Clinical Neurophysiology 133 (2022) 145–151

Contents lists available at ScienceDirect

Clinical Neurophysiology
journal homepage: www.elsevier.com/locate/clinph

Review

One century of healing currents into the brain from the scalp: From
electroconvulsive therapy to repetitive transcranial magnetic
stimulation for neuropsychiatric disorders
Riccardo Di Iorio a,⇑, Simone Rossi b, Paolo M. Rossini c
a
Neurology Unit, Policlinic A. Gemelli Foundation IRCCS, Rome, Italy
b
Siena Brain Investigation and Neuromodulation Lab (Si-BIN Lab), Department of Medicine, Surgery and Neuroscience, Section of Neurology and Clinical Neurophysiology, Policlinico
Le Scotte, University of Siena, Italy
c
Department of Neuroscience & Neurorehabilitation, IRCCS San Raffaele-Pisana, Rome, Italy

a r t i c l e i n f o h i g h l i g h t s

Article history:
 This article traces the development of ECT from its origin until today.
Accepted 30 October 2021
 The advent of rTMS in the neuropsychiatric field is described.
Available online 11 November 2021
 ECT and rTMS play a complementary role in treatment of neuropsychiatric disorders.

Keywords:
ECT
rTMS a b s t r a c t
Brain stimulation
Neuropsychiatric disorders
Electroconvulsive therapy (ECT) was applied for the first time in humans in 1938: after 80 years, it
Depression
remains conceptually similar today except for modifications of the original protocol aimed to reduce
adverse effects (as persistent memory deficits) without losing clinical efficacy. We illustrate the stages
of development as well as ups and downs of ECT use in the last eighty years, and the impact that it still
maintains for treatment of certain psychiatric conditions.
Targeted, individualized and safe noninvasive neuromodulatory interventions are now possible for
many neuropsychiatric disorders thanks to repetitive transcranial magnetic stimulation (rTMS) that
injects currents in the brain through electromagnetic induction, powerful enough to depolarize cortical
neurons and related networks.
Although ECT and rTMS differ in basic concepts, mechanisms, tolerability, side effects and acceptability,
and beyond their conceptual remoteness (ECT) or proximity (rTMS) to ‘‘precision medicine” approaches,
the two brain stimulation techniques may be considered as complementary rather than competing in the
current treatment of certain neuropsychiatric disorders.
Ó 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights
reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
2. Current applications of ECT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
3. The impact of rTMS in the neuropsychiatric setting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
4. Future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

⇑ Corresponding author. Fax: +39 0635501909.

E-mail addresses: r.diiorio@live.it, riccardo.diiorio@policlinicogemelli.it (R. Di Iorio).

https://doi.org/10.1016/j.clinph.2021.10.014
1388-2457/Ó 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.
R. Di Iorio, S. Rossi and P.M. Rossini
1. Introduction
Early attempts to treat mental disorders by inducing seizures
date back to the 16th century, when the Swiss alchemist Paracelsus
gave camphor in oil by mouth to induce convulsions and ‘‘cure
lunacy”. This approach became well rooted during the 18th and
19th centuries, when several cases of efficacious treatment were
documented (Abrams, 2002; Prudic, 2005). Starting by the studies
of Swiss researchers about the induction of seizures in dogs using
direct electrical current on the brain, two Italian scientists, Ugo
Cerletti and Luigi Bini, developed the idea of applying electrical
current to the scalp of human patients, powerful enough to pene-
trate the skull and extra-cerebral layers, reach the brain and pro-
voke a generalized epileptic seizure.
The hypothesis behind was that such a treatment could allevi-
ate psychotic and depressive symptoms. Indeed, at that time, the
Hungarian psychiatrist (and neuropathologist) Ladislas J. Meduna
had hypothesized that epilepsy and schizophrenia could not coex-
ist, thereby induced seizures could represent the rationale to pre-
vent schizophrenia. Cerletti capitalized this concept, together
with his own observation that electric currents applied to pigs’
brain -a custom of the Roman slaughterhouse at that time- induced
anesthesia in the animals without killing them (Bentivoglio and
Mazzarello, 2010).
