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Background/purpose: Gait impairments in Parkinson disease (PD) contribute to decreased quality of life. This randomized controlled trial examined immediate- and longer-term effects of a single joint robotic exoskeleton device (EXOD), the Honda Walking Assist device, on gait., Methods: Participants (n = 45) with PD (Hoehn and Yahr stages 1-3) were randomized to a robotic-assisted gait training (RAGT) group (n = 23) or control (CON) group (n = 22). The RAGT group was tested with and without the EXOD at baseline and then received supervised in-home and community training with the EXOD twice weekly for 8 weeks. The CON group received no interventions. Outcome measures included gait speed (primary), gait endurance (6-minute walk test), perceived ease of walking, and questionnaires and logs assessing performance of daily activities, freezing of gait, and daily activity levels., Results: Forty participants completed the study. No significant immediate impact of EXOD usage on participants' gait measures was found. Differences in gait speed and secondary outcome measures postintervention were not significantly different between the RAGT and CON groups. Participants with greater disease severity (worse baseline motor scores) had greater improvements in stride length during unassisted walking after the intervention than those with lower severity (mean difference: 3.22, 95% confidence interval: 0.05-6.40; P = 0.04)., Discussion and Conclusions: All RAGT participants could use the EXOD safely. The RAGT treatment used in this mostly low impairment population of people with PD may be ineffective and/or was insufficiently dosed to see a positive treatment effect. Our findings suggest that RAGT interventions in PD may be more effective in individuals with greater motor impairments., Competing Interests: All remaining authors had no conflicts of interest to report., (Copyright © 2024 Academy of Neurologic Physical Therapy, APTA.)

Background: Treadmill training may improve gait disorders associated with neurodegenerative diseases. In Parkinson's disease (PD), treadmill training alters gait patterns after one session, and long-term training improves gait parameters, fall risk, and quality of life., Research Question: What is the feasibility and safety of using this intervention for people with Lewy body dementia (LBD) or Huntington's disease (HD)?, Methods: In this observational study, 10 individuals with HD, 8 individuals with LBD, and 10 control individuals walked for 20 min on a treadmill using a speed dependent protocol starting at a slow comfortable speed and increasing incrementally toward their normal overground speed. Feasibility was determined by compliance to protocol and safety by no incidents of abnormal vital signs or expressions of distress. Changes in gait measures, Timed Up and Go (TUG) scores and quantitative motor function measures (Q-Motor; precision grasp force variability, finger and foot tapping frequency) before and after treadmill walking were analyzed using linear models., Results: Treadmill training is feasible and safe in LBD and HD; although, participants could not initiate treadmill walking at their comfortable overground speeds, and only 3 participants with HD were able to achieve their overground walking speed within the 20-minute session. No changes in gait measures, TUG times, and Q-Motor measures were found among LBD and HD participants after treadmill walking, although control participants demonstrated significant increases in several gait measures, and foot tap frequency (estimated difference = 0.290; p = 0.026)., Significance: Longer and more frequent treadmill sessions may be needed to see gait and motor function effects in LBD and HD. Motor and cognitive impairments associated with these diseases may make them less amenable to the effects of treadmill training., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Huntington's disease is associated with motor, cognitive and behavioral dysfunction. Behavioral symptoms may present before, after, or simultaneously with clinical disease manifestation. The relationship between age of onset and behavioral symptom presentation and severity was explored using the Enroll-HD database. Manifest individuals (n = 4469) were initially divided into three groups for preliminary analysis: early onset (<30 years; n = 479); mid-adult onset (30-59 years; n = 3478); and late onset (>59 years; n = 512). Incidence of behavioral symptoms reported at onset was highest in those with early onset symptoms at 26% (n = 126), compared with 19% (n = 678) for mid-adult onset and 11% (n = 56) for late onset (P < 0.0001). Refined analysis, looking across the continuum of ages rather than between categorical subgroups found that a one-year increase in age of onset was associated with a 5.6% decrease in the odds of behavioral symptoms being retrospectively reported as the presenting symptom (P < 0.0001). By the time of study enrollment, the odds of reporting severe behavioral symptoms decreased by 5.5% for each one-year increase in reported age of onset. Exploring environmental, genetic and epigenetic factors that affect age of onset and further characterizing types and severity of behavioral symptoms may improve treatment and understanding of Huntington's disease's impact on affected individuals., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington's disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington's Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression., Competing Interests: Funding: National Institute of Neurological Diseases and Stroke SBIR Fast-track award to Azevan Pharmaceuticals, Inc (U44NS090616), NINDS grants supporting the NeuroNext Network (Clinical Coordinating Center U01NS077179; Data Coordinating Center U01NS077352), the CHDI Foundation (grant to NGS) and Azevan Pharmaceuticals, Inc. The STAIR trial was sponsored by Azevan Pharmaceuticals, Inc. and was conducted through the NINDS NeuroNEXT Network (22 sites).

