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Original Paper
Cortical Plasticity in Depression: A
Neurochemical Perspective From
Transcranial Magnetic Stimulation
Mariagiovanna Cantone
1
, Alessia Bramanti
2
, Giuseppe Lanza
1
,
Manuela Pennisi
3
, Placido Bramanti
2
, Giovanni Pennisi
4
, and Rita Bella
5
Abstract
Neural plasticity is considered the neurophysiological correlate of learning and memory, although several studies have also
noted that it plays crucial roles in a number of neurological and psychiatric diseases. Indeed, impaired brain plasticity may be
one of the pathophysiological mechanisms that underlies both cognitive decline and major depression. Moreover, a degree of
cognitive impairment is frequently observed throughout the clinical spectrum of mood disorders, and the relationship
between depression and cognition is often bidirectional. However, most evidence for dysfunctional neural plasticity in
depression has been indirect. Transcranial magnetic stimulation has emerged as a noninvasive tool for investigating several
parameters of cortical excitability with the aim of exploring the functions of different neurotransmission pathways and for
probing in vivo plasticity in both healthy humans and those with pathological conditions. In particular, depressed patients
exhibit a significant interhemispheric difference in motor cortex excitability, an imbalanced inhibitory or excitatory intra-
cortical neurochemical circuitry, reduced postexercise facilitation, and an impaired long-term potentiation-like response to
paired-associative transcranial magnetic stimulation, and these symptoms may indicate disrupted plasticity. Research aimed at
disentangling the mechanism by which neuroplasticity plays a role in the pathological processes that lead to depression and
evaluating the effects of modulating neuroplasticity are needed for the field to facilitate more powerful translational research
studies and identify novel therapeutic targets.
Keywords
cortical excitability, major depression, mood disorders, non-invasive brain stimulation, synaptic plasticity
Received February 24, 2017; Received revised April 10, 2017; Accepted for publication April 18, 2017
Introduction
The cerebral cortex possesses the intrinsic ability to com-
pensate, adapt, and reorganize itself in response to envir-
onmental stimuli or pathological conditions. The term
neural plasticity refers to the dynamic and persistent
reorganization of cortical properties, including synaptic
connection strength, representation patterns, and func-
tional or structural neuronal activity. Several mechanisms
are involved in the origin and modulation of neural
plasticity, including long-term potentiation (LTP) and
long-term depression (LTD), second messenger pathway
activation, gene transcription, and morphological
changes in neuronal membranes, axons, and postsynaptic
cells. Studies aimed at determining when neural plasticity
plays a compensatory versus a maladaptive role would be
of substantial interest (Cohen et al., 1995).
Plastic cortical rearrangement is also considered one of
the substrates for learning and memory and is known to
be involved in major depressive disorder (MDD). Despite
1
Department of Neurology IC, IRCCS ‘‘Oasi’’ Institute for Research on
Mental Retardation and Brain Aging, Troina, Italy
2
IRCCS Centro Neurolesi Bonino-Pulejo, Messina, Italy
3
Spinal Unit, Emergency Hospital Cannizzaro, Catania, Italy
4
Department of Surgery and Medical-Surgical Specialties, University of
Catania, Catania, Italy
5
Department of Medical and Surgical Sciences and Advanced Technology,
Section of Neurosciences, University of Catania, Catania, Italy
Corresponding Author:
Giuseppe Lanza, Department of Neurology IC, IRCCS Oasi Institute for
Research on Mental Retardation and Brain Aging. Via Conte Ruggero, 73 –
94018 Troina (EN), Italy.
Email: glanza@oasi.en.it
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a considerable literature, the neurobiology of depression
and related cognitive-behavioral changes remains poorly
understood, and the evidence supporting the role of
impaired cortical plasticity has generally been indirect.
Neurotrophic changes, including the loss of pyramidal
neurons (Rajkowska, 2000) and glial cells in the dorsolat-
eral prefrontal cortex (dlPFC; Rajkowska and Stockmeier,
2013) in addition to a reduction in gamma-aminobutyric
acid (GABA)-ergic connections in the hippocampus
(Stockmeier et al., 2004), have been observed in postmor-
tem studies.
Other evidence is provided by studies using animal
models of depression and chronic stress (Liu and
Aghajanian, 2008). The abnormal chronic activation of
the hypothalamic-pituitary-adrenal axis can cause atro-
phy at the level of the PFC and hippocampus, and these
data provide support for the hypothesis that exposure to
chronic stress leads to negative effects, including struc-
tural modifications of the central nervous system (CNS;
McEwen et al., 2012). In this context, stress-related cor-
tical atrophy is frequently observed in patients with
MMD and is particularly prevalent at the level of the
frontal, medial temporal, and limbic areas (Treadway
et al., 2015), even in subjects with subclinical depressive
symptoms (Webb et al., 2014). A reduction in the number
of synapses within the dlPFC (Kang et al., 2012) in com-
bination with indirect signs of disrupted synaptic signal-
ing processes (Feyissa et al., 2009; Duric et al., 2013)
indicates that abnormal synaptic functioning is involved
in depressive disorders. In particular, impaired cortical
activity (He et al., 2016) and the dysregulation of the con-
nectivity between the PFC and limbic regions have been
observed (Price and Drevets, 2010), suggesting the loss of
physiological phenomena including cortical excitability
and plasticity.
The pathophysiological picture of depression becomes
more complex when considering the late-onset form of
depression. In patients in whom depression appears
later in life (Bella et al., 2010), the typical clinical presen-
tations include psychomotor retardation, difficulty at
work, apathy, lack of insight, and executive dysfunction.
