Top-down alteration of functional connectivity within the sensorimotor network in focal dystonia

Objectives To determine the directionality of regional interactions and influences of one region on another within the functionally abnormal sensorimotor network in isolated focal dystonia. Methods A total of 40 patients with spasmodic dysphonia with and without dystonic tremor of voice and 35 healthy controls participated in the study. Independent component analysis (ICA) of resting-state fMRI was used to identify 4 abnormally coupled brain regions within the functional sensorimotor network in all patients compared to controls. Follow-up spectral dynamic causal modeling (DCM) estimated regional effective connectivity between patients and controls and between patients with spasmodic dysphonia with and without dystonic tremor of voice to expand the understanding of symptomatologic variability associated with this disorder. Results ICA found abnormally reduced functional connectivity of the left inferior parietal cortex, putamen, and bilateral premotor cortex in all patients compared to controls, pointing to a largely overlapping pathophysiology of focal dystonia and dystonic tremor. DCM determined that the disruption of the sensorimotor network was both top-down, involving hyperexcitable parieto-putaminal influence, and interhemispheric, involving right-to-left hyperexcitable premotor coupling in all patients compared to controls. These regional alterations were associated with their abnormal self-inhibitory function when comparing patients with spasmodic dysphonia patients with and without dystonic tremor of voice. Conclusions Abnormal hyperexcitability of premotor-parietal-putaminal circuitry may be explained by altered information transfer between these regions due to underlying deficient connectivity. Identification of brain regions involved in processing of sensorimotor information in preparation for movement execution suggests that complex network disruption is staged well before the dystonic behavior is produced by the primary motor cortex.

[1]  Jeffery R Wickens,et al.  Inhibitory interactions between spiny projection neurons in the rat striatum. , 2002, Journal of neurophysiology.

[2]  Stephen M. Smith,et al.  Investigations into resting-state connectivity using independent component analysis , 2005, Philosophical Transactions of the Royal Society B: Biological Sciences.

[3]  M. Hallett.  Neurophysiology of dystonia: The role of inhibition , 2011, Neurobiology of Disease.

[4]  Kristina Simonyan,et al.  Abnormal structure-function relationship in spasmodic dysphonia. , 2012, Cerebral cortex.

[5]  J. Tepper,et al.  Inhibitory control of neostriatal projection neurons by GABAergic interneurons , 1999, Nature Neuroscience.

[6]  Giovanni Battistella,et al.  Polygenic Risk of Spasmodic Dysphonia is Associated With Vulnerable Sensorimotor Connectivity , 2018, Cerebral cortex.

[7]  K. Simonyan,et al.  Cortical sensorimotor alterations classify clinical phenotype and putative genotype of spasmodic dysphonia , 2016, European journal of neurology.

[8]  Ritesh A. Ramdhani,et al.  Isolated Focal Dystonia as a Disorder of Large‐Scale Functional Networks , 2015, Cerebral cortex.

[9]  P. Matthews,et al.  Distinct patterns of brain activity in young carriers of the APOE e4 allele , 2009, NeuroImage.

[10]  I. Bar-Gad,et al.  Loss of Balance between Striatal Feedforward Inhibition and Corticostriatal Excitation Leads to Tremor , 2018, The Journal of Neuroscience.

[11]  Karl J. Friston,et al.  Post hoc Bayesian model selection , 2011, NeuroImage.

[12]  A. Braun,et al.  Alterations in CNS activity induced by botulinum toxin treatment in spasmodic dysphonia: an H215O PET study. , 2006, Journal of speech, language, and hearing research : JSLHR.

[13]  P. Fransson.  Spontaneous low‐frequency BOLD signal fluctuations: An fMRI investigation of the resting‐state default mode of brain function hypothesis , 2005, Human brain mapping.

[14]  Mark Hallett,et al.  Focal white matter changes in spasmodic dysphonia: a combined diffusion tensor imaging and neuropathological study. , 2008, Brain : a journal of neurology.

[15]  S. Eickhoff,et al.  Altered sensorimotor activation patterns in idiopathic dystonia—an activation likelihood estimation meta‐analysis of functional brain imaging studies , 2015, Human brain mapping.

