Safety and Feasibility of Intradiscal Administration of Matrilin-3-Primed Adipose-Derived Mesenchymal Stromal Cell Spheroids for Chronic Discogenic Low Back Pain: Phase 1 Clinical Trial.

Functionally enhanced mesenchymal stromal cells participate in the repair of intervertebral disc. This study aimed to assess the safety and tolerability of intradiscal administration of matrilin-3-primed adipose-derived stromal cell (ASC) spheroids with hyaluronic acid (HA) in patients with chronic discogenic low back pain (LBP). In this single-arm, open-label phase I clinical trial, eight patients with chronic discogenic LBP were observed over 6 months. Each patient underwent a one-time intradiscal injection of 1 mL of 6.0 × 106 cells/disc combined with HA under real-time fluoroscopic guidance. Safety and feasibility were gauged using Visual Analogue Scale (VAS) pain and Oswestry Disability Index (ODI) scores and magnetic resonance imaging. All participants remained in the trial, with no reported adverse events linked to the procedure or stem cells. A successful outcome-marked by a minimum 2-point improvement in the VAS pain score and a 10-point improvement in ODI score from the start were observed in six participants. Although the modified Pfirrmann grade remained consistent across all participants, radiological improvements were evident in four patients. Specifically, two patients exhibited reduced high-intensity zones while another two demonstrated decreased disc protrusion. In conclusion, the intradiscal application of matrilin-3-primed ASC spheroids with HA is a safe and feasible treatment option for chronic discogenic LBP.

Fornix deep brain stimulation circuit effect is dependent on major excitatory transmission via the nucleus accumbens.

INTRODUCTION: Deep brain stimulation (DBS) is a circuit-based treatment shown to relieve symptoms from multiple neurologic and neuropsychiatric disorders. In order to treat the memory deficit associated with Alzheimer's disease (AD), several clinical trials have tested the efficacy of DBS near the fornix. Early results from these studies indicated that patients who received fornix DBS experienced an improvement in memory and quality of life, yet the mechanisms behind this effect remain controversial. It is known that transmission between the medial limbic and corticolimbic circuits plays an integral role in declarative memory, and dysfunction at the circuit level results in various forms of dementia, including AD. Here, we aimed to determine the potential underlying mechanism of fornix DBS by examining the functional circuitry and brain structures engaged by fornix DBS. METHODS: A multimodal approach was employed to examine global and local temporal changes that occur in an anesthetized swine model of fornix DBS. Changes in global functional activity were measured by functional MRI (fMRI), and local neurochemical changes were monitored by fast scan cyclic voltammetry (FSCV) during electrical stimulation of the fornix. Additionally, intracranial microinfusions into the nucleus accumbens (NAc) were performed to investigate the global activity changes that occur with dopamine and glutamate receptor-specific antagonism. RESULTS: Hemodynamic responses in both medial limbic and corticolimbic circuits measured by fMRI were induced by fornix DBS. Additionally, fornix DBS resulted in increases in dopamine oxidation current (corresponding to dopamine efflux) monitored by FSCV in the NAc. Finally, fornix DBS-evoked hemodynamic responses in the amygdala and hippocampus decreased following dopamine and glutamate receptor antagonism in the NAc. CONCLUSIONS: The present findings suggest that fornix DBS modulates dopamine release on presynaptic dopaminergic terminals in the NAc, involving excitatory glutamatergic input, and that the medial limbic and corticolimbic circuits interact in a functional loop.

Bilateral pallidal stimulation for "sticking-out tongue" feature in patients with primary focal tongue protrusion dystonia.