These clinical symptoms, in combination with neuroima-
ging evidence indicating vascular white matter lesions,
support the ‘‘vascular depression’’ (VD) hypothesis. It
has been hypothesized that cognitive-behavioral and
mood abnormalities reflect ischemic disruption at the
level of the dlPFC or the dorsal portion of the head of
the caudate nucleus, which are structures that have been
implicated in mood-affect regulation and cognition
(Cummings, 1993; Bella et al., 2010).
Finally, synaptic plasticity-related dysfunction is
also viewed as an early event during the development
and course of neurological disorders, and depression
and other neuropsychiatric symptoms are frequently
found to be comorbid manifestations or early symptoms
of a more disabling condition, such as Alzheimer’s dis-
ease (Pennisi et al., 2011a; Briggs et al., 2017), vascular
dementia (Pennisi et al., 2011b; Pennisi et al., 2015), and
atypical Parkinsonism (Cantone et al., 2014). These
symptoms may even present in the preclinical or early
stages of these diseases (Bella et al., 2011a, 2011b, 2013;
Lanza et al., 2013; Pennisi et al., 2016; Lanza et al., 2017).
Transcranial Magnetic Stimulation:
Basic Principles and Applications for
Exploring the Neurochemical
Correlates of Neural Plasticity
Among neurophysiological techniques, transcranial mag-
netic stimulation (TMS) was originally introduced as a
valuable noninvasive tool that was specifically useful
for evaluating excitability in the primary motor cortex
(M1) and conductivity along the cortical-spinal tract.
Nevertheless, today, the applications involving TMS go
well beyond the simple assessment of the pyramidal
tract (Pennisi et al., 2015). Indeed, TMS can be used to
provide novel insights into the pathophysiology of the
circuitries underlying neurological and psychiatric dis-
eases, to probe the in vivo excitability and plasticity
of the human brain, and to assess the functional integ-
rity of intracortical neuronal and callosal fibers
(Kobayashi and Pascual-Leone, 2003; Chen et al., 2008;
Pennisi et al., 2011a, 2011b; Lanza et al., 2013, 2015).
TMS is well suited for studies aimed at exploring and
monitoring motor system impairment during the preclin-
ical phase of several neurological disorders (Cantone
et al., 2014) or systemic diseases involving the CNS
(Pennisi et al., 2014; Bella et al., 2015). Moreover, when
integrated with other neurophysiological techniques (e.g.,
electroencephalography—EEG) or structural and func-
tional imaging, TMS also allows the exploration of
connectivities across motor and nonmotor areas
(Groppa, 2016; Kimiskidis, 2016). Finally, because it can
be used to evaluate the effects of drugs that are agonists or
antagonists for specific neurotransmitters, TMS can select-
ively test the activity of glutamatergic, GABAergic, mono-
aminergic, and cholinergic central circuits (e.g., so called
pharmaco-TMS; Ziemann et al., 2015).
In this article, we aim to critically and systematically
review the literature regarding the use of TMS to probe
cortical excitability and neural plasticity in depressive
disorders.
Technical principles and brief description
of a standard TMS exam
TMS is based on Faraday’s law of electromagnetic induc-
tion to activate cortical neurons (Barker et al., 1985). A
transducing coil attached to a high-voltage, high-current
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discharge system produces a strong time-varying and
short-lasting magnetic field at right angles to the stimu-
lation coil (Jalinous, 1991). When the stimulation coil is
placed tangential to the head, the magnetic field pene-
trates the scalp and skull with minimal attenuation
and induces a secondary eddy current in conductive intra-
cranial tissue. The electrical field in the tissue is oriented
perpendicular to the magnetic field and opposite the dir-
ection of the electrical current in the stimulation
coil (Groppa et al., 2012; Rossini et al., 2015). The two
following coil shapes are most commonly used: a figure-
eight-shaped coil and a circular coil. The former pro-
vides a more focal stimulation, which allows for fairly
detailed mapping of cortical representations, while the
latter induces a more widely distributed electric field,
which is desirable when evaluating central motor conduc-
tion times.
A standard examination involves bilateral recordings
from distal limb muscles while the patient is seated or
lying on a bed or armchair. Motor evoked potentials
(MEPs) are produced by stimulating M1 at the optimum
scalp position to elicit motor responses in the contralat-
eral target muscles. MEPs are usually recorded using
bipolar surface electrodes (e.g., Ag/AgCl cup electrodes)
and a belly tendon montage (Groppa et al., 2012). During
TMS, the operator can control the intensity of the current
flowing through the coil and thereby change the magni-
tude of both the induced magnetic field and the second-
arily induced electrical field. In addition to controlling its
intensity and focus, the operator can also manipulate the
frequency and interstimuli interval of the delivered sti-
muli, which together critically determine the effects of
TMS on the targeted brain region. Indeed, TMS can be
delivered as a single pulse, as a pair of stimuli applied to
the same or different brain areas, as paired cortical and
peripheral stimuli, or as trains of repetitive stimuli.
Anatomically precise localization of the stimulus can be
achieved by using a stereotactic neuro-navigational
system (Kobayashi and Pascual-Leone, 2003).
Single-pulse TMS
A single TMS pulse applied an adequate stimulator inten-
sity to M1 elicits a MEP in the contralateral target mus-
cles (Di Lazzaro et al., 2001). The MEP latency and
central motor conduction time are considered indexes
of the integrity of cortical-spinal pathways, whereas the
MEP amplitude is used to measure the excitation state of
the neurons connecting the motor cortex to the muscles
(Rossini et al., 2015). The resting motor threshold (rMT),
when defined according to the recommendations of the
International Federation of Clinical Neurophysiology
Committee (Rossini et al., 2015), is considered a global
parameter of brain excitability because it is a compound
measure of the membrane excitability of cortical-spinal
neurons, of neural inputs into pyramidal cells within
the cortex, and of spinal motor neurons, neuromuscular
junctions, and muscles (Ziemann et al., 1996; Rossini and
Rossi, 2007). The stimulus–response curve between
TMS stimulus intensity and MEP amplitude provides
another useful measurement of excitation (Ridding and
Rothwell, 1997).
