Revision Surgery of Deep Brain Stimulation Leads.

INTRODUCTION: Deep brain stimulation (DBS) is widely used for various movement disorders. DBS lead revisions are becoming more common as the indications and number of cases increases. METHODS: Patients undergoing DBS lead revisions at a single institution were retrospectively analyzed based on diagnosis, reason for revision, where the lead was relocated, and surgical technique. RESULTS: We reviewed 497 consecutive DBS lead placements and found that there was need for 25 DBS lead revisions with at least six months of follow-up. Loss of efficacy and development of adverse effects over time were the most common reasons for lead revision across all diagnosis. Lead malfunction was the least common. Ten patients requiring 19 DBS lead revisions that underwent their original surgery at another institution were also analyzed. Surgical technique dictated replacing with a new lead while maintaining brain position and tract with the old lead until final placement. Methods to seal exposed wire were developed. CONCLUSION: Surgical technique, as well as variable options are important in lead revision and can be dictated based on reason for revision. Over time patients who have had adequate relief with DBS placement may experience loss of efficacy and development of adverse effects requiring revision of the DBS lead to maintain its effects.

Long-Term Evaluation of Changes in Operative Technique and Hardware-Related Complications With Deep Brain Stimulation.

BACKGROUND: Deep brain stimulation is the most frequent neurosurgical procedure for movement disorders. OBJECTIVE: While this elective procedure carries a low-risk profile, it is not free of complications. As a new procedure, the pattern of complications changed with experience and modification of surgical technique and equipment. METHODS: This review analyzes the most common hardware-related complications that may occur and techniques to avoid them. It is a retrospective review of 432 patients undergoing 1077 procedures over a 14-year period by one surgeon with emphasis on the analysis of surgical technique and the changes over time. Comparisons were made pre and postimplementation of different surgical techniques over different time periods. The epochs relate to the learning curve, new equipment, and new techniques. RESULTS: Overall lead revision was observed at 5.7%, extension revision at 3.2%, infection rate at 1.2%, infarct without intracerebral hemorrhage at 0.8%, and intracerebral hemorrhage at 2.5% with a permanent deficit of 0.2%. An analysis and change in surgical technique which involved isolating the lead from the skin surface at both the cranial and retro-auricular incision also demonstrated a substantial decrease in lead fracture rate and infection rate. There was no mortality. CONCLUSION: This large series of patients and long-term follow-up demonstrates that risks are very low in comparison with other neurosurgical procedures, but DBS is still an elective procedure that necessitates extensive care and precision. In a rapidly evolving field, attention to surgical technique is imperative and will keep rates of complications at a minimum.

Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson's disease.

Parkinson's disease (PD) is a multifocal degenerative disorder for which there is no cure. The majority of cases are sporadic with unknown etiology. Recent data indicate that untreated patients with de novo PD have increased colonic permeability and that both de novo and premotor patients have pathological expression of α-synuclein (α-syn) in their colon. Both endpoints potentially can serve as disease biomarkers and even may initiate PD events through gut-derived, lipopolysaccharide (LPS)-induced neuronal injury. Animal models could be ideal for interrogating the potential role of the intestines in the pathogenesis of PD; however, few current animal models of PD encompass these nonmotor features. We sought to establish a progressive model of PD that includes the gastrointestinal (GI) dysfunction present in human patients. C57/BL6 mice were systemically administered one dose of either LPS (2.5 mg/kg) or saline and were sacrificed in monthly intervals (n = 5 mice for 5 months) to create a time-course. Small and large intestinal permeability was assessed by analyzing the urinary output of orally ingested sugar probes through capillary column gas chromatography. α-Syn expression was assessed by counting the number of mildly, moderately, and severely affected myenteric ganglia neurons throughout the GI tract, and the counts were validated by quantitative optical density measurements. Nigrostriatal integrity was assessed by tyrosine hydroxylase immunohistochemistry stereology and densitometry. LPS caused an immediate and progressive increase in α-syn expression in the large intestine but not in the small intestine. Intestinal permeability of the whole gut (large and small intestines) progressively increased between months 2 and 4 after LPS administration but returned to baseline levels at month 5. Selective measurements demonstrated that intestinal permeability in the small intestine remained largely intact, suggesting that gut leakiness was predominately in the large intestine. Phosphorylated serine 129-α-syn was identified in a subset of colonic myenteric neurons at months 4 and 5. Although these changes were observed in the absence of nigrostriatal degeneration, an abrupt but insignificant increase in brainstem α-syn was observed that paralleled the restoration of permeability. No changes were observed over time in controls. LPS, an endotoxin used to model PD, causes sequential increases in α-syn immunoreactivity, intestinal permeability, and pathological α-syn accumulation in the colon in a manner similar to that observed in patients with PD. These features are observed without nigrostriatal degeneration and incorporate PD features before the motor syndrome. This allows for the potential use of this model in testing neuroprotective and disease-modifying therapies, including intestinal-directed therapies to fortify intestinal barrier integrity.

