Social anxiety is associated with BNST response to unpredictability
Open accessAbstract
BACKGROUND: Anxiety disorders are highly prevalent and cause substantial suffering and impairment. Whereas the amygdala has well-established contributions to anxiety, evidence from rodent and nonhuman primate models suggests that the bed nucleus of the stria terminalis (BNST) may play a critical, and possibly distinct, role in human anxiety disorders. The BNST mediates hypervigilance and anticipatory anxiety in response to an unpredictable or ambiguous threat, core symptoms of social anxiety, yet little is known about the BNST's role in social anxiety. METHODS: Functional magnetic resonance imaging was used to measure neural responses during a cued anticipation task with an unpredictable, predictable threat, and predictable neutral cues followed by threat or neutral images. Social anxiety was examined using a dimensional approach (N = 44 adults). RESULTS: For unpredictable cues, higher social anxiety was associated with lower BNST-amygdala connectivity. For unpredictable images, higher social anxiety was associated with greater connectivity between the BNST and both the ventromedial prefrontal cortex and the posterior cingulate cortex and lower connectivity between the BNST and postcentral gyrus. Social anxiety moderated the BNST-amygdala dissociation for unpredictable images; higher social anxiety was associated with BNST > amygdala response to unpredictable threat relative to unpredictable neutral images. CONCLUSIONS: Social anxiety was associated with alterations in BNST responses to unpredictability, particularly in the BNST's interactions with other brain regions, including the amygdala and prefrontal cortex. To our knowledge, these findings provide the first evidence for the BNST's role in social anxiety, which may be a potential new target for prevention and intervention.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Our results align with imaging studies in nonhuman primates and humans reporting stronger BNST responses in individuals with elevated anxiety-related behaviors.
“Our results align with imaging studies in nonhuman primates (77) and humans (66) reporting stronger BNST responses in individuals with elevated anxiety-related behaviors.”
From Sexual differentiation of neural mechanisms of stress sensitivity during puberty (2023) · cites this paper as [66]
The Discussion (Social anxiety and the BNST-Amygdala Dissociation; page unavailable) describes a heightened BNST response to unpredictable threat images in participants with the highest social-anxiety scores. But the Results (BNST-Amygdala Comparison and BNST Activation; pages unavailable) establish a BNST response relative to the amygdala for threat versus neutral images, not a general increase in BNST activation with anxiety. This citation supports the human finding, not the separately cited nonhuman-primate finding. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThese data inform current debates on BNST function and are consistent with reports of increased reactivity of the BNST in humans diagnosed with anxiety disorders.
“These data inform current debates on BNST function (65) and are consistent with reports of increased reactivity of the BNST in humans diagnosed with anxiety disorders (66).”
From Sexual differentiation of neural mechanisms of stress sensitivity during puberty (2023) · cites this paper as [66]
The Results (BNST Connectivity) associate higher social anxiety with altered BNST connectivity and a greater BNST-than-amygdala response to certain unpredictable images. But the Methods (Participants) describe a sample spanning social-anxiety levels, only nine of whom met criteria for an anxiety disorder; the Results (BNST Activation) say social anxiety did not moderate BNST activation. Thus the paper does not establish generally increased BNST reactivity in people diagnosed with anxiety disorders. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Etkin, A., & Wager, T. D. (2007) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2007.07030504 · Cited by 3,391 · cited 1× · see citing works
“A decade of neuroimaging studies have dissected the fear neurocircuitry in humans and provided compelling evidence that anxiety disorders are associated with amygdala hyperactivity and amygdala‐frontal hypoconnectivity (Brühl, Delsignore, Komossa, & Weidt, 2014; Etkin & Wager, 2007).”
BackgroundA cognitive-behavioral model of anxiety in social phobia
Rapee, R. M., & Heimberg, R. G. (1997) · Behaviour Research and Therapy · doi:10.1016/s0005-7967(97)00022-3 · Cited by 2,987 · see citing works
Self-referential processing in our brain—A meta-analysis of imaging studies on the self
Northoff, G., Heinzel, A., de Greck, M., Bermpohl, F., Dobrowolny, H., & Panksepp, J. (2006) · NeuroImage · doi:10.1016/j.neuroimage.2005.12.002 · Cited by 2,792 · see citing works
Uncertainty and anticipation in anxiety: an integrated neurobiological and psychological perspective
Grupe, D. W., & Nitschke, J. B. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3524 · Cited by 2,007 · see citing works
Global prevalence of anxiety disorders: a systematic review and meta-regression
Baxter, A. J., Scott, K. M., Vos, T., & Whiteford, H. A. (2013) · Psychological Medicine · doi:10.1017/s003329171200147x · Cited by 1,537 · see citing works
Phasic vs Sustained Fear in Rats and Humans: Role of the Extended Amygdala in Fear vs Anxiety
Davis, M., Walker, D. L., Miles, L., & Grillon, C. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2009.109 · Cited by 1,488 · cited 4× · see citing works
“…responses to contextual, distant, or diffuse cues; in contrast to lesions to the amygdala which reduced responses to explicit or direct threats (Davis, Falls, Campeau, & Kim, 1993; Davis et al., 2010; Lee & Davis, 1997; Sullivan et al., 2004; Waddell, Morris, & Bouton, 2006; Walker & Davis, 1997).”
