# Exploratory structural neuroimaging examination of impulsivity in severe alcohol use disorder: Persistent implication of the ventral striatum

Nicolas Cabe, Shailendra Segobin, Céline Boudehent, Alice Laniepce, Anne

Lise Pitel

► To cite this version:

Nicolas Cabe, Shailendra Segobin, Céline Boudehent, Alice Laniepce, Anne Lise Pitel. Exploratory structural neuroimaging examination of impulsivity in severe alcohol use disorder: Persistent implication of the ventral striatum. Behavioural Brain Research, 2025, 483, pp.115452. 10.1016/j.bbr.2025.115452. hal-05266445

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Research article

# Exploratory structural neuroimaging examination of impulsivity in severe alcohol use disorder: Persistent implication of the ventral striatum

<figure><img src="image_3.png" /></figure>

Nicolas Cabe<sup>a,b,*</sup>, Shailendra Segobin<sup>c</sup>, Céline Boudehent<sup>a,b</sup>, Alice Laniepce<sup>a,d</sup>, Anne Lise Pitel<sup>a,e ID</sup>

ARTICLE INFO

Keywords:

Striatum

Nucleus Accumbens

Frontal cortex

Cerebellum

MRI

ABSTRACT

**Background:** While Alcohol Use Disorder (AUD) is frequently associated with impulsivity, its structural brain substrates are still poorly defined. The triadic model of addiction postulates that impulsive behavior is regulated by an amygdalo-striatal impulsive subcomponent, a prefrontal and cerebellar reflective subcomponent, and an insular regulatory subcomponent. The objective of this study was thus to examine the relationships between self-evaluated impulsivity and structural brain abnormalities in patients with severe AUD (sAUD) using the triadic model as a theoretical framework.

**Methods:** Twenty-two inpatients with sAUD and 17 Healthy Controls (HC) completed two impulsivity scales: the Barratt Impulsiveness Scale-11 (BIS-11), and the Urgency, Premeditation, Perseverance, Sensation Seeking, Positive Urgency Impulsive Behavior Scale (UPPS). They also underwent an anatomical MRI. The brain volumes of the regions described as involved in the three subcomponents of the triadic model were extracted.

**Results:** The two groups did not significantly differ on self-reported impulsivity measures. However, the volumes of the caudate nuclei, executive cerebellum and insula were smaller in sAUD than in HC. In the sAUD group there were significant positive correlations between certain impulsivity measures and gray matter volume of the nucleus accumbens.

**Conclusions:** In sAUD, self-evaluated impulsivity specifically relates to the integrity of the ventral striatum that belongs to the impulsive subcomponent of the triadic neurocognitive model of addiction. It is not related to the integrity or deterioration of the brain regions that underlie the reflexive or regulatory sub-component. Although these results have methodological limitations, they are consistent with the impulsive/compulsive model of addiction and confirms the persistence of the relationship between impulsivity and ventral striatum in sAUD.

1. Introduction

Alcohol Use Disorder (AUD) is a complex disease marked by an impulsive drive toward alcohol and a loss of control over alcohol consumption despite negative consequences [1-3]. Impulsivity is a multifaceted construct strongly associated with AUD and defined as a "tendency to react rapidly or in unplanned ways to stimuli without proper regard for consequences or risks" [4]. Impulsivity increases the risk for initial use, development of dependence, and relapse [4-6].

A theoretical neurocognitive model has been proposed to better

understand neural mechanisms in the addicted brain [7-9]. The triadic neurocognitive model [8] postulates that in addiction, decision-making processes involve three independent but interacting subcomponents 1) an impulsive subcomponent, driven by the amygdalo-striatal complex (i. e. amygdala, nucleus accumbens, caudate nucleus and putamen), involved in automatic-appetitive responses; 2) a reflective subcomponent, driven by the prefrontal cortex, the anterior cingulum and the cerebellum, involved in executive functions responsible for controlled-deliberate responses; and 3) a regulatory subcomponent, underpinned by the insula, that plays a regulatory role between the two

<footnote><sup>a</sup> Normandie Univ, UNICAEN, INSERM, PhIND "Physiopathology and Imaging of Neurological Disorders", Cyceron, Caen 14000, France</footnote>

<footnote><sup>b</sup> Service d'Addictologie, Centre Hospitalier Universitaire de Caen, Caen 14000, France</footnote>

<footnote><sup>c</sup> Normandie Univ, UNICAEN, PSL Université de Paris, EPHE, INSERM, U1077, CHU de Caen, GIP Cyceron, Neuropsychologie et Imagerie de la Mémoire Humaine, Caen 14000, France</footnote>

<footnote><sup>d</sup> UNIROUEN, CRFDP (EA 7475), Normandie University, Rouen 76000, France</footnote>

<footnote><sup>e</sup> Institut Universitaire de France (IUF), France</footnote>

<footnote>* Correspondence to: Centre Cyceron, Campus Jules Horowitz, Boulevard Henri Becquerel, BP 5229, Caen Cedex 5 14074, France.
E-mail address: cabe-n@chu-caen.fr (N. Cabe).</footnote>
other subcomponents. In this model, AUD is the consequence of an imbalance between the reflective and impulsive subcomponents with a weakening of the reflective subcomponent and/or an overactivation of the impulsive subcomponent. AUD can also result from a dysfunction of the regulatory subcomponent related to higher craving and causing an imbalance between the two other subcomponents [8,9].

