Functional compensation or pathology in cortico-subcortical interactions in preclinical Huntington's disease?

Huntington's disease (HD) is an autosomal dominant neurological disorder, with degeneration amongst others affecting the basal ganglia dopaminergic system. Recent findings suggest compensatory as well as pathogenetic mechanisms mediated via the adenosine receptor system in the presymptomatic stage (pHD) of HD. The adenosine receptor system is functionally related to the dopaminergic system. In this study, we assessed error processing, a dopamine-dependent cognitive function, using an event-related potential the error negativity (Ne/ERN) in pHD and controls. This was done by means of a flanker task. The Ne consists of a cognitive and a motor component, expressed via different frequency bands. Time-frequency decomposition of the Ne into delta and theta sub-components was applied to assess if degeneration or compensation predominantly involve cognitive or motor processes. No parameter of the behavioral data (reaction times, error frequency, corrections, post-error slowing) differed between the groups. A selective increase in the power of the cognitive delta-Ne component was found in pHD relative to controls inversely related to the estimated age of onset (eAO). Thus, the increase in the power of the cognitive delta-Ne component was stronger in pHD with an earlier eAO. An earlier eAO implies stronger pathogenetic mechanisms. Due to the behavioral data our results speak for a solely cognitive compensating-mechanism controlling performance monitoring in pHD. In contrast, correlations with eAO suggest that the increase in delta-Ne activity is also related to pathogenesis. It is proposed that compensation is a transient effect of the whole pathogenetic dynamics of HD, with these two processes not foreclosing each other.

[1]  Jane S. Paulsen,et al.  Preclinical Huntington's disease: Compensatory brain responses during learning , 2006, Annals of neurology.

[2]  B. Kopp,et al.  N200 in the flanker task as a neurobehavioral tool for investigating executive control. , 1996, Psychophysiology.

[3]  Jeff Miller,et al.  Jackknife-based method for measuring LRP onset latency differences. , 1998, Psychophysiology.

[4]  C D Good,et al.  The distribution of structural neuropathology in pre-clinical Huntington's disease. , 2002, Brain : a journal of neurology.

[5]  E. Borrelli,et al.  Genetic interdependence of adenosine and dopamine receptors: Evidence from receptor knockout mice , 2006, Neuroscience.

[6]  D. Tucker,et al.  EEG coherency. I: Statistics, reference electrode, volume conduction, Laplacians, cortical imaging, and interpretation at multiple scales. , 1997, Electroencephalography and clinical neurophysiology.

[7]  S. Schiffmann,et al.  A Dual Role of Adenosine A2A Receptors in 3-Nitropropionic Acid-Induced Striatal Lesions: Implications for the Neuroprotective Potential of A2A Antagonists , 2003, The Journal of Neuroscience.

[8]  F. Perrin,et al.  Spherical splines for scalp potential and current density mapping. , 1989, Electroencephalography and clinical neurophysiology.

[9]  S. Augood,et al.  Dopamine D1 and D2 receptor gene expression in the striatum in Huntington's disease , 1997, Annals of neurology.

[10]  R. Knight,et al.  Prefrontal–cingulate interactions in action monitoring , 2000, Nature Neuroscience.

[11]  Luigi F. Agnati,et al.  Adenosine A2A and dopamine D2 heteromeric receptor complexes and their function , 2007, Journal of Molecular Neuroscience.

[12]  J. Hohnsbein,et al.  Action monitoring, error detection, and the basal ganglia: an ERP study , 2001, Neuroreport.

[13]  D. Craufurd.  Huntington's disease , 1996, Prenatal diagnosis.

[14]  J. Pruim,et al.  Striatal dopamine D2 receptors, metabolism, and volume in preclinical Huntington disease , 2005, Neurology.

[15]  L. Frati,et al.  Adenosine A2A receptor dysfunction correlates with age at onset anticipation in blood platelets of subjects with Huntington's disease , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[16]  Paul D. Kieffaber,et al.  Haloperidol Impairs Learning and Error-related Negativity in Humans , 2004, Journal of Cognitive Neuroscience.

[17]  R. Yasuda,et al.  Regulation of proteins affecting NMDA receptor-induced excitotoxicity in a Huntington's mouse model. , 2003, Brain : a journal of neurology.

[18]  Guillén Fernández,et al.  Interaction between the Human Hippocampus and the Caudate Nucleus during Route Recognition , 2004, Neuron.

[19]  L. Bäckman,et al.  Cognitive deficits in Huntington's disease are predicted by dopaminergic PET markers and brain volumes. , 1997, Brain : a journal of neurology.

[20]  D. Meyer,et al.  A Neural System for Error Detection and Compensation , 1993 .

[21]  Jane S. Paulsen,et al.  fMRI biomarker of early neuronal dysfunction in presymptomatic Huntington's Disease. , 2004, AJNR. American journal of neuroradiology.

[22]  Juliana Yordanova,et al.  Parallel systems of error processing in the brain , 2004, NeuroImage.

[23]  Clay B. Holroyd,et al.  The neural basis of human error processing: reinforcement learning, dopamine, and the error-related negativity. , 2002, Psychological review.