BackgroundResultInfluentialAlheid, G. F., & Heimer, L. (1988) · Neuroscience · doi:10.1016/0306-4522(88)90217-5 · Cited by 1,217 · see citing works
Leech, R., Kamourieh, S., Beckmann, C. F., & Sharp, D. J. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.5626-10.2011 · Cited by 759 · see citing works
Intolerance of uncertainty and social anxiety
Boelen, P. A., & Reijntjes, A. (2009) · Journal of Anxiety Disorders · doi:10.1016/j.janxdis.2008.04.007 · Cited by 436 · cited 2× · see citing works
“…uncertainty and unpredictability are central to anxiety disorders in general (Grupe & Nitschke, 2013) and social anxiety more specifically (Boelen & Reijntjes, 2009; Carleton et al., 2010); thus greater sensitivity to contexts of unpredictability may be a trait that contributes to…”
BackgroundHuman Bed Nucleus of the Stria Terminalis Indexes Hypervigilant Threat Monitoring
Somerville, L. H., Whalen, P. J., & Kelley, W. M. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.04.002 · Cited by 351 · see citing works
Phasic and sustained fear in humans elicits distinct patterns of brain activity
Alvarez, R. P., Chen, G., Bodurka, J., Kaplan, R., & Grillon, C. (2011) · NeuroImage · doi:10.1016/j.neuroimage.2010.11.057 · Cited by 299 · see citing works
Waiting for spiders: Brain activation during anticipatory anxiety in spider phobics
Straube, T., Mentzel, H.-J., & Miltner, W. H. R. (2007) · NeuroImage · doi:10.1016/j.neuroimage.2007.06.023 · Cited by 282 · see citing works
Carleton, R. N., Collimore, K. C., & Asmundson, G. J. G. (2010) · Journal of Anxiety Disorders · doi:10.1016/j.janxdis.2009.10.007 · Cited by 268 · cited 2× · see citing works
“…are central to anxiety disorders in general (Grupe & Nitschke, 2013) and social anxiety more specifically (Boelen & Reijntjes, 2009; Carleton et al., 2010); thus greater sensitivity to contexts of unpredictability may be a trait that contributes to heightened social anxiety and may…”
BackgroundExploring the function of selective attention and hypervigilance for threat in anxiety
Richards, H. J., Benson, V., Donnelly, N., & Hadwin, J. A. (2014) · Clinical Psychology Review · doi:10.1016/j.cpr.2013.10.006 · Cited by 221 · see citing works
Craske, M. G., Niles, A. N., Burklund, L. J., Wolitzky-Taylor, K. B., Vilardaga, J. C. P., Arch, J. J., Saxbe, D. E., & Lieberman, M. D. (2014) · Journal of Consulting and Clinical Psychology · doi:10.1037/a0037212 · Cited by 206 · cited 1× · see citing works
“Approximately half of the individuals with anxiety disorders either fail to respond to treatment, only partially respond, or relapse (Blanco et al., 2010; Craske et al., 2015; Ginsburg et al., 2014).”
BackgroundBlanco, C., Heimberg, R. G., Schneier, F. R., Fresco, D. M., Chen, H., Turk, C. L., Vermes, D., Erwin, B. A., Schmidt, A. B., Juster, H. R., et al. (2010) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2010.11 · Cited by 206 · cited 1× · see citing works
“Approximately half of the individuals with anxiety disorders either fail to respond to treatment, only partially respond, or relapse (Blanco et al., 2010; Craske et al., 2015; Ginsburg et al., 2014).”
