Neural circuits in anxiety and stress disorders: a focused review

Figures & data

Table 1 Summary of studies reviewed reporting structural and functional differences across anxiety and stress disorders

Study	Thalamus	Amygdala	Insula	Hippocampus	Medial prefrontal cortex
Neural volume
Panic disorder		↓ Del Casale et al (2013)^Citation38 ↓ Kim et al (2012)^Citation39 ↓ Pannekoek et al (2013)^Citation40		↓ Del Casale et al (2013)^Citation38 ↓ Pannekoek et al (2013)^Citation40 –
Specific phobia  Social anxiety disorder		↓ Fisler et al (2013)^Citation41 ↓ Irle (2010)^Citation45 ↑ Machado-de-Sousa et al (2014)^Citation47 – Syal et al (2012)^Citation46	– Rosso et al (2010)^Citation67 ↑ Bruhl et al (2014)^Citation66 ↓ Syal et al (2012)^Citation46	↓ Irle (2010)^Citation45 – Syal et al (2012)^Citation46 ↑ Machado-de-Sousa et al (2014)^Citation47 ↑ Talati et al (2013)^Citation108 ↓ Liao et al (2011)^Citation90 ↓ Qiu et al (2011)^Citation104	↑ Liao et al (2011)^Citation90
Generalized anxiety disorder		↑ Schienle et al (2011)^Citation43		↓ Hettema et al (2012)^Citation106	– Cha et al (2014)^Citation91
Posttraumatic stress disorder		↑ Kuo et al (2014)^Citation44 ↓ Rajendra et al (2012)^Citation42	↓ Chao et al (2013)^Citation69 ↓ Kroes et al (2011)^Citation70	↓ Chao et al (2013)^Citation69 ↓ Kuhn et al (2013)^Citation80 ↓ Rajendra et al (2012)^Citation42 ↓ Thomaes et al (2013)^Citation107 ↓ Woon et al (2010)^Citation105	↓ Chen et al (2012)^Citation92 ↓ Kuhn et al (2013)^Citation80 ↓ Nardo et al (2013)^Citation77 ↓ Weber et al (2013)^Citation93
Neural activation
Panic disorder		↑ Kim et al (2012)^Citation39 ↓ Ottaviani et al (2012)^Citation64
Specific phobia	↑ Caseras et al (2010)^Citation26 ↑ Hilbert et al (2014)^Citation27 ↑ Lueken et al (2011)^Citation29 ↑ Schweckendiek et al (2011)^Citation28	↑ Lipka et al (2011)^Citation48 ↑ Lueken et al (2013)^Citation49 ↑ Schweckendiek et al (2011)^Citation28 ↑ Caseras et al (2010)^Citation26	↑ Hilbert et al (2014)^Citation27 ↑ Lipka et al (2013)^Citation71 ↑ Lueken et al (2011)^Citation29 ↑ Schweckendiek et al (2011)^Citation28	↑ Lueken et al (2013)^Citation49
Social anxiety disorder	↑ Bruhl et al (2011)^Citation24 ↑ Gimenez et al (2012)^Citation25	↑ Ball et al (2012)^Citation50 ↑ Bruhl et al (2011)^Citation24 – Klumpp et al (2013)^Citation65 ↑ Klumpp et al (2010)^Citation51 ↑ Labuschangne et al (2010)^Citation55 ↑ Mansson et al (2013)^Citation56 ↑ Phan et al (2013)^Citation57 ↑ Schmidt et al (2010)^Citation52 ↑ Taylor et al (2013)^Citation58	↑ Ball et al (2012)^Citation50 ↑ Carre et al (2014)^Citation72 ↑ Gimenez et al (2014)^Citation31 ↑ Klumpp et al (2012)^Citation73 ↑ Klumpp et al (2013)^Citation65 ↑ Schmidt et al (2010)^Citation52 ↑ Taylor et al (2013)^Citation58	↑ Bruhl et al (2011)^Citation24	↑ Blair et al (2010)^Citation96 ↓ Sripada et al (2009)^Citation97 ↓ Taylor et al (2013)^Citation58
Generalized anxiety disorder		↑ Holzel et al (2013)^Citation60 – Palm et al (2011)^Citation62			↓ Etkin et al (2011)^Citation98 ↓ Palm et al (2011)^Citation62 ↓ Price et al (2011)^Citation99 ↓ Schlund et al (2012)^Citation100
Posttraumatic stress disorder	↑ Patel et al (2012)^Citation30	↑ Milad et al (2010)^Citation53 ↑ Shvil et al (2013)^Citation54 ↑ Zantvoord et al (2013)^Citation59	↑ Fonzo et al (2010)^Citation74 ↑ Garrett et al (2012)^Citation75 ↑ Nardo et al (2013)^Citation77 ↑ Patel et al (2012)^Citation30 ↑ Rougemont-Bucking et al (2011)^Citation76 ↑ Shvil et al (2013)^Citation54	↑ Brohawn et al (2010)^Citation109 ↑ Felmingham et al (2010)^Citation95 ↑ Garrett et al (2012)^Citation75 – Hayes et al (2012)^Citation110 ↓ Milad et al (2009)^Citation53 ↑ Patel et al (2012)^Citation30 – Shvil et al (2013)^Citation54	↑ Felmingham et al (2010)^Citation95 ↑ Fonzo et al (2010)^Citation74 ↑ Garrett et al (2012)^Citation75 ↓ Jovanovic et al (2011)^Citation94 ↓ Patel et al (2012)^Citation30 ↓ Rougemont-Bucking et al (2011)^Citation76 ↓ Zantvoord et al (2013)^Citation59

