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Neurofisiologia Clinica:

presente e futuro dellaneurostimolazione non

invasiva diagnostica e terapeutica

Angelo Quartarone

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Studio delle vie motorie

MEP

TMS: quali strutture andiamo a stimolare?

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TMS: quali strutture andiamo a stimolare?

TMS

TES

1) latenza della risposta dopo stimolazione

corticale

1-2= Tempo di conduzione motoria

centrale

3-2= Tempo di conduzione radicolare

3) (F+M-1)/2tempo di conduzione

periferica totale

2) latenza della risposta dopo stimolazione

paravertebrale

1-3= Tempo di conduzione motoria

centrale da lat F

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Sensibilità dei potenziali evocati motori e dell ’esame cliniconel dimostrare alterazioni della via corticospinale

spinal cord disease (177)hereditary spastic paraplegia (31)

motor neuron diseases (129)sylvian stroke (33)

demyelinating diseases (162)progressive ataxias (34)

encephalitis (11)brain tumors (11)

muscular diseases (88)peripherl nerve disorders (87)

movement disorders (50)

MEP

ESAME CLINICO

Di Lazzaro et al 1999

Ulteriori applicazioni cliniche della TMS

MAPPING PRE-OPERATORIO DELL’AREA MOTORIA

PRIMARIA E DELLE AREE DEL LINGUAGGIO

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1. MR image loading

4. Result and Diagnosis

Areas eliciting responses

Areas that should be avoided

3. Targeted stimulation

3D Mapping of the brain

2. Guided registration

Alignment between MRI’s and head

3 min.

5. MR export to OR navigators

Medtronic BrainLAB

MRI’s IN

20 min.

RESULT

OUT

PROCEDURA DI NEURONAVIGAZIONE

Allineamento RMN-cranio del soggetto

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Ricerca dell ’Hot Spot

…..inizia la neuronavigazione

Mappatura dell ’area motoria primaria

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Mappatura superficiale dell ’area motoria primaria

STIMOLAZIONE CORTICALE DIRETTA

Gold standard 100% sensibilita’ e specificita’

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ANATOMICAL AND FUNCTIONAL CONNECTIVITY(TMS + DTI)

Asportazione radicale del tumore e preservazione delle vie corticospinali

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MAPPAGGIO DELLE AREE DEL LINGUAGGIO

Effetto della TMS sulla corteccia cerebrale: approc ci non neurofisiologici

…fMRI

…PET

…EEG &

MEG

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TMS a valuable tool in translational neurosciences

EMG fMRI EEG-NIRS-fMRI-PET EMG-EEG-NIRS-fMRI

TMS e riabilitazione: studio della

neuroplasticita’ e applicazioni terapeutiche

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connettività cortico-corticale e corticospinale e rimaneggiamento mappa corticale dopo procedure

riabilitative o dopo apprendimento di compiti motori

distruzione funzionale temporanea di aree corticali per vedere se contribuiscono al

recupero motorio del paziente.

Indurre cambiamenti a lungo termine

eccitabilità corticale

USO TERAPEUTICO?

Ruolo della TMS nello studio della neuroplasticità

TMS AS A TOOL TO ASSESS THE EFFECTS PRODUCED BY INTENSIVE

REHABILITATION

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EVALUTATION OF CORTICAL EXCITABILITY

CORTICO-CORTICAL CONNECTIVITY

Studio delle connessioni premotorie-motorie, trasncallosali motorie, parieto-

motorie, cerebello-motorie.

Futuro della ricerca: correlazione con I dati anatomici provenienti dalla trattografia

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ASSESSING MOTOR MAPS BEFORE AND AFTER REHABILITATION

Rossini et al 1999

TESTING EFFECTIVE CONNECTIVITY

Stimolazione su corteccia premotoria dorsale (dPMC), corteccia motoria primaria (M1), and lobo parietale superiore (SPL) interferiscono in maniera significante sulle performances motorie recuperate nei pazienti. In particolare la stimolazione su dPMC and M1 induce errori di tempo, mentre la stimolazione di SPL causa sia errori di timing che deficit di accuratezza.

Lotze et al 2006, J. Neurosci

Paz. con buon recupero dopo stroke

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Nitsche & Paulus, Neurology 57: 1899-901Nitsche et al. 2003, Clin Neurophysiol 114: 600-4

Anodal tDCS

Cathodal tDCS

Transcranial direct current stimulation (tDCS)

synaptic effect non-synaptic effect

NMDA receptor

Local membrane changes in ionic concentrations or alterations in transmembrane proteins resulting from electrolysis-related changes in [H(+)] induced by exposure to constant electric field.

Ardolino et al 2005

LTP-LTD like effects

Nietsche et al 2001

tDCS: mechanisms of action

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TMS AS THERAPEUTIC TOOL

TMS AS PLASTICITY PROMOTER

Reparative model Interactive model

The repair model posits that

neuromodulation corrects an

imbalance in function that has been

caused by the disease. In this case

neuromodulation should cause

permanent changes in a specific

neruonal pupulation, which

unfortunately is not the case.

