Frequency-correlated decreases of motor cortex activity associated with subthalamic nucleus stimulation in Parkinson's disease

According to the classical model of basal ganglia organization, deep brain stimulation (DBS) in the subthalamic nucleus (STN) for the treatment of Parkinson's disease (PD) blocks overactive excitatory projections to inhibitory basal ganglia output structures. This would release the break on thalamofrontal neurons alleviating the poverty of movement, the hallmark of PD. Such parallels to a functional lesion certainly simplify the mechanism of STN DBS. Here, we applied parametric analyses of H2(15)O positron emission tomography (PET) scans at rest while systematically varying stimulation frequency in 6 patients with STN DBS for akinetic PD. A strong positive correlation of rCBF to increasing stimulation frequency was detected around the STN bilaterally. More importantly, we show that gradual increases in STN stimulation frequency are tightly correlated with decreases in motor cortex activity. This demonstrates an active modulation of resting activity within the subcortical stimulation target and within motor cortex by STN DBS. Rather than a possible downstream effect, we propose to consider the tight correlations between DBS frequency and motor cortex activity in the context of an upstream modulation of direct efferents to the STN from primary motor and premotor cortices.     

Indication of surgical therapy for Parkinson's disease

We review the current status of surgical treatment of Parkinson's disease (PD). The advantages of deep brain stimulation (DBS) over ablative surgery include reversibility and controllability of stimulation. In addition, DBS carries a smaller risk of side effects, especially when employed bilaterally. DBS of the thalamus is useful to control tremor which is unresponsive to medication. DBS of the globus pallidus internus (GPi) or the subthalamic nucleus (STN) is useful to control wearing off of motor symptoms which is difficult to manage with medication alone. DBS of STN and GPi improves motor function mainly during the off-period. DBS of STN attenuates levodopa-induced dyskinesia through reduction of dopa requirement, whereas DBS of GPi attenuates dopa-induced dyskinesia directly. DBS of STN is also useful to control symptoms of PD in patients who are intolerant to dopa. However, DBS of either STN or GPi cannot reverse advanced symptoms of PD, which are unresponsive to dopa.     

脑深部电刺激治疗帕金森病患者的护理配合

目的：探讨脑深部电刺激（ DBS）治疗帕金森病（ PD）患者手术配合的要点,以期提高临床疗效,减少并发症。方法对2011年3月至2012年10月行DBS手术的187例帕金森病患者,进行缜密、细致的手术配合,并对部分手术方法进行改进。结果187例患者共植入325侧电极,单侧49例,双侧138例,全部患者术后均无颅内血肿和永久神经系统并发症出现。187例患者随访3～27个月,开机不服药和开机服药患者的UPDRSⅢ评分改善率分别为51％和63％,与术前相比,患者术后服用多巴胺类药物的剂量明显减少,平均减少62％。结论 DBS是治疗PD的有效手段。周到细致的手术护理配合对DBS治疗帕金森病的疗效提高具有重要作用。     

Is a failure to recognize an increase in food intake a key to understanding insulin-induced weight gain?

The present study aimed to assess the contribution of energy intake to positive energy balance and weight gain with insulin therapy. Changes in energy intake (self-report and weighed food intake), dietary behavior (auto-questionnaires), resting energy expenditure (REE) (indirect calorimetry), physical activity (accelerometry), and glucosuria were monitored over the first 6 months of insulin therapy in 46 diabetic adults. No change in REE, activity, or glucosuria could explain weight gain in the type 1 (4.1 +/- 0.6 kg, P < 0.0001) or type 2 (1.8 +/- 0.8 kg, P = 0.02) diabetic groups. An increase in energy intake provides the most likely explanation for weight gain with insulin. However, it is not being recognized because of significant underestimation of self-reported food intake, which appears to be associated with increased dietary restraint.     

