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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)