Faculty Bibliography

SOD1, ANG, TARDBP and FUS mutations have been associated with amyotrophic lateral sclerosis (ALS). Our goal was to extend molecular genetic analysis to newly identified ALS genetic loci and to determine the frequency of mutations, distribution of disease genes, and variant spectrum of these genes in a large United States ALS-phenotype cohort. We screened 1220 probands with an ALS phenotype, referred originally for SOD1 molecular genetic analysis. 1128 SOD1-negative probands were screened for ANG, and 277 and 223 SOD1- and ANG-negative samples were screened for TARDBP and FUS, respectively. One hundred additional probands were specifically screened only for FUS exon 15. We identified a total of 36 different SOD1 mutations, including three novel mutations, in 92 probands. ANG screening identified three mutations, including two novel mutations, and TARDBP screening identified two previously reported TARDBP mutations. We also identified four mutations in FUS, including the reported FUS in-frame deletion, c.430_447del, p.Gly144_Tyr149del, in a patient with inclusion body myositis, and two known FUS missense mutations. From this study, we estimate frequencies for SOD1, ANG, TARDBP and FUS mutations, in this United States cohort, to be 7.5%, 0.71%, 0.72% and 1.9%, respectively. In conclusion, we identify novel variants in SOD1, ANG, TARDBP and FUS, and expand the FUS-associated clinicopathologic phenotype.

Percutaneous balloon compression is a simple and effective treatment for trigeminal neuralgia. It is especially useful in patients with first-division pain because it does not injure the myelinated fibers that mediate the blink reflex. It is most helpful in patients with pain that has spread across multiple divisions because it does not require multiple lesions. It is also helpful in patients with whom it would be difficult to communicate during selective thermal rhizotomy. It is a relatively easy to perform once you understand the principles of the technique.

OBJECTIVE:Functional magnetic resonance imaging and transcranial magnetic stimulation studies suggest that human cortex shows evidence of neuroplasticity. Preclinical studies in rats and monkeys suggest that motor cortical stimulation can enhance plasticity and improve recovery after stroke. This study assesses the safety and preliminary efficacy of targeted subthreshold epidural cortical stimulation delivered concurrently with intensive rehabilitation therapy while using an investigational device in patients with chronic hemiparetic stroke. METHODS:This is a prospective, multicenter, and nonblinded trial randomizing patients to rehabilitation with or without cortical stimulation. Patients aged 20 to 75 years who had had an ischemic stroke at least 4 months previously causing persistent moderate weakness of the arm were included. Functional magnetic resonance imaging localized hand motor function before surgery to place an epidural cortical electrode. Both groups then underwent rehabilitation for 3 weeks after which the electrode was removed. Outcome measures were obtained at baseline, during therapy, and at 1, 4, 8, and 12 weeks postprocedure. RESULTS:Ten patients were randomized; six patients to surgery, four to the control group. No patient deaths, neurological deterioration, or seizures occurred. There were two infections from nonprotocol-related causes. Of the eight patients completing the treatment, the stimulation plus rehabilitation group improved significantly better than controls in the Upper Extremity Fugl-Meyer (P = 0.003 overall) and the hand function score of the Stroke Impact Scale (P =0.001 overall). CONCLUSION/CONCLUSIONS:The technique of cortical stimulation to enhance stroke recovery is well tolerated and safe.

Thioredoxin1 (Trx1) inhibits hypertrophy and exhibits protective functions in the heart. To elucidate further the cardiac functions of Trx1, we used a DNA microarray analysis, with hearts from transgenic mice with cardiac- specific overexpression of Trx1 (Tg-Trx1, n = 4) and nontransgenic controls (n = 4). Expression of a large number of genes is regulated in Tg-Trx1, with a greater number of genes downregulated, versus upregulated, at high-fold changes. The peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1gamma) gene was among the top 50 significantly upregulated genes. By pathway analyses, we found that genes involved in both mitochondrial oxidative phosphorylation and the TCA cycle were upregulated in Tg-Trx1. We confirmed upregulation of cytochrome c oxidase (COX) components and mitochondrial transcription factor A in Tg-Trx1. The activity of citrate synthase and COX and the cardiac ATP content were significantly higher in Tg-Trx1. A transcription factor binding-site analysis showed that upregulated genes frequently contained binding sites for nuclear respiratory factor 1 (NRF1). Expression of NRF1 and PGC-1gamma was upregulated in Tg-Trx1, and Trx1 stimulated the transcriptional activity of NRF1 and NRF2 in cardiac myocytes. These results suggest that, in cardiac myocytes, Trx1 upregulates mitochondrial proteins and enhances mitochondrial functions, possibly through PGC-1alpha and NRFs.