A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer's disease.

BACKGROUND: Nerve growth factor (NGF) is an endogenous neurotrophic-factor protein with the potential to restore function and to protect degenerating cholinergic neurons in Alzheimer's disease (AD), but safe and effective delivery has proved unsuccessful. METHODS: Gene transfer, combined with stereotactic surgery, offers a potential means to solve the long-standing delivery obstacles. An open-label clinical trial evaluated the safety and tolerability, and initial efficacy of three ascending doses of the genetically engineered gene-therapy vector adeno-associated virus serotype 2 delivering NGF (AAV2-NGF [CERE-110]). Ten subjects with AD received bilateral AAV2-NGF stereotactically into the nucleus basalis of Meynert. RESULTS: AAV2-NGF was safe and well-tolerated for 2 years. Positron emission tomographic imaging and neuropsychological testing showed no evidence of accelerated decline. Brain autopsy tissue confirmed long-term, targeted, gene-mediated NGF expression and bioactivity. CONCLUSIONS: This trial provides important evidence that bilateral stereotactic administration of AAV2-NGF to the nucleus basalis of Meynert is feasible, well-tolerated, and able to produce long-term, biologically active NGF expression, supporting the initiation of an ongoing multicenter, double-blind, sham-surgery-controlled trial.

Displacement of a deep brain stimulator lead during placement of an additional ipsilateral lead.

OBJECTIVE: The use of Deep Brain Stimulation (DBS) has been increasing. It follows the premise of neuromodulation in that it is reversible, as compared to previous lesioning procedures. MATERIALS AND METHODS: Complications with DBS are inherently low and range from short-term complications during surgery such as hemorrhage to long-term complications that include lead fractures and infection. Over time, the authors have experienced indications for additional lead placements or change in position of the lead on the ipsilateral side. There is the inherent possibility of direct contact between leads or the microelectrode. This can lead to malpositioning, displacement of a lead placed previously, and malfunctioning. RESULT: We report a case in which a lead placed previously becomes displaced during microelectrode recording on the ipsilateral side. CONCLUSION: This scenario was corrected and had no clinical or functional complication. Placement of an additional ipsilateral DBS lead can be a safe and effective treatment option.

Intraoperative x-ray to measure distance between DBS leads: A reliability study.

BACKGROUND: Many factors can jeopardize the accuracy of deep brain stimulation (DBS) lead placement. Confirmation of lead placement while the patient is still in the operating room would be advantageous. Intraoperative MRI or CT can identify placement errors, but these modalities can be cost- or time prohibitive. Intraoperative fluoroscopy may give information on the accuracy of the Y coordinate, but the accuracy of the X coordinate usually cannot be confirmed. When an object of known dimensions is present in the brain, such as a unilateral DBS lead, its dimensions can be used to calculate unknown distances. The objective of this study was to determine if intraoperative AP skull x-ray accurately predicts the distance between DBS electrodes using postoperative MRI as the gold standard. METHODS: The distance between 32 pairs of DBS leads was measured by 2 independent raters under blinded conditions on intraoperative AP x-ray and postoperative axial and coronal MRI. Variable x-ray magnification was accounted for using the formula: actual distance between 2 leads = (measured distance between DBS leads)/(average measured length of electrodes) × 7.5 mm. RESULTS: The mean (± SD) distance on x-ray was 22.62 ± 2.23 mm, on axial MRI 22.78 ± 1.90 mm, and on coronal MRI 22.79 ± 2.00 mm. ANOVA revealed no difference based on method (P = .887) or raters (P = .940). The intraclass correlation coefficient showed excellent interrater reliability, CONCLUSIONS: Intraoperative AP x-ray accurately predicts the distance between DBS leads. The technique is especially useful when the location of the first DBS lead relative to the midline is known, such as during staged bilateral procedures or lead replacement procedures.

