The Human Connectome Project Connectome Dysfunctions in PD

Connectome Dysfunction in Parkinson’s Disease

ADEMOLA A. OREMOSU MBBS, MSc, PhD.

International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA Tel: +1 414- 276-2145 | www.movementdisorders.org | [email protected] Objectives

.Define Connectomes .Describe the basic connnections of the Brain and Connectoctomics .Describe the disorders of Connectomes in Parkinson’s Disease Outline 3

• Parkinson’s disease: What is it? Brief History Clinical and Neuropathological features

• Synaptic and structural plasticity changes in PD Brain connectome and connectomics The Human Connectome Project Connectome dysfunctions in PD

• Summary/conclusions 4 What is Parkinson’s disease (PD)? 5

•Disorder of the nervous system that primarily affects movements and bodily coordination. Brief History of PD 6

• In 175 AD, Galen described a condition characterised by tremors as ‘Shaking Palsy’.

• Modern understanding of PD is attributed to James Parkinson and Jean-Martin Charcot. Types of PD 7 Global epidemiology of PD 8

• The most common movement disorder affecting 1 - 2 % of the general population over the age of 65 years.

• The second most common neurodegenerative disorder after Dorsey, E. R., Elbaz, A., Nichols, E., Abd-Allah, F., Abdelalim, A., Adsuar, J. C. & Dahodwala, N. (2018). Global, regional, and national burden of Parkinson's disease, 1990–2016: a systematic analysis for the Alzheimer’s disease (AD) Global Burden of Disease Study 2016. The Lancet Neurology, 17(11), 939-953. Epidemiology of PD in Africa 9

Oluwole, O. G., Kuivaniemi, H., Carr, J. A., Ross, O. A., Olaogun, M. O., Bardien, S., & Komolafe, M. A. (2019). Parkinson's disease in Nigeria: A review of published studies and recommendations for future research. Parkinsonism & related disorders, 62, 36-43. Neuropathological features of PD 10 PD is a multisystem synucleinopathy that produces degeneration in selectively vulnerable neuronal populations, such as dopaminergic neurons in the substantia nigra.

Patel, D., Sharma, K., Chauhan, C. S., & Jadon, G. (2014). A CHRONIC, PROGRESSIVE Dickson, D. W. (2018). Neuropathology of Parkinson NEUROLOGICAL DISORDER PARKINSON’S DISEASE-MECHANISMS AND disease. Parkinsonism & related disorders, 46, S30- TREATMENT. Journal of Drug Delivery and Therapeutics, 4(1), 84-91. S33. Neuropathological features of PD 11

Putative organization of the dopaminergic synapse in healthy condition and in PD.

Bellucci, A., Mercuri, N. B., Venneri, A., Faustini, G., Longhena, F., Pizzi, M., ... & Spano, P. (2016). Parkinson's disease: from synaptic loss to connectome dysfunction. Neuropathology and applied neurobiology, 42(1), 77-94. Brain Connectomes and Connectomics 12

Fox, M. D. (2018). Mapping symptoms to brain networks with the human connectome. New England Journal of Medicine, 379(23), 2237-2245. Brain Connectomes and Connectomics 13

• The present use of the term connectome refers to the large-scale connections between sections of cortex and possibly the subcortical structures. • Older adults show robust decreases in functional correlations in the default network.

• The ability to demonstrate the functional organization of the cortex before cutting into the brain has profound potential towards reducing morbidity of PD and of other NDs.

Eggermont, J. J. (2019). The Auditory Brain and Age-related Hearing Impairment. Sughrue, M. E., & Yang, I. (Eds.). (2019). New Techniques for Academic Press. Management of ‘Inoperable’Gliomas. Academic Press. Synaptic and structural plasticity changes in PD 14

• In the brain, the connectivity between neurons (synapses) and their transmission efficiencies determine information processing and storage in neural networks.