Postoperative Energy Intake in Patients after Colorectal Cancer Surgery

In a prospective noninterventional study of 75 consecutive patients (mean age 71 ± 12 years) undergoing surgery for colorectal cancer, standard postoperative energy intake was evaluated. Seventeen patients expended 40%–60% of estimated basal energy during hospitalization, 33 patients 60%–80%, 22 patients 80%–100% and three patients 100%–125%. Weight loss was observed in 67 patients (mean loss 4.7 ± 4.4%) during hospitalization. Men had a significantly higher mean total calorie deficit (p < 0.001), and mean weight loss percentage (p < 0.01), compared to women. Preoperative nutritional status, nutrition-associated complications and length of hospital stay did not change the nutritional support and intake. Correlation analyses resulted in significant associations between gender and total calorie deficit (r_s = 0.41, p < 0.01), postoperative weight loss and total calorie deficit (r_s = ?0.32, p<0.01), and between postoperative weight loss and length of stay (r_s = 0.27, p < 0.05). We concluded that the patients' energy intake was insufficient compared to estimated basal energy expenditure. These results suggest a need for individualized nutritional care, based on each patient's energy needs and on registration of daily calorie intake, all with the aim of increasing energy intake postoperatively in standard hospital care.     

Body composition and fuel metabolism after kidney grafting

Abstract. Kidney transplant patients display decreased muscle mass and increased fat mass. Whether this altered body composition is due to glucocorticoid induced altered fuel metabolism is unclear. To answer this question, 16 kidney transplant patients were examined immediately after kidney transplantation (12±4 days, mean ±SEM) and then during months 2, 5, 11 and 16, respectively, by whole body dual energy X-ray absorptiometry (Hologic QDR 1000W) and indirect calorimetry. Results were compared with those of 16 age, sex and body mass index matched healthy volunteers examined only once. All patients received dietary counselling with a step 1 diet of the American Heart Association and were advised to restrict their caloric intake to the resting energy expenditure plus 30%. Immediately after transplantation, lean mass of the trunk was higher by 7±1% (P<0.05) and that of the limbs was lower by more than 10% (P<0.01) in patients than in controls. In contrast, no difference in fat mass and resting energy expenditure could be detected between patients and controls. During the 16 months of observation, total fat mass increased in male (+4.9± 1.5 kg), but not in female patients (0.1 ±0.8 kg). The change in fat mass observed in men was due to an increase in all subregions of the body analysed (trunk, arms + legs as well as head + neck), whereas in women only an increase in head + neck by 9 ±2% (P= 0.05) was detected. Body fat distribution remained unchanged in both sexes over the 16 months of observation. Lean mass of the trunk mainly decreased between days 11 and 42 (P<0.01) and remained stable thereafter. After day 42, lean mass of arms and legs (mostly striated muscle) and head + neck progressively increased over the 14 months of observation by 1.6±0.6 kg (P < 0.05) and 0.4±0.l kg (P < 0.01). respectively. Resting energy expenditure was similar in controls and patients at 42 days (30.0 ±0.7 vs. 31.0±0.9 kcal kg^-1 lean mass) and did not change during the following 15 months of observation. However, composition of fuel used to sustain resting energy expenditure in the fasting state was altered in patients when compared with normal subjects, i.e. glucose oxidation was higher by more than 45% in patients (P<0.01) during the second month after grafting, but gradually declined (P<0.01) over the following 15 months to values similar to those observed in controls. Protein oxidation was elevated in renal transplant patients on prednisone at first measurement, a difference which tended to decline over the study period. In contrast to glucose and protein oxidation, fat oxidation was lower in patients 42 days after grafting (P<0.01), but increased by more than 100% reaching values similar to those observed in controls after 16 months of study. Mean daily dose of prednisone per kg body weight correlated with the three components of fuel oxidation (r>0.93, P<0.01), i.e. protein, glucose and fat oxidation. These results indicate that in prednisone treated renal transplant patients fuel metabolism is regulated in a dose-dependent manner. Moreover, dietary measures, such as caloric and fat intake restriction as well as increase of protein intake, can prevent muscle wasting as well as part of the usually observed fat accumulation. Furthermore, the concept of preferential upper body fat accumulation as consequence of prednisone therapy in renal transplant patients has to be revised.     

Comparison of resting energy expenditures and caloric intake in children with severe burns

Nutritional support is provided to children after severe burn injuries in amounts derived from empirical formulas or measurements of resting energy expenditure. To scrutinize these methods, indirect calorimetry measurements were performed on 74 survivors of burns (greater than or equal to 40% total body surface area) and compared to their actual caloric intake, percent weight change, and optimal caloric requirements formulated from the Curreri and Shriners' equations. These parameters showed that in spite of an initial deficit in actual caloric intake as compared to formulated goals, weight was maintained, whereas resting energy expenditures ranged from 30% to 40% below the actual caloric intake. Furthermore, a subgroup of patients (n = 42) who met +/- 20% of their formulated needs were stratified by extent of burn; this illustrated a significant weight gain in the more severely burned children. In conclusion, nutritional formulas in popular use overestimate caloric requirements in severe burns, whereas resting energy expenditure measurements require an additional factor of 30% to maintain body weight.     

