ORIGINAL RESEARCH
published: 05 September 2019
doi: 10.3389/fpsyt.2019.00621
rTMS Reduces Psychopathological
Burden and Cocaine Consumption
in Treatment-Seeking Subjects With
Cocaine Use Disorder: An Open
Label, Feasibility Study
Mauro Pettorruso 1,2†, Giovanni Martinotti 1,3†*, Rita Santacroce 1,3, Chiara Montemitro 1,
Fabrizio Fanella 2, Massimo di Giannantonio 1 and the rTMS stimulation group
Department of Neuroscience, Imaging and Clinical Sciences, G.d’Annunzio University, Chieti, Italy, 2 La Promessa o.n.l.u.s.,
Rome, Italy, 3 Department of Pharmacy, Pharmacology and Postgraduate Medicine, University of Hertfordshire, Hatfield,
United Kingdom
1
Edited by:
Carlos Roncero,
University of Salamanca Health
Care Complex, Spain
Reviewed by:
Carla Cannizzaro,
University of Palermo, Italy
Colleen A. Hanlon,
Medical University of South
Carolina, United States
*Correspondence:
Giovanni Martinotti
[email protected]
†These authors have contributed
equally to this work and share first
Specialty section:
This article was submitted to
Addictive Disorders,
a section of the journal
Frontiers in Psychiatry
Received: 02 November 2018
Accepted: 02 August 2019
Published: 05 September 2019
Citation:
Pettorruso M, Martinotti G,
Santacroce R, Montemitro C,
Fanella F, di Giannantonio M and the
rTMS stimulation group (2019)
rTMS Reduces Psychopathological
Burden and Cocaine Consumption
in Treatment-Seeking Subjects
With Cocaine Use Disorder:
An Open Label, Feasibility Study.
Front. Psychiatry 10:621.
doi: 10.3389/fpsyt.2019.00621
Frontiers in Psychiatry | www.frontiersin.org
Introduction: Cocaine use disorder (CUD) currently represents a notable public health
concern, linked with significant disability, high chances of chronicity, and lack of effective
pharmacological or psychological treatments. Repetitive transcranial magnetic stimulation
(rTMS) is supposed to be a potential therapeutic option for addictive disorders. Aim of this
study was to evaluate the feasibility of rTMS on (1) cocaine craving and consumption and
(2) other comorbid psychiatric symptoms.
Methods: Twenty treatment seeking CUD subjects underwent 2 weeks of intensive rTMS
treatment (15Hz; 5 days/week, twice a day for a total of 20 stimulation sessions) of the
left dorsolateral prefrontal cortex, followed by 2 weeks of maintenance treatment (15Hz,
1 day/week, twice a day). Sixteen patients completed the study. Patients were evaluated
at baseline (T0), after 2 weeks of treatment (T1), and at the end of the study (T2; 4 weeks),
with the following scales: Cocaine Selective Severity Assessment (CSSA), Zung SelfRating Anxiety Scale, Beck Depression Inventory (BDI), Symptom Checklist-90 (SCL-90),
and the Insomnia Severity Index.
Results: After four weeks of rTMS treatment, 9 out of 16 subjects (56.25%) had a negative
urinalysis test, with a significant conversion rate with respect to baseline (Z = −3.00;
p = 0.003). Craving scores significantly improved only at T2 (p = 0.020). The overall
psychopathological burden, as measured by the SCL-90 Global Severity Index (GSI),
significantly decreased during the study period (Z = −2.689; p = 0.007), with a relevant
improvement with regards to depressive symptoms, anhedonia, and anxiety. Subjects
exhibiting lower baseline scores on the SCL-90 were more likely to be in the positive
outcome group at the end of the study (Z = −3.334; p = 0.001).
Discussion: Findings from this study are consistent with previous contributions on rTMS
use in subjects with cocaine use disorder. We evidenced a specific action on some
psychopathological areas and a consequent indirect effect in terms of relapse prevention
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rTMS in Cocaine Use Disorder
and craving reduction. A double-blind, sham-controlled, neuro-navigated rTMS study
design is needed, in order to confirm the potential benefits of this technique, opening
new scenarios in substance use disorders treatment.