OBJECTIVE:Functional magnetic resonance imaging and transcranial magnetic stimulation studies suggest that human cortex shows evidence of neuroplasticity. Preclinical studies in rats and monkeys suggest that motor cortical stimulation can enhance plasticity and improve recovery after stroke. This study assesses the safety and preliminary efficacy of targeted subthreshold epidural cortical stimulation delivered concurrently with intensive rehabilitation therapy while using an investigational device in patients with chronic hemiparetic stroke. METHODS:This is a prospective, multicenter, and nonblinded trial randomizing patients to rehabilitation with or without cortical stimulation. Patients aged 20 to 75 years who had had an ischemic stroke at least 4 months previously causing persistent moderate weakness of the arm were included. Functional magnetic resonance imaging localized hand motor function before surgery to place an epidural cortical electrode. Both groups then underwent rehabilitation for 3 weeks after which the electrode was removed. Outcome measures were obtained at baseline, during therapy, and at 1, 4, 8, and 12 weeks postprocedure. RESULTS:Ten patients were randomized; six patients to surgery, four to the control group. No patient deaths, neurological deterioration, or seizures occurred. There were two infections from nonprotocol-related causes. Of the eight patients completing the treatment, the stimulation plus rehabilitation group improved significantly better than controls in the Upper Extremity Fugl-Meyer (P = 0.003 overall) and the hand function score of the Stroke Impact Scale (P = 0.001 overall). CONCLUSION/CONCLUSIONS:The technique of cortical stimulation to enhance stroke recovery is well tolerated and safe.

Improvement of motor activity may occur after stroke. It may be because of recovery of marginally functional neurons. It may also occur by relearning, a process that strengthens existing pathways and may lead to new functional or structural changes- neuroplasticity. Clinical investigation into the treatment of chronic pain after thalamic infarction has shown improvement in motor function when pain relief is achieved with motor cortex stimulation. More recently, laboratory studies in rats and primates demonstrate significant improvement in forelimb reaching tasks in rats and primates after induced ischemic cortical infarction when rehabilitation is paired with stimulation of the injured cortex and cortical margin at low frequency (50 Hz). Structural changes have also been observed. Dendritic density in layer V of the cortex near the lesion increases after cortical stimulation, consistent with a restorative cortical plasticity. Also, stimulation combined with rehabilitation increases the area of the injured cortex from which movements can be evoked in response to stimulation of the injured cortex in rats. Unilateral cortical stimulation reduces secondary cortical hyperexcitability in the impaired hemisphere after stroke. These findings form the basis for the first clinical study motor cortex stimulation after chronic stroke in humans. A prospective, randomized multicenter study of subthreshold motor cortical electrical stimulation during rehabilitation in patients has been completed. The eight patients entered into this study had weakness from a stroke that occurred at least four months before enrollment. Results demonstrate that the treatment is safe. In addition, there was significant improvement in upper extremity function. These improvements persisted through the 12-week follow-up assessment period after completion of stimulation and rehabilitation. Recently, non-invasive transcranial magnetic stimulation of the motor cortex demonstrates improvements in hand function that persist after stimulation for at least 25 minutes. Such work represents a paradigm shift in the approach towards rehabilitation of the stroke-injured brain away from pharmacologic flooding of neuronal receptors, instead towards targeted physiologic stimulation.

