Amsterdam, The Netherlands, June 24 27, Teaching Course 6. MDS-ES/EAN: Neuroimaging in movement disorders - Level 2. Imaging of dystonia

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Neuroimaging in movement disorders - Level 2 Imaging of

1 3 rd Congress of the European Academy of Neurology Amsterdam, The Netherlands, June 24 27, 2017 Teaching Course 6 MDS-ES/EAN: Neuroimaging in movement disorders - Level 2 Imaging of dystonia Stephane Lehericy Paris, France stephane.lehericy@upmc.fr

2 Imaging of primary dystonia Stéphane Lehéricy, M.D., Ph.D EAN Amsterdam June, Basal ganglia and cerebellar network dysfunction in dystonia Cortex Basal ganglia Cerebellum Shakkottai Cerebellum 2016 Prudente Neuroscience 2014 Lehericy Mov Disord 2013 Conflict of Interest: not received 1

3 Outline 1. Structural changes in dystonia 2. Loss of selectivity of neuronal representations 3. Neurotransmitter changes 4. Changes in functional connectivity in dystonia 5. Brain activation patterns in dystonia 6. Primary or secondary changes? 1. Anatomical changes in dystonia 2

4 Grey matter changes in primary dystonia Cervical dystonia - Basal ganglia - Motor cortex, - SMA, Premotor cortex - Thalamus - Cerebellum Draganski Neurology 2003 Blepharospasm - Basal ganglia - Cerebellum - Thalamus Obermann Mov Dis 2007 Grey matter changes in primary dystonia writer s cramp - Sensorimotor cortex Supplementary motor area Basal ganglia Thalamus Cerebellum Garraux et al. Ann Neurol 2004 R L Delmaire et al. Neurology

Basal ganglia volume changes in DYT1 carriers Subjects (11 symptomatic, 11 asymptomatic DYT1 carriers, 28 controls) VBM Increased putamen volume in

Neuroimage 2009 White matter changes in primary dystonias Diffusion Tensor Imaging (DTI) assesses water diffusion Anisotropy = directionality of water

5 Basal ganglia volume changes in DYT1 carriers Subjects (11 symptomatic, 11 asymptomatic DYT1 carriers, 28 controls) VBM Increased putamen volume in asymptomatic DYT1 carriers In DYT1 carriers, More severe dystonia! smaller putamen volume Draganski et al. Neuroimage 2009 White matter changes in primary dystonias Diffusion Tensor Imaging (DTI) assesses water diffusion Anisotropy = directionality of water diffusion (oriented in the WM) Bleph / Cervical dystonia Writer s cramp Increased / decreased anisotropy Increased anisotropy Thalamus Frontal white matter Internal capsule Ramdhani Mov Dis 2014 Delmaire Arch Neurol

White matter changes in inherited dystonias (DYT1/6) Decreased anisotropy Reduced connectivity Nonmanifesting Manifesting Non-manifesting Motor subcortical white matter Cerebello-thalamocortical

6 White matter changes in inherited dystonias (DYT1/6) Decreased anisotropy Reduced connectivity Nonmanifesting Manifesting Non-manifesting Motor subcortical white matter Cerebello-thalamocortical pathway Carbon Ann Neurol 2004 Argyelan et al. J NeuroSci 2009 What grey matter changes are task-specific in dystonia? Non-task specific dystonia - Blepharospasm - Cervical dystonia Task-specific dystonia - Writer s cramp - Laryngeal dystonia The cerebellum and primary sensorimotor areas are commonly affected in task-specific and non-task specific dystonias Ramdhani et al. Mov Dis

What grey matter changes are task-specific in dystonia?

dystonias: Brain regions responsible for sensorimotor control of

variability in primary dystonia Thalamo-cortical pathway C Leg dystonia

7 What grey matter changes are task-specific in dystonia? Regions specifically affected in task-specific dystonia Task-specific dystonias: Brain regions responsible for sensorimotor control of dystonic movement (writing and speaking) are also affected. Ramdhani et al. Mov Dis 2014 White matter changes in relation with phenotypic variability in primary dystonia Thalamo-cortical pathway C Leg dystonia Non-leg dystonia C Non-man carriers Leg Inherited Sporadic Reduced FA in clinically unaffected limb area Arm Normal FA in clinically affected limb area Vo et al. Cer Cor

