Objec.ves. Disclosures. Basal Ganglia: func.onal circuitries, neurotransmi9ers and early motor development

Transcription

1 Objec.ves Basal Ganglia: func.onal circuitries, neurotransmi9ers and early motor development Gabriella Horvath CNSF, Child Neurology Day Victoria, June 24, 2017 Disclosures Nothing to disclose Overview of basal ganglia anatomy Basal ganglia func.onal circuitries Neurotransmi9ers in the basal ganglia Developmental aspects of movement Cogni.ve-motor interac.ons of the basal ganglia in development Basal ganglia: orchestra for movement Basal ganglia circuitry: dance floor Neurotransmi9ers: music of the mind 1

2 It all starts here: 2

3 Dopaminergic modula.on of direct and indirect pathways Cholinergic modula.on of direct and indirect pathways The Rate Model Developed in the 1980s early 1990s Describes the connec.vity, neurochemistry and physiology of the BG (Albin et al, DeLong) The Rate Model Key components: interconnected network involved in motor and cogni.ve func.ons cortex generates motor demands, BG executes with posi.ve feedback system dopamine acts differen.ally in striatum compe.ng ac.ons suppressed network output is integrated at the level of Gpi and SNr, which inhibit or disinhibit thalamocor.cal and/or brainstem 3

4 The Rate Model Key concepts: Dopamine has opposing effects on the direct and indirect pathways Abla.on or inac.va.on of indirect pathway neurons leads to increased or excessive movement Abla.on of indirect pathway leads to decreased movement Ac.va.on of indirect pathway leads to decreased movement Ac.va.on of direct pathway leads to increased movement Decreases in BG output correlates with increased movement Increases in BG output correlates with decreased movement Inconsistencies of the Rate Model Lesioning or s.mula.on of the Gpi is therapeu.c in both hypokine.c and hyperkine.c movement disorders Further studies have shown that different groups of neurons within par.cular nucleus may be ac.vated or suppressed at the same.me in order to release different motor programs Neurotransmi9ers Neuromodulatory projec.on systems: Dopamine Serotonin Norepinephrine Classical neurotransmi9er systems: Glutamate GABA acetylcholine 4

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6 Developmental aspects of movement Developing sense of self Upright posi.on needs prior failed a9empts associated with pain The discomfort results in self-paced movements Using the correct combina.on to take the first successful step This will consolidate later into a more complex motor pa9ern Developmental aspects of movement The BG are key elements in the control of reward-based learning, sequencing, discrete elements that cons.tute a complete motor act and cogni.ve func.on Connec.ons between BG and cortex are organized into circuits loops reciprocally interconnect a large and diverse set of cor.cal areas with BG Neuronal ac.vity within BG associated with motor cortex correlates with movement Neuronal ac.vity within the BG and cerebellar loops associated with the prefrontal cortex is realted to cogni.ve func.on Need to understand: Phylogeny (evolu.on) and ontogeny (development) of the motor system Movement or mo.on is essen.al for the development of a func.onal musculoskeletal system in a fetus or infant Human fetus has 11 separate movement pa9erns of increasing complexity as gesta.on progresses: Twitching, independent limb, isolated head movement, combina.on movements, quazi-startle, hand-face movements, isolated body extension, thumb sucking, breathing Post-delivery: remodeling of the innerva.on of agonistantagonist muscle pairs of the peripheral neuromuscular system Centrally driven truncal, arm and leg flexor and extensor postural stages Newborn: Dystonic-Thalamic Man Persistent flexed trunk and limb postures asscoiated with thalamic and brainstem ac.vity 6

7 3-4 months: Choreiform Man (Riverdance) Trunk symmetrically straight posture, arms and legs hyperac.ve (physiological chorea) 6-8 months: Kung-Fu Man Directed and targeted swagng and kicking of arms and legs (prelocomotor equipoten.al phase of all four limbs) striatal toes 6-10 months: Ballerina Holding legs straight playing with the feet dissipates when legs are commi9ed to locomotor task 24 months: mature gait First hallmark: heel-strike Second hallmark: asynchronous hip flexion-kneeextension-ankle dorsiflec.on Third hallmark: contralateral arm swing Ini.al clumsy, goal-directed motor behaviours and movements transi.on to habitual movements (internalized, semi-automa.c) Ini.al co-contrac.on of most trunk and limb muscle groups are required Will gradually develop more fluent and economical movements replacing cocontrac.on with a graceful interplay of agonist-antagonist muscles Development of pathology Lack of selec.ve control and surround inhibi.on produces unwanted synergies (CP) Lack of selec.ve motor control, excessive plas.city (dystonia) Knowledge of diverse pathways and circuits advantageous when assessing neonatal brain injury 7

8 Summary Understanding basal ganglia anatomy, circuitry, neurotransmi9ers, development of movement in infancy, helps in: diagnosis and treatment of developmental movement disorders, such as CP primary gene.c movement disorders in children JP Lin, N Nardocci, 2016 References A Nelson, A Kreitzer. Reassessing models of basal ganglia func.on and dysfunc.on. Annu Rev Neurosci. 2014;37:117 L Brichta, P Greengard, M Flajolet. Advances in the pharmacological treatment of Parkinson s disease: targe.ng neurotransmi9er systems. Trends in Neurosci. 2013:36;9 G Leisman, O Braun-Benjamin, R Melillo. Cogni.ve-motor interac.ons of the basal ganglia in development. Front Syst Neurosci. 2014;8:16 JP Lin, N Nardocci. Recognizing the common origins of dystonia and the development of human movement: A manifesto of unmet needs in isolated childhood dystonias 8