{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T07:25:54Z","timestamp":1777793154071,"version":"3.51.4"},"reference-count":85,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T00:00:00Z","timestamp":1769817600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"US Department of Veterans Affairs Merit Review 5 I01","award":["CX002086-03"],"award-info":[{"award-number":["CX002086-03"]}]},{"DOI":"10.13039\/100005339","name":"The American Academy of Neurology","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100005339","id-type":"DOI","asserted-by":"crossref"}]},{"name":"American Parkinson\u2019s Disease Association George C Cotzias Memorial Fellowship"},{"name":"Dystonia Medical Research Foundation Research"},{"name":"Department of Neurology at University Hospitals"},{"name":"American Academy of Neurology Career Award"},{"name":"George C Cotzias Memorial Fellowship"},{"name":"Department of VA I01","award":["CX002086"],"award-info":[{"award-number":["CX002086"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) is a multifactorial neurodegenerative disorder characterized by complex interactions across molecular, cellular, circuit, and behavioral scales. While experimental and clinical studies have provided critical insights into PD pathology, integrating these heterogeneous data into coherent mechanistic frameworks and translational strategies remains a major challenge. Computational modeling offers a powerful approach to bridge these scales, enabling the systematic investigation of disease mechanisms, candidate biomarkers, and therapeutic strategies. In this review, we survey state-of-the-art computational approaches applied to PD, spanning molecular dynamics and biophysical models, cellular- and circuit-level network models, systems and abstract-level simulations of basal ganglia function, and whole-brain and data-driven models linked to clinical phenotypes. We highlight how multiscale and hybrid modeling strategies connect \u03b1-synuclein pathology, mitochondrial dysfunction, oxidative stress, and dopaminergic degeneration to alterations in neural dynamics and motor and non-motor symptoms. We further discuss the role of computational models in biomarker discovery, including imaging, electrophysiological, and digital biomarkers. In particular, eye-movement-based measures are highlighted as quantitative, reproducible behavioral signals that provide principled constraints for individualized computational modeling. We also review the emerging impact of computational approaches on drug discovery, target prioritization, and in silico clinical trials. Finally, we examine future directions toward personalized and precision medicine in PD, emphasizing digital twin frameworks, longitudinal validation, and the integration of patient-specific data with mechanistic and data-driven models. Together, these advances underscore the growing role of computational modeling as an integrative and hypothesis-generating framework, with the long-term goal of supporting data-constrained predictive approaches for biomarker development and translational applications.<\/jats:p>","DOI":"10.3390\/brainsci16020175","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T09:48:08Z","timestamp":1770025688000},"page":"175","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Computational Modeling of Parkinson\u2019s Disease Across Scales: From Mechanisms to Biomarkers, Drug Discovery, and Personalized Therapies"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7469-8331","authenticated-orcid":false,"given":"Sandeep Sathyanandan","family":"Nair","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA"},{"name":"Cleveland FES Center, Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA"},{"name":"Daroff-Dell\u2019Osso Ocular Motility Laboratory, Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0763-3758","authenticated-orcid":false,"given":"Aratrik","family":"Guha","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA"},{"name":"Cleveland FES Center, Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA"},{"name":"Daroff-Dell\u2019Osso Ocular Motility Laboratory, Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Srinivasa","family":"Chakravarthy","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Bhupat and Mehta Jyoti School of Biosciences, IIT Madras, Chennai 600036, India"},{"name":"Department of Medical Science and Technology, IIT Madras, Chennai 600036, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aasef G.","family":"Shaikh","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA"},{"name":"Cleveland