White matter changes in relation with phenotypic

Reduced number of fibers Fx M1-Thalamus for the

Structural Alterations in Spasmodic Dysphonia

sporadic vs familial forms Phenotype-specific: SMC

8 White matter changes in relation with phenotypic variability in primary dystonia 14% 61% 75% 82% Reduced number of fibers Fx M1-Thalamus for the clinically unaffected limb pathways Fx DN-Thalamus In all groups 61% 70% Vo et al. Cer Cor 2015 Phenotype- and Genotype-Specific Structural Alterations in Spasmodic Dysphonia Phenotype: Adductor vs Abductor forms Genotype: sporadic vs familial forms Phenotype-specific: SMC and superior corona radiata Genotype-specific: STG, SMA, sup long fasciculus Bianchi et al. Mov Disord

Deep brain stimulation targets in dystonia Globus pallidus target in Dystonia-choreoathetosis cerebral

Lancet Neurol 2009) Postero-lateroventral GPi Globus pallidus target in cervical dystonia (Schönecker et al.

observed at multiple levels of the sensorimotor network (VBM, diffusion, tractography) Basal

9 Deep brain stimulation targets in dystonia Globus pallidus target in Dystonia-choreoathetosis cerebral palsy (Vidailhet et al. Lancet Neurol 2009) Postero-lateroventral GPi Globus pallidus target in cervical dystonia (Schönecker et al. JNNP 2014) Summary of structural changes in dystonia Structural changes in primary dystonias are commonly observed at multiple levels of the sensorimotor network (VBM, diffusion, tractography) Basal ganglia-thalamo-cortical Sensorimotor Cerebello-thalamo-cortical cortex SMA Cerebellum and connections PMC Thalamus Striatum Globus pallidus Lehericy et al. Mov Dis 2013 Stoessl, Lehericy, Strafella Lancet

Cramp < HC Spasmodic dysphonia < HC Reduced 11 C-raclopride binding to D 2 /D 3 receptors in

10 2. Neurotransmitter dysfunction Dopamine GABA Reduced DA binding in the striatum of primary dystonia PET 11 C-raclopride (D 2 /D 3 antagonist ) Baseline D 2 /D 3 binding at rest Writer s Cramp < HC Spasmodic dysphonia < HC Reduced 11 C-raclopride binding to D 2 /D 3 receptors in bilateral striatum in both types of dystonia Berman et al. Brain 2013 Simonyan et al. J Neurosci

Reduced DA release in the striatum of primary dystonia during symptomatic movements Endogenous dopamine release during sequential finger tapping and speech production tasks Writer s Cramp Spasmodic

the asymptomatic task (compensatory adaptation) Berman et al. Brain 2013 Simonyan et al.

11 Reduced DA release in the striatum of primary dystonia during symptomatic movements Endogenous dopamine release during sequential finger tapping and speech production tasks Writer s Cramp Spasmodic dysphonia Finger tapping Speech Finger tapping Speech Divergent task-induced 11 C-raclopride response in the striatum : - Reduced in the symptomatic task (pathophysiological trait) - Increased in the asymptomatic task (compensatory adaptation) Berman et al. Brain 2013 Simonyan et al. J Neurosci 2013 Brain Dynamic Neurochemical Changes in Dystonic Patients assessed using 1 H-MR spectroscopy 5-Hz TMS over FDI hot spot in writer s cramp and controls Pu M1 HV WC After TMS, GABA concentrations in M1: - Decreased in patients - Increased in healthy volunteers Marjanska et al. Mov Dis

12 3. Loss of selectivity of neuronal representations Loss of the normal neuronal selectivity in the primary sensory cortex in writer s cramp Controls WC C 3b Writer s cramp MEG Electrical stimulation Meunier et al. Ann Neurol 2001 fmri Vibrotactile stimulation Nelson et al. Ann Neurol

basal ganglia Foot hand lips fmri movements of body parts Delmaire et

13 Loss of the normal neuronal selectivity in the basal ganglia in writer s cramp L R Affected R Hemisphere Representation of body parts in the basal ganglia Foot hand lips fmri movements of body parts Delmaire et al. Neurology Resting state functional connectivity in dystonia 12

Resting-state functional connectivity changes

Functional connectivity was reduced in the

Cervical dystonia (The Netherlands) - Executive

mode network (writer s cramp) Mohammadi 2011

Functional connectivity changes correlated with

Frontal (WC) Postcentral gyrus (WC) Delnooz et

14 Resting-state functional connectivity changes in dystonias 1. Functional connectivity was reduced in the sensorimotor network Basal ganglia / Cerebellum! Cortex Dresel 2014 (Germany) Parietal! Frontal Delnooz 2012 (The Netherlands) Mohammadi 2011 (Germany) 2. Functional connectivity increased Delnooz 2013 Cervical dystonia (The Netherlands) - Executive control network (cervical dystonia) - Default mode network (writer s cramp) Mohammadi 2011 (Germany) Resting-state functional connectivity changes in dystonias 3. Functional connectivity changes correlated with disease severity Parietal! Frontal (WC) Postcentral gyrus (WC) Delnooz et al. Mov Dis 2012 (The Netherlands) Dresel et al. JNNP 2014 (Germany) 4. BoNT had variable effects on rsfmri functional connectivity No effect (WC) Mohammadi HBM 2011 Increased in premotor cortex (CD) Delnooz PlosOne

