Jin Woo Chang

Highly efficient and large-scale generation of functional dopamine neurons from human embryonic stem cells

We developed a method for the efficient generation of functional dopaminergic (DA) neurons from human embryonic stem cells (hESCs) on a large scale. The most unique feature of this method is the generation of homogeneous spherical neural masses (SNMs) from the hESC-derived neural precursors. These SNMs provide several advantages: (i) they can be passaged for a long time without losing their differentiation capability into DA neurons; (ii) they can be coaxed into DA neurons at much higher efficiency than that from previous reports (86% tyrosine hydroxylase-positive neurons/total neurons); (iii) the induction of DA neurons from SNMs only takes 14 days; and (iv) no feeder cells are required during differentiation. These advantages allowed us to obtain a large number of DA neurons within a short time period and minimized potential contamination of unwanted cells or pathogens coming from the feeder layer. The highly efficient differentiation may not only enhance the efficacy of the cell therapy but also reduce the potential tumor formation from the undifferentiated residual hESCs. In line with this effect, we have never observed any tumor formation from the transplanted animals used in our study. When grafted into a parkinsonian rat model, the hESC-derived DA neurons elicited clear behavioral recovery in three behavioral tests. In summary, our study paves the way for the large-scale generation of purer and functional DA neurons for future clinical applications.

Factors related to complete occlusion of arteriovenous malformations after gamma knife radiosurgery

The purpose of this paper was to note a potential source of error in magnetic resonance (MR) imaging. Magnetic resonance images were acquired for stereotactic planning for GKS of a vestibular schwannoma in a female patient. The images were acquired using three-dimensional sequence, which has been shown to produce minimal distortion effects. The images were transferred to the planning workstation, but the coronal images were rejected. By examination of the raw data and reconstruction of sagittal images through the localizer side plate, it was clearly seen that the image of the square localizer system was grossly distorted. The patient was returned to the MR imager for further studies and a metal clasp on her brassiere was identified as the cause of the distortion.A-60-year-old man with medically intractable left-sided maxillary division trigeminal neuralgia had severe cardiac disease, was dependent on an internal defibrillator and could not undergo magnetic resonance imaging. The patient was successfully treated using computerized tomography (CT) cisternography and gamma knife radiosurgery. The patient was pain free 2 months after GKS. Contrast cisternography with CT scanning is an excellent alternative imaging modality for the treatment of patients with intractable trigeminal neuralgia who are unable to undergo MR imaging.The authors describe acute deterioration in facial and acoustic neuropathies following radiosurgery for acoustic neuromas. In May 1995, a 26-year-old man, who had no evidence of neurofibromatosis Type 2, was treated with gamma knife radiosurgery (GKS; maximum dose 20 Gy and margin dose 14 Gy) for a right-sided intracanalicular acoustic tumor. Two days after the treatment, he developed headache, vomiting, right-sided facial weakness, tinnitus, and right hearing loss. There was a deterioration of facial nerve function and hearing function from pretreatment values. The facial function worsened from House-Brackmann Grade 1 to 3. Hearing deteriorated from Grade 1 to 5. Magnetic resonance (MR) images, obtained at the same time revealed an obvious decrease in contrast enhancement of the tumor without any change in tumor size or peritumoral edema. Facial nerve function improved gradually and increased to House-Brackmann Grade 2 by 8 months post-GKS. The tumor has been unchanged in size for 5 years, and facial nerve function has also been maintained at Grade 2 with unchanged deafness. This is the first detailed report of immediate facial neuropathy after GKS for acoustic neuroma and MR imaging revealing early possibly toxic changes. Potential explanations for this phenomenon are presented.In clinical follow-up studies after radiosurgery, imaging modalities such as computerized tomography (CT) and magnetic resonance (MR) imaging are used. Accurate determination of the residual lesion volume is necessary for realistic assessment of the effects of treatment. Usually, the diameters rather than the volume of the lesion are measured. To determine the lesion volume without using stereotactically defined images, the software program VOLUMESERIES has been developed. VOLUMESERIES is a personal computer-based image analysis tool. Acquired DICOM CT scans and MR image series can be visualized. The region of interest is contoured with the help of the mouse, and then the system calculates the volume of the contoured region and the total volume is given in cubic centimeters. The defined volume is also displayed in reconstructed sagittal and coronal slices. In addition, distance measurements can be performed to measure tumor extent. The accuracy of VOLUMESERIES was checked against stereotactically defined images in the Leksell GammaPlan treatment planning program. A discrepancy in target volumes of approximately 8% was observed between the two methods. This discrepancy is of lesser interest because the method is used to determine the course of the target volume over time, rather than the absolute volume. Moreover, it could be shown that the method was more sensitive than the tumor diameter measurements currently in use. VOLUMESERIES appears to be a valuable tool for assessing residual lesion volume on follow-up images after gamma knife radiosurgery while avoiding the need for stereotactic definition.This study was conducted to evaluate the geometric distortion of angiographic images created from a commonly used digital x-ray imaging system and the performance of a commercially available distortion-correction computer program. A 12 x 12 x 12-cm wood phantom was constructed. Lead shots, 2 mm in diameter, were attached to the surfaces of the phantom. The phantom was then placed inside the angiographic localizer. Cut films (frontal and lateral analog films) of the phantom were obtained. The films were analyzed using GammaPlan target series 4.12. The same procedure was repeated with a digital x-ray imaging system equipped with a computer program to correct the geometric distortion. The distortion of the two sets of digital images was evaluated using the coordinates of the lead shots from the cut films as references. The coordinates of all lead shots obtained from digital images and corrected by the computer program coincided within 0.5 mm of those obtained from cut films. The average difference is 0.28 mm with a standard deviation of 0.01 mm. On the other hand, the coordinates obtained from digital images with and without correction can differ by as much as 3.4 mm. The average difference is 1.53 mm, with a standard deviation of 0.67 mm. The investigated computer program can reduce the geometric distortion of digital images from a commonly used x-ray imaging system to less than 0.5 mm. Therefore, they are suitable for the localization of arteriovenous malformations and other vascular targets in gamma knife radiosurgery.

