Freezing of gait it Pathophysiology Alice Nieuwboer - - PowerPoint PPT Presentation

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

Total = 166

25

Publications on neuroimaging of FOG in PD

2011

Freezing of f gait – imaging studies

Bharti K. et al 2019 Neuroimage Clinical

Freezing of f gait

Multi-faceted gait interruption

Manifestations

• Akinetic
• Shuffling forward
• Trembling on the spot

Triggers  subtypes?

• Turning
• Transitions - adaptation
• Distraction - stress

Multipathology

• Normal pressure hydrocephalus
• Primary progressive freezing
• Progressive Supranuclear Palsy
• Vascular Parkinsonism

Treatment

• Dopamine response
• Deep Brain Stimulation
• Tricks and cues
• Training of compensatory networks

Weiss D et al 2020, Brain; Nonnekes et al JAMA 2019;

Freezing types and fi final common pathway

Lewis S & Shine J 2014; Gilat M. et al 2019; Ehgoetz-Martens K. et al 2020

Context-dependent dysfunctional neural information influencing the locomotor network

Fin inal common pathway of f lo locomotor network

Lewis S & Shine J 2014; Gilat M. et al 2019; Ehgoetz-Martens K. et al 2020; Nieuwhof F. et al

Final common pathway  Exaggerated inhibition from the GPi/STN to MLR  Breakdown of gait & fine-tuning of central pattern generation OFF-FOG Loss of segregated neural processing in the striatum due to dopamine depletion bottleneck

MLR - lo locomotor network

Mesencephalic locomotor region

Shine JM et al 2013; Lau B et al Brain 2015; Bharti et al 2019; Bohnen N et al ANA 2019

Locomotion generating region Structural and functional abnormalities FRs

Cortical and striatal cholinergic denervation associated with FOG Pedunculo Pontine Nucleus (PPN)

STN – lo locomotor network

Subthalamic nucleus

Georgiades M et al Brain 2019; Pozzi et al Brain 2019; Anidi et al 2018; Fischer P. et al; JoNSC 2020

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 Direct neuronal recordings (LFPs)  modulatory role in locomotion Role = integrating information from cerebellum and cortical regions

STN hand brake function or reducing the fine-graded input downstream?

Deep brain stimulation – PPN/STN

Lau et al 2015, Brain; Golestanirad L Review 2016; Garcia-Rill et al 2019; Barbe et al 2019 MDJ

52% had FOG at baseline 34% still had FOG 2 yr > than best medical treatment

Effects of PPN – DBS  Modest but consistent effects on FOG and falls Effects of STN – DBS  Modest effects but not full alleviation

Fine-tuning network

• Sensorimotor integration

 gait adjustment

Motor fr freezing - lo locomotor network

Hinton DC et al Neuroimage 2019; Bohnen & Jahn 2013; Tard C et al 2015

Glu lucose metabolism - gait it adaptation

Hinton DC et al Neuroimage 2019

SBT> TBT

 Suppl. motor area (SMA),  Post. parietal cortex (PPC)  Ant. cingulate cortex (ACC)  Ant/Lat. cerebellum (CR) PET-scans Pre-Post Treadmill PET-scans Pre-Post Splitbelt speed changes Healthy young people

Glu lucose metabolism freezers vs non-freezers

Tard C et al Neuroscience 2015; Shine M et al 2013, Brain

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 PET-scans Pre-Post Complex gait in OFF 3*3*x

% Time Frozen was 39 % ± 24

Motor network malfunction - SMA

14

Bharti K. et al 2019; Matar et al 2018; Brugger et al 2020

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.

Motor network malfunction - cerebellum

15

Gilat et al 2019; Bharti et al 2019; Piramide N. et al 2020; Weiss D et al 2020; Fasano et al 2017

Cerebellum involved in multiple locomotive functions – gait rhythm The cerebellar locomotor region  most consistently gait-related activations

Overall abnormal functional activation & connectivity across the cerebellum FRs>NFRs  compensatory or pathological ?

Meta-analysis 16 studies

Cognitive network dysfunction

Loss of white matter integrity in frontostriatal network FRs>NFRs

16

 Functional coupling between cognitive and basal ganglia networks 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

Frontal executive function involved in complex gait

Cognitive network dysfunction

17

Morris R et al 2020 NPJ

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

Lim imbic network alt lterations

Gilat M et al 2018, Neuroscience; Ehgoetz-Martens et al 2019

18

 Coupling FRs>NFRs between limbic circuits and putamen  Top down control of the prefrontal cortex amygdala

Lagravinese et al 2018; Review Ehgoetz-Martens K. et al 2020

Limbic motor interference  FOG

FRs > NFRs showed delayed and smaller steps towards unpleasant image. Induced fear impacts on FOG episodes

Rs-connectivity Amygdala – Putamen

Freezing of f other effectors

Vercruysse S et al 2014; D’Cruz N et al 2020

Abnormal finger tapping is 1 of 2 principle components that predicts conversion to freezing of gait Freezing of feet and fingers  similar Episodes in feet & fingers  brain deficits overlap

Thalamus morphology  conversion

D’Cruz N et al 2020; in review NPJ

Inflations after 2 years

 Thalamo-cortical resting-state 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 Inflations at study entry

• L. Thalamus  predictor

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