Note: Arrows preceding citations indicate greater or less volume or activation in anxiety compared with healthy controls.

Del CasaleASerataDRapinesiCStructural neuroimaging in patients with panic disorder: findings and limitations of recent studiesPsychiatr Danub2013252108114 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23793273Accessed October 31, 201423793273

 PubMed Web of Science ®Google Scholar

KimJEDagerSRLyooIKThe role of the amygdala in the pathophysiology of panic disorder: evidence from neuroimaging studiesBiol Mood Anxiety Disord2012212023168129

 PubMedGoogle Scholar

PannekoekJNvan der WerffSJSteinDJvan der WeeNJAdvances in the neuroimaging of panic disorderHum Psychopharmacol201328660861124038132

 PubMed Web of Science ®Google Scholar

FislerMSFederspielAHornHSpider phobia is associated with decreased left amygdala volume: a cross-sectional studyBMC Psychiatry20131317023442196

 PubMedGoogle Scholar

IrleERuhlederMLangeCReduced amygdalar and hippocampal size in adults with generalized social phobiaJ Psychiatry Neurosci201035212613120184810

 PubMed Web of Science ®Google Scholar

Machado-de-SousaJPOsórioFLJackowskiAPIncreased amygdalar and hippocampal volumes in young adults with social anxietyPLoS ONE201492e8852324523911

 PubMed Web of Science ®Google Scholar

SyalSHattinghCJFouchéJ-PGrey matter abnormalities in social anxiety disorder: a pilot studyMetab Brain Dis201227329930922527992

 PubMed Web of Science ®Google Scholar

RossoIMMakrisNBrittonJCAnxiety sensitivity correlates with two indices of right anterior insula structure in specific animal phobiaDepress Anxiety201027121104111021132846

 PubMedGoogle Scholar

BrühlABHänggiJBaurVIncreased cortical thickness in a frontoparietal network in social anxiety disorderHum Brain Mapp20143572966297724039023

 PubMed Web of Science ®Google Scholar

TalatiAPantazatosSPSchneierFRWeissmanMMHirschJGray matter abnormalities in social anxiety disorder: primary, replication, and specificity studiesBiol Psychiatry2013731758422748614

 PubMed Web of Science ®Google Scholar

LiaoWXuQMantiniDAltered gray matter morphometry and resting-state functional and structural connectivity in social anxiety disorderBrain Res2011138816717721402057

 PubMed Web of Science ®Google Scholar

QiuCLiaoWDingJRegional homogeneity changes in social anxiety disorder: a resting-state fMRI studyPsychiatry Res20111941475321831605

