Pràcticum:

Recerca Neurociència
Cognitiva
Memòria Projecte Final

CRISTINA MARFÀ GIL

30/06/2023
Títle

Effects of cathodal transcranial direct current stimulation of the Orbitofrontal

cortex on relapse in subjects with alcohol addiction.

Acronym
ALOHA-tDCS

ALOHA (ALchOHol Addiction): a Hawaian word used when greeting or parting from
someone. In this study, it will be used to welcome or part form transcranial direct
current stimulation (tDCS). Results will decide.

Abstract

Alcohol addiction (AD) may use cognitive processes of learning and memory, through
reinforcing neural substrates (Redolar, 2012). The orbitofrontal cortex (OFC) seems
to facilitate the reinforcement system through the encoding and retrieval processes of
new information (Duarte et al, 2010).

Two independent meta-analysis of neuroimaging revealed that OFC is activated by

contextual stimuli related to alcohol consumption showing related high activity in the
ventral striatal (vSTR) (Dierkhof et al, 2012), specifically in the dopaminergic neurons
of the nucleus accumbens, what results in increased dopamine levels (Harel et al,
2021). This, repeatedly, creates a conditioned learned association (Volkow et al,
2003), which is why alcohol consumption is related to well-being and motivates the
person to consume again. Thus, ventral striatal activation might be associated with
the representation of reward magnitude and lead to subsequent behavioral
performance (Dierkhof et al, 2012).

The aim of this study is to interfere with this conditioned learned association,
throughout the application of transcranial direct current stimulation (tDCS) to
modulate the activation of the OFC during cue-induced alcohol craving to promote
correlated subcortical effects on vSTR, decreasing dopaminergic neurons activity of
the ventral striatum to low the release of dopamine and interfere with its reinforcing
effects, through two between-subject, single-blind, randomized, sham controlled
study, using fMRI to target OFT region using visual cues to induce alcohol craving
(assessed as maximal BOLD response) (Gorelick et al, 2014), with a pre-post
positron emission tomography (PET) of the dopamine system, assessing the
molecular changes associated to this intervention (Duarte et al, 2010).

Key words

positron emission tomography, alcohol addiction, transcranial direct current

stimulation, self-efficacy, orbitofrontal cortex

ALOHA-tDCS Marfà, Cristina page 2

Summary for a non-specialist audience

Alcohol addiction is the result of conditioned learning, the addicted subjects have
learned that when they consume alcohol, they feel better. In addition, when they stop
drinking, they start feeling physically and emotionally bad, and may experience
withdrawal symptoms, that can go from sweating, anxiety or shakes to severe
effects, as breathing problems or seizure. To relieve these symptoms, alcohol
dependents start drinking again, what leads to enter a vicious circle from which it is
very difficult to get out.

There are many factors that influence the success of the treatments, but several
studies show that motivation, and specifically self-efficacy, plays a very important
role. The aim of this project is to interfere in this conditioned learning by modifying
the brain excitability that occurs, in such a way that the addicted person is exposed to
contextual cues of alcohol consumption, so that they do not feel that impulse to drink.
In this way, the addicted person would receive an important information about the
plasticity of the brain and its capacity of reverse its functioning. This may result in an
increase of perceived self-efficacy and therefore in motivation and adherence to
treatments.

On a neural level, alcohol consumption use circuits that have been related to
reinforcement, learning and memory. When a person takes up the habit of drinking
alcohol, certain neural connections are reinforced, and this results in stable changes
at the molecular level. (Redolar, 2012). Dopamine is a substance that is related to
this reinforcement circuit, since it is released in these states of compulsion or when
exposed to contextual cues, and it may play an important role in behaviors of active
search for alcohol.

There is a region of our brain, the orbitofrontal cortex, that seems to be related to
addictive behaviors. This is activated when the alcohol addicted person is exposed to
contextual cues or the possibility of consumption, and it seems to be involved in the
release of Dopamine, so this would mean that OFT functions as a link between
reinforcement and the experience of pleasure (Redolar, 2012).

What we intend to do with this project is to break this link, applying cathodic
stimulation, which modulates neuronal excitation downwards, so that the addicted
person has the experience of not feeling pleasure under exposure of contextual
cues.

