Bed nucleus of the stria terminalis network responses to unpredictable threat in early alcohol abstinence.
abstinence
bed nucleus of the stria terminalis
sex differences
unpredictable threat
Journal
Alcohol, clinical & experimental research
ISSN: 2993-7175
Titre abrégé: Alcohol Clin Exp Res (Hoboken)
Pays: United States
ID NLM: 9918609780906676
Informations de publication
Date de publication:
24 Aug 2024
24 Aug 2024
Historique:
revised:
01
07
2024
received:
14
03
2024
accepted:
11
07
2024
medline:
24
8
2024
pubmed:
24
8
2024
entrez:
24
8
2024
Statut:
aheadofprint
Résumé
Anxiety during early alcohol abstinence, likely resulting from neural changes caused by chronic alcohol use, contributes to high relapse rates. Studies in rodents show heightened activation during early abstinence in the bed nucleus of the stria terminalis (BNST)-a neural hub for anxiety-and its extended anxiety-related corticolimbic network. Despite the clinical importance of early abstinence, few studies investigate the underlying neural mechanisms. To address this gap, we investigated brain function in early alcohol abstinence (EA = 20, 9 women) relative to controls (HC = 20, 11 women) using an unpredictable threat task shown to engage the BNST and corticolimbic brain regions involved in anxiety and alcohol use disorder (AUD). Group, anxiety, and sex were predictors used to determine whole-brain activation and BNST functional connectivity. We found widespread interactions of group × anxiety and group × anxiety × sex for both activation and BNST connectivity during unpredictable threat. In the EA group, higher anxiety was correlated with activation in the BNST, rostral anterior cingulate cortex (ACC), insula (men only), and dorsal ACC (men only). In the HC group, higher anxiety was negatively correlated with activation in the BNST, nucleus accumbens, thalamus, and insula (men only). For connectivity, anxiety was positively correlated in EA and negatively correlated in HC, between the BNST and the amygdala, ventromedial prefrontal cortex (PFC), and dorsomedial PFC; EA men showed stronger BNST-vmPFC connectivity than HC men. These novel findings provide preliminary evidence for alterations in the BNST and anxiety-related corticolimbic brain regions in early alcohol abstinence, adding to growing literature in humans supporting the BNST's role in anxiety and sex-dependent effects of chronic alcohol use.
Sections du résumé
BACKGROUND
BACKGROUND
Anxiety during early alcohol abstinence, likely resulting from neural changes caused by chronic alcohol use, contributes to high relapse rates. Studies in rodents show heightened activation during early abstinence in the bed nucleus of the stria terminalis (BNST)-a neural hub for anxiety-and its extended anxiety-related corticolimbic network. Despite the clinical importance of early abstinence, few studies investigate the underlying neural mechanisms.
METHODS
METHODS
To address this gap, we investigated brain function in early alcohol abstinence (EA = 20, 9 women) relative to controls (HC = 20, 11 women) using an unpredictable threat task shown to engage the BNST and corticolimbic brain regions involved in anxiety and alcohol use disorder (AUD). Group, anxiety, and sex were predictors used to determine whole-brain activation and BNST functional connectivity.
RESULTS
RESULTS
We found widespread interactions of group × anxiety and group × anxiety × sex for both activation and BNST connectivity during unpredictable threat. In the EA group, higher anxiety was correlated with activation in the BNST, rostral anterior cingulate cortex (ACC), insula (men only), and dorsal ACC (men only). In the HC group, higher anxiety was negatively correlated with activation in the BNST, nucleus accumbens, thalamus, and insula (men only). For connectivity, anxiety was positively correlated in EA and negatively correlated in HC, between the BNST and the amygdala, ventromedial prefrontal cortex (PFC), and dorsomedial PFC; EA men showed stronger BNST-vmPFC connectivity than HC men.
