaluated according to a semi-quantitative scale. A clinical evaluation by expert neurologists was performed at the same time.  Statistical analysis was performed using R software (RStudio,Version 1.0.136-2016)

Results: Imaging data were analyzable and reviewed for a total of 169 patients at one year follow-up.Complete neurological clinical evaluation were obtained for 91 patients. The median percentage of tremor reduction was 70% (0-100%, SD:30%).The median volume of the lesion at 12 months FU was 91,45 mm³ (Mean = 104, Min:0, Max :1120, SD:284).A correlation was established between the volume of the lesion and the percentage of tremor reduction (Pearson's coefficient of correlation r =+ 0,26 (p=0,0178).In patients regarded as clinical failure (< 45% of tremor improvement), the lesion volume was significantly smaller than in patients deemed responders (> 45% tremor reduction),p <0,0001).The amount of edema surrounding the lesion was significantly related to the clinical improvement (p = 0.022). The “cocade” pattern enhancement type was strongly related to good outcome (p<0,001) and the absence of enhancement to the absence of improvement (p<0,00001 ,62% vs 0,07%).

Conclusions: These data confirm our previous results derived from 50 patients with blinded analysis of clinical outcome (Witjas and al. Neurology, 2015). Even though a significant correlation exists between lesion volume,edema and clinical improvement,concordance is far from being very strong and linear between the imaging and clinical responses. These findings prompt to look for additional factors in order to better characterize the effects of Gammaknife that might also rest upon a delayed non-lesional neuromodulatory mechanism. These fascinating questions are of utmost importance and currently under investigation.

Deep Brain Stimulation (DBS) is a safe and effective therapy for movement disorders. Intraoperative imaging allows near realtime

assessment of stereotactic accuracy during implantation of intracranial leads. These technologies can be used to examine

factors impacting stereotactic error. This study quantifies and identifies factors contributing to stereotactic error during imageguided

DBS.

Intra-operative CT imaging was reviewed in patients undergoing DBS placement at OHSU. The AC/PC coordinates of the

target electrode were compared to the operative plan to characterize magnitude and direction of stereotactic error with respect

to side of implantation, target and electrode approach angles.

169 leads in 94 patients were examined. Targets were GPi (n=86), STN (n=31) and Vim (n=52); 85 were placed on the left and

84 on the right. Average Euclidean error was 1.63 mm (SD: 0.87). Error magnitude is higher for Vim (1.95 mm) than for GPi

(1.44 mm), while STN (1.65 mm) did not differ from either Vim or GPi (ANOVA: F=6.15, p=.003). Electrodes targeting Vim and

STN were significantly more likely to deviate medially compared to GPi (ANOVA: F=9.13, p<.001) Coronal approach angle

affects error when targeting Vim (rho=0.338, p=.01). These findings were confirmed during multivariate analyses.

This study shows a significant effect of target on the accuracy of electrode placement for DBS. Targeting Vim results in greater

Euclidean error and greater medial deviation off target. The degree of target-specific error appears to be related to penetration

of the internal capsule. These systematic deviations should be taken into account during electrode implantation.

Chronic electric deep brain stimulation (DBS) has been proposed to enable consciousness recovery, targeting mainly the central thalamus. Our aim was to study clinical effects of bilateral pallido-thalamic low frequency stimulation intended to overdrive neuronal activity in continuing disorders of consciousness.

Material-Methods: Five patients were included in a prospective, monocentric, 12-month clinical observational study, with blind cross-over period (NCT01718249): P1 male, 32 y/o, 12 years after traumatic brain injury (TBI), vegetative status (VS); P2 female, 62 y/o, 14 months after intracerebral hemorrhage (ICH), minimally conscious state (MCS); P3 male, 24 y/o, 3 years after TBI, MCS; P4 female, 22 y/o, 4 years after TBI, MCS; P5 female, 47 y/o, 27 months after ICH, MCS. Four phases were individualized: (1) Baseline, at least 2 months; (2) DBS surgery and titration, 1 month; (3) blind, random, 3-month cross over (CO) period with 1.5-month ON (CO-ON) and OFF (CO-OFF) conditions; (4) unblinded, at least 5 months, DBS period (DBS-ON). Electrodes (DBS 3389, Medtronic, USA) were placed within the right and left targets accounting for the lesions of patients. Two neuropacemakers (ACTIVA, Medtronic, USA) were implanted. Primary outcome was the analysis of scores of the Coma Recovery Scale Revised (CRS-R; 0-23): assessments 2 times per week; for the 5 patients, n=419, scores ranging from 1 to 18. Statistical analyses were conducted for a two-sided Type I error of 5% using random-effects models accounting between and within patient variability due to repeated measurements.

Results: No mortality related to surgery and DBS. By individual we observed statistically significant improvement of CRS-R during DBS-ON versus baseline (P1, P3) and CO-On versus baseline (P3). For the 5 patients (group analysis) auditory, visual, motor, oromotor-verbal, communication subscores of CRS-R were significantly improved during DBS-ON versus baseline. Cross-over analysis did not show statistically significant improvement of CRS-R and subscores during CO-ON versus CO-OFF, except P2 and P3 motor sub scores.