[16]  M. Hallett,et al.  Abnormal Striatal Dopaminergic Neurotransmission during Rest and Task Production in Spasmodic Dysphonia , 2013, The Journal of Neuroscience.

[17]  KouichiC . Nakamura,et al.  Dichotomous Organization of the External Globus Pallidus , 2012, Neuron.

[18]  C. Beckmann,et al.  Task-Free Functional MRI in Cervical Dystonia Reveals Multi-Network Changes That Partially Normalize with Botulinum Toxin , 2013, PloS one.

[19]  K. Simonyan,et al.  GNAL mutation in isolated laryngeal dystonia , 2016, Movement disorders : official journal of the Movement Disorder Society.

[20]  Richard B. Reilly,et al.  Neural correlates of abnormal sensory discrimination in laryngeal dystonia , 2015, NeuroImage: Clinical.

[21]  Karl J. Friston,et al.  Unified segmentation , 2005, NeuroImage.

[22]  Karl J. Friston,et al.  Resting state functional MRI in Parkinson’s disease: the impact of deep brain stimulation on ‘effective’ connectivity , 2014, Brain : a journal of neurology.

[23]  D. Sharp,et al.  Fractionating the Default Mode Network: Distinct Contributions of the Ventral and Dorsal Posterior Cingulate Cortex to Cognitive Control , 2011, The Journal of Neuroscience.

[24]  Kristina Simonyan,et al.  Connectome-Wide Phenotypical and Genotypical Associations in Focal Dystonia , 2017, The Journal of Neuroscience.

[25]  M. Gernert,et al.  Deficit of Striatal Parvalbumin-Reactive GABAergic Interneurons and Decreased Basal Ganglia Output in a Genetic Rodent Model of Idiopathic Paroxysmal Dystonia , 2000, The Journal of Neuroscience.

[26]  Mark Hallett,et al.  Impairment of a parieto‐premotor network specialized for handwriting in writer's cramp , 2016, Human brain mapping.

[27]  Massimo Filippi,et al.  Brain structural changes in spasmodic dysphonia: A multimodal magnetic resonance imaging study. , 2016, Parkinsonism & related disorders.

[28]  Adeel Razi,et al.  Bayesian model reduction and empirical Bayes for group (DCM) studies , 2016, NeuroImage.

[29]  Kristina Simonyan,et al.  What's special about task in dystonia? A voxel‐based morphometry and diffusion weighted imaging study , 2014, Movement disorders : official journal of the Movement Disorder Society.

[30]  A. O. Ceballos-Baumann,et al.  “Silent event-related” fMRI reveals reduced sensorimotor activation in laryngeal dystonia , 2005, Neurology.

[31]  C. Price.  The anatomy of language: contributions from functional neuroimaging , 2000, Journal of anatomy.

[32]  Giovanni Battistella,et al.  Neural correlates of dystonic tremor: a multimodal study of voice tremor in spasmodic dysphonia , 2017, Brain Imaging and Behavior.

[33]  Anatol C. Kreitzer,et al.  Selective Inhibition of Striatal Fast-Spiking Interneurons Causes Dyskinesias , 2011, The Journal of Neuroscience.

[34]  A M Graybiel,et al.  Cortically Driven Immediate-Early Gene Expression Reflects Modular Influence of Sensorimotor Cortex on Identified Striatal Neurons in the Squirrel Monkey , 1997, The Journal of Neuroscience.

[35]  G. Koch,et al.  Parieto-motor Cortical Dysfunction in Primary Cervical Dystonia , 2014, Brain Stimulation.

[36]  Mark Hallett,et al.  The direct basal ganglia pathway is hyperfunctional in focal dystonia , 2017, Brain : a journal of neurology.

[37]  Kristina Simonyan,et al.  Abnormal activation of the primary somatosensory cortex in spasmodic dysphonia: an fMRI study. , 2010, Cerebral cortex.

[38]  Oliver Granert,et al.  Dynamic causal modeling revealed dysfunctional effective connectivity in both, the cortico-basal-ganglia and the cerebello-cortical motor network in writers' cramp , 2018, NeuroImage: Clinical.