Pharmacologically altered Androgens, Brain Activation and Response Inhibition in a Stop-Signal Task in Male Heavy Drinkers

Pharmacologically altered Androgens, Brain Activation and Response Inhibition in a Stop-Signal Task in Male Heavy Drinkers | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Pharmacologically altered Androgens, Brain Activation and Response Inhibition in a Stop-Signal Task in Male Heavy Drinkers Sarah Gerhardt, Rafat Boroumand-Jazi, Sabine Hoffmann, Christiane Muhle, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8347303/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Heavy episodic drinking (HED) is highly prevalent in men and a major risk factor for Alcohol Use Disorder (AUD). Previous studies indicated an influence of testosterone (T) on AUD, and dihydrotestosterone (DHT) was linked to alcohol consumption, impulsivity, and response inhibition. As the role of androgens in AUD and the modulation thereof is not fully understood, this study investigated the effect of a pharmacological reduction in DHT by inhibition of the 5-alpha reductase II through finasteride on brain activation and response inhibition during a stop signal task. Fifty males with HED participated in a randomized, placebo-controlled, double blind, cross-over, functional magnetic resonance imaging (fMRI) study. Participants received either 5mg finasteride or placebo. Full factorial (fMRI) and linear mixed were used to estimate whole-brain effects of DHT and T following finasteride and placebo on neural correlates of behavioral control ( N = 45 analyzable participants). Lower levels of DHT and higher levels of T were related to stronger neural activation in temporal regions during response inhibition for successful or unsuccessful stop-trails, respectively. However, no significant influence of hormone levels on behavioral data of the stop signal task was observed. Although the precise mechanisms underlying the effects of pharmacologically altered DHT levels on neural correlates of response inhibition remain unresolved, both DHT and T appear to be specifically associated with neural activation during response inhibition. These findings stimulate the development of novel therapeutic approaches and treatment options based on pharmaceutical modulation of androgens addressing problem drinking, and possibly AUD. Health sciences/Diseases/Psychiatric disorders/Addiction Health sciences/Diseases/Psychiatric disorders Health sciences/Diseases/Psychiatric disorders/Addiction Health sciences/Diseases/Psychiatric disorders Figures Figure 1 Figure 2 Introduction Alcohol consumption is considered a significant health issue worldwide, and sex differences are recognized regarding prevalence of alcohol consumption and alcohol use disorder (AUD). Even though the gap between men and women is narrowing, 56.5% of men in Europe above the age of 15 years reported heavy drinking episodes (HED, defined as consuming at least 60 grams of pure alcohol on one drinking occasion at least once per month, [ 1 ]), as compared to 24.5% of the women. HED constitutes a major risk factor of AUD, as about 42% of individuals with HED develop AUD [ 2 ]. A multifactorial etiology of the disorder is assumed, and several studies implicated an important contribution of sex hormones. A systematic review observed that both, higher blood or salivary levels of testosterone (T), are generally related to higher levels of alcohol consumption [ 3 ]. Likewise, higher total blood T levels are associated with increased risk of alcohol use [ 3 ]. Male patients with AUD further have significantly higher levels of T than healthy controls [ 4 ]. Additionally, dihydrotestosterone (DHT), the activated derivative of T in the human body, is related to problematic alcohol consumption [ 5 ]. DHT is up to six times more potent than T, as it binds more strongly to the androgen receptor [ 6 ]. An increase in DHT levels during acute withdrawal treatment has been found to predict a worse 12-month outcome in male and female patients with AUD in terms of more and earlier alcohol-related hospital readmissions [ 5 ]. Nave and colleagues [ 7 ] showed that higher T levels also correlate with lower impulse control and impaired decision-making in healthy males. Impulsivity, as the overarching construct of impulse control, and response inhibition as an endophenotype thereof [ 8 , 9 ], have been shown to play an important role in the initiation and continuation of alcohol use and the development of AUD, for example by influencing the ability to inhibit unwanted behaviors [ 10 , 11 ]. The most widely used task to assess response inhibition, as well as its neural correlates thereof, is the stop signal task [ 12 ]. Functional magnetic resonance imaging (fMRI) studies using the SST observed that patients with AUD show less activation of regions responsible for impulse control, e.g., caudate [ 13 ]; opercular part of the inferior frontal gyrus [ 14 ]; subgenual anterior cingulate cortex [ 15 ]; anterior insula [ 16 ]. The role of androgens in the onset and progression of AUD as well as the underlying mechanisms such as neural correlates of response inhibition still remain unclear. Previous studies have demonstrated a negative impact of alcohol consumption on response inhibition and its neural correlates [ 13 – 16 ]. Likewise, the relationships of higher T levels and less inhibitory control as well as higher alcohol consumption are acknowledged [ 7 , 10 ]. This leads to the assumption that lower levels of DHT (the potent derivative of T) might positively influence behavioral control in individuals with HED via underlying neural mechanisms [ 17 ]. The present study explores the effects of lowered DHT levels induced by pharmacological inhibition of 5-alpha reductase II by finasteride on neural and behavioral correlates of response inhibition in males with HED. A recent study reported reduced alcohol intake in heavy drinking males under treatment with dutasteride, another 5-alpha reductase inhibitor [ 18 ], supporting the need for explaining underlying processes. We thus hypothesize that reduced DHT levels associate with increased neural activation in brain regions related to behavioral control during response inhibition. In exploratory analyses, we further analyze the influence of T levels as a predictor as well as behavioral data during response inhibition as outcome. The study only included males, who exhibit higher absolute levels of T and a more consistent relationship between AUD and T [ 3 ], as well as AUD and DHT [ 5 ], as compared to females. Materials and Methods Study design and participants This randomized, placebo-controlled, double-blind, crossover finasteride challenge experiment was part of the TRR 265 A08 project funded by the German Research Foundation [ 19 ]. Recruitment of the preregistered study (DRKS00020569) was conducted between February 2022 (first study visit) and February 2023 (last study visit). Ethics approval was obtained from the local ethics committee II of Heidelberg University, Germany (approval number 2021 − 654). For the recruitment of participants, a databank of participants from the TRR265 was used, and an advertisement was sent via e-Mail to students at the University of Mannheim. N = 50 males aged between 18 and 65 year were included in the study, if they (1) had a body mass index between 18.5 and 30 kg/m 2 , (2) were able to provide written informed consent after having received detailed information, (3) fulfilled the criteria for heavy drinking episodes according to the World Health Organization (i.e., a minimum of 60g of pure alcohol on a single occasion at least once per month), (4) were able to undergo fMRI measurements, and (5) met the requirements for the intake of a single dose of 5 mg of finasteride. For additional exclusion criteria, see supplementary material 1. Participants were invited to four study visits (V1 – V4, see Fig. 1 ). At V1, written informed consent was obtained, inclusion and exclusion criteria were checked, and participant information (sociodemographic information, substance use) were assessed. Participants were then randomized either to the finasteride – placebo or the placebo – finasteride sequence group. V1 and V2 took place on two subsequent days. After a washout phase of 21 to 42 days, V3 and V4 took place on two subsequent days as well. Time point V4 was matched to V2 in terms of daytime. Participants received either placebo or 5 mg of finasteride at V1 and V3. At V2 and V4, fMRI measurements were conducted. Blood samples were drawn at all four visits to assess DHT und T hormone levels. After the completion of the study of the last participant, data was preprocessed prior to obtaining the randomization list to unblind the data. [Figure 1 ] Psychometric measurements Psychometric measures included the Alcohol Use Disorder Identification Test at V1 and V3 (AUDIT; [ 20 ]; retest reliability .86 [ 21 ]) and the Barratt Impulsiveness Scale at V1 (BIS; [ 22 ]; good intrascale reliability of .82; [ 23 ]). Medication At V1 and V3, 5 mg of finasteride [ 24 ] or placebo were administered. By mainly inhibiting the 5-alpha reductase II enzyme, which is necessary for the transformation of T into its more potent derivative DHT, administration of finasteride has been suggested to decrease serum DHT levels by approximately 80% within approximately one to two days for up to one to two weeks [ 24 , 25 ]. A systematic review on finasteride did not observe changes in T levels after the intake of finasteride, while DHT levels were significantly decreased in men and women [ 26 ]. Finasteride can remain functionally active after single administration for up to 21 days [ 24 ]. Stop Signal Task The SST [ 14 , 27 ] was administered during an fMRI examination to assess response inhibition. During the task, participants responded to arrows pointing right or left by pressing the corresponding key on a remote control in their hand with their respective thumb. In 20% of trials, a ‘stop’ signal in form of an arrow pointing upwards appeared shortly after the arrow pointing right or left, requiring the participant to inhibit an initiated reaction of pressing a key [ 28 ]. In total, the SST lasted 10:39 minutes and included 320 ‘go’ and 80 ‘stop’ trials (see supplementary material 6 for more details about the