INTRODUCTION: Tongue protrusion dystonia can cause difficulty with speech, mastication, breathing, and swallowing. Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is a widespread therapeutic alternative for treating medically refractory dystonia. To our knowledge, detailed reports regarding DBS for tongue protrusion dystonia are rare. In this report, we describe two patients with "sticking out" tongue protrusion who had undergone bilateral GPi DBS. METHODS: Operations were performed with surface electromyographic (EMG) monitoring, microelectrode recording, and macrostimulation to identify the point at which tongue kinetic cells respond most effectively. The most effective location for active contacts was identified according to burst EMG response in the posteroventral GPi. RESULTS: Two years after DBS, total Burke, Fahn, and Marsden Dystonia Rating Scale scores of two patients were improved from 12.5 to 1 (92.0%) and from 13 to 1 (92.3%), respectively. One 58-year-old woman who lost 7 kg weight from not eating well improved enough to eat solid food and became free from choking. Another 54-year-old woman who had dysarthria and mumbled could speak more fluently and would not have complained difficulty in reading any more. CONCLUSION: Stimulation on posteroventral GPi for patients with idiopathic "sticking-out" tongue movement changes EMG pattern in orofacial muscles. This fact supports a reason for modulation of unknown circuit connecting tongue-specific area in motor cortex, and basal ganglia.

Simultaneous thalamic and posterior subthalamic electrode insertion with single deep brain stimulation electrode for essential tremor.

OBJECTIVES: The optimal target location of deep brain stimulation (DBS) is the subject of some controversy. We implanted electrodes that could stimulate both posterior subthalamic area (PSA) and ventralis intermedius nucleus of thalamus (Vim), and examined the benefits of bilateral DBS of Vim, PSA, and Vim + PSA in patients with essential tremor (ET). MATERIALS AND METHODS: Electrodes were inserted into the Vim and PSA in ten hemispheres of five consecutive patients. All patients were assessed for action tremor, including postural and kinetic tremors, both preoperatively and at six months and one year postoperatively. RESULTS: The preoperative mean postural tremor score was 1.9 (range 1.0-2.5) and kinetic tremor score was 2.6 (range 2.0-3.0). One year after surgery, these scores had decreased significantly to 0.1 (range 0.0-1.0) and 0.6 (range 0.0-1.5), respectively. The postural and kinetic tremor scores at six-months and one-year post-surgery were similar for Vim, PSA, and Vim + PSA stimulation. CONCLUSIONS: We were able to identify the optimal electrode placement site for each patient based on his or her individualized response to the stimulation. Overall, there was no statistically significant difference among the DBS sites in terms of the benefits afforded by the stimulation. We propose that our technique may be a useful surgical method to treat ET.

Impact of ventralis caudalis deep brain stimulation combined with stereotactic bilateral cingulotomy for treatment of post-stroke pain.

Stroke is the third leading cause of death worldwide. As the elderly population grows, interest in the quality of life, management and treatment of patients with post-stroke pain has grown. Pharmacological treatment is usually the first line of management in these patients. However, if medications fail to achieve appropriate pain relief, neuroablative or neuromodulating procedures are used as alternative methods to interrupt the transmission of pain. We performed unilateral ventralis caudalis deep brain stimulation combined with stereotactic bilateral cingulotomy to maximize the effects of treatment for 3 patients with intractable post-stroke pain.

Effects of relative low-frequency bilateral globus pallidus internus stimulation for treatment of cervical dystonia.

OBJECTIVE: To assess the effect of relative lower amplitude and frequency for globus pallidus internus (GPi) deep brain stimulation (DBS) of cervical dystonia (CD). MATERIALS AND METHODS: Between February 2005 and October 2008, 14 patients diagnosed with CD underwent bilateral GPi DBS and all the patients received low-frequency stimulation and were followed for more than 2 years. We activated the implantable pulse generator 3-4 days postoperatively and initial amplitude, pulse width, and frequency were set at 1.5 V, 120 µs, and 70 Hz. The Toronto Western Spasmodic Torticolis Rating Scale (TWSTRS) was applied preoperatively and at 1, 6, 12 and 24 months postoperatively. RESULTS: The overall TWSTRS scores improved 71.2% 2 years postoperatively (p = 0.001). The mean improvement was 78.4% in severity subscores, 68.4% in disability, and 66.8% in pain scores for the 2-year follow-up period. The TWSTRS scores were significantly reduced (p < 0.05), suggesting that the most significant improvement of the TWSTRS scores occurred within 1 month. The final amplitude was 2.9/2.7 V with the pulse width of 147.9/147.9 µs and the frequency of 101.1/100 Hz. CONCLUSION: According to our results, the initial settings of low amplitude and especially relatively low frequency are safe and effective for treatment of CD.