Loss of nigrostriatal dopaminergic projection neurons is a key pathology in Parkinson's disease, leading to abnormal function of basal ganglia motor circuits and the accompanying characteristic motor features. A number of intraparenchymally delivered gene therapies designed to modify underlying disease and/or improve clinical symptoms have shown promise in preclinical studies and subsequently were evaluated in clinical trials. Here we review the challenges with surgical delivery of gene therapy vectors that limited therapeutic outcomes in these trials, particularly the lack of real-time monitoring of vector administration. These challenges have recently been addressed during the evolution of novel techniques for vector delivery that include the use of intraoperative MRI. The preclinical development of these techniques are described in relation to recent clinical translation in an adeno-associated virus serotype 2-mediated human aromatic L-amino acid decarboxylase gene therapy development programme. This new paradigm allows visualisation of the accuracy and adequacy of viral vector delivery within target structures, enabling intertrial modifications in surgical approaches, cannula design, vector volumes and dosing. The rapid, data-driven evolution of these procedures is unique and has led to improved vector delivery., Competing Interests: Competing interests: RMR, CWC, ADVL, REG and SAF received grants from Voyager Therapeutics, Inc. KSB received grants and personal fees from Voyager Therapeutics. Voyager Therapeutics is funding this research and is developing products related to the research described in this paper. REG serves as a consultant to Voyager Therapeutics and personally receives compensation for these services. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict-of-interest policies. RL received consulting fees from Voyager Therapeutics. SKK has nothing to disclose. APK is a former employee of Voyager Therapeutics and owns stock in that company. BR is a former employee of Voyager Therapeutics. PSL has received grants from Voyager Therapeutics and non-financial support from ClearPoint Neuro (formerly MRI Interventions, Inc)., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The huntingtin gene ( HTT ) pathogenic cytosine-adenine-guanine (CAG) repeat expansion responsible for Huntington disease (HD) is phased with single nucleotide polymorphisms (SNPs), providing targets for allele-selective treatments., Objective: This prospective observational study defined the frequency at which rs362307 (SNP1) or rs362331 (SNP2) was found on the same allele with pathogenic CAG expansions., Methods: Across 7 US sites, 202 individuals with HD provided blood samples that were processed centrally to determine the number and size of CAG repeats, presence and heterozygosity of SNPs, and whether SNPs were present on the mutant HTT allele using long-read sequencing and phasing., Results: Heterozygosity of SNP1 and/or SNP2 was identified in 146 (72%) individuals. The 2 polymorphisms were associated only with the m HTT allele in 61% (95% high density interval: 55%, 67%) of individuals., Conclusions: These results are consistent with previous reports and demonstrate the feasibility of genotyping, phasing, and targeting of HTT SNPs for personalized treatment of HD., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Individuals with neurological disorders often have difficulty negotiating stairs that can lead to injurious falls. Clinicians lack a clinical tool to identify impairments in stair negotiation and to assist their decision making regarding treatment plans to improve stair performance and safety. We developed a new tool called the Step Test Evaluation of Performance on Stairs (STEPS) that is designed to assess stair performance and safety in neurological populations., Objectives: This study aimed to determine interrater and intrarater reliability of STEPS and its concurrent content validity to various clinical balance and mobility measures using individuals with Huntington's disease (HD) as the first test population., Methods: Forty individuals with HD (mean age 50.35) participated. Three observers rated live performances of the STEPS (interrater reliability) and seven observers rated videotaped performances twice (intrarater reliability). STEPS scores correlated with clinical mobility and balance test scores., Results: Excellent inter- and intrarater reliability (ICCs = 0.91 and 0.89 respectively) and good internal consistency (α = 0.83) were found. Better STEPS performance correlated with better performance on co-administered motor and mobility measures and Stair Self-Efficacy scores. Per multivariable regression analysis, the Unified Huntington's Disease Rating Scale modified motor score and descent time were significant predictors of STEPS performance., Conclusions: The STEPS tool is easy to administer, requires no special devices and can be completed in less than five minutes. In the HD test population, it shows high reliability and validity making it a potentially useful tool for assessing maneuverability and safety on stairs in HD. The results suggest that the STEPS tool warrants further study to determine STEPS cut-off values for fall prediction in HD and may prove useful as an assessment tool for other neurological disorders., Competing Interests: The STEPS instrument is copyrighted by the Ohio State University. Dr. Kegelmeyer is on the board of Neuvanta LLC. Dr. Kostyk reports funding from Robert A Vaughan Family Development Fund and the Huntington’s Disease Society of America. Meredith McCormack-Mager’s funding source related to this research was the Center for Biostatistics. All other authors have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Importance: Tetrabenazine is efficacious for chorea control; however, tolerability concerns exist. Deutetrabenazine, a novel molecule that reduces chorea, was well tolerated in a double-blind, placebo-controlled study., Objectives: To evaluate the safety and explore the efficacy of conversion from tetrabenazine to deutetrabenazine in patients with chorea associated with Huntington disease (HD)., Design, Setting, and Participants: In this ongoing, open-label, single-arm study that started on December 21, 2013, 37 patients at 13 Huntington Study Group sites in the United States and Australia who were taking stable doses of tetrabenazine that provided a therapeutic benefit were switched overnight to deutetrabenazine therapy. After week 1, the deutetrabenazine dose was titrated on a weekly basis for optimal chorea control., Interventions: Deutetrabenazine administration at a dosage thought to provide comparable systemic exposure to the active metabolites of the prior, stable tetrabenazine regimen., Main Outcomes and Measures: Safety measures included adverse events (AEs), clinical laboratory tests, vital signs, electrocardiograms, and validated scales. Changes in the Unified Huntington's Disease Rating Scale total maximal chorea score and total motor score were efficacy end points., Results: Of the 53 patients with HD screened for the study, 37 ambulatory patients with manifest HD (mean [SD] age, 52.4 [11.5] years; 22 [59%] male and 15 [41%] female; 36 white [97.3%]) were enrolled. Deutetrabenazine was generally well tolerated, with low rates of neuropsychiatric AEs. Safety scales did not reveal subclinical toxicity with deutetrabenazine treatment. Rates of dose reduction or suspension attributable to AEs were also low. Chorea control, as measured by the total maximal chorea score, was maintained at week 1 and significantly improved at week 8 (mean [SD] change from baseline, 2.1 [3.2]; P < .001)., Conclusions and Relevance: In patients with chorea, overnight conversion to deutetrabenazine therapy provided a favorable safety profile and effectively maintained chorea control.