Applying TMS after a brief period of exercise provides
valuable information regarding the cortical excitability
and intracortical synaptic reorganization that underlie
motor learning (Caramia et al., 2000). In particular, in
normal subjects, postexercise facilitation is defined as a
period of increased motor excitability that occurs after
transient muscle activation and decays to baseline over
2 to 4 min. This phenomenon is thought to originate in
the cortex because transcranial electric stimulation fails
to elicit exercise facilitation when cortical-spinal cells are
stimulated at their proximal axons (Samii et al., 1996).
The ability to perform focal stimulation using butter-
fly coils has allowed mapping studies to determine
muscle representation. The results can then be used to
determine the center of gravity of a motor representation
(Wassermann et al., 1992) that underlies a type of cortical
plasticity (Cohen et al., 1995). Experiments have repeat-
edly shown that neurons can assume the properties of
nearby neurons in other, usually adjacent, areas.
Cortical map plasticity has been demonstrated in both
animal models and human cortex, as have changes in
motor maps, such as those resulting from exercise or
practicing movement tasks (Classen et al., 1998).
Applying a suprathreshold TMS pulse to M1 during a
tonic voluntary contraction of contralateral muscles sup-
presses electromyographic activity in those muscles for a
few hundred milliseconds (Chen et al., 1999). This phe-
nomenon, called the contralateral silent period (CSP),
can be exploited to functionally measure intracortical
inhibitory circuits (Cantello et al., 1992), which are
mediated mainly by GABA-B transmission (Siebner
et al., 1998). If the pulse is delivered to the ipsilateral
M1, an electromyographic silence that lasts approximately
30 ms and is called the ipsilateral silent period (iSP) can be
recorded. The iSP is thought to reflect the ability of the
motor cortex to excite the inhibitory interneurons in its
contralateral counterpart, and it seems to be induced via
transcallosal pathways (Ferbert et al., 1992).
Paired-pulse TMS
Inhibitory and excitatory interneuronal activity within
the human cortex can be explored noninvasively using a
paired-pulse TMS paradigm (Kujirai et al., 1993;
Ziemann, 2004). The conventional protocol uses a
‘‘conditioning stimulus’’ (subthreshold) followed by a
‘‘test stimulus’’ (suprathreshold). By varying the intensity
of the conditioning stimulus and the interval between the
Cantone et al. 3
pair of TMS pulses (the interstimulus interval—ISI), a
number of measures of intracortical interneuronal
function and interaction can be obtained. At an ISI of
1–4 ms, the conditioning stimulus suppressed the MEP
amplitude, a phenomenon that has been called short-
latency intracortical inhibition (SICI). At a longer ISI
(7–20 ms), the stimulus results in intracortical facilitation
of motor responses (Kujirai et al., 1993). The mechanisms
underlying these phenomena are thought to reflect the
activity of distinctive neurochemical circuits. Hence,
while SICI is likely mediated by GABA-A interneuron
activity (Di Lazzaro et al., 2000), facilitation is more com-
plex (Di Lazzaro et al., 2006), although it does appear to
be produced mainly by the activation of glutamatergic cells
(Kujirai et al., 1993; Paulus et al., 2008).
Sensory-motor modulation
TMS can be used to test the functional connectivity
of different cortical areas and monitor how connectivity
changes over time. For instance, the short-latency
afferent inhibition (SAI) of MEP responses reflects the
sensory stimuli-mediated inhibitory modulation of M1
(Tokimura et al., 2000). This effect depends on the time
that elapses between the peripheral nerve electrical stimu-
lus and the TMS pulse, and it typically occurs at an ISI of
20 ms (Sailer et al., 2003).SAI may represent a neuro-
physiological correlate of central cholinergic activity
in vivo because it is reduced or abolished by the muscar-
inic receptor antagonist scopolamine (Di Lazzaro et al.,
2000) and positively modulated by acetylcholine (Di
Lazzaro et al., 2005).
TMS for measuring neural plasticity
Changes in cortical plasticity can be induced by and stu-
died using a repetitive TMS (rTMS) paradigm. Repetitive
TMS can be used to modify the excitability of the human
cortex in a predictable manner, with low frequencies
(stimulus rates <1 Hz) usually used to inhibit and high
frequencies (5–20 Hz) used to induce excitation in the
stimulated cortical area (Chen et al., 1997). The changes
in excitability that are produced by rTMS share several
characteristics with the induction of LTP and LTD
by tetanic stimulation in cortical slices (Wang et al.,
1996). Indeed, most, but not all, rTMS paradigms
are N-Methyl-D-aspartate (NMDA)-receptor activity
dependent (Cheeran et al., 2010) and modulated by
prior synaptic activation (Jung and Ziemann, 2009),
and the induced change in MEP amplitude is dependent
on the frequency of stimulation (Di Lazzaro et al., 2010).
Plasticity involves the rapid down-regulation of
GABA-related inhibitory circuits and short-term changes
in synaptic efficacy, which are dependent on sodium
and calcium channels (Ziemann et al., 1998).
The rTMS-induced long-lasting reduction in SICI
appears to involve the activation of NMDA receptors
and is probably associated with a LTP-like mechanism.
