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Gait: From Neurophysiology to Pathophysiology Laura Avanzino Department of Experimental Medicine, section of Human Physiology University of Genoa Centre for Parkinsons Disease and Movement Disorder - Policlinico San Martino Hospital,

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Laura Avanzino

Department of Experimental Medicine, section of Human Physiology – University of Genoa Centre for Parkinson’s Disease and Movement Disorder - Policlinico San Martino Hospital, Genova

Gait: From Neurophysiology to Pathophysiology

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DISCLOSURE INFORMATION

Nothing to declare

Laura Avanzino

Department of Experimental Medicine, section of Human Physiology – University of Genoa Centre for Parkinson’s Disease and Movement Disorder – IRCCS Ospedale Policlinico San Martino Genova

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ü Pathophysiology of Parkinson’s disease ü Physiology of gait and pathophysiology of gait disturbances in Parkinson disease ü Take home messages

OUTLINE

Gait: From Neurophysiology to Pathophysiology

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Laura Avanzino

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Parkinson’s disease

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Gait: From Neurophysiology to Pathophysiology

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Gait: From Neurophysiology to Pathophysiology

Basal Ganglia

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Gait: From Neurophysiology to Pathophysiology

Direct pathway

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Gait: From Neurophysiology to Pathophysiology

Indirect pathway

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Gait: From Neurophysiology to Pathophysiology

Nigro-striatal dopaminergic pathway

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Gait: From Neurophysiology to Pathophysiology

Basal Ganglia in PD

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Basal ganglia function in movement control

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Gait: From Neurophysiology to Pathophysiology

Mink, 1996 Blue: - Red: +

  • 1. ACTION SELECTION
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Basal ganglia function in movement control

Gait: From Neurophysiology to Pathophysiology

  • 2. HABITUAL AND GOAL DIRECTED CONTROL

Draganski et al., 2007; Redgrave et al., 2010

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Gait: From Neurophysiology to Pathophysiology

REVIEW ARTICLE

Parallel basal ganglia circuits for voluntary and automatic behaviour to reach rewards

Hyoung F . Kim and Okihide Hikosaka

doi:10.1093/brain/awv134 BRAIN 2015: 138; 1776–1800

|

1776

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Gait: From Neurophysiology to Pathophysiology

ü Pathophysiology of Parkinson’s disease ü Physiology of gait and pathophysiology of gait disturbances in Parkinson disease ü Take home messages

OUTLINE

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  • Normal gait requires a delicate balance between

various interacting neuronal systems and consists

  • f three primary components: locomotion,

including initiation and maintenance of rhythmic stepping; balance; and ability to adapt to the environment.

  • Dysfunction in any of these systems can disturb

gait and virtually all levels of the nervous system are needed for normal gait.

What is Gait?

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Gait: From Neurophysiology to Pathophysiology

Snijders et al., 2007

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Gait: From Neurophysiology to Pathophysiology

Physiology of Gait

Snijders et al., 2007

  • CPGs in the spinal cord generate “rhythmic

stepping” and provide the basic coordinated muscle activation patterns to generate locomotion.

  • Gait is regulated by cortico-basal ganglia-

brainstem-cerebellar circuits that modulate CPGs in the spinal cord.

Supraspinal Locomotor Network

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Gait: From Neurophysiology to Pathophysiology

Mesencephalic locomotor region

  • The MLR is located in the reticular formation and includes the peduncolopontine (PPN).
  • Mainly Cholinergic neurons (also GABA and GLU).
  • MLR has reciprocal connections with the basal ganglia and have major outputs to the

descending reticulo-spinal pathway and the ascending thalamo-cortical pathway.

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Mesencephalic locomotor region

  • The mesencephalic locomotor region (MLR) is

disinhibited from tonic basal ganglia control for gait initiation.

  • The pathway from frontal cortex via basal

ganglia to the brainstem locomotor centers allows modulation of the gait pattern in response to external demands.