Anterior cingulotomy for refractory obsessive-compulsive disorder.

Objective: This study was designed to prospectively investigate the efficacy and cognitive adverse effects of stereotactic bilateral anterior cingulotomy as a treatment for refractory obsessive–compulsive (OCD) patients for 12 months.

Bilateral Anterior Cingulotomy for Refractory Obsessive-Compulsive Disorder: Long-Term Follow-Up Results

Objective: To investigate the long-term efficacy and adverse cognitive effects of stereotactic bilateral anterior cingulotomy as a treatment for refractory obsessive-compulsive disorder (OCD) patients. Materials and Methods: Seventeen patients suffering from refractory OCD underwent stereotactic bilateral anterior cingulotomies and were followed for 24 months. The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Clinical Global Impression and other neuropsychological tests were used to assess the efficacy and cognitive changes of cingulotomy. The tests were taken before and 12 and 24 months after surgery. Results: The mean improvement rate of the Y-BOCS score achieved from the baseline was 48%. Eight patients out of 17 met the responder criteria. During the 24-month follow-up, there were no significant adverse effects observed after surgery. Conclusions: Bilateral anterior cingulotomy was effective for the treatment of refractory OCD, and no other significant adverse cognitive effects on long-term follow-up were found.

Unilateral magnetic resonance guided focused ultrasound thalamotomy for essential tremor: practices and clinicoradiological outcomes

Background Several options exist for surgical management of essential tremor (ET), including radiofrequency lesioning, deep brain stimulation and γ knife radiosurgery of the ventralis intermedius nucleus of the thalamus. Recently, magnetic resonance-guided focused ultrasound (MRgFUS) has been developed as a less-invasive surgical tool aimed to precisely generate focal thermal lesions in the brain. Methods Patients underwent tremor evaluation and neuroimaging study at baseline and up to 6 months after MRgFUS. Tremor severity and functional impairment were assessed at baseline and then at 1 week, 1 month, 3 months and 6 months after treatment. Adverse effects were also sought and ascertained by directed questions, neuroimaging results and neurological examination. Results The current feasibility study attempted MRgFUS thalamotomy in 11 patients with medication-resistant ET. Among them, eight patients completed treatment with MRgFUS, whereas three patients could not complete the treatment because of insufficient temperature. All patients who completed treatment with MRgFUS showed immediate and sustained improvements in tremors lasting for the 6-month follow-up period. Skull volume and maximum temperature rise were linearly correlated (linear regression, p=0.003). Other than one patient who had mild and delayed postoperative balance, no patient developed significant postsurgical complications; about half of the patients had bouts of dizziness during the MRgFUS. Conclusions Our results demonstrate that MRgFUS thalamotomy is a safe, effective and less-invasive surgical method for treating medication-refractory ET. However, several issues must be resolved before clinical application of MRgFUS, including optimal patient selection and management of patients during treatment.

Microvascular Decompression for Hemifacial Spasm: A Long-Term Follow-Up of 1,169 Consecutive Cases

We analyzed the records of 1,169 patients with hemifacial spasm (HFS) who underwent microvascular decompression (MVD) and were followed up for more than 6 months from January 1987. The mean follow-up duration was 23.8 months (6–145 months). Excellent surgical outcome was obtained in 90.5% and good in 4.5%, giving an overall success rate of 95.0%. There was statistically significant relationship between vertebral artery (VA) shift and side of symptom. Permanent facial weakness and hearing impairment were 1.4% and 2.3%, respectively. There were no anatomical differences at the root entry zone (REZ) and significant differences of surgical outcome in young HFS (34 patients). Factors such as type of offender, severity of compression on the facial nerve root, and the degree of decompression of the REZ on postoperative MRI did not correlate with surgical outcome.

