Basolateral Amygdala Connectivity With Subgenual Anterior Cingulate Cortex Represents Enhanced Fear-Related Memory Encoding in Anxious Humans

Published:November 26, 2019DOI:https://doi.org/10.1016/j.bpsc.2019.11.008

      Abstract

      Background

      The amygdala can enhance emotional memory encoding as well as anxiogenesis via corticotropin-releasing factor neurons. However, the amygdala’s explicit role in emotional encoding remains unclarified in humans. We examined how functional connectivity (FC) of amygdala subnuclei affects emotional encoding, considering its mechanism in which anxiety, attention, and cortisol conceivably participate.

      Methods

      A total of 65 healthy humans underwent resting-state functional magnetic resonance imaging scans and saliva collection at 10 points in time over 2 days. FC analysis was performed for basolateral amygdala subnucleus (BLA) and centromedial amygdala subnucleus. We assessed attentional control via an emotional Stroop task and assessed emotional encoding via a facial identification task that examines how strongly a neutral face is memorized when accompanied by an emotional face (fearful, sad, or happy). FC and task performance were compared between high-anxious and non-high-anxious groups classified by anxious personality scores.

      Results

      BLA connected with subgenual anterior cingulate cortex (sgACC) in proportion to the strength of fear-related encoding, whereas centromedial subnucleus connected with caudate nucleus for happy-related encoding. The high-anxious group showed more enhanced fear-related encoding but impaired happy-related encoding compared with the non-high-anxious group. BLA–sgACC FC was more intensified in the high-anxious group than in the non-high-anxious group; however, centromedial–caudate FC did not differ between them. Although emotional encoding was uncorrelated with either attentional control or cortisol, BLA–sgACC was positively correlated with cortisol increase after awakening.

      Conclusions

      The study revealed that neural interactions of BLA, specifically with sgACC, might play a critical role in fear-related memory encoding, depending on the individual’s level of anxiety. These findings aid in understanding the complicated mechanisms of emotional memory in anxiety disorders.