Conclusion: Bilateral low frequency DBS in severe continuing disorders of consciousness improved patients on the short term without irreversible adverse effects. Individual analysis seems preferable facing the complexity of clinical features and pathophysiology. Given the current state of knowledge, expectations of relatives, caregivers and physicians should be weighted. 

Objective: To define possible benefits of deep brain stimulation (DBS) of the Dentatorubrothalamic-Tract (DRT) using directional lead technology (DLT) in patients suffering from essential tremor (ET) compared to DBS with conventional, spherical current distribution (cDBS).

Methods and Material: From 04/2016 through 10/2016 8 ET-patients were treated with bilateral DBS of the DRT using DLT (St. Jude Medical) in our institution. 6/8 patients (median age: 74 years) with a minimum FU of 3 months (median: 8.5 months) were considered for analysis. We performed stereotactic implantation of the brain electrodes (two triple-segmented contacts and two spherical contacts) and impulse generator in one session. Targeting based upon preoperative probabilistic Fiber Tractography (pDTI) visualizing the DRT. We used intraoperative stereotactic X-ray to confirm the electrode position and to determine the 3D-arrangement of the segmented contacts. Three months after surgery, DBS-effects were analyzed according to a standardized protocol with monopolar stimulation of all contacts in the cDBS mode and of segmented contacts in the DLT-mode (individual stimulation in three directions). To define the therapeutic window we determined thresholds for tremor improvement and for side effects such as dysarthria, paresthesia or ataxia. Test results allowed ranking of different stimulation directions by therapeutic window for each contact. We compared results of stimulation in best direction vs. cDBS (n=12). 

Results: In 9 out of 12 tested electrodes, DLS of the most efficient segmented contact increased the therapeutic window. Compared to cDBS, the benefit gained by DLT was 0.81 mA (p<0.01). DLT increased the threshold for side effects significantly by 0.61 mA (p<0.05). 

Conclusions: DRT-DBS in ET-patients using segmented electrode contacts and DLT instead of spherical contacts increases the therapeutic window in comparison to cDBS. This result suggests that DLT allows steering current away from anatomic structures causing side effects while stimulating specifically in direction towards structures supposed to be responsible for improvement of symptoms.

Background and Objective

Deep brain stimulation (DBS) within the ventrolateral thalamus with directional leads may result in improved tremor suppression and reduced adverse events.

Methods         

Nine essential tremor patients (1 female; mean age 69 yrs; average disease duration 23 yrs; follow-up 1 to 8 months) were implanted bilaterally (8) with directional leads into the ventrolateral thalamus and subthalamic region (Infinity™; St. Jude Medical). Intraoperatively clinical effects elicited by stimulation in different directions via bipolar activation of corresponding segments pointing into the same direction (lower segment = cathode) were assessed. Monopolar reviews involved the assessment of tremor suppression, including quantitative accelerometer assessments to be completed for some patients, and side effects, in particular paraesthesias. Patients and raters were blinded with regard to the direction of DBS (chosen in random order) and stimulation amplitude. Clinical Global Impression (CGI; 1= very much improved, 7=very much worsened) scale was used to track subjective treatment responses over time. 

Results

There were no adverse events related to surgery or implanted hardware. All patients exhibited microlesioning effects followed by sustained tremor suppression with DBS. The improvement was rated CGI = 2.6±2.1. Intraoperative assessments revealed a lower threshold for paraesthesia if stimulation was performed into the posterior-(medial and lateral) direction. Monopolar review revealed differential thresholds for tremor suppression and paraesthesias that were very variable among patients, and for three electrodes paraesthesia thresholds did not differ between directions or were lower with stimulation in the anterior direction. Tetanic muscle contractions could not be elicited to an extent allowing meaningful comparisons. In two patients permanent stimulation with one of both electrodes was performed in a directional mode in order to widen the therapeutic window or because gait ataxia had worsened under ring mode stimulation.

Conclusions

Directional stimulation maps did not reveal a uniform pattern with regard to tremor suppression and thresholds for paraesthesia. In particular the influence of directional DBS on the therapeutic windows was highly variable among patients. This may be related to actual contact positions, electrode angulations, individual anatomy and biophysical characteristics of directional DBS that need to be unraveled.

Introduction: Intraoperative imagers provide neurosurgeons with real-time information required to maintain precise navigation during surgery. In this study, we assessed the stereotactic accuracy of a compact, intraoperative magnetic resonance imager (iMRI), the 0.15 Tesla (T) PoleStar N30 (PN30).

Methods: Images were acquired using a water-filled phantom model of the brain. The phantom was scanned using T1-weighted, T2-weighted, PSIF, and FLAIR sequences. Data collected with the PN30 were compared with those obtained in a previous study assessing the PoleStar N20 (PN20), an earlier model of this iMRI system. Additionally, the stereotactic accuracy of PN30 was measured against that of standard surgical navigation on a 1.5T diagnostic scan MRI using T1 weighted images (with the same water phantom).