Unusual causes and presentations of hemifacial spasm.

OBJECTIVETo evaluate unusual possible causes and clinical presentations of hemifacial spasm (HFS). METHODSThe authors reviewed 1642 cases of HFS. Assessments were based on clinical features, 3-dimensional time-of-flight magnetic resonance angiography, and surgical findings. Causes other than neurovascular compression at the root exit zone of the facial nerve were investigated and unusual clinical presentations were noted. RESULTSNine (0.5%) patients had a secondary causative structural lesion, 7 patients had a tumor, and the remaining 2 had a vascular malformation. Direct compression by dolichoectatic vertebrobasilar artery was noted in 12 (0.7%) patients. In 7 (0.4%) patients, only the distal portion of the facial nerve was compressed, and five (0.3%) had only venous compression. Bilateral HFS and tic convulsif were encountered in 7 (0.4%) and 6 (0.37%) patients, respectively. Fifty-six (3.4%) patients were younger than 30 years old at the time of microvascular decompression. CONCLUSIONHFS can result from tumor, vascular malformation, and dolichoectatic artery. Therefore, appropriate preoperative radiological investigations are crucial to achieve a correct diagnosis. The authors emphasize that distal compression or only venous compression can be responsible for persistent or recurrent symptoms postoperatively. In cases of bilateral HFS, a definite differential diagnosis is necessary for appropriate therapy. MVD is recommended as the treatment of choice in patients younger than 30 years old or patients with painful tic convulsif.

Microvascular decompression for hemifacial spasm: analyses of operative complications in 1582 consecutive patients

BACKGROUND Microvascular decompression is the most reliable treatment for HFS, but it may cause complications. The aim was to identify factors affecting the prognosis after MVD and to establish appropriate means to reduce complications. METHOD We retrospectively reviewed 1524 patients with HFS who underwent MVD and were followed for more than 6 months since January 1987. The mean follow-up duration was 30.9 months (6-197 months). RESULTS The effect of MVD was satisfying (excellent or good) in 94.6% (n = 1442). The failure and recurrence rates were 2.1% (n = 32) and 0.4% (n = 6), respectively. Postoperative complications were noted in 545 (35.8%) patients. Among them, facial palsy, hearing deficit, and low cranial nerve palsies were found in 18.6% (n = 283), 7.2% (n = 109), and 2.8% (n = 43), respectively. However, permanent facial weakness, hearing deficit, and lower cranial nerve palsies such as hoarseness and dysphagia were encountered in 1.2% (n = 18), 2.1% (n = 32), and 0.1% (n = 2), respectively. The more immediate and severe the facial palsy was, the more permanent it remained, with statistical significance (P < .05). There was a trend that the more immediate and severe the hearing deficit was, the more permanent the deficit remained, without statistical significance (P = .673). CONCLUSION Early (occurrence within 24 hours after operation) and severe cranial nerve deficits, including facial, hearing, and lower cranial nerve deficits after MVD, entail the risk to stay permanent.