So, exactly 83 year ago, in 1938 Cerletti and Bini gave the first
demonstration of electroconvulsive therapy (ECT) in Rome (Italy)
treating an unidentified 39-year-old man who was found delu-
sional in a train station. The treatment (original parameters of
stimulation were 125–135 Volts, 0.3–0.6 amperes for 1/10 second,
according to Medical Larousse Dictionary) was a great success: the
patient fully recovered after 11 sessions, apparently without
immediate adverse effects (Cerletti and Bini, 1938; Prudic, 2005;
Payne and Prudic, 2009).
ECT remains conceptually similar today after 80 years, except for
some improvements of the original protocol (pulsed waves rather
than alternating current, shorter pulses, hemiscalp stimulation rather
than whole brain, use of general anesthesia and muscle relaxants)
that have reduced its side-effects and the related ethical implications.
The common lay term ‘‘Electroshock” was given to ECT that well
reflects the curative concept behind it, obviously counteracting the
current line of thinking moving more and more towards individual-
ized and patient-oriented therapies (i.e., precision medicine).
After its diffusion in Europe, ECT spread rapidly to the United
States (US), because of the Second World War’s displacement of
several European psychiatrists to the ‘‘new world” (Shorter,
2009). Lothar Kalinowsky, a young German scientist who assisted
to the second ECT treatment carried out by Cerletti and Bini and
pioneered the early research on ECT, was probably the first intro-
ducing ECT in the US: in 1940, he was appointed at the New York
State Psychiatric Institute where he continued ECT treatments,
immediately followed by Renato Almansi and David Impastato at
Columbus Hospital in Manhattan (Abrams, 2002; Payne and
Prudic, 2009). In these early applications, ECT was confined to
the treatment of schizophrenia (according to the Meduna’s obser-
vation), but then it was extended to patients with other psychiatric
disorders, especially depression, for which the use and effective-
ness of ECT was established in 1941 (Hemphill and Walter,
1941). Up to the 1950s, ECT was then extensively used in the US,
becoming the main tool for the treatment of psychiatric disorders
(Abrams, 2002). The procedure’s methodology developed signifi-
cantly, with the introduction of anesthesia and the muscle relaxant
succinylcholine (thereafter termed modified ECT, as opposite to un-
modified ECT when anesthesia was not performed) in order to
reduce convulsions-related side effects, as bone fractures, teeth,
tendon, and muscular damage (Shorter, 2009).
146
Clinical Neurophysiology 133 (2022) 145–151
The use of ECT declined in the 1970s and 1980s when pharma-
cotherapy for severe mental disorders rapidly developed (McCall,
2001) and also for a growing stigmatization, mainly due to ECT
documented misuse and lack of appropriate information, and by
the progressive perception of the procedure in the general opinion:
indeed, it was regarded as a ‘‘coercive” method applied not only to
treat severe mental disorders, but also to suppress social behaviors
considered inappropriate for the rules in force at that time (Kerr
et al., 1982; Fink and Tasman, 1992; McDonald and Walter,
2001). Throughout the years, also its therapeutic indications chan-
ged, becoming a last-resort treatment for medication-resistant and
very severe life-threatening clinical conditions rather than a first-
line treatment (Kerr et al., 1982; Fink and Tasman, 1992;
McDonald and Walter, 2001; Cowen et al., 2012).