CONCLUSIONS
CONCLUSIONS
These novel findings provide preliminary evidence for alterations in the BNST and anxiety-related corticolimbic brain regions in early alcohol abstinence, adding to growing literature in humans supporting the BNST's role in anxiety and sex-dependent effects of chronic alcohol use.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAAA NIH HHS
ID : F30AA027418
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01AA029127
Pays : United States
Organisme : NIAAA NIH HHS
ID : R21AA025385
Pays : United States
Informations de copyright
© 2024 The Author(s). Alcohol, Clinical and Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcohol.
Références
Alvarez, R.P., Kirlic, N., Misaki, M., Bodurka, J., Rhudy, J.L., Paulus, M.P. et al. (2015) Increased anterior insula activity in anxious individuals is linked to diminished perceived control. Translational Psychiatry, 5, e591. Available from: https://doi.org/10.1038/tp.2015.84
Avery, S.N., Clauss, J.A. & Blackford, J.U. (2016) The human BNST: functional role in anxiety and addiction. Neuropsychopharmacology, 41, 126–141. Available from: https://doi.org/10.1038/npp.2015.185
Avery, S.N., Clauss, J.A., Winder, D.G., Woodward, N., Heckers, S. & Blackford, J.U. (2014) BNST neurocircuitry in humans. NeuroImage, 91, 311–323. Available from: https://doi.org/10.1016/j.neuroimage.2014.01.017
Babor, T.F., Higgins‐Biddle, J.C., Saunders, J.B. & Monteiro, M.G. (2001) AUDIT: the alcohol use disorders identification test: guidelines for use in primary health care (No. WHO/MSD/MSB/01.6a). Geneva: World Health Organization.
Barker, J.M. & Taylor, J.R. (2019) Sex differences in incentive motivation and the relationship to the development and maintenance of alcohol use disorders. Physiology & Behavior, 203, 91–99. Available from: https://doi.org/10.1016/j.physbeh.2017.09.027
Beck, A.T., Epstein, N., Brown, G. & Steer, R.A. (1988) An inventory for measuring clinical anxiety: psychometric properties. Journal of Consulting and Clinical Psychology, 56, 893–897. Available from: https://doi.org/10.1037/0022‐006X.56.6.893
Becker, J.B. & Koob, G.F. (2016) Sex differences in animal models: focus on addiction. Pharmacological Reviews, 68, 242–263. Available from: https://doi.org/10.1124/pr.115.011163
Camchong, J., Stenger, A. & Fein, G. (2013a) Resting‐state synchrony during early alcohol abstinence can predict subsequent relapse. Cerebral Cortex, 23, 2086–2099. Available from: https://doi.org/10.1093/cercor/bhs190
Camchong, J., Stenger, V.A. & Fein, G. (2013b) Resting state synchrony in long‐term abstinent alcoholics with versus without comorbid drug dependence. Drug and Alcohol Dependence, 131, 56–65. Available from: https://doi.org/10.1016/j.drugalcdep.2013.04.002
Carleton, R.N., Norton, M.A.P.J. & Asmundson, G.J.G. (2007) Fearing the unknown: a short version of the intolerance of uncertainty scale. Journal of Anxiety Disorders, 21, 105–117. Available from: https://doi.org/10.1016/j.janxdis.2006.03.014
Centanni, S.W., Morris, B.D., Luchsinger, J.R., Bedse, G., Fetterly, T.L., Patel, S. et al. (2019) Endocannabinoid control of the insular‐bed nucleus of the stria terminalis circuit regulates negative affective behavior associated with alcohol abstinence. Neuropsychopharmacology, 44, 526–537. Available from: https://doi.org/10.1038/s41386‐018‐0257‐8
Erol, A. & Karpyak, V.M. (2015) Sex and gender‐related differences in alcohol use and its consequences: contemporary knowledge and future research considerations. Drug and Alcohol Dependence, 156, 1–13. Available from: https://doi.org/10.1016/j.drugalcdep.2015.08.023
Feola, B., Flook, E.A., Gardner, H., Phan, K.L., Gwirtsman, H., Olatunji, B. et al. (2023) Altered bed nucleus of the stria terminalis and amygdala responses to threat in combat veterans with posttraumatic stress disorder. Journal of Traumatic Stress, 36, 359–372. Available from: https://doi.org/10.1002/jts.22918
Feola, B., McHugo, M., Armstrong, K., Noall, M.P., Flook, E.A., Woodward, N.D. et al. (2021) BNST and amygdala connectivity are altered during threat anticipation in schizophrenia. Behavioural Brain Research, 412, 113428. Available from: https://doi.org/10.1016/j.bbr.2021.113428
Feola, B., Melancon, S.N.T., Clauss, J.A., Noall, M.P., Mgboh, A., Flook, E.A. et al. (2021) Bed nucleus of the stria terminalis and amygdala responses to unpredictable threat in children. Developmental Psychobiology, 63, e22206. Available from: https://doi.org/10.1002/dev.22206
First, M.B. (1997) Structured clinical interview for the DSM‐IV axis I disorders: SCID/IP version 2.0. New York: Biometrics Research Dept., New York State Psychiatric Institute.