The effect of bilateral globus pallidus internus deep brain stimulation plus ventralis oralis thalamotomy on patients with cerebral palsy.

OBJECTIVE: We compared bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) with bilateral GPi DBS plus ventralis oralis (Vo) thalamotomy to analyze the effect of the combined Vo thalamotomy. METHODS: Between March 2003 and December 2008, 10 patients underwent DBS and/or Vo thalamotomy for treatment of cerebral palsy in our institute of neurosurgery and rehabilitation medicine. Four patients received bilateral posteroventral GPi DBS as group I and 6 patients received GPi DBS plus unilateral thalamotomy as group II. RESULTS: The movement and disability scores of group I improved by 32 and 14.3%, respectively, at the last follow-up compared with baseline. The movement and disability scores of group II improved by 31.5 and 0.18%. The BFMDRS-movement subscores of group II demonstrated statistically significant improvement in the contralateral arm compared to group I (p = 0.042). Body pain, vitality and mental health seemed to improve in group II, in terms of health-related quality of life. CONCLUSIONS: Contrary to our expectations, we were unable to demonstrate clear improvements in overall BFMDRS scores between group I and group II. However, movements of the contralateral upper extremities improved and health-related quality of life in group II showed satisfactory results.

The long-term surgical outcomes of secondary hemidystonia associated with post-traumatic brain injury.

BACKGROUND: The aim was to assess the effect of deep brain stimulation for secondary hemidystonias associated with focal post-traumatic brain injuries. METHODS: Four patients underwent deep brain stimulation for the treatment of medically refractory secondary hemidystonia associated with post-traumatic brain injury. Clinical outcome assessments were based on Burke-Fahn-Marsden Dystonia Rating Scale movement and disability scores. Health-related quality of life was assessed using a 36-item short-form general health survey questionnaire administered preoperatively and at the last follow-up visit. RESULTS: Burke-Fahn-Marsden Dystonia Rating Scale movement scores had improved by 73.2% (range, 38.1-94.1) and disability scores had improved by 75% (range, 60-100) at the 2-year follow-up visit. The health-related quality of life assessment revealed satisfactory results at follow-up, such that body pain, general health, vitality, social functioning, as well as emotional and mental health improved significantly. CONCLUSIONS: Globus pallidus internus deep brain stimulation can be used to modulate and ameliorate secondary hemidystonia associated with focal post-traumatic brain injury.

Outcomes of surgical treatment for hemifacial spasm associated with the vertebral artery: severity of compression, indentation, and color change.

OBJECT: The object of surgical treatment for hemifacial spasm (HFS) is the exclusion of pulsatile neurovascular compression of the root exit zone (REZ). However, spasm persists transiently or permanently in some cases even after complete decompression. In particular, we mainly experience these results when the vertebral artery (VA) is the offender. Hence, we verified color changes of the nerve and indentations from within the operative field in HFS patients with the VA as the offender. So, we reviewed retrospectively the records of those patients who were treated with microvascular decompression (MVD) in order to assess the relationship between operative findings and clinical results. METHODS: A total of 232 patients with HFS associated with the VA were treated with MVD between January 1994 and January 2009 at our institution. The patients were classified into one of the following three categories based on compression severity: Group I, mild; Group II, moderate; Group III, severe. The patients were also classified into one of the following four categories based on the existence of indentation and discoloration of nerve VII: Group A (-/-), B (+/-), C (-/+), or D (+/+). RESULTS: A total of 94.2% and 96.6% of the patients in Groups I and II, respectively, had improved to grades I-II at the last follow-up. The surgical outcomes of Group III were slightly poorer than those of Groups I and II. Group A showed the poorest outcomes with 60% of the patients classified as grades III-IV. In Group B, 98.4% of the patients showed a marked improvement and Groups C and D showed relatively poor outcomes compared with those of Group B. CONCLUSIONS: Severe deviations and color changes of the facial nerves may be the risk factors for poor surgical outcomes. Future studies with larger sample sizes and investigations of the pathophysiology underlying these findings are needed.