国内脑深部丘脑底核电刺激术治疗帕金森病的meta分析

目的应用meta分析方法,综合评价丘脑底核脑深部电刺激术(STN-DBS)治疗帕金森病(PD)的临床疗效。方法检索国内关于脑深部电刺激术(DBS)治疗PD的研究,对符合纳入标准的文献进行meta分析。结果共纳入9篇文献,总样本量为226例,其中"药物关"状态下对统一帕金森病评分量表(UPDRS)Ⅲ进行评分者226例,对UPDRSⅡ进行评分者159例。"药物开"状态下对UPDRSⅢ进行评分者156例,对UPDRSⅡ进行评分者102例。4种情况下STN-DBS前后合并指标加权均数差(WMD)及其95%CI分别为25.85(16.82~34.88)、17.28(12.37~22.18)、4.29(2.56~6.02)、3.03(0.57~5.48)。meta分析合并结果显示,"药物开"和"药物关"状态下,STN-DBS手术后UPDRSⅢ评分和UPDRSⅡ评分均比手术前显著降低,差异有统计学意义(P0.05)。结论STN-DBS用于治疗PD,能有效改善运动不能、肌肉僵直、步态不稳、姿势平衡性和肌张力障碍、异动症等。     

Normal levels of energy expenditure in patients with reported ‘low metabolism’

The present study examined the hypothesis that patients with apparent diet-resistant obesity have subnormal energy expenditure. Ten biochemically euthyroid patients (eight women and two men), aged 21–76 years, with either excessive gynoid fat distribution or obesity (BMI 23.8–41.0), were referred to the department thought to be suffering from a low metabolic rate syndrome since dietary records showed very low energy intake (<5 MJ day^?1) in combination with failure to lose weight on low-energy diets. Twenty-four-hour energy expenditure (24-h EE), basal energy expenditure (BEE) and sleeping energy expenditure (SEE) were measured in a respiration chamber on a fixed activity programme. The patients consumed a diet containing 37 energy-per cent (E%) fat, 47 E% carbohydrate and 16 E% protein. The individual energy intake was estimated from a previously established algorithm between 24-h EE and fat-free mass (FFM) estimated by bioimpedance. Results were compared with equivalent values in a reference population of 76 subjects ranging from normal weight to obese. No evidence of low metabolism was found in terms of adjusted 24-h EE in the patients with diet resistance when compared with the control group (9263±819 kJ vs. 9211±558 kJ). No differences were found when comparing adjusted BEE and SEE in the two groups (7655±727 vs. 7411±770 kJ 24 h^?1 and 7048±672 vs. 6911±408 kJ 24 h^?1). The physical activity index (PAI) during the chamber stay was likewise within normal values (1.32±0.07 vs. 1.34±0–04; NS).     

深部脑电刺激治疗帕金森病的FDGPET研究

目的研究双侧丘脑底核慢性电刺激术对晚期帕金森病患者脑局部糖代谢的影响及作用机制.方法对7例进行双侧STN DBS的晚期帕金森病患者,在术前和术后1个月电刺激条件下,分别进行18F-脱氧葡萄糖(18F-FDG)PET显像和UPDRS评分,通过SPM进行数据分析.结果 7例患者临床症状明显改善,同时FDG PET显像提示双侧豆状核、脑干、顶枕部、运动前区(BA6)及扣带回的脑代谢增加,而前额叶底部及海马的脑代谢减少(P<0.05).结论双侧STN DBS可使PD患者临床症状改善.FDG PET可作为PD进行STN治疗适应证选择的方法之一.     

Deep brain stimulation for advanced Parkinson's disease

Deep brain stimulation (DBS) is a new and promising technique for the treatment of movement disorders. Medically intractable Parkinson's disease (PD) is one of the most common indications for DBS. There are three possible subcortical targets for PD, depending on the symptomatology (i.e., the motor subdivision of the thalamus, the globus pallidus internus, the subthalamic nucleus [STN]). Thalamic stimulation has been well established as a safe and effective treatment for essential tremor and the tremor associated with PD. Globus pallidus internus and STN DBS are being investigated for the treatment of all the cardinal signs of PD. This article describes the pathophysiology of PD, the surgical treatment history of PD, surgical techniques used for DBS implants, and the role the perioperative nurse has in the care of the patients undergoing these procedures.     