 PubMed Web of Science ®Google Scholar

SchienleAEbnerFSchäferALocalized gray matter volume abnormalities in generalized anxiety disorderEur Arch Psychiatry Clin Neurosci2011261430330720820793

 PubMed Web of Science ®Google Scholar

HettemaJKettenmannBAhluwaliaVPilot multimodal twin imaging study of generalized anxiety disorderDepress Anxiety201229320220921994092

 PubMed Web of Science ®Google Scholar

ChaJGreenbergTCarlsonJMDedoraDJHajcakGMujica-ParodiLRCircuit-wide structural and functional measures predict ventromedial prefrontal cortex fear generalization: implications for generalized anxiety disorderJ Neurosci201434114043405324623781

 PubMed Web of Science ®Google Scholar

KuoJRKaloupekDGWoodwardSHAmygdala volume in combat-exposed veterans with and without posttraumatic stress disorder: a cross-sectional studyArch Gen Psychiatry201269101080108623026958

 PubMed Web of Science ®Google Scholar

MoreyRajendra AGoldAndrea LLaBarKevin SAmygdala volume changes with posttraumatic stress disorder in a large case-controlled veteran groupArch Gen Psychiatry201269111169117823117638

 PubMed Web of Science ®Google Scholar

ChaoLWeinerMNeylanTRegional cerebral volumes in veterans with current versus remitted posttraumatic stress disorderPsychiatry Res2013213319320123816189

 PubMed Web of Science ®Google Scholar

KroesMCWWhalleyMGRuggMDBrewinCRAssociation between flashbacks and structural brain abnormalities in posttraumatic stress disorderEur Psychiatry201126852553121592738

 PubMed Web of Science ®Google Scholar

KühnSGallinatJGray matter correlates of posttraumatic stress disorder: a quantitative meta-analysisBiol Psychiatry2013731707422840760

 PubMed Web of Science ®Google Scholar

ThomaesKDorrepaalEDraijerNIncreased anterior cingulate cortex and hippocampus activation in Complex PTSD during encoding of negative wordsSoc Cogn Affect Neurosci20138219020022156722

 PubMed Web of Science ®Google Scholar

WoonFLSoodSHedgesDWHippocampal volume deficits associated with exposure to psychological trauma and posttraumatic stress disorder in adults: a meta-analysisProg Neuropsychopharmacol Biol Psychiatry20103471181118820600466

 PubMed Web of Science ®Google Scholar

ChenYFuKFengCDifferent regional gray matter loss in recent onset PTSD and non PTSD after a single prolonged trauma exposurePLoS ONE2012711e4829823155380

 PubMed Web of Science ®Google Scholar

NardoDHögbergGLaniusRAGray matter volume alterations related to trait dissociation in PTSD and traumatized controlsActa Psychiatr Scand2013128322223323113800

 PubMed Web of Science ®Google Scholar

WeberMKillgoreWDSRossoIMVoxel-based morphometric gray matter correlates of posttraumatic stress disorderJ Anxiety Disord201327441341923746489

 PubMed Web of Science ®Google Scholar

OttavianiCCevolaniDNuciforaVAmygdala responses to masked and low spatial frequency fearful faces: a preliminary fMRI study in panic disorderPsychiatry Res20122032–315916522944369

 PubMed Web of Science ®Google Scholar

CaserasXGiampietroVLamasAThe functional neuroanatomy of blood-injection-injury phobia: a comparison with spider phobics and healthy controlsPsychol Med201040112513419435544

 PubMed Web of Science ®Google Scholar

HilbertKEvensRMaslowskiNIWittchenHULuekenUFear processing in dental phobia during crossmodal symptom provocation: an fMRI studyBiomed Res Int2014201419635324738049

 PubMed Web of Science ®Google Scholar

LuekenUKruschwitzJDMuehlhanMSiegertJHoyerJWittchenH-UHow specific is specific phobia? Different neural response patterns in two subtypes of specific phobiaNeuroimage201156136337221316468