      Keywords

      To read this article in full you will need to make a payment

      References

        • Mathews A.
        • MacLeod C.
        Cognitive vulnerability to emotional disorders.
        Annu Rev Clin Psychol. 2005; 1: 167-195
        • Beck A.
        Cognitive Therapy and the Emotional Disorders.
        International Universities Press, New York1976
        • Williams J.
        • Watts F.
        • MacLeod C.
        • Mathews A.
        Cognitive Psychology and Emotional Disorders.
        John Wiley, New York1997
        • Bar-Haim Y.
        • Lamy D.
        • Pergamin L.
        • Bakermans-Kranenburg M.
        • van IJzendoorn M.
        Threat-related attentional bias in anxious and nonanxious individuals: A meta-analytic study.
        Psychol Bull. 2007; 133: 1-24
        • Cisler J.M.
        • Koster E.H.
        Mechanisms of attentional biases towards threat in anxiety disorders: An integrative review.
        Clin Psychol Rev. 2010; 30: 203-216
        • Eysenck M.W.
        • Derakshan N.
        • Santos R.
        • Calvo M.G.
        Anxiety and cognitive performance: Attentional control theory.
        Emotion. 2007; 7: 336-353
        • Mathews A.
        • Mackintosh B.
        A cognitive model of selective processing in anxiety.
        Cogn Ther Res. 1998; 22: 539-560
        • Hakamata Y.
        • Lissek S.
        • Bar-Haim Y.
        • Britton J.C.
        • Fox N.A.
        • Leibenluft E.
        • et al.
        Attention bias modification treatment: A meta-analysis toward the establishment of novel treatment for anxiety.
        Biol Psychiatry. 2010; 68: 982-990
        • Hakamata Y.
        • Izawa S.
        • Sato E.
        • Komi S.
        • Murayama N.
        • Moriguchi Y.
        • et al.
        Higher cortisol levels at diurnal trough predict greater attentional bias towards threat in healthy young adults.
        J Affect Disord. 2013; 151: 775-779
        • Dandeneau S.D.
        • Baldwin M.W.
        • Baccus J.R.
        • Sakellaropoulo M.
        • Pruessner J.C.
        Cutting stress off at the pass: Reducing vigilance and responsiveness to social threat by manipulating attention.
        J Pers Soc Psychol. 2007; 93: 651-666
        • McHugh R.K.
        • Behar E.
        • Gutner C.A.
        • Geem D.
        • Otto M.W.
        Cortisol, stress, and attentional bias toward threat.
        Anxiety Stress Coping. 2010; 23: 529-545
        • Dennis-Tiwary T.A.
        • Denefrio S.
        • Gelber S.
        Salutary effects of an attention bias modification mobile application on biobehavioral measures of stress and anxiety during pregnancy.
        Biol Psychol. 2017; 127: 148-156
        • Talmi D.
        Enhanced emotional memory: Cognitive and neural mechanisms.
        Curr Dir Psychol Sci. 2013; 22: 430-436
        • Phelps E.A.
        Human emotion and memory: Interactions of the amygdala and hippocampal complex.
        Curr Opin Neurobiol. 2004; 14: 198-202
        • Hamann S.
        Cognitive and neural mechanisms of emotional memory.
        Trends Cogn Sci. 2001; 5: 394-400
        • LaBar K.
        • Cabeza R.
        Cognitive neuroscience of emotional memory.
        Nat Rev Neurosci. 2006; 7: 54-64
        • Blaut A.
        • Paulewicz B.
        • Szastok M.
        • Prochwicz K.
        • Koster E.
        Are attentional bias and memory bias for negative words causally related?.
        J Behav Ther Exp Psychiatry. 2013; 44: 293-299
        • Kensinger E.A.
        • Corkin S.
        Memory enhancement for emotional words: Are emotional words more vividly remembered than neutral words?.
        Mem Cognit. 2003; 31: 1169-1180
        • Kensinger E.A.
        • Garoff-Eaton R.J.
        • Schacter D.L.
        How negative emotion enhances the visual specificity of a memory.
        J Cogn Neurosci. 2007; 19: 1872-1887
        • Rimmele U.
        • Davachi L.
        • Petrov R.
        • Dougal S.
        • Phelps E.A.
        Emotion enhances the subjective feeling of remembering, despite lower accuracy for contextual details.
        Emotion. 2011; 11: 553-562
        • LeDoux J.E.
        Emotion circuits in the brain.
        Annu Rev Neurosci. 2000; 23: 155-184
        • LeDoux J.
        The amygdala.
        Curr Biol. 2007; 17: R868-R874
        • Yonelinas A.P.
        • Ritchey M.