2. Current applications of ECT
The last decade has seen a significant resumption of ECT, espe-
cially after the introduction of international established guidelines
(American Psychiatric Association, 2001; Milev et al., 2016; Royal
College of Psychiatrists, 2005; American Psychiatric Association,
2008), and thanks to the increasing knowledge about biological
effects of the technique. Particularly, it has been recommended
that brief-pulse wave ECT should be the standard treatment (UK
ECT Review Group, 2003), but alternative -generally less
harmful- procedures of stimulation have been proposed, as differ-
ential effects of right unilateral, bitemporal and bifrontal montages
of stimulating electrodes (Kellner et al., 2010; Dunne and
McLoughlin, 2012; Spaans et al., 2013). Moreover, anatomical brain
imaging and post mortem studies of patients after lengthy courses
of clinically successful ECT have partly confuted the notion that
ECT produces brain damage (Scalia et al., 2007; Anderson et al.,
2014), confirming the results of previous studies (Lippman et al.,
1985), although there is still a great socio-political and cultural
concern about this issue (Breggin, 2010; Goodman, 2011).
These knowledge advances helped to clarify several uncertain
aspects of the procedure, as the role of ECT in improving quality
of life in depressed patients (McCall et al., 2013), the role of con-
comitant medications in improving ECT outcomes (Chanpattana
et al., 1999; Sackeim et al., 2009), the importance of ECT in the
treatment of schizophrenia (especially in countries in the Eastern
hemisphere) (Pompili et al., 2013), and the role of ECT in maintain-
ing the benefits achieved during an acute course (Van Schaik et al.,
2012). It has also been advised that ECT should not only be used as
a last resort treatment and that situations of increased risk, such as
patients with disorders of the central nervous system (including
epilepsy), cardiovascular and respiratory system, need special
attention (American Psychiatric Association, 2001; Royal College
of Psychiatrists, 2005; Milev et al., 2016). In fact, ECT has unparal-
leled antidepressant efficacy, despite its cognitive side effects,
especially in the memory domains, may be persistent. Research
posits that the side effects may be at least partially dissociable
from the therapeutic effects of ECT (Sackeim et al., 2000; Nobler
and Sackeim, 2008), suggesting that distinct cortical networks
may underlie them and introducing a role for focal -rather than
generalized- seizure induction to minimize side effects, as theo-
rized in the application of magnetic seizure therapy (MST) via tran-
scranial magnetic stimulation (Rowny et al., 2009).
In MST, repetitive transcranial magnetic stimulation (rTMS) is
used with an intensity and duration leading to focal seizure induc-
tion. Safety testing of MST was aided by development of a nonhu-
man primate model of human ECT, and the validation of a cognitive
battery for the monkey that is sensitive to the range of effects of
ECT on human memory. Human testing has been facilitated by
the development of an international consortium addressing vari-
R. Di Iorio, S. Rossi and P.M. Rossini
ous aspects of the technique and dose/response relationships.
Challenges facing MST are common to other device-based thera-
pies: characterizing dose/response relationships, optimizing effi-
cacy, developing efficient and reliable methods to induce lasting
therapeutic change in the brain networks underlying depression,
and addressing safety of the procedure (Rossi et al., 2021).
ECT is currently widely administered worldwide, with Treated
Person Rates -number of ECTs per 10,000 resident population per
year- varying from 0.11 in Poland to 5.10 in USA (Leiknes et al.,
2012), and it is estimated that about one million patients receive
ECT annually (Prudic et al., 2001; Leiknes et al., 2012). ECT is
widely and historically cited to have an antidepressant effect
greater than 80% (Prudic et al., 1996), but more recently, remission
rate is estimated to vary between 50% and 70%: for example, a
recent meta-analysis found remission rates with ECT of 48% for
medication-refractory patients compared to 64.9% for patients
who have not yet received pharmacological treatment (Heijnen
et al., 2010). Although modified ECT significantly alleviates the dis-
comfort during the procedure and prevents severe adverse side
effects, unmodified ECT is still used in Asia, Africa, and Latin Amer-
ica (Leiknes et al., 2012). Bilateral electrode placement is currently
preferred worldwide (approximately 80%), except unilateral at
some places (US, Europe and Australia/New Zealand) (Leiknes
et al., 2012). Although sine-wave devices are still used, the most
modern devices are designed for a square-wave stimulation, con-
sidered more effective for inducing seizures (Abrams, 2002;
Coffey, 2008). In addition, the use of brief or ultra-brief pulse-
width stimulation (1 millisecond) is preferred to longer pulse-
width stimulation (>1 millisecond) as the former is associated with
a reduction of cognitive side effects (Abrams, 2002; Coffey, 2008).