While this imbalance theoretically accounts for rapid and impulsive behaviors in response to an alcohol cue in patients with AUD, the brain substrate of such impulsivity remains unclear notably because many studies evaluated impulsivity using behavioral tasks [10], which mainly involve executive functions relying on the prefrontal cortex. The choice of such experimental paradigms thus makes difficult to disentangle the contribution of the reflective and impulsive subcomponents of the triadic model.

Regarding the brain regions described as involved in the impulsive component of the triadic model, lower grey matter (GM) volumes were found in the striatum [11], in particular in putamen [12], in patients with severe AUD (sAUD) compared to healthy controls. In patients with mild AUD (short alcohol history and no dependence), there was no shrinkage of the brain regions underlying this subcomponent but larger white matter volume of the ventral striatum (nucleus accumbens and internal capsule), especially in patients with high impulsivity evaluated with the 11th version of the Barratt Impulsiveness Scale (BIS-11 [13]) [14]. To our knowledge, no studies have evaluated the relationships between regional brain volume and impulsivity in sAUD patients using the Urgency, Premeditation, Perseverance, Sensation Seeking, Positive Urgency Impulsive Behavior Scale (UPPS [15]), the more recent and second most widely used self-assessment scale for impulsivity. In sAUD patients, fMRI studies show increased activation of striatal regions related to the reward system [16].

Concerning regions involved in the reflective subcomponent, in adults ranging within a continuum of normal to harmful drinking behavior and alcohol dependence, higher alcohol consumption was related to lower GM volume in the right frontal pole and the left inferior frontal gyrus and these brain abnormalities correlated with higher impulsivity on the BIS-11 [17]. In patients with mild AUD, brain regions included in the reflective subcomponent were altered and smaller volumes correlated with higher BIS-11 scores [8,14]. In patients with sAUD, GM volume was lower than in healthy controls in the dorsal cingulate, medial prefrontal, and orbitofrontal cortices [12]. Chronic and heavy alcohol drinking was notably associated with GM, white matter and metabolic abnormalities in the brain regions underpinning the reflective subcomponent including the nodes and connections of the executive loop of the fronto-cerebellar circuit [16,18–20]. Early in abstinence, these brain alterations are associated with executive deficits and notably impaired inhibition abilities [21]. The MRI data are supplemented by EEG data showing slower activity in the parietal and frontal regions in sAUD patients [16].

The regulatory subcomponent of the triadic system is supposed to be related to craving. The insula may play a crucial role in subjective craving and drug seeking. Impulsive decision to drink alcohol despite negative consequences may thus result from craving and increased insular cortex activity. Craving exacerbates the drive and motivation to drink by activating the impulsive subcomponent and subverting the resources of the reflective subcomponent [8]. In young binge drinkers, craving was related to certain facets of the UPPS (positive urgency, and, in a less marked way, sensation seeking and negative urgency) [22]. Imaging studies suggest that activity of the insula correlates with subjects' rating of urge for cigarettes, cocaine, alcohol, and heroin [23,24]. In sAUD, chronic and heavy alcohol consumption has been reported to be associated with lower insula volume [11,16,19,25].

Concerning the model as a whole, an rsFMRI study identified specific resting-state functional connectivity patterns consistent with the triadic system in sAUD patients [26]. One of the pharmacological treatments for sAUD, nalmefene, was used in a study to successfully normalize rsFMRI patterns by weakening the impulsive system while strengthening the

reflective system [27].

To sum-up, there are brain alterations of the three subcomponents of the triadic neurocognitive model of addiction in patients with sAUD. Such pattern of brain abnormalities could lead to an imbalance and explain impulsivity in sAUD patients. However, this model still needs to be experimentally tested by exploring the links between impulsivity and the structural brain integrity of the three subcomponents. The objective of the present study was thus to examine the relationships between regional brain volumes and self-evaluated impulsivity in patients with sAUD using the triadic model as a theoretical framework. We conducted a neuroimaging study focusing on the volumes of the brain regions specifically described in this model and examined self-reported impulsivity using both the BIS-11 and the UPPS scales to provide a broader exploration of impulsivity.

We hypothesized that compared with HCs, sAUD patients show higher impulsivity and lower volumes in the different brain regions of the triadic model. We also hypothesized that there is a significant relationship between impulsivity scores and the ROI volumes in the triadic model, particularly for the impulsive sub-component. We did not have a strong a priori hypothesis concerning the laterality of the expected results based on the triadic model. To our knowledge, this is the first time that self-reported impulsivity is assessed in sAUD patients according to two different conceptual models and simultaneously with a brain imaging examination.

## 2. Material and methods

### 2.1. Participants

39 participants, all having French as their native language, were included in the present study: 22 patients with sAUD and 17 healthy controls (HC).