Flook, E.A., Feola, B., Avery, S.N., Winder, D.G., Woodward, N.D., Heckers, S. et al. (2020) BNST‐insula structural connectivity in humans. NeuroImage, 210, 116555. Available from: https://doi.org/10.1016/j.neuroimage.2020.116555
Flook, E.A., Feola, B., Benningfield, M.M., Silveri, M.M., Winder, D.G. & Blackford, J.U. (2021) Alterations in connectivity of the bed nucleus of the stria terminalis during early abstinence in individuals with alcohol use disorder. Alcoholism: Clinical and Experimental Research, 45, 1028–1038. Available from: https://doi.org/10.1111/acer.14596
Flook, E.A., Feola, B., Benningfield, M.M., Silveri, M.M., Winder, D.G. & Blackford, J.U. (2023) Alterations in BNST intrinsic functional connectivity in early abstinence from alcohol use disorder. Alcohol and Alcoholism, 58, 298–307. Available from: https://doi.org/10.1093/alcalc/agad006
Flores‐Bonilla, A. & Richardson, H.N. (2020) Sex differences in the neurobiology of alcohol use disorder. Alcohol Research, 40, 4. Available from: https://doi.org/10.35946/arcr.v40.2.04
Francesconi, W., Berton, F., Repunte‐Canonigo, V., Hagihara, K., Thurbon, D., Lekic, D. et al. (2009) Protracted withdrawal from alcohol and drugs of abuse impairs long‐term potentiation of intrinsic excitability in the juxtacapsular bed nucleus of the stria terminalis. The Journal of Neuroscience, 29, 5389–5401. Available from: https://doi.org/10.1523/JNEUROSCI.5129‐08.2009
Friston, K.J., Buechel, C., Fink, G.R., Morris, J., Rolls, E. & Dolan, R.J. (1997) Psychophysiological and modulatory interactions in neuroimaging. NeuroImage, 6, 218–229. Available from: https://doi.org/10.1006/nimg.1997.0291
Glover, L.R., McFadden, K.M., Bjorni, M., Smith, S.R., Rovero, N.G., Oreizi‐Esfahani, S. et al. (2020) A prefrontal‐bed nucleus of the stria terminalis circuit limits fear to uncertain threat. eLife, 9, e60812. Available from: https://doi.org/10.7554/eLife.60812
Goode, T.D., Ressler, R.L., Acca, G.M., Miles, O.W. & Maren, S. (2019) Bed nucleus of the stria terminalis regulates fear to unpredictable threat signals. eLife, 8, e46525. Available from: https://doi.org/10.7554/eLife.46525
Gorka, S.M., Kreutzer, K.A., Petrey, K.M., Radoman, M. & Phan, K.L. (2020) Behavioral and neural sensitivity to uncertain threat in individuals with alcohol use disorder: associations with drinking behaviors and motives. Addiction Biology, 25, e12774. Available from: https://doi.org/10.1111/adb.12774
Gorka, S.M., Lieberman, L., Phan, K.L. & Shankman, S.A. (2016) Association between problematic alcohol use and reactivity to uncertain threat in two independent samples. Drug and Alcohol Dependence, 164, 89–96. Available from: https://doi.org/10.1016/j.drugalcdep.2016.04.034
Gorka, S.M., Radoman, M., Jimmy, J., Kreutzer, K.A., Manzler, C. & Culp, S. (2023) Behavioral and brain reactivity to uncertain stress prospectively predicts binge drinking in youth. Neuropsychopharmacology, 48, 1194–1200. Available from: https://doi.org/10.1038/s41386‐023‐01571‐x
Heilig, M., Egli, M., Crabbe, J. & Becker, H. (2010) Acute withdrawal, protracted abstinence and negative affect in alcoholism: are they linked? Addiction Biology, 15, 169–184. Available from: https://doi.org/10.1111/j.1369‐1600.2009.00194.x