• Two major processes are responsible for connectivity changes: Structural/architectural plasticity Synaptic plasticity

• Structural plasticity can be seen as: The outgrowth and retraction of axons and dendrites primarily taking place during developmental phases or after injuries of the network structure. The process of creating and removing synapses

• Spines are highly motile structures, which can appear and disappear on a time scale of hours to days.

• Their lifetime depend on their head volume, which correlates with the strength of the excitatory postsynaptic potentials from the corresponding synapse.

Fauth M, Worgotter F, Tetzlaff C. The formation of multi-synaptic connections by the Matsuzaki M, Ellis-Davies GC, Nemoto T, Miyashita Y, Iino M, Kasai H. Dendritic spine interaction of synaptic and structural plasticity and their functional consequences. PLoS geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Comput Biol 2015; 11: e1004031. Nat Neurosci 2001; 4: 1086–92 Dendritic spines formation 17

Chen, C. C., Lu, J., & Zuo, Y. (2014). Spatiotemporal Spine remodeling at different stages of an animal’s life. dynamics of dendritic spines in the living brain. Frontiers in neuroanatomy, 8, 28. Synaptic plasticity changes in PD 18

• Synaptic plasticity is the ability of neurons to bring about changes in the connections between them in response to use or disuse. • It can be short-term or long-term. • Striatal spiny projection neurons (SPNs) exhibit long-term potentiation (LTP) and long-term depression (LTD) at corticostriatal synapses

• PD is a disorder of synapses and circuits. • Postmortem tissues from PD patients demonstrate apparent alterations in the morphologies of SPNs, such as a significant reduction in the length of the dendritic tree and a loss of spine density

Bliss, T. V., & Lømo, T. (1973). Long‐lasting potentiation of synaptic transmission Zucker, R. S., & Regehr, W. G. (2002). Short-term Stephens B, Mueller AJ, Shering AF, Hood SH, Taggart P, Arbuthnott GW, et al. in the dentate area of the anaesthetized rabbit following stimulation of the synaptic plasticity. Annual review of physiology, Evidence of a breakdown of corticostriatal connections in Parkinson’s disease. perforant path. The Journal of physiology, 232(2), 331-356. 64(1), 355-405. Neuroscience. 2005;132:741–54. Synaptic plasticity changes in PD 19

Dendritic spine dynamics in the mouse motor cortex in motor learning and Parkinson’s disease. (A) Illustration of an anesthetized animal under a 2-photon microscope. (B) Targeted area of the skull is marked with circle for in vivo imaging. (C) Blood vasculature under the chronic window was imaged using a charge-coupled device camera and was used as a landmark for relocating the same region during repeated imaging. (D) In vivo 2-photon imaging dendritic spines of layer V pyramidal neurons using Thy1-YFP transgenic mice. Two-photon image with low magnification of dendritic branches in the region indicated in the white box in (C). (E-H) I. Schematic of changes in spine formation and elimination in motor skill training and following dopamine depletion.

Xu, T., Wang, S., Lalchandani, R. R., & Ding, J. B. (2017). Motor learning in animal models of Parkinson's disease: Aberrant synaptic plasticity in the motor cortex. Movement Disorders, 32(4), 487-497. Synaptic plasticity changes in PD 20

• Spine formation is modulated by the activation of D2 receptor, and spine stabilization is regulated by D1 receptor activation.

• Motor learning induces activity-dependent spine formation and stabilization.

• Stabilization of newly formed is proposed to be one of the neural substrates for encoding long-lasting motor memory.

• In PD, the lack of dopamine receptor activation leads to increased rates of spine elimination.

• Xu et al. (2017) showed that skill training enhanced spine survival in the motor cortex that persists for many months.

• Thus, skill training might be beneficial for synaptic plasticity and maintenance of newly formed spines.