None of the participants had a history of neurological pathology, in particular history of brain lesions (stroke, traumatic brain injury with loss of consciousness > 30 min, epilepsy, etc. or neurochirurgical intervention), psychiatric disorders (Axis 1 of DSM-5, assessed by a clinical interview conducted by a psychiatrist), or endocrinal infectious which could have influenced their cognitive functioning. None of the participants had any type of substance use disorder, except alcohol for patients with sAUD and tobacco for all participants. None of them were under psychotropic treatments (benzodiazepines used during withdrawal were stopped at least 48 h before inclusion).

The investigation was reviewed by the local ethics committee of Caen University Hospital (CPP Nord-Ouest III, no. IDRCB: 2011-A00495–36). All participants were informed about the study prior to their inclusion and provided their written informed consent.

Patients were included by clinicians early in abstinence as inpatients at Caen Normandy University Hospital, where they were receiving alcohol withdrawal treatment. They were diagnosed according to the DSM-IV-TR criteria of “Alcohol dependence” or DSM-5 criteria of sAUD [1,28]. At inclusion, none of them presented physical symptoms of alcohol withdrawal as assessed by the Cushman's scale [29]. Alcohol history of patients with sAUD was explored using the Alcohol Use Disorder Identification Test (AUDIT) [30,31] and a semi-structured interview [32] (Table 1).

HC were recruited locally to match the patients for age, declared gender and education (Table 1). They did not meet the criteria for alcohol abuse (AUDIT <7 for men and <6 for women) or severe depression (Beck Depression Inventory (BDI-II) score ≤ 29 [33]).

### 2.2. Experimental design

#### 2.2.1. Impulsivity assessment

The BIS-11 [13] considers three impulsivity dimensions: attentional impulsivity (inability to focus attention or concentrate), motor impulsivity (involved in acting in the absence of reflection), and lack of
<table><caption>**Table 1**
Demographical, clinical, and alcohol-related variables in patients with sAUD and HC subjects.</caption><thead><tr><th></th><th>sAUD<br>(N = 22)</th><th>HC<br>(N = 17)</th><th>U</th><th>p</th></tr></thead><tbody><tr><td>Age (years)</td><td>47.64<br>(± 9.74)</td><td>43.53<br>(± 5.06)</td><td>134.0</td><td>0.14</td></tr><tr><td>Education (years of<br>schooling)</td><td>11.55<br>(± 2.18)</td><td>11.76<br>(± 0.83)</td><td>113.5</td><td>0.12</td></tr><tr><td>Declared gender (men/<br>women)</td><td>22/0</td><td>14/3</td><td>4,21</td><td>0.04</td></tr><tr><td>BDI</td><td>13.41<br>(± 9.84)</td><td>2.06<br>(± 2.33)</td><td>30.0</td><td>< 0.001*</td></tr><tr><td>AUDIT</td><td>28.55<br>(± 5.02)</td><td>2.29<br>(± 1.65)</td><td>0.0</td><td>< 0.001*</td></tr><tr><td>Duration of alcohol misuse<br>(number of years)</td><td>25.01<br>(± 11.20)</td><td>NA</td><td>-</td><td>-</td></tr><tr><td>Mean daily alcohol<br>consumption (units)</td><td>19.00<br>(± 8.28)</td><td>NA</td><td>-</td><td>-</td></tr><tr><td>Number of previous<br>detoxifications</td><td>1.82<br>(± 1.40)</td><td>NA</td><td>-</td><td>-</td></tr></tbody></table>

sAUD: patients with severe alcohol use disorder; HC: healthy controls; BDI: Beck Depression Index; NA: not applicable; AUDIT: Alcohol Use Disorder Identification Test; 1 alcohol unit= 10 g of pure ethanol

*: Significant result for a threshold set at p ≤ 0.05. Data were analyzed using Mann-Whitney U-tests, except for sex for which we used a Yates corrected Chi2 test.

planification (difficulty in considering the negative consequences of one's actions and decisions, orientation on the present and not the future). This self-report questionnaire includes 30 items (11 for the motor impulsivity, 8 for the attentional impulsivity and 11 the non-planification impulsivity), each rated on a 4-point Likert scale. We used the total and the three dimension scores (a high score reflecting a high level of impulsivity).

The UPPS-P [15,34] is based on a five facets model of impulsivity: the Negative urgency (tendency to act rashly under extreme negative emotions), Positive urgency (tendency to act rashly under extreme positive emotions), Lack of Perseverance (inability to remain focused on a task), Lack of Premeditation (tendency to act without thinking), and Sensation seeking (tendency to seek out novel and thrilling experiences). A French short version of the UPPS-P has been validated [35] referred here-after as the UPPS for the sake of simplicity. This scale proposes 4 items for each of 5 different facets of impulsivity, all rated on a 4-point Likert scale. It is not recommended to use the total score on this scale [35,36], we thus only used the five facet scores (a high score reflecting a high level of impulsivity).

### 2.2.2. Neuroimaging examination

#### 2.2.2.1. Data acquisition and preprocessing.
A high-resolution T1-weighted anatomical image was acquired for each subject on a Philips Achieva 3 T scanner (Philips Healthcare/Philips Medical Systems International B.V., Eindhoven, The Netherlands) using a 3-dimensional fast-field sequence (sagittal, repetition time = 20 ms; echo time = 4,6 ms; flip angle = 10°, 180 slices, slice thickness = 1 mm, field of view = 256 × 256 mm², matrix = 256 × 256).