        The slow forgetting of emotional episodic memories: An emotional binding account.
        Trends Cogn Sci. 2015; 19: 259-267
        • Shields G.S.
        • Sazma M.A.
        • McCullough A.M.
        • Yonelinas A.P.
        The effects of acute stress on episodic memory: A meta-analysis and integrative review.
        Psychol Bull. 2017; 143: 636-675
        • Wolf O.T.
        Stress and memory in humans: Twelve years of progress?.
        Brain Res. 2009; 1293: 142-154
        • Wolf O.T.
        • Atsak P.
        • de Quervain D.J.
        • Roozendaal B.
        • Wingenfeld K.
        Stress and memory: A selective review on recent developments in the understanding of stress hormone effects on memory and their clinical relevance.
        J Neuroendocrinol. 2016; 28: 12353
        • Hakamata Y.
        • Komi S.
        • Sato E.
        • Izawa S.
        • Mizukami S.
        • Moriguchi Y.
        • et al.
        Cortisol-related hippocampal-extrastriate functional connectivity explains the adverse effect of cortisol on visuospatial retrieval.
        Psychoneuroendocrinology. 2019; 109: 104310
        • Erickson K.
        • Drevets W.
        • Schulkin J.
        Glucocorticoid regulation of diverse cognitive functions in normal and pathological emotional states.
        Neurosci Biobehav Rev. 2003; 27: 233-246
        • Reul J.M.
        • de Kloet E.R.
        Two receptor systems for corticosterone in rat brain: Microdistribution and differential occupation.
        Endocrinology. 1985; 117: 2505-2511
        • Mosher C.P.
        • Zimmerman P.E.
        • Gothard K.M.
        Response characteristics of basolateral and centromedial neurons in the primate amygdala.
        J Neurosci. 2010; 30: 16197-16207
        • McDonald A.
        Cell types and intrinsic connections of the amygdala.
        in: Aggleton J. The Amygdala. Wiley–Liss, New York1992: 67-96
        • Johansen J.P.
        • Cain C.K.
        • Ostroff L.E.
        • LeDoux J.E.
        Molecular mechanisms of fear learning and memory.
        Cell. 2011; 147: 509-524
        • Herry C.
        • Johansen J.P.
        Encoding of fear learning and memory in distributed neuronal circuits.
        Nat Neurosci. 2014; 17: 1644-1654
        • Grosso A.
        • Santoni G.
        • Manassero E.
        • Renna A.
        • Sacchetti B.
        A neuronal basis for fear discrimination in the lateral amygdala.
        Nat Commun. 2018; 9: 1214
        • Resnik J.
        • Paz R.
        Fear generalization in the primate amygdala.
        Nat Neurosci. 2015; 18: 188-190
        • Sep M.S.C.
        • Steenmeijer A.
        • Kennis M.
        The relation between anxious personality traits and fear generalization in healthy subjects: A systematic review and meta-analysis.
        Neurosci Biobehav Rev. 2019; 107: 320-328
        • Roozendaal B.
        • McGaugh J.L.
        Memory modulation.
        Behav Neurosci. 2011; 125: 797-824
        • Roozendaal B.
        • Brunson K.L.
        • Holloway B.L.
        • McGaugh J.L.
        • Baram T.Z.
        Involvement of stress-released corticotropin-releasing hormone in the basolateral amygdala in regulating memory consolidation.
        Proc Natl Acad Sci U S A. 2002; 99: 13908-13913
        • Roozendaal B.
        • Okuda S.
        • Van der Zee E.
        • McGaugh J.
        Glucocorticoid enhancement of memory requires arousal-induced noradrenergic activation in the basolateral amygdala.
        Proc Natl Acad Sci U S A. 2006; 103: 6741-6746
        • Barsegyan A.
        • Mirone G.
        • Ronzoni G.
        • Guo C.
        • Song Q.
        • van Kuppeveld D.
        • et al.
        Glucocorticoid enhancement of recognition memory via basolateral amygdala-driven facilitation of prelimbic cortex interactions.
        Proc Natl Acad Sci U S A. 2019; 116: 7077-7082
        • Bishop S.J.
        • Jenkins R.
        • Lawrence A.D.
        Neural processing of fearful faces: Effects of anxiety are gated by perceptual capacity limitations.
        Cereb Cortex. 2007; 17: 1595-1603
        • Shin L.
        • Liberzon I.
        The neurocircuitry of fear, stress, and anxiety disorders.
        Neuropsychopharmacology. 2010; 35: 169-191
        • McGarry L.M.
        • Carter A.G.
        Inhibitory gating of basolateral amygdala inputs to the prefrontal cortex.