Metabolic and inflammatory responses to pulmonary exacerbation in adults with cystic fibrosis

BACKGROUND: We hypothesized that increased resting energy expenditure in adults with cystic fibrosis was related to chronic inflammation secondary to pulmonary infection and could be modified by treatment of the underlying infection. METHOD: To determine the relationship between resting energy expenditure and the inflammatory and metabolic responses, we studied 22 adults with cystic fibrosis and chronic Pseudomonas aeruginosa infection before and after treatment of a respiratory exacerbation. Resting energy expenditure was measured by indirect calorimetry. Spirometry and circulating concentrations of C-reactive protein, neutrophil elastase alpha1-antiproteinase complex, catecholamines, non-esterified fatty acids and glycerol were determined. RESULTS: The mean (95% confidence interval)% predicted FEV1 was 28.5% (20.6, 36.4) and mean body weight 50.7 kg (47.4, 54.1). Following treatment, 1-s forced expiratory volume (FEV1) and weight increased, while C-reactive protein (P<0.0001) and neutrophil elastase alpha1-antiproteinase complex concentrations (P<0.0001) were reduced. Resting energy expenditure decreased from 6.8 (6.3, 7.2) to 6.25 (5.9, 6.6) MJ day-1 by day 15 (P<0.001). Changes in resting energy expenditure and C-reactive protein were related (r = 0.66, P< 0.0001). Weight gain was inversely related to resting energy expenditure (r = 0.43, P = 0.02) and unrelated to energy intake (r = 0.02, P = 0.47). Post-treatment reduction in norepinephrine was related to changes in heart rate (r = 0.57, P<0.01), resting energy expenditure (r = 0.51, P = 0.001) and non-esterified fatty acids (r = 0.42, P< 0.05). CONCLUSIONS: A parallel reduction in the host inflammatory and catabolic responses followed treatment of a respiratory exacerbation and may have contributed to weight gain.     

A 24‐week randomised controlled trial comparing usual care and metabolic‐based diet plans in obese adults

Background: Usual care (UC) practice for weight management often includes providing standardised, ad libitum, low‐calorie nutrition plans. However, weight loss using such plans appears comparable with metabolic‐based diet (MD) plans that are closer to resting energy expenditure (REE) level. In addition, MD plans are approximately 250–750 kcal/day higher in caloric values compared with UC plans. Therefore, the purpose of this study was to compare weight loss and eating behaviour differences between UC and MD plans. Methods: Seventy‐four obese (30.0–51.7 kg/m²) adults (21–67 years) voluntarily participated in a 24‐week randomised study. UC men and women received a fixed, ad libitum, 1600 and 1200 kcal/day nutrient plan, respectively. MD participants received an individualised treatment plan based from measured REE. Bodyweight and eating behaviours (i.e. intake, restraint and uncontrolled eating) were assessed over time. Results: Intent‐to‐treat analysis indicated no significant difference in weight loss (UC: ?5.7 ± 6.3% vs. MD: ?5.3 ± 7.1% p = 0.67) between groups over time. There was no difference in daily energy intake (UC: 2490 ± 576 kcal/day vs. MD: 2525 ± 475 kcal/day) at 24 weeks between groups. Both groups experienced a significant improvement (p < 0.05) in eating dietary restraint and uncontrolled eating yet there was no difference between groups. Conclusion: From this study, UC calorie plans do not generate more weight loss or improve eating behaviours in comparison with MD calorie plans. As treatment effects are comparable, clinicians can select UC or MD plan options based on clinician and patient preference.     

脑深部电刺激治疗帕金森病的围手术期护理

目的 探讨脑深部电刺激（DBS）治疗帕金森病的护理方法及效果.方法 对我院2006年8月至2008年11月脑深部电刺激治疗的12例原发性帕金森病患者进行严谨的围手术期护理,重点加强患者的心理护理和知识宣教,严密观察病情,积极防范并发症的发生.结果 12例共植入22根电极（单侧2例,双侧10例）,刺激电极植入靶点均为丘脑底核（STN）,全部术后无颅内血肿出现,无感染及永久神经系统并发症,无刺激相关的不良反应;12例患者随访时间2～28个月,术后6个月UPDRSⅢ评分在开机不服药和开机服药的改善率分别是50%和67%.结论 周到细致的围手术期护理是STN-DBS治疗帕金森病良好疗效的保障.     

