Hostname: page-component-797576ffbb-pxgks Total loading time: 0 Render date: 2023-12-05T12:04:21.164Z Has data issue: false Feature Flags: { "corePageComponentGetUserInfoFromSharedSession": true, "coreDisableEcommerce": false, "useRatesEcommerce": true } hasContentIssue false

Neural correlates of learning accommodation and consolidation in generalised anxiety disorder

Published online by Cambridge University Press:  27 May 2022

Marta Migó
Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Tina Chou
Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Alik S. Widge
Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA
Amy T. Peters
Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Kristen Ellard
Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Darin D. Dougherty*
Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Thilo Deckersbach
Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA University of Applied Sciences, Diploma Hochschule, Germany
Corresponding author: Darin D. Dougherty; Email:



Anxiety can interfere with attention and working memory, which are components that affect learning. Statistical models have been designed to study learning, such as the Bayesian Learning Model, which takes into account prior possibilities and behaviours to determine how much of a new behaviour is determined by learning instead of chance. However, the neurobiological basis underlying how anxiety interferes with learning is not yet known. Accordingly, we aimed to use neuroimaging techniques and apply a Bayesian Learning Model to study learning in individuals with generalised anxiety disorder (GAD).


Participants were 25 controls and 14 individuals with GAD and comorbid disorders. During fMRI, participants completed a shape-button association learning and reversal task. Using a flexible factorial analysis in SPM, activation in the dorsolateral prefrontal cortex, basal ganglia, and hippocampus was compared between groups during first reversal. Beta values from the peak of these regions were extracted for all learning conditions and submitted to repeated measures analyses in SPSS.


Individuals with GAD showed less activation in the basal ganglia and the hippocampus only in the first reversal compared with controls. This difference was not present in the initial learning and second reversal.


Given that the basal ganglia is associated with initial learning, and the hippocampus with transfer of knowledge from short- to long-term memory, our results suggest that GAD may engage these regions to a lesser extent during early accommodation or consolidation of learning, but have no longer term effects in brain activation patterns during subsequent learning.

Original Article
© The Author(s), 2022. Published by Cambridge University Press on behalf of Scandinavian College of Neuropsychopharmacology

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)


