Synergy as a new and sensitive marker of basal ganglia dysfunction: A study of asymptomatic welders.

BACKGROUND Multi-digit synergies, a recently developed, theory-based method to quantify stability of motor action, are shown to reflect basal ganglia dysfunction associated with parkinsonian syndromes. In this study, we tested the hypothesis that multi-digit synergies may capture early and subclinical basal ganglia dysfunction. We chose asymptomatic welders to test the hypothesis because the basal ganglia are known to be most susceptible to neurotoxicity caused by welding-related metal accumulation (such as manganese and iron). METHODS Twenty right-handed welders and 13 matched controls were invited to perform single- and multi-finger pressing tasks using the fingers of the right or left hand. Unified Parkinson's Disease Rating Scale and Grooved Pegboard scores were used to gauge gross and fine motor dysfunction, respectively. High-resolution (3T) T1-weighted, T2-weighted, T1 mapping, susceptibility, and diffusion tensor MRIs were obtained to reflect manganese, iron accumulation, and microstructural changes in basal ganglia. The synergy index stabilizing total force and anticipatory synergy adjustments were computed, compared between groups, and correlated with estimates of basal ganglia manganese [the pallidal index, R1 (1/T1)], iron [R2* (1/T2*)], and microstructural changes [fractional anisotropy and mean diffusivity]. RESULTS There were no significant differences in Unified Parkinson's Disease Rating Scale (total or motor subscale) or Grooved Pegboard test scores between welders and controls. The synergy index during steady-state accurate force production was decreased significantly in the left hand of welders compared to controls (p=0.004) but did not reach statistical significance in the right hand (p=0.16). Anticipatory synergy adjustments, however, were not significantly different between groups. Among welders, higher synergy indices in the left hand were associated significantly with higher fractional anisotropy values in the left globus pallidus (R=0.731, p<0.001) but not with the pallidal index, R1, or R2* values in the basal ganglia. CONCLUSIONS These data suggest that multi-digit synergy metrics may serve as preclinical markers for basal ganglia dysfunction in welders and other populations at risk for neurodegenerative diseases involving parkinsonian symptoms. This finding may have important clinical, scientific, and public/occupational health implications.

[1]  M. Latash,et al.  Motor Control Strategies Revealed in the Structure of Motor Variability , 2002, Exercise and sport sciences reviews.

[2]  S. Mandel,et al.  Biomarkers for prediction and targeted prevention of Alzheimer’s and Parkinson’s diseases: evaluation of drug clinical efficacy , 2010, EPMA Journal.

[3]  R. Sainburg.  Evidence for a dynamic-dominance hypothesis of handedness , 2001, Experimental Brain Research.

[4]  Ravi S. Menon,et al.  Functional imaging of human motor cortex at high magnetic field. , 1993, Journal of neurophysiology.

[5]  Vladimir M. Zatsiorsky,et al.  Anticipatory covariation of finger forces during self-paced and reaction time force production , 2005, Neuroscience Letters.

[6]  M. Levin.  Interjoint coordination during pointing movements is disrupted in spastic hemiparesis. , 1996, Brain : a journal of neurology.

[7]  D. Bourbonnais,et al.  Weakness in patients with hemiparesis. , 1989, The American journal of occupational therapy : official publication of the American Occupational Therapy Association.

[8]  M L Latash,et al.  On the problem of adequate language in motor control. , 1998, Motor control.

[9]  Gregor Schöner,et al.  The uncontrolled manifold concept: identifying control variables for a functional task , 1999, Experimental Brain Research.

[10]  R. Lucchini,et al.  Neuropsychological testing for the assessment of manganese neurotoxicity: a review and a proposal. , 2007, American journal of industrial medicine.

[11]  D B Calne,et al.  Manganese neurotoxicity: a review of clinical features, imaging and pathology. , 1999, Neurotoxicology.

[12]  Jing Chen,et al.  Manganese exposure among smelting workers: relationship between blood manganese-iron ratio and early onset neurobehavioral alterations. , 2009, Neurotoxicology.

[13]  Guido Gerig,et al.  Unbiased diffeomorphic atlas construction for computational anatomy , 2004, NeuroImage.

[14]  Martin Styner,et al.  Subcortical structure segmentation using probabilistic atlas priors , 2007, SPIE Medical Imaging.

[15]  Mark L. Latash,et al.  Dopaminergic modulation of motor coordinaton in Parkinson's disease. , 2014, Parkinsonism & related disorders.

[16]  R. Mailman,et al.  Editor's Highlight: Lower Fractional Anisotropy in the Globus Pallidus of Asymptomatic Welders, a Marker for Long-Term Welding Exposure. , 2016, Toxicological sciences : an official journal of the Society of Toxicology.