ECT is largely considered to be a treatment for severe and drug-
resistant major depressive disorders (MDD) in most western coun-
tries, while in many eastern countries such as India, Thailand, and
Japan, as well as in parts of Africa, ECT is mainly applied as a first-
line treatment for schizophrenia: the majority of ECT treated
patients are older women with depression in Western countries,
versus younger men with schizophrenia in Asian countries (‘‘an-
tidepressant effect” vs. ‘‘antipsychotic effect”) (Leiknes et al.,
2012). Depression is the condition for which ECT is prescribed
most often (UK ECT Review Group, 2003; Leiknes et al., 2012); as
established by the most recent guidelines of the Canadian Network
for Mood and Anxiety Treatments (CANMAT), ECT remains a
second-line treatment for patients with drug-resistant major
depression, although in some situations it may be considered as
first line (Milev et al., 2016). ECT combined with antipsychotic
drugs is a treatment option in pharmacoresistant schizophrenia
or when a rapid improvement is desired (Tharyan and Adams
Clive, 2005). ECT is also used for other severe conditions such
refractory Parkinson’s disease, particularly with ‘‘on–off” syn-
drome (e.g., severe, unpredictable motor fluctuations), neuroleptic
malignant syndrome, and intractable seizure disorders, malignant
catatonia ad acute mania (Royal College of Psychiatrists, 2005;
Bartolommei et al., 2012; Lambrecq et al., 2012). Altogether,
regardless some existing guidelines, there is no worldwide unifor-
mity in terms of utilization rates, practice and ECT parameters, that
vary greatly throughout continents and countries (Leiknes et al.,
2012).
At present, it has been recognized that the induction of a gener-
alized tonic-clonic seizure is necessary to achieve both the benefi-
cial and adverse effects of ECT. Certain parameters like seizure
duration, electric stimuli, seizure threshold, ECT practice factors
and medication can influence its effectiveness (Spellman et al.,
2009; Peterchev et al., 2010). The degree to which electrical stim-
ulation exceeds the seizure threshold, the positioning of electrodes
on the head, pulse width, pulse frequency and seizure duration are
also other factors to take into account in evaluating the effective-
147
Clinical Neurophysiology 133 (2022) 145–151
ness of ECT (Spellman et al., 2009; Peterchev et al., 2010). It is
unclear, based on current evidence, what constitutes an adequate,
therapeutically valid seizure, but the presence of the following fac-
tors could suggest that the seizure is adequate: clinical response;
greater post-ictal suppression index (PSI) by visual analysis of
the electroencephalography (EEG); high amplitude of EEG record-
ing that indicate intensity of the seizure; inter-hemispheric EEG
coherence, i.e. the observable symmetry between the two EEG
traces indicating seizure activity in both cerebral hemispheres; a
seizure duration of at least 25–30 seconds. The knowledge of the
individual seizure threshold (IST), defined as the minimal electrical
dose that induces generalized tonic-clonic seizure activity
(Abrams, 2002), is crucial for the selection of the electrical stimulus
dose for ECT; in clinical applications the seizure threshold depends
on individual patient characteristics, treatment history, and other
stimulus factors. Because, on the one hand, the extent of the elec-
trical dose above the IST is associated with more short-term cogni-
tive side effects (Sackeim et al., 1993) and, on the other,
subconvulsive stimulus administration may induce cardiac
arrhythmia (McCall et al., 1994), better knowledge of the factors
determining the individual IST would be clinically useful in
weighting the expected effectiveness against the risks of side
effects of ECT (Van Waarde et al., 2013). Initiation of a course of
ECT treatment should routinely involve the estimation of the IST
by gradual dose titration (stimulus dosing) and then treatment
by using the supra threshold dose. Once seizure threshold is deter-
mined a dose of 1.5 to 2 times the seizure threshold for bilateral
ECT and at least 2.5 to 3 times (up to a maximum of 6) the seizure
threshold for unilateral ECT may provide the best balance of max-
imal clinical efficacy and minimal cognitive side effects (Sackeim
et al, 1993). This is supposed to be a better practice compared to