The volumetric magnetic resonance imaging (MRI) data were analyzed using the Statistical Parametric Mapping software (SPM12). Preprocessing steps included segmentation and spatial normalization to the MNI template (voxel size = 1.5 mm³, matrix = 121 x 145 x 121). The normalized GM images were modulated and a mask was obtained by taking the unmodulated GM images of HC in MNI space, averaging them, and thresholding the resultant mean image at 0.5. The resulting GM mask was applied to all GM data analyses.

#### 2.2.2.2. Extraction of the ROI volumes.
The whole brain pattern of volume deficits of the patients included in the present study has been

described elsewhere [37,38]. In the present study, we chose a region of interest (ROI) analysis approach to focus on the brain regions corresponding to the three subcomponents of the neurocognitive triadic model of addiction.

For each patient, the GM volumes of cortical and sub-cortical regions that constitute the critical components of the triadic model [8] were extracted from the Hammers's atlas [39]. The cerebellum was analyzed using the AAL atlas to specifically study the executive cerebellum, (AAL 91, 92, 93 and 94) [40]. We summed the right and left parts of each region since we had no specific hypotheses regarding a laterality effect (Fig. 1). Thus, 10 ROIs were studied: 4 for the impulsive (amygdala, nucleus accumbens, caudate nuclei and putamen), 5 for the reflective (orbitofrontal cortices OFC, dorsolateral prefrontal cortices DLPC, ventromedial prefrontal cortices VMPC, anterior cingular cortices and executive cerebellum) and one for the regulatory (insula) subcomponents. The volume of each ROI was considered as being the sum of voxels from the modulated GM maps (if mm³, each value must be multiplied by the voxel size (1.5×1.5×1.5)). The detailed analyses for the left and right sides are presented in the supplementary material (Supplementary Material 1 and 2).

### 2.3. Statistical analysis

Given the fact that all data were not normally distributed according to Shapiro Wilk tests, we conducted non-parametric tests. We compared AUD patients and HC subjects on impulsivity measures and GM ROI volume using Mann-Whitney tests. Effect size was estimated by computing biserial rank correlation. Correlational analyses with volumetric measurements were conducted using Spearman's tests, with age and total intracranial volume (TIV) used as covariates. Statistical analyses were performed with JAMOVI [41,42] and Statistica [43]. Due to the exploratory nature of our analyses, and in order to control for the increased risk of Type-I errors related to the number of analyses without exacerbating Type-II errors, we used a statistical threshold set at 0.025 (0.05 divided by 2 impulsivity scales) for the impulsivity analysis and p ≤ 0.017 for the analysis involving neuroimaging data (0.05 divided by 3 subcomponents).

## 3. Results

### 3.1. Impulsivity assessment

We did not find any significant difference between sAUD patients and HC on the BIS-11 total score and its sub-scores. The two groups did not differ on the UPPS facet scores (Table 2).

### 3.2. Regional GM brain volumes

TIV did not differ between groups (U=163, p = 0.51).

Group comparisons showed that GM volumes of the ROIs were consistently lower in sAUD compared with HC, although not systematically reaching significance. The volumes of the ROI were significantly lower in the caudate nuclei (U=82.0, p = 0.002, effect size=0.56), the executive cerebellum (U=77.0, p = 0.001, effect size=0.59) and the insula (U=101.0, p = 0.01, effect size=0.46) (Table 3).

### 3.3. Relationships between impulsivity and regional gm brain volumes

In the sAUD group, the GM volume of the nucleus accumbens (ventral part of the striatum) positively correlated with the BIS-11 attentional sub-score (rho=0.60, p = 0.005), as well as with the lack of premeditation sub-score of the UPPS (rho=0.66, p = 0.002, Fig. 2). Correlations between impulsivity scores and the volumes of the dorsal striatum (putamen) or amygdala, as well as other correlations with the volumes of the nucleus accumbens did not survive the correction for multiple comparisons (Table 4).
<figure><img src="image_4.png" /><figcaption>**Fig. 1.** Brain regions of interest (ROI) corresponding to the neurocognitive triadic model. We used the Hammers's atlas to extract the ROIs, except for the cerebellum for which we used the AAL atlas (left and right added in all cases). DLPC: dorsolateral prefrontal cortex; VMPC: ventromedial prefrontal cortex; OFC: orbitofrontal cortex.</figcaption></figure>

<caption>**Table 2 –**</caption>

Comparison of impulsivity measures (mean ± SD) in patients with sAUD and HC subjects.

