Gait: From Neurophysiology to Pathophysiology 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
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
Gait: From Neurophysiology to Pathophysiology OUTLINE ü Pathophysiology of Parkinson’s disease ü Physiology of gait and pathophysiology of gait disturbances in Parkinson disease ü Take home messages 3 Laura Avanzino
Gait: From Neurophysiology to Pathophysiology Parkinson’s disease 4 4 Laura Avanzino
Gait: From Neurophysiology to Pathophysiology Basal Ganglia 5 Laura Avanzino
Gait: From Neurophysiology to Pathophysiology Direct pathway 6 Laura Avanzino
Gait: From Neurophysiology to Pathophysiology Indirect pathway 7 Laura Avanzino
Gait: From Neurophysiology to Pathophysiology Nigro-striatal dopaminergic pathway 8 Laura Avanzino
Gait: From Neurophysiology to Pathophysiology Basal Ganglia in PD 9 Laura Avanzino
Gait: From Neurophysiology to Pathophysiology Basal ganglia function in movement control 1. ACTION SELECTION Mink, 1996 Blue: - Red: + 10 Laura Avanzino
Gait: From Neurophysiology to Pathophysiology Basal ganglia function in movement control 2. HABITUAL AND GOAL DIRECTED CONTROL Draganski et al., 2007; Redgrave et al., 2010 11 Laura Avanzino
Gait: From Neurophysiology to Pathophysiology | doi:10.1093/brain/awv134 BRAIN 2015: 138; 1776–1800 1776 REVIEW ARTICLE Parallel basal ganglia circuits for voluntary and automatic behaviour to reach rewards Hyoung F . Kim and Okihide Hikosaka 12 Laura Avanzino
Gait: From Neurophysiology to Pathophysiology OUTLINE ü Pathophysiology of Parkinson’s disease ü Physiology of gait and pathophysiology of gait disturbances in Parkinson disease ü Take home messages 13 Laura Avanzino
Gait: From Neurophysiology to Pathophysiology What is Gait? • Normal gait requires a delicate balance between various interacting neuronal systems and consists of 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. Snijders et al., 2007 14 Laura Avanzino
Gait: From Neurophysiology to Pathophysiology Physiology of Gait • 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 Snijders et al., 2007 15 Laura Avanzino
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. 16 Laura Avanzino
Gait: From Neurophysiology to Pathophysiology 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. 17 Laura Avanzino
Gait: From Neurophysiology to Pathophysiology Gait Disorders in PD CONTINUOUS GAIT DISTURBANCES • 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) 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 18 Laura Avanzino
Gait: From Neurophysiology to Pathophysiology Gait Disorders in PD ↓ ↓ Step LENGTH ↓ ↓ Step HEIGHT ↑ ↑ ASIMMETRY ↑ ↑ VARIABILITY ↑ ↑ CADENCE ↓ ↓ VELOCITY ↓ ↓ SWING PHASE DURATION ↑ ↑ DOUBLE LIMB SUPPORT ↓ ↓ ARM SWING ↓ ↓ APA MDS Library 19 Laura Avanzino
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 20 Laura Avanzino
Gait: From Neurophysiology to Pathophysiology Gait Disorders in PD Peterson & Horak 2016 21 Laura Avanzino
Gait: From Neurophysiology to Pathophysiology Neurobiology of Disease 82 (2015) 226 – 234 Goal-directed and habitual control Contents lists available at ScienceDirect Neurobiology of Disease in the basal ganglia: implications journal homepage: www.elsevier.com/locate/ynbdi for Parkinson’s disease Review Motor automaticity in Parkinson's disease Peter Redgrave*, Manuel Rodriguez ‡§ , Yoland Smith ||¶ , Maria C. Rodriguez-Oroz §# , Tao Wu a,b, ⁎ , Mark Hallett c , Piu Chan a,b Stephane Lehericy**, Hagai Bergman ‡‡ , Yves Agid §§ , Mahlon R. DeLong ¶ a Department of Neurobiology, Key Laboratory on Neurodegenerative Disorders of Ministry of Education, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, Beijing, China and Jose A. Obeso §# 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 Sensory input s– • Blinking a b Control Patient Goal-directed Stimulus–response tly control habitual control ons Frontal cortex Sensorimotor cortex • Arm-swinging of de- Thalamus ms • Facial expression hat ms Functional loops Dysfunctional loops • Pacing of gait ruc- Associative BG Sensorimotor BG op- Distorted inhibitory are • Speech modulation output ath’ Figure 4 | Striatal dopamine innervation assessed by PET imaging at the onset Brainstem motor output Behaviour 22 Laura Avanzino
Gait: From Neurophysiology to Pathophysiology Gait slowness: responsivness to LDOPA Curtze et al., 2015 23 Laura Avanzino
Gait: From Neurophysiology to Pathophysiology Gait Disorders in PD GAIT VARIABILITY AND ASYMMETRY Magnocellular basal forebrain cholinergic system includeing the nucleus Basalis of Meynert (nBM) that has extensive diffuse projections to neocortex. Brainstem cholinergic system: the brainstem cholinergic system includes the pedunculopontine tegmental nucleus (PPN) and laterodorsal pontine tegmentum (LDT). 24 Laura Avanzino
Gait: From Neurophysiology to Pathophysiology Cholynergic dysfunction 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 Tommasi 1,2,3 , Mirta Fiorio 1 , Jérôme Yelnik 4 , Paul Krack 2 , Francesca Sala 3 , Emmanuelle Schmitt 2 , Valérie Fraix 2 , Laura Bertolasi 3 , Jean-François Le Bas 2 , Giuseppe Kenneth Ricciardi 3 , Antonio Fiaschi 1 , Jan Theeuwes 5 , Pierre Pollak 2,6 , and Leonardo Chelazzi 1,7 25 Laura Avanzino
Gait: From Neurophysiology to Pathophysiology Dual task and Dynamic balance Yogev et al., 2005 26 Laura Avanzino
Gait: From Neurophysiology to Pathophysiology Cholynergic dysfunction and gait Cholinergic hypofunction is History of falls in Parkinson disease is associated with fall status in PD. associated with reduced cholinergic activity Thalamic AChE activity in part Bohnen et al., 2009 represents cholinergic output of the pedunculopontine nucleus (PPN), a key node for gait control. In PD cortical cholinergic denervation (PET imaging) is correlated to gait slowing more than nigrostriatal denervation. Bohnen et al., 2013 Thalamic cholinergic deficits associated with falling history and emphasized role of right visual thalamus complex changes, Bohnen et al., 2019 including the right LGN. 27 Laura Avanzino
Modulators of cortical plasticity Gait: From Neurophysiology to Pathophysiology Nucleus basalis of Meynert 28 Laura Avanzino
Modulators of cortical plasticity Gait: From Neurophysiology to Pathophysiology Transcranial magnetic stimulation (TMS) was used to estimate Cholinergic activity in the cortex • 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, TMS elicited by TMS, of the motor cortex, with electrical stimuli delivered to the contralateral median nerve. ES-TMS 29 Laura Avanzino
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