TMS for Addiction Treatment: Driving Innovation

Journal of Neural Transmission (2024) 131:505–508
https://doi.org/10.1007/s00702-023-02734-2
PSYCHIATRY AND PRECLINICAL PSYCHIATRIC STUDIES - SHORT COMMUNICATION
Driving innovation in addiction treatment: role of transcranial
magnetic stimulation
Graziella Madeo1
· Antonello Bonci1,2
Received: 29 October 2023 / Accepted: 20 December 2023 / Published online: 17 January 2024
© The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature 2024
Abstract
Addictions comprises heterogenous psychiatric conditions caused by the complex interaction of genetic, neurobiological,
psychological, and environmental factors with a chronic relapsing-remitting pattern. Despite the long-standing efforts of
preclinical and clinical research studies, addiction field has seen relatively slow progress when it comes to the development
of new therapeutic interventions, most of which failed to demonstrate a significant efficacy. This is likely due to the very
complex interplay of many factors that contribute to both the development and expression of addictions. The imbalance
between the salience and the reward brain network circuitry has been proposed as the neurobiological mechanisms explaining
the pathognomonic symptoms of addictions.Non-invasive neuromodulation techniques have been proposed as a promising
therapeutic intervention to restore these brain circuits dysfunctions. Here, we propose a multi-level strategy to innovate the
diagnosis and the treatment of addictive disorders.
Keywords Addiction · Reward · Non-invasive brain stimulation · Transcranial magnetic stimulation · Brain plasticity
Addictions comprise heterogenous psychiatric conditions
caused by the complex interaction of genetic, neurobiological, psychological, and environmental factors with a chronic
relapsing–remitting pattern. Addictive disorders remain at a
global level a significant socioeconomic burden representing
one of the main causes of decreasing disability-adjusted life
years (Rate of Disease Burden from Drug Use Disorders
2019). According to the latest World Drug Report of 2021,
296 million people, or approximately 5.8% of the global
adult population aged 15–64 years, used illicit drugs at least
once, with an increase of 23% in the last 10 years (World
Drug Report, Executive Summary 2023). In 2021 alone, the
harm caused by drug use led to an estimated 28 million years
of healthy life lost worldwide as a result of premature death
and disability. Cannabis remains the most consumed drug
worldwide, but opioids hold the place as the most harmful
drugs accounted for nearly 70% of the 128,000 deaths attributed to drug use disorders in 2019 ( World Drug Report,
Executive Summary 2023).
* Graziella Madeo
[email protected]
1
Brain & Care Group, Rimini, Italy
2
GIA Healthcare, 1501 Biscayne Blvd, Miami 33137, USA
Despite the long-standing efforts of preclinical and clinical research studies, the addiction field has seen relatively
slow progress when it comes to the development of new
therapeutic interventions, most of which failed to demonstrate significant efficacy. This is likely due to the very
complex interplay of many factors that contribute to both
the development and expression of addictions. Indeed, the
current approach to addictions involves psychosocial and
pharmacological interventions (Brooks and Mchenry 2023).
To note, some addictions to substances like cannabis and
cocaine are still “orphan” in the sense that they do not have
targeted pharmacological treatment (Douaihy et al. 2013).
In the case of alcohol, however, medications with an anticraving effect do exist but have limited efficacy (Burnette
et al. 2022). One of the main problems in finding effective
molecular targets for pharmacological treatments is linked
to the complex pathophysiological alterations underlying
addiction. Decades of preclinical and clinical research have
allowed a better comprehension of the brain circuits changes
occurring within the salience and reward networks leading
to the widely accepted concept that addiction is a brain disease (Goldstein and Volkow 2011; Koob and Volkow 2016).
The salience and the reward networks involve brain areas
such as dorsolateral prefrontal cortex (DLPFC), anterior
cingulate cortex, insula, ventromedial prefrontal cortex
Vol.:(0123456789)
506
(VMPFC), orbitofrontal cortex, and nucleus accumbens,
which are implicated in the cognitive control and response
inhibition of actions, as well as reward-related behaviors
(Dosenbach et al. 2006; Menon and Uddin 2010; Volkow
et al. 2011). The dynamic imbalance between these two circuits is thought to be one of the main dysfunctions leading
to poor cognitive control in the decision-making process
and the powerful desire to consume addictive substances
(Hu et al. 2015). This imbalance offers not only an explanation for the most pathognomonic symptoms of addictions,
the uncontrolled compulsive consumption of drug and the
incoercible craving but also the basis for developing therapeutic strategies aiming at reinforcing the salience network
to improve cognitive control and inhibiting the overactive
reward pathway to negatively impact on craving.
Looking at the neurobiology of addiction, neuromodulation techniques have been proposed as a promising therapeutic intervention to restore brain circuits dysfunctions.
Particularly, non-invasive brain stimulation techniques, such
as transcranial magnetic stimulation (TMS) has the ability
to modulate circuit network activity through the plasticity
changes within key brain areas (Diana et al. 2017; Ekhtiari et al. 2019). These techniques, particularly TMS, have
already obtained the American Federal Drug Administration (FDA) and European regulatory agency approval for
the treatment of other psychiatric conditions, such as resistant major depressive disorder, obsessive–compulsive disorder, and more recently for smoking cessation (Cohen et al.