However, rTMS is also able to avoid saturation by indu-
cing LTD-like responses that decrease the efficacy of con-
nections between synapses. LTD refers to a prolonged
use-dependent decrease in the strength of excitatory syn-
apses and is predominantly mediated by the activation of
synaptic NMDA receptors or metabotropic glutamate
receptors at the level of hippocampal CA3:CA1 synapses
(Gladding et al., 2009). However, because rTMS affects a
wide range of cell types that possess a variety of proper-
ties, obtaining a comprehensive understanding of the
induction of LTP or LTD is not enough to determine
the actual impact of rTMS on the human brain. The
powerful role of TMS in modulating human neuroplasti-
city is of crucial clinical relevance because it could be used
to support plasticity where it is needed or, conversely, to
down-regulate neuronal excitability where it such excita-
tion is found to be maladaptive. However, TMS can also
be used to induce long-lasting effects in cerebral regions
outside M1, such as the prefrontal areas or the cerebellum
(Kobayashi and Pascual-Leone, 2003).
These findings reflect an interest in identifying
therapeutic applications in neurological or psychiatric
disorders. This interest is also demonstrated by the devel-
opment of paired associative stimulation (PAS), which is
considered a repetitive application of SAI (Stefan et al.,
2002). The PAS protocol includes applying an electrical
stimulus to a peripheral nerve (usually the median nerve)
and then a single TMS pulse over the hand area of M1.
PAS induces long-lasting LTP-/LTD-like changes in sen-
sory-motor pathways, which are considered a marker of
motor cortex plasticity.
Finally, new rTMS paradigms have recently been
developed to facilitate further investigations into cortical
excitability and synaptic plasticity. For example, theta
burst stimulation (TBS) and quadripulse stimulation
(QPS) can be used to produce neuroplastic effects that
range broadly from MEP suppression to MEP facilita-
tion, depending on the interval of the pulses within a
burst. Moreover, they can be used to measure so called
metaplasticity, which refers to the ability of a synapse to
undergo a second plastic change subsequent to a recent
induction of plasticity (Yger and Gilson, 2015).
Data Source and Selection
We performed a PubMed-based literature review to iden-
tify all studies that have been published on neural plasti-
city and MDD. The following keywords were used:
‘‘transcranial magnetic stimulation,’’ ‘‘plasticity,’’ and
‘‘depression.’’ The following data were extracted: (a)
study design; (b) patient characteristics, such as sample
size and the age, gender, laterality, diagnostic criteria,
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and drug exposure of participants; (c) TMS features; and
(d) results and main translational findings. In an initial
search performed using the above-mentioned keywords, a
total of 212 articles were screened. We then excluded art-
icles on TMS and plasticity that were performed in
healthy subjects or studies conducted using animals
because their content did not fit the aim of this review.
Moreover, we excluded preliminary or low-quality data
to avoid drawing misleading conclusions. We also
excluded articles that were not research studies (e.g.,
reviews, letters to the Editor, and commentaries) and
papers published in language other than English.
Publications that addressed only the treatment of psychi-
atric disorders were also excluded. Finally, we reviewed
the articles listed in the reference sections of the selected
papers to locate any further relevant data. We identified
25 studies as a result of this process.
Tables 1 and 2 provide a summary of the main findings
of the identified TMS studies related to cortical excitability
and synaptic plasticity, respectively, in depressive dis-
orders. Figure 1 provides a summary overview of the
main findings regarding the use of TMS techniques and
the implications of these findings for therapeutic strategies.
TMS in Depression
Global Cortical Excitability and Interhemispheric
Asymmetry
Studies that used rMT in depression (Abarbanel et al.,
1996; Lefaucheur et al., 2008; Bajwa et al., 2008; Navarro
et al., 2009) revealed that in these individuals, there is a
global reduction in cortical excitability in the frontal
cortex (Maeda et al., 2000; Fitzgerald et al., 2004;
Levinson et al., 2010; Spampinato et al., 2013; Concerto
et al., 2013; Croarkin et al., 2013; Veronezi et al., 2016),
an interhemispheric imbalance between the prefrontal
and motor cortices that manifested as reduced excitability
in the left hemisphere (Maeda et al., 2000; Fitzgerald
et al., 2004; Levinson et al., 2010; Spampinato et al.,
2013; Concerto et al., 2013) or increased excitability in
the right hemisphere (Bajbouj et al., 2006). In one study
that investigated interhemispheric asymmetry in the pre-
frontal and motor cortices, 1 Hz (inhibitory) rTMS was
applied to the left M1, and the results showed that the
rTMS reduced cortical excitability in the ipsilateral side
but did not induce any change (i.e., an increase in excit-
ability) in the right hemisphere (Bajwa et al., 2008). These
data suggest that normal interhemispheric modulation
had been lost in these individuals.
In other investigations, rMT was reevaluated after
rTMS. In one study, high-frequency rTMS was applied
to the left prefrontal area, and the results showed that
treatment was associated with a significant increase in cor-
tical excitability in the ipsilateral hemisphere (Triggs et al.,
1999). In line with these results, another recent study
showed that applying high-frequency rTMS to the left
dlPFC for 1 month reduced the difference in excitability
between the left and right hemispheres (Spampinato et al.,
2013) and was associated with clinical improvements that
persisted over time (Concerto et al., 2015).
Measures of Cortical Inhibition
Unlike measures of excitation, conflicting results have
emerged regarding indexes of inhibition, namely CSP
and SICI. In particular, in some studies, patients with
either unipolar or bipolar depression have a prolonged
CSP (Steele et al., 2000), while other studies, both a
reduced CSP and SICI were observed (Fitzgerald et al.,
2004; Bajbouj et al., 2006; Lefaucheur et al., 2008).