Postural instability is common in individuals with Huntington's disease (HD), yet little is known about control of the trunk during static and dynamic activities. We compared the trunk motion of 41 individuals with HD and 36 controls at thoracic and pelvic levels during sitting, standing, and walking using wearable iPod sensors. We also examined the ability of individuals with HD to respond to an auditory cue to modify trunk position when the pelvis moved >8° in sagittal or frontal planes during sitting using custom software. We found that amplitude of thoracic and pelvic trunk movements was significantly greater in participants with HD, and differences were more pronounced during static (i.e. sitting, standing) than dynamic (i.e. walking) tasks. In contrast to the slow, smooth sinusoidal trunk movements of controls, individuals with HD demonstrated rapid movements with varying amplitudes that continuously increased without stabilizing. Ninety-seven percent of participants with HD were able to modify their trunk position in response to auditory cues. Our results demonstrate that wearable iPod sensors are clinically useful for rehabilitation professionals to measure and monitor trunk stability in persons with HD. Additionally, auditory cueing holds potential as a useful training tool to improve trunk stability in HD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

BACKGROUND. We report the 12-month clinical and imaging data on the effects of bilateral delivery of the glutamic acid decarboxylase gene into the subthalamic nuclei (STN) of advanced Parkinson's disease (PD) patients. METHODS. 45 PD patients were enrolled in a 6-month double-blind randomized trial of bilateral AAV2- GAD delivery into the STN compared with sham surgery and were followed for 12 months in open-label fashion. Subjects were assessed with clinical outcome measures and 18 F-fluorodeoxyglucose (FDG) PET imaging. RESULTS. Improvements under the blind in Unified Parkinson's Disease Rating Scale (UPDRS) motor scores in the AAV2- GAD group compared with the sham group continued at 12 months [time effect: F (4,138) = 11.55, P < 0.001; group effect: F (1,35) = 5.45, P < 0.03; repeated-measures ANOVA (RMANOVA)]. Daily duration of levodopa-induced dyskinesias significantly declined at 12 months in the AAV2- GAD group ( P = 0.03; post-hoc Bonferroni test), while the sham group was unchanged. Analysis of all FDG PET images over 12 months revealed significant metabolic declines ( P < 0.001; statistical parametric mapping RMANOVA) in the thalamus, striatum, and prefrontal, anterior cingulate, and orbitofrontal cortices in the AAV2- GAD group compared with the sham group. Across all time points, changes in regional metabolism differed for the two groups in all areas, with significant declines only in the AAV2- GAD group ( P < 0.005; post-hoc Bonferroni tests). Furthermore, baseline metabolism in the prefrontal cortex (PFC) correlated with changes in motor UPDRS scores; the higher the baseline PFC metabolism, the better the clinical outcome. CONCLUSION. These findings show that clinical benefits after gene therapy with STN AAV2- GAD in PD patients persist at 12 months. TRIAL REGISTRATION. ClinicalTrials.gov NCT00643890. FUNDING. Neurologix Inc., Competing Interests: Conflict of interest: C.C. Tang, P.A. Le Witt, M.A. Leehey, S.G. Ojemann, A.W. Flaherty, S.K. Kostyk, M.S. Siddiqui, S.B. Tatter, J.M. Schwalb, K.L. Poston, I.H. Richard, M.J. During, and M.G. Kaplitt have received funding from funding from Neurologix Inc. M.J. During and M.G. Kaplitt are coinventors on the patent re: Glutamic acid decarboxylase (GAD) based delivery systems (United States Patent No. 7,695,959 B2). D. Eidelberg is a coinventor on the patents re: Markers for use in screening patients for nervous system dysfunction and a method and apparatus for using same (United States Patent No. 5,632,276 and No. 5,873,823). Additional COI information is reported in the supplemental materials.

Background: Huntington's disease (HD) is a progressive neurodegenerative disorder that results in a gradual decline in mobility and balance. Increasing evidence has documented an important role of executive function in the safe ambulation of the elderly and people with a variety of neurological disorders. Little is known about the contribution of cognitive deficits to decline in mobility over time in HD., Objective: This study examined the relationships of mobility, motor and cognitive function measures at baseline, and of mobility and cognitive measures over four years., Methods: A retrospective chart review was performed on 70 patients with genetically confirmed HD (age 20-75 years old) across 121 HD clinic visits. Correlations between Unified Huntington's Disease Rating Scale - Total Motor, Tinetti Mobility Test (TMT), and cognitive measures (Letter Verbal Fluency, Symbol Digit Modalities Test (SDMT), and Stroop Test) were analyzed. Longitudinal relationships between TMT and cognitive measures were examined using mixed effect regression models., Results: Gait and balance measures representing domains of mobility (TMT scores) were significantly correlated with each of the cognitive measures with the exception of the Verbal Fluency score. Mixed effects regression modeling showed that the Stroop Interference sub-test and SDMT were significant predictors (p-values <0.01) of TMT total scores., Conclusions: Impairments in executive function measures correlate highly with measures of gait, balance and mobility in individuals with HD. Interventions designed to improve mobility and decrease fall risk should also address issues of cognitive impairments with particular consideration given to interventions that may focus on motor-cognitive dual task training.

Limited data compares clinical profiles of Lewy Body Dementia (LBD) with Alzheimer's disease (AD) and Parkinson's disease (PD). Twenty-one mildly demented ambulatory LBD subjects were individually matched by MMSE score with 21 AD subjects and by UPDRS motor score with 21 PD subjects. Matched by age, gender, education, and race, pairs were compared using cognitive, functional, behavioral, and motor measures. LBD group performed worse than PD on axial motor, gait, and balance measures. AD had more amnesia and orientation impairments, but less executive and visuospatial deficits than LBD subjects. LBD group had more sleepiness, cognitive/behavioral fluctuations, hallucinations, and sleep apnea than AD or PD. Axial motor, gait, and balance disturbances correlated with executive, visuospatial, and global cognition deficits. LBD is differentiated from AD and PD by retrieval memory, visuospatial, and executive deficits; axial motor, gait and balance impairments; sleepiness, cognitive/behavioral fluctuations, hallucinations, and sleep apnea.