task). Functional MRI acquisition While performing the SST, 725 brain scans were acquired in a 3T whole-body tomograph at the Central Institute of Mental Health in Mannheim (MAGNETOM 3.0T XR Numaris, Siemens Medical Systems, Erlangen, Germany) using T2*-weighted multi-band echo-planar imaging (mb-EPI) sequences (repetition time (TR) = 869 ms, echo time (TE) = 38 ms, flip angle = 58°, 60 slices, slice thickness 2.4 mm, voxel dimensions 2.4 × 2.4 × 2.4 mm 3 , no inter-slice gap, field of view (FOV) = 210 × 210 mm 2 , matrix size 88 × 88 in-plane resolution, acquisition orientation T > C with 20° clockwise to anterior commissure – posterior commissure (AC-PC) line, interleaved slice order, acceleration factor slice = 6, flip angle = 58°, bandwidth = 1832 Hz/Px, prescan normalize, weak raw data filter, LeakBlock kernel, fat sat). Blood sampling and hormonal analysis To assess levels of DHT and T at each study visit, venous blood samples were collected and concentrations were quantified in serum aliquots stored at -80°C. Androgens were determined using a competitive enzyme-linked immunosorbent assay (ELISA) specified as follows (with indicated serum volumes in duplicates, standard ranges and achieved intra- and inter-assay coefficients of variation (cv)): 5a-Dihydrotestosterone ELISA (DB52021; IBL International GmbH, Hamburg, Germany; 50 µl, standard 6-2500 pg/ml, 1.5%, 2.2%) and Testosterone ELISA (DRG-EIA-1559; DRG Instruments GmbH, Marburg, Germany; 25 µl, standard 0,1–16 ng/ml, 1.9%, 3.4%). Statistical analyses A-priori sample size estimation was based on a previous publication examining inhibitory control in a placebo-controlled cross-over design using the SST in N = 50 alcohol consuming individuals [ 14 ] and previous studies with moderate to large treatment effect size of d = 0.71 and a power of 80% examining pharmacological effects in individuals with AUD (alpha = .05 [ 29 , 30 ]). SPSS (Statistics for Windows, Version 29.0. IBM Corp., Armonk, NY, USA) was used to perform descriptive and statistical analyses. Linear mixed models analyzed behavioral data within the cross-over experimental study design. These analyses accounted for the nested structure of the data, as data from two measurement time points, T1 and T2, were available per participant. Separate mixed models were computed for the dependent variables, stop signal delay (SSD), go reaction time (RT), stop signal reaction time (SSRT, calculated with mean GoRT). We first analyzed models including only hormone level (DHT or T after intake of medication or placebo) and age along with the dependent variables. Then, the factors time point (V2 and V4), medication (finasteride or placebo), and sequence (finasteride first or placebo first) were added to the linear mixed models. fMRI pre-processing and first-level fMRI analyses fMRI data was preprocessed in SPM12 (Statistical Parametrical Mapping; Wellcome Centre for Human Neuroimaging, at University College, London, UK) using a standardized pipeline including slice timing, spatial realignment, normalization (template: SPM12 tissue probability map according to the Montreal Neurological Institute), and spatial smoothing (Gaussian kernel of 8mm full width at half maximum). Quality checks were performed and individuals with excessive head movement (> 3 mm/3°) or other artefacts were excluded from further analyses (see supplementary material 2). On the first level (single subject), the obtained and pre-processed data were analyzed by modeling the three contrasts: ‘stop success’, ‘stop error’, and ‘stop success vs. stop error’. This involved examining neural reactivity during successful and unsuccessful response inhibition, as well as the difference in reactivity between successful and unsuccessful inhibition. To this end, convolution with the canonical hemodynamic response function was performed, a high-pass filter (with a cutoff at 128 s) was applied, and a general linear model (GLM) was calculated on a voxel-by-voxel basis, including the task condition and six motion regressors. fMRI whole brain analyses Prior to the hypothesis-driven analyses, a whole brain one-sample t -test using data from the placebo intervention was conducted in SPM12 to confirm the successful implementation of the SST paradigm (contrasts ‘stop success’, ‘stop error’, and ‘stop success vs. stop error’). The time point of measurement (T1/T2 referring to V2/V4) was entered as covariate. To test our hypothesis and to account for the cross-over design of the study, flexible factorial models were then calculated in SPM12 separately for each of the three contrast. Subject, time point (V2 and V4), medication (finasteride or placebo), and sequence (finasteride first or placebo first) were included as factors. Individual DHT or T levels were included as covariates. For exact contrast specification, see supplementary material 3. Age was added as a covariate to all models, as brain activation is known to significantly differ depending on age in the context of response inhibition [ 31 ]. To account for multiple testing, the analyses were corrected combing a voxel-wise-threshold of p < 0.001 with a cluster-extend-threshold determined with random field theory in SPM12 corresponding to a family-wise error (FWE)-rate of pFWE < 0.05. Results Sample characteristics Eighty-five eligible participants were invited to participate in the study and a total of 50 participants were randomized to either the finasteride – placebo or the placebo – finasteride sequence. fMRI data was available from 47 participants (see CONSORT flow diagram, supplementary material 2 for more details regarding allocation and exclusion). No severe adverse events were reported following intake of finasteride or placebo. Participants were on average 34.8 years old (SD = 14.0). They exhibited a mean AUDIT sum score of 10.9 (SD = 4.9) indicating a hazardous and harmful consumption of alcohol. BIS scores (M = 29.9, SD = 5.5) were similar to those of a normative sample (M = 30.0, SD = 6.1). For additional sociodemographic data, see Table 1. No significant group differences regarding the medication sequence (finasteride or placebo first) were observed at baseline (see supplementary material 4). DHT levels were significantly reduced by 9.6% as compared to placebo (from 353 to 318 pg/mL on average; F (1, 42.02) = 12.50, p = .001). No significant change in T levels was observed ( F (1, 42.24) = 1.05, p = .311)). [Table 1] fMRI results fMRI whole brain analyses The stop-signal paradigm was successfully applied, as demonstrated by the placebo only analyses, see Supplementary Table 3. Percentage of stop success rate varied between 40 und 60% indicating an adequate performance during the task. The full factorial models including DHT or T as a covariate of interest yielded a significant influence of both, DHT and T, on individual neural reactivity, see Table 2 and Figure 2. Regarding the influence of DHT, a negative association was observed in left temporal regions for the contrast ‘stop error’. A positive relation was observed regarding T in right temporal regions for the contrast ‘stop success’. There was also a positive relation observed for several regions regarding the contrast stop success > stop error, which is difficult to interpret as the significance for this contrast could be driven by higher activation during stop success or lower activation during stop error. No significant effect of medication was observed. [Table 2] [Figure 2] Behavioral results The linear mixed models including with and without the factors time point, medication and sequence, as well as DHT or T did not yield significant results with respect to behavioral measures (SSRT, go RT, SSD), except for an effect of age on the mean reaction times in go trials. Please see Supplementary Table 4 for more details. Discussion Previous research demonstrated an association between impaired response inhibition and higher alcohol, between impaired response inhibition and higher androgen levels, as well as between higher alcohol consumption and higher androgen levels. We demonstrated an association between lower DHT concentrations and higher activation in left temporal brain regions during a failure to inhibit. Additionally, we also observed that higher T levels related to higher activation in right temporal regions during successful inhibitions. No significant findings were observed for behavioral variables. In previous studies, patients with AUD showed increased activation in the middle temporal gyrus [ 32 ] and decreased gray matter volume in this area compared to HCs [ 33 ]. Right temporal regions, such as the right middle temporal gyrus,, have been implicated in behavioral inhibition studies using the SST [ 14 , 34 ], and have further been found to be activated in inhibition studies using no-go trials [ 35 ]. The middle temporal gyrus has been connected to alcohol-induced impaired functioning in the SST [ 14 ]. The left side of the middle temporal gyrus is not typically related to response inhibition. However, fetal androgen level (T) was found to predict grey matter volumes in the left middle temporal gyrus [ 36 ], making it seem likely that the activation of the left middle temporal gyrus in our study is driven by mechanisms related to T and DHT. Following the observation by Moffat and Resnick in older men [ 37 ], higher free T levels could be associated with increased cerebral blood flow in our sample. Previous research indicates different regional responses for the contrasts ‘stop success’ and ‘stop error’ [ 38 ] and distinct neural networks for stop success and stop error trials have been suggested [ 39 ]. In agreement with our results, the right middle temporal gyrus forms a part of the network accounting for most variance in stop success trials as the right hemispheric network is more involved in attention to the stop signal, whereas the left hemispheric network is involved in response inhibition [ 39 ]. Thus, our findings provide first evidence for an interaction of specific androgens with distinct neural processes during the SST, i.e., an influence of T during attention to the stop signal (as supported more from the right hemisphere), and an influence of DHT during response inhibition (as supported more from the left hemisphere). In line with this argumentation, T has