Evaluation of mechanisms behind elevated energy expenditure in cancer patients with solid tumours

Abstract. The aim of this study was to demonstrate significant factors behind elevated resting energy expenditure in weight-losing cancer patients. There tore, weight-losing cancer patients (n= 60), with normal liver and kidney function tests, were randomized to receive one of four drug treatments for 5 days: (a) Propranolol 80 mg × 2 (β-adreneceptor blockade); (b) Indomethacin 50 mg × 2 (prostaglandin synthesis inhibition); (c) Morphine 5 mg × 3 (pain reliet) or (d) Placebo x 2. A reterence group of healthy well-nourished individuals were examined outside the formal randomization protocol and they received Propranolol 80 mg × 2. The cancer patients were randomized by a computer based algorithm stratifying for measured resting energy expenditure (REE), body composition, biochemical tests, previous therapy, tumour type and tumour stage. Resting energy expenditure was measured by indirect calorimetry in the morning after an overnight fast betore and after drug treatment. β-blockade reduced REE significantly in cancer patients from 1416 ± 95 kcal day^-1 to 1160 ± 63 kcal day^-1 (P <0.02) and from 1472 ± 69 vs. 1398 ± 62 kcal day^-1, (P <0.01) in the well-nourished reterence individuals. The reduction found in cancer patients (10%) was significantly larger than that in the group of reterence patients (5%), (P <0.01). Indomethacin, morphine or placebo did not induce any significant alteration in energy expenditure in our cancer patients. Propranolol treatment was associated with a significant reduction in plasma concentrations of free fatty acids (FFA), but not in plasma glycerol. Our results support the suggestion that adrenergic factors are the most important mediators behind elevated resting energy expenditure in weight-losing cancer patients. Such factors were more important than inflammation and cytokine production related to prostaglandin dependent pathways.     

Distinct oscillatory STN-cortical loops revealed by simultaneous MEG and local field potential recordings in patients with Parkinson's disease

Neuronal oscillations are assumed to play a pivotal role in the pathophysiology of Parkinson's disease (PD). Neurons in the subthalamic nucleus (STN) generate oscillations which are coupled to rhythmic population activity both in other basal ganglia nuclei and cortical areas. In order to localize these cortical areas, we recorded local field potentials (LFPs) and magnetoencephalography (MEG) simultaneously in PD patients undergoing surgery for deep brain stimulation (DBS). Patients were withdrawn from antiparkinsonian medication and recorded at rest. We scanned the entire brain for oscillations coherent with LFPs recorded from the STN with a frequency domain beamformer. Coherent activity in the low (12-20 Hz) and high (20-35 Hz) beta range was found in the ipsilateral sensorimotor and the premotor cortex. Coherence in the alpha range (7-12 Hz) was observed at various locations in the ipsilateral temporal lobe. In a subset of subjects, the superior temporal gyrus consistently showed coherent alpha oscillations. Our findings provide new insights into patterns of frequency-specific functional connectivity between basal ganglia and cortex and suggest that simultaneous inter-regional interactions may be segregated in the frequency domain. Furthermore, they demonstrate that simultaneous MEG-LFP recordings are a powerful tool to study interactions between brain areas in PD patients undergoing surgery for DBS.     

Resting energy expenditure and body mass changes in women during adjuvant chemotherapy for breast cancer

Weight gain is a commonly reported side effect of adjuvant chemotherapy. A change in resting energy expenditure during treatment has been a suggested mechanism for weight gain. We prospectively measured resting energy expenditure, weight change, and body composition (dual-energy x-ray absorptiometry) in 10 women undergoing adjuvant chemotherapy for breast cancer. There was no change in resting energy expenditure across cycles of chemotherapy (P =.78) or from baseline to the end of treatment (1,189.68 +/- 80.27 vs 1,205.76 +/- 56.71 kcal/d; P =.74). Overall, participants did not gain weight across treatment. However, there was an overall trend toward weight gain (66.3 +/- 5.1 vs 68.2 +/- 5.0 kg; P =.09), and participants did show an increase in total fat mass (24.2 +/- 3.8 vs 26.5 +/- 3.2 kg; P =.04), whereas muscle mass remained the same. Although no change in resting energy expenditure was seen, the observed increase in total fat mass is consistent with a decrease in physical activity level commonly reported with adjuvant chemotherapy treatment of breast cancer, and these body composition changes may have important health implications for survivors.     