Delayed recurrence of hemifacial spasm after successful microvascular decompression: follow-up results at least 5 years after surgery.

BACKGROUND: Microvascular decompression (MVD) for hemifacial spasm (HFS) is regarded as the gold-standard treatment due to its efficacy and durability. However, some patients still suffer from delayed recurrence after initially successful MVD.In this study, we describe our clinical experience in a single institute following up initially successful MVD for HFS 5 or more years after surgery. We analyzed the probability of, risk/predisposing factors for, and timing of delayed recurrence. METHODS: We retrospectively reviewed data from 587 patients meeting our inclusion criteria who underwent MVD for HFS from March, 1999, to June, 2006. We evaluated the time-dependent probability of recurrence and factors affecting delayed recurrence and time of recurrence. RESULTS: The probability of delayed recurrence was 1.0, 1.7, and 2.9 % at 1 year, 2 years, and 5 years after surgery, respectively. Mean time to recurrence was 153.1 months (95 % confidence interval [151.4-154.9]). The probability of late recurrence was increased in patients with co-morbid arterial hypertension (p = 0.036). However, there was a trend towards an association of delayed recurrence with co-existence of young age, male gender, vein or VA offender, and experience of transient facial weakness. CONCLUSIONS: Delayed recurrence of HFS after initially successful MVD is rare; however, there are patients who experience delayed recurrence more than 2 years after MVD, even until 5 years after MVD. Our results suggest that arterial hypertension contributes to late recurrence. We did not find a statistically significant relationship between recurrence and other putative risk/predisposing factors.

Bilateral globus pallidus internus deep brain stimulation for DYT1+ generalized dystonia with previously received bilateral thalamotomy and unilateral pallidotomy.

Ablation of the globus pallidus internus (GPi) and thalamotomy have been extensively used in the past. Posteroventral GPi deep brain stimulation has been considered as a treatment for dystonia. However, to date, there is no report in the literature of any dystonia patient who underwent GPi deep brain stimulation who had previously undergone staged bilateral thalamotomy and unilateral pallidotomy. The authors of the present study have acquired relatively good clinical results, even in patients who previously received bilateral thalamotomy and unilateral pallidotomy for DYT1+ primary generalized dystonia.

A combination procedure with double C-shaped skin incision and dual-floor burr hole method to prevent skin erosion on the scalp and reduce postoperative skin complications in deep brain stimulation.

BACKGROUND: The purpose of this study was to introduce a combination procedure with double C-shaped skin incision and an adjusted dual-floor burr hole to prevent skin complications on the scalp with deep brain stimulation (DBS) surgery. METHODS: Between March 2000 and March 2010, 504 DBS electrodes were implanted in 268 patients. We included both bilateral and unilateral DBS surgery cases for Parkinson's disease, tremor, pain, obsessive-compulsive disorder and intractable seizure accompanied with cranial and IPG insertion procedure, but excluded motor cortex stimulation, and spinal cord stimulation. We used a straight skin incision in 118 patients, double C-shaped skin incision only in 113 patients since March 2006, and combined a double C-shaped skin incision and dual-floor burr hole in 37 patients since August 2009. We compared scalp wound complications and the height subscale of the Vancouver Scar Scale between previous straight or C-shaped skin incision and the combination procedure. RESULTS: We had eight scalp erosions associated with infection (3.0%) and six disconnection (2.2%) cases among 268 patients. Before the use of the double C-skin incision or adjusted dual-floor burr hole technique, we had 5 (4.2%) scalp erosion cases among 118 patients. With the introduction of the C-shaped incision, only 3 patients (2.7%) developed scalp erosion. However, no patient among 37 patients developed scalp erosion after using both double C-shaped skin incision and dual-floor burr hole technique. Scalp bump measured by the height subscale of the Vancouver Scar Scale was more cosmetic in the combination procedure. CONCLUSION: The combination procedure prevents skin complications associated with DBS surgery, with tensile strength, less impaired vascular supply and better cosmetic outcome. This promising approach prevents unwanted skin complications associated with DBS surgery and improves patient satisfaction.

