Utilizzo della Transcranial Magnetic Stimulation (TMS) nei … · 2019-03-06 · Utilizzo della...
Transcript of Utilizzo della Transcranial Magnetic Stimulation (TMS) nei … · 2019-03-06 · Utilizzo della...
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.