Shortened CSP has also been reported in patients with
a previous diagnosis of MDD and in those with treat-
ment-resistant depression. Interestingly, only the latter
group exhibited significantly reduced SICI (Levinson
et al., 2010). These results are consistent with the ‘‘cor-
tical disinhibition’’ hypothesis, in which GABAergic
transmission is involved in the pathophysiology of
depression, as was previously suggested by animal, neuro-
chemical, and neuroimaging studies (Brambilla et al.,
2003; Croarkin et al., 2011).
The influences of physiological, technical, and experi-
mental factors should be taken into account because vari-
ability in these measures has been observed even in healthy
individuals. For instance, because CSP duration is known
to be dependent on stimulus intensity and type of stimulat-
ing coil that is used (Kimiskidis et al., 2005), these param-
eters need to be considered. Moreover, different TMS
methods have been employed, and differences in the ages,
clinical presentation, and severity of included patients as
well as the effects of neuroactive drugs on measures of cor-
tical excitation and inhibition may contribute to differences
in conclusions between studies (for recent comprehensive
reviews, see Ziemann et al., 2015; Bhandari et al., 2016).
Indexes of Neuroplasticity
The impaired postexercise facilitation of MEPs is char-
acterized by an initial facilitation followed by an early
return to the baseline MEP amplitude. This sequence
has been demonstrated in both nonmedicated and medi-
cated MDD subjects (Shajahan et al., 1999a; Reid et al.,
2002). These studies support the view that the motor
cortex is less dynamically excitable in depressed patients
and that this phenomenon may be a neurophysiological
sign of an imbalance between the excitatory and inhibi-
tory mechanisms involved in plasticity. A subsequent
study revealed that this facilitation was normalized in
previously depressed patients who had clinically recov-
ered (Shajahan et al., 1999b).
Cantone et al. 5
Table 1. TMS Studies of Cortical Excitability in Depressed Subjects.
Study
Number of
participants (M/F)
Age (years)
mean SD
(or range)
Diagnosis/
diagnostic
criteria used
Drug
exposure
Measures of
plasticity
investigated
Results in
depressed
subjects Main translational findings
Pennisi et al.,
2016
16 VD (NR)
vs
11 VCI-ND (NR)
vs
15 controls (NR)
68.1 8.6
vs
70.0 7.0
vs
63.8 7.2
DSM-IV-TR N rMT
CSP
Paired-pulse
curve
nrMT
nCSP
#SICI
#ICF
The mechanisms that enhance the risk
of dementia in VD might be related
to either subcortical vascular lesions
or a lack of compensatory functional
cortical changes.
Veronezi et al.,
2016
60 patients (19/41)
vs
21 controls (11/10)
37
vs
28
MDD subtypes/
DSM-V
N rMT
CSP
Paired-pulse
curve
mrMT
nCSP
nSICI
mICF
Cortical excitability, glutamatergic and
GABA-ergic balance are neuro-
physiological markers of different
subtypes of depression.
Concerto et al.,
2013
11 VD (6/5)
vs
11 MDD (5/6)
vs
11 controls (6/5)
67.72 3.29
vs
57.18 7.12
vs
67.36 3.75
DSM-IV-TR Y rMT
CSP
Paired-pulse
curve
mrMT (L)
mCSP (R)
#SICI
#ICF
Distinctive TMS patterns between late-
onset depression with subcortical
vascular disease and early-onset
drug-resistant MDD. Possible drug
effects of inhibitory measures.
Croarkin et al.,
2013
24 patients (10/14)
vs
22 controls (11/11)
13.9 2.1
vs
13.8 2.2
MDD/K-SADS-PL
and CDRS-R
N rMT
CSP
Paired-pulse
curve
#rMT
nCSP (L)
#SICI
mICF
Neurophysiological abnormalities are
also present in children and
adolescents.
Bella et al., 2011 15 VD (7/8)
vs
10 VCI-ND (6/4)
vs
10 controls (5/5)
70.5 6.6
vs
70.8 6.3
vs
67.7 3.9
DSM-IV-TR N rMT
CSP
Paired-pulse
curve
#rMT
#CSP
nSICI
#CSP
The neurophysiological mechanisms
underlying VD differ from those
reported in MDD and seem to be
similar to those in patients with
subcortical ischemic vascular
disease.
Levinson et al.,
2010
60 patients (22/38)
vs
25 controls (12/13)
47.2 11.2
vs
43.8 8.9
MDD/DSM-IV Y rMT
CSP
Paired-pulse
curve
mrMT (L)
nCSP
nSICI
#ICF
Cortical excitability and glutamatergic
and GABAergic balance are neuro-
physiological markers of different
subtypes of depression.
Navarro et al.,
2009
91 patients (39/52)
No control group
46.1 10.5 MDD/DSM-IV Y rMT #rMT A trend toward a lower rMTon the left
hemisphere. Probable influence of
long-term benzodiazepine intake.
Lefaucheur
et al., 2008
35 patients (14/21)
vs
35 controls (17/18)
56 2.8
vs
43
MDD/DSM-IV Y rMT
CSP
Paired-pulse
curve
mrMT (L)
nCSP (L)
nSICI (L)
nICF (L)
Significant reduction of excitability of
both inhibitory and facilitatory inputs
in the left hemisphere that correlates
with depression severity.
Levinson et al.,
2007
15 patients (9/6)
vs
15 controls (11/4)
36.8 9.1
vs
35.1 9.2
Bipolar disorder Y CSP
Paired-pulse
curve
transcallosal
inhibition
nCSP
nSICI
#ICF
niSP
Bipolar patients exhibited impairment
of inhibitory pathways
(continued)
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Table 1. Continued
Study
Number of
participants (M/F)
Age (years)
mean SD
(or range)
Diagnosis/
diagnostic
criteria used
Drug
exposure
Measures of
plasticity
investigated
Results in
depressed
subjects Main translational findings
Bajbouj et al.,
2006
20 patients (14/6)
vs
20 controls (14/6)
42.9 11.9
vs
44 14.6
MDD/DSM-IV N rMT
CSP
Paired-pulse
curve
nrMT (R)
nCSP
nICI (B)
Reduction of GABAergic TMS param-
eters, suggesting a central inhibitory
deficit in medication-free MDD
patients.