        J Neurosci. 2016; 36: 9391-9406
        • Sotres-Bayon F.
        • Quirk G.J.
        Prefrontal control of fear: More than just extinction.
        Curr Opin Neurobiol. 2010; 20: 231-235
        • Bishop S.J.
        Neural mechanisms underlying selective attention to threat.
        Ann N Y Acad Sci. 2008; 1129: 141-152
        • Marusak H.A.
        • Thomason M.E.
        • Peters C.
        • Zundel C.
        • Elrahal F.
        • Rabinak C.A.
        You say “prefrontal cortex” and I say “anterior cingulate”: Meta-analysis of spatial overlap in amygdala-to-prefrontal connectivity and internalizing symptomology.
        Transl Psychiatry. 2016; 6: e944
        • Felix-Ortiz A.C.
        • Burgos-Robles A.
        • Bhagat N.D.
        • Leppla C.A.
        • Tye K.M.
        Bidirectional modulation of anxiety-related and social behaviors by amygdala projections to the medial prefrontal cortex.
        Neuroscience. 2016; 321: 197-209
        • Likhtik E.
        • Stujenske J.M.
        • Topiwala M.A.
        • Harris A.Z.
        • Gordon J.A.
        Prefrontal entrainment of amygdala activity signals safety in learned fear and innate anxiety.
        Nat Neurosci. 2014; 17: 106-113
        • Reznikov R.
        • Bambico F.R.
        • Diwan M.
        • Raymond R.J.
        • Nashed M.G.
        • Nobrega J.N.
        • et al.
        Prefrontal cortex deep brain stimulation improves fear and anxiety-like behavior and reduces basolateral amygdala activity in a preclinical model of posttraumatic stress disorder.
        Neuropsychopharmacology. 2018; 43: 1099-1106
        • Hakamata Y.
        • Komi S.
        • Moriguchi Y.
        • Izawa S.
        • Motomura Y.
        • Sato E.
        • et al.
        Amygdala-centred functional connectivity affects daily cortisol concentrations: A putative link with anxiety.
        Sci Rep. 2017; 7: 8313
        • Veer I.M.
        • Oei N.Y.
        • Spinhoven P.
        • van Buchem M.A.
        • Elzinga B.M.
        • Rombouts S.A.
        Endogenous cortisol is associated with functional connectivity between the amygdala and medial prefrontal cortex.
        Psychoneuroendocrinology. 2012; 37: 1039-1047
        • Laird A.R.
        • Eickhoff S.B.
        • Li K.
        • Robin D.A.
        • Glahn D.C.
        • Fox P.T.
        Investigating the functional heterogeneity of the default mode network using coordinate-based meta-analytic modeling.
        J Neurosci. 2009; 29: 14496-14505
        • Sheehan D.V.
        • Lecrubier Y.
        • Sheehan K.H.
        • Amorim P.
        • Janavs J.
        • Weiller E.
        • et al.
        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.
        J Clin Psychiatry. 1998; 59 (quiz 34–57): 22-33
        • Oldfield R.C.
        The assessment and analysis of handedness: The Edinburgh inventory.
        Neuropsychologia. 1971; 9: 97-113
        • Temple J.L.
        • Bernard C.
        • Lipshultz S.E.
        • Czachor J.D.
        • Westphal J.A.
        • Mestre M.A.
        The safety of ingested caffeine: A comprehensive review.
        Front Psychiatry. 2017; 8: 80
        • Costa P.
        • McCrae R.
        Revised NEO Personality Inventory and Five-Factor Inventory Professional Manual.
        Psychological Assessment Resources, Odessa, FL1992
        • Shimonaka J.
        • Nagazato K.
        • Gondo Y.
        • Takayama M.
        Construction and factorial validity of the Japanese NEO-PI-R.
        Jpn J Pers. 1998; 6: 138-147
        • Costa P.
        • McCrae R.
        The NEO Personality Inventory Manual.
        Psychological Assessment Resources, Odessa, FL1985
        • Hansen C.H.
        • Hansen R.D.
        Finding the face in the crowd: An anger superiority effect.
        J Pers Soc Psychol. 1988; 54: 917-924
        • Gilboa-Schechtman E.
        • Foa E.
        • Amir N.
        Attentional biases for facial expressions in social phobia: The face-in-the-crowd paradigm.
        Cogn Emot. 1999; 13: 305-318
        • Dodd H.F.
        • Vogt J.
        • Turkileri N.
        • Notebaert L.
        Task relevance of emotional information affects anxiety-linked attention bias in visual search.
        Biol Psychol. 2017; 122: 13-20
        • Tottenham N.
        • Tanaka J.W.
        • Leon A.C.
        • McCarry T.
        • Nurse M.
        • Hare T.A.