 PubMed Web of Science ®Google Scholar

SchweckendiekJKluckenTMerzCJWeaving the (neuronal) web: fear learning in spider phobiaNeuroimage201154168168820673801

 PubMed Web of Science ®Google Scholar

LipkaJMiltnerWHRStraubeTVigilance for threat interacts with amygdala responses to subliminal threat cues in specific phobiaBiol Psychiatry201170547247821601831

 PubMed Web of Science ®Google Scholar

LuekenUHilbertKStolyarVMaslowskiNIBeesdo-BaumKWittchenHUNeural substrates of defensive reactivity in two subtypes of specific phobiaSoc Cogn Affect Neurosci Epub20131114

 PubMed Web of Science ®Google Scholar

LipkaJHoffmannMMiltnerWHStraubeTEffects of Cognitive-Behavioral Therapy on Brain Responses to Subliminal and Supraliminal Threat and Their Functional Significance in Specific PhobiaBiol Psychiatry Epub20131114

 PubMed Web of Science ®Google Scholar

BrühlABRuferMDelsignoreAKaffenbergerTJänckeLHerwigUNeural correlates of altered general emotion processing in social anxiety disorderBrain Res20111378728321215728

 PubMed Web of Science ®Google Scholar

GiménezMPujolJOrtizHAltered brain functional connectivity in relation to perception of scrutiny in social anxiety disorderPsychiatry Res2012202321422322809740

 PubMed Web of Science ®Google Scholar

BallTMSullivanSFlaganTSelective effects of social anxiety, anxiety sensitivity, and negative affectivity on the neural bases of emotional face processingNeuroimage20125921879188721920442

 PubMed Web of Science ®Google Scholar

KlumppHPostDAngstadtMFitzgeraldDAPhanKLAnterior cingulate cortex and insula response during indirect and direct processing of emotional faces in generalized social anxiety disorderBiol Mood Anxiety Disord201331723547713

 PubMedGoogle Scholar

KlumppHAngstadtMNathanPJPhanKLAmygdala reactivity to faces at varying intensities of threat in generalized social phobia: an event-related functional MRI studyPsychiatry Res2010183216716920609570

 PubMed Web of Science ®Google Scholar

LabuschagneIPhanKLWoodAOxytocin attenuates amygdala reactivity to fear in generalized social anxiety disorderNeuropsychopharmacology201035122403241320720535

 PubMed Web of Science ®Google Scholar

MånssonKNTCarlbringPFrickAAltered neural correlates of affective processing after internet-delivered cognitive behavior therapy for social anxiety disorderPsychiatry Res2013214322923724064198

 PubMed Web of Science ®Google Scholar

PhanKLCoccaroEFAngstadtMCorticolimbic brain reactivity to social signals of threat before and after sertraline treatment in generalized social phobiaBiol Psychiatry201373432933623164370

 PubMed Web of Science ®Google Scholar

SchmidtSMohrAMiltnerWHRStraubeTTask-dependent neural correlates of the processing of verbal threat-related stimuli in social phobiaBiol Psychol201084230431220227458

 PubMed Web of Science ®Google Scholar

TaylorCTAupperleRLFlaganTNeural correlates of a computerized attention modification program in anxious subjectsSoc Cogn Affect Neurosci2014991379138723934417

 PubMed Web of Science ®Google Scholar

CarréAGierskiFLemogneCLinear association between social anxiety symptoms and neural activations to angry faces: from subclinical to clinical levelsSoc Cogn Affect Neurosci20149688088623651705

 PubMed Web of Science ®Google Scholar

GiménezMOrtizHSoriano-MasCFunctional effects of chronic paroxetine versus placebo on the fear, stress and anxiety brain circuit in Social Anxiety Disorder: initial validation of an imaging protocol for drug discoveryEur Neuropsychopharmacol201424110511624332890

 PubMed Web of Science ®Google Scholar

KlumppHAngstadtMPhanKLInsula reactivity and connectivity to anterior cingulate cortex when processing threat in generalized social anxiety disorderBiol Psychol201289127327622027088

 PubMed Web of Science ®Google Scholar

BlairKSGeraciMOteroMAtypical modulation of medial prefrontal cortex to self-referential comments in generalized social phobiaPsychiatry Res20111931384521601433