An evaluation of hardware and surgical complications with deep brain stimulation based on diagnosis and lead location.

INTRODUCTION: Deep brain stimulation is the most frequently performed neurosurgical procedure for movement disorders. This procedure is well tolerated, but not free of complications. Analysis of hardware complications based on patient diagnosis and lead location could prove valuable in recognizing potential pitfalls and patients at higher risk. METHODS: This review analyzes the most common surgery-related complications that may occur based on diagnosis and lead location. Patients were categorized based on diagnosis - Parkinson's disease (PD), dystonia, and essential tremor (ET) - as well as by lead location - subthalamic nucleus (STN), globus pallidus interna (GPi), and ventral intermediate nucleus of the thalamus (Vim). It is a retrospective review of 326 patients undergoing 949 procedures over a 10-year period by one surgeon. Fisher's exact test and χ(2) test were employed and multivariate logistic regression analysis was performed to identify the significant variables of correlation. RESULTS: Overall lead revision was observed at 5.7%, but was observed at 11.9% of GPi lead placements, and 10.7% of dystonia patients with only 4.6% of STN lead placements. Total extension revision was at 2.5%, but observed at 5.3% for dystonia patients and at only 1.4% for ET patients. Overall infection rate was at 1.9% with the highest rate observed in dystonia and ET patients. Postoperative complications with hardware, erosion, infection, and delayed stimulation failure were observed more often with ET and dystonia than with PD. This difference was statistically significant between dystonia and PD (p < 0.03) but not between the other disease entities (p > 0.05). On multivariate analysis, age and gender had no correlation with these complications. PD had significantly fewer complications on forward selection regression analysis (p = 0.004). Asymptomatic intracerebral hemorrhage was at 2.5% with the majority in Vim and none observed in GPi placements. There was only one symptomatic hemorrhage with a permanent deficit. Infarcts were observed at 0.8%. There were no mortalities. CONCLUSION: This large series of patients and long-term follow-up demonstrate that risks of complications are not universal among movement disorder patients. Diagnosis and lead location are important risk stratification factors in determining complications.

Effects of five years of chronic STN stimulation on muscle strength and movement speed.

This study examined the long-term effects of chronic subthalamic nucleus (STN) deep brain stimulation (DBS) using both clinical evaluation and laboratory motor control measures. Over a 5-year time period, changes in the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS) and movement speed and strength at the ankle joint were evaluated on and off STN DBS in eight patients with Parkinson's disease (PD). Four patients were also studied at the elbow joint. Patients with PD originally received unilateral STN DBS between years 2001 and 2003. They were re-evaluated after 5 years of long-term STN DBS between years 2006-2008. At baseline (year 0) and after 5 years, patients with PD were tested off treatment and on STN DBS. In each testing condition, patients performed ballistic, single degree of freedom ankle dorsiflexion and ankle plantarflexion movements and peak velocity was calculated. Patients also performed maximal voluntary contractions at the ankle joint in both directions, and peak torque was calculated. Results showed increased motor UPDRS scores from year 0 to year 5, but STN DBS was efficacious in reducing them. In contrast to the increase in motor UPDRS scores, motor control results showed a marked improvement in peak velocity and peak torque over the 5-year time period in the off treatment condition, and STN DBS was efficacious by improving both peak velocity and peak torque. The current findings suggest that 5 years of chronic STN DBS can have beneficial effects on the motor system over the long term in discrete motor tasks in which maximal effort and maximal neural output is required.

Stimulation-induced parkinsonism after posteroventral deep brain stimulation of the globus pallidus internus for craniocervical dystonia.