Safety and efficacy evaluation of a human acellular nerve graft as a digital nerve scaffold: a prospective,multicentre controlled clinical trial

This study developed a human acellular nerve graft (hANG) as an alternative to autogenous nerve and reports on its safety and efficacy. There were two groups comprised of 72 patients that received digital nerve repair with hANG (test) and 81 that received conventional direct tension‐free suture repair of the nerve defect (control). The efficacy of the treatment was evaluated by static 2‐point discrimination (s2PD) and Semmes‐Weinstein monofilament testing. Safety was evaluated by local wound response and laboratory testing. Mean age of patients in the test group was 33.0 ± 11.1 years (range 18‐61 years) and in the control group 36.9 ± 13.4 years (range 15‐77 years) (p = 0.0470). Mean time from injury to repair in the test group was 23.7 ± 52 days (range 0‐200 days) and in the control group 1.5 ± 10.4 days (range 0‐91 days) (p = 0.0005). Mean length of nerve graft was 1.80 ± 0.82 cm (range 1‐5 cm). All surgeries were performed successfully and without complications. The excellent and good rate of s2PD in the test group was 65.28% and 95% CI was 51.98‐78.93%. s2PD in the test group improved over time and average distance was 12.81 ± 5.99 mm at 6 months postoperatively. No serious adverse or product‐related events were reported. These results indicate that hANG is a safe and effective for the repair of nerve defects of 1‐5 cm in size. © 2015 The Authors. Journal of Tissue Engineering and Regenerative Medicine published by John Wiley & Sons, Ltd.     

Metabolic predictors of obesity. Contribution of resting energy expenditure, thermic effect of food, and fuel utilization to four-year weight gain of post-obese and never-obese women.

This prospective study was designed to identify abnormalities of energy expenditure and fuel utilization which distinguish post-obese women from never-obese controls. 24 moderately obese, postmenopausal, nondiabetic women with a familial predisposition to obesity underwent assessments of body composition, fasting and postprandial energy expenditure, and fuel utilization in the obese state and after weight loss (mean 12.9 kg) to a post-obese, normal-weight state. The post-obese women were compared with 24 never-obese women of comparable age and body composition. Four years later, without intervention, body weight was reassessed in both groups. Results indicated that all parameters measured in the post-obese women were similar to the never-obese controls: mean resting energy expenditure, thermic effect of food, and fasting and postprandial substrate oxidation and insulin-glucose patterns. Four years later, post-obese women regained a mean of 10.9 kg while control subjects remained lean (mean gain 1.7 kg) (P < 0.001 between groups). Neither energy expenditure nor fuel oxidation correlated with 4-yr weight changes, whereas self-reported physical inactivity was associated with greater weight regain. The data suggest that weight gain in obesity-prone women may be due to maladaptive responses to the environment, such as physical inactivity or excess energy intake, rather than to reduced energy requirements.     

Subthalamic GAD gene transfer in Parkinson disease patients who are candidates for deep brain stimulation