FES Center, Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA"},{"name":"Daroff-Dell\u2019Osso Ocular Motility Laboratory, Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA"},{"name":"Department of Neurology, University Hospitals, Cleveland, OH 44106, USA"},{"name":"Department of Neurology, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1136\/jnnp.2007.131045","article-title":"Parkinson\u2019s disease: Clinical features and diagnosis","volume":"79","author":"Jankovic","year":"2008","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.freeradbiomed.2013.01.018","article-title":"Parkinson disease: From pathology to molecular disease mechanisms","volume":"62","author":"Dexter","year":"2013","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1007\/s10483-020-2689-9","article-title":"A review of computational modeling and deep brain stimulation: Applications to Parkinson\u2019s disease","volume":"41","author":"Yu","year":"2020","journal-title":"Appl. Math. Mech."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1152\/physrev.2000.80.3.953","article-title":"Role of the basal ganglia in the control of purposive saccadic eye movements","volume":"80","author":"Hikosaka","year":"2000","journal-title":"Physiol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Sieger, T., Bonnet, C., Serranov\u00e1, T., Wild, J., Nov\u00e1k, D., R\u016f\u017ei\u010dka, F., Urgo\u0161\u00edk, D., R\u016f\u017ei\u010dka, E., Gaymard, B., and Jech, R. (2013). Basal ganglia neuronal activity during scanning eye movements in Parkinson\u2019s disease. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0078581"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Pinkhardt, E.H., J\u00fcrgens, R., Lul\u00e9, D., Heimrath, J., Ludolph, A.C., Becker, W., and Kassubek, J. (2012). Eye movement impairments in Parkinson\u2019s disease: Possible role of extradopaminergic mechanisms. BMC Neurol., 12.","DOI":"10.1186\/1471-2377-12-5"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7105","DOI":"10.1523\/JNEUROSCI.0264-07.2007","article-title":"Why don\u2019t we move faster? Parkinson\u2019s disease, movement vigor, and implicit motivation","volume":"27","author":"Mazzoni","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.conb.2008.08.003","article-title":"Reinforcement learning: The good, the bad and the ugly","volume":"18","author":"Dayan","year":"2008","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1936","DOI":"10.1523\/JNEUROSCI.16-05-01936.1996","article-title":"A framework for mesencephalic dopamine systems based on predictive Hebbian learning","volume":"16","author":"Montague","year":"1996","journal-title":"J. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1126\/science.275.5306.1593","article-title":"A neural substrate of prediction and reward","volume":"275","author":"Schultz","year":"1997","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/S0893-6080(02)00047-3","article-title":"Actor-critic models of the basal ganglia: New anatomical and computational perspectives","volume":"15","author":"Joel","year":"2002","journal-title":"Neural Networks"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1940","DOI":"10.1126\/science.1102941","article-title":"By carrot or by stick: Cognitive reinforcement learning in Parkinsonism","volume":"306","author":"Frank","year":"2004","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1162\/0898929052880093","article-title":"Dynamic dopamine modulation in the basal ganglia: A neurocomputational account of cognitive deficits in medicated and nonmedicated Parkinsonism","volume":"17","author":"Frank","year":"2005","journal-title":"Cogn. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/S0301-0082(96)00042-1","article-title":"The basal ganglia: Focused selection and inhibition of competing motor programs","volume":"50","author":"Mink","year":"1996","journal-title":"Prog. Neurobiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1007\/s00213-006-0502-4","article-title":"Tonic dopamine: Opportunity costs and the control of response vigor","volume":"191","author":"Niv","year":"2007","journal-title":"Psychopharmacology"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Rigoux, L., and Guigon, E. (2012). A Model of Reward- and Effort-Based Optimal Decision Making and Motor Control. PLoS Comput. Biol., 8.","DOI":"10.1371\/journal.pcbi.1002716"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1038\/nn963","article-title":"Optimal feedback control as a theory of motor coordination","volume":"5","author":"Todorov","year":"2002","journal-title":"Nat. