basal ganglia and motor control - mondino · dopamine bg circuitry can release inhibition in a...
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Gangli della Base: un network multifunzionale
Prof. Giovanni Abbruzzese
Centro per la Malattia di Parkinson e i Disordini del Movimento
DiNOGMI, Università di Genova
IRCCS – AOU San Martino IST
Basal Ganglia and Motor Control
Striatal necrosis causing dystonia and
parkinsonism
Wilson 1925
Akinesia and bilateral pallidal lesions
Denny-Brown 1962
Sub-thalamic lesions producing
hemiballism
Purdon-Martin 1934
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Parallel and Segregated Organization of Basal Ganglia – Thalamocortical circuits
Alexander, DeLong & Strick - Ann. Rev. Neurosci. 1986
Basal Ganglia
Movement
preparation
Movement selection
and focusing
Scaling of movement parameters
Internal cues generation
Motor Learning
Reward
Behaviour
Affectivity
Executive Functions
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Major connections within the BG
BG have no direct sensory inputs or motor outputs
Rothwell 2011
Basal Ganglia Disorders
Akinetic-rigidSyndromes Hyperkinetic Syndromes
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Dopamine
BG circuitry can release inhibition in a highly selective way (both in space and time)
so that appropriate movements are facilitated whereas others are suppressed.
PHASIC FACILITATION OF (desired ) MOTOR ACTIVITY
STRIATUM
GPi
BG are seen as providing
a general inhibitory
output to movement:
TONIC INHIBITION OF
(competing ) MOTOR
ACTIVITIES
CORTEX
modified from: Mink, Arch Neurol 2003
Ind Dir
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BG represent are a complex network with highly patterned axon collaterals:
parallel projections somatotopically organized but also horizontal internal
circuits for excitability modulation and stabilization
Obeso et al. 2000
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MOTOR CORTEX
WHAT TO DO
WHAT NOT TO DO
TIMING OF WHAT IS TO BE
DONE
Basal Ganglia Cerebellum
Motor
Command
Via Thalamus Via Thalamus
Neurology 1982
“… the basal ganglia are responsible for the
automatic execution of learned motor plans”
PD patients have difficulty in "automatic execution
of learned motor plans”
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GOAL-DIRECTED CONTROL
• Conscious
• Voluntary - High cognitive effort
• Explicit - Early acquisition
• Internally generated
• Controlled
• Slow & serial
HABITUAL CONTROL
• Unconscious
• Involuntary - Low cognitive effort
• Implicit - Extended training
• Externally generated
• Automatic
• Fast & parallel
These two types of motor control appear to be represented in slightly
different parts of the cortico-basal ganglia cortex loop.
Redgrave et al. 2010
Redgrave et al 2010
Encoding motor and
probabilistic
asociations
LATE IMPLICIT
LEARNING
HABITUAL CONTROL
Response selection
and evaluation of
outcome or reward
EARLY EXPLICIT
LEARNING
GOAL DIRECTED
CONTROL
ASSOCIATIVE CIRCUIT
Dorso-medial striatum
Anterior Putamen
& Caudate
Frontal/Pre-motor
cortices
SENSORIMOTOR
CIRCUIT
Dorso-lateral striatum
Posterior Putamen
Sensorimotor/Parietal
cortices
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Redgrave et al 2010
• Automaticity is the ability to perform movements without attention directed
toward the details of the movement, particularly for movements that require
low levels of precision or for movements that are commonly made
• Motor automaticity is impaired in early PD
• Blinking, Arm-swinging, Facial expression, Writing, Pacing of gait, Speech modulation
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Basal Ganglia modulate all the three domains by selection of
the most appropriate and inhibition of inappropriate circuits
Parkinsonism
DyskinesiaApathy
Impulsivity
Jahanshahi et al. 2015
Indirect fronto–striato–pallido– thalamo–cortical pathway
Prospective, Intentional and goal directedHyperdirect cortico–subthalamic–pallidal–thalamo– cortical pathway
Built up through learning and experience, more automatic and habitual
Jahanshahi et al. 2015
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Dysfunction in the Associative striato-frontal loop
• Dysexecutive syndrome• Shifting attention• Planning• Problem solving• Suppressing habitual responses• Dividing attention (Dual tasking)• Time estimation• Implicit learning
• Psychiatric Manifestations• Depression• Anxiety• Psychosis• Social integration (ToM)
Impulse Control Disorders
ICD
Shopping
Gambling Punding
Eating
Sexuality
• The combination of nigrostriatal denervation and dopaminergic drugs is likely to induce behavioural disorders in PD via abnormal activation of the associative (limbic) loops between the BG and the cortex and reduced inhibitory activity in the connections between the frontal cortex and the STN nucleus.
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Exploring functional organization of BG
• Anatomical connectivity assessed using tractography, allowing
reconstruction of fibre bundles in the brain, and diffusion metrics within
the tracts (number of tracks, connection probability between regions).
• Functional connectivity assessed with fMRI to ascertain temporal
correlations of low-frequency, spontaneous BOLD signal fluctuations
between spatially remote regions measured at rest (resting state fMRI)
or during task performance, and correlation coefficient of signals within
regions belonging to a particular network.
Parkinson’s disease-related pattern (PDRP)
• ↑ Metabolic ac?vity
• Putamen/GP, Thalamus, Cerebellum, SM Cortex
• ↓ Metabolic ac?vity
• PMC and parietal association cortex
• ↓ Func?onal connec?vity between posterior putamen and PMC/SMA
• ↑ Func?onal connec?vity between cor?cal motor areas and cerebellum
Dopamine replacement and STN-DBS are associated with changes (↓) of PDRP
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Abnormal connectivity in PD
• In de novo PD patients, 1 Hz-rTMS to PMd reduced in the ipsilateral M1 the abnormal baseline intracorticalexcitability Buhmann et al. 2004
• Differently from healthy subjects, in PD 5 Hz-rTMS over the PMd, failed to facilitate MEPs elicited by single pulses over M1 Mir et al. 2005
• Dopaminergic treatment partly restored normal PMd-to-M1 modulatory patterns Buhmann et al. 2004; Mir et al. 2005
M1
PM
2.5 cm
Parkinson’s disease-related cognitive pattern (PDCP)
• ↓ Metabolic ac?vity
• Pre-SMA, PFC, precuneus and parietal association cortex
• ↑ Metabolic ac?vity
• Cerebellum (dentate N.)
Not altered by pharmacotherapy or DBS
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• STN-DBS is an effective treatment for late-stage PD.
• Stimulation reduces the abnormal hyperactivity of the STN in PD and can be used to interfere reversibly with the neuronal activity in the STN.
• Despite the clinical benefits of DBS in PD, individuals with PD who undergo STN-DBS show impaired performance on several motor tasks that involve inhibitory and executive control.
Holtbernd and Eidelberg 2012
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Holtbernd and Eidelberg 2012
Heterogeneity of phenotypic manifestations of PD
• Tremor dominant vs. non-tremor dominant
• Unilateral vs. bilateral
• Segmental vs. axial involvement
• Early-onset vs. late-onset
• MCI vs. non-MCI
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2016
BG and Gait/Postural Control
Takakusaki JMD 2017
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DAergic cell death in the retrorubral area causes DA depletion in the pallidum and leads to emergence of pathological activity in the striato-pallidal circuit, which triggers (SWITCH) activity in the cerebello-thalamo-cortical circuit through the primary motor cortex (DIMMER)
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It is likely that the major roles of cerebellum in PD include
pathological (induced by DA-denervation) and compensatory
effects (to maintain better motor and non-motor functions)