been found to correlate positively with activation during spatial tasks and mental rotation in fMRI studies [ 17 ], tasks which also involve attention. This study is the first to examine the role of DHT and the intertwining of androgens and inhibitory control in heavily drinking individuals. Thus, interpretations often need to infer from findings on effects of T and further examination is warranted, e.g., using spectroscopy neuroimaging methods as well as confirmatory studies, as research on DHT mechanisms is still sparse. Hence, several aspects merit attention in this context: First, mechanisms underlying androgen effects, especially DHT and its reduction through finasteride, are still unclear, and as chronic alcohol consumption can lead to aromatization of androgens and T is metabolized to estradiol [ 40 ], it is possible that estradiol, which has also been suggested to play a role in problem drinking of males [ 41 , 42 ], partly mediated the influence of T in our study. Contrarily, DHT as the more potent derivative of T therefore solely reflects an androgen-effect. Second, finasteride may not only exert its effects via the mechanism of 5-alpha reductase inhibition. Diviccaro and colleagues [ 43 ] stated that finasteride does not only alter neuroactive steroid levels themselves but also their mechanisms of action. Indeed, finasteride acts on dopaminergic neurotransmitter systems, e.g. by blocking the effects of dopamine receptors in the mesolimbic system [ 44 ], and influences the inhibitory neurotransmitter system modulated by gamma-aminobutyric acid [ 45 ]. Interestingly, previous research also suggested that finasteride interferes with functioning of the hypothalamus-pituitary-adrenal axis and thus impairs stress reactivity and reduces impulsive behavior [ 46 ]. Third and while the specific mechanisms are still not clear, additional neural regions have previously been connected to behavioral inhibition, androgens and/or alcohol consumption. For instance, a significant association between higher T levels and greater grey matter thickness in male adolescents were observed in the calcarine sulcus [ 47 ], an area known to contain a high number of androgen receptors [ 47 ], and sensitive to chronic effects of alcohol [ 48 ]. The supplementary motor area (SMA) is frequently associated with inhibition, showing greater activation during successful inhibition in a group with shorter SSRTs [ 49 ]. In healthy adults, the preSMA is generally more active during successful stopping [ 50 ]. Hu and colleagues [ 51 ] observed significantly greater activation in the preSMA in participants with AUD than in healthy controls during expectation of a stop signal - which they suggested to be a compensatory mechanism for cognitive control. Lastly, T has been shown to influence uncertain social situations by acting on interpersonal trust via neuropeptide systems, thereby increasing social vigilance [ 52 ], thus indicating learning effects or neuroplasticity processes. Speculatively, finasteride could have triggered processes influencing social behavior in the unknown experimental situation. As vigilance is a key component of behavioral inhibition [ 53 ], the androgen effect of finasteride on social behavior might have influenced neural activation in the SST. Further, alcohol is used to facilitate social interaction [ 54 , 55 ] and modulation of DHT by alcohol use has been suggested as an underlying mechanism [ 56 ]. However, a previous study demonstrated that learning effects, in case of performing the SST multiple times, are not likely [ 57 ]. Likewise, a pharmacological carry-over effect could be excluded, as the second examination day took place after at least 21 days; finasteride can remain functionally active after single administration for one to two weeks [ 24 ]. Limitations As previous research on the effect of 5-alpha reductase inhibition by finasteride on brain activation is very scarce, our findings are based on exploratory considerations. While in our sample a significant reduction of DHT after administration of finasteride was observed, the relative reduction was estimated at 9.6% on average, thus being smaller than the expected 80% [ 24 ]. The resulting effect on behavioral and neural activity might thus have been too small to be detected in our sample (N = 45) and finasteride might have a generally smaller effect on neural activation during response inhibition in males with HED than expected. Additionally, the test-retest reliability of the SST varies according to task contrast and brain region [ 58 ], which might interfere with possible small medication effects. Finally, we included only male subjects with HED. More research in larger samples is necessary to examine the effect of 5-alpha reductase inhibition by finasteride on brain activation in females and in other specific populations (i.e., AUD and HC), as well as additional mechanisms underlying the effect of finasteride on neural activity during response inhibition. Clinical implications The high prevalence of HED [ 59 ] and the fact that it is considered a major risk factor for AUD [ 2 ] underline the importance of developing novel preventive and therapeutic approaches. While a previous study reported positive effects of an inhibitor of 5-alpha reductase enzymes on abstinence and drinking outcomes in heavily drinking males [ 18 ], our study demonstrated a potential therapeutic approach as the pharmacological modulation of DHT influences neural correlates of response inhibition. However, the clinical and therapeutic potential of finasteride needs to examined further. Conclusion We observe distinct relations of DHT and T levels with activation patterns of temporal regions during a task measuring behavioral inhibition. These regions are involved in response inhibition, alcohol consumption, and androgen mechanisms, and results may point towards a role of DHT and T in distinct hemispheric networks during the task. Though with warranted precaution in interpretation, the results of this study can guide future research with respect to understanding the mechanisms of androgens, especially DHT and T (and the DHT-to-T ratio), more deeply, and developing novel therapeutic approaches and treatment options based on pharmaceutical modulation of androgens. Declarations Data availability statement The data that support the findings of this study are available on request from BL or the corresponding author SG. Acknowledgements : We thank Johanna Klein, Luke Bregulla, and Pauline Salg for their assistance with the collection of the experimental data and Sarah Sheldrick for support with hormone quantification. Authors contributions: Designed the current study: MK, RBJ, FK, BL, SG. Analyzed the data: MK, SG. Supported the data analysis: SH, CM, IR, HT, PB, SVK, BL. Interpreted the data: MK, SH, PB, SVK, BL, SG. Wrote the paper: MK and SG. Supported the writing of the paper: BL. Procured the funding of the original studies: BL. Commented on the manuscript and provided intellectual input: MK, RBJ, SH, CM, IR, MR, LW, HT, PB, SVK, GWA, FK, BL, SG. Funding : The project was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project-ID 402170461 – TRR265 (Heinz et al. 2021; Spanagel et al. 2024). The funders had no role in the study design, data collection, analysis, decision to publish, or preparation of the manuscript. Competing interests : The authors have no competing interests to declare. Ethics approval and patient consent statement : Ethics approval was obtained from the local ethics committee II of Heidelberg University, Germany (approval number 2021-654). Written informed consent was obtained was obtained from all participants prior to study participation. Clinical trial registration : DRKS00020569; https://drks.de/search/de/trial/DRKS00020569 References WHO (2018). Global status report on alcohol and health 2018. Linden-Carmichael, A.N., Vasilenko, S.A., Lanza, S.T. and Maggs, J.L. (2017). High-Intensity Drinking Versus Heavy Episodic Drinking: Prevalence Rates and Relative Odds of Alcohol Use Disorder Across Adulthood. Alcoholism: Clinical and Experimental Research, 41 (10), 1754-1759. doi:10.1111/acer.13475 Erol, A., Ho, A.M.C., Winham, S.J. and Karpyak, V.M. (2019). Sex hormones in alcohol consumption: a systematic review of evidence. 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Unbiased nonlinear average age-appropriate brain templates from birth to adulthood. NeuroImage, 47 , S102. doi:https://doi.org/10.1016/S1053-8119(09)70884-5 Tables Table 1 Sample characteristics at V1 M SD % of sample N Age 33.5 13.5 High school diploma (“Abitur”) 70 33 Employment in the last three months 94 44 Single/divorced/living apart : married/in relationship 70 : 30 35 : 14 Having children (yes) 34 16 Smokers 36 17 AUDIT (sum score) 11.3 5.0 BIS (sum score) 30.1 5.4 Note. M , mean. N , Number. SD , standard deviation. AUDIT , Alcohol Use Identification Test. BIS , Barratt Impulsiveness Scale. Heavy drinking days were defined as consuming at least 60g of alcohol per drinking occasion. Table 2 Results from the full factorial fMRI analysis with factors subject, time point, sequence, and medication, including hormone levels as covariate of interest and age as covariate of no interest Predictor Peak MNI-Coordinates x y z Brain area Nr. of voxels k Peak-Level t (74) Cluster-Level p FWE-corrected Stop error Absolute DHT - -48 -22 -6 Middle temporal gyrus L 353 4.75 .005 Sequence (Placebo first < Finasteride first) -20 -74 14 Calcarine sulcus L, lingual gyrus L 927 4.41 stop error Absolute DHT + -48 -22 -6 -2 -86 4 56 -20 4 -28 -32 38 Middle temporal gyrus L Calcarine sulcus L, lingual gyrus L, cuneus L Superior temporal gyrus Postcentral gyrus L 282 587 386 535 4.65 4..23 4.36 4.34 .016 <.001 .003 <.001 Stop success Absolute T + 54 -78 12 Middle temporal gyrus R 321 4.34 .004 Sequence (Placebo first T2) 16 -10 6 Thalamus R 210 4.96 .033 Note . + implicates positive prediction of brain activation; - implicates negative prediction of brain activation. Only activated areas of significant voxel size in relation to total voxel size of a cluster are reported. Brain areas correspond to the Aal3 atlas (automated anatomic labelling atlas 3 [60]). L , left. R , right. No specification, both R and L. MNI-Coordinates , Montreal Neurological Institute [61]. An uncorrected threshold of p < 0.001 in combination with a cluster-extend threshold of (a) 353 voxels and (b) 321 voxels was used, corresponding to pFWE < 0.05. Additional Declarations The authors have declared there is NO conflict of interest to disclose Supplementary Files Kundlacz2025SSTAndrogensSupplement.docx Suppelmentary Material Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Visit 2 and 3 were scheduled with a washout phase of 21-42 days in between (M 25.8, SD 6.7 days).