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Movement Disorders

The Movement Disorders group bridges clinical, computational and cognitive neuroscience to advance the pathophysiological understanding of movement disorders.

The Movement Disorders group is headed by David Meder. It is situated both at DRCMR and the Department of Neurology at Copenhagen University Hospital Bispebjerg. Our research primarily focuses on Parkinson´s disease and dystonia. 

The mission of the Movement Disorders group is to use advanced brain mapping techniques in combination with computational modeling to investigate how movement disorders alter brain function and structure in motor, cognitive and limbic systems. We use the ultra-high field (7 tesla) MR scanner in order to map the structural integrity of midbrain nuclei at high resolution. This allows us to investigate the relationship between the individual spatial pattern of neurodegeneration in Parkinson’s disease and the patient’s clinical symptoms.

We apply computational models of learning and decision-making to probe disease-induced changes in brain and behavior. Traditionally, clinical neuroimaging has often taken a predominantly descriptive approach, describing that there is a change in brain or behavior observed in the disorder. Computational neurology goes one step further: We create computer algorithms that mimic how the function under investigation might be solved by the brain. If such a model then fits to the observed behavior and neural activity, we can infer that the brain (approximately) uses the kind of algorithm we defined in the model. Observing which parameters of the model are changed in the disease can then lead to a mechanistic understanding, explaining not only that there are disease-induced changes, but how the changes occur at the neural and symptomatic level.

We are not only interested in studying primary dysfunction directly caused by the movement disorder but also secondary dysfunctions of brain networks that are associated with therapy. We wish to exploit this knowledge to advance personalized medicine and precision treatment. 

Many members of the Movement Disorders group are part of the ADAPT-PD project.

Key projects

Unravelling altered network dynamics in the mid-brain and striatum in Parkinson's disease with ultra-high field MRI

In this project, we use ultra-high field (7T) functional and structural MRI to map the individual degree and spatial pattern of neurodegeneration in PD patients and relate it to the patient’s motor and non-motor symptoms. We focus on two neurotransmitter systems, the dopaminergic and the noradrenergic system.

The large majority of dopamine neurons are situated in two midbrain nuclei, the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc). While the neurodegeneration in the latter is mostly responsible for the motor symptoms in PD, VTA neurons are associated with reward-based learning. Here, we interrogate the relation between the neurodegeneration in these regions measured with structural MRI and the functional activation during a task that requires learning about the values of certain actions and stimuli.

The locus coeruleus (LC), a small nucleus in the brain stem, is the main source of noradrenergic projection neurons and it is also heavily affected by neurodegeneration in PD. Noradrenaline lies at the core of eliciting an arousal response to novel and surprising events and has a tight coupling to the sympathetic nervous system. Novel ultra-high field imaging procedures allow the quantification of degeneration along the structure. We can show that the LC does not degenerate uniformly and that cell death in different parts of the structure correlate with different non-motor symptoms. We furthermore acquire functional images of the LC while participants are presented with surprising and emotionally arousing auditory and visual stimuli which we then will relate to the individual structural disintegration.

Tracing the emergence of dyskinesia in Parkinson´s disease

Dopamine replacement therapy with levodopa is a cornerstone in the treatment for Parkinson’s disease. While dopamine replacement therapy is effective, a large subgroup of patients develops involuntary movements (dyskinesia) as a side effect after several years of treatment. Our research group has recently implicated the pre-supplementary motor area (pre-SMA) in the pathophysiology of levodopa-induced dyskinesia (Herz et al., 2014). Using functional magnetic resonance imaging (fMRI), which reflects regional cerebral activity, we showed that a single oral dose of levodopa gave rise to an abnormal activation of the pre-SMA and the putamen during a response inhibition (NoGo) task in PD patients who would later develop dyskinesia. This hyperactivity emerged rapidly within a few minutes after the intake of levodopa. At the individual level, the excessive neural activation during the pre-dyskinesia period predicted the severity of patient´s day-to-day dyskinetic movements.

In a subsequent study (Lohse et al., 2020), we then suppressed this abnormal pre-SMA activation with repetitive TMS. We found this inhibitory TMS to both reduce dyskinesia severity as well as delay its onset. This effect was directly related to the efficiency of the inhibitory stimulation: First, the more dyskinesia severity was reduced, the more was preSMA activity suppressed. Second, the longer the onset of dyskinesia was delayed, the stronger the electrical field induced by TMS in the preSMA. We are now building on these results to further elucidate the potential of personalized precision stimulation as a treatment in PD in the ADAPT-PD project.