Keywords: transcranial magnetic stimulation, cocaine use disorder, addiction, anhedonia, anxiety, depression
INTRODUCTION
To date, the largest clinical trial in the addiction field revealed
that after 13 sessions of 10 Hz stimulation, a group of cigarette
smokers significantly reduced their self-reported smoking habit,
and their 6-month abstinence rates were better when compared
to sham group (21). With regards to stimulants use disorders,
studies on animal models, applying ontogenetic stimulation to
the medial prefrontal cortex (mPFC) of cocaine-addicted rats,
demonstrated it was able to prevent compulsive cocaine seeking
behaviors (22). The therapeutic effect may be due to a combination
of variables, including a modulation on the activity of the reward
circuit via the glutamatergic PFC efferents. High frequency rTMS
of the right DLPFC has been able to reduce craving in a sample
of cocaine addicted patients (this was not true for rTMS of the
left DLPFC) (23). A study by Politi and colleagues, published in
2008, highlighted a notable self-reported reduction in craving
among thirty-six cocaine users who underwent 10 sessions of
15 Hz TMS on the left DLPFC (600 pulses, 100% rMT) (24). There
was, however, no active sham control in this study. Another study
investigating the effects of rTMS on the DLPFC in cocaine users
included thirty-two individuals with cocaine use disorder, who
were randomized to receive either rTMS (eight sessions, 15 Hz
DLPFC TMS, 2,400 pulses, 100% rMT, daily for the first 5 d, once
a week for the following 3 weeks) or a pharmacological treatment.
After 29 d, the rTMS group reported significantly less craving
and was significantly more abstinent than the pharmacotherapy
group. Other studies confirmed these preliminary data, suggesting
that rTMS of the PFC may determine a reduction in cocaine
consumption and minimize relapse risk (25–27).
Aim of our research is 1) to evaluate the effectiveness
of rTMS targeting the left DLPFC on cocaine craving and
consumption; 2) to evaluate its effect on other psychiatric
variables (general symptomatology, hedonic state, mood, anxiety,
insomnia, suicidality).
Cocaine use disorder (CUD) currently represents a notable
public health concern, linked with significant disability,
high chances of chronicity, and considerable mortality (1).
In Italy, it has been recently estimated that up to 4.8% of
subjects aged 15–64 consumed cocaine at least once in their
lifetime, whereas 1.3% has been diagnosed with CUD (2).
Unfortunately, so far there is still uncertainty with regards to
the actual effectiveness of pharmacological or psychological
treatments proposed for CUD. In the past few years, both
preclinical and human neuroimaging studies evidenced a
relationship between altered brain functions and behaviors
observed in addicted patients, such as lack of impulse
control, drug-seeking compulsions, and inability to modulate
behaviors according to the different circumstances. More
specifically, cocaine consumption, especially if long-term,
has been associated with structural (e.g., brain volume
reduction) (3, 4) and functional [e.g., reduced cortical
activity (5–7), impaired executive functions, and dysregulated
neurotransmission (8–10)]. Moreover, preclinical researches
highlighted that a dysregulated inhibitory control, which may
be due to impaired prefrontal cortex (PFC) functions, has a
key role in compulsive drug-seeking behaviors, increasing
drug intake and addiction severity (11).
Neuromodulation interventions have greatly developed in
light of these new insights. In fact, they may offer researchers and
clinicians the possibility not only to study altered brain pathways,
but also to act on them, directly focusing on affected circuits
needing to be reshaped. Transcranial magnetic stimulation (TMS)
is a noninvasive technique able to induce an electric flow in targeted
brain regions (12). TMS pulses may be delivered in sequences: this
can determine long‐term changes, modifying cellular excitability
and resulting behaviors. The promoting or suppressing effect
depends on a number of parameters, such as stimulation site and
type of sequence. In psychiatry, most of the research involving
TMS has been performed on mood disorders, and in particular
Major Depressive Disorder, while few studies investigated the
potential application of TMS in manic episodes (13). rTMS has
also been applied as a therapeutic option in schizophrenia (14),
obsessive–compulsive disorder (15), and impulsive-compulsive
disorders (16, 17). rTMS is still at a very early stage of study in the
field of addiction; it has been mostly investigated for its potential
anti-craving action. So far, most studies on human samples
have dealt with nicotine, stimulants and alcohol use disorders,
targeting left or right dorsolateral prefrontal cortex (DLPFC) (18–
20). Notable limitations of these studies are that the vast majority
only included one or two stimulation sessions, the sample sizes
were rather limited, and frequently there was no control group.