Gamma knife radiosurgery for idiopathic and secondary trigeminal neuralgia

The purpose of this paper was to note a potential source of error in magnetic resonance (MR) imaging. Magnetic resonance images were acquired for stereotactic planning for GKS of a vestibular schwannoma in a female patient. The images were acquired using three-dimensional sequence, which has been shown to produce minimal distortion effects. The images were transferred to the planning workstation, but the coronal images were rejected. By examination of the raw data and reconstruction of sagittal images through the localizer side plate, it was clearly seen that the image of the square localizer system was grossly distorted. The patient was returned to the MR imager for further studies and a metal clasp on her brassiere was identified as the cause of the distortion.A-60-year-old man with medically intractable left-sided maxillary division trigeminal neuralgia had severe cardiac disease, was dependent on an internal defibrillator and could not undergo magnetic resonance imaging. The patient was successfully treated using computerized tomography (CT) cisternography and gamma knife radiosurgery. The patient was pain free 2 months after GKS. Contrast cisternography with CT scanning is an excellent alternative imaging modality for the treatment of patients with intractable trigeminal neuralgia who are unable to undergo MR imaging.The authors describe acute deterioration in facial and acoustic neuropathies following radiosurgery for acoustic neuromas. In May 1995, a 26-year-old man, who had no evidence of neurofibromatosis Type 2, was treated with gamma knife radiosurgery (GKS; maximum dose 20 Gy and margin dose 14 Gy) for a right-sided intracanalicular acoustic tumor. Two days after the treatment, he developed headache, vomiting, right-sided facial weakness, tinnitus, and right hearing loss. There was a deterioration of facial nerve function and hearing function from pretreatment values. The facial function worsened from House-Brackmann Grade 1 to 3. Hearing deteriorated from Grade 1 to 5. Magnetic resonance (MR) images, obtained at the same time revealed an obvious decrease in contrast enhancement of the tumor without any change in tumor size or peritumoral edema. Facial nerve function improved gradually and increased to House-Brackmann Grade 2 by 8 months post-GKS. The tumor has been unchanged in size for 5 years, and facial nerve function has also been maintained at Grade 2 with unchanged deafness. This is the first detailed report of immediate facial neuropathy after GKS for acoustic neuroma and MR imaging revealing early possibly toxic changes. Potential explanations for this phenomenon are presented.In clinical follow-up studies after radiosurgery, imaging modalities such as computerized tomography (CT) and magnetic resonance (MR) imaging are used. Accurate determination of the residual lesion volume is necessary for realistic assessment of the effects of treatment. Usually, the diameters rather than the volume of the lesion are measured. To determine the lesion volume without using stereotactically defined images, the software program VOLUMESERIES has been developed. VOLUMESERIES is a personal computer-based image analysis tool. Acquired DICOM CT scans and MR image series can be visualized. The region of interest is contoured with the help of the mouse, and then the system calculates the volume of the contoured region and the total volume is given in cubic centimeters. The defined volume is also displayed in reconstructed sagittal and coronal slices. In addition, distance measurements can be performed to measure tumor extent. The accuracy of VOLUMESERIES was checked against stereotactically defined images in the Leksell GammaPlan treatment planning program. A discrepancy in target volumes of approximately 8% was observed between the two methods. This discrepancy is of lesser interest because the method is used to determine the course of the target volume over time, rather than the absolute volume. Moreover, it could be shown that the method was more sensitive than the tumor diameter measurements currently in use. VOLUMESERIES appears to be a valuable tool for assessing residual lesion volume on follow-up images after gamma knife radiosurgery while avoiding the need for stereotactic definition.This study was conducted to evaluate the geometric distortion of angiographic images created from a commonly used digital x-ray imaging system and the performance of a commercially available distortion-correction computer program. A 12 x 12 x 12-cm wood phantom was constructed. Lead shots, 2 mm in diameter, were attached to the surfaces of the phantom. The phantom was then placed inside the angiographic localizer. Cut films (frontal and lateral analog films) of the phantom were obtained. The films were analyzed using GammaPlan target series 4.12. The same procedure was repeated with a digital x-ray imaging system equipped with a computer program to correct the geometric distortion. The distortion of the two sets of digital images was evaluated using the coordinates of the lead shots from the cut films as references. The coordinates of all lead shots obtained from digital images and corrected by the computer program coincided within 0.5 mm of those obtained from cut films. The average difference is 0.28 mm with a standard deviation of 0.01 mm. On the other hand, the coordinates obtained from digital images with and without correction can differ by as much as 3.4 mm. The average difference is 1.53 mm, with a standard deviation of 0.67 mm. The investigated computer program can reduce the geometric distortion of digital images from a commonly used x-ray imaging system to less than 0.5 mm. Therefore, they are suitable for the localization of arteriovenous malformations and other vascular targets in gamma knife radiosurgery.

Enhanced expression of glutamate decarboxylase 65 improves symptoms of rat parkinsonian models

In this study, we report the amelioration of parkinsonian symptoms in rat Parkinsons disease (PD) models, as a result of the expression of glutamate decarboxylase (GAD) 65 with a modified cytomegalovirus (CMV) promoter. The transfer of the gene for gamma-amino butryic acid (GAD), the rate-limiting enzyme in gama-amino butrylic acid (GABA) production, has been investigated as a means to increase inhibitory synaptic activity. Electrophysiological evidence suggests that the transfer of the GAD65 gene to the subthalamic nucleus (STN) can change the excitatory output of this nucleus to inhibitory output. Our in vitro results also demonstrated higher GAD65 expression in cells transfected with the JDK promoter, as compared to cells transfected with the CMV promoter. Also, a rat PD model in which recombinant adeno-associated virus-2 (rAAV2)-JDK-GAD65 was delivered into the STN exhibited significant behavioral improvements, as compared to the saline-injected group. Interestingly, we observed that these behavioral improvements were more obvious in rat PD models in which rAAV2-JDK-GAD65 was injected into the STN than in rat PD models in which rAAV2-CMV-GAD65 was injected into the STN. Moreover, according to electrophysiological data, the rAAV2-JDK-GAD65-injected group exhibited more constant improvements in firing rates than did the rAAV2-CMV-GAD65-injected group. These data indicate that the JDK promoter, when coupled with GAD65 expression, is more effective with regard to parkinsonian symptoms than is the CMV promoter.