\u003c/p\u003e","description":"","filename":"Figure1300dpi.png","url":"https://assets-eu.researchsquare.com/files/rs-8347303/v1/4aea4e179643183c4a6bd567.png"},{"id":100366371,"identity":"e143633b-b2e1-4a8b-87d6-ec22dd76fbd2","added_by":"auto","created_at":"2026-01-16 07:56:17","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":288223,"visible":true,"origin":"","legend":"\u003cp\u003e(a) lower levels of DHT were associated with higher activation in left temporal regions for the contrast ‘stop error’. (b) higher levels of T were associated with higher activation in right temporal regions for the contrast ‘stop success’.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNote\u003c/em\u003e: N = 45. An uncorrected threshold of p \u0026lt; 0.001 in combination with a cluster-extend threshold of (a) 353 voxels and (b) 321 voxels was used, corresponding to pFWE \u0026lt; 0.05. Coordinates: (a) xyz [-48, -22, -6], (b) xyz [54, -78, 12].\u003c/p\u003e","description":"","filename":"Figure2300dpi.png","url":"https://assets-eu.researchsquare.com/files/rs-8347303/v1/5d6981ed252a3f3b39e35f34.png"},{"id":103049358,"identity":"0e31114e-05a9-469b-b872-d81ac1eadde5","added_by":"auto","created_at":"2026-02-20 07:40:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1367568,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8347303/v1/79cd69bb-1ede-47e3-a8f4-340fcdf0e688.pdf"},{"id":100110734,"identity":"c92fbcce-9db8-4e13-8ffd-d52fc1ac127e","added_by":"auto","created_at":"2026-01-13 06:26:31","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":181502,"visible":true,"origin":"","legend":"Suppelmentary Material","description":"","filename":"Kundlacz2025SSTAndrogensSupplement.docx","url":"https://assets-eu.researchsquare.com/files/rs-8347303/v1/df7e07419e8cea7d7c39ab64.docx"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose","formattedTitle":"Pharmacologically altered Androgens, Brain Activation and Response Inhibition in a Stop-Signal Task in Male Heavy Drinkers","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAlcohol consumption is considered a significant health issue worldwide, and sex differences are recognized regarding prevalence of alcohol consumption and alcohol use disorder (AUD). Even though the gap between men and women is narrowing, 56.5% of men in Europe above the age of 15 years reported heavy drinking episodes (HED, defined as consuming at least 60 grams of pure alcohol on one drinking occasion at least once per month, [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]), as compared to 24.5% of the women. HED constitutes a major risk factor of AUD, as about 42% of individuals with HED develop AUD [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA multifactorial etiology of the disorder is assumed, and several studies implicated an important contribution of sex hormones. A systematic review observed that both, higher blood or salivary levels of testosterone (T), are generally related to higher levels of alcohol consumption [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Likewise, higher total blood T levels are associated with increased risk of alcohol use [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Male patients with AUD further have significantly higher levels of T than healthy controls [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Additionally, dihydrotestosterone (DHT), the activated derivative of T in the human body, is related to problematic alcohol consumption [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. DHT is up to six times more potent than T, as it binds more strongly to the androgen receptor [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. An increase in DHT levels during acute withdrawal treatment has been found to predict a worse 12-month outcome in male and female patients with AUD in terms of more and earlier alcohol-related hospital readmissions [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNave and colleagues [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] showed that higher T levels also correlate with lower impulse control and impaired decision-making in healthy males. Impulsivity, as the overarching construct of impulse control, and response inhibition as an endophenotype thereof [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], have been shown to play an important role in the initiation and continuation of alcohol use and the development of AUD, for example by influencing the ability to inhibit unwanted behaviors [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The most widely used task to assess response inhibition, as well as its neural correlates thereof, is the stop signal task [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Functional magnetic resonance imaging (fMRI) studies using the SST observed that patients with AUD show less activation of regions responsible for impulse control, e.g., caudate [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]; opercular part of the inferior frontal gyrus [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]; subgenual anterior cingulate cortex [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]; anterior insula [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The role of androgens in the onset and progression of AUD as well as the underlying mechanisms such as neural correlates of response inhibition still remain unclear. Previous studies have demonstrated a negative impact of alcohol consumption on response inhibition and its neural correlates [\u003cspan additionalcitationids=\"CR14 CR15\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Likewise, the relationships of higher T levels and less inhibitory control as well as higher alcohol consumption are acknowledged [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This leads to the assumption that lower levels of DHT (the potent derivative of T) might positively influence behavioral control in individuals with HED via underlying neural mechanisms [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe present study explores the effects of lowered DHT levels induced by pharmacological inhibition of 5-alpha reductase II by finasteride on neural and behavioral correlates of response inhibition in males with HED. A recent study reported reduced alcohol intake in heavy drinking males under treatment with dutasteride, another 5-alpha reductase inhibitor [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], supporting the need for explaining underlying processes.\u003c/p\u003e \u003cp\u003eWe thus hypothesize that reduced DHT levels associate with increased neural activation in brain regions related to behavioral control during response inhibition. In exploratory analyses, we further analyze the influence of T levels as a predictor as well as behavioral data during response inhibition as outcome. The study only included males, who exhibit higher absolute levels of T and a more consistent relationship between AUD and T [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], as well as AUD and DHT [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], as compared to females.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and participants\u003c/h2\u003e \u003cp\u003eThis randomized, placebo-controlled, double-blind, crossover finasteride challenge experiment was part of the TRR 265 A08 project funded by the German Research Foundation [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Recruitment of the preregistered study (DRKS00020569) was conducted between February 2022 (first study visit) and February 2023 (last study visit). Ethics approval was obtained from the local ethics committee II of Heidelberg University, Germany (approval number 2021\u0026thinsp;\u0026minus;\u0026thinsp;654). For the recruitment of participants, a databank of participants from the TRR265 was used, and an advertisement was sent via e-Mail to students at the University of Mannheim.\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;50 males aged between 18 and 65 year were included in the study, if they (1) had a body mass index between 18.5 and 30 kg/m\u003csup\u003e2\u003c/sup\u003e, (2) were able to provide written informed consent after having received detailed information, (3) fulfilled the criteria for heavy drinking episodes according to the World Health Organization (i.e., a minimum of 60g of pure alcohol on a single occasion at least once per month), (4) were able to undergo fMRI measurements, and (5) met the requirements for the intake of a single dose of 5 mg of finasteride. For additional exclusion criteria, see supplementary material 1.\u003c/p\u003e \u003cp\u003eParticipants were invited to four study visits (V1 \u0026ndash; V4, see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). At V1, written informed consent was obtained, inclusion and exclusion criteria were checked, and participant information (sociodemographic information, substance use) were assessed. Participants were then randomized either to the finasteride \u0026ndash; placebo or the placebo \u0026ndash; finasteride sequence group. V1 and V2 took place on two subsequent days. After a washout phase of 21 to 42 days, V3 and V4 took place on two subsequent days as well. Time point V4 was matched to V2 in terms of daytime. Participants received either placebo or 5 mg of finasteride at V1 and V3. At V2 and V4, fMRI measurements were conducted. Blood samples were drawn at all four visits to assess DHT und T hormone levels. After the completion of the study of the last participant, data was preprocessed prior to obtaining the randomization list to unblind the data.