        • et al.
        The NimStim set of facial expressions: Judgments from untrained research participants.
        Psychiatry Res. 2009; 168: 242-249
        • Peer P.
        Computer Vision Laboratory Face Database.
        University of Ljubljana, Ljubljana, Slovenia1999
        • Gotlib I.H.
        • McCann C.D.
        Construct accessibility and depression: An examination of cognitive and affective factors.
        J Pers Soc Psychol. 1984; 47: 427-439
        • Algom D.
        • Chajut E.
        • Lev S.
        A rational look at the emotional Stroop phenomenon: A generic slowdown, not a Stroop effect.
        J Exp Psychol Gen. 2004; 133: 323-338
        • McKenna F.P.
        • Sharma D.
        Reversing the emotional Stroop effect reveals that it is not what it seems: The role of fast and slow components.
        J Exp Psychol Learn Mem Cogn. 2004; 30: 382-392
        • Sharma D.
        • McKenna F.P.
        The role of time pressure on the emotional Stroop task.
        Br J Psychol. 2001; 92: 471-481
        • Hakamata Y.
        • Mizukami S.
        • Komi S.
        • Sato E.
        • Moriguchi Y.
        • Motomura Y.
        • et al.
        Attentional bias modification alters intrinsic functional network of attentional control: A randomized controlled trial.
        J Affect Disord. 2018; 238: 472-481
        • Pruessner J.C.
        • Kirschbaum C.
        • Meinlschmid G.
        • Hellhammer D.H.
        Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change.
        Psychoneuroendocrinology. 2003; 28: 916-931
        • Likhtik E.
        • Paz R.
        Amygdala-prefrontal interactions in (mal)adaptive learning.
        Trends Neurosci. 2015; 38: 158-166
        • Howell D.
        Statistical Methods for Psychology.
        8th ed. Cengage Learning, Belmont, CA2012
        • Benjamini Y.
        • Hochberg Y.
        Controlling the false discovery rate: A practical and powerful approach to multiple testing.
        J R Statist Soc B Methodol. 1995; 57: 289-300
        • Bissière S.
        • Plachta N.
        • Hoyer D.
        • McAllister K.H.
        • Olpe H.R.
        • Grace A.A.
        • et al.
        The rostral anterior cingulate cortex modulates the efficiency of amygdala-dependent fear learning.
        Biol Psychiatry. 2008; 63: 821-831
        • Beckmann M.
        • Johansen-Berg H.
        • Rushworth M.F.
        Connectivity-based parcellation of human cingulate cortex and its relation to functional specialization.
        J Neurosci. 2009; 29: 1175-1190
        • Fillinger C.
        • Yalcin I.
        • Barrot M.
        • Veinante P.
        Efferents of anterior cingulate areas 24a and 24b and midcingulate areas 24a' and 24b' in the mouse.
        Brain Struct Funct. 2018; 223: 1747-1778
        • Allsop S.A.
        • Wichmann R.
        • Mills F.
        • Burgos-Robles A.
        • Chang C.J.
        • Felix-Ortiz A.C.
        • et al.
        Corticoamygdala transfer of socially derived information gates observational learning.
        Cell. 2018; 173: 1329-1342.e18
        • Jhang J.
        • Lee H.
        • Kang M.S.
        • Lee H.S.
        • Park H.
        • Han J.H.
        Anterior cingulate cortex and its input to the basolateral amygdala control innate fear response.
        Nat Commun. 2018; 9: 2744
        • Burgos-Robles A.
        • Vidal-Gonzalez I.
        • Quirk G.J.
        Sustained conditioned responses in prelimbic prefrontal neurons are correlated with fear expression and extinction failure.
        J Neurosci. 2009; 29: 8474-8482
        • Herry C.
        • Vouimba R.M.
        • Garcia R.
        Plasticity in the mediodorsal thalamo-prefrontal cortical transmission in behaving mice.
        J Neurophysiol. 1999; 82: 2827-2832
        • Morgan M.A.
        • LeDoux J.E.
        Differential contribution of dorsal and ventral medial prefrontal cortex to the acquisition and extinction of conditioned fear in rats.
        Behav Neurosci. 1995; 109: 681-688
        • Fullana M.A.
        • Harrison B.J.
        • Soriano-Mas C.
        • Vervliet B.
        • Cardoner N.
        • Àvila-Parcet A.
        • et al.
        Neural signatures of human fear conditioning: An updated and extended meta-analysis of fMRI studies.
        Mol Psychiatry. 2016; 21: 500-508
        • Suarez-Jimenez B.