<table><thead><tr><th></th><th></th><th></th><th>sAUD (N = 22)</th><th>HC (N = 17)</th><th>U</th><th>p</th></tr></thead><tbody><tr><td rowspan="5">IMPULSIVITY</td><td rowspan="5">BIS-11</td><td>Total Score</td><td>61.55<br>(± 8.54)</td><td>56.94<br>(± 14.52)</td><td>133.0</td><td>0.13</td></tr><tr><td>Attentional</td><td>16.41<br>(± 2.84)</td><td>16.06<br>(± 3.65)</td><td>159.0</td><td>0.43</td></tr><tr><td>Motor</td><td>19.45<br>(± 3.58)</td><td>22.83<br>(± 9.72)</td><td>159.0</td><td>0.44</td></tr><tr><td>Non Planification</td><td>25.68<br>(± 4.04)</td><td>22.06<br>(± 6.29)</td><td>129.5</td><td>0.06</td></tr><tr><td>Positive Urgency</td><td>10.41<br>(± 2.02)</td><td>9.71<br>(± 2.09)</td><td>157.5</td><td>0.41</td></tr><tr><td rowspan="5">UPPS</td><td rowspan="5"></td><td>Negative Urgency</td><td>8.77<br>(± 2.86)</td><td>8.35<br>(± 3.22)</td><td>167.0</td><td>0.58</td></tr><tr><td>Lack Of Premeditation</td><td>7.68<br>(± 1.78)</td><td>7.59<br>(± 1.70)</td><td>175.0</td><td>0.73</td></tr><tr><td>Lack Of Perseverance</td><td>7.14<br>(± 2.17)</td><td>7.18<br>(± 2.72)</td><td>174.5</td><td>0.73</td></tr><tr><td>Sensation Seeking</td><td>9.50<br>(± 2.50)</td><td>9.76<br>(± 2.08)</td><td>184.5</td><td>0.95</td></tr></tbody></table>

sAUD: patients with severe alcohol use disorder; HC: healthy controls; BIS-11: Barratt Impulsiveness Scale 11th version; UPPS: short version of the UPPS-P
Data were analyzed using Mann-Whitney U-tests.

No significant difference at p < 0.025.

## 4. Discussion

The main objective of the present study was to identify the structural brain substrate of impulsivity in sAUD using the triadic model of addiction as a theoretical framework. We thus analyzed, in recently detoxified sAUD patients, the relationships between self-reported impulsivity, using two scales based on two distinct models of impulsivity, and the GM volumes of the brain regions underpinning each subcomponent of this model.

The absence of a significant difference in impulsivity between sAUD patients and HC patients was not expected. It may be due to a lack of statistical power, even though the comparison tests were very far from reaching significance except for BIS-11 non planification. It also illustrates the great heterogeneity of impulsivity in the general population and in the AUD population, which results by the absence of a consensus threshold [15,44]. In our study, the most impulsive subject was a HC and not a sAUD patient. It is also possible that the methods and timing used

to assess impulsivity (hospitalized and detoxified sAUD patients) impacted the assessment. For example, the most impulsive patients are those who can least tolerate the constraints of hospitalization, which may have led to a recruitment bias. Moreover, sAUD patients may have difficulty self-evaluating their impulsive behaviors [45]. The caudate nucleus was the only region of the impulsive subcomponent that differed significantly in volume between sAUD patients and HC in accordance with previous studies [11,46]. We did not find any other evidence of volume deficits for the other striatal regions or amygdala. Such relative preservation of these brain regions may explain the fact that in our study, sAUD patients were not significantly more impulsive than HC, certainly reflecting the high heterogeneity of this clinical population. Another explanation could be that during the evolution of sAUD, individuals move from impulsivity to compulsivity alongside a shift from positive to negative reinforcement [2,47]. This hypothesis refers to the impulsive/compulsive model of addiction [2] and to the long duration of the evolution of the addictive illness of sAUD patients in our sample
<table><caption>**Table 3**
Comparison of GM volume (mean ± SD) in each ROI of the triadic model between patients with sAUD and HC subjects.</caption><thead><tr><th></th><th>Regions of Interest<br>Hammers atlas<sup>a</sup></th><th></th><th>sAUD (N = 22)</th><th>HC (N = 17)</th><th>U</th><th>p</th></tr></thead><tbody><tr><td rowspan="4">Impulsive</td><td>3, 4</td><td>Amygdala</td><td>846.47<br>(± 51.55)</td><td>863.81<br>(± 71.07)</td><td>149.0</td><td>0.292</td></tr><tr><td>34, 35</td><td>Caudate nucleus</td><td>1704.65<br>(± 234.12)</td><td>1939.80<br>(± 182.76)</td><td><strong>82.0</strong></td><td><strong>0.002*</strong></td></tr><tr><td>36,37</td><td>Nucleus accumbens</td><td>204.76<br>(± 15.75)</td><td>206.39<br>(± 20.01)</td><td>178.0</td><td>0.812</td></tr><tr><td>38, 39</td><td>Putamen</td><td>1871.41<br>(± 195.65)</td><td>1963.85<br>(± 160.33)</td><td>132.0</td><td>0.124</td></tr><tr><td rowspan="5">Reflective</td><td>91–94<sup>a</sup></td><td>Executive cerebellum</td><td>9342.32<br>(± 901.93)</td><td>10174.40<br>(± 1392.26)</td><td><strong>77.0</strong></td><td><strong>0.001*</strong></td></tr><tr><td>24, 25</td><td>Anterior Cingulate gyrus</td><td>2470.76<br>(± 295.51)</td><td>2661.42<br>(± 310.72)</td><td>122.0</td><td>0.067</td></tr><tr><td>28, 29, 50, 51, 58, 59</td><td>DLPC</td><td>23076.65<br>(± 2675.02)</td><td>24859.15<br>(± 2423.31)</td><td>126.0</td><td>0.087</td></tr><tr><td>52, 53, 56, 57, 76, 77, 80, 81</td><td>VMPC</td><td>6161.61<br>(± 680.48)</td><td>6693.93<br>(± 568.84)</td><td>103.0</td><td>0.017</td></tr><tr><td>54, 55, 68–73</td><td>OFC</td><td>5723.27<br>(± 587.19)</td><td>5904.63<br>(± 532.18)</td><td>160.0</td><td>0.457</td></tr><tr><td>Regulatory</td><td>20, 21</td><td>Insula</td><td>4094.64<br>(± 435.51)</td><td>4444.41<br>(± 394.39)</td><td>101.0</td><td><strong>0.014*</strong></td></tr></tbody></table>