• Compelling evidences have shown that in PD, there is: • Pathological accumulation of α- synuclein, and • Reduction in NMDA receptor activity • These result in alterations of synaptic and structural plasticity that could then lead to connectome deficits

• The “connectome” is a name coined in analogy to the genome, and basically comprises the structural, functional, and affective neural networks in the brain. • It is simply put, a comprehensive map of neural connections in the brain • Connectomics borrows the “-omics” suffix from genomics as it is a big data approach for analyzing the massive datasets produced by functional and structural brain imaging

Eggermont, J. J. (2019). The Auditory Brain and Age-related Hearing Impairment. Sughrue, M. E., & Yang, I. (Eds.). (2019). New Techniques for Management Academic Press. of ‘Inoperable’Gliomas. Academic Press. Brain Connectomes and Connectomics 24

• The connectome can be studied as a network by means of graph theory consisting of nodes (neurons) and edges (synapses/connections)

• Thus connectomes are sometimes referred to as brain graphs.

Greenough, W. T., & Bailey, C. H. (1988). The anatomy of a memory: convergence Components of the Human Connectome Project - Network Modeling - Connectome of results across a diversity of tests. Trends in Neurosciences, 11(4), 142-147. https://www.humanconnectome.org/study/hcp-young-adult/project-protocol/network- modeling. Accessed: 2020-08-29 Plasticity of the connectome 25

• Neural connectivity is subject to change - neuroplasticity.

• There are two ways that the brain can rewire: • Microscale rewiring (formation and removal of synapses in an established connection) • Macroscale rewiring (formation or removal of entire connections between neurons)

Greenough, W. T., & Bailey, C. H. (1988). The anatomy of a memory: convergence Sughrue, M. E., & Yang, I. (Eds.). (2019). New Techniques for of results across a diversity of tests. Trends in Neurosciences, 11(4), 142-147. Management of ‘Inoperable’Gliomas. Academic Press. The Human Connectome Project (HCP) 26

Human Connectome Project | About Human Connectome Project marks its first phase | National Institutes of Health (NIH) http://www.humanconnectomeproject.org/about/ https://www.nih.gov/news-events/news-releases/human-connectome-project-marks-its-first-phase Accessed: 2020-08-29 Accessed: 2020-08-29 The Human Connectome Project (HCP) 27

• The HCP is a project to construct a map of the complete structural and functional neural connections in vivo within and across individuals.

• It was a five-year project that began in September, 2010, sponsored by sixteen components of the National Institutes of Health.

• It was the first large-scale attempt to collect and share data about human connectional anatomy and variation.

• The study of focal brain lesions has traditionally been used to map neurologic symptoms to specific regions.

• However, many neurologic and psychiatric symptoms correspond more closely to networks of connected regions, hence the need for the human connectome

Fox, M. D. (2018). Mapping symptoms to brain networks with the human connectome. New England Journal of Medicine, 379(23), 2237-2245. The Human Connectome Project (HCP) 29

• Over time, it became apparent that lesion-based localization (LBL) is sometimes flawed because similar symptoms can result from lesions in different brain locations

• LBL is also limited by the fact that many complex symptoms occur in patients without overt brain lesions.

Fox, M. D. (2018). Mapping symptoms to brain networks with the human connectome. New England Journal of Medicine, 379(23), 2237-2245. Functional Neuroimaging 30

• Functional neuroimaging can detect imagingStructural regional changes in brain metabolism, blood flow, blood oxygenation, water diffusion, and electrical activity.

• Because these physiological changes can be identified in regions that appear Functional imaging anatomically intact, neuroimaging can localize symptoms in patients who have no structural brain lesions.

Fox, M. D. (2018). Mapping symptoms to brain networks with the human Biran, I., Admon, R., Gazit, T., & Fahoum, F. (2020). Interaction of Temporal Lobe connectome. New England Journal of Medicine, 379(23), 2237-2245. Epilepsy and Posttraumatic Stress Disorder: Network Analysis of a Single Case. Frontiers in Psychology, 11, 1010. Functional Neuroimaging 31

• Two types of connectivity have been explored: 1. Anatomical connectivity is derived from MRI sequences (sensitive to water diffusion) 2. Functional connectivity is derived from MRI sequences (sensitive to spontaneous fluctuations in blood oxygenation, an indirect marker of neuronal activity)

Fox, M. D. (2018). Mapping symptoms to brain networks with the human connectome. New England Journal of Medicine, 379(23), 2237-2245. Mapping Symptoms to Brain Networks with the Human Connectome 32 • Over time, it became apparent that lesion-based localization (LBL) is sometimes flawed because similar symptoms can result from lesions in different brain locations

• LBL is also limited by the fact that many complex symptoms occur in patients without overt brain lesions.

