Thomas7272. Thomas KM, Drevets WC, Dahl RE, Ryan ND, Birmaher B, Eccard CH, et al. Amygdala response to fearful faces in anxious and depressed children. Arch Gen Psychiatry. 2001;58:1057-63.
|
GAD + PD = 12, 12.8±2.1 HC = 12, 12.1±2.6 |
GAD + PD = 5/7 HC = 5/7 |
SP = 1 |
No current psychotropic drug use |
1.5 T fMRI Task = facial emotion processing task |
Greater amygdala response to fearful faces in patients with anxiety vs. HC |
Hoehn-Saric7373. Hoehn-Saric R, Schlund MW, Wong SH. Effects of citalopram on worry and brain activation in patients with generalized anxiety disorder. Psychiatry Res. 2004;131:11-21.
|
GAD = 6, 36.0 No control group |
GAD = 3/3 |
No psychiatric comorbidity |
No current psychotropic drug use |
1.5 T fMRI Task = verbal descriptions of a personal worry or a neutral statement Seven weeks of therapy with citalopram |
Post-treatment: reduced activation in prefrontal regions, striatum, insula, and paralimbic regions during processing of worry sentences |
Monk7474. Monk CS, Nelson EE, McClure EB, Mogg K, Bradley BP, Leibenluft E, et al. Ventrolateral prefrontal cortex activation and attentional bias in response to angry faces in adolescents with generalized anxiety disorder. Am J Psychiatry. 2006;163:1091-7.
|
GAD = 18, 12.28±2.0 HC = 15, 13.53±2.4 |
GAD = 8/10 HC = 8/7 |
MDD = 9 SP = 10 SAD = 8 |
No current psychotropic drug use |
3 T fMRI Task = facial emotion processing task |
Greater VLPFC response to angry faces in GAD patients vs. HC |
McClure7575. McClure EB, Monk CS, Nelson EE, Parrish JM, Adler A, Blair RJ, et al. Abnormal attention modulation of fear circuit function in pediatric generalized anxiety disorder. Arch Gen Psychiatry. 2007;64:97-106.
|
GAD = 15, 11.67±1.97 HC = 20, 12.19±2.1 |
GAD = 7/8 HC = 11/9 |
SAD = 5 SP = 6 Specific phobia = 3 ADHD = 3 Other = 5 |
Unknown |
3 T fMRI Task = facial emotion processing task |
Greater response to fearful faces in amygdala, vPFC, ACC in GAD patients vs. HC |
Krain7676. Krain AL, Gotimer K, Hefton S, Ernst M, Castellanos FX, Pine DS, et al. A functional magnetic resonance imaging investigation of uncertainty in adolescents with anxiety disorders. Biol Psychiatry. 2008;63:563-8.
|
GAD + SP = 16, 15.2±1.3 HC = 13, 15.4±1.4 |
GAD + SP = 7/9 HC = 8/5 |
SP = 10 SP without GAD = 5 SAD = 1 Specific phobia = 3 OCD = 1 ADHD = 3 Oppositional defiant disorder = 2 Dysthymia = 2 |
Unknown |
3 T fMRI Task = decision-making task |
No brain hyperactivation in patients with anxiety vs. HC High level of intolerance to uncertainty associated with higher activation of amygdala, rostral, and subgenual ACC in patients with anxiety vs. HC |
Monk7777. Monk CS, Telzer EH, Mogg K, Bradley BP, Mai X, Louro H, et al. Amygdala and ventrolateral prefrontal cortex activation to masked angry faces in children and adolescents with generalized anxiety disorder. Arch Gen Psychiatry. 2008;65:568-76.
|
GAD = 17, 13.12±2.09 HC = 12, 14.33±1.67 |
GAD = 6/11 HC = 6/6 |
MDD = number not known |
No current psychotropic drug use |
3 T fMRI Task = facial emotion processing task |
Greater response in amygdala while viewing masked angry faces in GAD patients vs. HC. Amygdala and VLPFC showed strong negative coupling specifically to masked angry faces in GAD patients vs. HC |
Blair7878. Blair K, Shaywitz J, Smith BW, Rhodes R, Geraci M, Jones M, et al. Response to emotional expressions in generalized social phobia and generalized anxiety disorder: evidence for separate disorders. Am J Psychiatry. 2008;165:1193-202.
|
GAD = 17, 35.0±10.6 HC = 17, 31.2±9.1 GSAD = 17, 29.0±8.7 |
GAD = 11/6 HC = 8/9 GSAD = 8/9 |
SP = 7 MDD = 1 |
No current psychotropic drug use |
1.5 T fMRI Task = facial emotion processing task |
Greater response in angry expression in right middle frontal gyrus in GAD patients vs. HC |
Whalen6969. Whalen PJ, Johnstone T, Somerville LH, Nitschke JB, Polis S, Alexander AL, et al. A functional magnetic resonance imaging predictor of treatment response to venlafaxine in generalized anxiety disorder. Biol Psychiatry. 2008;63:858-63.
|
GAD = 15, 27.0±7.0 HC = 15, 33.0±11.0 |
GAD = 12/3 HC = 12/3 |
No other current disorder |
No current psychotropic drug use |
3 T fMRI Task = facial emotion processing task eight weeks of therapy with venlafaxine |
No different amygdala and rACC reactivity to threatening stimuli in GAD patients vs. HC Individual pre-treatment responsivity (greater rACC and lesser amygdala) predicted by treatment response in GAD patients vs. HC |
Etkin1515. Etkin A, Prater KE, Schatzberg AF, Menon V, Greicius MD. Disrupted amygdalar subregion functional connectivity and evidence of a compensatory network in generalized anxiety disorder. Arch Gen Psychiatry. 2009;66:1361-72.
|
GAD = 16, 30.6±1.7 GAD-controls = 17, 32.5±2.0 HC = 31, 20.5±0.2 |
GAD = 14/2 GAD-controls = 15/2 HC = 13/18 |
MDD = 4 SP = 5 PD = 2 Dysthymia = 2 OCD = 1 |
Four subjects exposed to AD at the moment of the study |
3 T rs-fMRI and MRI |
BLA and CMA disconnectivity in GAD patients vs. HC with: DLPFC and posterior parietal cortex (increased);insula and cingulate (decreased); larger amygdalar GM (in particular right CMA) |
Nitschke7979. Nitschke JB, Sarinopoulos I, Oathes DJ, Johnstone T, Whalen PJ, Davidson RJ, et al. Anticipatory activation in the amygdala and anterior cingulate in generalized anxiety disorder and prediction of treatment response. Am J Psychiatry. 2009;166:302-10.
