Utilizzo della Transcranial Magnetic

Stimulation (TMS) nei Disturbi

Psichiatrici: lo stato dell’arte

Dr B. Dell’Osso

Università degli Studi di Milano

Dipartimento di Neuroscienze,

U.O. di Psichiatria,

Fondazione IRCCS Ospedale Maggiore Policlinico;

Bipolar Disorders Clinic, Stanford Medical School,

Stanford University, CA, USA.

Introduction

i) Duration of trial

ii) High vs Low Frequency

Summary

iii) Navigated TMS

iv) Other stimulation parameters

v) Clinical indications and future perspectives

vi) Clinical trials at Milan Policlinico

Conclusions

Number of pubblications on brain stimulation (TMS,

tDCS, ECT, VNS, DBS) in Pub-Med from 1994 to 2015

Brain Stimulation Techniques in

Psychiatric Disorders

Brain Stimulation,

unlike systemic

pharmacology

delivered orally or delivered orally or

parentally, focuses on

electrical mechanisms

of the brain, which

then cause localized

neurochemical

changes.

(WFSBP Guidelines Brain Sttim 2010)

Transcranial Magnetic Transcranial Magnetic

Stimulation (TMS)Stimulation (TMS)

Different techniques, with the Different techniques, with the

common feature to provide a common feature to provide a

selective electric stimulation of selective electric stimulation of

specific brain areasspecific brain areas

Vagus Nerve Stimulation Vagus Nerve Stimulation (VNS)(VNS)

Deep Brain Stimulation Deep Brain Stimulation (DBS)(DBS)TranscranialTranscranial Direct Direct

Current Stimulation (Current Stimulation (tDCStDCS))

BRAIN STIMULATIONBRAIN STIMULATION

TECHNIQUESTECHNIQUES

Stimolazione Magnetica Trancranica (TMS)Stimolazione Magnetica Trancranica (TMS)

Transcranial Direct Current Stimulation (tDCS)Transcranial Direct Current Stimulation (tDCS)

CO

NV

UL

SIV

AN

TI

CO

N

IMP

IAN

TO

MA

GN

ET

ICH

E

CO

NT

INU

E

EL

ET

RIC

HE

Transcranial Direct Current Stimulation (tDCS)Transcranial Direct Current Stimulation (tDCS)

Stimolazione del Nervo Vago (VNS)Stimolazione del Nervo Vago (VNS)

Stimolazione Cerebrale Profonda (DBS)Stimolazione Cerebrale Profonda (DBS)

Terapia Elettroconvulsivante (ECT)Terapia Elettroconvulsivante (ECT)

Magnetic Seizure Therapy (MST)Magnetic Seizure Therapy (MST)

Focal Electrically Applied Seizure Therapy (FEAST)Focal Electrically Applied Seizure Therapy (FEAST)

TMS e tDCS

-

ECT

Light Therapy

Richiedono

Richiede anestesia

generale. Può dare

effetti collaterali di

tipo cognitivo

Non richiedono

anestesia, sono

indolori (possibili

rari eventi eversi)

Non Invasive

Brain Stimulation

Invasività

(tollerabilità ed

effetti collaterali)

+

VNS

DBS

Neurochirurgia

Funzionale

Richiedono

intervento

chirurgico

d’impianto:

-Extracranico

(VNS)

-Intra-

parenchimale

(DBS)

Una condizione di reale farmaco-resistenza deve essere sempre accertata prima di

considerare interventi di 2° livello. In tal senso, occorre:

- verificare la diagnosi principale, nonché la presenza di altri disturbi in comorbidità (ad

es., disturbi di personalità, abuso di alcool/sostanze) tramite interviste diagnostiche

strutturate (SCID, MINI, CIDI).

Valutazione della non risposta al trattamento nel paziente

candidato alla Brain Stimulation

- escludere una condizione di pseudoresistenza (dovuta a problemi di

aderenza/compliance).

- effettuare un’accurata caratterizzazione quantitativa della patologia tramite scale

psicometriche (HAMD, MADRS, CGI).