BackgroundWaddell, J., Morris, R. W., & Bouton, M. E. (2006) · Behavioral Neuroscience · doi:10.1037/0735-7044.120.2.324 · Cited by 183 · see citing works
Yassa, M. A., Hazlett, R. L., Stark, C. E. L., & Hoehn-Saric, R. (2012) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2012.04.013 · Cited by 155 · see citing works
Flagged first, then by citations
Research works printed but not linked: 39
- Avery SN, Clauss JA, & Blackford JU (2016). The human BNST: functional role in anxiety and addiction. Neuropsychopharmacology, 41(February), 126– 141. 26105138 PMC4677124
- Avery SN, Clauss JA, Winder DG, Woodward N, Heckers S, & Blackford JU (2014). BNST neurocircuitry in humans. NeuroImage, 91, 311– 323. 24444996 PMC4214684
- Brinkmann L, Buff C, Feldker K, Neumeister P, Heitmann CY, Hofmann D, … Straube T (2018). Inter-individual differences in trait anxiety shape the functional connectivity between the bed nucleus of the stria terminalis and the amygdala during brief threat processing. NeuroImage, 166(6 2017), 110– 116. 29107120
- Brinkmann L, Poller H, Herrmann MJ, Miltner W, & Straube T (2017). Initial and sustained brain responses to threat anticipation in blood-injection-injury phobia. NeuroImage: Clinical, 13(2017), 320– 329. 28066706 PMC5200881
- Brühl AB, Delsignore A, Komossa K, & Weidt S (2014). Neuroimaging in Social Anxiety Disorder–a meta-analytic review resulting in a new neurofunctional model. Neuroscience & Biobehavioral Reviews, 47, 260– 280. 25124509
- Buff C, Brinkmann L, Bruchmann M, Becker MPI, Tupak S, Herrmann MJ, & Straube T (2017). Activity alterations in the bed nucleus of the stria terminalis and amygdala during threat anticipation in generalized anxiety disorder. Social Cognitive and Affective Neuroscience, (1), 1766– 1774. 28981839 PMC5714227
- Choi JM, Padmala S, & Pessoa L (2012). Impact of state anxiety on the interaction between threat monitoring and cognition. NeuroImage, 59(2), 1912– 1923. 21939773 PMC3230669
- Clauss JA, Avery SN, Vanderklok RM, Rogers BP, Cowan RL, Benningfield MM, & Blackford JU (2014). Neurocircuitry underlying risk and resilience to social anxiety disorder. Depression and Anxiety, 31(10), 822– 833. 24753211 PMC4314099
- Davis M, Falls WA, Campeau S, & Kim M (1993). Fear-potentiated startle: A neural and pharmacological analysis. Behavioural Brain Research, 58(1–2), 175– 198. 8136044
- First MB, Spitzer RL, Gibbon M, & Williams JBW (2002). Structured Clinical Interview For DSM-IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P). New York: Biometrics Research, New York State Psychiatric Institute.
- Fox AS, & Kalin NH (2014). A translational neuroscience approach to understanding the development of social anxiety disorder and its pathophysiology. The American Journal of Psychiatry, 171(11), 1162. 25157566 PMC4342310
- Fox AS, Oler JA, Birn RM, Shackman AJ, Alexander AL, & Kalin NH (2018). Functional connectivity within the primate extended amygdala is heritable and associated with early-life anxious temperament. The Journal of Neuroscience, 0102– 18. PMC6113902 30061190
- Fox AS, Oler JA, Shackman AJ, Shelton SE, Raveendran M, McKay DR, … Kalin NH (2015). Intergenerational neural mediators of early-life anxious temperament. Proceedings of the National Academy of Sciences of the United States of America, 201508593. PMC4517228 26150480
- Fox AS, Shelton SE, Oakes TR, Converse AK, Davidson RJ, & Kalin NH (2010). Orbitofrontal cortex lesions alter anxiety-related activity in the primate bed nucleus of stria terminalis. Journal of Neuroscience, 30(20), 7023– 7027. 20484644 PMC2915894
- Ganella DE, Drummond KD, Ganella EP, Whittle S, & Kim JH (2018). Extinction of conditioned fear in adolescents and adults: a human fMRI study. Frontiers in Human Neuroscience, 11(1), 1– 13. PMC5766664 29358913
- Ginsburg GS, Becker EM, Keeton CP, Sakolsky D, Piacentini J, Albano AM, … Kendall PC (2014). Naturalistic follow-up of youths treated for pediatric anxiety disorders. JAMA Psychiatry, 21205, 1– 9. PMC3969570 24477837
- Gorka AX, Torrisi S, Shackman AJ, Grillon C, & Ernst M (2017). Intrinsic functional connectivity of the central nucleus of the amygdala and bed nucleus of the stria terminalis. NeuroImage, (9), 1– 22. PMC5630489 28392491
- Grupe DW, Oathes DJ, & Nitschke JB (2013). Dissecting the anticipation of aversion reveals dissociable neural networks. Cerebral Cortex, 23(8), 1874– 83. 22763169 PMC3698367