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MATERIALS AND METHODS
Twenty treatment-seeking patients, aged 18–65 and meeting the
diagnostic criteria for Cocaine Use Disorder (CUD) according
to DSM-5, were enrolled in the study. All participants were
physically healthy, and had no other current major Axis I
diagnosis (schizophrenia spectrum disorders, bipolar I disorder,
post-traumatic stress disorder), including current abuse or
dependence to other substances (with the exception of nicotine).
The patients were selected according to the following criteria:
• aged 18–65;
• diagnosed with a moderate to severe Cocaine Use Disorder
according to DSM-5 criteria;
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rTMS in Cocaine Use Disorder
• no comorbid diagnosis of other Substance Use Disorders
(besides nicotine), Bipolar Disorder type 1, Schizophrenia, or
other psychotic disorders;
• no history of seizures or other relevant neurological disorders,
including organic brain disease, epilepsy, stroke, brain
lesions, multiple sclerosis, previous neurosurgery, or personal
history of head trauma that resulted in loss of consciousness
for >5 min and retrograde amnesia for >30 min;
• ferromagnetic, or other magnetic-sensitive metal implants;
• no current use of pro-convulsant drugs;
• for female patients: no pregnancy/breastfeeding.
and instructed to focus and inhibit any craving elicited by
the cues. These procedures were proposed in reason of several
evidences suggesting the use of a cue-exposure paradigm to engage
targeted circuits and to improve stimulation outcomes (31).
In fact, cue-induced craving is linked to impaired activity in
prefrontal areas and fronto-striatal circuits. Eliciting cocainerelated cues in cocaine addicts was supposed to elicit activation
of the executive control network and to increase the ability to
modulate craving in a circuit-specific manner through noninvasive brain stimulation techniques (32). Also, at the end of
the session, the ‘Side Effect” questionnaire was administered to
evaluate potential side effects.
The Ethic Committee of the University “G.d’Annunzio” of
Chieti-Pescara approved this study. All subjects signed a written
informed consent according to the Declaration of Helsinki.
The study was approved by the local Ethical Committee
and all participants were informed about study procedures and
provided written informed consent before the beginning of the
experiment, in line with the Helsinki Declaration.
PSYCHOMETRIC ASSESSMENT
STUDY PROCEDURES
Clinical and psychometric data were acquired at baseline
(T0), after two (T1) and four weeks (T2) of rTMS treatment.
The psychometric assessment included self-administered and
physician-administered tests, chosen to evaluate cocaine-related
withdrawal symptoms and psychopathologic symptoms.
All the patients underwent the following psychometric
evaluation:
The study consisted of: 1) an outpatient screening phase, during
which patients were screened to assess their eligibility to be enrolled
in the study, 2) an intensive rTMS treatment phase, during which
the subjects received 20 stimulation sessions (2 daily, 5 d/week)
for 2 weeks, 3) a maintenance phase of 2 weeks, during which the
subjects received two consecutive rTMS sessions once a week.
• the Cocaine Selective Severity Assessment (CSSA), a clinicianadministered scale aimed at evaluating cocaine withdrawal
signs and symptoms; it includes items exploring craving,
hedonic tone, suicidal ideation, appetite, irritability, energy;
• the Beck Depression Inventory, to assess depressive symptoms,
such as hopelessness, irritability and guilt, as well as physical
symptoms such as fatigue, weight loss, and diminished interest
in sexual activities;
• the Zung Self-Rating Anxiety Scale, to assess anxiety levels
in terms of cognitive, autonomic, motor and central nervous
system symptoms;
• global psychopathology was explored by using the Symptom
Checklist-90 (SCL-90), a self-report psychometric instrument
used to measure broad range of psychopathological distress
into nine symptomatic dimensions;
• the Insomnia Severity Index insomnia (ISI), a seven-item
questionnaire evaluating the severity of nighttime and daytime
components of sleep disorders.
rTMS DEVICE AND PROTOCOL
Repetitive TMS was delivered using a MagPro R30 with the
Cool-B80 figure-of-eight coil (MagVenture, Falun, Denmark),
allowing for a focal stimulation of the DLPFC.
Every session began with the determination of resting motor
threshold (RMT), used to calculate the intensity of stimulation.