the fixed dose method originally used to establish ECT treatment
in psychiatry (Royal College of Psychiatrists, 2005). Few studies
have measured the seizure threshold in terms of pulse amplitude
in humans, but available data support the presence of significant
individual variability and the adequacy of currents lower than
800/900 mA. Despite a wide range of current amplitudes reported
in some studies, it seems clear that current amplitudes below the
conventionally used 800/900 mA can elicit adequate seizures and
that there is variability in the individual current amplitude thresh-
old, that could be due to differences in head anatomy, age, neural
excitability, and other physiological factors (Peterchev et al.,
2010). Generally, bilateral (bitemporal or bifrontal) and unilateral
ECT are effective when dosed adequately (Semkovska et al.,
2016) but cognitive side effects are greater with bilateral place-
ment and with higher stimulus doses. In general, bilateral place-
ment is preferred when rapid improvement of clinical symptoms
is needed, whereas right (or non-dominant) unilateral placement
is selected in cases where cognitive side effects should be mini-
mized (Kolshus et al., 2017). In clinical practice, the switch from
unilateral to bilateral placement is recommended if there is an
inadequate response after 4–6 treatments (Lapidus and Kellner,
2011).
Despite research efforts addressing the mechanisms underlying
the effect of ECT treatment via determining the levels of neuro-
transmitters and cytokines and using genetic and epigenetic tools,
as well as structural and functional neuroimaging, general mecha-
nisms of action remain poorly understood (Jiang et al., 2017). Sev-
eral theories have been postulated: - the anticonvulsant hypothesis,
which hypothesizes a therapeutic effect of anticonvulsant proper-
ties of ECT (Bolwig, 2011); - the generalized seizure (GS) theory,
which states that the induction of a GS is the hinge for ECT’s ther-
apeutic effect (Bolwig, 2011); a combined anatomo-ictal theory,
which integrates the induction of a GS with an effect on critical
brain regions (Bolwig, 2011); psychological theories (Frais, 2010;
Bolwig, 2011); a neuroendocrine model, in which ECT is thought
R. Di Iorio, S. Rossi and P.M. Rossini
to correct a state of neuroendocrine dysfunction inherent to
depression (Bolwig, 2011; Haskett, 2014); the monoamine hypothe-
sis and other neurotransmitter effects, which postulates that ECT
exerts its effect by a modulation of aberrant neurotransmission
(Kato, 2009; Zarate et al., 2010; Baldinger et al., 2014); and the neu-
rotrophic hypothesis, in which ECT is thought to produce potent
neuroplasticity and neurogenesis, correcting structural and func-
tional abnormalities seen in several brain diseases (Kato, 2009;
Bouckaert et al., 2014; McCall et al., 2014).
ECT may also exert its therapeutic efficacy through resetting the
aberrant functional connectivity and promoting the generation of
new and healthy connections in brain regions implicated in
depression pathophysiology, a mechanism that may be in part
mediated by the ECT-induced activation of inhibitory and neuro-
plasticity mechanisms (Bai et al., 2019; Hill et al., 2020; Fu et al.,
2021). Promising findings come from molecular biomarkers: neu-
rotrophins as brain-derived neurotrophic factor (BDNF) (Brunoni
et al., 2014; Luan et al., 2020) and vascular endothelial growth fac-
tor (VEGF) (Maffioletti et al., 2020) increase in blood after ECT, with
positive correlations with symptoms improvement. Also structural,
as changes of the hippocampus and amygdala, and functional
imaging biomarkers, as increased connectivity of the resting state
networks correlated with clinical improvement (Jiang et al.,
2017; Andrade, 2014a, 2014b). Some authors (Ousdal et al.,
2020) recently reported that the structural changes following ECT
in depression are broadly distributed, observing volumetric
increases in widespread cortical and subcortical gray matter areas
that varied based on the number of ECTs and mode of electrode
placement; besides, the subcortical gray matter changes were
inversely associated with changes in ventricle volumes, while
white matter volume remained unchanged. These findings support
the assumption that ECT could induce trophic processes in brain
gray matter.