[24]  E. Bézard,et al.  Compensatory mechanisms in experimental and human Parkinsonism: towards a dynamic approach , 1998, Progress in Neurobiology.

[25]  P. Svenningsson,et al.  Distribution, biochemistry and function of striatal adenosine A2A receptors , 1999, Progress in Neurobiology.

[26]  K. Richard Ridderinkhof,et al.  Alcohol Consumption Impairs Detection of Performance Errors in Mediofrontal Cortex , 2002, Science.

[27]  J. Hohnsbein,et al.  ERP components on reaction errors and their functional significance: a tutorial , 2000, Biological Psychology.

[28]  J. Hohnsbein,et al.  Effects of crossmodal divided attention on late ERP components. II. Error processing in choice reaction tasks. , 1991, Electroencephalography and clinical neurophysiology.

[29]  G. Sedvall,et al.  PET study of the pre- and post-synaptic dopaminergic markers for the neurodegenerative process in Huntington's disease. , 1997, Brain : a journal of neurology.

[30]  G. Bates,et al.  Early and transient alteration of adenosine A2A receptor signaling in a mouse model of Huntington disease , 2006, Neurobiology of Disease.

[31]  M. Botvinick,et al.  Anterior cingulate cortex, error detection, and the online monitoring of performance. , 1998, Science.

[32]  Erwan Bezard,et al.  Presymptomatic compensation in Parkinson's disease is not dopamine-mediated , 2003, Trends in Neurosciences.

[33]  J. Pernier,et al.  Oscillatory γ-Band (30–70 Hz) Activity Induced by a Visual Search Task in Humans , 1997, The Journal of Neuroscience.

[34]  Claire-Anne Gutekunst,et al.  Huntington’s disease , 2007 .

[35]  Jane S. Paulsen,et al.  Clinical markers of early disease in persons near onset of Huntington’s disease , 2001, Neurology.

[36]  Manish S. Shah,et al.  A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes , 1993, Cell.

[37]  Julie S. Snowden,et al.  Neuropsychological and neuropsychiatric aspects of Huntington's disease , 2002 .

[38]  Jan Kassubek,et al.  Global cerebral atrophy in early stages of Huntington's disease: quantitative MRI study , 2004, Neuroreport.

[39]  W. Hulstijn,et al.  Effects of antipsychotic and antidepressant drugs on action monitoring in healthy volunteers , 2006, Brain Research.

[40]  K. Fuxe,et al.  Involvement of adenosine A2A and dopamine receptors in the locomotor and sensitizing effects of cocaine , 2006, Brain Research.

[41]  H. Gibbons,et al.  The application of jackknife-based onset detection of lateralized readiness potential in correlative approaches. , 2004, Psychophysiology.

[42]  V. Samar,et al.  Wavelet Analysis of Neuroelectric Waveforms: A Conceptual Tutorial , 1999, Brain and Language.

[43]  Jeff Miller,et al.  Using the jackknife-based scoring method for measuring LRP onset effects in factorial designs. , 2001, Psychophysiology.

[44]  J. Brandt,et al.  Onset and rate of striatal atrophy in preclinical Huntington disease , 2004, Neurology.

[45]  J. Hohnsbein,et al.  Sensorimotor slowing with ageing is mediated by a functional dysregulation of motor-generation processes: evidence from high-resolution event-related potentials. , 2004, Brain : a journal of neurology.

[46]  R. Hari,et al.  Visually Evoked Gamma Responses in the Human Brain Are Enhanced during Voluntary Hyperventilation , 2002, NeuroImage.

[47]  S. Folstein,et al.  Anticipation and instability of IT-15 (CAG)n repeats in parent-offspring pairs with Huntington disease. , 1995, American journal of human genetics.

[48]  D. Brooks,et al.  Striatal D1 and D2 receptor binding in patients with Huntington's disease and other choreas. A PET study. , 1995, Brain : a journal of neurology.

[49]  Nick Yeung,et al.  Alcohol and error processing , 2003, Trends in Neurosciences.

[50]  David Blum,et al.  Adenosine receptors and Huntington's disease: implications for pathogenesis and therapeutics , 2003, The Lancet Neurology.

[51]  M. F. Perutz,et al.  Cause of neural death in neurodegenerative diseases attributable to expansion of glutamine repeats , 2001, Nature.

[52]  M. Falkenstein,et al.  Levels of error processing in Huntington's disease: A combined study using event‐related potentials and voxel‐based morphometry , 2008, Human brain mapping.

[53]  M. Falkenstein,et al.  Error Processing in Huntington's Disease , 2006, PloS one.

[54]  E Donchin,et al.  A new method for off-line removal of ocular artifact. , 1983, Electroencephalography and clinical neurophysiology.

[55]  R. Shadmehr,et al.  Motor disorder in Huntington's disease begins as a dysfunction in error feedback control , 2000, Nature.

[56]  K. R. Ridderinkhof,et al.  The Role of the Medial Frontal Cortex in Cognitive Control , 2004, Science.

[57]  D. F. Andrews,et al.  A one-hit model of cell death in inherited neuronal degenerations , 2000, Nature.

[58]  M. Beal,et al.  Experimental therapeutics in transgenic mouse models of Huntington's disease , 2004, Nature Reviews Neuroscience.