        • Albajes-Eizagirre A.
        • Lazarov A.
        • Zhu X.
        • Harrison B.J.
        • Radua J.
        • et al.
        Neural signatures of conditioning, extinction learning, and extinction recall in posttraumatic stress disorder: A meta-analysis of functional magnetic resonance imaging studies [published online ahead of print Jul 1].
        Psychol Med. 2019;
        • Picó-Pérez M.
        • Alemany-Navarro M.
        • Dunsmoor J.E.
        • Radua J.
        • Albajes-Eizagirre A.
        • Vervliet B.
        • et al.
        Common and distinct neural correlates of fear extinction and cognitive reappraisal: A meta-analysis of fMRI studies.
        Neurosci Biobehav Rev. 2019; 104: 102-115
        • Sharma K.K.
        • Kelly E.A.
        • Pfeifer C.W.
        • Fudge J.L.
        Translating fear circuitry: Amygdala projections to subgenual and perigenual anterior cingulate in the macaque [published online ahead of print Jun 20].
        Cereb Cortex. 2019;
        • Talmi D.
        • Schimmack U.
        • Paterson T.
        • Moscovitch M.
        The role of attention and relatedness in emotionally enhanced memory.
        Emotion. 2007; 7: 89-102
        • Sharot T.
        • Phelps E.A.
        How arousal modulates memory: Disentangling the effects of attention and retention.
        Cogn Affect Behav Neurosci. 2004; 4: 294-306
        • Baczkowski B.M.
        • Johnstone T.
        • Walter H.
        • Erk S.
        • Veer I.M.
        Sliding-window analysis tracks fluctuations in amygdala functional connectivity associated with physiological arousal and vigilance during fear conditioning.
        NeuroImage. 2017; 153: 168-178
        • Schultz D.H.
        • Balderston N.L.
        • Helmstetter F.J.
        Resting-state connectivity of the amygdala is altered following Pavlovian fear conditioning.
        Front Hum Neurosci. 2012; 6: 242
        • Tzschoppe J.
        • Nees F.
        • Banaschewski T.
        • Barker G.J.
        • Büchel C.
        • Conrod P.J.
        • et al.
        Aversive learning in adolescents: Modulation by amygdala-prefrontal and amygdala-hippocampal connectivity and neuroticism.
        Neuropsychopharmacology. 2014; 39: 875-884
        • Boggero I.A.
        • Hostinar C.E.
        • Haak E.A.
        • Murphy M.L.M.
        • Segerstrom S.C.
        Psychosocial functioning and the cortisol awakening response: Meta-analysis, P-curve analysis, and evaluation of the evidential value in existing studies.
        Biol Psychol. 2017; 129: 207-230
        • Chida Y.
        • Steptoe A.
        Cortisol awakening response and psychosocial factors: A systematic review and meta-analysis.
        Biol Psychol. 2009; 80: 265-278
        • Fries E.
        • Dettenborn L.
        • Kirschbaum C.
        The cortisol awakening response (CAR): Facts and future directions.
        Int J Psychophysiol. 2009; 72: 67-73
        • Clow A.
        • Hucklebridge F.
        • Thorn L.
        The cortisol awakening response in context.
        Int Rev Neurobiol. 2010; 93: 153-175
        • Stalder T.
        • Kirschbaum C.
        • Kudielka B.M.
        • Adam E.K.
        • Pruessner J.C.
        • Wüst S.
        • et al.
        Assessment of the cortisol awakening response: Expert consensus guidelines.
        Psychoneuroendocrinology. 2016; 63: 414-432
        • Mather M.
        • Knight M.
        The emotional harbinger effect: Poor context memory for cues that previously predicted something arousing.
        Emotion. 2008; 8: 850-860
        • Touryan S.R.
        • Marian D.E.
        • Shimamura A.P.
        Effect of negative emotional pictures on associative memory for peripheral information.
        Memory. 2007; 15: 154-166
        • Richman H.
        • Frueh B.C.
        Personality and PTSD II: Personality assessment of PTSD-diagnosed Vietnam veterans using the Cloninger Tridimensional Personality Questionnaire (TPQ).
        Depress Anxiety. 1997; 6: 70-77
        • Brewin C.R.
        Memory and forgetting.
        Curr Psychiatry Rep. 2018; 20: 87
        • Crespo M.
        • Fernández-Lansac V.
        Memory and narrative of traumatic events: A literature review.
        Psychol Trauma. 2016; 8: 149-156
        • Wolf O.
        Stress and memory retrieval: Mechanisms and consequences.
        Curr Opin Behav Sci. 2017; 14: 40-46