15 5. Abnormal brain function in dystonia Overview of functional changes during task performance in dystonia PET / fmri activation changes were observed in - Sensorimotor cortex - SMA/premotor Cerebellum - Parietal cortex - Thalamus - Basal ganglia - Cerebellum SMA Thalamus Parietal cortex Sensorimotor cortex Premotor cortex Basal ganglia Activation changes were variable Overall (but not always), tasks that - induced dystonia! activation increase - did not induce dystonia! activation decrease Zoons et al. Neuroimage

Overview of functional changes in dystonia 1) Task that did not induce

in blepharospasm during eyelid spasms (fmri) Schmidt et al.

(fmri) Dresel Brain 2006 Abnormal cerebello-cortical motor network

non-manifesting DYT1 carriers presented learning deficits.

16 Overview of functional changes in dystonia 1) Task that did not induce dystonia Patient Control Underactivation M1 and SMA in writer s cramp (fmri) Oga et al. Brain ) Task that induced dystonia Overactivation in the striatum in blepharospasm during eyelid spasms (fmri) Schmidt et al. Neurology 2003 Underactivation in M1 in Meige syndrome during whistling (fmri) Dresel Brain 2006 Abnormal cerebello-cortical motor network function during sequence learning in DYT1-6 dystonia - Manifesting and non-manifesting DYT1 carriers presented learning deficits. - In manifesting DYT1 learning-related activation increased in - the left lateral cerebellar cortex - the right premotor and inferior parietal regions. Carbon et al. Brain

Basal ganglia dysfunction during finger movement in WC Writer s cramp Individuated versus coupled finger movement

Increased Left Putamen (motor)! SM1/Cereb Moore, Gallea et al.

during fmri recording Right hand Left hand Right foot Writing Connectivity analysis: * 40 Writer s cramp Reduced Pu

17 Basal ganglia dysfunction during finger movement in WC Writer s cramp Individuated versus coupled finger movement Individuated finger movement in patients Activation Reduced in left posterior Putamen (motor) Functional connectivity Increased Left Putamen (motor)! SM1/Cereb Moore, Gallea et al. Neuroimage 2012 (NIH) Impairment of parieto-premotor network during handwriting in writer s cramp Zig-zagging Tasks during fmri recording Right hand Left hand Right foot Writing Connectivity analysis: * 40 Writer s cramp Reduced Pu activation Reduced Pu Left S1 functional connectivity Reduced Par PM activation deficit during writing Effective connectivity IPL-PMv (%) HV WC Gallea et al. HBM

Basal ganglia dysfunction during motor learning in writer s cramp 8-move

controls Activation Reduced in anterior Putamen Activation Increased in

ganglia function during motor sequence learning and individuated finger

) function in motor-related cortical areas Gallea et al.

cramp Consolidation of memory trace: comparison of performances before and

PMd Δ error (%) Fractional anisotropy Δ intertap interval (%) Fractional

18 Basal ganglia dysfunction during motor learning in writer s cramp 8-move finger sequence explicit learning task Equiperformance between patients and controls Activation Reduced in anterior Putamen Activation Increased in Par-PM areas Functional connectivity Increased Striatum - PMd Impaired basal ganglia function during motor sequence learning and individuated finger movement tasks Increased (compensatory?) function in motor-related cortical areas Gallea et al. Neuroimage Clin 2015 Abnormal consolidation of motor memory trace in writer s cramp Consolidation of memory trace: comparison of performances before and after a night sleep Controls: Striatum Hippocampus WC patients: Striatum - PMd Δ error (%) Fractional anisotropy Δ intertap interval (%) Fractional anisotropy Consolidation of finger sequence is achieved using alternate cortico-basal ganglia circuits in writer s cramp Gallea et al. Neuroimage Clin

Cerebellar dysfunction during visuospatial task in CD

Visuospatial task requiring predictive motor timing X

Increased in lobule IV-V/vermis Activation Reduced in

visuospatial motor task Impaired cerebellar basal ganglia

19 Cerebellar dysfunction during visuospatial task in CD Visuospatial task Control task Cervical dystonia Visuospatial task requiring predictive motor timing X Visuospatial tracking task Grey matter Reduced in dentate Increased in lobule IV-V/vermis Activation Reduced in cerebellum Functional connectivity Decreased cerebellum and basal ganglia! parietal lobe Impaired cerebellar function during visuospatial motor task Impaired cerebellar basal ganglia connectivity Filip, Gallea et al. Mov Disord 2017 (Brno, Czech Republic) 6. Are changes primary or secondary phenomenon? 18

Structural changes: cause or consequence?