Subjects were seated in a recliner with their hands in a comfortable
resting position, wearing earplugs and a cap over the scalp, and
electrodes were taped over the region of the abductor pollicis brevis
(APB) belly and associated tendon of the right hand. The RMT was
considered as the minimum single-pulse stimulator output intensity
resulting in motor evoked potentials (MEPs) of the abductor pollicis
brevis (APB) of at least 50 μV peak-to-peak amplitude in ≥50% of
pursued trials (≥5/10; Rossini-Rothwell method) (28).
To localize DLPFC, we used the BeamF3 method (29) a
system to find the F3 position using three skull measurements. By
using the circumference and distances between skull anatomical
landmarks, it locates DLPFC with a reasonable approximation to
MRI-guided neuronavigation system (30). This coil location was
marked on the cap, in order to ensure accuracy and consistency
across sessions.
Two consecutive rTMS sessions lasting 13 min each were
performed, with a minimum of 60 min interval between sessions.
Each rTMS session was delivered at the intensity of 100% of
the individual resting motor threshold, for a total of 40 trains
(60 stimuli per train, inter-train interval of 15 s, for a total of
2,400 stimuli). At the beginning of each session, participants
were exposed to cocaine-related cues for approximately 2 min
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STATISTICAL ANALYSIS
Statistical analysis was performed using SPSS for Windows,
Version 20.0 (SPSS Inc, Chicago, Illinois). All analyses were
conducted using non-parametric testing. Descriptive statistical
analyses were provided at baseline for categorical (number and
percentage) and continuous (mean, standard deviation, range
min-max) data. Wilcoxon Test for paired variables was used
to monitor changes in scores on psychometric scales between
baseline and follow-up measures. Mann-Whitney U test was
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Pettorruso et al.
rTMS in Cocaine Use Disorder
used to investigate overall psychopathological differences
between subjects reaching or not a positive outcome at the end of
the study. The significance threshold was set at 0.05.
intense desire to consume cocaine, evaluated by the CSSA craving
subscale, highlighted an after-treatment significant improvement
from baseline to T2 (T0 mean score: 4.43; T2 mean score: 2.93 —
ΔT2-T0: p = 0.02), but not from baseline to T1.
RESULTS
PSYCHIATRIC SYMPTOMS
Twenty patients were enrolled, sixteen (80%) completing all the
follow-up visits during the study period, while four had an early
drop-out and were excluded from the trial. The treated subjects
reported no significant side effect. Fourteen out of sixteen patients
were male (87.5%), mean age of the sample was 36.63 years old
(SD: 6.29, range 27–51). Mean educational level was 12.12 years
(SD: 2.87, range 8–18); most of the subjects (62.5%) were employed
during their participation to the study. Subjects had a mean
duration of cocaine addiction of 15.37 years (SD: 5.58, range 8–27);
half of the sample had an ongoing pharmacological treatment
(33). Subjects did not report any specific psychotherapeutic
regimen in the month before the recruitment in the study. Other
demographic and clinical data are reported in Table 1.
The overall psychopathological burden, as measured by the
SCL-90 Global Severity Index (GSI), significantly decreased
within the study period (Z = −2.689; p = 0.007).
Comorbid depressive symptoms in the sample were assessed
by the BDI and the SCL-90 Depression subscale: both confirmed
a significant reduction from T0 to T2. BDI mean score at T0 was
17.19, suggestive of mild depression; mean scores at T1 (7.25) and
T2 (7.38) indicated no signs of depression (ΔT1-T0: p = 0.003;
ΔT2-T0: p = 0.008). Similarly, SCL-90 Depression subscale had
a mean score of 1.24 at T0, which decreased to 0.54 and 0.67 at
T1 and T2, respectively (ΔT1-T0: p = 0.004; ΔT2-T0: p = 0.003).
Anhedonia, described as the reduced ability to feel pleasure for
natural rewards, was assessed by means of a CSSA subscale, and a
statistically significant improvement of this symptom was evidenced
at both T1 and T2 (ΔT1-T0: p = 0.027; ΔT2-T0: p = 0.033).
Suicidal ideation, evaluated by the CSSA subscale, did not
reach an after-treatment significant improvement (ΔT1-T0:
p = 0.059). However, mean score was extremely lower since the
beginning of the study (see Table 2).