 PubMed Web of Science ®Google Scholar

SripadaCSAngstadtMBanksSNathanPJLiberzonIPhanKLFunctional neuroimaging of mentalizing during the trust game in social anxiety disorderNeuroreport2009201198498919521264

 PubMed Web of Science ®Google Scholar

HölzelBKHogeEAGreveDNNeural mechanisms of symptom improvements in generalized anxiety disorder following mindfulness trainingNeuroimage Clin2013244845824179799

 PubMed Web of Science ®Google Scholar

PalmMEElliottRMcKieSDeakinJFWAndersonIMAttenuated responses to emotional expressions in women with generalized anxiety disorderPsychol Med20114151009101820716396

 PubMed Web of Science ®Google Scholar

EtkinASchatzbergAFCommon abnormalities and disorder-specific compensation during implicit regulation of emotional processing in generalized anxiety and major depressive disordersAm J Psychiatry2011168996897821632648

 PubMed Web of Science ®Google Scholar

PriceRBEldrethDAMohlmanJDeficient prefrontal attentional control in late-life generalized anxiety disorder: an fMRI investigationTransl Psychiatry2011110e4622833192

 PubMedGoogle Scholar

SchlundMWVerduzcoGCataldoMFHoehn-SaricRGeneralized anxiety modulates frontal and limbic activation in major depressionBehav Brain Funct201281822321875

 PubMedGoogle Scholar

PatelRSprengRNShinLMGirardTANeurocircuitry models of posttraumatic stress disorder and beyond: a meta-analysis of functional neuroimaging studiesNeurosci Biobehav Rev20123692130214222766141

 PubMed Web of Science ®Google Scholar

MiladMRPitmanRKEllisCBNeurobiological basis of failure to recall extinction memory in posttraumatic stress disorderBiol Psychiatry200966121075108219748076

 PubMed Web of Science ®Google Scholar

ShvilERuschHLSullivanGMNeriaYNeural, psychophysiological, and behavioral markers of fear processing in PTSD: a review of the literatureCurr Psychiatry Rep201315535837423619614

 PubMed Web of Science ®Google Scholar

ZantvoordJBDiehleJLindauerRJLUsing neurobiological measures to predict and assess treatment outcome of psychotherapy in posttraumatic stress disorder: systematic reviewPsychother Psychosom201382314215123548778

 PubMed Web of Science ®Google Scholar

FonzoGASimmonsANThorpSRNormanSBPaulusMPSteinMBExaggerated and disconnected insular-amygdalar blood oxygenation level-dependent response to threat-related emotional faces in women with intimate-partner violence posttraumatic stress disorderBiol Psychiatry201068543344120573339

 PubMed Web of Science ®Google Scholar

GarrettASCarrionVKletterHKarchemskiyAWeemsCFReissABrain activation to facial expressions in youth with PTSD symptomsDepress Anxiety201229544945922553009

 PubMed Web of Science ®Google Scholar

Rougemont-BückingALinnmanCZeffiroTAAltered processing of contextual information during fear extinction in PTSD: an fMRI studyCNS Neurosci Ther201117422723620406268

 PubMed Web of Science ®Google Scholar

BrohawnKHOffringaRPfaffDLHughesKCShinLMThe neural correlates of emotional memory in posttraumatic stress disorderBiol Psychiatry201068111023103020855060

 PubMed Web of Science ®Google Scholar

FelminghamKWilliamsLMKempAHNeural responses to masked fear faces: sex differences and trauma exposure in posttraumatic stress disorderJ Abnorm Psychol2010119124124720141261

 PubMed Web of Science ®Google Scholar

HayesJPVanelzakkerMBShinLMEmotion and cognition interactions in PTSD: a review of neurocognitive and neuroimaging studiesFront Integr Neurosci201268923087624

 PubMedGoogle Scholar

JovanovicTNorrholmSDNeural mechanisms of impaired fear inhibition in posttraumatic stress disorderFront Behav Neurosci201154421845177

 PubMedGoogle Scholar