Results: Navigation with PN30 images was more accurate than that using diagnostic MRI. Mean error with the PN30 using T1W images was 1.24 ± 0.47 mm and 1.28 ± 0.49 mm with T2W images, vs 2.43 ± 0.81 mm for navigation based on T1W images from the 1.5 T scan (95% CI, p = 0.016 and 0.001, respectively). This higher degree of accuracy with iMRI-based navigation may reflect the ability to bypass the registration that is needed when employing a scan acquired before surgery, a step that introduces another source of error into the process. In addition, we found that T2W images from the PN30 yielded a lower navigation error than those acquired with the PN20, 1.28 ± 0.49 mm vs. 3.15 ± 0.63 mm at the 95% CI, p < 0.0001.

Conclusion: A high degree of stereotactic accuracy can be achieved with a compact, low field iMRI. Improvements in magnet design can yield progressive increases in accuracy, validating the concept of these devices designed for use during intracranial surgery. Avoiding the need for registration between image and surgical space also can increase navigation accuracy.

Background and Objective     

To determine the rate of adverse events (AEs) related to deep brain stimulation (DBS) surgery and implanted devices in the literature.

Methods         

Three categories were used for a systematic review of 103 publications retrieved from the PubMed database and reference lists: (1) inctracranial AEs (hemorrhages, infarction, abscess, edema) because these might result in neurological deficit or death; (2) infections requiring (partial) hardware removal with interruption of DBS; (3) lead revisions due to fracture, misplacement or migration since this involves an additional intracranial procedure. AE incidences were related to the number of patients (not procedures or electrodes) to prevent dilution of AEs rates. Cumulative patient-years were also used to assess hardware-related AE rates and to compare studies with different follow-up. For non-pooled analysis AE rates from studies were averaged giving equal weight to each study irrespective of cohort size. For pooled analysis AE rates from all applicable studies were summed up and divided by the total number of patients included in these studies.

Results

Exact rates could not be derived from the majority of studies including most monitored trials. The average rate of intracranial AEs was 3.8% (non-pooled) and 3.4% (pooled). Only with pooled analysis intracranial AEs were less frequent in studies with >200 patients (3.1%; p> 0.05) compared to studies with 500 patient-years) exhibited significantly (p< 0.05) lower infection rates than smaller studies (≤100 patients and/or 5%). Lead revision rates were 5.8% (non-pooled) and 4.5% (non-pooled). Analysis based on patient-years revealed lower rates in larger (>500 patient-years) than smaller studies (≤100 patients and/or 0.05).

Conclusions

Although the analyzed AEs cover severe and serious complications, a heterogeneous reporting practice and poor information in several publications including tightly monitored prospective trials prevented clear assessments. For purposes of benchmarking and proper patient counseling clear AE categories are required. The proposed triad has the following advantages: (1) unequivocal definition of AEs; (2) coverage of the most relevant DBS surgery and hardware-related complications; (3) insensitivity to study design and quality; (4) postoperative imaging and a complete set of surgical records are the only requirements making accurate retrospective assessments possible.

Objective:

Deep Brain Stimulation (DBS) systems have traditionally used ring-shaped electrodes that produce a spherical stimulation field which can only be varied in intensity, thereby limiting the extent of volume of tissue activated. A pilot study of 7 PD subjects reported that a novel, directional permanently implanted DBS system, combining an eight-contact directional lead and an implantable pulse generator (IPG) capable of multiple independent current control (MICC), can accomplish directional current steering (Steigerwald F. et al., Mov Disord, 2016). This study was conducted to evaluate clinical outcomes in subjects implanted with a directional lead for use in the management of motor symptoms of levodopa-responsive Parkinson’s disease (PD) as part of an on-going registry.

Materials/Methods:

The Vercise DBS Registry is a prospective, on-label, multi-center, international registry sponsored by Boston Scientific Corporation. The Vercise PC system (Boston Scientific) is a CE-marked, MICC-based DBS system with a non-rechargeable battery. Subjects will be followed up out to 3 years post-implantation. Clinical endpoints will be evaluated at baseline and during study follow up that include Unified Parkinson's disease Rating Scale (UPDRS), MDS-UPDRS, Parkinson's disease Questionnaire (PDQ-39), and Global Impression of Change. Adverse events are also collected. Subjects in this specific cohort were implanted with a directional lead included as part of a directional DBS system (Vercise Cartesia, Boston Scientific) for bilateral STN-DBS.

Results:

Subjects from several European centers and implanted with a directional lead as part of an on-going Registry study will be evaluated. Preliminary data suggests an overall improvement in quality of life as assessed by PDQ-39. Baseline data for this cohort as well as follow up data at 6 mos. (n = 50) and 12 mos. (n = 20) post-implant as available will be presented. Preliminary analysis shows improvement of quality of life comparable to conventional leads.

Discussion:

A DBS device that enables fractionalization of current using a multiple source mode of delivery (MICC) can permit the application of a well-defined, shaped electrical field. Additionally, use of a directional lead allows for the steering of current in horizontal directions by combining segmented leads and MICC, which is thought to permit increased stimulation thresholds for side effects as compared to using standard ring-shaped electrodes.