Treatment of secondary dystonia with a combined stereotactic procedure: long-term surgical outcomes.

OBJECTIVE: There is some debate about the effects of pallidal deep brain stimulation (DBS) or lesioning on secondary dystonia. We applied a multimodal method to maximize the treatment effects of deep brain stimulation in patients with secondary dystonia. METHODS: Between March 2003 and January 2009, four patients underwent bilateral globus pallidus internus (GPi) DBS and six patients underwent bilateral GPi DBS plus unilateral thalamotomy for treatment of cerebral palsy (CP). Among the patients with secondary dystonia without CP, five were also treated by DBS. We classified patients with generalized secondary dystonia with cerebral palsy into group I and patients with focal dystonia without CP into group II. Clinical outcome assessments were based on Burke-Fahn-Marsden Dystonia Rating Scale movement and disability scores. Heath-related quality of life was assessed with a 36-item short-form general health survey questionnaire preoperatively and at the last follow-up. RESULTS: The movement and disability scores of group I-A had improved by 32.0% (P = 0.285) and 14.3% (P = 0.593), respectively, at the last follow-up compared with baseline. The movement and disability scores of group I-B had improved by 31.5% and 0.18% at the last follow-up compared with baseline, respectively. In comparison with patients in group I-A, patients in group I-B showed a significant improvement in movement scores for the contralateral arm (P = 0.042). Group II patients showed a marked improvement in movement and disability scores of 77.7% (P = 0.039) and 80.0% (P = 0.041), respectively. CONCLUSIONS: We demonstrated that DBS plus unilateral ventralis oralis thalamotomy for CP patients with fixed states in the upper extremities is useful not only to treat secondary dystonic movement but also to improve quality of life. In group II patients with post-traumatic dystonia and tardive dyskinesia, we achieved excellent clinical outcomes using a stereotactic procedure.

Bilateral subthalamic deep brain stimulation using single track microelectrode recording.

BACKGROUND: Microelectrode recording (MER) is widely used during deep brain stimulation (DBS) procedures because MER can identify structural borders and eloquent structures, localize somatotopic arrangements, and provide an outline of the three-dimensional shapes of target nuclei. However, MER may cause intracranial hemorrhage. We preformed single track MER during DBS procedures, analyzed the accuracy of electrode positioning with MRI, and compared the amount of air and the potential risk of intracranial hemorrhage. METHOD: A total of 46 electrodes were placed in 23 patients who suffered from advanced Parkinson's disease and who underwent bilateral subthalamic nucleus DBS using single track MER. Each patient's Unified Parkinson's Disease Rating Scale (UPDRS) score and levo-dopa equivalent dosage (LED) were estimated pre- and postoperatively. The accuracy of electrode positioning and fontal air thickness was measured by a pre- or postoperative magnetic resonance imaging (MRI) merging technique. FINDINGS: The mean electrode positioning error was 0.92 mm (0.3-2.94 mm). The mean frontal air thickness on postoperative MRI was 3.85 mm (0-10.3 mm), which did not affect the electrode accuracy statistically (p = 0.730). A total of nine electrodes required repositioning after single-track MER because they affected microstimulation or because an abnormally short STN length was observed during MER. In this series, one patient suffered from an intracranial hemorrhage after surgery that appeared to be due to venous infarction rather than related to MER. CONCLUSIONS: Although MER can facilitate accurate positioning of electrodes, multi-track MER may increase the risk of intracranial hemorrhage. The accuracy of electrode positioning appears to be acceptable under single track MER during STN DBS with careful electrophysiological and neurological monitoring. The risk of intracranial hemorrhage appears to be minimal, especially in elderly patients with atrophic brains.

Management of a DBS system in patients with traumatic brain injury: case report.