Introduction: Differential diagnosis of dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), Parkinson's disease (PD) and Alzheimer's disease (AD) is challenging. Comparative motor profiles of these neurodegenerative disorders may aid in earlier diagnosis but have not been extensively studied., Methods: Groups were rigorously matched by age, education, and sex. DLB/PDD participants were matched by Mini-Mental State Examination Score to individuals with AD and by Unified Parkinson's Disease Rating Scale motor scores to individuals with PD. Gait, balance, dual task walking and hand dexterity measures were compared between a combined group (n=21) of individuals with Lewy body dementia (LBD) consisting of those with DLB (n=11) and PDD (n=10) to individuals with PD (n=21) or AD (n=21)., Results: Individuals at the same disease stage with LBD walked significantly slower with shorter stride lengths (p<0.05), demonstrated poorer balance on both the Tinetti and Berg Balance Scale, and poorer performance on dual-task and figure-of-eight walking compared to PD and AD (p<0.05 for all) groups. Upper extremity coordination on the 9-hole peg test differentiated LBD from both PD and AD and was the only motor test in which individuals with AD performed worse than those with PD. Tinetti balance subscores were significantly lower in PDD compared to DLB participants (10.4±2.3 versus 12.8±2.3; p=0.027)., Conclusions: Motor features distinguish individuals with LBD from those with AD and PD. Measures of gait, balance and finger dexterity provide an additional means of differentiating individuals with LBD from those with AD and PD., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Chorea may contribute to balance problems and walking difficulties that lead to higher fall rates in individuals with Huntington's disease (HD). Few studies have examined the effects of tetrabenazine (TBZ), an anti-choreic drug, on function and mobility in HD. The purpose of this study was to compare: 1) gait measures in forward walking, 2) balance and mobility measures, and 3) hand and forearm function measures on and off TBZ. We hypothesized that use of TBZ would improve gait, transfers and hand and forearm function. Eleven individuals with HD on stable doses of TBZ were evaluated while off medication and again following resumption of medication. Significant improvements were found on the Unified Huntington's Disease Rating Scale (UHDRS) motor scores, Tinetti Mobility Test (TMT) total (t=4.20, p=0.002) and balance subscale (t=-4.61, p=0.001) scores, and the Five Times Sit-to-Stand test (5TSST, t=3.20, p=.009) when on-TBZ compared to off-TBZ. Spatiotemporal gait measures, the Six Condition Romberg test, and UHDRS hand and forearm function items were not changed by TBZ use. Improved TMT and 5TSST performance when on drug indicates that TBZ use may improve balance and functional mobility in individuals with HD., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Individuals with Huntington's disease (HD) experience balance and gait problems that lead to falls. Clinicians currently have very little information about the reliability and validity of outcome measures to determine the efficacy of interventions that aim to reduce balance and gait impairments in HD. This study examined the reliability and concurrent validity of spatiotemporal gait measures, the Tinetti Mobility Test (TMT), Four Square Step Test (FSST), and Activities-specific Balance Confidence (ABC) Scale in individuals with HD., Methods: Participants with HD [n = 20; mean age ± SD=50.9 ± 13.7; 7 male] were tested on spatiotemporal gait measures and the TMT, FSST, and ABC Scale before and after a six week period to determine test-retest reliability and minimal detectable change (MDC) values. Linear relationships between gait and clinical measures were estimated using Pearson's correlation coefficients., Results: Spatiotemporal gait measures, the TMT total and the FSST showed good to excellent test-retest reliability (ICC > 0.75). MDC values were 0.30 m/s and 0.17 m/s for velocity in forward and backward walking respectively, four points for the TMT, and 3s for the FSST. The TMT and FSST were highly correlated with most spatiotemporal measures. The ABC Scale demonstrated lower reliability and less concurrent validity than other measures., Conclusions: The high test-retest reliability over a six week period and concurrent validity between the TMT, FSST, and spatiotemporal gait measures suggest that the TMT and FSST may be useful outcome measures for future intervention studies in ambulatory individuals with HD., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Importance: Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit., Objective: To examine whether CoQ10 could slow disease progression in early PD., Design, Setting, and Participants: A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson's Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation., Interventions: The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E., Main Outcomes and Measures: Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo., Results: The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo)., Conclusions and Relevance: Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit., Trial Registration: clinicaltrials.gov Identifier: NCT00740714.

Objective: To investigate the feasibility, acceptability, and safety of a supervised video game exercise program administered via Dance Dance Revolution in individuals with Huntington's disease., Design: A cross-over, controlled, single-blinded, six-week trial., Setting: Home-based., Participants: Eighteen ambulatory individuals with Huntington's disease (seven male, mean age 50.7 SD 14.7)., Interventions: Participants played the Dance Dance Revolution game with supervision and the handheld game without supervision for 45 minutes, two days per week for six weeks., Outcome Measures: Game play performance and adherence, participant perceptions of the game, safety (vital signs, adverse health changes), spatiotemporal gait measures, Four-Square Step Test, Tinetti Mobility Test, Activities-Specific Balance Confidence Scale, and World Health Organization Quality of Life - Bref, before and after each intervention., Results: Most participants improved on game play, enjoyed playing the game, and wanted to continue playing after study completion. After playing Dance Dance Revolution, participants showed significant reductions in double support percentage (adjusted mean difference (95% confidence intervals): -2.54% (-4.75, -0.34) for forward walking and -4.18 (-6.89, -0.48) for backward walking) and those with less severe motor symptoms had reductions in heel-to-heel base of support during forward walking. The remaining measures were not significantly impacted by the intervention., Conclusion: Dance Dance Revolution appears to be a feasible, motivating, and safe exercise intervention for individuals with Huntington's disease.