|
GAD = 14, 33.7±10.2 HC = 14, 33.1±10.3 |
GAD = 12/2 HC = 12/2 |
No other current disorder Past MDD = 10 |
No current psychotropic drug use |
3 T fMRI Tasks = warning cue that preceded aversive pictures and a second cue that preceded neutral pictures Eight weeks of therapy with venlafaxine |
Greater bilateral dorsal amygdala activation during anticipation of both aversive and neutral pictures in GAD patients (aversive>neutral) vs. HCGreater pre-treatment pgACC activation during anticipation of both aversive and neutral trials predicted better treatment response in GAD patients vs. HC |
Paulesu8080. Paulesu E, Sambugaro E, Torti T, Danelli L, Ferri F, Scialfa G, et al. Neural correlates of worry in generalized anxiety disorder and in normal controls: a functional MRI study. Psychol Med. 2010;40:117-24.
|
GAD = 8, 24.1±6.6 HC = 12, 23.6±3.4 |
GAD = 5/3 HC = 6/6 |
Not known |
No current psychotropic drug use |
1.5 T fMRI Task = mood induction paradigm |
Hyperactivation of ACC and DMPFC after worry stimulation in both GAD patients and HC Persistent activation after stimulation in GAD patients only |
Etkin[81] |
GAD = 17, 31.5±9.9 HC = 24, 36.5±11.8 |
GAD = 11/6 HC = 18/6 |
Dysthymia = 2 SP = 6 PD = 2 OCD = 1 |
Five subjects had never received AD No psychotropic drugs within at least 48 h |
3 T fMRI Task = emotional conflict task |
Failure to activate pgACC during emotional conflict in GAD patients vs. HC |
Maslowsky8282. Maslowsky J, Mogg K, Bradley BP, McClure-Tone E, Ernst M, Pine DS, et al. A preliminary investigation of neural correlates of treatment in adolescents with generalized anxiety disorder. J Child Adolesc Psychopharmacol. 2010;20:105-11.
|
GAD-CBT = 7, 13.4±1.7 GAD-fluoxetine = 7, 13.3±2.5 HC = 10, 14.5±1.4 |
GAD-CBT = 4/3 GAD-fluoxetine = 3/4 HC = 6/4 |
SP = 6 SAD = 10 ADHD = 4 MDD = 8 |
No current psychotropic drug use |
3 T fMRI Task = facial emotion processing task Eight weeks of therapy with fluoxetine or CBT |
Increased right VLPFC activation after treatment (CBT and SSRI) in GAD patients vs. HC |
Guyer8383. Guyer AE, Choate VR, Detloff A, Benson B, Nelson EE, Perez-Edgar K, et al. Striatal functional alteration during incentive anticipation in pediatric anxiety disorders. Am J Psychiatry. 2012;169:205-12.
|
GAD = 18, 12.91±2.67 SP = 14, 13.13±3.02 HC = 26, 13.99±2.44 |
GAD = 10/8 SP = 9/5 HC = 11/15 |
MDD = 5 SAD = 8 Specific phobia = 8 |
No current psychotropic drug use |
3 T fMRI Task = monetary incentive delay task |
Hyperactivation of putamen in response to valence in GAD patients vs. SP patients and HC No caudate increased activation as incentive increased in GAD patients and HC vs. SP patients |
Etkin & Schatzberg8484. Etkin A, Schatzberg AF. Common abnormalities and disorder-specific compensation during implicit regulation of emotional processing in generalized anxiety and major depressive disorders. Am J Psychiatry. 2011;168:968-78.
|
GAD = 18, 31.3±9.5 MDD = 14, 32.2 ± 11.7 HC = 32, 35.6±11.1 |
GAD = 11/7 MDD = 10/4 HC = 23/9 |
Dysthymia = 2 SP = 5 PD = 2 OCD = 1 |
No current psychotropic drug use |
3 T fMRI Task = emotional conflict task |
Hyperactivation of ventral ACC and amygdala in GAD and MDD patients vs. HC |
Palm8585. Palm ME, Elliott R, McKie S, Deakin JF, Anderson IM. Attenuated responses to emotional expressions in women with generalized anxiety disorder. Psychol Med. 2011;41:1009-18.
|
GAD = 15, 34±13 HC = 16, 34±13 |
n=15/0 HC = 16/0 |
Past MDD = 1 Past alcohol dependence = 1 Other anxiety disorder (PD, SP, specific phobia) = 10 |
Three subjects exposed to AD at the moment of the study |
1.5 T fMRI Task = facial emotion processing task |
Hypoactivation of VLPFC, MPFC, and ACC across emotional expression, especially happy faces in GAD patients vs. HC No amygdala dysregulation in GAD patients vs. HC |
Andreescu8686. Andreescu C, Gross JJ, Lenze E, Edelman KD, Snyder S, Tanase C, et al. Altered cerebral blood flow patterns associated with pathologic worry in the elderly. Depress Anxiety. 2011;28:202-9.
|
GAD = 7, 63.3±3.9 HC = 10, 76.3±4.0 |
GAD = 5/2 HC = 6/4 |
SP = 3 Specific phobia = 2 OCD = 1 |
No current psychotropic drug use |
fMRI-pulse arterial spin labelling perfusion at rest and during task Task = worry modulation task |
Resting-state: increased activity during worry induction in the associative temporo-occipital areas, but not in the insulaor the amygdala in GAD patients vs. HC Worry suppression: Increased activity in dorsal ACC, but not in PFC in GAD patients vs. HC |
Blair8787. Blair KS, Geraci M, Smith B, Hollon N, DeVido J, Otero M. Reduced dorsal anterior cingulate cortical activity during emotional regulation and top-down attentional control in generalized social phobia, generalized anxiety disorder and comorbid generalized social phobia/generalized anxiety disorder. Biol Psychiatry. 2012;72:476-82.