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1162\/089976600300015961","article-title":"Reinforcement learning in continuous time and space","volume":"12","author":"Doya","year":"2000","journal-title":"Neural Comput."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"30","DOI":"10.2976\/1.2732246\/10.2976\/1","article-title":"Reinforcement learning: Computational theory and biological mechanisms","volume":"1","author":"Doya","year":"2007","journal-title":"HFSP J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3208","DOI":"10.1523\/JNEUROSCI.14-05-03208.1994","article-title":"Adaptive representation of dynamics during learning of a motor task","volume":"14","author":"Shadmehr","year":"1994","journal-title":"J. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1109\/TSMC.1983.6313077","article-title":"Neuronlike Adaptive Elements That Can Solve Difficult Learning Control Problems","volume":"SMC-13","author":"Barto","year":"1983","journal-title":"IEEE Trans. Syst. Man Cybern."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Chakravarthy, V.S., and Moustafa, A.A. (2018). Computational Neuroscience Models of the Basal Ganglia. Movement Disorders: Official Journal of the Movement Disorder Society, Springer.","DOI":"10.1007\/978-981-10-8494-2"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1142\/S0129065706000548","article-title":"The role of the basal ganglia in exploration in A neural model based on reinforcement learning","volume":"16","author":"Sridharan","year":"2006","journal-title":"Int. J. Neural Syst."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1146\/annurev.ne.09.030186.002041","article-title":"Parallel organization of functionally segregated circuits linking basal ganglia and cortex","volume":"9","author":"DeLong","year":"1986","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1007\/s11571-023-10056-y","article-title":"A Basal Ganglia model for understanding working memory functions in healthy and Parkinson\u2019s conditions","volume":"18","author":"Vigneswaran","year":"2024","journal-title":"Cogn. Neurodynamics"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Mandali, A., Chakravarthy, V.S., Rajan, R., Sarma, S., and Kishore, A. (2016). Electrode position and current amplitude modulate impulsivity after subthalamic stimulation in Parkinsons disease-A computational study. Front. Physiol., 7.","DOI":"10.3389\/fphys.2016.00585"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-023-32234-y","article-title":"A generalized reinforcement learning based deep neural network agent model for diverse cognitive constructs","volume":"13","author":"Nair","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Balasubramani, P.P., Chakravarthy, V.S., Ali, M., Ravindran, B., and Moustafa, A.A. (2015). Identifying the basal ganglia network model markers for medication-induced impulsivity in Parkinson\u2019s disease patients. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0127542"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Leigh, R.J., and Zee, D.S. (2015). The Neurology of Eye Movements, Oxford University Press.","DOI":"10.1093\/med\/9780199969289.001.0001"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.tins.2023.11.001","article-title":"Eye movements in Parkinson\u2019s disease: From neurophysiological mechanisms to diagnostic tools","volume":"47","author":"Antoniades","year":"2024","journal-title":"Trends Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1880","DOI":"10.1126\/science.7569931","article-title":"An internal model for sensorimotor integration","volume":"269","author":"Wolpert","year":"1995","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1007\/s00221-008-1280-5","article-title":"A computational neuroanatomy for motor control","volume":"185","author":"Shadmehr","year":"2008","journal-title":"Exp. Brain Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"12921","DOI":"10.1523\/JNEUROSCI.3486-06.2006","article-title":"A physiologically plausible model of action selection and oscillatory activity in the basal ganglia","volume":"26","author":"Humphries","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1523\/ENEURO.0156-16.2016","article-title":"Untangling basal ganglia network dynamics and function: Role of dopamine depletion and inhibition investigated in a spiking network model","volume":"3","author":"Lindahl","year":"2016","journal-title":"eNeuro"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"S44","DOI":"10.1016\/S1353-8020(13)70013-0","article-title":"The functional role of beta oscillations in Parkinson\u2019s disease","volume":"20","author":"Little","year":"2014","journal-title":"Park. Relat. Disord."