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e[Figure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e]\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePsychometric measurements\u003c/h3\u003e\n\u003cp\u003ePsychometric measures included the Alcohol Use Disorder Identification Test at V1 and V3 (AUDIT; [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]; retest reliability .86 [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]) and the Barratt Impulsiveness Scale at V1 (BIS; [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]; good intrascale reliability of .82; [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]).\u003c/p\u003e\n\u003ch3\u003eMedication\u003c/h3\u003e\n\u003cp\u003eAt V1 and V3, 5 mg of finasteride [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] or placebo were administered. By mainly inhibiting the 5-alpha reductase II enzyme, which is necessary for the transformation of T into its more potent derivative DHT, administration of finasteride has been suggested to decrease serum DHT levels by approximately 80% within approximately one to two days for up to one to two weeks [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. A systematic review on finasteride did not observe changes in T levels after the intake of finasteride, while DHT levels were significantly decreased in men and women [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Finasteride can remain functionally active after single administration for up to 21 days [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eStop Signal Task\u003c/h3\u003e\n\u003cp\u003eThe SST [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] was administered during an fMRI examination to assess response inhibition. During the task, participants responded to arrows pointing right or left by pressing the corresponding key on a remote control in their hand with their respective thumb. In 20% of trials, a \u0026lsquo;stop\u0026rsquo; signal in form of an arrow pointing upwards appeared shortly after the arrow pointing right or left, requiring the participant to inhibit an initiated reaction of pressing a key [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In total, the SST lasted 10:39 minutes and included 320 \u0026lsquo;go\u0026rsquo; and 80 \u0026lsquo;stop\u0026rsquo; trials (see supplementary material 6 for more details about the task).\u003c/p\u003e\n\u003ch3\u003eFunctional MRI acquisition\u003c/h3\u003e\n\u003cp\u003eWhile performing the SST, 725 brain scans were acquired in a 3T whole-body tomograph at the Central Institute of Mental Health in Mannheim (MAGNETOM 3.0T XR Numaris, Siemens Medical Systems, Erlangen, Germany) using T2*-weighted multi-band echo-planar imaging (mb-EPI) sequences (repetition time (TR)\u0026thinsp;=\u0026thinsp;869 ms, echo time (TE)\u0026thinsp;=\u0026thinsp;38 ms, flip angle\u0026thinsp;=\u0026thinsp;58\u0026deg;, 60 slices, slice thickness 2.4 mm, voxel dimensions 2.4 \u0026times; 2.4 \u0026times; 2.4 mm\u003csup\u003e3\u003c/sup\u003e, no inter-slice gap, field of view (FOV)\u0026thinsp;=\u0026thinsp;210 \u0026times; 210 mm\u003csup\u003e2\u003c/sup\u003e, matrix size 88 \u0026times; 88 in-plane resolution, acquisition orientation T\u0026thinsp;\u0026gt;\u0026thinsp;C with 20\u0026deg; clockwise to anterior commissure \u0026ndash; posterior commissure (AC-PC) line, interleaved slice order, acceleration factor slice\u0026thinsp;=\u0026thinsp;6, flip angle\u0026thinsp;=\u0026thinsp;58\u0026deg;, bandwidth\u0026thinsp;=\u0026thinsp;1832 Hz/Px, prescan normalize, weak raw data filter, LeakBlock kernel, fat sat).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eBlood sampling and hormonal analysis\u003c/h2\u003e \u003cp\u003eTo assess levels of DHT and T at each study visit, venous blood samples were collected and concentrations were quantified in serum aliquots stored at -80\u0026deg;C. Androgens were determined using a competitive enzyme-linked immunosorbent assay (ELISA) specified as follows (with indicated serum volumes in duplicates, standard ranges and achieved intra- and inter-assay coefficients of variation (cv)): 5a-Dihydrotestosterone ELISA (DB52021; IBL International GmbH, Hamburg, Germany; 50 \u0026micro;l, standard 6-2500 pg/ml, 1.5%, 2.2%) and Testosterone ELISA (DRG-EIA-1559; DRG Instruments GmbH, Marburg, Germany; 25 \u0026micro;l, standard 0,1\u0026ndash;16 ng/ml, 1.9%, 3.4%).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eA-priori sample size estimation was based on a previous publication examining inhibitory control in a placebo-controlled cross-over design using the SST in \u003cem\u003eN\u0026thinsp;=\u0026thinsp;50\u003c/em\u003e alcohol consuming individuals [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] and previous studies with moderate to large treatment effect size of d\u0026thinsp;=\u0026thinsp;0.71 and a power of 80% examining pharmacological effects in individuals with AUD (alpha\u0026thinsp;=\u0026thinsp;.05 [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]). SPSS (Statistics for Windows, Version 29.0. IBM Corp., Armonk, NY, USA) was used to perform descriptive and statistical analyses. Linear mixed models analyzed behavioral data within the cross-over experimental study design. These analyses accounted for the nested structure of the data, as data from two measurement time points, T1 and T2, were available per participant. Separate mixed models were computed for the dependent variables, stop signal delay (SSD), go reaction time (RT), stop signal reaction time (SSRT, calculated with mean GoRT). We first analyzed models including only hormone level (DHT or T after intake of medication or placebo) and age along with the dependent variables. Then, the factors time point (V2 and V4), medication (finasteride or placebo), and sequence (finasteride first or placebo first) were added to the linear mixed models.\u003c/p\u003e\n\u003ch3\u003efMRI pre-processing and first-level fMRI analyses\u003c/h3\u003e\n\u003cp\u003efMRI data was preprocessed in SPM12 (Statistical Parametrical Mapping; Wellcome Centre for Human Neuroimaging, at University College, London, UK) using a standardized pipeline including slice timing, spatial realignment, normalization (template: SPM12 tissue probability map according to the Montreal Neurological Institute), and spatial smoothing (Gaussian kernel of 8mm full width at half maximum). Quality checks were performed and individuals with excessive head movement (\u0026gt;\u0026thinsp;3 mm/3\u0026deg;) or other artefacts were excluded from further analyses (see supplementary material 2). On the first level (single subject), the obtained and pre-processed data were analyzed by modeling the three contrasts: \u0026lsquo;stop success\u0026rsquo;, \u0026lsquo;stop error\u0026rsquo;, and \u0026lsquo;stop success vs. stop error\u0026rsquo;. This involved examining neural reactivity during successful and unsuccessful response inhibition, as well as the difference in reactivity between successful and unsuccessful inhibition. To this end, convolution with the canonical hemodynamic response function was performed, a high-pass filter (with a cutoff at 128 s) was applied, and a general linear model (GLM) was calculated on a voxel-by-voxel basis, including the task condition and six motion regressors.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003efMRI whole brain analyses\u003c/h2\u003e \u003cp\u003ePrior to the hypothesis-driven analyses, a whole brain one-sample \u003cem\u003et\u003c/em\u003e-test using data from the placebo intervention was conducted in SPM12 to confirm the successful implementation of the SST paradigm (contrasts \u0026lsquo;stop success\u0026rsquo;, \u0026lsquo;stop error\u0026rsquo;, and \u0026lsquo;stop success vs. stop error\u0026rsquo;). The time point of measurement (T1/T2 referring to V2/V4) was entered as covariate.\u003c/p\u003e \u003cp\u003eTo test our hypothesis and to account for the cross-over design of the study, flexible factorial models were then calculated in SPM12 separately for each of the three contrast. Subject, time point (V2 and V4), medication (finasteride or placebo), and sequence (finasteride first or placebo first) were included as factors. Individual DHT or T levels were included as covariates. For exact contrast specification, see supplementary material 3.\u003c/p\u003e \u003cp\u003eAge was added as a covariate to all models, as brain activation is known to significantly differ depending on age in the context of response inhibition [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. To account for multiple testing, the analyses were corrected combing a voxel-wise-threshold of p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 with a cluster-extend-threshold determined with random field theory in SPM12 corresponding to a family-wise error (FWE)-rate of pFWE\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eSample characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEighty-five eligible participants were invited to participate in the study and a total of 50 participants were randomized to either the finasteride – placebo or the placebo – finasteride sequence. fMRI data was available from 47 participants (see CONSORT flow diagram, supplementary\u0026nbsp;material 2 for more details regarding allocation and exclusion). No severe adverse events were reported following intake of finasteride or placebo.\u003c/p\u003e\n\u003cp\u003eParticipants were on average 34.8 years old (SD = 14.0). They exhibited a mean AUDIT sum score of 10.9 (SD = 4.9) indicating a hazardous and harmful consumption of alcohol. BIS scores (M = 29.9, SD = 5.5) were similar to those of a normative sample (M = 30.0, SD = 6.1). For additional sociodemographic data, see Table 1.\u0026nbsp;No significant group differences regarding the medication sequence (finasteride or placebo first) were observed at baseline (see supplementary material 4). DHT levels were significantly reduced by 9.6% as compared to placebo (from 353 to 318 pg/mL on average; \u003cem\u003eF\u003c/em\u003e(1, 42.02) = 12.50, \u003cem\u003ep\u003c/em\u003e = .001). No significant change in T levels was observed (\u003cem\u003eF\u003c/em\u003e(1, 42.24)\u0026nbsp;= 1.05, \u003cem\u003ep\u003c/em\u003e = .311)).\u003c/p\u003e\n\u003cp\u003e[Table 1]\u003c/p\u003e\n\u003ch2\u003efMRI results\u003c/h2\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003efMRI whole brain analyses\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe stop-signal paradigm was successfully applied, as demonstrated by the placebo only analyses, see Supplementary Table 3. Percentage of stop success rate varied between 40 und 60% indicating an adequate performance during the task.