sAUD: patients with severe alcohol use disorder; HC: healthy controls; DLPC: dorsolateral prefrontal cortex; VMPC: ventromedial prefrontal cortex; OFC: orbitofrontal cortex.

The volume of each ROI was considered as being the sum of voxels from the modulated GM maps.ª: AAL atlas was used to measure the executive part of the cerebellum.

*: Significant result for a threshold set at p ≤ 0.017. Data were analyzed using Mann-Whitney U-tests.

<figure><img src="image_5.png" /><figcaption>**Fig. 2.** Significant correlations between impulsivity measures and the volume of nucleus accumbens in patients with sAUD. sAUD: severe alcohol use disorder; BIS-11: Barratt Impulsiveness Scale 11th version; UPPS: short version of the UPPS-P.</figcaption></figure>

(25.1 years on average). The high impulsivity exhibited by patients shifted to compulsivity over the course of the disease progression, which was not the case in control subjects. However, this shift appears to be gradual, or at least heterogeneous, as some sAUD patients remain impulsive. Impulsivity and compulsivity therefore seem to co-exist. A simultaneous study of the 2 parameters, ideally on a longitudinal basis, would be interesting.

The correlations carried out in the sAUD group showed that the more impulsive the patient, the larger the ventral striatum (nucleus accumbens) volume. The relationships with the dorsal striatum (putamen) also tended to be significant. The striatum is currently described as playing a key role in the development and progression of AUD [48–50], which could be conceptualized as a transition from an impulsive drinking behavior linked to a positive reinforcement (hedonic effect) underpinned by the ventral striatum (nucleus accumbens), to a more compulsive and automatic behavior driven by the dorsal striatum (caudate nuclei and putamen) [2,47,51]. The relationship we found between impulsivity and the ventral striatum could therefore be present at the start of the disease and persists beyond the early stage to the more chronic stage of patients with sAUD. These results support this impulsive/compulsive model of AUD [47], with the possibility of a

co-existence between impulsivity and compulsivity (“perseverative, repetitive actions that are excessive and inappropriate”), especially in AUD patients with a long evolution of the addictive disease [52] but not particularly in patients with high impulsivity. Further investigations should explore the relationships between compulsivity (measured with the Obsessive-Compulsive Drinking Scale [53], for example) and the dorsal part of the striatum. Since the core and shell of the nucleus accumbens may play distinct and sometimes opposing roles in the clinical expression of impulsivity [54], future imaging studies with high resolution will have to differentiate their potential contributions.

The significant relationships between impulsivity and ROI volumes were observed only with the BIS-11 attentional sub-score and the UPPS lack of premeditation sub-score. Among the multiple dimensions of impulsivity, it seems that only the ability to focus on the task at hand and not to act without considering the consequences are linked to the regional brain volume of the impulsive subcomponent. The ventral striatum could therefore be involved in the early phases of impulsive decision making, before committing to an act.

The absence of association between impulsivity evaluated by the BIS-11 and amygdala volume is not surprising. Barratt had conceptualized this tool as being independent of emotional factors, which are largely underpinned by the amygdala [13]. However, this lack of association is more unexpected when evaluated with the UPPS, as this scale was designed to integrate emotional factors into the evaluation of impulsivity. It is possible to consider that the emotional items of the UPPS reflect decision making in an emotional context rather than emotional experience underpinned by the amygdala [15]. Amygdala is in charge of the evaluation and integration of emotional state rather than a personality trait as explored by self-report scales of impulsivity [48,55].

