Freezing of gait

PathophysiologyAlice 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 gait – imaging studies

Total = 16625

0

Publications on neuroimaging of FOG in PD

2011

Freezing of gait – imaging studies

Bharti K. et al 2019 Neuroimage Clinical

Freezing of gaitMulti-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 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

Final common pathway of 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 - 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 – 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 freezing - locomotor network

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

Glucose metabolism - gait 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

Glucose 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

14Bharti 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

15Gilat 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

Limbic network alterations

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 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 researchers