This gene transfer experiment is the first Parkinson's Disease (PD) protocol to be submitted to the Recombinant DNA Advisory Committee. The principal investigators have uniquely focused their careers on both pre-clinical work on gene transfer in the brain and clinical expertise in management and surgical treatment of patients with PD. They have extensively used rodent models of PD for proof-of-principle experiments on the utility of different vector systems. PD is an excellent target for gene therapy, because it is a complex acquired disease of unknown etiology (apart from some rare familial cases) yet it is characterized by a specific neuroanatomical pathology, the degeneration of dopamine neurons of the substantia nigra (SN) with loss of dopamine input to the striatum. This pathology results in focal changes in the function of several deep brain nuclei, which have been well-characterized in humans and animal models and which account for many of the motor symptoms of PD. Our original approaches, largely to validate in vivo gene transfer in the brain, were designed to facilitate dopamine transmission in the striatum using an AAV vector expressing dopamine-synthetic enzymes. Although these confirmed the safety and potential efficacy of AAV, complex patient responses to dopamine augmenting medication as well as poor results and complications of human transplant studies suggested that this would be a difficult and potentially dangerous clinical strategy using current approaches. Subsequently, we and others investigated the use of growth factors, including GDNF. These showed some encouraging effects on dopamine neuron survival and regeneration in both rodent and primate models; however, uncertain consequences of long-term growth factor expression and question regarding timing of therapy in the disease course must be resolved before any clinical study can be contemplated. We now propose to infuse into the subthalamic nucleus (STN) recombinant AAV vectors expressing the two isoforms of the enzyme glutamic acid decarboxylase (GAD-65 and GAD-67), which synthesizes the major inhibitory neurotransmitter in the brain, GABA. The STN is a very small nucleus (140 cubic mm or 0.02% of the total brain volume, consisting of approximately 300,000 neurons) which is disinhibited in PD, leading to pathological excitation of its targets, the internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata (SNpr). Increased GPi/SNpr outflow is believed responsible for many of the cardinal symptoms of PD, i.e., tremor, rigidity, bradykinesia, and gait disturbance. A large amount of data based on lesioning, electrical stimulation, and local drug infusion studies with GABA-agonists in human PD patients have reinforced this circuit model of PD and the central role of the STN. Moreover, the closest conventional surgical intervention to our proposal, deep brain stimulation (DBS) of the STN, has shown remarkable efficacy in even late stage PD, unlike the early failures associated with recombinant GDNF infusion or cell transplantation approaches in PD. We believe that our gene transfer strategy will not only palliate symptoms by inhibiting STN activity, as with DBS, but we also have evidence that the vector converts excitatory STN projections to inhibitory projections. This additional dampening of outflow GPi/SNpr outflow may provide an additional advantage over DBS. Moreover, of perhaps the greatest interest, our preclinical data suggests that this strategy may also be neuroprotective, so this therapy may slow the degeneration of dopaminergic neurons. We will use both GAD isoforms since both are typically expressed in inhibitory neurons in the brain, and our data suggest that the combination of both isoforms is likely to be most beneficial. Our preclinical data includes three model systems: (1) old, chronically lesioned parkinsonian rats in which intraSTN GAD gene transfer results not only in improvement in both drug-induced asymmetrical behavior (apomorphine symmetrical rotations), but also in spontaneous behaviors. In our second model, GAD gene transfer precedes the generation of a dopamine lesion. Here GAD gene transfer showed remarkable neuroprotection. Finally, we carried out a study where GAD-65 and GAD-67 were used separately in monkeys that were resistant to MPTP lesioning and hence showed minimal symptomatology. Nevertheless GAD gene transfer showed no adverse effects and small improvements in both Parkinson rating scales and activity measures were obtained. In the proposed clinical trial, all patients will have met criteria for and will have given consent for STN DBS elective surgery. Twenty patients will all receive DBS electrodes, but in addition they will be randomized into two groups, to receive either a solution containing rAAV-GAD, or a solution which consists just of the vector vehicle, physiological saline. Patients, care providers, and physicians will be blind as to which solution any one patient receives. All patients, regardless of group, will agree to not have the DBS activated until the completion and unblinding of the study. Patients will be assessed with a core clinical assessment program modeled on the CAPSIT, and in addition will also undergo a preop and several postop PET scans. At the conclusion of the study, if any patient with sufficient symptomatic improvement will be offered DBS removal if they so desire. Any patients with no benefit will simply have their stimulators activated, which would normally be appropriate therapy for them and which requires no additional operations. If any unforeseen symptoms occur from STN production of GABA, this might be controlled by blocking STN GABA release with DBS, or STN lesioning could be performed using the DBS electrode. Again, this treatment would not subject the patient to additional invasive brain surgery. The trial described here reflects an evolution in our thinking about the best strategy to make a positive impact in Parkinson Disease by minimizing risk and maximizing potential benefit. To our knowledge, this proposal represents the first truly blinded, completely controlled gene or cell therapy study in the brain, which still provides the patient with the same surgical procedure which they would normally receive and should not subject the patient to additional surgical procedures regardless of the success or failure of the study. This study first and foremost aims to maximally serve the safety interests of the individual patient while simultaneously serving the public interest in rigorously determining in a scientific fashion if gene therapy can be effective to any degree in treating Parkinson's disease.