Holleran, K.M. & Winder, D.G. (2017) Preclinical voluntary drinking models for alcohol abstinence‐induced affective disturbances in mice. Genes, Brain and Behavior, 16, 8–14. Available from: https://doi.org/10.1111/gbb.12338
Huang, M.M., Overstreet, D.H., Knapp, D.J., Angel, R., Wills, T.A., Navarro, M. et al. (2010) Corticotropin‐releasing factor (CRF) sensitization of ethanol withdrawal‐induced anxiety‐like behavior is brain site specific and mediated by CRF‐1 receptors: relation to stress‐induced sensitization. Journal of Pharmacology and Experimental Therapeutics, 332, 298–307. Available from: https://doi.org/10.1124/jpet.109.159186
Kash, T.L., Baucum, A.J., Conrad, K.L., Colbran, R.J. & Winder, D.G. (2009) Alcohol exposure alters NMDAR function in the bed nucleus of the stria terminalis. Neuropsychopharmacology, 34, 2420–2429. Available from: https://doi.org/10.1038/npp.2009.69
Klumpers, F., Kroes, M.C.W., Baas, J.M.P. & Fernández, G. (2017) How human amygdala and bed nucleus of the stria terminalis may drive distinct defensive responses. The Journal of Neuroscience, 37, 9645–9656. Available from: https://doi.org/10.1523/JNEUROSCI.3830‐16.2017
Koob, G.F. & Volkow, N.D. (2016) Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry, 3, 760–773. Available from: https://doi.org/10.1016/S2215‐0366(16)00104‐8
Kushner, M.G., Abrams, K. & Borchardt, C. (2000) The relationship between anxiety disorders and alcohol use disorders: a review of major perspectives and findings. Clinical Psychology Review, 20, 149–171. Available from: https://doi.org/10.1016/s0272‐7358(99)00027‐6
Leary, M.R. (1983) A brief version of the fear of negative evaluation scale. Personality and Social Psychology Bulletin, 9, 371–375. Available from: https://doi.org/10.1177/0146167283093007
Liebowitz, M.R. (1987) Social phobia. Modern Problems of Pharmacopsychiatry, 22, 141–173. Available from: https://doi.org/10.1159/000414022
Lundqvist, D., Flykt, A. & Öhman, A. (1998) Karolinska directed emotional faces. PsycTESTS Dataset, 91, 630. Available from: https://doi.org/10.1037/t27732‐000
Luyten, L., Casteels, C., Vansteenwegen, D., Kuyck, K., Koole, M., Laere, K.V. et al. (2012) Micro‐positron emission tomography imaging of rat brain metabolism during expression of contextual conditioning. The Journal of Neuroscience, 32, 254–263. Available from: https://doi.org/10.1523/JNEUROSCI.3701‐11.2012
Marcinkiewcz, C.A., Mazzone, C.M., D'Agostino, G., Halladay, L.R., Hardaway, J.A., DiBerto, J.F. et al. (2016) Serotonin engages an anxiety and fear‐promoting circuit in the extended amygdala. Nature, 537, 97–101. Available from: https://doi.org/10.1038/nature19318
McLaren, D.G., Ries, M.L., Xu, G. & Johnson, S.C. (2012) A generalized form of context‐dependent psychophysiological interactions (gPPI): a comparison to standard approaches. NeuroImage, 61, 1277–1286. Available from: https://doi.org/10.1016/j.neuroimage.2012.03.068
Meyer, T.J., Miller, M.L., Metzger, R.L. & Borkovec, T.D. (1990) Development and validation of the penn state worry questionnaire. Behaviour Research and Therapy, 28, 487–495. Available from: https://doi.org/10.1016/0005‐7967(90)90135‐6