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1093\/brain\/awz417","article-title":"Subthalamic nucleus activity dynamics and limb movement prediction in Parkinson\u2019s disease","volume":"143","author":"Khawaldeh","year":"2020","journal-title":"Brain"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.neuroimage.2013.05.084","article-title":"Oscillations and the basal ganglia: Motor control and beyond","volume":"85","author":"Brittain","year":"2014","journal-title":"NeuroImage"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"E4885","DOI":"10.1073\/pnas.1604135113","article-title":"Neural mechanisms of transient neocortical beta rhythms: Converging evidence from humans, computational modeling, monkeys, and mice","volume":"113","author":"Sherman","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","unstructured":"van Wijk, B.C.M., Beek, P.J., and Daffertshofer, A. (2016). Neural synchrony within the motor system: What have we learned so far?. Front. Hum. Neurosci., 10."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/j.conb.2007.12.001","article-title":"Abnormal oscillatory synchronisation in the motor system leads to impaired movement","volume":"17","author":"Brown","year":"2007","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"11620","DOI":"10.1073\/pnas.1107748108","article-title":"Striatal origin of the pathologic beta oscillations in Parkinson\u2019s disease","volume":"108","author":"McCarthy","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/PL00007984","article-title":"A computational model of action selection in the basal ganglia. I. A new functional anatomy","volume":"84","author":"Gurney","year":"2001","journal-title":"Biol. Cybern."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1109\/TNN.2003.820440","article-title":"Simple model of spiking neurons","volume":"14","author":"Izhikevich","year":"2003","journal-title":"IEEE Trans. Neural Networks"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"12340","DOI":"10.1523\/JNEUROSCI.0817-10.2010","article-title":"Conditions for the generation of beta oscillations in the subthalamic nucleus-globus pallidus network","volume":"30","author":"Holgado","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1016\/j.clinph.2003.12.024","article-title":"Uncovering the mechanism(s) of action of deep brain stimulation: Activation, inhibition, or both","volume":"115","author":"McIntyre","year":"2004","journal-title":"Clin. Neurophysiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1023\/B:JCNS.0000025686.47117.67","article-title":"High frequency stimulation of the subthalamic nucleus eliminates pathological thalamic rhythmicity in a computational model","volume":"16","author":"Rubin","year":"2004","journal-title":"J. Comput. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00221-025-07026-7","article-title":"Computational model for control of hand movement in Parkinson\u2019s disease using deep brain stimulation","volume":"243","author":"Chanu","year":"2025","journal-title":"Exp. Brain Res."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Nair, S.S., and Chakravarthy, S. (2024). A Computational Model of Deep Brain Stimulation for Parkinson\u2019s Disease Tremor and Bradykinesia. Brain Sci., 14.","DOI":"10.1101\/2024.04.26.591059"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/35041687","article-title":"Oxidants, oxidative stress and the biology of ageing","volume":"408","author":"Finkel","year":"2000","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1002\/mds.23732","article-title":"Etiology and pathogenesis of Parkinson\u2019s disease","volume":"26","author":"Schapira","year":"2011","journal-title":"Mov. Disord."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-021-81185-9","article-title":"Influence of energy deficiency on the subcellular processes of Substantia Nigra Pars Compacta cell for understanding Parkinsonian neurodegeneration","volume":"11","author":"Muddapu","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_52","first-page":"2003","article-title":"Oxidative stress, mitochondrial damage and neurodegenerative diseases","volume":"8","author":"Guo","year":"2013","journal-title":"Neural Regen. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1002\/mds.25095","article-title":"Neuronal vulnerability, pathogenesis, and Parkinson\u2019s disease","volume":"28","author":"Sulzer","year":"2013","journal-title":"Mov. Disord."