We hope that this experience by itself has a motivational effect: learning about the
plasticity of the brain and being conscious that change is a real possibility. This may
increase the self-efficacy, that is, believing that you oneself is capable of fighting
addiction.

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Introduction

Alcohol is a psychoactive substance that produces dependence and causes 3 million

deaths every year Worldwide, what represents a 5,3% of all deaths. It is also the
causal factor of more than 200 disease and injury conditions, and has significant
social and economic consequence (WHO, 2022), what implies an urgent need to
better understand the mechanisms underlying addiction to offer further
effective treatments.

Brain reinforcement systems are an important component of motivation, since most

addictive substances act on the neural pathways that mediate survival-motivated
behaviors in the animal. The electrical stimulation of the places in the brain where
many of the drugs of abuse interact is shown to be pleasurable, since it is capable of
evoking certain motivational states and of activating the neural systems that, as a
rule, are involved in “natural” reinforcing stimuli. Therefore, the phenomenon of
addiction must be understood within the framework of motivated behaviors. It
appears that repeated episodes of dopamine release can consolidate drug self-
administration behaviors into long-term compulsive use. During addiction, a series of
associations between different stimuli and substances of abuse take place. These
stimuli become clues that predict the drug and that can explain different motivational
and emotional states of the addicted subject. (Redolar, 2012).

Prochaska and Di Clemente's transtheoretical model of change continues to be a

main reference when it comes to explain the processes of change that people who
decide to start a drug addiction treatment program follow. The model has a three-
dimensional character as it identifies three aspects of the change in the addictive
behaviors: the stages of change, that is, the temporal division of the process into
stages according to a criterion based on the motivation of the person to modify his
behavior (Ibáñez & Álvarez 2009).

The model of Prochaska and Di Clemente's stages are: precontemplation, that

reflects the unmotivated people that are unaware and do not believe there is an
addiction problem, so there is no intention of making a change in the next six months
(Raijan & Cogburn, 2023) so if a person in this stage goes for help it is likely to be
due to the pressure of others. This is important because one of our inclusion criteria
is that the subjects are motivated and respond to our advertisements by themselves.
The next stage of change, the contemplation, there is conscience of the problem and
the need for a change but still does not do anything, they remain in behavioural
procrastination. On the determination stage, the subject acknowledge that the
behaviour is problematic and is determined to do something about, so starts to
develop a plan, and if it is completed, intend to act in the next thirty days. The next
stage, action, there are strong efforts to change, and total abstinence is the
expectation for a period of fewer than six months. People in this stage are willing to
receive assistance and support, and if it is successful, the go to last stage,

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Maintenance, where individuals have maintained total abstinence for more than six
months Those stages are not lineal, but performed on a spiral way, as there is
always the possibility of relapse and the subject can regress to any of the stages,
although eighty-five percent of individuals return to the contemplation stage (Raijan &
Cogburn, 2023).

Once the addicted person is aware of the problem, maintaining a high level of
motivation is necessary. Conceptual models of addiction focus on self-efficacy and
motivation as key variables important during a quit attempt and many studies have
highlighted self-efficacy as an important predictor of substance use (Kadden & Litt
2011; Greenfield et al, 2000; Oei et al, 2007). Self-efficacy is the belief that you can
achieve something.

On a neural level, the orbitofrontal cortex (OFT) is involved in emotion and in

motivation, but the relationship between these functions performed by these brain
structures is not clear (Rolls, 2023). Imaging studies show that addictive state is
related to a dysfunction of the OFC, being hypoactive in alcohol dependent subjects
via the striato-thalamo-orbitofrontal circuit and showing hypermetabolic during
craving (Volkow and Fowler, 2000; Martinez et al, 2005) what results in increased
dopamine levels in the ventral striatum (vSTR) (Harel et al, 2021) and increases the
risk of relapse (Hüpen et al, 2022), because Dopamine signals represent rewards
prediction and act on downstream structures to control behaviour (Brombert-Martin et
al, 2010).
So, it seems that the OFC has an implication in the formation of long-term
associative memories, being involved in the release of dopamine and functioning as
a link between reinforcement and the experience of pleasure (Redolar, 2012), what is
crucial for the maintenance of addictive disorders (Redolar, 2012; Schoenbaum &
Shaham, 2008; Duarte et al, 2010).