Fox, M. D. (2018). Mapping symptoms to brain networks with the human connectome. New England Journal of Medicine, 379(23), 2237-2245. Mapping Symptoms to Brain Networks with the Human Connectome 33

Using the Human Brain Connectome to Localize Symptoms from Focal Brain Lesions. • Functional connectivity between each lesion location and the rest of the brain is computed with the use of the connectome (Panel D, middle column). • Lesion network maps can then be overlapped to identify common connections (Panel D, right column). • In this example, lesion locations that cause visual hallucinations are functionally connected to a part of the brain involved in visual imagery (red circles).

Fox, M. D. (2018). Mapping symptoms to brain networks with the human Boes, A. D., Prasad, S., Liu, H., Liu, Q., Pascual-Leone, A., Caviness Jr, V. S., & Fox, connectome. New England Journal of Medicine, 379(23), 2237-2245. M. D. (2015). Network localization of neurological symptoms from focal brain lesions. Brain, 138(10), 3061-3075. Connectome Dysfunction in PD 34

• In PD, neurodegeneration not only affects dopaminergic projections from the substantia nigra, but also impacts the integrity of white matter fiber bundles. • Functional connectivity studies in PD have shown disruption of various subnetworks, including the: • Default mode network (DMN) • Sensorimotor network (SMN) Dysfunction of these subnetworks • Fronto-parietal network (FPN), and have been correlated with cognitive • Attention networks (AN) impairments in PD.

Weingarten CP, Sundman MH, Hickey P, Chen NK (2015) Neuroimaging of Parkinson’s disease: expanding views. Neurosci Biobehav Rev 59:16–52. Connectome Dysfunction in PD 35

• The integrity of subnetworks is dependent on the white matter tracts that connect the different areas of the brain.

Significant decreased white matter connectivity in PD patients compared to healthy volunteers (HV). BG: basal ganglia, Cb: cerebellum, Fron: frontal, Occip: occipital, Orb: orbital, Par: parietal, PF: prefrontal, PM: premotor, Temp: temporal, d: dorsal, l: lateral, m: medial, v: ventral.

Vriend, C., van den Heuvel, O. A., Berendse, H. W., van der Werf, Y. D., & Douw, L. Tinaz, S., Lauro, P. M., Ghosh, P., Lungu, C., & Horovitz, S. G. (2017). Changes in functional (2018). Global and subnetwork changes of the structural connectome in de organization and white matter integrity in the connectome in Parkinson's disease. novo Parkinson’s disease. Neuroscience, 386, 295-308. Neuroimage: Clinical, 13, 395-404. Connectome Dysfunction in PD 36

• Vriend et al. (2018) demonstrated that PD patients exhibit lower global and subnetwork efficiency, especially in the DMN and FPN, compared with healthy controls.

Vriend, C., van den Heuvel, O. A., Berendse, H. W., van der Werf, Y. D., & Douw, L. (2018). Global and subnetwork changes of the structural connectome in de novo Parkinson’s disease. Neuroscience, 386, 295-308. Connectome Dysfunction in PD 37

• There are significant correlations between cognitive performance – memory and planning – and subnetwork topology in PD.

• PD patients with lower clustering of the nodes in the DMN exhibit worse memory performance, while lower clustering of the nodes in the FPN is associated with better accuracy on a task, but only in healthy controls.