Moberg, C.A., Bradford, D.E., Kaye, J.T. & Curtin, J.J. (2017) Increased startle potentiation to unpredictable stressors in alcohol dependence: possible stress neuroadaptation in humans. Journal of Abnormal Psychology, 126, 441. Available from: https://doi.org/10.1037/abn0000265
Motzkin, J.C., Philippi, C.L., Wolf, R.C., Baskaya, M.K. & Koenigs, M. (2015) Ventromedial prefrontal cortex is critical for the regulation of amygdala activity in humans. Biological Psychiatry, 77, 276–284. Available from: https://doi.org/10.1016/j.biopsych.2014.02.014
Orban, C., McGonigle, J., Kalk, N.J., Erritzoe, D., Waldman, A.D., Nutt, D.J. et al. (2013) Resting state synchrony in anxiety‐related circuits of abstinent alcohol‐dependent patients. The American Journal of Drug and Alcohol Abuse, 39, 433–440. Available from: https://doi.org/10.3109/00952990.2013.846348
Padula, C.B., Anthenelli, R.M., Eliassen, J.C., Nelson, E. & Lisdahl, K.M. (2015) Gender effects in alcohol dependence: an fMRI pilot study examining affective processing. Alcoholism: Clinical and Experimental Research, 39, 272–281. Available from: https://doi.org/10.1111/acer.12626
Paulus, M.P., Hozack, N., Zauscher, B., McDowell, J.E., Frank, L., Brown, G.G. et al. (2001) Prefrontal, parietal, and temporal cortex networks underlie decision‐making in the presence of uncertainty. NeuroImage, 13, 91–100. Available from: https://doi.org/10.1006/nimg.2000.0667
Peltier, M.R., Verplaetse, T.L., Mineur, Y.S., Petrakis, I.L., Cosgrove, K.P., Picciotto, M.R. et al. (2019) Sex differences in stress‐related alcohol use. Neurobiology of Stress, 10, Article 100149. Available from: https://doi.org/10.1016/j.ynstr.2019.100149
Pleil, K.E., Rinker, J.A., Lowery‐Gionta, E.G., Mazzone, C.M., McCall, N.M., Kendra, A.M. et al. (2015) NPY signaling inhibits extended amygdala CRF neurons to suppress binge alcohol drinking. Nature Neuroscience, 18, 545–552. Available from: https://doi.org/10.1038/nn.3972
Radoman, M., Fogelman, N., Lacadie, C., Seo, D. & Sinha, R. (2024) Neural correlates of stress and alcohol Cue‐induced alcohol craving and of future heavy drinking: evidence of sex differences. AJP, 181, 412–422. Available from: https://doi.org/10.1176/appi.ajp.20230849
Ressler, R.L., Goode, T.D., Evemy, C. & Maren, S. (2020) NMDA receptors in the CeA and BNST differentially regulate fear conditioning to predictable and unpredictable threats. Neurobiology of Learning and Memory, 174, 107281. Available from: https://doi.org/10.1016/j.nlm.2020.107281
Rivas‐Grajales, A.M., Sawyer, K.S., Karmacharya, S., Papadimitriou, G., Camprodon, J.A., Harris, G.J. et al. (2018) Sexually dimorphic structural abnormalities in major connections of the medial forebrain bundle in alcoholism. NeuroImage: Clinical, 19, 98–105. Available from: https://doi.org/10.1016/j.nicl.2018.03.025
Ruiz, S.M., Oscar‐Berman, M., Sawyer, K.S., Valmas, M., Urban, T. & Harris, G.J. (2013) Drinking history associations with regional white matter volumes in alcoholic men and women. Alcoholism: Clinical and Experimental Research, 37, 110–122. Available from: https://doi.org/10.1111/j.1530‐0277.2012.01862.x