- a quel punto è possibile proporre al paziente un programma di cure con interventi di

secondo livello:

- augmentation farmacologica

- terapia farmacologica EV

- interventi di neuromodulazione (diversa invasività)

Scarsa Risposta (“poor response”) e

Farmacoresistenza nella Depressione Maggiore

• L’obiettivo di un trattamento di primo livello (SSRI/psicoterapia) è la

remissione (scomparsa dei sintomi) e non la semplice risposta (miglioramento

dei sintomi del 50%).

• L’efficacia complessiva degli attuali antidepressivi è, tuttavia, modesta con

solo 1/3 dei pazienti sottoposti a terapia con SSRI in grado di raggiungere

una condizione di remissione.

• In molti casi vi puo essere una risposta parziale o scarsa (< 50% o < 25%).

• Fino al 15% dei pazienti depressi può presentare Depressione Resistente al

Trattamento (TRD), ovvero una condizione di assenza di risposta ad uno o

più trial con antidepressivi di diverse classi.

• In tali casi si prendono in considerazione strategie terapeutiche di secondo e

terzo livello.

Alterazioni neurofisologiche nella Depressione Maggiore

• Current pathophysiological models converge in suggesting that 2

major groups of brain regions - a "dorsal" and "ventral" network -

account for the formation of the varied symptoms of affective illness.

• Within this theoretical framework, depression is hypothesized to • Within this theoretical framework, depression is hypothesized to

involve concurrent hypoactivation of dorsal prefrontal regions and

hyperactivation of ventral prefrontal regions, particularly in the left

hemisphere.

• Symptom remission may require facilitation of hypoactive dorsal brain

regions and inhibition of hyperactive ventral areas.

(Mayberg HS. Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci. 1997;9:471-481; Davidson RJ. Anterior electrophysiological asymmetries, emotion, and depression: conceptual and methodological conundrums. Psychophysiology. 1998;35:607-614; Blumberg et al. Increased anterior cingulate and caudate activity in bipolar

mania. Biol Psychiatry. 2000;48:1045-1052)

Transcranial stimulation (TMS and tDCS): a

common rational for use in MD

Ultimately, transcranial

neuromodulatory techniques, like TMS

and tDCS, though with different and tDCS, though with different

mechanisms of action, are supposed to

restore the functional balance between

the 2 hemispheres.

(Mayberg HS. Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci. 1997;9:471-481; Davidson RJ. Anterior

electrophysiological asymmetries, emotion, and depression: conceptual and methodological conundrums. Psychophysiology. 1998;35:607-614; Blumberg et

al. Increased anterior cingulate and caudate activity in bipolar mania. Biol Psychiatry. 2000;48:1045-1052)

Brain Stimulation: First Guidelines

Transcranial Magnetic Stimulation (TMS)

Repetitive TMS and stimulation parametrsRepetitive TMS and stimulation parametrs

Slow Slow ≤≤ 1 Hz 1 Hz Fast > 1 Hz Fast > 1 Hz -- 30 Hz30 Hz

80% 80% --120% of Individual Motor Threshold120% of Individual Motor ThresholdIntensity

Frequency Slow Slow ≤≤ 1 Hz 1 Hz Fast > 1 Hz Fast > 1 Hz -- 30 Hz30 Hz

seconds seconds -- minutesminutes

absentabsent-- present (30present (30--60 sec)60 sec)Intertrain Interval

Frequency

Length

In October 2008, the FDA approved

TMS Therapy for patients suffering

from Major Depressive

Disorder who have failed to achieve

satisfactory improvement from

antidepressant treatment.antidepressant treatment.

Depression approvals outside the U.S.A.: Canada,

Brazil, Australia, Israel, Finland, Germany, Serbia

To date, 3 TMS devices are currently approved in the

U.S. for the treatment of Major Depressive Episodes

Duration of TrialDuration of Trial

TMS Efficacy Yet to Be Established:TMS Efficacy Yet to Be Established:

MetaMeta--analysis of 14 Controlled Trialsanalysis of 14 Controlled TrialsTwo weeks

Avery et al, 1999 4 2

Berman et al, 2000 10 10

Garcia-Toro et al, 200lb 11 11

Garcia-Toro et al, 200la 17 18

George et al, 1997 7 5

George et al, 2000 20 10

Kimbrell et al, 1999 5 3

Loo et al, 1999 9 9

Mosimann et al, in preparation 9 9

-1.02 (-2.99 to 0.94)