MT/ V5 region following juggling Draganski Nature 2004 - White matter: extensive piano

ganglia volume changes in asymptomatic DYT1 carriers Subjects (11 symptomatic, 11

20 Structural changes: cause or consequence? Structural changes are observed following normal training - Grey matter: increased in MT/ V5 region following juggling Draganski Nature White matter: extensive piano practicing increases FA in the internal capsule Bengtsson Nature Neurosci 2005 Basal ganglia volume changes in asymptomatic DYT1 carriers Subjects (11 symptomatic, 11 asymptomatic DYT1 carriers, 28 controls) VBM Increased putamen volume in asymptomatic DYT1 carriers Draganski et al. Neuroimage

Temporal Discrimination Threshold: VBM evidence for an endophenotype in adult onset primary torsion dystonia Temporal Discrimination Threshold: shortest time interval at which two

normal TDT Abnormal TDT! "putamen in unaffected 1st-degree relatives Suggests that putaminal enlargement is a primary phenomenon Bradley et al. Brain 2009, Kimmisch et al.

21 Temporal Discrimination Threshold: VBM evidence for an endophenotype in adult onset primary torsion dystonia Temporal Discrimination Threshold: shortest time interval at which two stimuli are detected to be asynchronous, visual or tactile Control > 50 years 30 ms AOPTD patients/relatives 70 / 52 ms Abnormal TDT (%pop) 86% 52% unaffected relatives abnormal TDT > normal TDT Abnormal TDT! "putamen in unaffected 1st-degree relatives Suggests that putaminal enlargement is a primary phenomenon Bradley et al. Brain 2009, Kimmisch et al. Brain 2011 White matter changes in non-manifesting DYT1/6 dystonia Reduced connectivity Manifesting Non-manifesting Non-manifesting Cerebello-thalamo-cortical pathway Argyelan et al. J NeuroSci

22 Structural and functional changes pre-existing to the occurrence of dystonia Altered S1 finger somatotopy in the non dominant hemisphere of writer s cramp patient controlling the normal hand Topoggraphic order of the fingers Meunier et al. Ann Neurol 2001 Somatosensory cortical remodelling after rehabilitation and clinical benefit in writer's cramp Healthy subject Normal Untreated WC Disorganized Rehabiitated WC Normal Bleton et al. JNNP

Summary of structural and functional changes in primary dystonia Structural and functional changes in primary dystonias are commonly observed at multiple levels of the sensorimotor network (VBM,

23 Summary of structural and functional changes in primary dystonia Structural and functional changes in primary dystonias are commonly observed at multiple levels of the sensorimotor network (VBM, diffusion, tractography, fmri) Sensorimotor Basal ganglia-thalamo-cortical cortex Cerebello-thalamo-cortical SMA Cerebellum and connections PMC Thalamus Striatum Globus pallidus Zoons et al. Neuroimage 2011 Lehericy et al. Mov Disord 2013 Stoessl, Lehericy, Strafella Lancet 2014 Take home messages Structural changes are present in the basal ganglia and cerebellar networks => dystonia as a network disorder Altered selectivity of neuronal representation Reduced functional connectivity in the sensorimotor network Increased functional connectivity in other circuits (may be compensatory) Abnormal movement and motor learning circuits Primary and secondary changes 22

ICM Brain and Spine Institute / CENIR Centre for NeuroImaging Research Denis Schwartz Romain Valabrègue ICM U1127, Inserm, CNRS, Université Pierre et Marie Curie

24 ICM Brain and Spine Institute / CENIR Centre for NeuroImaging Research Denis Schwartz Romain Valabrègue ICM U1127, Inserm, CNRS, Université Pierre et Marie Curie Paris 6 Cécile Gallea Sabine Meunier Emmanuel Roze Marie Vidailhet INSERM U678 Habib Benali Mélanie Pélégrini-Issac Vincent Perlbarg CHRU Lille Christine Delmaire 23

Telencephalon (Cerebral Hemisphere)

Telencephalon (Cerebral Hemisphere) OUTLINE The Cortex - Lobes, Sulci & Gyri - Functional Subdivisions - Limbic Lobe & Limbic System The Subcortex - Basal Ganglia - White Matter (Internal Capsule) - Relations