Anxiety, assessed by means of the Zung Self-Rating Anxiety
Scale (SAS), was apparently not a primary symptom in the
selected sample: the mean score (36.37) at T0 is considered to
be in the normal range. However, it showed a steady decrease
after treatment (T1: 33.2; T2: 28 — ΔT2-T0: p = 0.001). On the
other hand, considering the Anxiety subscale of the SCL-90,
the mean score registered at T0 was 1.05, which indicates the
presence of anxiety symptoms. T1 mean score was 0.42, and T2
mean score was 0.54, highlighting a complete resolution of the
symptomatology (ΔT1-T0: .007; ΔT2-T0: p = 0.001).
Insomnia was evaluated using the Insomnia Severity Index
(ISI): despite a global improvement in the mean scores beforeand after-treatment (T0: 7.43; T1: 4.53; T2: 2.25), this did not
reach statistical significance (see Table 3).
Finally, in order to explore the potential impact of baseline
psychopathology on clinical outcome, we included in the positive
outcome group all subjects who tested negative at the urinalysis at
the end of the study (N = 9), and in the negative outcome group all
patients who relapsed in cocaine use after rTMS treatment (N = 7).
No impact of current pharmacological treatment was detected on
treatment outcome. In terms of overall psychopathological burden,
subjects who had baseline lower scores at SCL-90 scale were more
likely to be in the positive outcome group at the end of the study (Z =
-3.334; p = 0.001) (Figure 1).
COCAINE USE AND CRAVING
At the baseline, all patients declared cocaine use in the previous
week, and all had a positive urinalysis test for cocaine. After
four weeks of rTMS treatment, 9 out of 16 subjects (56.25%)
had a negative urinalysis test, with a significant conversion rate
with respect to baseline (Z = −3.00; p = 0.003). With regards to
cocaine-related withdrawal symptoms, as measured by the CSSA
scale, mean total score at the baseline (T0) was 36.07 (SD 18.39).
Patients were re-evaluated after two (T1) and four (T2) weeks of
rTMS treatment: CSSA mean total score showed a consisted and
statistically significant decrease (T1: 17.43; T2: 16:44—ΔT1-T0:
p = 0.002; ΔT2-T0: p = 0.008). Craving, described as the urge or
TABLE 1 | Demographic and clinical characteristics at baseline (M ± SD and ranges).
Mean ± SD (range)
N.
Gender (M/F; %M)
Age
Education
Employed (Yes; %)
Marital Status
Married
Separated/divorced
Single
Duration of cocaine addiction
Form of cocaine assumed (Powder/Crack)
Nicotine Use (n.; %)
Addiction comorbidity (n.; %)
Cannabis Use
Alcohol Use
Benzodiazepine Abuse
Audit
Current pharmacological treatment (n.; %)
Antidepressants
Mood stabilizers
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16
14/2 (87, 5%)
36.63 ± 6.29 (27–51)
12.12 ± 2.87 (8–18)
10 (62.5%)
6 (38%)
2 (13%)
8 (50%)
15.37 ± 5.58 (8–27)
14/2
10 (62.5%)
3 (18.8%)
0 (0%)
3 (19%)
1 (6%)
6 ± 5.02
8 (50%)
3 (18.7%)
7 (43.7%)
DISCUSSION AND CONCLUSIONS
In this study, we confirmed the efficacy of high-frequency rTMS
of the DLPF in Cocaine Use Disorder, showing a peculiar effect
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TABLE 2 | Cocaine-related withdrawal symptoms as measured by Cocaine Selective Symptoms Assessment (CSSA) at the baseline and after two weeks (T1) and four
weeks (T2) of rTMS treatment. Relevant subscales have been reported.
CSSA total score
Craving
Anhedonia
Suicidal ideation
T0
T1
T2
% ΔT1-T0
% ΔT2-T0
Sig. ΔT1-T0
Sig. ΔT2-T0
36.07 ± 18.39
4.43 ± 3.63
2.69 ± 2.92
0.93 ±1.54
17.43 ± 10.55
3.29 ± 3.26
0.60 ± 1.24
0±0
16.44 ± 8.48
2.93 ± 3.24
0.69 ± 1.31
0.31 ± 1.1
–51.7%
–25.7%
–77.7%
–100.0%
–54.4%
–33.9%
–74.3%
–66.7%
.002
.342
.027
.059
.008
.020
.033
.083
Bolded text: p < 0.05
TABLE 3 | Changes in psychopathological symptoms in subjects with Cocaine Use Disorder during rTMS treatment.
