Gangli della Base: un network multifunzionale

Transcription

1 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

2 Parallel and Segregated Organization of Basal Ganglia Thalamocortical circuits Alexander, DeLong & Strick - Ann. Rev. Neurosci Movement selection and focusing Movement preparation Motor Learning Basal Ganglia Executive Functions Scaling of movement parameters Internal cues generation Reward Behaviour Affectivity 2

3 Major connections within the BG Rothwell 2011 BG have no direct sensory inputs or motor outputs Basal Ganglia Disorders Akinetic-rigid Syndromes Hyperkinetic Syndromes 3

4 Dopamine 7 STRIATUM CORTEX GPi BG are seen as providing a general inhibitory output to movement: TONIC INHIBITION OF (competing ) MOTOR ACTIVITIES Ind Dir modified from: Mink, Arch Neurol 2003 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 4

5 Obeso et al BG represent are a complex network with highly patterned axon collaterals: parallel projections somatotopicallyorganized but also horizontal internal circuits for excitability modulation and stabilization 5

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7 MOTOR CORTEX Via Thalamus Via Thalamus Basal Ganglia Cerebellum WHAT TO DO WHAT NOT TO DO TIMING OF WHAT IS TO BE DONE Motor Command 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 7

8 Redgrave et al 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. ASSOCIATIVE CIRCUIT Dorso-medial striatum Anterior Putamen & Caudate SENSORIMOTOR CIRCUIT Dorso-lateral striatum Posterior Putamen Frontal/Pre-motor cortices Response selection and evaluation of outcome or reward EARLY EXPLICIT LEARNING Sensorimotor/Parietal cortices Encoding motor and probabilistic asociations LATE IMPLICIT LEARNING GOAL DIRECTED CONTROL HABITUAL CONTROL Redgrave et al

9 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 9

10 Basal Ganglia modulate all the three domains by selection of the most appropriate and inhibition of inappropriate circuits Parkinsonism Dyskinesia Apathy Impulsivity Jahanshahi et al Jahanshahi et al Indirect fronto striato pallido thalamo cortical pathway Prospective, Intentional Hyperdirect and goal cortico subthalamic pallidal thalamo directed cortical pathway Built up through learning and experience, more automatic and habitual 10

11 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 Gambling Punding The combination of nigrostriatal denervation and dopaminergic drugs is likely to induce behaviouraldisorders 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. Shopping ICD Eating Sexuality 11

12 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 12

13 Abnormal connectivity in PD In de novo PD patients, 1 Hz-rTMSto PMdreduced in the ipsilateral M1 the abnormal baseline intracortical excitability Buhmann et al Differently from healthy subjects, in PD 5 Hz-rTMSover the PMd, failed to facilitate MEPs elicited by single pulses over M1 Mir et al cm PM M1 Dopaminergic treatment partly restored normal PMd-to-M1 modulatory patterns Buhmann et al. 2004; Mir et al 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 13

14 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

15 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 15

16 2016 BG and Gait/Postural Control Takakusaki JMD

17 DAergic cell death in the retrorubralarea causes DA depletion in the pallidum and leads to emergence of pathological activity in the striatopallidalcircuit, which triggers (SWITCH) activity in the cerebello-thalamo-cortical circuit through the primary motor cortex (DIMMER) 17

18 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) 18