|
- EER GAD = 17, 36.1±11.75 GSAD = 19, 29.4±8.7 GAD/GSAD = 17, 35.7±9.54 HC = 18, 33.4±9.65 - TAC GAD = 17, 34.9±10.93 GSAD = 18, 31.8±9.10 GAD/GSAD = 15, 33.5±10.57 HC = 18, 30.4±6.86 |
- EER GAD = 13/4 GSAD = 10/8 GAD/GSAD = 12/5 HC = 10/8 - TAC GAD = 10/7 GSAD = 8/10 GAD/GSAD = 10/5 HC = 9/9 |
No other current psychiatric disorders |
No current psychotropic drug use |
1.5 T fMRI Task1 = EER Task2 = TAC |
HC showed significantly increased recruitment during emotion regulation, relative to emotion- picture viewing. GAD, SP, and SP/GAD patients showed no such increases. Decreased amygdala activation to negative stimuli only for GAD patients vs. HC |
Strawn8888. Strawn JR, Bitter SM, Weber WA, Chu WJ, Whitsel RM, Adler C, et al. Neurocircuitry of generalized anxiety disorder in adolescents: a pilot functional neuroimaging and functional connectivity study. Depress Anxiety. 2012;29:939-47.
|
GAD = 10, 14±2.2 HC = 10, 14.5±2.3 |
GAD = 6/4 HC = 6/4 |
No other current psychiatric disorders |
No current psychotropic drug use |
4 T fMRI Task = continuous performance task with emotional and neutral distractors |
Increased activation in left medial PFC and right VLPFC in response to emotional images in GAD patients vs. HC Decreased connectivity between VLPFC and bilateral medial PFC in GAD patients vs. HC Decreased correlation between right amygdala and PCC in GAD patients vs. HC Increased correlation between left amygdala and ipsilateral PCu in GAD patients vs. HC |
Yassa8989. Yassa MA, Hazlett RL, Stark CE, Hoehn-Saric R. Functional MRI of the amygdala and bed nucleus of the stria terminalis during conditions of uncertainty in generalized anxiety disorder. J Psychiatr Res. 2012;46:1045-52.
|
GAD = 15, 34.7±9.51 HC = 15, 32.4±8.7 |
GAD = 12/3 HC = 9/6 |
No other current psychiatric disorders |
No current psychotropic drug use |
3 T fMRI Task = gambling game with non-contingent monetary loss |
Decreased amygdala and BNST activity in GAD patients vs. HC |
Roy9090. Roy AK, Fudge JL, Kelly C, Perry JS, Daniele T, Carlisi C, et al. Intrinsic functional connectivity of amygdala-based networks in adolescent generalized anxiety disorder. J Am Acad Child Adolesc Psychiatry. 2013;52:290-9.
|
GAD = 15, 14.9±1.7 HC = 20, 14.8±1.7 |
GAD = 10/5 HC = 13/7 |
SP = 5 Specific phobia = 2 PD = 1 OCD = 1 SAD = 2 MDD = 3 ADHD = 1 |
No current psychotropic drugs |
3 T rs-fMRI |
Disruption in amygdala connectivity with medial PFC, insula, and cerebellum in GAD patients vs. HC Positive correlation between anxiety severity scores and connectivity between amygdala, insula, and STG in GAD patients vs. HC |
Chen & Etkin9191. Chen AC, Etkin A. Hippocampal network connectivity and activation differentiates post-traumatic stress disorder from generalized anxiety disorder. Neuropsychopharmacology. 2013;38:1889-98.
|
GAD = 39, 32.4±1.5 HC = 38, 30.7±2.6 PTSD = 17, 34.4±3.4 |
GAD = 27/12 HC = 27/11 PTSD = 13/14 |
MDD = 23 |
No current psychotropic drug use |
3 T fMRI resting-state + fMRI Task 1 = flashing checker board Task 2 = facial emotion processing task |
Disturbed posterior hippocampus and default-mode network connectivity during resting-state and task execution in PTSD, but not in GAD patients or HC |
Hölzel9292. Hölzel BK, Hoge EA, Greve DN, Gard T, Creswell JD, Brown KW, et al. Neural mechanisms of symptom improvements in generalized anxiety disorder following mindfulness training. Neuroimage Clin. 2013;2:448-58.
|
GAD = 26, 37.9±12.2 HC = 26, 35.7±9.3 |
GAD = 14/12 HC = 16/10 |
MDD = 4 PD = 1 SP = 6 |
Four subjects exposed to AD at the moment of the study |
1.5 T fMRI Task = facial emotion processing task Eight weeks of MBSR and SME therapy |
Pre-treatment: higher amygdala activation in response to neutral, but not angry faces in GAD patients vs. HC Post-treatment: reduction of amygdala activation in response to neutral faces in GAD patients vs. HC Higher VLPFC activation after MBSR vs. SME in GAD patients vs. HC Increased connectivity between amygdala and PFC after MBSR in GAD patients vs. HC Correlation between activation/ connectivity and symptoms in GAD patients vs. HC |
Ball1818. Ball TM, Ramsawh HJ, Campbell-Sills L, Paulus MP, Stein MB. Prefrontal dysfunction during emotion regulation in generalized anxiety and panic disorders. Psychol Med. 2013;43:1475-86.
|
GAD = 23, 35±11 PD = 18, 29±7 HC = 22, 27±9 |
GAD = 17/5 PD = 13/6 HC = 11/11 |
GAD group: MDD=2 OCD=2 GSAD=8 PD group: MDD =2 OCD=1 GSAD=2 |
No current psychotropic drug use |
3 T fMRI Task: negative emotion processing task |
PFC hypoactivation in GAD and PD patients vs. HC HC demonstrated greater activation during both reappraisal and maintenance of negative emotions then GAD patients in DMPFC, bilateral dorsolateral and ventrolateral PFC, and dorsal ACC |
Andreescu9393. Andreescu C, Sheu LK, Tudorascu D, Walker S, Aizenstein H. The ages of anxiety--differences across the lifespan in the default mode network functional connectivity in generalized anxiety disorder. Int J Geriatr Psychiatry. 2014;29:704-12.
|
GAD-old = 15, 67.4±6.52 GAD-young = 9, 31.67±10.06 HC-old = 21, 70.76±7.33 HC-young = 10, 33.6±10.49 |
GAD-old = 11/4 GAD-young = 8/1 HC-old = 12/9 HC-young = 6/4 |
PD = 4 SP = 1 MDD past = 5 |
No current psychotropic drug use |
3 T rs-fMRI |
Greater anxiety effect on connectivity between PCC and MPFC in older GAD patients vs. young subjects Positive correlation between duration of illness and greater connectivity between PCC and insula |
Andreescu9494. Andreescu C, Sheu LK, Tudorascu D, Gross JJ, Walker S, Banihashemi L, et al. Emotion reactivity and regulation in late-life generalized anxiety disorder: functional connectivity at baseline and post-treatment. Am J Geriatr Psychiatry. 2015;23:200-14.