Fitzgerald et al.,
2004
60 patients (NR)
No control group
- MDD (unipolar or
bipolar)/DSM-
IV
Y rMT
CSP
Paired-pulse
curve
rTMS
mrMT (R)
nCSP
nICI (L)
Relationship between excitability of the
right hemisphere and the severity of
psychopathology, and between
inhibition in the left hemisphere and
poor response to rTMS.
Maeda et al.,
2000
8 patients (5/3)
vs
8 controls (6/2)
46.8
vs
44.9
MDD/DSM-IV N rMT
Paired-pulse
curve
mrMT (L)
mSICI (L)
nICF (L)
Significant interhemispheric difference
that correlates with depression
severity.
Steele et al.,
2000
16 patients (4/12)
vs
19 controls (6/13)
43.1 8.9
vs
40.2 11.5
MDD/DSM-IV Y rMT
CSP
mCSP Data do not support motor retardation
due to a dopaminergic parkinsonian-
like mechanism.
Abarbanel et al.,
1996
10 patients (7/3)
vs
10 controls (6/4)
39.4 11.3
vs
39.7 6.7
MDD Y rMT
CMCT
Neither
asymmetry
nor variation
Motor cortex as an intriguing window
into neuropsychiatric disorders.
Note. TMS ¼transcranial magnetic stimulation; rTMS ¼repetitive TMS; M ¼male; F ¼female; SD ¼standard deviation; R ¼right hemisphere; L ¼left hemisphere; Y ¼yes; N ¼no; MDD ¼Major Depressive
Disorder; DSM-IV ¼Diagnostic and Statistical Manual of Mental Disorders – Fourth Edition; DSM-IV-TR ¼DSM – Fourth Edition – Text Revision; DSM-V ¼DSM – Fifth Edition; K-SADS-PL ¼Kiddie-Sads-
Present and Lifetime Version; CDRS-R ¼Children’s Depression Rating Scale–Revised; rMT ¼resting motor threshold; CSP ¼cortical silent period; iSP ¼ipsilateral silent period; SICI ¼short-latency afferent
inhibition; ICI ¼intracortical inhibition; ICF ¼intracortical facilitation; CMCT ¼central motor conduction time; GABA ¼gamma-aminobutyric acid; VD ¼patients with vascular depression; VCI-
ND ¼patients with vascular cognitive impairment – no dementia; NR ¼not reported; m¼increase/enhancement; n¼decrease/reduction; #¼no significant change.
Cantone et al. 7
Table 2. Investigations of Neural Plasticity That Used TMS-Related Protocols in Patients With Depression.
Study
Number of
participants (M/F)
Age (years)
mean SD
(or range)
Diagnosis/
diagnostic
criteria used
Drug
exposure
Measures of p
lasticity investigated
Results in depressed
subjects Main translational findings
Kuhn et al., 2016 27 patients (15/12)
vs
27 controls (14/13)
19-58
vs
18-55
MDD/ICD-10 Y PAS nLTP-like plasticity
restored after
remission
State-dependent synaptic
plasticity as a treatment
target.
Player et al., 2013 23 patients (10/13)
vs
23 controls (NR)
38.0 12.8
vs
38.5 13.1
MDD (20) and
bipolar disorder
(3)/DSM-IV
YPAS nLTP-like plasticity Altered plasticity in depres-
sion might influence
learning or response to
treatment.
Spampinato
et al., 2013
12 drug-resistant MDD
(8/4)
vs
10 drug-free patients
(6/4)
50.5 8.7
vs
55.6 8.8
MDD/DSM-IV-TR Y rMT, paired-pulse curve
before and after 10-Hz
rTMS to the dlPFC
Restored rMT
asymmetry and
paired-pulse curve
imbalance
Brain stimulation techniques
are clinically effective for
modulating altered excit-
ability and plasticity in
drug-resistant MDD.
Croarkin
et al., 2013
8 patients (1/7)
No control group
16.1 1.1 MDD/
K-SADS-PL
and CDRS-R
Y rMT after 10-Hz rTMS to
the left M1
nrMT rTMS is safe for studying and
treating affective disorders
in children.
Bajwa et al., 2008 13 patients (1/12)
vs
14 controls (2/12)
36.3 12.9
vs
33.7 7.1
MDD/DSM-IV Y rMT before and after 1-
Hz rTMS to the left M1
#rMT baseline
mrMT bilateral after
rTMS
Brain stimulation techniques
are valid tools for restor-
ing plasticity
Reid et al., 2002 10 patients (4/6)
vs
13 controls (4/9)
48.3 12.8 vs
35.1 7.9
MDD
(unipolar or
bipolar)/DSM-IV
Y Postexercise facilitation nfacilitation Fatigue as a phenomenon of
cortical origin in
depression.
Shajahan
et al., 1999a
10 patients (2/8)
vs
10 controls (3/7)
41.1 10.9 vs
39.3 10.8
MDD
(unipolar or
bipolar)/DSM-IV
Y Postexercise facilitation nfacilitation Fatigue as a phenomenon of
cortical origin in
depression.
Triggs et al., 1999 10 patients (5/5)
No control group
52 MDD/DSM-IV N rMT after 20-Hz rTMS to
the left dlPFC
nrMT Brain stimulation techniques
are valid tools for restor-
ing plasticity.