• The FPN alters its functional connectivity with other subnetworks depending on the task

Vriend, C., van den Heuvel, O. A., Berendse, H. W., van der Werf, Y. D., & Douw, L. Zanto, T. P., & Gazzaley, A. (2013). Fronto-parietal network: flexible hub of cognitive control. (2018). Global and subnetwork changes of the structural connectome in de Trends in cognitive sciences, 17(12), 602-603. novo Parkinson’s disease. Neuroscience, 386, 295-308. Connectome Dysfunction in PD 38

• At the global level, Vriend et al. (2018) observed higher modularity in PD patients versus healthy controls. Modularity measures the division of a network into separate modules. Modules are defined as having denser connections between nodes within a module but sparser connections with nodes outside the module. • Higher modularity in PD patients may therefore indicate fewer connections between modules.

Between-group differences in global network topology. Values on the Y-axis represent the area under the curve (AUC) of the graph indices across a range of thresholds. Diamond represents the group mean. Abbreviations: PD = Parkinson’s disease, HC = healthy controls.

• Resting state functional magnetic resonance studies (fMRI) have been shown to be useful to discriminate PD patients from controls as they reveal changes in the basal ganglia networks.

ICA consistently identified a BGN including the putamen and caudate bilaterally as well as anterior parts of the thalamus

Szewczyk-Krolikowski, K., Menke, R. A., Rolinski, M., Duff, E., Salimi-Khorshidi, G., ICA: independent component analysis Filippini, N., ... & Mackay, C. E. (2014). Functional connectivity in the basal ganglia BGN: Basal ganglia network network differentiates PD patients from controls. Neurology, 83(3), 208-214. Connectome Dysfunction in PD 41

• Szewczyk-Krolikowski et al. (2014) demonstrated a widely reduced functional connectivity in the BGN in cognitively intact patients with PD.

• The difference in connectivity separates the PD group off- medication from controls. Group comparison between patients with Parkinson disease “off” medication and the healthy control group: Significant clusters are located in the putamina bilaterally, medial frontal area, bilateral prefrontal areas, and precuneus.

• Administration of dopaminergic medication improved deficient connectivity in the BGN.

Medication effect: Clusters with increased connectivity after medication (red−yellow) are shown on the background of the mask of significantly different clusters from the Parkinson disease−“off” vs healthy controls comparison (green).

• Jech et al. (2013) Showed that L- Dopa treatment improved connectome dysfunction in the cerebellum and brainstem of PD patients.

Functional connectivity increase in the cerebellum and brainstem after levodopa in patients with Parkinson’s disease (n = 24) analysed with eigenvector centrality mapping. Results show the contrast between ON versus OFF levodopa treatment (P 50.05 family wise error corrected at cluster level)

Jech, R., Mueller, K., Schroeter, M. L., & Růžička, E. (2013). Levodopa increases functional connectivity in the cerebellum and brainstem in Parkinson’s disease. Brain, 136(7), e234-e234. Summary/Conclusions 44

• Current sets of evidence indicate that functional connectome deficits underlie the onset of PD symptoms.

• This suggests that the loss of synaptic connections, and not the so ‘blazoned’ neurodegeneration, constitutes the crucial neuropathological event in the brain of PD patients. Summary/Conclusions 45

• From a molecular point of view, collective evidence supports that in sporadic PD, synaptic loss is mainly correlated with the pathological deposition of α-synuclein at the synapse, which can both impair neurotransmission and synaptic plasticity

Schematic representation of the two cascades of events that could link a-synuclein accumulation to connectome dysfunction.

Szewczyk-Krolikowski, K., Menke, R. A., Rolinski, M., Duff, E., Salimi-Khorshidi, G., Filippini, N., ... & Mackay, C. E. (2014). Functional connectivity in the basal ganglia network differentiates PD patients from controls. Neurology, 83(3), 208-214. Summary/Conclusions 46 Taken together, these findings suggest that PD is primarily a disorder of the synapse and circuits and that effective therapeutic approaches should target the diseased connectomes. 47

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