2022; Johnson et al. 2013). In 2021, TMS has also received
the European CE mark for the treatment of psychoactive
substances use disorders (Cotovio et al. 2023). Regarding
TMS, the ability to modulate brain activity with long-lasting
effects is based on the generation of brief and intense magnetic pulses producing a secondary electrical current in the
brain, which in turn modifies the cortical excitability of the
cerebral cortex area where the pulses are directed (Diana
et al. 2017). There are several types of TMS modalities:
single, paired and repetitive. Single and paired modalities
are mainly used for diagnostic purposes, whereas repetitive
patterns are applied for therapeutic intervention due to their
ability to induce long-term changes in synaptic plasticity
(Hallett 2007). So far clinical studies have explored the efficacy of TMS in addictions using two main approaches. One
approach focused on reinforcing key brain areas in the salience network by using excitatory stimulation protocols, such
as the DLPFC, that should increase the cognitive control
of individuals with addiction (Dunlop et al. 2017; Hanlon
et al. 2015). Targeting DLPFC with excitatory stimulation
protocols has been associated with a significant reduction
in cigarette smoking (Dinur-Klein et al. 2014; Zangen et al.
2021), or other drug consumption like cocaine (Madeo et al.
2020; Steele et al. 2019; Lolli et al. 2021; Scarpino et al.
2019; Garza-Villarreal et al. 2021). Using Deep TMS coils,
G. Madeo, A. Bonci
allowing the simultaneous stimulation of several brain areas,
including DLPFC and insula, similar effects on the reduction of drug consumption have been obtained (Dinur-Klein
et al. 2014; Suñer-Soler et al. 2022). The complementary
approach focusing on the reward circuit has targeted the
VMPFC to attenuate craving (Hanlon et al. 2013). However,
studies focusing on the efficacy of anti-craving interventions
have shon a great level of variability in response suggesting
that the observed effects may depend on various psychoneuro-biological factors (Kearney-Ramos et al. 2019). Studies using TMS combined withneuroimaging have shown several biological factors contributing to individual variability,
including differences in the activation of intracortical networks (Hamada et al. 2013), in the resting state connectivity
between brain nodes (Nettekoven et al. 2015), in cortical
excitability (Jannati et al. 2017), and genetic background
(Abellaneda-Pérez et al. 2019). Technical advances in TMS
procedures, involving new coils, protocol parameters, neuro
navigation software, and the combination of TMS with other
advanced tools, like neuroimaging or neurophysiology, will
allow a better and deeper understanding of the neurobiology underlying the individual variability seen in people with
addiction with diagnostic, therapeutic, and prognostic implications. The idea is that neuromodulation protocols may help
maximize treatment success.
Furthermore, it is important to mention that the variability seen across the studies focusing on the TMS efficacy for
addiction treatment, does not take into account the intersubject variability, such as distinct personality traits, the
level of expression of co-morbidities, personal history, and
environmental factors.
In this framework, we wish to emphasize that non-invasive neuromodulation should be implemented in clinical
practice as adjunctive intervention, combined with traditional pharmacotherapy and psychosocial support in the vast
majority of cases.
This may sound a bit forward, but this idea is based on
the fact that the majority of these patients often manifest
co-morbidities, such as anxiety, post-traumatic stress disorder (PTSD), depression, insomnia, or obsessive–compulsive
disorder (OCD), all conditions where TMS can also help
medications (when in existence) as well as compliance to
psychological therapy.
Finally, using this approach, clinicians will have a strong
opportunity to better identify biomarkers helping the diagnostic characterization and the prediction of response to a
specific treatment.
Novel and additional approaches such as TMS are needed
in the addiction field to carry forward a concrete and efficacious precision medicine-based intervention.
To achieve this goal, two parallel levels of work should be
carried out. First, clinicians should disentangle the complex
co-morbidities, often associated with addiction and tackle
Driving innovation in addiction treatment: role of transcranial magnetic stimulation
the social components contributing to the persistence of the
disorder. In this view, with a transversal effort, clinical centers, academic institutions, and scientific associations should
work together to harmonize data collection, clinical assessment, and general protocol of interventions. If data harmonization is not feasible in the short-term, fast-track avenues
for publishing non-harmonized clinical data should also be
readily available to clinicians, provided careful and rigorous
data quality control.
The second level of work should focus on improving the
application of neuroimaging and/or neurophysiological techniques to identify the specific brain networks that need to
be stimulated/inhibited/modulated to achieve a reduction of
craving and increase the cognitive control of patients with
substance use disorders and addictions.
In conclusion, in addiction medicine, non-invasive neuromodulation, psychological interventions along neuropharmacological agents represent the most successful multi-level
strategy to treat and target the neurobiological underpinning of addiction. This multilevel strategy could also help
identify biomarkers of individual variability and to tackle
the complex comorbidities present in the majority of these
patients, leading to both a personalized and a comprehensive
therapeutic approach. This approach in treating people struggling with addiction needs to be pursued along with a focus
on prevention, involvement of patients and relatives, and a
proactive attitude from scientists and clinicians.
Data availability Not applicable.
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