Gait abnormalities are a hallmark of Parkinson's disease (PD) and contribute to fall risk. Therapy and exercise are often encouraged to increase mobility and decrease falls. As disease symptoms progress, assistive devices are often prescribed. There are no guidelines for choosing appropriate ambulatory devices. This unique study systematically examined the impact of a broad range of assistive devices on gait measures during walking in both a straight path and around obstacles in individuals with PD. Quantitative gait measures, including velocity, stride length, percent swing and double support time, and coefficients of variation were assessed in 27 individuals with PD with or without one of six different devices including canes, standard and wheeled walkers (two, four or U-Step). Data were collected using the GAITRite and on a figure-of-eight course. All devices, with the exception of four-wheeled and U-Step walkers significantly decreased gait velocity. The four-wheeled walker resulted in less variability in gait measures and had less impact on spontaneous unassisted gait patterns. The U-Step walker exhibited the highest variability across all parameters followed by the two-wheeled and standard walkers. Higher variability has been correlated with increased falls. Though subjects performed better on a figure-of-eight course using either the four-wheeled or the U-Step walker, the four-wheeled walker resulted in the most consistent improvement in overall gait variables. Laser light use on a U-Step walker did not improve gait measures or safety in figure-of-eight compared to other devices. Of the devices tested, the four-wheeled-walker offered the most consistent advantages for improving mobility and safety., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Gait and balance impairments lead to frequent falls and injuries in individuals with Huntington's disease (HD). Assistive devices (ADs) such as canes and walkers are often prescribed to prevent falls, but their efficacy is unknown. We systematically examined the effects of different types of ADs on quantitative gait measures during walking in a straight path and around obstacles., Methods: Spatial and temporal gait parameters were measured in 21 subjects with HD as they walked across a GAITRite walkway under 7 conditions (i.e., using no AD and 6 commonly prescribed ADs: a cane, a weighted cane, a standard walker, and a 2, 3 or 4 wheeled walker). Subjects also were timed and observed for number of stumbles and falls while walking around two obstacles in a figure-of-eight pattern., Results: Gait measure variability (i.e., coefficient of variation), an indicator of fall risk, was consistently better when using the 4WW compared to other ADs. Subjects also walked the fastest and had the fewest number of stumbles and falls when using the 4WW in the figure-of-eight course. Subjects walked significantly slower using ADs compared to no AD both across the GAITRite and in the figure-of-eight. Measures reflecting gait stability and safety improved with the 4WW but were made worse by some other ADs.

Background: Gene transfer of glutamic acid decarboxylase (GAD) and other methods that modulate production of GABA in the subthalamic nucleus improve basal ganglia function in parkinsonism in animal models. We aimed to assess the effect of bilateral delivery of AAV2-GAD in the subthalamic nucleus compared with sham surgery in patients with advanced Parkinson's disease., Methods: Patients aged 30-75 years who had progressive levodopa-responsive Parkinson's disease and an overnight off-medication unified Parkinson's disease rating scale (UPDRS) motor score of 25 or more were enrolled into this double-blind, phase 2, randomised controlled trial, which took place at seven centres in the USA between Nov 17, 2008, and May 11, 2010. Infusion failure or catheter tip location beyond a predefined target zone led to exclusion of patients before unmasking for the efficacy analysis. The primary outcome measure was the 6-month change from baseline in double-blind assessment of off-medication UPDRS motor scores. This trial is registered with ClinicalTrials.gov, NCT00643890., Findings: Of 66 patients assessed for eligibility, 23 were randomly assigned to sham surgery and 22 to AAV2-GAD infusions; of those, 21 and 16, respectively, were analysed. At the 6-month endpoint, UPDRS score for the AAV2-GAD group decreased by 8·1 points (SD 1·7, 23·1%; p<0·0001) and by 4·7 points in the sham group (1·5, 12·7%; p=0·003). The AAV2-GAD group showed a significantly greater improvement from baseline in UPDRS scores compared with the sham group over the 6-month course of the study (RMANOVA, p=0·04). One serious adverse event occurred within 6 months of surgery; this case of bowel obstruction occurred in the AAV2-GAD group, was not attributed to treatment or the surgical procedure, and fully resolved. Other adverse events were mild or moderate, likely related to surgery and resolved; the most common were headache (seven patients in the AAV2-GAD group vs two in the sham group) and nausea (six vs two)., Interpretation: The efficacy and safety of bilateral infusion of AAV2-GAD in the subthalamic nucleus supports its further development for Parkinson's disease and shows the promise for gene therapy for neurological disorders., Funding: Neurologix., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The Tinetti Mobility Test (TMT) is a clinical balance and gait test that predicts fall risk in the elderly. This study examined the concurrent validity, usefulness of the TMT as a fall risk screening tool, and the potential ability of the TMT to predict falls in individuals with Huntington's disease (HD). Data from a retrospective review of 94 patient records were used. TMT scores were correlated with Unified Huntington Disease Rating Scale (UHDRS) motor scores. The ability of the TMT to accurately assess fall risk was determined using validity index measures. Logistic regression was used to assess the ability of the TMT to predict falls. TMT scores correlated with UHDRS motor scores (r(s) = -0.751, P < 0.0001). Using a cutoff value of 21, the TMT had a sensitivity of 74% and a specificity of 60% to identify fallers. Lower TMT scores and younger age were significant predictors of falls. The TMT is a valid tool for assessing balance and gait status and fall risk of individuals with HD., (© 2010 Movement Disorder Society.)

Progranulin (proepithelin) is a pleiotropic growth-factor associated with inflammation and wound repair in peripheral tissues. It also has been implicated in the response to acute traumatic brain injury as well as to chronic neurodegenerative diseases. To determine whether changes in progranulin expression also accompany acute spinal cord injury, C57BL/6 mice were subjected to mid-thoracic (T9 level) contusion spinal cord injury and analyzed by immunohistochemical and biochemical methods. Whereas spinal cord sections prepared from non-injured laminectomy control animals contained low basal levels of progranulin immunoreactivity in gray matter, sections from injured animals contained intense immunoreactivity throughout the injury epicenter that peaked 7-14 days post injury. Progranulin immunoreactivity colocalized with myeloid cell markers CD11b and CD68, indicating that expression increased primarily in activated microglia and macrophages. Immunoblot analysis confirmed that progranulin protein levels rose after injury. On the basis of quantitative polymerase chain reaction analysis, increased protein levels resulted from a tenfold rise in progranulin transcripts. These data demonstrate that progranulin is dramatically induced in myeloid cells after experimental spinal cord injury and is positioned appropriately both spatially and temporally to influence recovery after injury.