The authors report on a patient with craniocervical dystonia who was treated with bilateral GPi stimulation, with excellent improvement in dystonia but at the cost of stimulation-induced, reversible parkinsonism. Stimulation through ventral contacts resulted in maximal relief of craniocervical dystonia but induced considerable hypophonia, bradykinesia, rigidity, freezing, and impaired postural reflexes. Stimulation through dorsal contacts alleviated parkinsonism, but resulted in the return of dystonia. No stimulation parameters could alleviate the dystonia without inducing parkinsonism over the course of his 4-year follow-up.

Effect of short and long term STN stimulation periods on parkinsonian signs.

Currently, no study of subthalamic nucleus (STN) stimulation has compared continuous stimulation with a period of short-term stimulation, which is frequently employed in the clinic and in research studies. Therefore, this study examined the effects of STN stimulation over 90 min (short) and greater than 3 months (long) on the cardinal signs of Parkinson's disease. The 90 min time period immediately followed a 12 hour withdrawal from both STN stimulation and medication. Ten PD patients who received STN stimulation were studied. Bradykinesia, rigidity, and tremor were evaluated using the UPDRS and motor control measures which included peak velocity (bradykinesia), work (rigidity), and amplitude (tremor). Results showed no difference between 90 min and greater than 3 months of STN stimulation for the UPDRS or motor control measures. This finding confirms that the treatment efficacy that is derived from a relatively short time course of stimulation generalizes to longer time periods of high frequency STN stimulation that patients experience in their daily lives. As such, it is reasonable to evaluate the effect of DBS after 90 min of stimulation in clinical trials and research studies.

Factors involved in long-term efficacy of deep brain stimulation of the thalamus for essential tremor.

OBJECT: Although nucleus ventralis intermedius stimulation has been shown to be safe and efficacious in the treatment of essential tremor, there is a subset of patients who eventually lose benefit from their stimulation. Proposed causes for this phenomenon include tolerance, disease progression, and suboptimal location. The goal of this study was to assess the factors that may lead to both stimulation failure, defined as loss of meaningful tremor relief, and less satisfactory outcomes, defined as leads requiring voltages>3.6 V for effective tremor control. METHODS: The authors present their clinical outcomes from 31 leads in 27 patients who had effective tremor control for >1 year following nucleus ventralis intermedius stimulation. All patients postoperatively had a mean decrease in both the writing and drawing subscales of the Fahn-Tolosa-Marin Tremor Rating Scale (p<0.001). RESULTS: After a mean follow-up of 40 months, 22 patients continued to have tremor control with stimulation. Four patients eventually lost efficacy of their stimulation at a mean of 39 months. There was no difference in age, duration of disease, or disease severity between the groups. Examination of perioperative factors revealed that suboptimal anteroposterior positioning as evidenced on intraoperative fluoroscopy occurred significantly more frequently in patients with stimulation failure (p=0.018). In patients with less satisfactory outcomes, no difference was seen between group demographics. Fluoroscopy again revealed suboptimal positioning more frequently in these patients (p=0.005). CONCLUSIONS: This study provides further evidence that suboptimal lead position in combination with disease progression or tolerance may result in less satisfactory long-term outcomes.

Effects of STN DBS on memory guided force control in Parkinson's disease (June 2007).

This study examined the control of elbow force in nine patients with Parkinson's disease when visual feedback was available and when visual feedback was removed to determine how medication (Meds) and unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) affect memory guided force control. Patients were examined in each of four treatment conditions: 1) off treatment; 2) Meds; 3) STN DBS; and 4) Meds plus STN DBS. With visual feedback available, there was no difference in force output across treatment conditions. When visual feedback was removed force output drifted under the target in both the off-treatment and the Meds conditions. However, when on STN DBS or Meds plus STN DBS force output drifted above the target. As such, only STN DBS had a significant effect on force output in the vision removed condition. Increased force output when on STN DBS may have occurred due to disruptions in the basal ganglia-thalamo-cortical circuitry. We suggest that modulation of output of the internal segment of the globus pallidus by STN DBS may drive the effect of STN DBS on memory guided force control.