|
Elderly GAD = 28, 64±6.75 HC = 31, 69±12.50 |
GAD = 17/11 HC = 19/12 |
SP = 1 PD = 2 PTSD = 1 |
No current psychotropic drug use |
3 T rs-fMRI |
Higher connectivity in GAD patients in the DLPFC and several prefrontal regions during worry reappraisal, after 12 weeks of treatment vs. HC |
Fonzo9595. Fonzo GA, Ramsawh HJ, Flagan TM, Sullivan SG, Simmons AN, Paulus MP, et al. Cognitive-behavioral therapy for generalized anxiety disorder is associated with attenuation of limbic activation to threat-related facial emotions. J Affect Disord. 2014;169:76-85.
|
GAD = 21, 34.29±11.27 HC = 12, 27.58±3.00 |
GAD = 16/5 HC = 7/5 |
Anxiety or mood disorder comorbidity permitted for GAD participants |
No current psychotropic drug use |
3 T fMRI Task: facial emotion processing task |
Pre-treatment: GAD patients showed blunted responses in amygdala, insula, and ACC to the happy faces and greater amygdalo-insular connectivity vs. HC Post-treatment: CBT attenuated amygdalar and subgenual ACC activation by fear/angry faces and heightened insular responses to the happy face comparison condition, but no apparent effects on connectivity in GAD patients vs. HC |
Cha9696. Cha J, Carlson JM, Dedora DJ, Greenberg T, Proudfit GH, Mujica-Parodi LR. Hyper-reactive human ventral tegmental area and aberrant mesocorticolimbic connectivity in overgeneralization of fear in generalized anxiety disorder. J Neurosci. 2014;34:5855-60.
|
GAD = 32, 22.3±5.14 HC = 25, 21.3±4.56 |
GAD = 32/0 HC = 25/0 |
MDD = 17 |
No current psychotropic drug use |
3 T fMRI Task: fear generalization task |
Higher and less discriminating VTA reactivity to generalized stimuli in GAD patients vs. HC Increased connectivity in VTA-nucleus accumbens in GAD patients vs. HC |
Cha5454. Cha J, Greenberg T, Carlson JM, Dedora DJ, Hajcak G, Mujica-Parodi LR. Circuit-wide structural and functional measures predict ventromedial prefrontal cortex fear generalization: implications for generalized anxiety disorder. J Neurosci. 2014;34:4043-53.
|
GAD = 32, 22.3±5.14 HC = 25, 21.3±4.56 |
GAD = 32/0 HC = 25/0 |
MDD = 17 |
No current psychotropic drug use |
3 T fMRI, DTI, and MRI Task: fear generalization task |
GAD patients with thicker VMPFC display more discriminate VMPFC reactivity during the fear task vs. HC Increased connectivity VMPFC in GAD vs. HC |
Brown9797. Brown GG, Ostrowitzki S, Stein MB, Von Kienlin M, Liu T, Simmons A, et al. Temporal profile of brain response to alprazolam in patients with generalized anxiety disorder. Psychiatry Res. 2015;233:394-401. Double-blind design |
GAD = 30 BDZ = 19 PLC = 111 8-64 years |
BDZ = 9/10 PLC = 9/2 |
No other current psychiatric disorders |
No current psychotropic drug use |
3 T fMRI Task: EFMT and affective STIMEX were performed at baseline, 1 hour after initial drug administration and 28 days later |
Activation of amygdala during EFMT in GAD patients vs. HC Decreased activation of amygdala after treatment with BDZ in GAD patients vs. HC Significant treatment differences in brain activity during the STIMEX on day 28 in frontal lobe, caudate nucleus, middle temporal gyrus, secondary visual cortex, and SMG in GAD patients vs. HC |
Liu9898. Liu WJ, Yin DZ, Cheng WH, Fan MX, You MN, Men WW, et al. Abnormal functional connectivity of the amygdala-based network in resting-state fMRI in adolescents with generalized anxiety disorder. Med Sci Monit. 2015;21:459-67.
|
GAD = 26, 15.54±1.53 HC = 20, 15.55±1.67 |
GAD = 16/10 HC = 11/9 |
No other current psychiatric disorders |
No current psychotropic drug use |
3 T rs-fMRI |
Decreased functional connectivity between left amygdala and left DLPFC in GAD patients vs. HC Increased functional connectivity between right amygdala and right posterior and anterior lobes of the cerebellum, insula, STG, and putamen in GAD patients vs. HC |
Makovac9999. Makovac E, Meeten F, Watson RA, Herman D, Garfinkel SN, D Critchley H, et al. Alterations in amygdala-prefrontal functional connectivity account for excessive worry and autonomic dysregulation in generalized anxiety disorder. Biol Psychiatry. 2016;80:786-95.
|
GAD = 19, 29.58±6.93 HC = 21, 28.67±9.45 |
GAD = 17/2 HC = 18/3 |
No other current psychiatric disorders |
No current psychotropic drug use |
1.5 T fMRI resting-state + task Task = visuomotor tracking task |
Before induction: lower connectivity between right amygdala and right SFG, right paracingulate ACC, and right SMG and decreased connectivity between VLPFC and amygdala in GAD patients vs. HC After induction: connectivity increased in GAD patients but decreased in HC |
Moon5555. Moon CM, Yang JC, Jeong GW. Explicit verbal memory impairments associated with brain functional deficits and morphological alterations in patients with generalized anxiety disorder. J Affect Disord. 2015;186:328-36.