Spinal cord injury (SCI) in mammals leads to a robust inflammatory response followed by the formation of a glial and connective tissue scar that comprises a barrier to axonal regeneration. The inbred MRL/MpJ mouse strain exhibits reduced inflammation after peripheral injury and shows true regeneration without tissue scar formation following an ear punch wound. We hypothesized that following SCI, the unique genetic wound healing traits of this strain would result in reduced glial and connective tissue scar formation, increased axonal growth, and improved functional recovery. Adult MRL/MpJ and C57BL/6J mice were subjected to a mid-thoracic spinal contusion and the distribution of axon profiles and selected cellular and extracellular matrix components was compared at 1, 2, 4 and 6 weeks post-injury. Recovery of hind-limb locomotor function was assessed over the same time period. The MRL/MpJ mice exhibited robust axon growth within the lesion, beginning at 4 weeks post-injury. This growth was accompanied by reduced macrophage staining at 1, 2, 4 and 6 weeks post-injury, decreased chondroitin sulfate proteoglycan staining at 1-2 weeks and increased laminin staining throughout the lesion at 2-6 weeks post-injury. Paradoxically, the extent of locomotor recovery was impaired in the MRL/MpJ mice. Close examination of the chronic lesion site revealed evidence of ongoing degeneration both within and surrounding the lesion site. Thus, the regenerative genetic wound healing traits of the MRL/MpJ mice contribute to the evolution of a lesion environment that supports enhanced axon growth after SCI. However, this response occurs at the expense of meaningful functional recovery.

Objective: Our purpose is to examine the effect of D2/D3 agonists on semantic priming., Background: Dopamine seems to restrict the semantic network in semantic priming. However, which dopamine receptor mediates this effect is unknown., Methods: To better understand the receptors involved, 15 nondemented Parkinson disease patients performed a lexical decision task before and 1 hour after they received their first morning medication dose, 8 after D2 and D3 agonists pramipexole or ropinirole, and 7 after L-dopa. Semantic priming was measured for closely, distantly, and unrelated word pairs across a stimulus onset asynchrony of 700 ms., Results: Closely related pairs were recognized significantly faster than unrelated and distantly related pairs before the drugs, as well as after D2/D3 agents. After L-dopa, closely related pairs remained faster than unrelated, but not faster than distantly related pairs., Conclusions: This suggests that D1 receptors may mediate the dopaminergic modulation of semantic priming.

Background and Purpose: This study examined the interrater and intrarater reliability, concurrent validity, and criterion validity of the Tinetti Mobility Test (TMT) as a fall risk screening tool in individuals with Parkinson disease (PD)., Subjects: Thirty individuals with PD voluntarily participated in the study, and data from a retrospective review of 126 patient records were included., Methods: Physical therapists and physical therapist students rated live and videotaped performances of the TMT. Tinetti Mobility Test scores were correlated with Unified Parkinson's Disease Rating Scale (UPDRS) motor scores and comfortable gait speed. The ability of the TMT to accurately assess fall risk was determined., Results: Interrater and intrarater reliability was good to excellent (intraclass correlation coefficient of >.80). Tinetti Mobility Test scores correlated with UPDRS motor scores (r(s)=-.45) and gait speed (r(s)=.53). The sensitivity and specificity of the TMT to identify fallers were 76% and 66%, respectively., Discussion and Conclusion: The TMT is a reliable and valid tool for assessing the mobility status of and fall risk for individuals with PD.

Purpose: The purpose of this study was to characterize the effects of implantation of a collagen tube on healing and scar formation following transection of tbc adult rat spinal cord., Methods: The spinal cords of adult rats were completely transected at the mid-thoracic level. At 30 days after injury, the cellular and extra-cellular components of repair tissue present within tubulated and non-tubulated (control) wounds were compared using qualitative and quantitative histological techniques., Results: The presence of the tube reduced fibrocollagenous scar invasion into the gap, promoted astrocyte migration, and oriented axonal and connective tissue components of the repair tissue. Tube implants supported the regeneration of a substantial number of myelinated axons. A notable finding was the identification of cells containing a contractile actin isoform in the healing spinal cord., Conclusions: The tubulation model allows for the study of spinal cord wound healing and axon elongation in a controlled experimental environment within the tube lumen. Using this model, it will be possible to study manipulation of the healing response by the introduction of exogenous agents within the tube.

To test the hypothesis that cortical remapping supports phantom sensations, we examined referred phantom sensations and cortical activation in humans after spinal-cord injury (SCI) at the thoracic level (T3-T12). Of 12 SCI subjects, 9 reported phantom sensations, and 2 reported referred phantom sensations. In both of these subjects, referred phantom sensations were evoked by contact in reference zones (RZ) that were not adjacent in the periphery and were not predicted to be adjacent in the postcentral gyrus (PoCG), suggesting that representations separated by centimeters of cortical space were simultaneously engaged. This finding was supported by functional MRI (fMRI). In a subject with a T6-level complete SCI, contact in RZ on the left or right forearm projected referred phantom sensations to the ipsilateral chest. During fMRI, contact in either forearm RZ evoked activity in the central PoCG (the position of the forearm representation) and the medial PoCG (the position of the chest representation) with >/=1.6 cm of nonresponsive cortex intervening. In contrast, stimulation in non-RZ forearm and palm regions in this subject and in lesion-matched SCI subjects evoked central but not medial PoCG activation. Our findings support a relation between PoCG activation and the percept of referred phantom sensations. These results, however, present an alternative to somatotopic cortical reorganization, namely, cortical plasticity expressed in coactivation of nonadjacent representations. The observed pattern suggests that somatotopic subcortical remapping, projected to the cortex, can support perceptual and cortical reorganization after deafferentation in humans.