Effects of STN DBS on rigidity in Parkinson's disease.

We quantified the effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN) and medication on Parkinsonian rigidity using an objective measure of work about the elbow joint during a complete cycle of imposed 1-Hz sinusoidal oscillations. Resting and activated rigidity were analyzed in four experimental conditions: 1) off treatment; 2) on DBS; 3) on medication; and 4) on DBS plus medication. Rigidity at the elbow joint was also assessed using the Unified Parkinson's Disease Rating Scale (UPDRS). We tested ten patients who received STN DBS and ten age-matched neurologically healthy control subjects. The activated rigidity condition increased work in both Parkinson's disease (PD) patients and control subjects. In PD patients, STN DBS reduced both resting and activated rigidity as indicated by work and the UPDRS rigidity score. This is the first demonstration that STN stimulation reduces rigidity using an objective measure such as work. In contrast, the presurgery dose of antiparkinsonian medication did not significantly improve the UPDRS rigidity score and reduced work only in the activated rigidity condition. Our results suggest that STN DBS may be more effective in alleviating rigidity in the upper limb of PD patients than medications administered at presurgery dosage level.

Deep brain stimulation for treatment of obesity in rats.

OBJECT: Given the success of deep brain stimulation (DBS) in a variety of applications (for example, Parkinson disease and essential tremor), other indications for which there is currently little effective therapy are being evaluated for clinical use of DBS. Obesity may be one such indication. Studies of the control of feeding and appetite by neurosurgical lesioning have been completed previously. This study was conducted to test the authors' hypothesis that continuous bilateral stimulatory inhibition of the rat lateral hypothalamic nucleus (LH) would lead to significant and sustained decrease in food intake and subsequent weight loss. METHODS: Sixteen Sprague-Dawley rats were maintained on a high-fat diet. Daily food intake and weight gain were measured for 7 days, at which time the animals underwent stereotactic placement of 0.25-mm-diameter bipolar stimulating electrodes bilaterally in the LH. On postoperative Day 7, eight animals began to receive continuous stimulation of the LH. The remaining eight animals were left unstimulated as the control group. Individual animal weight, food intake, and water intake were monitored daily and continuously throughout the experiment until postoperative Day 24. RESULTS: There was a decreased rate of weight gain after surgery in all animals, but the unstimulated group recovered and resumed a linear weight gain curve. The stimulated group, however, failed to show weight gain and remained below the mean baseline for body mass. There was a significant weight loss between the stimulated and unstimulated groups. On postoperative Day 24, compared with the day of surgery (Day 0), the unstimulated group had a mean weight gain of 13.8%, whereas the stimulated group had a 2.3% weight loss on average (p = 0.001), yielding a 16.1% weight difference between the two groups. CONCLUSIONS: Bilateral electrical stimulatory inhibition of the LH is effective in causing significant and sustained weight loss in rats.

Limits of brain-computer interface. Case report.

Most patients who are candidates for brain-computer interface studies have an injury to their central nervous system and therefore may not be ideal for rigorous testing of the full abilities and limits of the interface. This is a report on a quadriplegic patient who appeared to be a reasonable candidate for intracranial implantation of neurotrophic electrodes. He had significant cortical atrophy in both the motor and parietal cortical areas but was able to generate signal changes on functional magnetic resonance images by thinking about hand movements. Only a few low-amplitude action potentials were obtained, however, and he was unable to achieve single-unit control. Despite this failure, the use of field potentials offered an alternative method of control and allowed him some limited computer interactions. There are clearly limits to what can be achieved with brain-computer interfaces, and the presence of cortical atrophy should serve as a warning for future investigators that less invasive techniques may be a more prudent approach for this type of patient.

Hemisphere-Specific Effects of Subthalamic Nucleus Deep Brain Stimulation on Speaking Rate and Articulatory Accuracy of Syllable Repetitions in Parkinson's Disease.