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/S0140-6736(23)01478-2","article-title":"The pathogenesis of Parkinson\u2019s disease","volume":"403","author":"Morris","year":"2024","journal-title":"Lancet"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Nair, S.S., Muddapu, V.R., and Chakravarthy, V.S. (2022). A Multiscale, Systems-Level, Neuropharmacological Model of Cortico-Basal Ganglia System for Arm Reaching Under Normal, Parkinsonian, and Levodopa Medication Conditions. Front. Comput. Neurosci., 15.","DOI":"10.3389\/fncom.2021.756881"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Muddapu, V.R., Dharshini, S.A.P., Chakravarthy, V.S., and Gromiha, M.M. (2020). Neurodegenerative Diseases\u2014Is Metabolic Deficiency the Root Cause?. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.00213"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"105686","DOI":"10.1016\/j.nbd.2022.105686","article-title":"Striatal synaptic adaptations in Parkinson\u2019s disease","volume":"167","author":"Shen","year":"2022","journal-title":"Neurobiol. Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1016\/j.neuron.2012.03.017","article-title":"Whole-Brain Mapping of Direct Inputs to Midbrain Dopamine Neurons","volume":"74","author":"Zhu","year":"2012","journal-title":"Neuron"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3567","DOI":"10.1523\/JNEUROSCI.5050-05.2006","article-title":"Competition between feedback loops underlies normal and pathological dynamics in the basal ganglia","volume":"26","author":"Leblois","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.conb.2017.08.004","article-title":"Striatal synapses, circuits, and Parkinson\u2019s disease","volume":"48","author":"Zhai","year":"2018","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/1742-4682-6-21","article-title":"Homeostatic mechanisms in dopamine synthesis and release: A mathematical model","volume":"6","author":"Best","year":"2009","journal-title":"Theor. Biol. Med. Model."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Reed, M.C., Nijhout, H.F., and Best, J.A. (2012). Mathematical insights into the effects of levodopa. Front. Integr. Neurosci., 6.","DOI":"10.3389\/fnint.2012.00021"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Baston, C., Contin, M., Buonaura, G.C., Cortelli, P., and Ursino, M. (2016). A mathematical model of levodopa medication effect on basal ganglia in parkinson\u2019s disease: An application to the alternate finger tapping task. Front. Hum. Neurosci., 10.","DOI":"10.3389\/fnhum.2016.00280"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1111\/ner.13476","article-title":"Increased Subthalamic Nucleus Deep Brain Stimulation Amplitude Impairs Inhibitory Control of Eye Movements in Parkinson\u2019s Disease","volume":"25","author":"Munoz","year":"2022","journal-title":"Neuromodulation"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"101","DOI":"10.2147\/EB.S384763","article-title":"Monitoring Eye Movement in Patients with Parkinson\u2019s Disease: What Can It Tell Us?","volume":"ume 15","author":"Sun","year":"2023","journal-title":"Eye Brain"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Gupta, P., Murray, J.M., Beylergil, S.B., Jacobs, J., Kilbane, C.W., Shaikh, A.G., and Ghasia, F.F. (2023). Objective assessment of eye alignment and disparity-driven vergence in Parkinson\u2019s disease. Front. Aging Neurosci., 15.","DOI":"10.3389\/fnagi.2023.1217765"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/s10827-020-00773-2","article-title":"Effects of subthalamic deep brain stimulation on fixational eye movements in Parkinson\u2019s disease","volume":"49","author":"Beylergil","year":"2021","journal-title":"J. Comput. Neurosci."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Muralidharan, V., Balasubramani, P.P., Chakravarthy, V.S., Lewis, S.J.G., and Moustafa, A.A. (2014). A computational model of altered gait patterns in parkinson\u2019s disease patients negotiating narrow doorways. Front. Comput. Neurosci., 7.","DOI":"10.3389\/fncom.2013.00190"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Pratihar, R., and Sankar, R. (2024). Advancements in Parkinson\u2019s Disease Diagnosis: A Comprehensive Survey on Biomarker Integration and Machine Learning. Computers, 13.","DOI":"10.3390\/computers13110293"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Nair, S.S., Muddapu, V.R.J., Sriram, M., Aditya, R., Gupta, R., and Chakravarthy, S. (2022). Is There a Better Way to Assess Parkinsonian Motor Symptoms?