|
GAD = 17, 37.4±11.3 HC = 17, 35.6±6.1 |
GAD = 6/11 HC = 6/11 |
All patients had primary GAD with mild depression |
Eleven patients had prescriptions for multiple psychiatric medications, including anxiolytics (buspirone [n=5/; alprazolam [n=2]; lorazepam [n=1]; tofisopam [n=2]) and/or antidepressants (escitalopram [n=9]; bupropion [n=1], fluvoxamine [n=1], duloxetine [n=2], mirtazapine [n=1], paroxetine [n=3]). |
3 T MRI + fMRI Task: explicit verbal memory tasks with emotionally neutral and anxiety-inducing words |
In response to neutral words, GAD patients showed lower activity in hippocampus, middle cingulate gyrus, putamen, and head of caudate nucleus vs. HC In response to anxiety-inducing words, GAD patients showed higher activities in VLPFC and precentral gyrus vs. HC Significant reduction in GM volumes, especially in the hippocampus midbrain, thalamus, insula, and STG in GAD patients vs. HC |
Park100100. Park JI, Kim GW, Jeong GW, Chung GH, Yang JC. Brain activation patterns associated with the effects of emotional distracters during working memory maintenance in patients with generalized anxiety disorder. Psychiatry Investig. 2016;13:152-6.
|
GAD = 15, 36.4±11.2 No control group |
GAD = 7/8 |
No other current psychiatric disorders |
Fourteen patients had prescriptions for multiple psychiatric medications, including antidepressants (escitalopram [n=8]; paroxetine [n=2], bupropion [n=1]; fluvoxamine [n=1]; duloxetine [n=1]; mirtazapine [n=1]) and/or anxiolytics (buspirone [n=6], alprazolam [n=5], zolpidem [n=1]). |
3 T fMRI Task: explicit verbal memory tasks with emotionally neutral and anxiety-inducing words |
Increased activation with anxiety-provoking pictures vs. neutral pictures in: VLPFC, middle temporal gyrus, inferior occipital gyrus, inferior temporal gyrus, middle occipital gyrus, hippocampus, PHG, FuG, DLPFC, STG amygdala, cerebellar cortex, LiG, PCu, SPG |
Buff101101. Buff C, Brinkmann L, Neumeister P, Feldker K, Heitmann C, Gathmann B, et al. Specifically altered brain responses to threat in generalized anxiety disorder relative to social anxiety disorder and panic disorder. Neuroimage Clin. 2016;12:698-706.
|
GAD = 20, 28.10±8.73 PD = 21, 27.10±6.40 SAD = 21, 29.86±8.12 HC = 21, 27.33±3.84 |
GAD = 16/4 PD = 17/4 SAD = 17/4 HC = 17/4 |
No other current psychiatric disorders |
Six to seven patients per group took long-term medication (antidepressive medication, one GAD patient used Pregabalin) and had been stabilized on such medication for at least 4 weeks prior to study participation. |
3 T fMRI Task: explicit verbal memory tasks with emotionally neutral and anxiety-inducing words |
Elevated activity with threat vs. neutral in cingulate cortex, dorsal anterior insula/frontal operculum, and posterior DLPFC in GAD patients vs. other groups Increased functional connectivity between posterior DLPFC and VLPFC, between cingulate cortex and amygdala, between cingulate cortex and anterior insula in GAD patients vs. other groups |
Cui102102. Cui H, Zhang J, Liu Y, Li Q, Li H, Zhang L, et al. Differential alterations of resting-state functional connectivity in generalized anxiety disorder and panic disorder. Hum Brain Mapp. 2016;37:1459-73.
|
GAD = 21, 39.95±12.24 PD = 18, 37.17±11.31 HC = 22, 38.05±10.32 |
GAD = 7/13 PD = 6/12 HC = 8/14 |
No other current psychiatric disorders |
No current psychotropic drug use |
3 T rs-fMRI |
Increased functional connectivity between hippocampus/parahippocampus and FuG in GAD patients vs. PD patients and HC |
Kujawa103103. Kujawa A, Swain JE, Hanna GL, Koschmann E, Simpson D, Connolly S, et al. Prefrontal reactivity to social signals of threat as a predictor of treatment response in anxious youth. Neuropsychopharmacology. 2016;41:1983-90.
|
GAD+SAD+GSAD = 4 17-19 years |
Not specified |
Participants with secondary comorbidity were included: 70.7% of the sample had current diagnoses of GAD, 58.5% GSAD, and 17.1% SAD, 7.3% had comorbid PD, 9.8% OCD, 24.4% specific phobia, 2.4% PTSD, 2.4% depression, and 12.2% ADHD |
No current psychotropic drug use |
3 T fMRI Task: flanker task to elicit error-related negativity Twelve weeks of SSRI or 18 sessions (max) of CBT |
Greater activation of inferior and SFG, including DLPFC and VLPFC, precentral/postcentral gyri during processing of threating faces predicted greater response to CBT and SSRI treatment |
Makovac104104. Makovac E, Watson DR, Meeten F, Garfinkel SN, Cercignani M., Critchley HD, et al. Amygdala functional connectivity as a longitudinal biomarker of symptom changes in generalized anxiety. Soc Cogn Affect Neurosci. 2016;11:1719-28.
|
GAD = 16, 29.62±7.51 HC = 16, 28.12±10.11 |
GAD = 14/2 HC = 13/3 |
No other current psychiatric disorders |
Two GAD patients using long-term medications (one citalopram, one pregabalin) at both sessions of the study. All other patients and controls were medication free. |
1.5 T fMRI resting-state + task Task = visuomotor tracking task |
After induction: reduction in connectivity between right amygdala and VMPFC in GAD patients vs. HC At follow-up: enhanced coupling between left amygdala and VTA Amplified physiological response to induction predicted increased connectivity between right amygdala and thalamus in GAD patients vs. HC |
Wang105105. Wang W, Hou J, Qian S, Liu K, Li B, Li M, et al. Aberrant regional neural fluctuations and functional connectivity in generalized anxiety disorder revealed by resting-state functional magnetic resonance imaging. Neurosci Lett. 2016;624:78-84.
|
GAD = 28, 32.93±4.13 HC = 28, 33.21±5.25 |
GAD = 14/14 GAD = 14/14 |
No other current psychiatric disorders |
No current psychotropic drug use |
3 T rs-fMRI |
Higher amplitude of low frequency fluctuations in bilateral DMPFC and DLPFC, as well as left PCu/PCC in GAD patients vs. HC Lower connectivity in prefrontal gyrus, in prefrontal-limbic and cingulate and higher prefrontal-hippocampus resting-state functional connectivity was correlated with symptom severity in GAD patients |
Moon & Jeong5656. Moon CM, Jeong. GW. Functional and morphological alterations associated with working memory dysfunction in patients with generalized anxiety disorder. Acta Radiol. 2017;58:344-52.