Several regions of the reflective subcomponent were smaller in sAUD patients than in controls but the differences reached significance after correction for multiple comparisons for the executive cerebellum only. Our results are not consistent with the frequent observation of frontal shrinkage in sAUD [11,19,46,48], potentially due to the use of a ROI approach, to the sample size or to the inherent heterogeneity of the structural brain alterations in sAUD patients [46]. Abnormalities in the reflective subcomponent are known to be associated with executive impairments [18], including a lack of inhibitory control. Despite the use of two different self-reported impulsivity scales, we did not find any
<table><caption>Table 4 -
Correlations (Spearman's Rho) between impulsivity measures and ROI volumes in patients with AUD (N = 22).</caption><thead><tr><th rowspan="3"></th><th rowspan="3"></th><th colspan="5">BIS-11</th><th colspan="5">UPPS</th></tr><tr><th rowspan="2">Total score</th><th rowspan="2">Motor</th><th rowspan="2">Attentional</th><th rowspan="2">Non<br>Planification</th><th rowspan="2">Urgency<br>(negative)</th><th rowspan="2">Urgency<br>(positive)</th><th rowspan="2">Premeditation<br>(lack<br>of)</th><th rowspan="2">Perseverance<br>(lack<br>of)</th><th rowspan="2">Sensation<br>Seeking</th></tr><tr><th>rho = 0.070<br>p = 0.768<br>rho = -0.184<br>p = 0.437<br>rho = 0.469<br>p = 0.037<br>rho = 0.286<br>p = 0.221<br>rho = 0.393<br>p = 0.087<br>rho = 0.056<br>p = 0.815<br>rho = 0.154<br>p = 0.516<br>rho = 0.091<br>p = 0.703<br>rho = 0.294<br>p = 0.208<br>rho = 0.087<br>p = 0.716</th><th>rho = -0.090<br>p = 0.705<br>rho = -0.185<br>p = 0.434<br>rho = 0.292<br>p = 0.212<br>rho = 0.182<br>p = 0.442<br>rho = 0.327<br>p = 0.160<br>rho = -0.075<br>p = 0.753<br>rho = 0.108<br>p = 0.649<br>rho = 0.138<br>p = 0.563<br>rho = 0.259<br>p = 0.269<br>rho = 0.101<br>p = 0.671</th><th>rho = 0.361<br>p = 0.118<br>rho = 0.176<br>p = 0.459<br>rho = 0.604<br>p = 0.005*<br>rho = 0.481<br>p = 0.032<br>p = 0.032<br>p = 0.061<br>rho = 0.521<br>p = 0.019<br>rho = 0.375<br>p = 0.103<br>rho = 0.359<br>p = 0.120<br>rho = 0.338<br>p = 0.138<br>rho = 0.138<br>p = 0.563<br>rho = 0.259<br>p = 0.084<br>rho = 0.326<br>p = 0.373</th><th>rho = -0.135<br>p = 0.570<br>rho = -0.310<br>p = 0.184<br>rho = 0.224<br>p = 0.343<br>rho = 0.015<br>p = 0.948<br>p = 0.170<br>p = 0.112<br>rho = 0.061<br>p = 0.799<br>rho = -0.080<br>p = 0.739<br>rho = -0.050<br>p = 0.838<br>rho = 0.190<br>p = 0.423<br>rho = 0.069<br>p = 0.773<br>rho = -0.21<br>p = 0.560</th><th>rho = 0.273<br>p = 0.244<br>rho = 0.102<br>p = 0.669<br>rho = 0.483<br>p = 0.491<br>rho = 0.491<br>p = 0.319<br>p = 0.313<br>p = 0.368<br>p = 0.180<br>rho = 0.112<br>rho = 0.637<br>p = 0.637<br>rho = 0.210<br>p = 0.375<br>rho = 0.252<br>p = 0.284<br>rho = 0.118<br>p = 0.620<br>p = 0.428<br>rho = 0.274<br>p = 0.242<br>rho = 0.14</th><th>rho = 0.230<br>p = 0.328<br>rho = -0.079<br>p = 0.741<br>rho = 0.491<br>p = 0.028<br>rho = 0.213<br>p = 0.366<br>p = 0.393<br>rho = 0.086<br>rho = 0.447<br>rho = 0.181<br>p = 0.444<br>rho = 0.211<br>p = 0.372<br>rho = 0.188<br>p = 0.428<br>rho = 0.324<br>p = 0.164<br>rho = 0.11</th><th>rho = 0.305<br>p = 0.191<br>rho = 0.057<br>p = 0.810<br>rho = 0.655<br>p = 0.002*<br>rho = 0.472<br>p = 0.036<br>p = 0.393<br>p = 0.086<br>rho = 0.324<br>p = 0.164<br>rho = 0.421<br>p = 0.064<br>p = 0.265<br>p = 0.620<br>rho = 0.274<br>p = 0.242<br>rho = 0.11</th><th>rho = -0.152<br>p = 0.522<br>rho = 0.038<br>p = 0.873<br>rho = 0.051<br>p = 0.830<br>rho = 0.081<br>p = 0.736<br>p = 0.005<br>p = 0.984<br>rho = 0.008<br>p = 0.972<br>rho = 0.164<br>p = 0.490<br>p = 0.107<br>p = 0.652<br>rho = 0.189<br>p = 0.424<br>rho = 0.22</th><th>rho = 0.043<br>p = 0.857<br>rho = 0.004<br>p = 0.988<br>rho = 0.178<br>p = 0.453<br>rho = 0.096<br>p = 0.687<br>rho = 0.216<br>p = 0.360<br>rho = 0.156<br>p = 0.511<br>rho = 0.179<br>p = 0.451<br>rho = 0.179<br>p = 0.449<br>rho = 0.217<br>p = 0.359<br>rho = 0.004<br>p = 0.987<br>rho = 0.083<br>p = 0.728</th></tr><tr><th>Impulsive</th><th>Caudate nuclei</th><th>Nuclei accumbens</th><th>Putamen</th><th>Executive cerebellum</th><th>Anterior Cingulate<br>Syri</th><th>DLPFC</th><th>VMPC</th><th>OFC</th><th>Regulatory<br>Insula</th></tr></thead><tbody><tr><td>Amygdala</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Caudate nuclei</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Nuclei accumbens</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Putamen</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Reflective</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Executive cerebellum</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Anterior Cingulate</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Syri</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>DLPFC</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>VMPC</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>OFC</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Regulatory</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>