This study tested the hypothesis that left versus right deep brain stimulation (DBS) of the subthalamic nucleus (STN) would have differential effects on speech. Twenty right-handed individuals with advanced Parkinson's disease (PD) underwent unilateral STN DBS. Ten were operated on the right and 10 on the left hemisphere as indicated by severity of nonspeech motor function. Speech was evaluated before surgery and 3 to 6 months after surgery with stimulator-off and with stimulator-on, with all participants off anti-parkinsonian medication for 12 hours before evaluation. Evaluators and patient speakers were blinded to the stimulator status at the postsurgery evaluations. Motor performance was assessed with UPDRS-III. Each participant produced three samples of diadochokinetic syllables. Syllable rate, syllable and vowel duration, VOT, and F0 were obtained. The diadochokinetic syllables were rated for articulatory accuracy and speaking rate. Twenty graduate clinicians served as judges. The samples were randomly presented via headphones. A mixed ANOVA with repeated measures was used to assess the significance of the changes in UPRS-III scores and speech measures. The results indicated that unilateral STN DBS produced improvement in nonspeech motor function regardless of the side of stimulation. In contrast, the changes in articulatory accuracy and syllable rate associated with the STN DBS were hemisphere specific.

Intrastriatal implantation of human retinal pigment epithelial cells attached to microcarriers in advanced Parkinson disease.

BACKGROUND: Human retinal pigment epithelial (RPE) cells produce levodopa and can be isolated from postmortem human eye tissue, grown in culture, and implanted into the brain attached to microcarriers. These implants ameliorated the motor deficits in rodent and nonhuman primate models of Parkinson disease. OBJECTIVE: To evaluate the safety and efficacy of unilateral implantation of human RPE cells attached to gelatin microcarriers into the putamen contralateral to the more symptomatic side of patients with Parkinson disease. DESIGN: Open-label pilot study. SETTING: A tertiary referral center for movement disorders. PATIENTS: Six patients with advanced Parkinson disease. INTERVENTIONS: We performed stereotactic intrastriatal implantation of approximately 325,000 RPE cells on microcarriers. MAIN OUTCOME MEASURE: Change from baseline to 12 months in the Unified Parkinson's Disease Rating Scale motor subscore with the patients in the practically defined off state (not taking antiparkinsonian medications for at least 12 hours overnight). RESULTS: The implants were well tolerated. We observed an average improvement of 48% at 12 months after implantation in the Unified Parkinson's Disease Rating Scale motor subscore with the patient in the off state, which was sustained through 24 months. Improvement was also observed in activities of daily living, quality of life, and motor fluctuations. No off-state dyskinesias were observed. CONCLUSIONS: Implants of human RPE cells attached to gelatin microcarriers appear to be safe and well tolerated, and they improved motor symptoms in patients with Parkinson disease. On the basis of these results, a randomized, double-blind, placebo-controlled study has been initiated.

Stimulation of the subthalamic nucleus in a patient with Parkinson disease and essential tremor.

BACKGROUND: The preferred surgical target for the treatment of Parkinson disease (PD) is either the internal globus pallidus or the subthalamic nucleus (STN); the target for treatment of essential tremor (ET) is the thalamic subnucleus ventralis intermedius (Vim). Some patients with PD have coexistent ET, and the identification of a single surgical target to treat both parkinsonian motor symptoms and ET would be of practical importance. OBJECTIVE: To describe the use of the STN target in deep brain stimulator (DBS) surgery to treat PD motor symptoms and the action-postural tremor of ET. DESIGN: Case report. PATIENT: A 62-year-old man had a greater than 30-year history of action-postural tremor in both hands, well controlled with beta-blockers for more than 20 years. He developed resting tremor, bradykinesia, and rigidity on his right side that progressed to his left side during the past 10 years. Dopaminergic medication improved his rigidity and bradykinesia, with only mild improvement of his resting tremor and no effect on his action-postural tremor. INTERVENTIONS: Left pallidotomy followed by placement of a left DBS in the Vim and subsequent placement of a right STN DBS. MAIN OUTCOME MEASURES: Control of symptoms of PD and ET. RESULTS: The left pallidotomy controlled the patient's parkinsonian motor symptoms on the right side of his body, but did not affect the action-postural component of his tremor. The symptoms on the left side of the body, including both an action-postural and a resting tremor (as well as the rigidity and bradykinesia), improved after placement of a single right STN DBS. CONCLUSION: Placement of an STN DBS should be considered as the procedure of choice for surgical treatment of patients with a combination of PD and ET.