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GAD = 17, 38.1±10.4 HC = 17, 36.9±7.7 |
GAD = 9/8 HC = 9/8 |
All patients had primary GAD with mild depression |
Eleven patients had prescriptions for multiple psychiatric medications, including anxiolytics (buspirone [n=4]; alprazolam [n=1]; lorazepam [n=2]; tofisopam [n=2]) and/or antidepressants (escitalopram [n=9]; bupropion [n=1]; fluvoxamine [n=2]; duloxetine [n=1]; mirtazapine [n=1]; paroxetine [n=3]), and six patients used one psy-qj;chiatric medication each. |
3 T MRI and fMRI Task: verbal working memory task with emotionally neutral and anxiety-inducing words |
Lower activity in FuG, SPG, PCu, SOG, LiG, Cun, CaC, PHG, and Cb in GAD patients vs. HC In response to anxiety-inducing distractors, higher activity in hippocampus and lower activities in DLPFC, FuG, SPG, PCu, SOG, and Cb in GAD patients vs. HC |
Moon106106. Moon CM, Sundaram T, Choi NG, Jeong GW. Working memory dysfunction associated with brain functional deficits and cellular metabolic changes in patients with generalized anxiety disorder. Psychiatry Res Neuroimaging. 2016;254:137-44.
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GAD = 14, 36.6±8.8 HC = 14, 37.8±7.8 |
GAD = 6/8 HC = 6/8 |
All patients had primary GAD with mild depression |
Eleven patients had prescriptions for multiple psychiatric medications including anxiolytics (buspirone [n=7]; alprazolam [n=3]; tofisopam [n=1]) and/or antidepressants (escitalopram [n=10]; bupropion [n=3]; fluvoxamine [n=2]; duloxetine [n=1]) and three patients used a single psychiatric medication. |
3 T fMRI Task: working memory task with emotion- inducing distractors |
In response to emotional distractors higher activity in the hippocampus and lower activities in the SOG, SPG, DLPFC, and precentral gyrus was found in GAD patients vs. HC |
Cha5757. Cha J, Greenberg T, Song I, Blair Simpson H, Posner J, Mujica-Parodi LR. Abnormal hippocampal structure and function in clinical anxiety and comorbid depression. Hippocampus. 2016;26:545-53.
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GAD + GAD/MDD = 32 GAD = 15, 22.1±1.20 GAD/MDD = 17, 22.5±1.12 HC = 25, 21.5±1.07 |
GAD = 32/0 HC = 25/0 |
MDD = 17 |
No current psychotropic drug use |
3 T MRI, DTI and fMRI (multimodal MRI) Task: threat-associative learning task |
Decreased activity in left anterior hippocampus to cue repetition in GAD patients (with or without comorbidity with MDD) during a threat-associative learning task |
Burkhouse107107. Burkhouse KL, Kujawa A, Klumpp H, Fitzgerald KD, Monk CS, Phan KL. Neural correlates of explicit and implicit emotion processing in relation to treatment response in pediatric anxiety. J Child Psychol Psychiatry. 2017;58:546-54.
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GAD + GSAD = 37 (7-19 age) SSRI = 21, 14.43±2.87 CBT = 16, 14.50±3.03 |
GAD + GSAD = 22/15 SSRI = 11/10 CBR = 11/5 |
10.8% SAD; 10.8% PD; Specific phobia 18.9%, MDD 5.4%, ADHD 16.2% |
No current psychotropic drug use |
3 T fMRI Task: emotional faces shifting attention tasksTen weeks (minimum) of SSRI or CBT |
Reduced activation in SFG, ACC, and DMPFC during implicit processing of emotional faces after treatment (both CBT and SSRI) |
Meeten108108. Meeten F, Davey GC, Makovac E, Watson DR, Garfinkel SN, Critchley HD, et al. Goal directed worry rules are associated with distinct patterns of amygdala functional connectivity and vagal modulation during perseverative cognition. Front Hum Neurosci. 2016;10:553.
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GAD = 19, 29.58±6.93 HC = 21, 28.67±9.45 |
GAD = 17/2 HC = 18/3 |
Patients had primary GAD with mild depression |
Two GAD patients with long-term medication (one citalopram, one pregabalin) |
3 T rs-fMRI |
Increased connectivity between right amygdala and brainstream in GAD patients vs. HC |
Moon109109. Moon CM, Yang JC, Jeong GW. Functional neuroanatomy associated with the interaction between emotion and cognition in explicit memory tasks in patients with generalized anxiety disorder. Acta Radiol. 2017;58:98-106.
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GAD = 15, 37.6±11.9 HC = 15, 35.4±5.6 |
GAD = 5/10 HC = 5/10 |
All patients had primary GAD with mild depression |
Eight patients had prescriptions for multiple psychiatric medications, including anxiolytics (buspirone [n=2]; alprazolam [n=2]; lorazepam [n=1]; and tofisopam [n=1]) and/or antidepressants (escitalopram [n=7]; bupropion [n=1]; fluvoxamine [n=1]; duloxetine [n=1]; mirtazapine [n=1]; and paroxetine [n=3]). Seven patients were taking one psychotropic medication. |
3 T fMRI Task: explicit memory task with neutral and anxiety-inducing words |
Decreased activity in putamen, head of the caudate nucleus, hippocampus, and middle cingulate gyrus during the memory tasks with the neutral and anxiety-inducing words in GAD patients vs. HC Increased activity in VLPFC and precentral gyrus only in the memory task with the anxiety-inducing words in GAD patients vs. HC |
Li110110. Li W, Cui H, Zhu Z, Kong L, Guo Q, Zhu Y, et al. Aberrant functional connectivity between the amygdala and the temporal pole in drug-free generalized anxiety disorder. Front Hum Neurosci. 2016;10:549.
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GAD = 21, 39.90±12.24 HC = 22, 38.05±10.32 |
GAD = 7/13 HC = 8/14 |
No other current psychiatric disorders |
No current psychotropic drug use |
3 T rs-fMRI |
Increased functional connectivity between left amygdala and temporal pole in GAD patients vs. HC In both eyes-open and eyes-closed conditions, the brain regions showed altered FC with amygdala/DLPFC in GAD patients vs. HC |
Karim111111. Karim H, Tudorascu DL, Aizenstein H, Walker S, Good R, Andreescu C. Emotion reactivity and cerebrovascular burden in late-life GAD: a neuroimaging study. Am J Geriatr Psychiatry. 2016;24:1040-50.