In this model neuromodulation help the

brain to restore itself as an adjuvant

treatment to rehabilitation.

need a neural population capable of

showing plastic NMDA- nonNMDA LTP

related phenomena

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Effects of rTMS on BDNF-TrkB

•Chronic high-frequency rTMS increased the binding affinity between BDNF and its cognate receptor TrkB and augmented NMDA receptor-TrkB association in rat prefrontal cortex and in human and rat lymphocytes .

rTMS treatments increase BDNF affinity to TrkB in rat prefrontal cortex.

Wang HY et al.,2011, J. Neurosci

Effects of rTMS on BDNF-TrkB pathway in prefrontal cortex

rTMS treatments increase BDNF-TrkB signaling in rat prefrontal cortex.

Wang HY et al.,2011, J. Neurosci

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rTMS treatments increase BDNF induced association of the NMDARs and NMDAR synaptic anchoring protein PSD95 with TrkB in rat prefrontal cortex.

Collectively, these data indicate that a 5 d rTMS treatment improves the efficacy of BDNF–TrkB signaling and TrkB–NMDAR interaction in the rat PFCX.

Effects of rTMS on glutamate transmission

Wang HY et al.,2011, J. Neurosci

Effects of rTMS on BDNF-TrkB pathway in rats and human lymphocytes

rTMS treatments increase BDNF-TrkB signaling in rat lymphocytes.

rTMS treatments increase BDNF-TrkB signaling in lymphocytes from healthy human subjects .

Wang HY et al.,2011, J. Neurosci

rats humans

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Paired associative stimulation (PAS)

Anodal TDCS

given continuously for > 5 min

Transcranial direct current stimulation (TDCS)+

--

+

25 ms10 msISI of ~25 ms

given every 3 to 20 s

Continuous TBS (40s)1 s

Theta burst stimulation (TBS)

Intermittent TBS every 10 s2 s

8 s

Repetitive TMS (rTMS)

Low-frequency rTMS (~1Hz)2 s

ISI of ~10 ms

Cathodal TDCS

High-frequency rTMS ( ≥ 5Hz)2 s

Promoting plasticity in the brain

Variability of induced plastic effects

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IMPROVING THE PRECISION AND EFFICACY OF TMS

CLOSED LOOP STIMULATION

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rTMS and neuroprotection

•Chronic rTMS increases hippocampal neurogenesis in rats ( Ueyama et al 2011)

•Chronic rTMS in a rat transient middle cerebral artery occlusion of cerebral ischemic model significantly reduced cortical and striatal infarct volumes, and increased the anti-apoptotic Bcl-2/pro-apoptotic Bax ratio (Gao F et al.,2010, Yoon KJ et al.,2011).

•rTMS preconditioning followed by transient common carotid artery occlusion significantly increased the neuron density in the CA1 region and prevented ischemic neuronal damage (Fugiki M et al.,2003).

•high frequency stimulation in rat hippocampal slices shown protective effect by attenuating beta-amyloid protein 1-42 neurotoxicity (Kim DK et al.,2010)

•pretreatment with low frequency stimulation increased the Bcl-2 level in epileptic rat model (Ke S et al.,2010)

•Pre-tretament of 5Hz RTMS in a model of brain trauma induce a significant neuroprotective effect a prevent brain damage (Soundara Rajan et al 2013 in preparation).

Chronic rTMS significantly increased bromodeoxyuridine -positive cells in the dentate gyrus.

Antidepressant effect of rTMS on hippocampal neurogenesis

Ueyama et al 2011 Psychiatry and Clinical Neurosciences

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anti-apoptotic effect of rTMS

Low (1Hz; a) and high (5Hz; b) frequency rTMS increase anti-apoptotic protein Bcl-2 in rat via CaMKII and CREB activation (CaMKII-CREB-Bcl-2 pathw ay). Fortunately bax level in both sham and real arms after rTMS were undetectable!!! This could be the basis for treating several neurological diseases.

Anti-apoptotic effect in normal rats

Soundara Rajan T et al submitted

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Is this anti-apoptotic effect relevant for therapeutic applications in humans?

The TMS after effects even in rats are massive and not comparable with humans…is this just a compensatory reaction of these small brains?????

Anti-apoptotic effect of TMS on a TBI model

After traumatic brain injury, a first behavioral test was performed at postoperative day4. Sham or rTMS stimulation was applied for 4 days, which was followed by second behavioral test at postoperative day 8.

Soundara Rajan T et al in preparation

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Anti-apoptotic effect of TMS on a TBI model

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rct a

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Coronal slice (mm)

TBI +sham

TBI +rTMS

Soundara Rajan T et al in preparation

TBI +sham TBI +rTMS

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