ALOHA-tDCS Marfà, Cristina page 5

Main goal
The main goal is to evaluate whether targeting the OFC with cathodal
transcranial direct current stimulation (tDCS) has the potential to produce
relapse prevention in patients with alcohol addiction, by increasing self-
efficacy and motivation.

We expect to interfere with the activation of this neuronal circuit of reward (striato-
thalamo-orbitofrontal) through the creation of a new conditioned response, so that
alcohol dependent subjects do not feel a strong desire of consuming alcohol during
the exposure to visual alcohol- associated cues. We believe that the fact of not
experiencing craving makes alcohol dependent subjects conscious of a competing
possible response that increases the self-efficacy and motivation, what acts as a
predictor for relapse (Abdollahi et al, 2014), thus reversing the long-term learned
representation of the reward magnitude related to alcohol (Duarte et al, 2010).

Secondary goals

As secondary goals, to further understand the neural mechanism underlying

addiction, (1) to determine whether decreased activation of the OFC downregulates
by itself the dopamine release in the ventral striatum so that both areas can be
consistently associated and (2) identify the down-top effects in terms of activation
that the consequent decreased levels of dopamine in the vSTR have on the
frontocortical structures (OFC and adjacent areas related to executive functions).

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Hipòtesis

1) Cathodal tDCS of the OFT during exposure to visual cues related to alcohol
consumption will enable the phasic response of dopamine firing in the vSTR, what
will downregulate the release on dopamine.

2) Low concentrations of dopamine in the vSTR will correlate with increasing

motivation for treatment and reduce relapse.

Methodology

Participants

Inclusion criteria
for the alcohol-dependent (AD) subjects are as follows:
1) age 18- 60 years (Mejldal et al, 2020).; 2) ability to understand the study
procedures 3) DSM-5 criteria for alcohol dependence and no other significant
medical illness 4) they are in the Action stage according to the Prochaska and Di
Clemente's stages model
Exclusion criteria
(a) current psychotic symptoms, (b) acute severe major depression, (c) lifetime
bipolar disorder, (d) current suicidal thoughts/behaviour, (e) the use of illegal opioids
and/or stimulants, (f) past 30 days psychosocial alcohol treatment (g) treated with
tDCS before (g) pregnancy (h) has been through any cerebral intervention or neural
disease i) Claustrophobia

Sample
A total of 40 participants are recruited from advertisements. All subjects provided
written informed consent.

15 alcohol addicted participants will receive the treatment.

15 alcohol addicted participants sham-control.
10 normal control participants

Materials and procedures

Participants will be recruited through advertisement and will pass a screening to

meet criteria, that includes the Mini International Neuropsychiatric Interview (MINI
7.0.2), Alcohol Dependence Scale (ADC), the Stages of Change Readiness and
Treatment Eagerness questionnaire (SOCRATES) and General Self-Efficacy Scale.
A medical report will be also required.

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Participants will be divided into two groups randomly. 1 group will receive the
treatment (tDCS) and the other will follow same procedures but will only receive
some low tDCS, just to simulate treatment. Another group of non-alcoholic subjects
will receive tDCS.

Treatment will last two months and will consist on a weekly session on tDCS with
pre-post MRI/PET. Follow up will take place every 6 months, when participants will
be called to repeat SOCRATES questionnaire, General Self-Efficacy Scale and will
have a short interview to know about general state and possible relapse. They will
also receive a control session of MRI/PET.

Questionnaires
Diagnostic assessment: To determine DSM-5 criteria and exclusion criteria a) to e)
apply the Mini International Neuropsychiatric Interview (MINI 7.0.2), and we also
assess the severity with the Alcohol Dependence Scale (ADC). The raw score
interpretation provides cutoff points of 1–13 suggesting a low level, 14–21 an
intermediate level, 22–30 a substantial level, and 31–47 a severe level of alcohol
dependence (Mejldal et al, 2020).