INTRODUCTION: The use of deep brain stimulation (DBS) is growing. While these patients may suffer from traumatic brain injuries, treatment guidelines for these patients have not yet been reported. This case report demonstrates a strategy for traumatic brain injury after DBS implantation. CLINICAL PRESENTATION: A 46-year-old man underwent bilateral DBS in the posterior subthalamic area for essential tremor, which improved both distal and proximal tremor. Two years later, he underwent emergent hematoma evacuation due to a motor vehicle associated injury. A 23-year-old male patient presented with severe Tourette's syndrome characterized by a vocal and self lip biting motor tic. There was a good effect of chronic bilateral thalamic DBS at CM-Pf. Five months later, he had acute subdural hematoma after a motorcycle accident. Instead of removing stimulation electrodes immediately after traumatic brain injury, the patient was reassessed after recovery. Merged preoperative magnetic resonance images and brain computed tomography images, and clinical reassessments were used to plan future treatment. CONCLUSION: We recommend removing only the hematoma, leaving the electrodes in position, and then reassessing the electrode position using merged images. The clinical correlation with electrode migration also should be checked. If the patient can tolerate stimulation with a minor displacement, the electrodes should be left in position and the stimulation parameter needs to be adjusted. If not, the stimulation electrodes should be deactivated or repositioned appropriately, depending on the patient's conditions.

Centromedian-parafascicular deep brain stimulation induces differential functional inhibition of the motor, associative, and limbic circuits in large animals.

BACKGROUND: Deep brain stimulation (DBS) of the centromedian-parafascicular (CM-Pf) thalamic nuclei has been considered an option for treating Tourette syndrome. Using a large animal DBS model, this study was designed to explore the network effects of CM-Pf DBS. METHODS: The combination of DBS and functional magnetic resonance imaging is a powerful means of tracing brain circuitry and testing the modulatory effects of electrical stimulation on a neuronal network in vivo. With a within-subjects design, we tested the proportional effects of CM and Pf DBS by manipulating current spread and varying stimulation contacts in healthy pigs (n = 5). RESULTS: Our results suggests that CM-Pf DBS has an inhibitory modulating effect in areas that have been suggested as contributing to impaired sensory-motor and emotional processing. The results also help to define the differential neural circuitry effects of the CM and Pf with evidence of prominent sensorimotor/associative effects for CM DBS and prominent limbic/associative effects for Pf DBS. CONCLUSIONS: Our results support the notion that stimulation of deep brain structures, such as the CM-Pf, modulates multiple networks with cortical effects. The networks affected by CM-Pf stimulation in this study reinforce the conceptualization of Tourette syndrome as a condition with psychiatric and motor symptoms and of CM-Pf DBS as a potentially effective tool for treating both types of symptoms.

Assessment of the effects of unilateral electrode dysfunction in patients with Parkinson disease undergoing bilateral subthalamic nucleus deep brain stimulation.

BACKGROUND: Bilateral subthalamic nucleus deep brain stimulation (STN-DBS) is the gold standard surgical treatment for medically intractable Parkinson disease, and unilateral electrodes are reported to have beneficial effects. However, assessment of patients after electrode failure needs to be established. OBJECTIVE: To assess the effects of the remaining unilateral electrode in Parkinson disease after bilateral STN-DBS. METHODS: Between May 2000 and March 2009, 8 patients had unilateral STN-DBS after bilateral STN-DBS. We assessed clinical outcome by comparing the Unified Parkinson Disease Rating Scale (UPDRS) motor score, activities of daily living, levodopa-equivalent daily dosages, and quality of life according to the Short-Form 36 Health Survey between patients with unilateral and bilateral electrodes. RESULTS: Although ipsilateral and axial UPDRS motor scores were compromised, UPDRS motor scores contralateral to the side of the implant remained unaltered after removal of 1 electrode. Although physical aspects of quality of life declined significantly with a unilateral electrode, pain and social functioning were not significantly affected. No significant changes in activities of daily living, Hoehn and Yahr stage, or levodopa-equivalent daily dosage were observed after removal of 1 electrode. CONCLUSION: The UPDRS motor score with unilateral STN-DBS was compromised relative to bilateral STN-DBS for ipsilateral motor and axial symptoms. When 1 electrode is compromised, revision of that electrode will eventually be required, but not immediately in all patients. If a patient tolerates loss of 1 electrode according to motor score while maintaining activities of daily living and quality of life, it is possible to wait and observe the situation instead of immediately revising the electrode.