SAMHSA. (2022) Center for Behavioral Health Statistics and Quality. 2022 National Survey on Drug Use and Health. Table 5.9A—Alcohol Use Disorder in Past Year among Persons Aged 12 or Older, by Age Group and Demographic Characteristics: Numbers in Thousands. Available from https://www.samhsa.gov/data/sites/default/files/reports/rpt42728/NSDUHDetailedTabs2022/NSDUHDetailedTabs2022/NSDUHDetTabsSect5pe2022.htm?s=5.9&#tab5.9a [Accessed 24th May 2023]
Sawyer, K.S., Maleki, N., Urban, T., Marinkovic, K., Karson, S., Ruiz, S.M. et al. (2019) Alcoholism gender differences in brain responsivity to emotional stimuli. eLife, 8, e41723. Available from: https://doi.org/10.7554/eLife.41723
Sawyer, K.S., Oscar‐Berman, M., Barthelemy, O.J., Papadimitriou, G.M., Harris, G.J. & Makris, N. (2017) Gender dimorphism of brain reward system volumes in alcoholism. Psychiatry Research: Neuroimaging, 263, 15–25. Available from: https://doi.org/10.1016/j.pscychresns.2017.03.001
Schmitz, A. & Grillon, C. (2012) Assessing fear and anxiety in humans using the threat of predictable and unpredictable aversive events (the NPU‐threat test). Nature Protocols, 7, 527–532. Available from: https://doi.org/10.1038/nprot.2012.001
Silberman, Y., Matthews, R.T. & Winder, D.G. (2013) A corticotropin releasing factor pathway for ethanol regulation of the ventral tegmental area in the bed nucleus of the stria terminalis. The Journal of Neuroscience, 33, 950–960. Available from: https://doi.org/10.1523/JNEUROSCI.2949‐12.2013
Skinner, H.A. & Sheu, W.J. (1982) Reliability of alcohol use indices. The lifetime drinking history and the MAST. Journal of Studies on Alcohol, 43, 1157–1170. Available from: https://doi.org/10.15288/jsa.1982.43.1157
Spielberger, C.D., Gorsuch, R.L., Luschene, R., Vagg, P.R. & Jacobs, G.A. (1983) Manual for the state‐trait anxiety inventory (form Y).
Torrisi, S., O'Connell, K., Davis, A., Reynolds, R., Balderston, N., Fudge, J.L. et al. (2015) Resting state connectivity of the bed nucleus of the stria terminalis at ultra‐high field. Human Brain Mapping, 36, 4076–4088. Available from: https://doi.org/10.1002/hbm.22899
Williams, L.E., Oler, J.A., Fox, A.S., McFarlin, D.R., Rogers, G.M., Jesson, M.A. et al. (2015) Fear of the unknown: uncertain anticipation reveals amygdala alterations in childhood anxiety disorders. Neuropsychopharmacology, 40, 1428–1435. Available from: https://doi.org/10.1038/npp.2014.328
Wills, T.A., Klug, J.R., Silberman, Y., Baucum, A.J., Weitlauf, C., Colbran, R.J. et al. (2012) GluN2B subunit deletion reveals key role in acute and chronic ethanol sensitivity of glutamate synapses in bed nucleus of the stria terminalis. Proceedings of the National Academy of Sciences of the United States of America, 109, E278–E287. Available from: https://doi.org/10.1073/pnas.1113820109
Zhao, W., Makowski, C., Hagler, D.J., Garavan, H.P., Thompson, W.K., Greene, D.J. et al. (2023) Task fMRI paradigms may capture more behaviorally relevant information than resting‐state functional connectivity. NeuroImage, 270, 119946. Available from: https://doi.org/10.1016/j.neuroimage.2023.119946