\u003c/p\u003e\n\u003cp\u003eThe full factorial models including DHT or T as a covariate of interest yielded a significant influence of both, DHT and T, on individual neural reactivity, see Table 2 and Figure 2. Regarding the influence of DHT, a negative association was observed in left temporal regions for the contrast ‘stop error’. A positive relation was observed regarding T in right temporal regions for the contrast ‘stop success’. There was also a positive relation observed for several regions regarding the contrast stop success \u0026gt; stop error, which is difficult to interpret as the significance for this contrast could be driven by higher activation during stop success or lower activation during stop error. No significant effect of medication was observed.\u003c/p\u003e\n\u003cp\u003e[Table 2]\u003c/p\u003e\n\u003cp\u003e[Figure 2]\u003c/p\u003e\n\u003ch2\u003eBehavioral results\u003c/h2\u003e\n\u003cp\u003eThe linear mixed models including with and without the factors time point, medication and sequence, as well as DHT or T did not yield significant results with respect to behavioral measures (SSRT, go RT, SSD), except for an effect of age on the mean reaction times in go trials. Please see Supplementary Table 4 for more details.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePrevious research demonstrated an association between impaired response inhibition and higher alcohol, between impaired response inhibition and higher androgen levels, as well as between higher alcohol consumption and higher androgen levels. We demonstrated an association between lower DHT concentrations and higher activation in left temporal brain regions during a failure to inhibit. Additionally, we also observed that higher T levels related to higher activation in right temporal regions during successful inhibitions. No significant findings were observed for behavioral variables.\u003c/p\u003e \u003cp\u003eIn previous studies, patients with AUD showed increased activation in the middle temporal gyrus [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] and decreased gray matter volume in this area compared to HCs [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Right temporal regions, such as the right middle temporal gyrus,, have been implicated in behavioral inhibition studies using the SST [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], and have further been found to be activated in inhibition studies using no-go trials [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. The middle temporal gyrus has been connected to alcohol-induced impaired functioning in the SST [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The left side of the middle temporal gyrus is not typically related to response inhibition. However, fetal androgen level (T) was found to predict grey matter volumes in the left middle temporal gyrus [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], making it seem likely that the activation of the left middle temporal gyrus in our study is driven by mechanisms related to T and DHT. Following the observation by Moffat and Resnick in older men [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], higher free T levels could be associated with increased cerebral blood flow in our sample.\u003c/p\u003e \u003cp\u003ePrevious research indicates different regional responses for the contrasts \u0026lsquo;stop success\u0026rsquo; and \u0026lsquo;stop error\u0026rsquo; [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] and distinct neural networks for stop success and stop error trials have been suggested [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. In agreement with our results, the right middle temporal gyrus forms a part of the network accounting for most variance in stop success trials as the right hemispheric network is more involved in attention to the stop signal, whereas the left hemispheric network is involved in response inhibition [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Thus, our findings provide first evidence for an interaction of specific androgens with distinct neural processes during the SST, i.e., an influence of T during attention to the stop signal (as supported more from the right hemisphere), and an influence of DHT during response inhibition (as supported more from the left hemisphere). In line with this argumentation, T has been found to correlate positively with activation during spatial tasks and mental rotation in fMRI studies [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], tasks which also involve attention.\u003c/p\u003e \u003cp\u003eThis study is the first to examine the role of DHT and the intertwining of androgens and inhibitory control in heavily drinking individuals. Thus, interpretations often need to infer from findings on effects of T and further examination is warranted, e.g., using spectroscopy neuroimaging methods as well as confirmatory studies, as research on DHT mechanisms is still sparse. Hence, several aspects merit attention in this context: First, mechanisms underlying androgen effects, especially DHT and its reduction through finasteride, are still unclear, and as chronic alcohol consumption can lead to aromatization of androgens and T is metabolized to estradiol [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e], it is possible that estradiol, which has also been suggested to play a role in problem drinking of males [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e], partly mediated the influence of T in our study. Contrarily, DHT as the more potent derivative of T therefore solely reflects an androgen-effect. Second, finasteride may not only exert its effects via the mechanism of 5-alpha reductase inhibition. Diviccaro and colleagues [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e] stated that finasteride does not only alter neuroactive steroid levels themselves but also their mechanisms of action. Indeed, finasteride acts on dopaminergic neurotransmitter systems, e.g. by blocking the effects of dopamine receptors in the mesolimbic system [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e], and influences the inhibitory neurotransmitter system modulated by gamma-aminobutyric acid [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Interestingly, previous research also suggested that finasteride interferes with functioning of the hypothalamus-pituitary-adrenal axis and thus impairs stress reactivity and reduces impulsive behavior [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. Third and while the specific mechanisms are still not clear, additional neural regions have previously been connected to behavioral inhibition, androgens and/or alcohol consumption. For instance, a significant association between higher T levels and greater grey matter thickness in male adolescents were observed in the calcarine sulcus [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e], an area known to contain a high number of androgen receptors [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e], and sensitive to chronic effects of alcohol [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. The supplementary motor area (SMA) is frequently associated with inhibition, showing greater activation during successful inhibition in a group with shorter SSRTs [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. In healthy adults, the preSMA is generally more active during successful stopping [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. Hu and colleagues [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e] observed significantly greater activation in the preSMA in participants with AUD than in healthy controls during expectation of a stop signal - which they suggested to be a compensatory mechanism for cognitive control. Lastly, T has been shown to influence uncertain social situations by acting on interpersonal trust via neuropeptide systems, thereby increasing social vigilance [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e], thus indicating learning effects or neuroplasticity processes. Speculatively, finasteride could have triggered processes influencing social behavior in the unknown experimental situation. As vigilance is a key component of behavioral inhibition [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e], the androgen effect of finasteride on social behavior might have influenced neural activation in the SST. Further, alcohol is used to facilitate social interaction [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e] and modulation of DHT by alcohol use has been suggested as an underlying mechanism [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. However, a previous study demonstrated that learning effects, in case of performing the SST multiple times, are not likely [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. Likewise, a pharmacological carry-over effect could be excluded, as the second examination day took place after at least 21 days; finasteride can remain functionally active after single administration for one to two weeks [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eAs previous research on the effect of 5-alpha reductase inhibition by finasteride on brain activation is very scarce, our findings are based on exploratory considerations. While in our sample a significant reduction of DHT after administration of finasteride was observed, the relative reduction was estimated at 9.6% on average, thus being smaller than the expected 80% [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The resulting effect on behavioral and neural activity might thus have been too small to be detected in our sample (N\u0026thinsp;=\u0026thinsp;45) and finasteride might have a generally smaller effect on neural activation during response inhibition in males with HED than expected. Additionally, the test-retest reliability of the SST varies according to task contrast and brain region [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e], which might interfere with possible small medication effects. Finally, we included only male subjects with HED. More research in larger samples is necessary to examine the effect of 5-alpha reductase inhibition by finasteride on brain activation in females and in other specific populations (i.e., AUD and HC), as well as additional mechanisms underlying the effect of finasteride on neural activity during response inhibition.