To determine inclusion criteria 4) participants must be in Action stage of change, we

need to determine the motivational stage. We use The 3-factors and 19-item version
of The Stages of Change Readiness and Treatment Eagerness questionnaire
(SOCRATES). It is an instrument designed to assess (motivation), seen as
readiness for change in alcohol abusers. The instrument yields three factorially-
derived scale scores: Recognition (Re), Ambivalence (Am), and Taking Steps (Ts). It
is a public domain instrument and may be used without special permission (Bertholet
et al, 2009). Each item response is based on a 5-point Likert scale (i.e., 1=strongly
disagree, 2=disagree, 3=undecided or unsure, 4=agree, 5=strongly agree) and the
result permits to identify the AD subject into one of the 4 stages of Prochaska and Di
Clemente.

To correlate the results of SOCRATES with the stages of motivation to change we

make a table of correspondences that would allow us to make a comprehensible
analysis without never lose sight of the Prochaska and Di Clemente model. The five
values (Very low, Low, Medium, High and Very High) in the scores given to each of
the three variables (recognition, ambivalence and first steps), we have reduced them
to two (High and Low). For the average scores, in Recognition one was distributed
for each value (32 low and 33 high). Regarding those of Ambivalence (15) and First
Steps (33), both were considered high values, considering that to reach that score
the user has to answer positively to the less than 75% of the questions. In the
correlation with the stages of change we also make a reduction to three:
Precontemplation, Contemplation and Action. We have included the Preparation for
Action phase in Action, considering that beyond the significance of the changes
made up to the date, there is a clear recognition of the problem and doubts about it

ALOHA-tDCS Marfà, Cristina page 8

have been resolved. The phase Maintenance would form part of the subsequent
process, the treatment itself.

Precontemplative would be all those with a low recognition of the problem, except
those who show doubts, -high ambivalence- and have initiated changes. These
would be considered contemplatives. Users with a high degree of recognition and
ambivalence. The rest of the options, -all with high recognition- are considered the
stage of Action (Ibáñez & Álvarez2009).

General Self-Efficacy Scale. It consists of ten questions. study score above 35

indicate high efficacy and below 30 low efficacies and the rest are average.

Imaging Techniques
tDCS
We choose tDCS because it is non-invasive, cheap and easy to apply so it could be
a treatment that could provide a large-scale solution to a huge problem in society
(Moreno et al, 2017). Aware of the importance of montage, we will apply both
electrodes on different regions to avoid cross-network influence but across the same
network (Chase et al, 2020;): cathodal stimulation is intended to downregulate the
OFT, so the electrode will be placed to the OFT, and anodal stimulation is intended
to produce facilitatory effects, so the reference electrode is applied to the
Somatosensory Cortex (SC), as it has been identified as area of interest being
altered in individuals with substance-related addictions (SRAs) (Hüpen et al, 2022)
and it seems to associate bodily states with experiences (Gowin et al, 2013).

Stimulation parameters of cathodal tDCS: According to las investigations

(Salehinejad & Ghanavati, 2020; Mosayebi et al., 2020; ), Interval and repetition
might be relevant to prolongue after effects on cathodal tDCS, going from early-
phase LTD (lasting for up to 3 h after intervention) to late-phase LTD (longer-lasting
aftereffects), so once a week we will apply 4 repetitions of 1 mA during 10 minutes
with relatively short intervals of 20 min each, expecting to induce cumulative effects.
The anodal electrode parameters are (1,5 mA), both with 5x5 cm electrodes

Coregistered MRI-PET images

MRI will be used to provide anatomical reference to each individual to minimize

interindividual differences.

Coregistered MRI-PET images using a hybrid PET/MRI device will provide with
complementary information and reinforce each other. MRI provides high-quality,
high-resolution images of soft tissue morphology, which is very useful for locating
lesions in the human body. On the other hand, PET images offer information about
the physiological processes that take place in different organs and substructures.
minimized exposure to radiation (Zhu & Zhu, 2019).
To have a successful in vivo PET imaging of dopaminergic function in the vSTR, we

ALOHA-tDCS Marfà, Cristina page 9

must choose the optimal radiotracer. An intra-venous administration of the
radiotracer is made at rest (baseline) and the second after the last stimulation, each
session, so subjects undergo two PET scans a week.
A radiotracer is a radioactive designed substance that is capable to unite to a certain
molecule that is our target of interest, specific for the intended binding site, and that
can be radiolabelled. We dismiss [11C] DTBZ and [18F] AV-133 ligands, that are
specific for a single binding site (VMAT2) but not for specific nerve terminals, as the
VMAT2 is common to all monoaminergic neurons (Nag et al., 2021).
[11C] Raclopride is a D2/D3 antagonist with a moderate binding affinity, useful for
studying estimated striatal D2/D3 receptor availability (Yoder et al., 2011), [11C]
Raclopride binding has made it useful for studies examining the effects of alterations
of endogenous dopamine (3,4-dihydroxyphenethylamine) (DA) levels, as the
magnitude of the decrease correlates with the change in extracellular dopamine. To
take into account that the short half-life of carbon-11 limits the length of the imaging
study (about 20 minuts).