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Fig. 1: Graphical summary of the results of inhibitory TMS over preSMA on dyskinesia symptoms in PD (Lohse et al., 2020).

 

Medication-induced impulse control disorders in Parkinson's disease

Over the recent years it has become evident that a substantial fraction of patients with Parkinson's disease develop impulse control disorders (ICD) as a result of dopaminergic medication. Most common ICD manifestations in Parkinson's disease are pathological gambling, compulsive buying, compulsive sexual behaviours and eating disorders. These impulsive behaviours have serious psycho-social and economic consequences for the patients and their relatives. It is widely thought that impulsive behaviours result from a dysfunction of brain networks involved in response inhibition.  

Using a novel sequential gambling paradigm for fMRI (see figure), we studied task-induced activation of the response inhibition networks in patients with and without ICD (Haagensen et al., 2020).

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Fig. 2: Changes in inhibition networks in ICD. Patients with Parkinson´s Disease (PD) played a sequential dice gambling task.  In each round, patients accumulated reward in proportion to the number of eyes on the dice from throw to throw. If patients threw a “1”, all earnings accumulated in that round would be lost.  At each throw patients had the choice between continuing the gamble (CONTINUE) or to stop. 

On two separate days, we scanned patients with Parkinson´s disease, while they were taking their usual dopaminergic treatment and after treatment had been paused. This allowed us to investigate how response inhibition networks were affected by dopaminergic treatment in the two groups. We found several differences in activity and connectivity patterns that might make PD patients with ICD more vulnerable to the emergence of ICD: Independent of medication, we found that the inhibitory control network showed reduced activity in patients with ICD as they took risky choices. Furthermore, in all PD patients, dopamine replacement therapy reduced pre-SMA connectivity with two other subcortical structures, However, in patients with ICD, medication additionally reduced cortico-subcortical connectivity in a second network.

Movement Disorders gruppe billede 3 

Research Funding

We wish to thank for the generous support by the Danish Parkinson Association, Augustinusfonden, the Jascha Foundation, and the Danish Council for Independent Research - Health and Disease (grant. 09-072163 and 7016-00226B), the NovoNordisk Foundation (grant NNF16OC0023090) and Social Sciences (“Ludomaniprogrammet”, grant. 10-088255).

Selected Publications

Siebner, Thomas Hartwig, Stefan Fuglsang, Christopher Fugl Madelung, Annemette Løkkegaard, Flemming Bendtsen, Jens Dahlgaard Hove, Morten Damgaard, Jan Lysgård Madsen, and Hartwig Roman Siebner. “Gastric Emptying Is Not Delayed and Does Not Correlate With Attenuated Postprandial Blood Flow Increase in Medicated Patients With Early Parkinson’s Disease.” Frontiers in Neurology 13 (2022). https://www.frontiersin.org/article/10.3389/fneur.2022.828069.

Madelung, Christopher F., David Meder, Søren A. Fuglsang, Marta M. Marques, Vincent O. Boer, Kristoffer H. Madsen, Esben T. Petersen, Anne-Mette Hejl, Annemette Løkkegaard, and Hartwig R. Siebner. “Locus Coeruleus Shows a Spatial Pattern of Structural Disintegration in Parkinson’s Disease.” Movement Disorders 37, no. 3 (2022): 479–89. https://doi.org/10.1002/mds.28945.

Siebner, Thomas Hartwig, Christopher Fugl Madelung, Flemming Bendtsen, Annemette Løkkegaard, Jens Dahlgaard Hove, and Hartwig Roman Siebner. “Postprandial Increase in Mesenteric Blood Flow Is Attenuated in Parkinson’s Disease: A Dynamic PC-MRI Study.” Journal of Parkinson’s Disease 11, no. 2 (January 1, 2021): 545–57. https://doi.org/10.3233/JPD-202341.

Herz, Damian M., David Meder, Julia A. Camilleri, Simon B. Eickhoff, and Hartwig R. Siebner. “Brain Motor Network Changes in Parkinson’s Disease: Evidence from Meta-Analytic Modeling.” Movement Disorders 36, no. 5 (2021): 1180–90. https://doi.org/10.1002/mds.28468.