-1.30 (-2.29 to -0.32)

-0.21 (-1.05 to 0.63)

-0.52 (-1.20 to 0.15)

-0.75 (-1.95 to 0.45)

-0.08 (-0.84 to 0.68)

0.29 (-1.16 to1.73)

-0.57 (-1.52 to 0.38)

0.39 (-0.44 to 1.23)

-0.35 (-0.66 to -0.04), P=0.03

(Martin JLR et al. Br J Psychiatry. 2003, 182, 480-491)

Total 98 77 overall effect

Heterogeneity x2.P=0.32

Two-week follow-up

(after 2 weeks of treatment)

Avery et al, 1999 4 2

Garcia-Toro et al, 200 lb 11 11

Garcia-Toro et al, 200 la 17 18

Total 32 31 overall effect

Heterogeneity x2.P=0.54

-0.35 (-0.66 to -0.04), P=0.03

0.00 (-1.70 to 1.70)

-0.02 (-0.86 to 0.81)

-0.59 (-1.27 to 0.09)

-0.33 (-0.84 to 0.17), P=0.2

-10 5 0 5 10Favour treatment (95% CI) Favour control

“recent rTMS trials have

shown larger antidepressant

effects when compared

with the earlier studies”

“recent rTMS trials used “recent rTMS trials used

novel parameters of

stimulation, such as more

sessions of rTMS”

(Gross et al., 2007; Acta Psychiatr Scand)(Gross et al., 2007; Acta Psychiatr Scand)

Large TMS RCTs (i)Large TMS RCTs (i)

SampleSample: n=301 medication: n=301 medication--free free

outpatients with MDD with no outpatients with MDD with no

benefit from prior treatment benefit from prior treatment

(4(4--6 weeks, 10 Hz, 120% MT, 6 weeks, 10 Hz, 120% MT,

3000 impulses/session, left 3000 impulses/session, left

DLPFC). DLPFC).

(O(O’’Reardon et al., 2007; Biol Psychiatry)Reardon et al., 2007; Biol Psychiatry)

HAM-D

Daily left prefrontal transcranial magnetic stimulation therapy for major

Depressive disorder: a sham-controlled randomized trial

George MS, Lisanby SH, Avery D, et al. Arch Gen Psychiatry 2010;67(5):507-16.

Prospective, multisite, randomized, active sham-controlled study, with 3 weeks of daily TMS,

followed by continued blinded treatment for up to another 3 weeks in improvers.

199 antidepressant drug-free patients with nonpsychotic MDD were treated with rTMS to the left

DLPFC at 120% motor threshold (10 Hz, 4-second train duration, and 26-second intertrain

interval) for 37.5 minutes (3000 pulses per session) using an 8 coil. Sham rTMS used.

Large TMS RCTs (ii)Large TMS RCTs (ii)

interval) for 37.5 minutes (3000 pulses per session) using an 8 coil. Sham rTMS used.

Results: Minimal adverse effects did not differ by treatment arm, with an 88% retention rate (90%

sham and 86% active).

A significant effect of treatment on the proportion of remitters was found:

14.1% active rTMS and 5.1% sham.

The odds of attaining remission were 4.2 times greater with active rTMS than

with sham. The NNT was 12. Most remitters had low antidepressant

treatment resistance.

Almost 30% of patients remitted in the open-label follow-up.

Research clues for

clinical aplications of

rTMS:

1) The longer (3-4

weeks) the patient stays

in treatment the higher in treatment the higher

the improvement rate

2) The higher the level

of treatment resistance

the lower the response

rate

High vs Low FrequencyHigh vs Low Frequency

Navigated TMSNavigated TMS

TARGET LOCALIZATION: the ‘5 cm rule’

Motor Cortex

Herwig et al, 2001

Motor Cortex

DLPFC

Other Stimulation ParametersOther Stimulation Parameters

Coil Shape and Field DistributionCoil Shape and Field Distribution

Jalinous, 1995Jalinous, 1995

Depth of Penetration

Depth of penetration ~2 cm, at junction between grey and white matter

Depth of penetration ~2 cm, at junction between grey and white matter

In January 2013, the FDA

approved Deep TMS for the

treatment of depressive

episodes in adult patients

suffering from MDD, who

failed to achieve satisfactory

improvement from 1-4 previous

antidepressant treatments in the

current episode.