[17]  M. L. Latash,et al.  Neural control of movement stability: Lessons from studies of neurological patients , 2015, Neuroscience.

[18]  Yongmin Chang,et al.  High signal intensity on magnetic resonance imaging is a better predictor of neurobehavioral performances than blood manganese in asymptomatic welders. , 2009, Neurotoxicology.

[19]  Edgar Erdfelder,et al.  G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences , 2007, Behavior research methods.

[20]  M. Latash,et al.  Effects of Parkinson’s disease on optimization and structure of variance in multi-finger tasks , 2013, Experimental Brain Research.

[21]  M. L. Latash,et al.  Effects of unilateral stroke on multi-finger synergies and their feed-forward adjustments , 2016, Neuroscience.

[22]  C. Ostiguy,et al.  The emergence of manganese-related health problems in Quebec: an integrated approach to evaluation, diagnosis, management and control. , 2006, Neurotoxicology.

[23]  M Hallett,et al.  Changes in motor cortex excitability during ipsilateral hand muscle activation in humans , 2000, Clinical Neurophysiology.

[24]  Alvaro Pascual-Leone,et al.  Ipsilateral motor cortex activation on functional magnetic resonance imaging during unilateral hand movements is related to interhemispheric interactions , 2003, NeuroImage.

[25]  M Davare,et al.  Role of the ipsilateral primary motor cortex in controlling the timing of hand muscle recruitment. , 2006, Cerebral cortex.

[26]  Robert L. Sainburg,et al.  Convergent models of handedness and brain lateralization , 2014, Front. Psychol..

[27]  T. Guilarte.  Manganese neurotoxicity: new perspectives from behavioral, neuroimaging, and neuropathological studies in humans and non-human primates , 2013, Front. Aging Neurosci..

[28]  M. Latash,et al.  Changes in multifinger interaction and coordination in Parkinson's disease. , 2012, Journal of neurophysiology.

[29]  John P Scholz,et al.  Aspects of joint coordination are preserved during pointing in persons with post-stroke hemiparesis. , 2003, Brain : a journal of neurology.

[30]  D. Krieger,et al.  Manganese and chronic hepatic encephalopathy , 1995, The Lancet.

[31]  Darcy S. Reisman,et al.  Workspace location influences joint coordination during reaching in post-stroke hemiparesis , 2006, Experimental Brain Research.

[32]  M. Hallett,et al.  The cerebellum in Parkinson’s disease , 2013, Brain : a journal of neurology.

[33]  R Tardif,et al.  Nervous system dysfunction among workers with long-term exposure to manganese. , 1994, Environmental research.

[34]  R. Bowler,et al.  Dose–effect relationships between manganese exposure and neurological, neuropsychological and pulmonary function in confined space bridge welders , 2006, Occupational and Environmental Medicine.

[35]  Mark L Latash,et al.  Elderly show decreased adjustments of motor synergies in preparation to action. , 2007, Clinical biomechanics.

[36]  Halla B. Olafsdottir,et al.  Age-related changes in multifinger synergies in accurate moment of force production tasks. , 2007, Journal of applied physiology.

[37]  R. Mailman,et al.  Microstructural changes in the substantia nigra of asymptomatic agricultural workers. , 2014, Neurotoxicology and teratology.

[38]  M. Hallett,et al.  Involvement of the ipsilateral motor cortex in finger movements of different complexities , 1997, Annals of neurology.

[39]  Vladimir M. Zatsiorsky,et al.  Finger interaction during accurate multi-finger force production tasks in young and elderly persons , 2004, Experimental Brain Research.

[40]  M. Swash,et al.  Amyotrophic lateral sclerosis: a long preclinical period? , 2014, Journal of Neurology, Neurosurgery & Psychiatry.

[41]  Mark L. Latash,et al.  Prehension synergies and hand function in early-stage Parkinson’s disease , 2014, Experimental Brain Research.

[42]  W. Koller,et al.  The diagnosis of manganese-induced parkinsonism. , 2006, Neurotoxicology.

[43]  R. Mailman,et al.  Increased R2* in the Caudate Nucleus of Asymptomatic Welders. , 2016, Toxicological sciences : an official journal of the Society of Toxicology.

[44]  D. Le Bihan,et al.  Diffusion tensor imaging: Concepts and applications , 2001, Journal of magnetic resonance imaging : JMRI.

[45]  P. Eslinger,et al.  Early cortical gray matter loss and cognitive correlates in non-demented Parkinson's patients. , 2013, Parkinsonism & related disorders.