Lohse, Allan, David Meder, Silas Nielsen, Anders Elkjær Lund, Damian M Herz, Annemette Løkkegaard, and Hartwig R Siebner. “Low-Frequency Transcranial Stimulation of Pre-Supplementary Motor Area Alleviates Levodopa-Induced Dyskinesia in Parkinson’s Disease: A Randomized Cross-over Trial.” Brain Communications 2, no. 2 (July 1, 2020): fcaa147. https://doi.org/10.1093/braincomms/fcaa147.

Haagensen, Brian N., Damian M. Herz, David Meder, Kristoffer H. Madsen, Annemette Løkkegaard, and Hartwig R. Siebner. “Linking Brain Activity during Sequential Gambling to Impulse Control in Parkinson’s Disease.” NeuroImage: Clinical 27 (January 1, 2020): 102330. https://doi.org/10.1016/j.nicl.2020.102330.

Betts, Matthew J., Evgeniya Kirilina, Maria C. G. Otaduy, Dimo Ivanov, Julio Acosta-Cabronero, Martina F. Callaghan, Christian Lambert, et al. “Locus Coeruleus Imaging as a Biomarker for Noradrenergic Dysfunction in Neurodegenerative Diseases.” Brain 142, no. 9 (September 1, 2019): 2558–71. https://doi.org/10.1093/brain/awz193.

Meder, David, Damian Marc Herz, James Benedict Rowe, Stéphane Lehéricy, and Hartwig Roman Siebner. “The Role of Dopamine in the Brain - Lessons Learned from Parkinson’s Disease.” NeuroImage, Mapping diseased brains, 190 (April 15, 2019): 79–93. https://doi.org/10.1016/j.neuroimage.2018.11.021.

Irmen, Friederike, Andreas Horn, David Meder, Wolf-Julian Neumann, Philip Plettig, Gerd-Helge Schneider, Hartwig Roman Siebner, and Andrea A. Kühn. “Sensorimotor Subthalamic Stimulation Restores Risk-Reward Trade-off in Parkinson’s Disease.” Movement Disorders 34, no. 3 (2019): 366–76. https://doi.org/10.1002/mds.27576.

Meder, David, and Hartwig Roman Siebner. “Spectral Signatures of Neurodegenerative Diseases: How to Decipher Them?” Brain 141, no. 8 (August 1, 2018): 2241–44. https://doi.org/10.1093/brain/awy195.

Lehericy, Stéphane, David E. Vaillancourt, Klaus Seppi, Oury Monchi, Irena Rektorova, Angelo Antonini, Martin J. McKeown, et al. “The Role of High-Field Magnetic Resonance Imaging in Parkinsonian Disorders: Pushing the Boundaries Forward.” Movement Disorders 32, no. 4 (April 1, 2017): 510–25. https://doi.org/10.1002/mds.26968.

Correia, M. M., Rittman, T., Barnes, C. L., Coyle-Gilchrist, I. T., Ghosh, B., Hughes, L. E. & Rowe, J. B.
Towards accurate and unbiased imaging-based differentiation of Parkinson's disease, progressive supranuclear palsy and corticobasal syndrome.
Brain communications. 2, 1, p. 1-18, fcaa051. 2020.

Kaalund, S. S., Passamonti, L., Allinson, K. S. J., Murley, A. G., Robbins, T. W., Spillantini, M. G. & Rowe, J. B.
Locus coeruleus pathology in progressive supranuclear palsy, and its relation to disease severity.
Acta neuropathologica communications. 8, 1, p. 1-11, 11. 2020.

van der Vegt, J. P. M., Hulme, O. J., Madsen, K. H., Buhmann, C., Bloem, B. R., Münchau, A., Helmich, R. C. & Siebner, H. R.
Dopamine agonist treatment increases sensitivity to gamble outcomes in the hippocampus in de novo Parkinson's disease.
NeuroImage. Clinical. 28, p. 1-8, 102362. 2020.

Dogonowski, A. M., Andersen, K. W., Sellebjerg, F., Schreiber, K., Madsen, K. H. & Siebner, H. R.
Functional neuroimaging of recovery from motor conversion disorder: A case report.
NeuroImage. 190, p. 269-274, 2019.