Patients with spinal cord injury (SCI) have an increased prevalence of cholelithiasis. The goal of this study was to clarify the presentation and management of symptomatic gallstone disease in patients with SCI. We performed a retrospective study of presentation of gallstone complications in patients with SCI who underwent cholecystectomy for complications of gallstone disease. The West Roxbury Veterans Administration Medical Center SCI registry (605 patients) was searched for patients who had undergone cholecystectomy more than 1 year after SCI (35 patients). Gallbladder disease profiles for the 35 patients undergoing cholecystectomy for complications of gallstone disease were prepared, including demographics, clinical presentation, diagnostic studies, operative and pathologic findings, and postoperative complications. All patients were white. Thirty-four were male and the mean age was 50 years (range 35 to 65 years). The majority of patients (66%) complained of right upper quadrant abdominal pain, even those patients with SCI at high (i.e., cervical) levels. Of the 35 patients in our study group, 22 (63%) had biliary colic and chronic cholecystitis, nine (26%) had acute cholecystitis (gangrenous cholecystitis in two), two (6%) had choledocholithiasis symptoms or cholangitis, and two (6%) had gallstone pancreatitis. Major perioperative morbidity occurred in two (6%) of the 35 patients (pulmonary embolus; intraoperative hemorrhage), and there were no deaths. In the great majority of patients with SCI, cholelithiasis presents with chronic pain and not with life-threatening complications. Our findings suggest that presentation is no more acute in patients with SCI than in the general population. Characteristic symptoms and signs are not necessarily obscured by SCI injury, regardless of the level.

The Hu paraneoplastic antigen is an RNA binding protein important in the development and maintenance of neurons. Hu has homology with the product of Elav, a gene that is essential for Drosophila visual system development. Using immunohistochemical staining, the Hu antigen was identified in most retinal neurons but was not detected in the photoreceptors. Hu is, therefore, not essential for the maintenance of all differentiated neurons. Hu immunolabeling was consistently found in glia in the optic nerve. The presence of the Hu antigen in a subset of glial cells emphasizes the heterogeneity of glial phenotype and raises the possibility that these cells may retain properties of undifferentiated neural stem cells.

Basic fibroblast growth factor (bFGF) and nitric oxide (NO) are expressed by endothelial cells (EC) and are involved in regulation of endothelial functions. In vivo, bFGF has a hypotensive effect which is mediated, in part, through activation of nitric oxide synthase (NOS) and the subsequent generation of NO. Thus we hypothesized that regulation of NOS in EC might be modulated by bFGF. bFGF treatment of EC in vitro resulted in increased NADPH diaphorase staining, a histochemical marker associated with the presence of NOS. Using cGMP generation in a reporter cell as a bioassay for NO release, we demonstrated that bFGF treatment of EC leads to increased production of biologically active NO. Furthermore, bFGF treatment of EC resulted in an increase in cellular content of the endothelial form of NOS as shown by Western blot analysis. Finally, Northern blot analysis was used to demonstrate that message levels of the constitutive, calcium-dependent, endothelial form of NOS is increased in EC by treatment with bFGF in vitro. These results suggest that bFGF has potential to regulate vascular tone through the modulation of levels of endothelial NOS.

Normal blood vessel tone is maintained by a balance of vasoconstrictors and vasodilators produced by endothelial cells in the vasculature. Nitric oxide (NO) is a potent vasodilator that causes vascular smooth muscle cell relaxation by elevating intracellular guanosine 3',5'-cyclic monophosphate (cGMP) levels. The physiological mechanisms regulating NO production in the vasculature are not completely understood. We report here that production of this vasodilator by vascular endothelial cells can be significantly suppressed by hypoxia. Exposing human endothelial cells to low PO2 results in 40-60% reduction in the steady-state mRNA levels of endothelial constitutive NO synthase (eNOS), the major enzyme responsible for NO production in these cells. The lower levels of eNOS mRNA result from decreased transcription of the gene as well as reduced message stability. In endothelial-smooth muscle cell co-culture experiments, hypoxic endothelial cells stimulated significantly less cGMP production by smooth muscle cells than the corresponding normoxic controls. This inhibitory effect of hypoxia on NOS production by endothelial cells occurs after 24 h of hypoxia and persists for at least 48 h. These new findings suggest that hypoxia might cause changes in blood vessel tone through compound mechanisms: by increasing the production of endothelium-derived vasoconstrictors and, as shown here, by suppressing the production of vasodilators like NO.

Purpose: To develop oxygen-induced retinopathy in the mouse with reproducible and quantifiable proliferative retinal neovascularization suitable for examining pathogenesis and therapeutic intervention for retinal neovascularization in retinopathy of prematurity (ROP) and other vasculopathologies., Methods: One-week-old C57BL/6J mice were exposed to 75% oxygen for 5 days and then to room air. A novel fluorescein-dextran perfusion method has been developed to assess the vascular pattern. The proliferative neovascular response was quantified by counting the nuclei of new vessels extending from the retina into the vitreous in 6 microns sagittal cross-sections. Cross-sections were also stained for glial fibrillary acidic protein (GFAP)., Results: Fluorescein-dextran angiography delineated the entire vascular pattern, including neovascular tufts in flat-mounted retinas. Hyperoxia-induced neovascularization occurred at the junction between the vascularized and avascular retina in the mid-periphery. Retinal neovascularization occurred in all the pups between postnatal day 17 and postnatal day 21. There was a mean of 89 neovascular nuclei per cross-section of 9 eyes in hyperoxia compared to less than 1 nucleus per cross-section of 8 eyes in the normoxia control (P < 0.0001). Proliferative vessels were not associated with GFAP-positive astrocyte processes., Conclusions: The authors have described a reproducible and quantifiable mouse model of oxygen-induced retinal neovascularization that should prove useful for the study of pathogenesis of retinal neovascularization as well as for the study of medical intervention for ROP and other retinal angiopathies.

We have studied the visual prey acquisition behavior of frogs with unilateral optic nerve section, unilateral tectal lobe ablation, and unilateral transverse hemisection at a level between the tectum and the cerebellum. The first two groups of animals oriented normally to stimuli throughout the region of visual field overlap and failed to respond to more peripheral stimuli on one side. Hemisected animals responded to stimuli at all positions in the visual field. For stimuli located contralateral to the lesion, the frogs oriented normally. For ipsilateral stimuli, the frogs oriented forward.