9 studies selected: HF-DTMS

showed acute antidepressant

effects after 20 sessions in

mostly unipolar and treatment-

resistant patients.

Concurrent treatment with

antidepressants might enhance

the efficacy of DTMS.Results are based on data from a

low number of open-label studies.

Coil design considerat ions for deep transcranial magnetic st imulat ion

Zhi-De Deng a, Sarah H. Lisanby a,b, Angel V. Peterchev a,c,d,�

aDepartment of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USAbDepartment of Psychology and Neuroscience, Duke University, Durham, NC, USAcDepartment of Biomedical Engineering, Duke University, Durham, NC, USAdDepartment of Electrical and Computer Engineering, Duke University, Durham, NC, USA

Clinical Neurophysiology 125 (2014) 1202–1212

Contents lists available at ScienceDirect

Clinical Neurophysiology

journal homepage: www.elsevier.com/locate/cl inph

Direct TMS of targets at

depths of ~4 cm or more

results in superficial

stimulation strength that

exceeds the upper limit

in current safety

guidelines.

Approaching depths of

~6 cm is almost

certainly unsafe

considering the

excessive superficial

stimulation strength and

activated brain volume.

Clinical indications Clinical indications

and future perspectives

Patterned rTMS

(Rossi et al, 2009)

The standard theta burst pattern consists of three bursts of pulses given at 50Hz and

repeated every 200 ms.

- Efficacy of rTMS in Bipolar vs Unipolar

Depression (few studies, mixed results)

- Usefulness of Maintenance Treatment (Taper

Other aspects to be further clarified

Sessions, Relapese Rate)

- Interaction with Antidepressant (combination vs

augmentation) and other psychotropic drugs

(BDZ, Mood Stabilizers and Antipsychotics)

(Lefauchneur et al, 2014)

Guidelines

Clinical Neurophysiology 125 (2014) 2150–2206

Contents lists available at ScienceDirect

Clinical Neurophysiology

j ournal homepage: www.elsevier.com/locate/cl inph

TMS Guidelines

Guidelines

Evidence-based guidelines on the therapeutic use of repet it ive

transcranial magnet ic st imulat ion (rTMS)

Jean-Pascal Lefaucheur a,b,�, Nathalie André-Obadia c,d, Andrea Antal e, Samar S. Ayache a,b, Chris Baeken f,g,

David H. Benninger h, Roberto M. Cantello i, Massimo Cincotta j, Mamede de Carvalho k, Dirk De Ridder l,m,

Hervé Devannen,o, Vincenzo Di Lazzaro p, Saša R. Fil ipovic q, Friedhelm C. Hummel r, Satu K. Jääskeläinen s,

Vasilios K. Kimiskidis t, Giacomo Koch u, Berthold Langguth v, Thomas Nyffeler w, Antonio Oliviero x,

Frank Padberg y, Emmanuel Poulet z,aa, Simone Rossi ab, Paolo Maria Rossini ac,ad, John C. Rothwell ae,

Carlos Schönfeldt-Lecuona af, Hartw ig R. Siebner ag,ah, Christ ina W. Slotema ai, Charlotte J. Stagg aj,

Josep Valls-Sole ak, Ulf Ziemann al, Walter Pauluse,1, Luis Garcia-Larrea d,am,1

Recommendation 1: TMS therapy is recommended as an acute treatment for symptomatic

relief of depression in the indicated patient population.relief of depression in the indicated patient population.

Recommendation 2: TMS therapy is recommended for use as a subsequent option in patients

who previously benefited from an acute treatment course and are experiencing a recurrence

of their illness (continuation or maintenance).

Recommendation 3: TMS therapy can be administered with or without the concomitant

administration of antidepressant or other psychotropic medications.

Recommendation 4: TMS therapy can be used as a continuation or maintenance treatment

for patients who benefit from an acute course.

Recommendation 5: TMS therapy can be reintroduced in patients who are relapsing into

depression after initially responding to TMS treatment.