Gait: From Neurophysiology to Pathophysiology

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Gait Disorders in PD

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Gait: From Neurophysiology to Pathophysiology

  • Gait slowness (pace and rhytm)
  • Increased variability and asymmetry

(spatial and temporal parameters)

  • Poor postural control (increased

sway, poor anticipatory and reactive control, altered coupling of posture and locomotion)

CONTINUOUS GAIT DISTURBANCES

SV, step velocity; SL, step length; Swi, swing time; ST, Step time; Sta, Stance time; Wid, Step width; sd, standard deviation (gait variability); as, asymmetry.

Galna et al., 2015

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Gait Disorders in PD

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Gait: From Neurophysiology to Pathophysiology

↓ ↓ Step LENGTH ↓ ↓ Step HEIGHT

↑ ↑ ASIMMETRY ↑ ↑ VARIABILITY

↓ ↓ ARM SWING ↓ ↓ APA

↑ ↑ CADENCE

↓ ↓ VELOCITY ↓ ↓ SWING PHASE DURATION

↑ ↑ DOUBLE LIMB SUPPORT

MDS Library

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Gait: From Neurophysiology to Pathophysiology

Gait Disorders in PD

GAIT SLOWNESS

  • Bradykinesia/ Hypokinesia/ Rigidity
  • Deficit in internal generation of adapted step
  • Abnormal balance between direct and

indirect pathways does not allow adequate adaptation of gait to environmental demands Bohnen & Jahn 2013

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Gait: From Neurophysiology to Pathophysiology

Gait Disorders in PD

Peterson & Horak 2016

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Gait: From Neurophysiology to Pathophysiology

Review

Motor automaticity in Parkinson's disease

Tao Wu a,b,⁎, Mark Hallett c, Piu Chan a,b

a Department of Neurobiology, Key Laboratory on Neurodegenerative Disorders of Ministry of Education, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, Beijing, China b Beijing Key Laboratory on Parkinson's Disease, Parkinson Disease Center of Beijing Institute for Brain Disorders, Beijing, China c Human Motor Control Section, Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

Neurobiology of Disease 82 (2015) 226–234

Contents lists available at ScienceDirect

Neurobiology of Disease

journal homepage: www.elsevier.com/locate/ynbdi

Goal-directed and habitual control in the basal ganglia: implications for Parkinson’s disease

Peter Redgrave*, Manuel Rodriguez‡§, Yoland Smith||¶, Maria C. Rodriguez-Oroz

§#,

Stephane Lehericy**, Hagai Bergman‡‡, Yves Agid§§, Mahlon R. DeLong¶ and Jose A. Obeso§#

  • Blinking
  • Arm-swinging
  • Facial expression
  • Pacing of gait
  • Speech modulation

Control Patient

a b s– tly

  • ns
  • f

de- ms hat ms ruc-

  • p-

are ath’

Figure 4 | Striatal dopamine innervation assessed by

Thalamus Behaviour Goal-directed control Stimulus–response habitual control Frontal cortex Functional loops Dysfunctional loops Associative BG Sensorimotor BG Distorted inhibitory

  • utput

Brainstem motor output Sensorimotor cortex Sensory input

PET imaging at the onset

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Gait slowness: responsivness to LDOPA

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Gait: From Neurophysiology to Pathophysiology

Curtze et al., 2015

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Gait: From Neurophysiology to Pathophysiology

Gait Disorders in PD

GAIT VARIABILITY AND ASYMMETRY

Brainstem cholinergic system: the brainstem cholinergic system includes the pedunculopontine tegmental nucleus (PPN) and laterodorsal pontine tegmentum (LDT). Magnocellular basal forebrain cholinergic system includeing the nucleus Basalis of Meynert (nBM) that has extensive diffuse projections to neocortex.

