Freezing of gait it Pathophysiology Alice Nieuwboer Rehabilitation Sciences KU Leuven, Belgium
Disclosure - None Learning objective Understand the pathophysiological mechanism of freezing of gait Examine the abnormal changes in brain function concomitant to freezing of gait
Freezing of f gait – imaging studies Publications on neuroimaging of FOG in PD 25 Total = 166 2011 0
Freezing of f gait – imaging studies Bharti K. et al 2019 Neuroimage Clinical
Freezing of f gait Multi-faceted gait interruption Triggers subtypes? Manifestations • Turning • Akinetic • Transitions - adaptation • Shuffling forward • Distraction - stress • Trembling on the spot Treatment Multipathology • Dopamine response • Normal pressure hydrocephalus • Deep Brain Stimulation • Primary progressive freezing • Progressive Supranuclear Palsy • Tricks and cues • Training of compensatory networks • Vascular Parkinsonism Weiss D et al 2020, Brain; Nonnekes et al JAMA 2019;
Freezing types and fi final common pathway Context-dependent dysfunctional neural information influencing the locomotor network Lewis S & Shine J 2014; Gilat M. et al 2019; Ehgoetz-Martens K. et al 2020
Fin inal common pathway of f lo locomotor network OFF-FOG Loss of segregated neural processing in the striatum due to dopamine depletion bottleneck Final common pathway Exaggerated inhibition from the GPi/STN to MLR Breakdown of gait & fine-tuning of central pattern generation Lewis S & Shine J 2014; Gilat M. et al 2019; Ehgoetz-Martens K. et al 2020; Nieuwhof F. et al
MLR - lo locomotor network Mesencephalic locomotor region Locomotion generating region Structural and functional abnormalities FRs Pedunculo Pontine Nucleus (PPN) Cortical and striatal cholinergic denervation associated with FOG Shine JM et al 2013; Lau B et al Brain 2015; Bharti et al 2019; Bohnen N et al ANA 2019
STN – lo locomotor network Subthalamic nucleus Direct neuronal recordings (LFPs) modulatory role in locomotion Role = integrating information from cerebellum and cortical regions Abnormal STN activity in FOG STN-burst of firing ( β -band) prolonged in FOG-episodes • • Firing rates were elevated during freezing of foot pedalling • Sudden decoupling between cortical - STN neuronal firing in freezing in contrast to normal gait STN hand brake function or reducing the fine-graded input downstream? Georgiades M et al Brain 2019; Pozzi et al Brain 2019; Anidi et al 2018; Fischer P. et al; JoNSC 2020
Deep brain stimulation – PPN/STN Effects of PPN – DBS Modest but consistent effects on FOG and falls Effects of STN – DBS Modest effects but not full alleviation 52% had FOG at baseline 34% still had FOG 2 yr > than best medical treatment Lau et al 2015, Brain; Golestanirad L Review 2016; Garcia-Rill et al 2019; Barbe et al 2019 MDJ
Motor fr freezing - lo locomotor network Fine-tuning network • Sensorimotor integration gait adjustment Hinton DC et al Neuroimage 2019; Bohnen & Jahn 2013; Tard C et al 2015
Glu lucose metabolism - gait it adaptation PET-scans PET-scans Pre-Post Pre-Post Splitbelt speed changes Treadmill Healthy young people SBT> TBT Suppl. motor area (SMA), Post. parietal cortex (PPC) Ant. cingulate cortex (ACC) Ant/Lat. cerebellum (CR) Hinton DC et al Neuroimage 2019
Glu lucose metabolism freezers vs non-freezers PET-scans 3*3*x Pre-Post % Time Frozen was 39 % ± 24 Complex gait in OFF Frontoparietal fine-tuning circuit is altered in FR > NFR Suppl. motor area and prefrontal cortex Parietal cortex Cortico-subcortical decoupling Cerebellum (CR) MLR and GP Tard C et al Neuroscience 2015; Shine M et al 2013, Brain
Motor network malfunction - SMA Supplementary Motor Area closely connected to the basal ganglia Mediates self-guided (automatic) motion, bilateral coordination Abnormal freezer-related structural and functional changes Gait initiation - Neural firing rates were overly synchronized at motion initiation (EEG- β -band) coding capacity in FRs Doorways – Functional decoupling of pSMA and STN when freezers were foot pedalling through virtual narrow but not wide doorways. Bharti K. et al 2019; Matar et al 2018; Brugger et al 2020 14
Motor network malfunction - cerebellum Cerebellum involved in multiple locomotive functions – gait rhythm The cerebellar locomotor region most consistently gait-related activations Meta-analysis 16 studies Overall abnormal functional activation & connectivity across the cerebellum FRs>NFRs compensatory or pathological ? Gilat et al 2019; Bharti et al 2019; Piramide N. et al 2020; Weiss D et al 2020; Fasano et al 2017 15
Cognitive network dysfunction Frontal executive function involved in complex gait Functional coupling between Loss of white matter integrity in frontostriatal network cognitive and basal ganglia networks FRs>NFRs in FRs>NFRs during rest and actual episodes Tessitore et al 2012; Vercruysse S et al 2015 MDJ; Shine M. et al 2013, Brain; Ehgoetz Martens K et al 2018 16
Cognitive network dysfunction No behavioral evidence on FRs - NFRs differences in cognitive scores after control for DS & few correlations with FOG-severity Direct or indirect or both? Increased reliance on non-motor resources to compensate for depleted sensorimotor locomotion circuitry predisposing to FOG Morris R et al 2020 NPJ 17
Lim imbic network alt lterations Limbic motor interference FOG Rs-connectivity Amygdala – Putamen Coupling FRs>NFRs between limbic circuits and putamen FRs > NFRs showed delayed and smaller Top down control of the prefrontal cortex amygdala steps towards unpleasant image. Induced fear impacts on FOG episodes Lagravinese et al 2018; Review Ehgoetz-Martens K. et al 2020 Gilat M et al 2018, Neuroscience; Ehgoetz-Martens et al 2019 18
Freezing of f other effectors Freezing of feet and fingers similar Episodes in feet & fingers brain deficits overlap Abnormal finger tapping is 1 of 2 principle components that predicts conversion to freezing of gait Vercruysse S et al 2014; D’Cruz N et al 2020
Thalamus morphology conversion Inflations at study entry L. Thalamus predictor Thalamo-cortical resting-state Inflations after 2 years coupling (medial and dorsolateral PFC) at baseline in Conv>Nconv Coupling cognitive-limbic network with thalamus with time in converters > non-converters Thalamic inflation driven by non-motor compensation for loss of dopaminergic motor control D’Cruz N et al 2020; in review NPJ
Take home message • No specific FOG-related neuroanatomical structure • Why turning – thalamic/vestibular? • Widespread structural and functional impairments in locomotor network vulnerable to limbic interference and cognitive network decline Inspiration for personalized and early rehabilitation for FOG
My team of f researchers
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