Dubbioso, R., Manganelli, F., Siebner, H. R. & Di Lazzaro, V.
Fast Intracortical Sensory-Motor Integration: A Window Into the Pathophysiology of Parkinson's Disease.
Frontiers in Human Neuroscience. 13, p. 1-14, 111. 2019.

van Eimeren, T., Antonini, A., Berg, D., Bohnen, N., Ceravolo, R., Drzezga, A., Höglinger, G. U., Higuchi, M., Lehericy, S., Lewis, S., Monchi, O., Nestor, P., Ondrus, M., Pavese, N., Peralta, M. C., Piccini, P., Pineda-Pardo, J. Á., Rektorová, I., Rodríguez-Oroz, M., Rominger, A., Seppi, K., Stoessl, A. J., Tessitore, A., Thobois, S., Kaasinen, V., Wenning, G., Siebner, H. R., Strafella, A. P. & Rowe, J. B.
Neuroimaging biomarkers for clinical trials in atypical parkinsonian disorders: Proposal for a Neuroimaging Biomarker Utility System.
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. 11, p. 301-309, 2019.

Siebner, Hartwig R., David Meder, and Damian M. Herz. “FMRI in Parkinson’s Disease.” In FMRI: Basics and Clinical Applications, edited by Stephan Ulmer and Olav Jansen, 417–31. Cham: Springer International Publishing, 2020. https://doi.org/10.1007/978-3-030-41874-8_26

Thomsen, B. L. C., Herz, D. M., Siebner, H. R. & Løkkegaard, A.
Dyskinesier ved Parkinsons sygdom: opdatering om nye billeddannende metoder og behandlingsmuligheder.
Ugeskrift for Laeger. 12, 2017, p. 2-6, 2017.

Lehéricy, S., Vaillancourt, D. E., Seppi, K., Monchi, O., Rektorova, I., Antonini, A., McKeown, M. J., Masellis, M., Berg, D., Rowe, J. B., Lewis, S. J. G., Williams-Gray, C. H., Tessitore, A., Siebner, H. R. & International Parkinson and Movement Disorder Society -Neuroimaging Study Group.
The role of high-field magnetic resonance imaging in parkinsonian disorders: Pushing the boundaries forward.
Movement disorders. 32, 4, p. 510-525, 2017.

Løkkegaard A, Herz DM, Haagensen BN, Lorentzen AK, Eickhoff SB, Siebner HR (2016) Altered sensorimotor activation patterns in idiopathic dystonia - an activation likelihood estimation meta-analysis of functional brain imaging studies. Hum Brain Mapp 37:547-557.

Herz DM,  Haagensen BN, Nielsen SH, Madsen KH, Løkkegaard A, Siebner HR (2016) Resting-state connectivity predicts levodopa-induced dyskinesias in Parkinson’s disease. Mov Disord 31:521-529.

Herz DM, Haagensen BN, Christensen MS, Madsen KH, Rowe JB, Løkkegaard A, Siebner HR (2015) Abnormal dopaminergic modulation of striato-cortical networks underlies levodopa-induced dyskinesias in humans. Brain 138:1658-1666.

Herz DM, Haagensen BN,Christensen MS, Madsen KH, Rowe J, Løkkegaard A, Siebner HR (2014) The acute brain response to levodopa heralds dyskinesias in Parkinson’s disease. Ann Neurol 75:829-836.

Herz DM, Eickhoff SB, Løkkegaard A, Siebner HR (2014) Functional neuroimaging of motor control in Parkinson’s disease: A meta-analysis. Hum Brain Mapp 35:3227-3237. 

van der Vegt JPM, Hulme OJ, Zittel S, Madsen KH, Weiss MM, Buhmann C, Bloem BR, Münchau A, Siebner HR (2013) Attenuated neural response to gamble outcomes in drug-naive patients with Parkinson’s disease. Brain 136:1192-1203.

 

 

Group Members

David Meder

Group Leader

Hartwig R. Siebner

Anders Elkjær Lund

Rozerin Sarihan

Show all group members (22)

External Collaborators

Assoc. Prof. Annemette Løkkegaard

Copenhagen University Hospital Bispebjerg


Damian M. Herz, MD, PhD

Nuffield Department of Clinical Neurosciences
University of Oxford


Prof. Stéphane Lehericy, MD, PhD

Institut du Cerveau et de la Moelle épinière – ICM, 
Centre de NeuroImagerie de Recherche – CENIR, Sorbonne Universités, Paris


Prof. James Rowe

Behavioural and Clinical Neuroscience Institute
Dept. of Clinical Neurosciences, University of Cambridge


Prof. Angela Cenci Nilsson

Lund University


Prof. Andrea Kühn,

Charité - Universitätsmedizin Berlin
Movement Disorders and Neuromodulation Section