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GAD = 17, 64±6 HC = 20, 67.5±8.5 |
GAD = 10/7 HC = 10/10 |
Patients with other anxiety disorders were included if GAD was the principal diagnosis |
No current psychotropic drug use |
3 T fMRI Task: facial emotion processing task |
Positive association between the faces > shapes and global anxiety in PHG, precuneus, and superior occipital gyrus Negative association between the faces > shapes and worry severity in precuneus |
Diwadkar112112. Diwadkar VA, Re M, Cecchetto F, Garzitto M, Piccin S, Bonivento C, et al. Attempts at memory control induce dysfunctional brain activation profiles in generalized anxiety disorder: an exploratory fMRI study. Psychiatry Res Neuroimaging. 2017;266:42-52.
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GAD = 10, 41.65±12.47 HC = 10, 44.10±15.33 |
GAD = 6/4 HC = 7/3 |
No other current psychiatric disorders |
Seven patients receiving antidepressants at the time of MRI (three on venlafaxine, one on amitriptyline, three on SSRIs: sertraline, citalopram, and escitalopram). Five patients were taking benzodiazepines, two patients were medication free. |
3 T fMRI Task: explicit verbal memory tasks with emotionally neutral and anxiety-inducing words |
Hypoactivation in dorsal ACC, VLPFC, and cerebellum, more pronounced during suppression than retrieval memories in GAD patients vs. HC |
Ellard113113. Ellard KK, Barlow DH, Whitfield-Gabrieli S, Gabrieli JD, Deckersbach T. Neural correlates of emotion acceptance vs worry or suppression in generalized anxiety disorder. Soc Cogn Affect Neurosci. 2017;12:1009-21.
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GAD = 21, 29.48±8.44 No control group |
GAD = 21/0 |
No other current psychiatric disorders |
No current psychotropic drug use |
3 T fMRI Task: worry or emotion suppression |
Emotion acceptance resulted in lower ratings of distress than worry and was associated with increased dorsal ACC activation and increased VLPFC-amygdala functional connectivity Worry showed greater distress ratings than acceptance or suppression and was associated with increased PCu, VLPFC, amygdala, and hippocampal activation |
Fitzgerald114114. Fitzgerald JM, Phan KL, Kennedy AE, Shankman SA, Langenecker SA, Klumpp H. Prefrontal and amygdala engagement during emotional reactivity and regulation in generalized anxiety disorder. J Affect Disord. 2017;218:398-406.
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GAD = 30, 27.20±7.57 HC = 30, 25.43±10.02 |
GAD = 18/12 HC = 23/7 |
GAD = 13 MDD = 6 PD = 3 Specific phobia =3 PTSD = 2 OCD = 2 |
No current psychotropic drug use |
3 T fMRI Task: negative emotion processing task |
GAD patients exhibited over-engagement of amygdala and frontal regions during the viewing of negative images vs. HC |
MacNamara115115. MacNamara A, Klumpp H, Kennedy AE, Langenecker SA, Phan KL. Transdiagnostic neural correlates of affective face processing in anxiety and depression. Depress Anxiety. 2017;34:621-31.
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Patients = 142, 25.9±6.9 GAD = 20 SAD = 79 MDD = 43 HC = 57, 27.5± 9.8 |
HC = 40/17 Patients = 104/38 No other specifications |
No other current psychiatric disorders |
No current psychotropic drug use |
3 T fMRI Task: facial emotion processing task |
Anxiety symptom scores were associated with increased anger>shape activation in bilateral insula, anterior/midcingulate, and DLPFC, while depressive symptom scores were associated with reduced DLPFC activation for Angry > Shapes across the three disorders |
Carlson116116. Carlson JM, Rubin D, Mujica-Parodi LR. Lost emotion: disrupted brain-based tracking of dynamic affective episodes in anxiety and depression. Psychiatry Res Neuroimaging. 2017;260:37-48.
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GAD = 17, 23±4.47 MDD = 15, 26±9.08 GAD/MDD = 15, 21±2.63 HC = 13, 20±1.07 |
GAD = 17/0 MDD = 15/0 GAD/MDD = 15/0 HC = 13/0 |
MDD = 15 |
No current psychotropic drug use |
3 T fMRI Task: entire pilot episode of ABC's TV- series Lost |
Decreased activity of amygdala in GAD and MDD patients vs. HC Higher coupling with negative valence in PCC, DMPFC, PCu in HC vs. GAD patients and MDD |
Blair117117. Blair KS, Otero M, Teng C, Geraci M, Ernst M, Blair RJ, et al. Reduced optimism and a heightened neural response to everyday worries are specific to generalized anxiety disorder, and not seen in social anxiety. Psychol Med. 2017;47:1806-15.
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GAD = 18, 31.0±7.78 SAD = 18, 32.4±9.48 HC 18, 31.9 ±7.78 |
GAD = 8/10 SAD = 13/5 HC = 10/8 |
No other current psychiatric disorders |
No current psychotropic drugs |
1.5 T fMRI Task: fear generalization and positive tasks |
Reduced mPFC in GAD patients vs. HC and SAD patients Increased activity for low relative to high positive and negative impact events in rostral mPFC, right IFG/anterior insula, bilateral frontal cortex in GAD patients vs. HC |
White118118. White SF, Geraci M, Lewis E, Leshin J, Teng C, Averbeck B, et al. Prediction error representation in individuals with generalized anxiety disorder during passive avoidance. Am J Psychiatry. 2017;174:110-7.
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GAD = 46, 30.78±9.69 HC = 32, 28.85±9.69 |
GAD = 35/11 HC = 22/10 |
GSAD = 18 |
No current psychotropic drug use |
3 T fMRI Task: passive avoidance task |
Reduced correlation between prediction error within VMPFC, ventral striatum, dACC/DMPCF, anterior insular cortex, and PCC in GAD patients vs. HC Lower correlations within lentiform nucleus/putamen in GAD patients vs. HC |
Mohlman119119. Mohlman J, Eldreth DA, Price RB, Staples AM, Hanson C. Prefrontal-limbic connectivity during worry in older adults with generalized anxiety disorder. Aging Ment Health. 2017;21:426-38.