\u2014Experimental and Modelling Approach. Techniques for Assessment of Parkinsonism for Diagnosis and Rehabilitation, Springer.","DOI":"10.1007\/978-981-16-3056-9_10"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1016\/j.neuropsychologia.2011.03.002","article-title":"Initiation and inhibitory control of saccades with the progression of Parkinson\u2019s disease\u2014Changes in three major drives converging on the superior colliculus","volume":"49","author":"Terao","year":"2011","journal-title":"Neuropsychologia"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/nrn1345","article-title":"Look away: The anti-saccade task and the voluntary control of eye movement","volume":"5","author":"Munoz","year":"2004","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1093\/brain\/awf168","article-title":"Adaptive modification of saccade amplitude in Parkinson\u2019s disease","volume":"125","author":"MacAskill","year":"2002","journal-title":"Brain"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.pneurobio.2005.09.005","article-title":"The functional role of the subthalamic nucleus in cognitive and limbic circuits","volume":"76","author":"Temel","year":"2005","journal-title":"Prog. Neurobiol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1162\/neco.2007.19.2.442","article-title":"The basal ganglia and cortex implement optimal decision making between alternative actions","volume":"19","author":"Bogacz","year":"2007","journal-title":"Neural Comput."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1162\/NECO_a_00270","article-title":"Reinforcement-based decision making in corticostriatal circuits: Mutual constraints by neurocomputational and diffusion models","volume":"24","author":"Ratcliff","year":"2012","journal-title":"Neural Comput."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s00221-006-0412-z","article-title":"Saccadic latency distributions in Parkinson\u2019s disease and the effects of L-dopa","volume":"174","author":"Michell","year":"2006","journal-title":"Exp. Brain Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.nbd.2011.01.032","article-title":"Saccadic latency in Parkinson\u2019s disease correlates with executive function and brain atrophy, but not motor severity","volume":"43","author":"Perneczky","year":"2011","journal-title":"Neurobiol. Dis."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1007\/s11065-021-09489-1","article-title":"Antisaccades in Parkinson\u2019s Disease: A Meta-Analysis","volume":"31","author":"Waldthaler","year":"2021","journal-title":"Neuropsychol. Rev."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.1212\/WNL.44.12.2285","article-title":"Relationship between antisaccades and the clinical symptoms in Parkinson\u2019s disease","volume":"44","author":"Kitagawa","year":"1994","journal-title":"Neurology"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Yu, Y., Yan, W., Xu, X., Zhang, K., Si, L., Liu, X., Wang, J., Song, J., Sun, H., and Li, X. (2022). Response times for reflexive saccades correlate with cognition in Parkinson\u2019s disease, not disease severity or duration. Front. Neurol., 13.","DOI":"10.3389\/fneur.2022.945201"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1136\/jnnp.2007.117192","article-title":"A case report on fixation instability in Parkinson\u2019s disease with bilateral deep brain stimulation implants","volume":"79","author":"Wark","year":"2008","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_83","first-page":"100085","article-title":"Abnormalities of smooth pursuit in Parkinson\u2019s disease: A systematic review","volume":"4","author":"Frei","year":"2021","journal-title":"Clin. Park. Relat. Disord."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1093\/brain\/awad429","article-title":"At home adaptive dual target deep brain stimulation in Parkinson\u2019s disease with proportional control","volume":"147","author":"Schmidt","year":"2024","journal-title":"Brain"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"3345","DOI":"10.1038\/s41591-024-03196-z","article-title":"Chronic adaptive deep brain stimulation versus conventional stimulation in Parkinson\u2019s disease: A blinded randomized feasibility trial","volume":"30","author":"Oehrn","year":"2024","journal-title":"Nat. Med."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/2\/175\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T05:12:13Z","timestamp":1770095533000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/2\/175"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,31]]},"references-count":85,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["brainsci16020175"],"URL":"https:\/\/doi.org\/10.3390\/brainsci16020175","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,31]]}}}