- Herrmann MJ, Boehme S, Becker MPI, Tupak SV, Guhn A, Schmidt B, … Straube T (2016). Phasic and sustained brain responses in the amygdala and the bed nucleus of the stria terminalis during threat anticipation. Human Brain Mapping, 37(3), 1091– 1102. 26678871 PMC6867277
- Kessler RC, Chiu WT, Demler O, & Walters EE (2005). Prevalence, severity, and comorbidity of twelve-month DSM-IV disorders in the National Comorbidity Survey Replication (NCS-R). Archives of General Psychiatry, 62(6), 617– 627. 15939839 PMC2847357
- Klumpers F, Kroes MC, Heitland I, Everaerd D, Akkermans SEA, Oosting RS, … Baas JMP (2015). Dorsomedial prefrontal cortex mediates the impact of serotonin transporter linked polymorphic region genotype on anticipatory threat reactions. Biological Psychiatry, 78(8), 582– 589. 25444169
- Klumpers F, Kroes MCW, Baas J, & Fernández G (2017). How human amygdala and bed nucleus of the stria terminalis may drive distinct defensive responses. The Journal of Neuroscience, 37(40), 3830– 16. PMC6596617 28893930
- Lee Y, & Davis M (1997). Role of the hippocampus, the bed nucleus of the stria terminalis, and the amygdala in the excitatory effect of corticotropin-releasing hormone on the acoustic startle reflex. The Journal of Neuroscience, 17(16), 6434– 6446. 9236251 PMC6568348
- Mcmenamin BW, Langeslag SJE, Sirbu M, Padmala S, & Pessoa XL (2014). Network organization unfolds over time during periods of anxious anticipation. Journal of Neuroscience, 34(34), 11261– 11273. 25143607 PMC4138337
- Motzkin JC, Philippi CL, Oler JA, Kalin NH, Baskaya MK, & Koenigs M (2015). Ventromedial prefrontal cortex damage alters resting blood flow to the bed nucleus of stria terminalis. Cortex, 64, 281– 288. 25569763 PMC4346536
- Münsterkötter AL, Notzon S, Redlich R, Grotegerd D, Dohm K, Arolt V, … Dannlowski U (2015). Spider or no spider? neural correlates of sustained and phasic fear in spider phobia. Depression and Anxiety, 32(9), 656– 663. 26115440
- Pedersen WS, Balderston NL, Miskovich TA, Belleau EL, Helmstetter FJ, & Larson CL (2017). The effects of stimulus novelty and negativity on BOLD activity in the amygdala, hippocampus, and bed nucleus of the stria terminalis. Social Cognitive and Affective Neuroscience, 12(5), 748– 757. 28008079 PMC5460050
- Pedersen WS, Tugan Muftuler L, & Larson CL (2017). Disentangling the effects of novelty, valence and trait anxiety in the bed nucleus of the stria terminalis, amygdala and hippocampus with high resolution 7T fMRI. NeuroImage, 156, 293– 301. 28502843 PMC5548630
- Shackman AJ, & Fox AS (2016). Contributions of the Central Extended Amygdala to Fear and Anxiety. Journal of Neuroscience, 36(31), 8050– 8063. 27488625 PMC4971357
- Somerville LH, Wagner DD, Wig GS, Moran JM, Whalen PJ, & Kelley WM (2013). Interactions between transient and sustained neural signals support the generation and regulation of anxious emotion. Cerebral Cortex, 23(1), 49– 60. 22250290 PMC3513951
- Stein MB, & Kean YM (2000). Disability and quality of life in social phobia: epidemiologic findings. American Journal of Psychiatry, 157(10), 1606– 1613. 11007714
- Sullivan GM, Apergis J, Bush DEA, Johnson LR, Hou M, & Ledoux JE (2004). Lesions in the bed nucleus of the stria terminalis disrupt corticosterone and freezing responses elicited by a contextual but not by a specific cue-conditioned fear stimulus. Neuroscience, 128(1), 7– 14. 15450349
- Tillman RM, Stockbridge MD, Nacewicz BM, Torrisi S, Fox AS, Smith JF, & Shackman AJ (2018). Intrinsic functional connectivity of the central extended amygdala. Human Brain Mapping, 39(3), 1291– 1312. 29235190 PMC5807241
- Torrisi S, Gorka AX, Gonzalez-Castillo J, Balderston N, Grillon C, & Ernst M (2017). Extended amygdala connectivity changes during sustained shock anticipation. Translational Psychiatry. PMC5802685 29382815
- Torrisi S, O’Connell K, Davis A, Reynolds R, Balderston N, Fudge JL, … Ernst M (2015). Resting state connectivity of the bed nucleus of the stria terminalis at ultra-high field. Human Brain Mapping, 36(10), 4076– 4088. 26178381 PMC4583367
- Turner SM, Beidel DC, Dancu CV, & Stanley MA (1989). An empirically derived inventory to measure social fears and anxiety: The social phobia and anxiety inventory. Psychological Assessment, 1(1), 35– 40.