3. The impact of rTMS in the neuropsychiatric setting
A new era for brain stimulation has opened in 1985 with the
introduction of transcranial magnetic stimulation (TMS) by Antony
Barker which is well-tolerated, experienced as painless by most
participants (Barker et al., 1985), and generally safe (Rossi et al.,
2021a, 2021b). Initially thought for exploring corticospinal motor
function in healthy and diseased individuals when applied on the
motor cortex, TMS became popular as an antidepressant treatment
-possibly alternative to ECT- after a first study published in Brain in
1994 in which long-lasting excitability changes were demon-
strated for the first time (Pascual-Leone et al., 1994). Authors used
a technically advanced form of TMS called repetitive (rTMS), deliv-
ering several recurring TMS pulses, spaced at regular and pro-
grammable time intervals, with long-lasting, controllable,
excitatory or inhibitory after-effects depending on the frequency
of stimulation (Rossi et al., 2009). rTMS is a safe -within interna-
tional standards (Rossi et al., 2009, 2021a, 2021b)- well-
tolerated, non-invasive treatment. Powered by a rapidly pulsed
current, the magnetic field passes unimpeded and without discom-
fort through the skull and the other extracerebral layers and stim-
ulates brain tissue beneath, inducing depolarizing currents in
superficial cortical neurons that may help normalize synaptic
activity not only in the stimulation site but even in neural net-
works connected with the target (Rossini et al., 1994, 2015).
rTMS after effects represent the rationale for its therapeutic
applications. Depending on underlying brain dysfunction to be
treated, rTMS can be used in an ‘‘inhibitory” mode, as low-
frequency (LF) stimulation (1 Hz), or in an ‘‘excitatory” one, as
high-frequency (HF) stimulation (5 Hz), with some nuances as
a function of the intensity of stimulation and the number of deliv-
148
Clinical Neurophysiology 133 (2022) 145–151
ered pulses (Siebner and Rothwell, 2003). Such a dichotomy
(‘‘inhibitory’’ LF-rTMS vs. ‘‘excitatory’’ HF-rTMS) is appealing, as
it is closely reminiscent of the effects of long-term potentiation
(LTP) and long-term depression (LTD) of synaptic transmission
obtained in the hippocampus or cerebellum in experimental set-
tings (Bliss and Lomo, 1973; Malenka, 1991). The duration of such
after-effects increases with the number of stimuli delivered, and
may persist minutes to hours or even days after the end of an rTMS
session (Chen et al., 1997; Maeda et al., 2000; Touge et al., 2001;
Gangitano et al. 2002) similarly to LTP following repetitive trains
of electrical stimulation (Bliss and Lomo, 1973). At this regard,
Hoogendam et al. (Hoogendam et al., 2010) presented a link
between the after effects induced by rTMS and the induction of
synaptic plasticity in experimental models, although there is no
currently direct evidence for this hypothesis. Moreover, modified
coil shapes allowed to reach more focal types of current induction
within the brain allowing relatively selective involvement of pre-
determined nodes of neural networks connectivity (Rossini et al.,
1994, 2015, 2019).
Since its introduction for depression (Pascual-Leone et al.,
1996), rTMS was hoped to offer clinical benefits similar to ECT,
without the disadvantages associated with it, such as the persis-
tent impact on memory function, that has been never described
for rTMS, and without the need for general anesthesia to limit
the onset of convulsions that ECT induces, as well as muscle relax-
ants to prevent bone/tendons complications. As a consequence,
rTMS can be considered as a method that does not need any hospi-
talization, but can be applied in an outpatient population.
