Post on 27-Feb-2021
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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