The Dopaminergic system is measured through [11C]raclopride Binding potential

(BPND). (Kikbourn, 2021; Martinez. 2005).
PET data mainly relies upon invasive arterial blood sampling procedure, that is an
invasive and cumbersome procedure that requires dedicated personnel and
expensive equipment and is often uncomfortable or even painful for the patient
(Schain et al, 2017). This dual methodology allows to acquire estimated arterial input
function (AIF) through an image-derived input function (IDIF), without arterial
cannulisation (Zhu & Zhu, 2019).

Quantitative analysis
Multiple Linear Regression to compare cathodal stimulation, self-efficacy, motivation,
[11C]raclopride Binding potential (BPND) and time for relapse.

Materials and Equipment

Questionnaires
Mini International Neuropsychiatric Interview (MINI 7.0.2)
Alcohol Dependence Scale (ADC)
The Stages of Change Readiness and Treatment Eagerness questionnaire
(SOCRATES).
General Self-Efficacy Scale. It consists of ten questions. study score above 35
indicate high efficacy and below 30 low efficacies and the rest are average.

Equipment
A PET/MRI scanner, placed in Bellvitge Hospital Universitari. It is the first PET/MRI
scanner in the Catalan public healthcare network (Bellvitge Hospital Universitari,
2022). tDCS equipment

ALOHA-tDCS Marfà, Cristina page 10

Justification of the team of researchers and institutions involved

Collaborative research with Bellvitge Hospital Universitari (BHU) and University of

Barcelona (UB). BH incorporated in 2022 a PET/MRI scanner to facilitates the
development of new research and teaching projects.

TEAM:
2 students of master’s degree in Precision Diagnostic Medicine along with the
University of Barcelona (UB)
1 student of psychology degree of Universitat Oberta de Catalunya (UOC)
1 doctor of Research Committee of BHU

Project Impact

We hope to find clinically significance differences among the three groups. If the two
hypotheses are confirmed, this would make a big impact at a clinical and social level,
because tDCS is a non-invasive and cheap technique and the treatment could be
applied massively. Moreover, self-efficacy and motivation could be reinforced by
other means and thus obtain even better results.

Identified risks and contingency plan

With the incorporation of a MRI, we minimize anatomical interindividual variability but
we cannot control these differences on a physiological level, the stimulation itself
could have different effects in clinical populations in whom baseline brain activity,
and excitability might differ from healthy human ((Salehinejad & Ghanavati 2020), so
one potential risk about cathodal intervention is to apply suboptimal stimulation
parameters and contribute to the variability of tDCS results which are not
systematically covered by the literature (Salehinejad & Ghanavati 2020), thus
obtaining null effects.

Participants are free to leave the process at any time.

Ethical implications

Ethics approval is obtained from the Hospital Universitari de Bellvitge in Barcelona.

ALOHA-tDCS Marfà, Cristina page 11

Calendar

ALOHA-tDCS Marfà, Cristina page 12

Gantt Diagram

ALOHA-tDCS Marfà, Cristina page 13

Budget

Bellvitge Hospital Universitari (BHU) is a public medical center and the master’s
degree in Precision Diagnostic Medicine along with the University of Barcelona (UB)
is made in collaboration with the BHU. Due that 2 students of the master are in this
project, the costs will reduce significantly.

BUDGET

Training in Neuroimaging techniques 1.500€

Training in data analysis 1.500€
MRI/PET 0€
tDCS 0€
Questionnaires 2.400€
Staff 0€
Total 5.400€

Disclosure statement

The authors declare no conflict of interest

ALOHA-tDCS Marfà, Cristina page 14

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