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eClinical implications\u003c/h2\u003e \u003cp\u003eThe high prevalence of HED [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e] and the fact that it is considered a major risk factor for AUD [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] underline the importance of developing novel preventive and therapeutic approaches. While a previous study reported positive effects of an inhibitor of 5-alpha reductase enzymes on abstinence and drinking outcomes in heavily drinking males [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], our study demonstrated a potential therapeutic approach as the pharmacological modulation of DHT influences neural correlates of response inhibition. However, the clinical and therapeutic potential of finasteride needs to examined further.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe observe distinct relations of DHT and T levels with activation patterns of temporal regions during a task measuring behavioral inhibition. These regions are involved in response inhibition, alcohol consumption, and androgen mechanisms, and results may point towards a role of DHT and T in distinct hemispheric networks during the task. Though with warranted precaution in interpretation, the results of this study can guide future research with respect to understanding the mechanisms of androgens, especially DHT and T (and the DHT-to-T ratio), more deeply, and developing novel therapeutic approaches and treatment options based on pharmaceutical modulation of androgens.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available on request from BL or the corresponding author SG.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: We thank Johanna Klein, Luke Bregulla, and Pauline Salg for their assistance with the collection of the experimental data and Sarah Sheldrick for support with hormone quantification.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contributions:\u0026nbsp;\u003c/strong\u003eDesigned the current study: MK, RBJ, FK, BL, SG. Analyzed the data: MK, SG. Supported the data analysis: SH, CM, IR, HT, PB, SVK, BL. Interpreted the data: MK, SH, PB, SVK, BL, SG. Wrote the paper: MK and SG. Supported the writing of the paper: BL. Procured the funding of the original studies: BL. Commented on the manuscript and provided intellectual input: MK, RBJ, SH, CM, IR, MR, LW, HT, PB, SVK, GWA, FK, BL, SG.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: The project was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project-ID 402170461 – TRR265 (Heinz et al. 2021; Spanagel et al. 2024). The funders had no role in the study design, data collection, analysis, decision to publish, or preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e: The authors have no competing interests to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and patient consent statement\u003c/strong\u003e: Ethics approval was obtained from the local ethics committee II of Heidelberg University, Germany (approval number 2021-654). Written informed consent was obtained was obtained from all participants prior to study participation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial registration\u003c/strong\u003e: DRKS00020569; https://drks.de/search/de/trial/DRKS00020569\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWHO (2018). 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The connection of 5-alpha reductase inhibitors to the development of depression. \u003cem\u003eBiomed Pharmacother, 143\u003c/em\u003e, 112100. doi:10.1016/j.biopha.2021.112100\u003c/li\u003e\n\u003cli\u003eGodar, S.C., et al. (2019). The Steroidogenesis Inhibitor Finasteride Reduces the Response to Both Stressful and Rewarding Stimuli. \u003cem\u003eBiomolecules, 9\u003c/em\u003e(11), 749. doi:10.3390/biom9110749\u003c/li\u003e\n\u003cli\u003eBramen, J.E., et al. (2012). Sex Matters during Adolescence: Testosterone-Related Cortical Thickness Maturation Differs between Boys and Girls. \u003cem\u003ePLoS ONE, 7\u003c/em\u003e(3), e33850. doi:10.1371/journal.pone.0033850\u003c/li\u003e\n\u003cli\u003eShokri-Kojori, E., Tomasi, D., Wiers, C.E., Wang, G.J. and Volkow, N.D. (2017). Alcohol affects brain functional connectivity and its coupling with behavior: greater effects in male heavy drinkers. \u003cem\u003eMolecular Psychiatry, 22\u003c/em\u003e(8), 1185-1195. doi:10.1038/mp.2016.25\u003c/li\u003e\n\u003cli\u003eLi, C.S.R., Huang, C., Constable, R.T. and Sinha, R. (2006). Imaging response inhibition in a stop-signal task: neural correlates independent of signal monitoring and post-response processing. \u003cem\u003eJournal of Neuroscience, 26\u003c/em\u003e(1), 186-192.\u003c/li\u003e\n\u003cli\u003eSharp, D.J., et al. (2010). Distinct frontal systems for response inhibition, attentional capture, and error processing. \u003cem\u003eProceedings of the National Academy of Sciences, 107\u003c/em\u003e(13), 6106-6111. doi:doi:10.1073/pnas.1000175107\u003c/li\u003e\n\u003cli\u003eHu, S., Ide, J.S., Zhang, S., Sinha, R. and Li, C.S. (2015). Conflict anticipation in alcohol dependence - A model-based fMRI study of stop signal task. \u003cem\u003eNeuroimage Clin, 8\u003c/em\u003e, 39-50. doi:10.1016/j.nicl.2015.03.008\u003c/li\u003e\n\u003cli\u003eBos, P.A., Hermans, E.J., Ramsey, N.F. and van Honk, J. (2012). The neural mechanisms by which testosterone acts on interpersonal trust. \u003cem\u003eNeuroimage, 61\u003c/em\u003e(3), 730-7. doi:10.1016/j.neuroimage.2012.04.002\u003c/li\u003e\n\u003cli\u003eWilliams, A.V., et al. (2020). Social approach and social vigilance are differentially regulated by oxytocin receptors in the nucleus accumbens. \u003cem\u003eNeuropsychopharmacology, 45\u003c/em\u003e(9), 1423-1430. doi:10.1038/s41386-020-0657-4\u003c/li\u003e\n\u003cli\u003eM\u0026uuml;ller, C.P., M\u0026uuml;hle, C., Kornhuber, J. and Lenz, B. (2021). Sex‐Dependent Alcohol Instrumentalization Goals in Non‐Addicted Alcohol Consumers versus Patients with Alcohol Use Disorder: Longitudinal Change and Outcome Prediction. \u003cem\u003eAlcoholism: Clinical and Experimental Research, 45\u003c/em\u003e(3), 577-586. doi:10.1111/acer.14550\u003c/li\u003e\n\u003cli\u003eM\u0026uuml;ller, C.P., Schumann, G., Rehm, J., Kornhuber, J. and Lenz, B. (2023). Self-management with alcohol over lifespan: psychological mechanisms, neurobiological underpinnings, and risk assessment. \u003cem\u003eMolecular Psychiatry, 28\u003c/em\u003e(7), 2683-2696. doi:10.1038/s41380-023-02074-3\u003c/li\u003e\n\u003cli\u003eWenger, L.P., et al. (2023). Alcohol does not influence trust in others or oxytocin, but increases positive affect and risk-taking: a randomized, controlled, within-subject trial. \u003cem\u003eEuropean Archives of Psychiatry and Clinical Neuroscience\u003c/em\u003e. doi:10.1007/s00406-023-01676-w\u003c/li\u003e\n\u003cli\u003eYou, Y., Failla, A. and van der Kamp, J. (2023). No training effects of top-down controlled response inhibition by practicing on the stop-signal task. \u003cem\u003eActa Psychologica, 235\u003c/em\u003e, 103878. doi:https://doi.org/10.1016/j.actpsy.2023.103878\u003c/li\u003e\n\u003cli\u003eKorucuoglu, O., et al. (2021). Test-Retest Reliability of Neural Correlates of Response Inhibition and Error Monitoring: An fMRI Study of a Stop-Signal Task. \u003cem\u003eFrontiers in Neuroscience, 15\u003c/em\u003e. doi:10.3389/fnins.2021.624911\u003c/li\u003e\n\u003cli\u003eMatos, E.G.D., Atzendorf, J., Kraus, L. and Piontek, D. (2016). Substanzkonsum in der Allgemeinbev\u0026ouml;lkerung in Deutschland. \u003cem\u003eSUCHT, 62\u003c/em\u003e(5), 271-281. doi:10.1024/0939-5911/a000445\u003c/li\u003e\n\u003cli\u003eRolls, E.T., Huang, C.-C., Lin, C.-P., Feng, J. and Joliot, M. (2020). Automated anatomical labelling atlas 3. \u003cem\u003eNeuroImage, 206\u003c/em\u003e, 116189. doi:https://doi.org/10.1016/j.neuroimage.2019.116189\u003c/li\u003e\n\u003cli\u003eFonov, V.S., Evans, A.C., McKinstry, R.C., Almli, C.R. and Collins, D.L. (2009). Unbiased nonlinear average age-appropriate brain templates from birth to adulthood. \u003cem\u003eNeuroImage, 47\u003c/em\u003e, S102. doi:https://doi.org/10.1016/S1053-8119(09)70884-5\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1\u0026nbsp;\u003c/strong\u003e\u003cem\u003eSample characteristics at V1\u003c/em\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8647%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.92079%;\"\u003e\n \u003cp\u003e\u003cem\u003eM\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8911%;\"\u003e\n \u003cp\u003e\u003cem\u003eSD\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.9868%;\"\u003e\n \u003cp\u003e% of sample\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.3366%;\"\u003e\n \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8647%;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.92079%;\"\u003e\n \u003cp\u003e33.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8911%;\"\u003e\n \u003cp\u003e13.