Effects of subthalamic nucleus stimulation and medication on resting and postural tremor in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and antiparkinsonian medication have proved to be effective treatments for tremor in Parkinson's disease. To date it is not known how and to what extent STN DBS alone and in combination with antiparkinsonian medication alters the pathophysiology of resting and postural tremor in idiopathic Parkinson's disease. The purpose of this study was to examine the effects of STN DBS and antiparkinsonian medication on the neurophysiological characteristics of resting and postural hand tremor in Parkinson's disease. Resting and postural hand tremor were recorded using accelerometry and surface electromyography (EMG) from 10 Parkinson's disease patients and 10 matched control subjects. The Parkinson's disease subjects were examined under four treatment conditions: (i) off treatment; (ii) STN DBS; (iii) medication; and (iv) medication plus STN DBS. The amplitude, EMG frequency, regularity, and 1-8 Hz tremor-EMG coherence were analysed. Both STN DBS and medication reduced the amplitude, regularity and tremor-EMG coherence, and increased the EMG frequency of resting and postural tremor in Parkinson's disease. STN DBS was more effective than medication in reducing the amplitude and increasing the frequency of resting and postural tremor to healthy physiological levels. These findings provide strong evidence that effective STN DBS normalizes the amplitude and frequency of tremor. The findings suggest that neural activity in the STN is an important modulator of the neural network(s) responsible for both resting and postural tremor genesis in Parkinson's disease.

Nerve Growth Factor Gene Therapy: Activation of Neuronal Responses in Alzheimer Disease.

IMPORTANCE: Alzheimer disease (AD) is the most common neurodegenerative disorder and lacks effective disease-modifying therapies. In 2001, we initiated a clinical trial of nerve growth factor (NGF) gene therapy in AD, the first effort at gene delivery in an adult neurodegenerative disorder. This program aimed to determine whether a nervous system growth factor prevents or reduces cholinergic neuronal degeneration in patients with AD. We present postmortem findings in 10 patients with survival times ranging from 1 to 10 years after treatment. OBJECTIVE: To determine whether degenerating neurons in AD retain an ability to respond to a nervous system growth factor delivered after disease onset. DESIGN, SETTING, AND PARTICIPANTS: Patients in this anatomicopathological study were enrolled in clinical trials from March 2001 to October 2012 at the University of California, San Diego, Medical Center in La Jolla. Ten patients with early AD underwent NGF gene therapy using ex vivo or in vivo gene transfer. The brains of all 8 patients in the first phase 1 ex vivo trial and of 2 patients in a subsequent phase 1 in vivo trial were examined. MAIN OUTCOMES AND MEASURES: Brains were immunolabeled to evaluate in vivo gene expression, cholinergic neuronal responses to NGF, and activation of NGF-related cell signaling. In 2 patients, NGF protein levels were measured by enzyme-linked immunosorbent assay. RESULTS: Among 10 patients, degenerating neurons in the AD brain responded to NGF. All patients exhibited a trophic response to NGF in the form of axonal sprouting toward the NGF source. Comparing treated and nontreated sides of the brain in 3 patients who underwent unilateral gene transfer, cholinergic neuronal hypertrophy occurred on the NGF-treated side (P < .05). Activation of cellular signaling and functional markers was present in 2 patients who underwent adeno-associated viral vectors (serotype 2)-mediated NGF gene transfer. Neurons exhibiting tau pathology and neurons free of tau expressed NGF, indicating that degenerating cells can be infected with therapeutic genes, with resultant activation of cell signaling. No adverse pathological effects related to NGF were observed. CONCLUSIONS AND RELEVANCE: These findings indicate that neurons of the degenerating brain retain the ability to respond to growth factors with axonal sprouting, cell hypertrophy, and activation of functional markers. Sprouting induced by NGF persists for 10 years after gene transfer. Growth factor therapy appears safe over extended periods and merits continued testing as a means of treating neurodegenerative disorders.