Global Severity
Index (SCL-90)
Depressive
symptoms
BDI scores
SCL-90 Depression
Scale
Anxiety
symptoms
SAS scores
SCL-90 Anxiety
Scale
Insomnia
Insomnia Severity
Index
T0
T1
T2
Z
T1-T0
Z
T2-T0
Sig.
T1-T0
Sig.
T2-T0
0.98 ± 0.74
0.47 ± 0.29
0.47 ± 0.44
−2.715
−2.689
0.007
0.007
17.19 ± 12.40
7.25 ± 6.54
7.38 ± 6.74
0.67 ± 0.59
−2.672
−2.989
0.008
0.54 ± 0.45
−3.018
−2.867
0.003
1.24 ± 0.94
0.004
0.003
36.37 ± 10.34
33.20 ± 8.92
28 ± 4.53
0.54 ± 0.46
−3.183
−3.197
0.001
0.42 ± 0.37
−0.825
−2.708
0.410
1.05 ± 0.77
0.007
0.001
7.43 ± 6.51
4.53 ± 3.7
2.25 ± 2.86
−1.301
−1.768
0.193
0.077
Bolded text: p < 0.05
sessions was preferred (24, 25, 34, 35). Our protocol was
designed on the basis of recent findings in the area of depressive
disorders, where a higher number of rTMS sessions was positively
linked to rTMS effectiveness in reducing depressive symptom
severity (36).
In comparison to other studies on CUD (24, 25, 34, 35), our
sample is in line with gender ratio, with a higher prevalence of
males. This gender difference is consistent with the epidemiology of
cocaine consumption in Italy, according to the Drug Report for our
country recently published by the EMCDDA (37). In fact, 92% of
the clients accessing treatment services for cocaine use disorder in
2015 were men, with a majority of cocaine users snorting cocaine.
In this open sample, rTMS appears to elicit its more notable
effects on depressive and anxiety symptoms, confirming previous
data from our group, according to which the pro-hedonic effect
of rTMS is crucial and directly related to the reduction of cocaine
craving (27). On the other hand, the improvement of depressive
symptoms was not evidenced in similar studies (24, 35), whereas
other studies, which used deep TMS and were limited by the low
number of participants, did not evaluate these aspects (25, 34). As
a whole, it should be taken into account that CUD and depression
have a high comorbidity (38), and a reduction of cocaine craving
may also be an indirect outcome of rTMS via an improvement of
depressive symptoms. Multiple findings suggest that symptoms
pertaining to the area of depression may predict drug use outcomes:
the presence of depressive symptoms worsens cocaine use outcomes
in patients treated with a 12-step focused group continuing care
FIGURE 1 | Psychopathology at baseline – as measured by the Global
Severity Index (GSI) of Symptom Checklist-90 (SCL-90) – may predict
outcome of rTMS treatment.
on specific psychiatric symptoms that may, to some extent,
contribute to its anti-craving and relapse preventing properties.
In our study, a protocol characterized by an intensive
stimulation treatment of twenty sessions over two weeks was
proposed for the first time, showing a differentiating aspect with
respect to other studies, in which a lower number of intensive
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(39), and depression severity significantly influences future increase
in drug use (40). Moreover, patients who score higher in depressive
scales are more likely to fail abstinence after treatment in outpatient
substance misuse services (41). On the other hand, we should
consider that in cocaine use disorders pharmacological treatments
based on antidepressants did not evidence significant data in terms
of craving reduction and relapse prevention (42, 43). Therefore,
the hypothesis of an “indirect” effects of rTMS on craving via an
improvement of depressive symptoms should be taken into account
with caution, hypothesizing for rTMS an adjunctive independent
effect on different pathways, with frequent overlaps and cumulative
effects. However, in order to clarify these aspects, further larger trials
are needed.
Another hypothesis that may explain our results follows the
theories by Hanlon and colleagues (44, 45). As reported in their
recent studies, two neurobehavioral systems may be targeted by
TMS in order to treat cocaine use disorders: an executive control
system, namely the dorsal lateral frontal–striatal, likely involved
in resisting drug use, and an impulsive system, namely the ventral
medial frontal–striatal, likely involved in drug-associated craving
and use. It may therefore be useful to either increase activity in
the DLPFC-dorsal striatal circuit, as in most of the previous trials
in cocaine use disorders and in the present study, or to decrease
the activity in the ventral medial prefrontal cortex–caudate circuit
using an inhibitory rTMS (1 Hz or cTBS) (45). It is therefore a
possibility that the stimulation of the DLPFC may be less associated
with a direct anti-craving effect, probably exerting its action in
terms of relapse prevention partially through other mechanisms,
as evidenced in this paper. In this regard, it is also of some interest
that subjects exhibiting baseline lower scores of psychiatric burden
were more likely to be in the positive outcome group at the end
of the study, confirming a specific role of rTMS in Cocaine Use
Disorder, regardless of its direct effect on other psychopathological
dimensions. However, it should be also considered as a limitation
of our study that craving was evaluated with an unspecific
scale (CSSA), and that the small sample size and the lack of
neuronavigation could have tempered the magnitude of the effect.