Samii et al., 1996 10 patients (NR)
vs
18 controls (NR)
42
vs
42
MDD
(unipolar or
bipolar)/
DSM-III-TR
N Postexercise facilitation nfacilitation Neurophysiological correl-
ates of fatigue and motor
inertia in depression.
Note. TMS ¼transcranial magnetic stimulation; rTMS ¼repetitive TMS; PAS ¼paired-associative stimulation; M ¼male; F ¼female; SD ¼standard deviation; Y ¼yes; N ¼no; MDD ¼Major Depressive
Disorder; DSM-III-TR ¼Diagnostic and Statistical Manual of Mental Disorders – Third Edition – Text Revision; DSM-IV ¼DSM – Fourth Edition; DSM-IV-TR ¼DSM – Fourth Edition – Text Revision; K-
SADS-PL ¼Kiddie-Sads-Present and Lifetime Version; CDRS-R ¼Children’s Depression Rating Scale–Revised; ICD-10 ¼International Statistical Classification of Diseases and Related Health Problems –
Tenth revision; LTP¼long-term potentiation; dlPFC ¼dorsolateral prefrontal cortex; M1 ¼primary motor cortex; rMT ¼resting motor threshold; NR ¼not reported; m¼increase/enhancement;
n¼decrease/reduction; #¼no significant change.
8ASN Neuro
Using a PAS protocol in a sample of 23 medicated
depressed patients, Player et al. (2013) observed that neu-
roplasticity was significantly lower in these patients
than in age- and gender-matched healthy controls.
More recently, an investigation using a PAS protocol in
patients with MDD further supported this hypothesis by
showing that cortical LTP-like plasticity was significantly
decreased in a state-dependent manner in a group of
27 patients who suffered an acute episode of MDD.
Interestingly, this study clearly showed that LTP-like
plasticity was restored after remission (Kuhn et al.,
2016). Finally, after facilitatory PAS, changes in cortical
excitability were linked to associative LTP. This connec-
tion is believed to involve glutamate signaling and the
postsynaptic depolarization of cells via the activation of
NMDA and a-amino-3-hydroxy-5-methylisoxazole pro-
pionate (AMPA) receptors (Stefan et al., 2002).
Vascular Depression and TMS
Few data are available regarding cortical excitability in
VD, and the relevant studies have not provided any evi-
dence demonstrating overall changes in motor cortical
excitability or interhemispheric asymmetry. Hence, in
these patients, there is a pattern of cortical excitability
that is clearly different from that in MDD, as described
earlier. Moreover, the normality of CSP and SICI in
VD patients indicates that the mechanisms regulating
GABAergic intracortical inhibitory circuits are not
involved in these individuals. These data provide a new
and intriguing neurophysiological explanation for the dif-
ferences in the neurobiological processes that underlie
nonvascular early onset major depression and late-onset
VD (Bella et al., 2011; Concerto et al., 2013; Lanza et al.,
2017). Furthermore, a longitudinal study evaluated the
electrophysiological changes and progression of cognitive
decline in patients with subcortical cerebrovascular
lesions, and the results showed that glutamate-related
neuroplasticity was differentially enhanced between
patients with and without VD. In particular, a high
level of intracortical facilitation was observed in the non-
depressed patients, and this seemed to provide a relative
level of protection from cognitive and functional deteri-
oration (Pennisi et al., 2016).
Discussion
Main Findings
The articles reviewed here provide neurophysiological
evidence for altered cortical excitability (Maeda et al.,
2000; Fitzgerald et al., 2004; Levinson et al., 2010;
Figure 1. Imbalance in the ‘‘depressed brain’’: a summary overview of the main findings related to TMS techniques and their implications
for therapeutic strategies.
TMS ¼transcranial magnetic stimulation; GABA ¼gamma-amino-butyric acid; MDD ¼major depressive disorder; rMT ¼resting motor
threshold; LTP ¼long-term potentiation.
Cantone et al. 9
Spampinato et al., 2013; Concerto et al., 2013; Croarkin
et al., 2013; Veronezi et al., 2016) and synaptic plasticity
(Chroni et al., 2008; Bajwa et al., 2008; Spampinato et al.,
2013; Croarkin et al., 2013; Player et al., 2013; Kuhn et al.,
2016) in MDD. These data confirm the findings of previ-
ous investigations that have used different approaches
(Debener et al., 2000; Normann et al., 2007; Teyler and
Cavus, 2007; Salustri et al., 2007; Nissen et al., 2010).
Moreover, a number of studies have shown that there
is a significant decrease in postexercise facilitation in
these individuals (Samii et al., 1996; Shajahan et al.,
1999a, 1999b; Reid et al., 2002; Chroni et al., 2008) that
is probably linked to an imbalance between inhibitory and
excitatory inputs at the level of cortical-spinal neurons.
This observation, which has also been reported in schizo-
phrenia (Reid et al., 2002; Chroni et al., 2002), might
explain the symptoms reported by these patients, which
can include fatigue, weakness, motor inertia, and apathy,
and indicates the existence of a potentially strong relation-
ship between psychiatric disorders and motor output.
Finally, it should be kept in mind that changes in cor-
tical measures of inhibition may also provide important
contributions to these conditions. Accordingly, applying
electroconvulsive therapy in combination with 3 Hz or
10 Hz rTMS (i.e., facilitatory rTMS) to the left prefrontal
cortex of subjects with MDD led not only to clinical
improvement and enhanced cortical excitability in the
left motor cortex (indicated by an increased MEP/M-
wave ratio and decreased motor threshold but also to
the modulation of measures of GABA-mediated intracor-
tical inhibition (i.e., shortened CSP and reduced SICI;
Chistyakov et al., 2005a, 2005b). Taken together, these
data suggest that in depressed subjects, the motor cortex
is more refractory to modulatory inputs from both adjacent
areas and other nonmotor areas within the CNS.