- Walker DL, & Davis M (1997). Double dissociation between the involvement of the bed nucleus of the stria terminalis and the central nucleus of the amygdala in startle increases produced by conditioned versus unconditioned fear. The Journal of Neuroscience, 17(23), 9375– 9383. 9364083 PMC6573581
- Yarkoni T (2009). Big correlations in little studies. Perspect. Psychol. Stud, 4(3), 294– 298. 26158966
- Zald DH (2003). The human amygdala and the emotional evaluation of sensory stimuli. Brain Research Reviews, 41(1), 88– 123. 12505650
Cited by
Sorted by citations
Extrahypothalamic oxytocin neurons drive stress-induced social vigilance and avoidance
Duque-Wilckens, N., Torres, L. Y., Yokoyama, S., Minie, V. A., Tran, A. M., Petkova, S. P., Hao, R., Ramos-Maciel, S., Rios, R. A., Jackson, K., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2011890117 · Cited by 139 · see citing works
Hu, P., Liu, J., Maita, I., Kwok, C., Gu, E., Gergues, M. M., Kelada, F., Phan, M., Zhou, J.-N., Swaab, D. F., et al. (2020) · The Journal of Neuroscience · doi:10.1523/jneurosci.2410-19.2020 · Cited by 71 · see citing works
Neural systems that facilitate the representation of social rank
Dwortz, M. F., Curley, J. P., Tye, K. M., & Padilla-Coreano, N. (2022) · Philosophical Transactions of the Royal Society B · doi:10.1098/rstb.2020.0444 · Cited by 64 · see citing works
Borie, A. M., Dromard, Y., Guillon, G., Olma, A., Manning, M., Muscatelli, F., Desarménien, M. G., & Jeanneteau, F. (2021) · Journal of Clinical Investigation · doi:10.1172/jci144450 · Cited by 41 · see citing works
Sexual differentiation of neural mechanisms of stress sensitivity during puberty
Wright, E. C., Luo, P. X., Zakharenkov, H. C., Serna Godoy, A., Lake, A. A., Prince, Z. D., Sekar, S., Culkin, H. I., Ramirez, A. V., Dwyer, T., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2306475120 · Cited by 34 · see citing works
- Authors
- Clauss, J. A., Avery, S. N., Benningfield, M. M., & Blackford, J. U.
- Affiliations
- Harvard University (US)
- Vanderbilt University (US)
- Corresponding author
- Blackford, Jennifer U.
- Venue
- Depression and Anxiety
- Publisher
- Wiley
- Published
- 2019-04-06
- Volume
- 36
- Issue
- 8
- Pages
- 666-675
- ISSN
- 1091-4269 (ISSN-L)
- 1520-6394
- PMC
- PMC6679811
- OpenAlex
- W2928149567
- Cited by
- 75
- References
- 18
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 7 · 2023: 17 · 2022: 12 · 2021: 16 · 2020: 10 · 2019: 6
- FWCI
- 12.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Depression and Anxiety (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Veterans Affairs (CX001226)
- National Institute of Mental Health (MH018921, MH097344, MH083052)
- National Center for Research Resources (RR024975, RR024978)
- National Institute of General Medical Sciences (GM07347)
- Topics
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- social anxiety, bed nucleus of the stria terminalis, unpredictability, threat anticipation, ventromedial prefrontal cortex, posterior cingulate cortex, postcentral gyrus, anxiety disorders
- MeSH terms
- Phobia, Social, Adolescent, Adult, Animals, Cues, Fear, Female, Humans, Magnetic Resonance Imaging, Male, Septal Nuclei, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