We have studied the effects on frog orienting behavior of three lesions: unilateral optic nerve section, unilateral tectal lobe ablation, and unilateral transverse hemisection of the neuraxis at a level just caudal to the optic tectum. Unilateral optic nerve section and unilateral tectal lobe ablation produce very similar deficits in visually elicited responses to prey items, an absence of responses for stimuli at locations within the monocular field of one eye. Unilateral hemisection, in contrast, results in abnormalities in visually elicited responses over a wider area, encompassing the entire ipsilateral visual hemifield. The hemisection deficit also differs in character from that following optic nerve section or tectal lesion. Within the affected hemifield, frogs do not fail to respond to stimuli but rather respond with abnormally directed movements. The movements, regardless of stimulus eccentricity on the horizontal, are always forwardly directed. While not varying with horizontal eccentricity, the movements do vary with stimulus elevation and distance. The variation with stimulus distance in the affected hemifield is somewhat different from that in the opposite hemifield. We conclude from the behavior that remains after hemisection lesions that there must exist bilateral descending tectofugal paths capable of triggering movements which vary with stimulus elevation and distance, and a crossed descending tectofugal path capable of triggering turns into one visual hemifield. That the deficit area is larger following a hemisection than following tectal lobe ablation indicates that the hemisection has affected the ability of both tectal lobes to trigger turns in one direction. A possible interpretation of this finding is that the lesion has interrupted not only the crossed descending tectofugal path from one tectal lobe but an uncrossed descending tectofugal path from the other. This hypothetical pathway as well as the others mentioned is incorporated in a model of the organization of the post-tectal circuitry involved in orienting.

Substance P (SP)-like immunoreactive cells were identified in postmortem white matter tissue from patients with multiple sclerosis (MS). Labelled cells, which by morphologic criteria could be identified as astrocytes, were located at the edge of both active (e.g. inflammatory) and inactive (e.g. non-inflammatory) MS lesions. By contrast, SP-immunoreactive astrocytes were not found in normal controls and were only occasionally present in other conditions associated with astrogliosis. These data suggest that SP, a potent mediator of vasodilatation and local immune responses, may play a role in the genesis of the MS plaque. These results also extend the repertoire of potential interactions which may occur between astrocytes and cells of the immune system.

A complete transverse hemisection of the neuraxis just caudal to the optic tectum in the frog, Rana pipiens, results in a failure to orient toward stimuli in one visual hemifield [Kostyk and Grobstein (1986) Neuroscience 21, 41-55]. The extent of the deficit area implies disturbances in the outputs triggered by both tectal lobes. In this paper we report studies aimed at determining more precisely what damage is involved in producing the hemisection deficit, with the broader objective of identifying particular neural structures which may be important in visually elicited orienting. Small lesions at the level of the hemisection which are restricted to the ventromedial white tracts result in an orienting deficit identical to that produced by a complete hemisection. Large lesions which spare the ventromedial white tracts are without significant effect on orienting turns. The finding is consistent with the hypothesis that the hemisection deficit results from interruption of tectal outflow paths. Interestingly, partial damage of the ventromedial white tracts does not result in disconnection of any local tectal region from premotor circuitry but instead systematically alters the turns triggered from all tectal regions. Ventrolateral lesions at the same level do not produce deficits in orienting but do disturb optokinetic behavior. Introduction of horseradish peroxidase into ventromedial lesions produces retrograde labeling in a large number of structures both rostral and caudal of the lesion. Labeling patterns following introduction of horseradish peroxidase into ventrolateral lesions, which do not affect orienting turns, were qualitatively similar but differed quantitatively. The observed patterns of tectal cell labeling make it unlikely that the hemisection deficit can be accounted for in terms of interruption of direct projections deriving from complementary regions of the two tectal lobes. They also indicate that if there exists an uncrossed tectal outflow adequate to trigger orienting turns, it must be by way of an indirect projection. A more general analysis of the labeling patterns suggests that a crossed tectal projection and uncrossed projections from three midbrain tegmental nuclei (the anterodorsal tegmental nucleus, the nucleus profunds lateralis and the nucleus of the medial longitudinal fasciculus) are likely to be involved in triggering orienting turns. The three midbrain tegmental nuclei are of particular interest in that they provide possible anatomical substrates for an indirect uncrossed descending tectal outflow path.

We have studied the orienting behavior of juvenile Rana pipiens in which one eye was rotated at late larval stages and the other eye left intact. Such frogs orient accurately to stimuli falling solely in the visual field of the intact eye and systematically misorient to stimuli falling solely in the field of the rotated eye. Stimuli within the area of visual field overlap elicited two distinct sets of responses, one attributable to the normal and the other to the rotated eye.

A complete transverse hemisection of the neuraxis just caudal to the optic tectum in the frog, Rana pipiens, results in a failure to orient toward stimuli in one visual hemifield [Kostyk and Grobstein (1986) Neuroscience 21, 41-55]. This finding indicates that each tectal lobe gives rise to a crossed descending pathway adequate to cause turns in a direction contralateral to that tectal lobe, and suggests that each may also give rise to an uncrossed descending pathway adequate to cause turns in the ipsilateral direction. To determine whether there is in fact such an uncrossed pathway, we have studied the orienting behavior of frogs after lesions which interrupt crossed pathways. Two groups of animals were studied. In one group we made midline lesions of the ansulate commissure, through which run the major crossed descending projections from both tectal lobes. In the other group, we combined a complete transverse hemisection with removal of the tectal lobe on the same side of the brain, leaving intact only an uncrossed pathway from one tectal lobe. A persistence of orienting turns was observed in both groups of animals. In both, the direction of the turns was that expected on the assumption that an uncrossed pathway would cause ipsilateral turns. We conclude that such a pathway exists. While both groups of animals turned in the expected directions, they did so for stimuli at unexpected locations. Increasingly eccentric stimulus locations to one side of the mid-sagittal plane were associated with increasing amplitude turns to the other. The observation suggests that tectal regions mapping areas of visual space to one side of the mid-sagittal plane are capable of triggering turns not only in that direction but in the opposite direction as well. In the case of ansulate commissure section, mirrored orienting responses were observed for tactile stimuli as well. These and other behavioral anomalies described in the preceding papers [Kostyk and Grobstein (1986) Neuroscience 21, 41-55 and 57-82] suggest that between the topographic retinotectal projection and the premotor circuitry for orienting there may exist an intermediate processing step, one in which stimulus location is represented in a generalized spatial coordinate frame.