Use of rTMS beyond MDD

Disorder Level of Evidence

Schizophrenia Possible Efficacy

(auditory hallucinations)

Probable Efficacy

(negative symptoms)

Bipolar Disorder Insufficient

Panic Disorder Insufficient

Target

- Left LF

Temporoparietal Cortex

- DLPFC

- Left HF DLPFC (Depr.)

Panic Disorder Insufficient

Generalized Anxiety Disorder Insufficient

Post-traumatic Stress Disorder Possible Efficacy

Obsessive-Compulsive Disorder Mixed (different targets)

Cigarette craving and consumption Possible Efficacy

(Dell’Osso et al, 2016)

- Left HF DLPFC

- Left HF DLPFC

- Left and right DLPFC

- SMA, OFC, DLPFC

- HF DLPFC

Double-blind, parallel group, study investigating the effects of 1 session of

sham-controlled HF rTMS to the left DLPFC in 60 individuals with AN. A food

exposure task was administered before and after the procedure to elicit AN-

related symptoms.

RESULTS: 49 participants completed the study. Individuals who received real

vs sham rTMS had reduced symptoms post-rTMS and at 24-hour follow-up.

rTMS was safe, well-tolerated and was considered an acceptable intervention.

Recovery in AN is frequently characterized by

weight gain; however, this physical symptom is

a consequence of psychological factors like

body dysmorphia. Ignoring psychological

recovery is partly responsible for the high rate of

relapse.

rTMS of the DLPFC in AN may reduce the

sensation of feeling full and anxiety in response

to food stimuli, encouraging weight gain, rather

than reducing the psychological symptoms, like

the intense fear of gaining weight or the the intense fear of gaining weight or the

perception of being overweight.

An accurate body representation stems from

different neural systems, but the parietal cortex

is the brain region most consistently involved in

AN according to functional neuroimaging. TMS

may provide a safe, non-invasive mean to

stimulate the under-active parietal cortex and

restore an accurate body-image, with a lower

rate of relapse.

A Lack of Clinical Effect of High-frequency rTMS to DLPFC on Bulimic

Symptoms: A Randomised, Double-blind Trial

Gay, Jaussent, Sigaud et al., Eur Eat Disord Rev. 2016 Nov

Studies suggest that stimulation of the left DLPFC reduces food craving in

bulimic patients. The safety and therapeutic efficacy of an adjunct HF rTMS

programme targeting the left DLPFC was investigated.

47 women with bulimia nervosa were randomised to real or sham stimulation.

The real group underwent 10 rTMS sessions (20 trains of 5 seconds with 55-second

intervals between trains, at a frequency of 10 Hz). The main outcome was the # of

binge episodes in the 15 days following the end of stimulation.

No significant improvement in bingeing and purging symptoms was noted

after the programme. rTMS was well tolerated. This suggests that 10 sessions

of HF-rTMS to the left DLPFC provide no greater benefit than placebo.

Future studies should consider methodological issues and alternative targets.

Clinical Trials at Policlinico

IRCCS of MilanIRCCS of Milan

After the completion of an acute trial with augmentative, low-frequency, navigated rTMS, 11 drug-resistant

depressed bipolar subjects (DSM-IV-TR criteria) entered a naturalistic follow-up with monthly evaluations

through the HDRS and the YMRS.

RESULTS: After 1 year of follow-up, results showed that the achievement of remission after

acute rTMS was predictive of maintenance of response at 1 year. On the other hand, the

absence of acute rTMS response predicted the absence of subsequent response in the long-term.

Conclusions

• TMS is among the brain stimulation techniques that have shown the major

development in the field of clinical psychiatry.

•Its favorable tolerability has played a major role in the increasing use of TMS in

clinical practice.

•Large RCTs indicated that patients with poor/partial response to standard •Large RCTs indicated that patients with poor/partial response to standard

antidepressant treatment are likely the best candidates for TMS when they are

treated for 4-6 weeks of treatment.

Meta-analyses and International Guidelines support the efficacy of TMS in Major

Depression, with accumulating evidence also in other fields (SKZ, PTSD).

Further research and guidance are needed for the use of patterned TMS and deep

TMS, for the use of maintenance sessions and for the efficacy in other psychiatric

disorders.