OBJECT/OBJECTIVE:Percutaneous balloon compression is an effective and technically simple method for treating trigeminal neuralgia (TN). Nevertheless, dysesthesias (10-20%) and masseter muscle weakness (66%) following the procedure have been noted. The purpose of this study was to evaluate the results of testing TN with percutaneous balloon compression aided by intraluminal pressure monitoring. METHODS:In this study the authors review the results and complications associated with percutaneous balloon compression by using intraluminal pressure monitoring data obtained in 65 procedures performed in 56 consecutive patients over 4 years. The mean patient age was 71 years (range 37-92 years), and the mean follow-up duration was 17 months (range 3-38 months). The mean intraluminal compression pressure was (1160 +/- 62 mm Hg), and the mean duration of compression was 1.15 +/- 0.27 minutes. The trigeminal depressor response was observed in 60 (92%) of 65 procedures, and initial pain relief occurred in 92% of patients. The recurrence rate in patients who had initial relief was 16% (nine of 56). The mean time until recurrence in patients who experienced pain relief after surgery was 13 months (range 3-23 months). Mild numbness immediately after surgery was observed in 83% of patients. At the most recent evaluation, 17% of patients reported persistent, nontroublesome numbness and none had moderate or severe numbness. Minor dysesthesia was present in two patients (4%). Mild masseter muscle weakness occurred in 24% of patients and resolved within a maximum period of 1 year. No patient experienced anesthesia dolorosa, corneal keratitis, or other cranial nerve deficits. These morbidity rates are lower than the incidence reported in the literature when pressure monitoring is not used. CONCLUSIONS:These data show that by monitoring compression pressure and limiting the duration of compression, it is possible to reduce the incidence of dysesthesias, severe numbness, and masseter weakness after surgery without increasing the rate of recurrent pain in patients with classic TN.

BACKGROUND AND PURPOSE/OBJECTIVE:An investigational trial examined safety and efficacy of targeted subthreshold cortical stimulation in patients with chronic stroke. The anatomical location for the target, hand motor area, varies across subjects, and so was localized with functional MRI (fMRI). This report describes the experience of incorporating standardized fMRI into a multisite stroke trial. METHODS:At 3 enrollment centers, patients moved (0.25 Hz) the affected hand during fMRI. Hand motor function was localized at a fourth center guiding intervention for those randomized to stimulation. RESULTS:The fMRI results were available within 24 hours. Across 12 patients, activation site variability was substantial (12, 23, and 11 mm in x, y, and z directions), exceeding stimulating electrode dimensions. CONCLUSIONS:Use of fMRI to guide decision-making in a clinical stroke trial is feasible.

OBJECTIVE:For more than a decade, motor cortex stimulation has been used to treat difficult central and peripheral neuropathic pain syndromes. This prospective study uses the McGill Pain Questionnaire, a visual analog scale (VAS) score, and an inventory of drug consumption to review the results of treating patients with trigeminal neuropathic pain via motor cortex stimulation. METHODS:Ten patients underwent motor cortex stimulation between 1999 and 2002. Implantation was performed via intraoperative neuronavigation and cortical mapping for stimulation site targeting. Nine patients had trigeminal neuropathic pain from postherpetic neuralgia, surgical injury, or unknown cause, and one patient had pain of central origin. Patients were evaluated with multimodality scales before, immediately after, and at designated intervals after surgery. Eight patients underwent permanent implantation after a trial evaluation. In two patients, the stimulating electrodes were removed after an unsuccessful trial. One of these patients had a lateral medullary infarct leading to central pain, and in another patient, there was no explanation for the pain. RESULTS:The average duration of pain before surgery was 6 years. Postoperatively, there was an 88% rate of immediate pain relief (>50% on VAS) and a 75% rate of pain relief at mean follow-up of 10 months (range, 3-24 mo). Mean preoperative McGill Pain Questionnaire total pain rating index was 57 (higher than that observed in causalgia) for patients who did not undergo implantation and 53 for those who underwent implantation. Mean McGill Pain Questionnaire pain rating index at mean follow-up of 10 months was 24 (55% decrease). Mean VAS preoperatively was 9 in patients with stimulator implants and 8 in those whose stimulator was removed after the trial. Immediate postoperative mean VAS score was 1. This score stabilized 3 months after surgery. Patients with implanted stimulators reduced their pain medication dose by a mean of more than 50%. Three patients with facial weakness and sensory loss regained both strength and discriminative sensation during stimulation. In another patient, dysarthria improved. In a review of the literature, 29 (76%) of 38 patients with neuropathic facial pain treated with motor cortex stimulation achieved greater than 50% pain relief. CONCLUSION/CONCLUSIONS:These results provide further support for the use of motor cortex stimulation in facial neuropathic pain and document pain improvement as measured by multidimensional scales. Observations of motor and sensory improvements during stimulation suggest that stimulation alters cortical plasticity and inhibits thalamic hyperactivity.