[46]  C. Martínez,et al.  Blood Manganese Correlates with Brain Magnetic Resonance Imaging Changes in Patients with Liver Disease , 1996, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[47]  Stephen M. Rao,et al.  Motor Sequence Complexity and Performing Hand Produce Differential Patterns of Hemispheric Lateralization , 2004, Journal of Cognitive Neuroscience.

[48]  Sanae Nakagawa,et al.  Manganese exposure: neuropsychological and neurological symptoms and effects in welders. , 2006, Neurotoxicology.

[49]  M. Latash,et al.  Structure of motor variability in marginally redundant multifinger force production tasks , 2001, Experimental Brain Research.

[50]  J. Troncoso,et al.  The prevalence of the neuropathological lesions of Alzheimer’s disease is independent of race and gender , 2001, Neurobiology of Aging.

[51]  D Mergler,et al.  Early manifestations of manganese neurotoxicity in humans: an update. , 1997, Environmental research.

[52]  M. Aschner,et al.  Manganese exposure among smelting workers: blood manganese–iron ratio as a novel tool for manganese exposure assessment , 2009, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[53]  Mark L. Latash,et al.  Effects of olivo-ponto-cerebellar atrophy (OPCA) on finger interaction and coordination , 2013, Clinical Neurophysiology.

[54]  M. McDonnell,et al.  Use of Objective Psychomotor Tests in Health Professionals , 2014, Perceptual and motor skills.

[55]  Sonja W. Scholz,et al.  Genome-Wide Association Study reveals genetic risk underlying Parkinson’s disease , 2009, Nature Genetics.

[56]  D B Calne,et al.  Progression after chronic manganese exposure , 1993, Neurology.

[57]  Gregor Schöner,et al.  Toward a new theory of motor synergies. , 2007, Motor control.

[58]  Mark L. Latash,et al.  The bliss (not the problem) of motor abundance (not redundancy) , 2012, Experimental Brain Research.

[59]  Maryse Bouchard,et al.  Sequelae of fume exposure in confined space welding: a neurological and neuropsychological case series. , 2007, Neurotoxicology.

[60]  D. Harrington,et al.  Hemispheric asymmetry of movement , 1996, Current Opinion in Neurobiology.

[61]  P. Schulz,et al.  Parkinsonism due to manganism in a welder: neurological and neuropsychological sequelae. , 2006, Neurotoxicology.

[62]  S Takahashi,et al.  Functional MR imaging of cortical activation of the cerebral hemispheres during motor tasks. , 1998, AJNR. American journal of neuroradiology.

[63]  C. W. Hess,et al.  Magnetic stimulation of the human brain: Facilitation of motor responses by voluntary contraction of ipsilateral and contralateral muscles with additional observations on an amputee , 1986, Neuroscience Letters.

[64]  M. Panisset,et al.  Neurobehavioral functioning after cessation of manganese exposure: a follow-up after 14 years. , 2007, American journal of industrial medicine.

[65]  Yngvar Thomassen,et al.  A neurobehavioral study of current and former welders exposed to manganese. , 2008, Neurotoxicology.

[66]  Mark L Latash,et al.  The effects of strength training on finger strength and hand dexterity in healthy elderly individuals. , 2008, Journal of applied physiology.

[67]  J. Perlmutter,et al.  Basal ganglia intensity indices and diffusion weighted imaging in manganese-exposed welders , 2011, Occupational and Environmental Medicine.

[68]  L. Sheppard,et al.  Neurological outcomes associated with low-level manganese exposure in an inception cohort of asymptomatic welding trainees. , 2015, Scandinavian journal of work, environment & health.

[69]  S. Holm.  A Simple Sequentially Rejective Multiple Test Procedure , 1979 .

[70]  M. Latash,et al.  Enslaving effects in multi-finger force production , 2000, Experimental Brain Research.

[71]  D. Dorman,et al.  Tissue manganese concentrations in young male rhesus monkeys following subchronic manganese sulfate inhalation. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[72]  G. Schöner.  Recent Developments and Problems in Human Movement Science and Their Conceptual Implications , 1995 .

[73]  A. Sunderland.  Recovery of ipsilateral dexterity after stroke. , 2000, Stroke.

[74]  R M Ruff,et al.  Gender- and Age-Specific Changes in Motor Speed and Eye-Hand Coordination in Adults: Normative Values for the Finger Tapping and Grooved Pegboard Tests , 1993, Perceptual and motor skills.

[75]  R. Mailman,et al.  T1 Relaxation Rate (R1) Indicates Nonlinear Mn Accumulation in Brain Tissue of Welders With Low-Level Exposure. , 2015, Toxicological sciences : an official journal of the Society of Toxicology.