The idea of applying rTMS in the treatment of depression capi-
talized from the results of previous neuroimaging and neurophys-
iological studies that had revealed structural and functional
abnormalities in widely distributed brain networks and regions,
including the anterior cingulate cortex and the limbic system
(Koenigs and Grafman, 2009; Pandya et al., 2012). Particularly,
functional brain imaging studies in depression had revealed an
interhemispheric asymmetry between the brain networks relaying
in the frontal regions, showing a hypometabolic state in the left
ones -indicated by the decrease in regional cerebral blood flow
(rCBF) as well as glucose and oxygen consumption- (Kennedy
et al., 1997), with concomitant hypermetabolism in the right ones
(Bench et al., 1995). Several electroencephalographic studies have
shown similar interhemispheric unbalance of frontal oscillatory
activities in favor of an activation of the left hemisphere, besides
correlating the rate of asymmetry with clinical scores of depression
(Koek et al., 1999; Diego et al., 2001; Knott et al., 2001). Within this
framework, the most investigated potential target for rTMS has
been the dorsolateral prefrontal cortex (DLPFC), which is easily
accessible to rTMS thanks to neuronavigated pointing systems,
and is integral part of a network including the limbic system
involved in mood regulation (striatum, thalamus, and anterior cin-
gulate cortex) (Petrides and Pandya, 1999; Paus et al., 2001). Start-
ing from the initial hypothesis that rTMS of the DLPFC could
modulate brain networks activity implicated in the pathophysiol-
ogy of depression (Nobler et al., 2000), two main therapeutic
strategies have been developed: inhibitory LF-rTMS on the right
DLPFC (presumably hyperactive in depression) and excitatory HF-
rTMS on the left DLPFC (presumably hypoactive in depression),
or a combination of the two stimulation paradigms (Klein et al.,
1999; George et al., 2000; Speer et al., 2000). To date, more than
1000 scientific papers, with the study of several ten thousands
patients, have been published; both strategies of intervention have
met the best evidence-based criteria of established efficacy in
treating depression (Lefaucheur et al., 2014, 2020).
The first endorsement of rTMS in this field occurred in 2008 in
the US, were the Food and Drug Administration (FDA) cleared a
TMS device for treating patients with unipolar major depression
R. Di Iorio, S. Rossi and P.M. Rossini Clinical Neurophysiology 133 (2022) 145–151

who have failed one type of medical treatment. More recently, sim- Table 1
ilar approvals were made in Canada, Israel, Brazil, Australia, and in The table summarizes the main features of electroconvulsive therapy (ECT) and
transcranial magnetic stimulation (TMS).
some European Countries. Now, this indication has been endorsed
by the guidelines provide by CANMAT, which recommends rTMS as Electroconvulsive Therapy Transcranial magnetic
a first-line treatment for patients with MDD who have failed to (ECT) stimulation (TMS)

respond to at least one antidepressant (Milev et al., 2016) and is Mechanism Electrically induced seizures Non-convulsive
considered as an accepted, evidence-based treatment option also electromagnetic stimulation
Stimulation Spread Personalized (focal target/
by the American Psychiatric Association (APA) and by the World target individual threshold/
Federation of Societies of Biological Psychiatry (WFSBP). In general, neuronavigation)
it is assumed that rTMS has higher success rates when applied in Setting Requires hospitalization Performed in an outpatient
the acute stage (an ongoing depressive episode of less than one setting
Medical Requires general No anaesthesia or sedation
year in duration), in relatively young individuals (less than 65 years
procedure anaesthesia
old), with a limited level of treatment resistance (one or two Recovery time Hours Minutes
unsuccessful medical interventions, with or without the combina- after each
tion of focused psychotherapy), or with only partial treatment treatment
response (Nahas et al., 2000; George et al., 2013; Milev et al., Major after- Short- and long-term None (seizure very rare)
effects memory loss
2016). There is not yet a unique protocol for the treatment of
Minor side- Headaches, muscle and jaw Little, transient, discomfort
depression: rTMS sessions usually last 20–40 minutes, 5 days a effects aches, feeling confused, ill on the stimulation site,
week, typically for 4–6 weeks. Although the literature suggests and nauseous headaches, fatigue
that daily prefrontal rTMS has a significant antidepressant effect Treatment 2–3 times a week (max. 15 Daily (Monday-Friday) for 4–
plan sessions) 6 weeks
compared to sham (placebo) and also compared to already existing
depression treatments (including pharmacotherapy), many issues
remain unresolved, such as the best target identification, the ade-
quate stimulation intensity and duration of series, and the efficacy than ECT, as demonstrated in small randomized comparative, but
of rTMS as a maintenance treatment in depression (Li et al., 2004; not resolutive studies (Kedzior et al., 2017; Abdel Latif et al., 2020).