Ahn, WY, Haines, N and Zhang, L (2017) Revealing neurocomputational mechanisms of reinforcement learning and decision-making with the HBayesDM Package. Computational Psychiatry 1(0), 2457. DOI: 10.1162/CPSY_a_00002.CrossRefGoogle ScholarPubMed
American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders, 5th edn. American Psychiatric Association.Google Scholar
Ashcraft, MH and Kirk, EP (2001) The relationships among working memory, math anxiety, and performance. Journal of Experimental Psychology: General 130(2), 224237. DOI: 10.1037/0096-3445.130.2.224.CrossRefGoogle ScholarPubMed
Aylward, J, Valton, V, Ahn, WY, Bond, RL, Dayan, P, Roiser, JP and Robinson, OJ (2019) Altered learning under uncertainty in unmedicated mood and anxiety disorders. Nature Human Behaviour 3(10), 11161123. DOI: 10.1038/s41562-019-0628-0.CrossRefGoogle ScholarPubMed
Balderston, NL, Vytal, KE, O’Connell, K, Torrisi, S, Letkiewicz, A, Ernst, M and Grillon, C (2017) Anxiety patients show reduced working memory related DlPFC activation during safety and threat: research article: anxiety patients show reduced DlPFC activity. Depression and Anxiety 34(1), 2536. DOI: 10.1002/da.22518.CrossRefGoogle Scholar
Bannerman, DM, Rawlins, JNP, McHugh, SB, Deacon, RMJ, Yee, BK, Bast, T, Zhang, WN, Pothuizen, HHJ and Feldon, J (2004) Regional dissociations within the hippocampus—memory and anxiety. Neuroscience & Biobehavioral Reviews 28(3), 273283. DOI: 10.1016/j.neubiorev.2004.03.004.CrossRefGoogle ScholarPubMed
Barbey, AK, Koenigs, M and Grafman, J (2013) Dorsolateral prefrontal contributions to human working memory. Cortex 49(5), 11951205. DOI: 10.1016/j.cortex.2012.05.022.CrossRefGoogle ScholarPubMed
Bartolo, R and Averbeck, BB (2020) Prefrontal cortex predicts state switches during reversal learning. Neuron 106(6), 10441054. DOI: 10.1016/j.neuron.2020.03.024.CrossRefGoogle ScholarPubMed
Bertoglio, LJ, Joca, SRL and Guimarães, FS (2006) Further evidence that anxiety and memory are regionally dissociated within the hippocampus. Behavioural Brain Research 175(1), 183188. DOI: 10.1016/j.bbr.2006.08.021.CrossRefGoogle ScholarPubMed
Bishop, SJ (2009) Trait anxiety and impoverished prefrontal control of attention. Nature Neuroscience 12(1), 9298. DOI: 10.1038/nn.2242.CrossRefGoogle ScholarPubMed
Cools, R, Clark, L, Owen, AM and Robbins, TW (2002) Defining the Neural Mechanisms of Probabilistic Reversal Learning Using Event-Related Functional Magnetic Resonance Imaging. The Journal of Neuroscience 22(11), 45634567. DOI: 10.1523/JNEUROSCI.22-11-04563.2002.CrossRefGoogle ScholarPubMed
Cox, RW (1996) AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. Computers and Biomedical Research 29(3), 162173. DOI: 10.1006/cbmr.1996.0014.CrossRefGoogle ScholarPubMed
Derakshan, N and Eysenck, MW (2009) Anxiety, processing efficiency, and cognitive performance: new developments from attentional control theory. European Psychologist 14(2), 168176. DOI: 10.1027/1016-9040.14.2.168.CrossRefGoogle Scholar
Engin, E and Treit, D (2007) The role of hippocampus in anxiety: intracerebral infusion studies. Behavioural Pharmacology 18(5-6), 365374. DOI: 10.1097/FBP.0b013e3282de7929.CrossRefGoogle ScholarPubMed
Eysenck, MW, Derakshan, N, Santos, R and Calvo, MG (2007) Anxiety and cognitive performance: attentional control theory. Emotion 7(2), 336353. DOI: 10.1037/1528-3542.7.2.336.CrossRefGoogle ScholarPubMed
Fales, CL, Barch, DM, Burgess, GC, Schaefer, A, Mennin, DS, Gray, JR and Braver, TS (2008) Anxiety and cognitive efficiency: differential modulation of transient and sustained neural activity during a working memory task. Cognitive, Affective, & Behavioral Neuroscience 8(3), 239253. DOI: 10.3758/CABN.8.3.239.CrossRefGoogle ScholarPubMed
Forman, SD, Cohen, JD, Fitzgerald, M, Eddy, WF, Mintun, MA and Noll, DC (1995) Improved assessment of significant activation in Functional Magnetic Resonance Imaging (FMRI): use of a cluster-size threshold. Magnetic Resonance in Medicine 33(5), 636647. DOI: 10.1002/mrm.1910330508.CrossRefGoogle ScholarPubMed
Graybiel, AM (1995) Building action repertoires: memory and learning functions of the basal ganglia. Current Opinion in Neurobiology 5(6), 733741. DOI: 10.1016/0959-4388(95)80100-6.CrossRefGoogle ScholarPubMed
Harlé, KM, Guo, D, Zhang, S, Paulus, MP and Yu, AJ (2017) "Anhedonia and anxiety underlying depressive symptomatology have distinct effects on reward-based decision-making” edited by E. Vasilaki. PLoS One 12, e0186473. DOI: 10.1371/journal.pone.0186473.CrossRefGoogle Scholar
Jarrard, LE (1993) On the role of the hippocampus in learning and memory in the rat. Behavioral and Neural Biology 60(1), 926. DOI: 10.1016/0163-1047(93)90664-4.CrossRefGoogle ScholarPubMed
LaFreniere, LS and Newman, MG (2019) Probabilistic learning by positive and negative reinforcement in generalized anxiety disorder. Clinical Psychological Science 7(3), 502515. DOI: 10.1177/2167702618809366.CrossRefGoogle ScholarPubMed
Mah, L, Szabuniewicz, C and Fiocco, AJ (2016) Can anxiety damage the brain? Current Opinion in Psychiatry 29(1), 5663. DOI: 10.1097/YCO.0000000000000223.CrossRefGoogle ScholarPubMed