AUD: patients with alcohol use disorder; HC: healthy controls; BIS-11: Barratt Impulsiveness Scale 11th version; UPPS: short version of the UPPS-P; DLPFC: dorsolateral prefrontal cortex; VMPC: ventromedial prefrontal cortex; OFC: orbitofrontal cortex.

*: Significant result for a threshold set at $p \le 0.017$

significant correlation between impulsivity measures and the GM volumes of regions described as sustaining the reflective component. These results, which are not in accordance with previous investigations [12,14,17,56], suggest that in recently detoxified sAUD inpatients, self-reported impulsivity may not be the result of structural abnormalities in brain regions underlying the reflective subcomponent. The impulsivity expressed by the patients through a questionnaire would not therefore be the direct consequence of a dysexecutive syndrome. This is in line with the triadic model, which postulates the existence of independent impulsive and reflexive sub-components [7–9]. However, it should be borne in mind that self-reported impulsivity is only one part of the concept of impulsivity and may be subject to bias. Objective tasks have also been proposed to assess impulsivity [10]. Different results could be obtained using such measures of impulsivity but these tasks require executive abilities and their use may thus lead to circular reasoning when the goal is to examine the links between impulsivity and brain regions underlying the reflective subcomponent of the triadic model [10]. In clinical practice, impulsivity should be assessed in a way that is not limited to subjective questionnaire measures on the one hand and objective tasks on the other. This would make it possible to capture the different facets of impulsivity [10,57].

The regulatory sub-component is underpinned by the insula, theoretically involved in craving [8,23]. We confirm shrinkage of the insula [11,19,46,48] but we did not find any significant correlation between the insular volume and impulsivity. Conflicting results have been found in healthy young drinkers [58], in AUD patients [59], and in healthy or obese adults [60] with significant (either positive or negative) or insignificant correlations [56]. Our data suggest that impulsivity may mainly be related to reward, whereas craving would be primarily associated to compulsivity [2,47]. Some authors propose to differentiate reward craving from relief craving, the first one being preferentially linked to impulsivity and the second to compulsivity [53,61,62].

The present study has several methodological considerations. Because of the relatively small sample size, our investigation should be considered as exploratory which guided our choice of correction method. Our results should be replicated in further studies with larger and more gender-balanced samples. All sAUD patients were men, which is representative of the gender distribution in addiction department in France but does not allow to generalize to women not least because alcohol appears to have a gender-differentiated effect on the brain [16]. We chose to focus on subjective measures of impulsivity, using the tools most used in clinical practice and based on different models. However, the subjective nature of impulsivity measures illustrates the patients’ perception of their functioning but it may have induced a declarative bias or be related to metacognitive abilities [63]). The present study complements previous investigations that used behavioral impulsivity tasks. In the future, it would be important to use both self-reported and behavioral measures within the same study to better disentangle the contribution of the different sub-components of the triadic system to the different facets/dimensions of impulsivity in sAUD patients. The cross-sectional nature of the study means that it is not possible to conclude whether there is a causal relationship. Longitudinal studies or studies in other populations (binge, other substances, behavioral addictions) would be interesting. Finally, our neuroimaging analyses are limited to the grey matter volume. It could be interesting to study the structural and functional connectivity between the regions of the triadic model.

To sum-up, self-evaluated impulsivity was specifically related to the volume of the regions underpinning the impulsive subcomponent of the neurocognitive triadic model of addiction, which is in ligne with an independent functioning of the impulsive subcomponent with regard to the reflective and regulatory subcomponents [7–9]. The ventral striatum (nucleus accumbens) seems to play a key role in self-evaluated impulsivity, in accordance with the impulsive/compulsive model of AUD [47].
## Role of the funding source

This work was supported by the Conseil Régional de Normande and Agence Nationale de la Recherche (ANR).

The funding source had no role in the study design, collection, analysis or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication.

## CRediT authorship contribution statement

**Cabé Nicolas:** Writing – review & editing, Writing – original draft, Visualization, Validation, Resources, Methodology, Formal analysis, Conceptualization. **segobin Shailendra:** Writing – review & editing, Software, Methodology, Formal analysis, Data curation. **PITEL Anne Lise:** Writing – review & editing, Supervision, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Conceptualization. **Boudehent Céline:** Writing – review & editing, Resources, Methodology. **Laniepce Alice:** Writing – review & editing, Resources, Methodology.

## Declaration of Competing Interest

none

## Appendix A. Supporting information

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.bbr.2025.115452.

## Data availability

Data will be made available on request.

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