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.9868%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.3366%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8647%;\"\u003e\n \u003cp\u003eHigh school diploma (\u0026ldquo;Abitur\u0026rdquo;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.92079%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8911%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.9868%;\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.3366%;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8647%;\"\u003e\n \u003cp\u003eEmployment in the last three months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.92079%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8911%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.9868%;\"\u003e\n \u003cp\u003e94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.3366%;\"\u003e\n \u003cp\u003e44\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8647%;\"\u003e\n \u003cp\u003eSingle/divorced/living apart : married/in relationship\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.92079%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8911%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.9868%;\"\u003e\n \u003cp\u003e70 : 30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.3366%;\"\u003e\n \u003cp\u003e35 : 14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8647%;\"\u003e\n \u003cp\u003eHaving children (yes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.92079%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8911%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.9868%;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.3366%;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8647%;\"\u003e\n \u003cp\u003eSmokers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.92079%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8911%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.9868%;\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.3366%;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8647%;\"\u003e\n \u003cp\u003eAUDIT (sum score)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.92079%;\"\u003e\n \u003cp\u003e11.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8911%;\"\u003e\n \u003cp\u003e5.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.9868%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.3366%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 46.8647%;\"\u003e\n \u003cp\u003eBIS (sum score)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.92079%;\"\u003e\n \u003cp\u003e30.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.8911%;\"\u003e\n \u003cp\u003e5.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.9868%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.3366%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eNote.\u0026nbsp;\u003c/em\u003e\u003cem\u003eM\u003c/em\u003e, mean. \u003cem\u003eN\u003c/em\u003e, Number. \u003cem\u003eSD\u003c/em\u003e, standard deviation. \u003cem\u003eAUDIT\u003c/em\u003e, Alcohol Use Identification Test. \u003cem\u003eBIS\u003c/em\u003e, Barratt Impulsiveness Scale.\u0026nbsp;Heavy drinking days were defined as consuming at least 60g of alcohol per drinking occasion.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTable 2 Results from the full factorial fMRI analysis with factors subject, time point, sequence, and medication, including hormone levels as covariate of interest and age as covariate of no interest\u003c/em\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"576\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ePredictor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003ePeak MNI-Coordinates\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ex y z\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eBrain area\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eNr. of voxels\u003cem\u003e\u0026nbsp;k\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003ePeak-Level \u003cem\u003et\u003c/em\u003e(74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eCluster-Level \u003cem\u003ep\u003c/em\u003e\u003csub\u003eFWE-corrected\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStop error\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eAbsolute DHT -\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-48 -22 -6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eMiddle temporal gyrus L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e4.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.005\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eSequence (Placebo first \u0026lt; Finasteride first)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-20 -74 14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eCalcarine sulcus L, lingual gyrus L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e927\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e4.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStop success \u0026gt; stop error\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eAbsolute DHT +\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-48 -22 -6\u003c/p\u003e\n \u003cp\u003e-2 -86 4\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e56 -20 4\u003c/p\u003e\n \u003cp\u003e-28 -32 38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eMiddle temporal gyrus L\u003c/p\u003e\n \u003cp\u003eCalcarine sulcus L, lingual gyrus L, cuneus L\u003c/p\u003e\n \u003cp\u003eSuperior temporal gyrus\u003c/p\u003e\n \u003cp\u003ePostcentral gyrus L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e282\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e587\u003c/p\u003e\n \u003cp\u003e386\u003c/p\u003e\n \u003cp\u003e535\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e4.65\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4..23\u003c/p\u003e\n \u003cp\u003e4.36\u003c/p\u003e\n \u003cp\u003e4.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.016\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003cp\u003e.003\u003c/p\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStop success\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eAbsolute T +\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e54 -78 12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eMiddle temporal gyrus R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e321\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e4.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eSequence (Placebo first \u0026lt; Finasteride first)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-22 -72 10\u003c/p\u003e\n \u003cp\u003e46 -4 24\u003c/p\u003e\n \u003cp\u003e14 -6 54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eCalcarine sulcus L\u003c/p\u003e\n \u003cp\u003ePrecentral gyrus R\u003c/p\u003e\n \u003cp\u003eSupplementary motor area R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e215\u003c/p\u003e\n \u003cp\u003e277\u003c/p\u003e\n \u003cp\u003e192\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e4.39\u003c/p\u003e\n \u003cp\u003e4.10\u003c/p\u003e\n \u003cp\u003e4.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.030\u003c/p\u003e\n \u003cp\u003e.009\u003c/p\u003e\n \u003cp\u003e.047\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eTime point (T1 \u0026gt; T2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e16 -10 6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eThalamus R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e210\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e4.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e.033\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eNote\u003c/em\u003e. \u003cem\u003e+\u003c/em\u003e implicates positive prediction of brain activation; - implicates negative prediction of brain activation. Only activated areas of significant voxel size in relation to total voxel size of a cluster are reported. Brain areas correspond to the Aal3 atlas (automated anatomic labelling atlas 3 [60]). \u003cem\u003eL\u003c/em\u003e, left. \u003cem\u003eR\u003c/em\u003e, right. No specification, both R and L. \u003cem\u003eMNI-Coordinates\u003c/em\u003e, Montreal Neurological Institute [61]. An uncorrected threshold of p \u0026lt; 0.001 in combination with a cluster-extend threshold of (a) 353 voxels and (b) 321 voxels was used, corresponding to pFWE \u0026lt; 0.05.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8347303/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8347303/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHeavy episodic drinking (HED) is highly prevalent in men and a major risk factor for Alcohol Use Disorder (AUD). Previous studies indicated an influence of testosterone (T) on AUD, and dihydrotestosterone (DHT) was linked to alcohol consumption, impulsivity, and response inhibition. As the role of androgens in AUD and the modulation thereof is not fully understood, this study investigated the effect of a pharmacological reduction in DHT by inhibition of the 5-alpha reductase II through finasteride on brain activation and response inhibition during a stop signal task. Fifty males with HED participated in a randomized, placebo-controlled, double blind, cross-over, functional magnetic resonance imaging (fMRI) study. Participants received either 5mg finasteride or placebo. Full factorial (fMRI) and linear mixed were used to estimate whole-brain effects of DHT and T following finasteride and placebo on neural correlates of behavioral control (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;45 analyzable participants). Lower levels of DHT and higher levels of T were related to stronger neural activation in temporal regions during response inhibition for successful or unsuccessful stop-trails, respectively. However, no significant influence of hormone levels on behavioral data of the stop signal task was observed. Although the precise mechanisms underlying the effects of pharmacologically altered DHT levels on neural correlates of response inhibition remain unresolved, both DHT and T appear to be specifically associated with neural activation during response inhibition. These findings stimulate the development of novel therapeutic approaches and treatment options based on pharmaceutical modulation of androgens addressing problem drinking, and possibly AUD.\u003c/p\u003e","manuscriptTitle":"Pharmacologically altered Androgens, Brain Activation and Response Inhibition in a Stop-Signal Task in Male Heavy Drinkers","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-13 06:26:27","doi":"10.21203/rs.3.rs-8347303/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ef63aaeb-013c-4923-a70c-4a02453e80fa","owner":[],"postedDate":"January 13th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":60678847,"name":"Health sciences/Diseases/Psychiatric disorders/Addiction"},{"id":60678848,"name":"Health sciences/Diseases/Psychiatric disorders"},{"id":60678849,"name":"Health sciences/Diseases/Psychiatric disorders/Addiction"},{"id":60678850,"name":"Health sciences/Diseases/Psychiatric disorders"}],"tags":[],"updatedAt":"2026-02-16T12:22:28+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-13 06:26:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8347303","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8347303","identity":"rs-8347303","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}