Consistently with previous pilot evaluations by our group
(27, 46), we observed an improvement in the hedonic tone of the
subjects. As previously mentioned, anhedonia is a condition in
which a subject shows a lost or diminished ability of experiencing
pleasure; it represents one of the two main diagnostic features of
depressive disorders. This symptom was significantly reduced
between T0 and T2. Anhedonia is believed to have a role in
relapsing, and it may also be involved in transitioning from a
recreational substance misuse to an actual substance use disorder.
Moreover, in addicted patients, anhedonia has been positively
correlated with craving, intensity of withdrawal symptoms, and
some temperamental factors (38, 47). Anhedonia appears to have
a peculiar association with stimulant use: in CUD patients, the
anhedonia-cocaine relationship remains significant after adjusting
for demographic, psychiatric, and non-stimulant substance use
(48). This has also been evidenced in animal models; in fact,
cocaine-sensitized rats show anhedonia-like behaviors, which may
be reversed by the administration of imipramine (49).
Anxiety appeared to be not a primarily relevant symptom in
our sample, as only few (17.6%) of the patients scored for mild/
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moderate anxiety at the Zung Self-Rating Anxiety Scale; on the
other hand, however, mean scores for the anxiety subscale of
the SCL-90 revealed the presence of clinically relevant anxiety
symptoms. Anxiety may represent a core clinical feature of cocaine
withdrawal, possibly related to the hyper-activation of brain stress
systems mediated by corticotropin-releasing factor, noradrenaline
and dynorphin (50, 51), combined with the inactivation of
Neuropeptide Y (NPY) and the brain anti-stress system (50),
and other hormones and modulators dysregulation (52). Anxiety
sensitivity is considered to be a prospective predictor of treatment
dropout in crack/cocaine users: individuals with higher anxiety are
more likely not to succeed in completing detoxification treatments
(53). A reduction in anxiety scores may therefore predict a positive
outcome with respect to cocaine use relapse. To this respect,
insomnia may represent a relevant issue in terms of cocaine relapse,
too. However, in this study we did not evidence a significant
effect of rTMS on this dimension but only a general trend. This is
probably due to the small sample size and the presence of different
confounders (depressive symptoms, anxiety, anhedonia).
This study has several limitations: 1) the open design and
the limited number of participants narrow the interpretation of
results; 2) the follow-up period is limited, and this does not allow
to draw long-term prevision for a chronic relapsing disorder as
cocaine addiction; 3) rTMS stimulation of the DLPF was not
neuro-navigated; although the standard evaluation of the area
pertaining the DLPFC has shown a good level of reliability (30),
the absence of a precise methodology does not consent a rigorous
evaluation of the area, which is mostly associated with therapeutic
improvements, as recently showed (54), and could represent a
limiting factor to the potentiality of this protocol in terms of craving
reduction; 4) the lack of a distance-adjusted motor threshold may
mean that patients were under-stimulated and that they did not
receive the same TMS dose. Interestingly, this limitation may
explain, to some extent, the high number of non-responders in our
sample. It is well known that the distance between the scalp and
the cortex may influence TMS effectiveness. In fact, the skull and
scalp may influence the impedance and, consequently, the TMSinduced electric current within the cerebral cortex (55). In this
context, several shreds of evidence suggest that the resting motor
threshold (which depends on the motor cortex depth) should be
adjusted for the differences in depth between nonmotor cortical
regions and the motor cortex (M1) (55). In our feasibility study,
subjects did not undergo MRI. The lack of structural imaging data
has prevented us from adjusting the stimulation intensity based
on the distance between scalp and cortex at the target and this
may account for differences in TMS dose between subjects and,
even more critical, an insufficient stimulation of the DLPFC.