Moreover, several studies have demonstrated that struc-
tural and functional abnormalities in trans-callosal connec-
tions may play crucial roles in patients with depression and
other mood disorders (Bajwa et al., 2008; Yasuno et al.
2016; Zalsman et al., 2016; Matsuoka et al., 2017).
In summary, when tested using TMS, both glutama-
tergic and GABAergic pathways seem to be impaired in
MDD. Abnormal activity in the glutamatergic system
that regulates synaptic plasticity is centrally important
to the pathological mechanism underlying and treatment
for MDD (Sanacora et al., 2008). The excessive glutama-
tergic activation of NMDA receptors induces LTD,
which may be responsible for the disruptions observed
in glutamatergic receptor plasticity-related processes,
including reduced motor cortex excitability and postex-
ercise facilitation and insensitivity to PAS protocols
(Samii et al., 1996; Shajahan et al., 1999a; Maeda et al.,
2000; Reid et al., 2002; Fitzgerald et al., 2004; Chroni
et al., 2008; Levinson et al., 2010; Spampinato et al.,
2013; Concerto et al., 2013; Player et al., 2013).
Neurotrophin and Metaplasticity: The Contribution
of Repetitive TMS
Another possible mechanism by which noninvasive brain
stimulation techniques may operate is the modulation of
neurotrophin release, which is particularly relevant in
depression. It is widely accepted that brain-derived
neurotrophic factor (BDNF) is implicated in neuronal
survivability and the functions involved in activity-depen-
dent synaptic plasticity, which affects dendrite complexity
and spine density (Li et al., 2010; Dumas, 2012).
Exposure to stress decreases BDNF expression in the
hippocampus and PFC, and different studies have
shown that there is a deficit of this neurotrophin in
depressed patients. These data further support the con-
cept that dysfunctional neuroplasticity contributes to
both mood and cognitive disorders (Pittenger and
Duman, 2008; Krishnan and Nestler, 2008; Li et al.,
2010; Dumas, 2012). In this regard, rTMS has been
shown to increase serum BDNF concentrations in
depressed patients (Zanardini et al., 2006) and to improve
refractory depression by influencing the release of cat-
echolamines and BDNF (Yukimasa et al., 2006).
Finally, applying low-frequency rTMS in model rats
with vascular dementia improved learning and memory,
protected pyramidal cells from apoptosis, and promoted
hippocampal plasticity by increasing Bcl-2 expression and
reducing Bax expression (Yang et al., 2015).
Finally, relatively little is currently known regarding
aberrant metaplasticity phenomena in mood disorders or
other neuropsychiatric diseases. It is widely accepted that
metaplasticity is necessary to modulate the excitability
and functions of neuronal networks. Hence, the modula-
tion of metaplasticity might increase or even restore
the innate ability of neurons to exhibit synaptic plasti-
city under pathological conditions. Based on the
recently introduced concept of ‘‘interhemispheric rivalry’’
in stroke, several studies have used a ‘‘priming’’ proto-
col to enhance recovery in stroke survivors (Di
Lazzaro et al., 2013). The application of a protocol
including TBS or QPS may be useful for modulating
brain regions exhibiting disrupted plasticity in depressed
subjects.
Limitations and Critical Aspects
Although TMS provides exciting insights into different
aspects of neural excitability and plasticity, the following
limitations and aspects critical to both the techniques and
designs or methodologies used in different studies should
be taken into account:
a. as previously shown, the spatial resolution of TMS is
more limited than that of neuroimaging techniques,
even when a figure-eight-shaped coil is used;
10 ASN Neuro
b. an absence of changes in TMS measures does not
necessarily rule out the presence of subtle neuroplastic
changes;
c. TMS is primarily useful for assessing the motor cortex,
which is not always the most-involved area in patients
with depression or other psychiatric disorders; general-
izing findings from motor to nonmotor areas therefore
requires caution, although TMS has been shown to reli-
ably probe the excitability and connectivity of both
motor and nonmotor cortical-subcortical networks
(Reis et al., 2008);
d. there is a degree of variability in the results of the studies
reviewed here that might be explained by the heteroge-
neous phenotypes of the included affective disorders and
the diagnostic overlap among them;
e. the depressed patients included in the studies were often
on antidepressant medications and other psychotropic
drugs that may have affected TMS measures of excit-
ability and plasticity. Furthermore, only a few studies
have evaluated patients in a remission state, and it is
therefore difficult to determine whether neuroplasticity
may be an underlying pathophysiological mechanism of
the disease or a state-dependent phenomenon.
f. finally, although the hypothesis that disrupted synaptic
plasticity contributes to depression may open paths to
novel TMS-driven drugs, very few such studies have
so far been carried out.
Conclusions
Studying cortical excitability and synaptic plasticity using
TMS may lead to new insights into the electrophysiology
and neurochemistry underlying a wide spectrum of
depressive disorders. The observed TMS patterns may
indicate the different pathological substrates of neuro-
psychiatric diseases and explain some symptoms, such
as fatigue and motor inertia, which are frequently
reported in depressed patients. In the near future, inter-
ventions aimed at enhancing neuroplasticity should merit
special attention. Particular consideration should be
given to the role of noninvasive brain stimulation tech-
niques, the genetic profiles of subjects, and the pharma-
cological effects of drugs that act on multiple
neurotransmission pathways.
Summary statement
Transcranial magnetic stimulation sheds light on the
in vivo neurochemical mechanisms underlying cortical
plasticity in patients with major depression.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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