Maldjian, JA, Laurienti, PJ, Kraft, RA and Burdette, JH (2003) An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of FMRI data sets. NeuroImage 19(3), 12331239. DOI: 10.1016/S1053-8119(03)00169-1.CrossRefGoogle ScholarPubMed
Marchand, WR (2010) Cortico-basal ganglia circuitry: a review of key research and implications for functional connectivity studies of mood and anxiety disorders. Brain Structure and Function 215(2), 7396. DOI: 10.1007/s00429-010-0280-y.CrossRefGoogle ScholarPubMed
McHugh, SB, Deacon, RMJ, Rawlins, JNP and Bannerman, DM (2004) Amygdala and ventral hippocampus contribute differentially to mechanisms of fear and anxiety. Behavioral Neuroscience 118(1), 6378. DOI: 10.1037/0735-7044.118.1.63.CrossRefGoogle ScholarPubMed
McNab, F and Klingberg, T (2008) Prefrontal cortex and basal ganglia control access to working memory. Nature Neuroscience 11(1), 103107. DOI: 10.1038/nn2024.CrossRefGoogle ScholarPubMed
Moore, AB, Li, Z, Tyner, CE, Hu, X and Crosson, B (2013) Bilateral basal ganglia activity in verbal working memory. Brain and Language 125(3), 316323. DOI: 10.1016/j.bandl.2012.05.003.CrossRefGoogle ScholarPubMed
Morris, BH and Rottenberg, J (2015) Heightened reward learning under stress in generalized anxiety disorder: a predictor of depression resistance? Journal of Abnormal Psychology 124(1), 115127. DOI: 10.1037/a0036934.CrossRefGoogle ScholarPubMed
Myers, CE, Shohamy, D, Gluck, MA, Grossman, S, Kluger, A, Ferris, S, Golomb, J, Schnirman, G and Schwartz, R (2003) Dissociating hippocampal versus basal ganglia contributions to learning and transfer. Journal of Cognitive Neuroscience 15(2), 185193. DOI: 10.1162/089892903321208123.CrossRefGoogle ScholarPubMed
Packard, MG and Knowlton, BJ (2002) Learning and memory functions of the basal ganglia. Annual Review of Neuroscience 25(1), 563593. DOI: 10.1146/annurev.neuro.25.112701.142937.CrossRefGoogle ScholarPubMed
Piray, P, Ly, V, Roelofs, K, Cools, R and Toni, I (2019) Emotionally aversive cues suppress neural systems underlying optimal learning in socially anxious individuals. The Journal of Neuroscience 39(8), 14451456. DOI: 10.1523/JNEUROSCI.1394-18.2018.CrossRefGoogle ScholarPubMed
Seger, CA (2006) The basal ganglia in human learning. The Neuroscientist 12(4), 285290. DOI: 10.1177/1073858405285632.CrossRefGoogle ScholarPubMed
Sheehan, DV, Lecrubier, Y, Sheehan, KH, Amorim, P, Janavs, J, Weiller, E, Hergueta, T, Baker, R and Dunbar, GC (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. The Journal of Clinical Psychiatry 59, 2233; quiz 34-57.Google ScholarPubMed
Van Der Kouwe, AJW, Benner, T, Salat, DH and Fischl, B (2008) Brain morphometry with multiecho MPRAGE. NeuroImage, 40(2), 559569. DOI: 10.1016/j.neuroimage.2007.12.025.CrossRefGoogle ScholarPubMed
Vytal, KE, Arkin, NE, Overstreet, C, Lieberman, L and Grillon, C (2016) Induced-anxiety differentially disrupts working memory in generalized anxiety disorder. BMC Psychiatry 16(1), 62. DOI: 10.1186/s12888-016-0748-2.CrossRefGoogle ScholarPubMed
Wheelock, MD, Sreenivasan, KR, Wood, KH, Hoef, LWV, Deshpande, G and Knight, DC (2014) Threat-related learning relies on distinct dorsal prefrontal cortex network connectivity. NeuroImage 102, 904912. DOI: 10.1016/j.neuroimage.2014.08.005.CrossRefGoogle ScholarPubMed
Widge, AS, Ellard, KK, Paulk, AC, Basu, I, Yousefi, A, Zorowitz, S, Gilmour, A, Afzal, A, Deckersbach, T, Cash, SS, Kramer, MA, Eden, UT, Dougherty, DD, Eskandar, EN (2017) Treating refractory mental illness with closed-loop brain stimulation: progress towards a patient-specific transdiagnostic approach. Experimental Neurology 287(Pt 4), 461472. DOI: 10.1016/j.expneurol.2016.07.021.CrossRefGoogle ScholarPubMed
Wilson, A, Fern, A, Ray, S and Tadepalli, P (2007) Multi-Task Reinforcement Learning: A Hierarchical Bayesian Approach. Proceedings of the 24th international conference on Machine learning - ICML ’07, Corvalis, Oregon: ACM Press, 1015–22.CrossRefGoogle Scholar
Wu, JC, Buchsbaum, MS, Hershey, TG, Hazlett, E, Sicotte, N and Johnson, JC (1991) PET in generalized anxiety disorder. Biological Psychiatry 29(12), 11811199. DOI: 10.1016/0006-3223(91)90326-H.CrossRefGoogle ScholarPubMed
Xue, G, Xue, F, Droutman, V, Lu, Z-L, Bechara, A and Read, S (2013) "Common neural mechanisms underlying reversal learning by reward and punishment” edited by S. A. Simon. PLoS One 8, e82169. DOI: 10.1371/journal.pone.0082169.CrossRefGoogle Scholar
Yousefi, A, Paulk, AC, Basu, I, Mirsky, JL, Dougherty, DD, Eskandar, EN, Eden, UT and Widge, A-S (2019) COMPASS: an open-source, general-purpose software toolkit for computational psychiatry. Frontiers in Neuroscience 12, 957. DOI: 10.3389/fnins.2018.00957.CrossRefGoogle ScholarPubMed
Zorowitz, S, Rockhill, AP, Ellard, KK, Link, KE, Herrington, T, Pizzagalli, DA, Widge, AS, Deckersbach, T and Dougherty, DD (2019) The neural basis of approach-avoidance conflict: a model based analysis. Eneuro 6(4). DOI: 10.1523/ENEURO.0115-19.2019.CrossRefGoogle ScholarPubMed
Supplementary material: File

Migó et al. supplementary material

Migó et al. supplementary material

Download Migó et al. supplementary material(File)
File 16 KB