O’Reardon et al., 2005; Berlim et al., 2013). A strategy that is gaining momentum is the use of rTMS follow-
It remains that with rTMS the antidepressant treatment did a ing acute series of ECT in patients who require maintenance treat-
step towards a personalized intervention, in terms of cortical target ment above psychopharmacology or, conversely, the use of rTMS
-that can be individually identified via Magnetic Resonance Imag- as an ‘‘augmentation” method prior to ECT, to reduce seizure
ing (MRI)-, thresholding of stimulation (individual threshold of threshold. A recent meta-analysis addressed these issues: rTMS
brain excitability to TMS) (Ter Braack et al., 2019), frequency of proved helpful for the acute and maintenance treatment of
stimulation (i.e. on the basis of the underlying EEG rhythms) patients affected by catatonic schizophrenia who failed pharmaco-
(Saari et al., 2018) and application of protocols of TMS that require logic interventions and had safety concerns with continuing main-
shorter session, as the theta burst stimulation (TBS) (Huang et al., tenance ECT (Stip et al., 2018). Furthermore, a latest retrospective
2005). About that, some authors recently reported excellent results work suggests that history of the past ECT, regardless of respon-
testing a high-dose resting-state functional connectivity MRI siveness, may not independently predict differential rTMS treat-
(fcMRI)–guided intermittent TBS protocol for treatment- ment outcomes (Yuan et al., 2020). Instead, in order to test the
resistant-depression (Cole et al., 2020). Moreover, research is mov- application of rTMS as an augmentation method, a recent random-
ing to use individual target-network brain connectivity to identify ized, double-blinded, sham controlled study showed that HF-rTMS
patients that might benefit more by rTMS (Fox et al., 2012; prior to ECT lowers the seizure threshold (Buday et al., 2020).
Mantovani et al., 2021). All these latest findings suggest that although rTMS and ECT dif-
fer in basic concepts, mechanism, tolerability, adverse effects and
acceptability by patients and society (Table 1 summarizes the main
4. Future perspectives features of both), may be best considered as complementary rather
than competing techniques, at least for certain psychiatric
Despite the proven efficacy of both rTMS and ECT in the treat- conditions when psychotic features predominate.
ment of affective disorders, it remains difficult to compare their
relative efficacy, because ECT has few placebo-controlled studies Declaration of Competing Interest
and direct comparisons are impossible, as ECT, unlike rTMS (unless
MST is used), requires anesthesia. Several open-label or random- The authors declare the following financial interests/personal
ized but single-blinded trials (therefore of limited value) reported relationships which may be considered as potential competing
no significant differences between ECT and rTMS: these results interests: PMR and RDI do not have potential conflicts of interest
are probably influenced by the small sample sizes and by a lower to be disclosed. SR is consultant for the Neurocare Italy Group.
than usual efficacy of ECT observed in these studies (Ren et al.,
2014). However, a recent meta-analysis (Ren et al., 2014) based Acknowledgements
on 9 randomized controlled trials directly comparing rTMS and
ECT on a total sample of 425 patients has shown: i) a greater effi- None.
cacy of ECT than rTMS applied on left DLPFC in terms of response
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