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GAD = 20, 67.85±4.55 HC = 16, 67.38±5.46 |
GAD = 75/25% HC = 69/31% |
No other current psychiatric disorders |
Three participants (two in the GAD group and one in the control group) were taking medication for sleep problems. |
3 T fMRI Task: neutral and worry tasks |
Activation in frontal regions, amygdala, and insula in GAD patients vs. HC Effective connectivity analysis in GAD from DLPFC, VMPFC until amygdala in GAD patients vs. HC |
Buff120120. Buff C, Schmidt C, Brinkmann L, Gathmann B, Tupak S, Straube T. Directed threat imagery in generalized anxiety disorder. Psychol Med. 2018;48:617-28.
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GAD = 19, 28.2±8.9 HC = 19, 27.6±8.3 |
GAD = 14/5 HC = 14/5 |
All patients had primary GAD with mild depression |
No current psychotropic drugs |
3 T fMRI Task: disorder-related vs. neutral scripts |
Increased activation in amygdala, DMPFC, VLPFC, and thalamus in GAD patients vs. HC Reduced activation in VMPFC/ subgenual ACC in GAD vs. HC |
Rabany121121. Rabany L, Diefenbach GJ, Bragdon LB, Pittman BP, Zertuche L, Tolin DF, et al. Resting-state functional connectivity in generalized anxiety disorder and social anxiety disorder: evidence for a dimensional approach. Brain Connect. 2017;7:289-98.
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GAD = 10, 41.90±5.1 GSAD = 8, 33.0±3.5 HC = 19, 40.47±3.5 |
GAD = 2/8 GSAD = 3/5 HC = 6/13 |
No other current psychiatric disorders |
No current psychotropic drug use |
3 T rs-fMRI |
Altered connectivity between amygdala and all regions of the default mode network and salience network in GAD patients vs. HC |
Yin122122. Yin D, Liu W, Zeljic K, Lv Q, Wang Z, You M, et al. Failure in cognitive suppression of negative affect in adolescents with generalized anxiety disorder. Sci Rep. 2017;7:6583.
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GAD = 20, 15.7±1.7 HC = 14, 15.5±1.7 |
GAD = 15/5 HC = 8/6 |
Specific phobia = 4 SP = 3 Agoraphobia = 3 PD = 2 SAD = 2 Oppositional defiant = 1 |
No current psychotropic drug use |
3 T fMRI Task = emotional valence-evaluation tasks |
Evaluation of negative vs. neutral stimuli: increased activation of bilateral amygdala in GAD patients; reduced activation of right IFG in GAD patients vs. HC; magnitude of IFG activity negatively correlated with symptom severity Psychophysiological interaction analysis: decreased functional interaction in right IFG, ACC, and VMPFC in GAD vs. HC |
Qiao123123. Qiao J, Li A, Cao C, Wang Z, Sun J, Xu G. Aberrant functional network connectivity as a biomarker of generalized anxiety disorder. Front Hum Neurosci. 2017;11:626.
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GAD = 20, 41.5±10.7 HC = 20, 40.1±9.8 |
GAD = 13/7 HC = 13/7 |
No other current psychiatric disorders |
No current psychotropic drug use |
3 T rs-fMRI |
Increased functional connectivity in amygdala, insula, putamen, thalamus, and PCC in GAD patients vs. HC Decreased functional connectivity in frontal and temporal cortex in GAD patients vs. HC |
Xia124124. Xia L, Li S, Wang T, Guo Y, Meng L, Feng Y, et al. Spontaneous alterations of regional brain activity in patients with adult generalized anxiety disorder. Neuropsychiatr Dis Treat. 2017;13:1957-65.
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GAD = 31, 36.87±9.16 HC = 36, 39.53±8.83 |
GAD = 16/15 HC = 23/13 |
No other current psychiatric disorders |
No current psychotropic drugs |
3 T rs-fMRI |
Decreased ReHo values in right orbital middle frontal gyrus, left ACC, right middle frontal gyrus and supplementary motor areas as well as decreased ReHo values in left middle temporal gyrus, left superior temporal gyrus, and right superior occipital gyrus in GAD patients vs. HC |
Buff125125. Buff C, Brinkmann L, Bruchmann M, Becker MP, Tupak S, Hermann MJ, et al. Activity alterations in the bed nucleus of the stria terminalis and amygdala during threat anticipation in generalized anxiety disorder. Soc Cogn Affect Neurosci. 2017;12:1766-74.
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GAD = 19, 28.26±8.93 HC = 19, 28± 5.28 |
GAD = 15/4 HC = 15/4 |
MDD = 3 PTSD = 1 Specific phobia =1eating disorder=1 |
Seven GAD patients took long-term medication |
3 T fMRI Task: fear conditioning tasks |
Increased activation of amygdala and BNST during threat anticipation in GAD patients vs. HC |
Karim126126. Karim HT, Tudorascu DL, Butters MA, Walker S, Aizenstein HJ, Andreescu C. In the grip of worry: cerebral blood flow changes during worry induction and reappraisal in late-life generalized anxiety disorder. Transl Psychiatry. 2017;7:e1204.
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GAD = 20, 67 HC = 20, 68 |
GAD = 13/7 HC = 10/10 |
Patients with other anxiety disorders or unipolar depression were included if GAD was the principal diagnosis, but participants with current MDD at the time of scanning were excluded. Patients with a past history of alcohol or substance abuse who were in full remission for at least 3 months were included. |
No current psychotropic drug use |
3 T fMRI Task: worry induction task |
Increased activation of visual cortex, thalamus, caudate, and medial frontal cortex in GAD patients vs. HC Decreased activation during reappraisal in supplemental motor area, middle cingulate gyrus, insula, and putamen in GAD patients vs. HC |
Burkhouse127127. Burkhouse KL, Kujawa A, Hosseini B, Klumpp H, Fitzgerald KD, Langenecker SA, et al. Anterior cingulate activation to implicit threat before and after treatment for pediatric anxiety disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2018;84:250-6.
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GAD+SAD+ GSAD = 25, 15.28±2.65 HC = 25, 15.92±2.81 |
GAD+SAD+ GSAD = 16/9 HC = 17/8 |
No other current psychiatric disorders |
No current psychotropic drug use |
3 T fMRI Task: facial emotion processing task Between scans, anxious youth were treated with SSRI or CBT |
Pre-treatment: Increased activation in rostral ACC when matching shapes in the context of threat distractors in the anxious group vs HC. Post-treatment (SSRI or CBT): activation in the rostral ACC increased in the anxious group but not in HC |