Cocaine users usually exhibit significantly higher RMTs than
healthy controls (56, 57). Even if the effects of cocaine on cortical
inhibitory and excitatory circuit has not been well explained,
cocaine abuse has been proved to increase cortical excitability
(increased intracortical facilitation) (56, 57) and it has been
suggested that the increased RMT is an adaptation mechanism
to this increased excitability (56). Moreover, Hanlon et al. showed
that RMTs do not respect the correlation with brain-scalp distance
among cocaine users (57). Given the lack of scalp–brain distance
adjusted RMT and in order to reduce the risk of adverse effects
6
September 2019 | Volume 10 | Article 621
Pettorruso et al.
rTMS in Cocaine Use Disorder
ETHICS STATEMENT
such as seizures (58), we decided to set stimulation intensity to
100% of RMT, lower than the 120% RMT intensity suggested by
depression protocols.
In conclusion, this study is consistent with previous contributions
concerning the use of rTMS in subjects with cocaine use disorders,
showing a lower but significant effect on craving for the whole
sample, and a more specific action in other psychopathological areas
able to exert an indirect effect in terms of relapse prevention. Our
results also allow to speculate that TMS on the DLPC may be more
effective in selected subgroups of addicted patients, namely those
with concurrent mild depressive symptoms and, more probably, a
relief-type craving (59). In the next few years, TMS should undergo
scrupulous evaluations through hypothesis-driven research, in
order to proceed with its validation as a therapeutic option for
addictive disorders (60). A double-blind, sham-controlled, neuronavigated rTMS study design is mostly needed, in order to confirm
the potential benefits of this technique, opening new scenarios in
substance use disorders treatment.
The study was approved by the Department Review Board and
by the “University of Chieti” Ethic Committee. All subjects gave
written informed consent in accordance with the Declaration
of Helsinki.
AUTHOR CONTRIBUTIONS
GM, MP and MdG designed the study protocol. The rTMS
stimulation group assessed the patients and delivered
neuromodulation protocol. MP and RS performed the
statistical analysis: RS and CM wrote the introduction. MP
wrote the Materials and Methods, and Results sections. GM,
MP, CM and RS wrote the discussion. MG and FF reviewed
the discussion.
FUNDING
rTMS STIMULATION GROUP
COLLABORATORS
This work was supported by the “Departments of Excellence
2018-2022” initiative of the Italian Ministry of Education,
University and Research for the Department of Neuroscience,
Imaging and Clinical Sciences (DNISC) of the University of
Chieti-Pescara.
Luisa De Risio, Ilaria Petrucci, Gaia Tourjansky, Patrizia
Capicotto, Francesca Neri, Gianluca Ruggiero, Barbara Cassiani,
Silvia Fraticelli, Valentina Moroni.
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Conflict of Interest Statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Copyright © 2019 Pettorruso, Martinotti, Santacroce, Montemitro, Fanella, di
Giannantonio and the rTMS stimulation group. This is an open-access article
distributed under the terms of the Creative Commons Attribution License (CC
BY). The use, distribution or reproduction in other forums is permitted, provided
the original author(s) and the copyright owner(s) are credited and that the
original publication in this journal is cited, in accordance with accepted academic
practice. No use, distribution or reproduction is permitted which does not comply
with these terms.
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Example of Comments:
1. This is a super interesting conclusion. I wonder if this biomarker and genetic testing
could be used to predict PD and possibly prevent it?
2. I find rigidity being “commonly misdiagnosed” rather concerning… while I can
understand why medical professionals would not want to immediately conclude
someone has PD, shouldn’t it still not be immediately ruled out either? Could
recognizing it as a possibility help those patients who actually may be at a greater risk
for PD?
3. These imagines leave me unsettled but curious. So this instance of camptocormia is
caused by flexion which I would assume is a continued contraction of the muscle. So
when the person is pushing themselves are the muscles still contracting? Does this
cause long-term muscle atrophy?
4. If a patient were to experience non motor or cognitive symptoms, what kind of things
might they experience? Would they be able to be diagnosed on just the cognitive
abilities?
5. I thought this was interesting because I was unaware that PD patients could have
trouble initiating their swallowing reflex. Because of this I was wondering, is choking a
common concern for people with PD?
6. If these symptoms are attributed to dopamine agonists in particular, how would they
overcome this issue? Would they switch the drug given to the patient. change the
overall treatment, stop the administration of all dopamine agonists?

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