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Cholynergic dysfunction

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Attention

Disentangling the Role of Cortico-Basal Ganglia Loops in Top–Down and Bottom–Up Visual Attention: An Investigation of Attention Deficits in Parkinson Disease

Giorgio Tommasi1,2,3, Mirta Fiorio1, Jérôme Yelnik4, Paul Krack2, Francesca Sala3, Emmanuelle Schmitt2, Valérie Fraix2, Laura Bertolasi3, Jean-François Le Bas2, Giuseppe Kenneth Ricciardi3, Antonio Fiaschi1, Jan Theeuwes5, Pierre Pollak2,6, and Leonardo Chelazzi1,7

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Gait: From Neurophysiology to Pathophysiology

Dual task and Dynamic balance

Yogev et al., 2005

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Gait: From Neurophysiology to Pathophysiology Bohnen et al., 2013

In PD cortical cholinergic denervation (PET imaging) is correlated to gait slowing more than nigrostriatal denervation. Cholinergic hypofunction is associated with fall status in PD. Thalamic AChE activity in part represents cholinergic output of the pedunculopontine nucleus (PPN), a key node for gait control.

History of falls in Parkinson disease is associated with reduced cholinergic activity

Bohnen et al., 2009 Bohnen et al., 2019

Thalamic cholinergic deficits associated with falling history and emphasized role of right visual thalamus complex changes, including the right LGN.

Cholynergic dysfunction and gait

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Modulators of cortical plasticity

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Nucleus basalis of Meynert

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Modulators of cortical plasticity Gait: From Neurophysiology to Pathophysiology

  • Short Latency Afferent Inhibition (SAI) is a TMS

technique that assesses an inhibitory circuit in the sensorimotor cortex that is dependent on cholinergic activity (Tokimura et al., 2000; Chen et al., 2008).

  • It consists in conditioning motor evoked potentials,

elicited by TMS, of the motor cortex, with electrical stimuli delivered to the contralateral median nerve.

Transcranial magnetic stimulation (TMS) was used to estimate Cholinergic activity in the cortex

TMS ES-TMS

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Modulators of cortical plasticity Gait: From Neurophysiology to Pathophysiology

ORIGINAL RESEARCH published: 09 May 2016 doi: 10.3389/fnagi.2016.00104

Attentional Control of Gait and Falls: Is Cholinergic Dysfunction a Common Substrate in the Elderly and Parkinson’s Disease?

Elisa Pelosin 1, Carla Ogliastro 1, Giovanna Lagravinese 1, Gaia Bonassi 2, Anat Mirelman 3,4, Jeffrey M. Hausdorff 3,4, Giovanni Abbruzzese 1 and Laura Avanzino 2*

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Modulators of cortical plasticity Gait: From Neurophysiology to Pathophysiology

ü Pathophysiology of Parkinson’s disease ü Physiology of gait and pathophysiology of gait disturbances in Parkinson disease ü Take home messages

OUTLINE

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TAKE HOME MESSAGES

  • Gait is not an automatic task as considered before.
  • Gait slowness and increased variability and asymmetry are somewhat distinct

phenomenon with different pathophysiological mechanisms.

  • Gait slowness in PD is related to dysfunction of basal ganglia- cortex and PPN (that

does not allow adequate adaptation of gait).

  • Degeneration of cholinergic structures plays a role in attentional control of gait and

seems to underpin gait variability and asymmetry and worsening of gait performance under dual task.

  • To better understand gait pathophysiology to better treat gait disturbances.

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Modulators of cortical plasticity Gait: From Neurophysiology to Pathophysiology

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Department of Experimental Medicine, UNIGE: Ambra Bisio Gaia Bonassi Alessandro Botta Marco Bove Piero Ruggeri Movement Disorders Clinic UNIGE & IRCCS Ospedale Policlinico San Martino: Giovanni Abbruzzese Ottavia Baldi Carola Cosentino Francesca Di Biasio Carla Ogliastro Giovanna Lagravinese Roberta Marchese Elisa Pelosin Chiara Ponte Martina Putzolu Andrea Ravaschio

Thanks for your attention!