Prefrontoparietal dysfunction during emotion regulation in anxiety disorder: a meta-analysis of functional magnetic resonance imaging studies

Figures & data

Figure 1 Search strategy used for the inclusion of the studies considered in the meta-analysis.

Abbreviations: ASL, arterial spin labeling; re-fMRI, resting-state functional magnetic resonance imaging; ROI, region of interest.

Table 1 Demographic and clinical characteristics of the task-based fMRI studies included in the current meta-analysis

Study	Anxiety disorder	Subjects, n		Mean age of patients (SD)		Females (%)		Medication status (subgroup)	Comorbidity (%)	Software (subgroup)	MRI (sub-group)	Statistical threshold	Quality score
		Patient	HC	Patient	HC	Patient	HC
New et al^Citation23	PTSD	14	14	38.7 (11.2)	31.7 (10.3)	100	100	Treatment-naive (unmedicated)	Pure PTSD	SPM 2	3.0 T	p<0.05 Corrected	11.5
Gaebler et al^Citation5	SAD	21	23	30.5 (7.17)	30.0 (7.99)	76	78	17 patients treatment naive; 4 patients on medication (medicated)	38	SPM 8	3.0 T	p<0.05 Corrected	12
Ziv et al^Citation21	SAD	27	27	31.1 (7.6)	32.6 (9.5)	44	48	Treatment-naive for 3 months prior to scan (unmedicated)	30	AFNI	3.0 T	p<0.005 Corrected	11.5
Blair et al^Citation22	SAD	19	18	29.4 (8.70)	33.4 (9.65)	53	56	Treatment-naive (unmedicated)	Pure SAD	AFNI	1.5 T	p<0.05 Corrected	10.5
Goldin et al^Citation20	SAD	15	17	31.6 (9.7)	32.1 (9.3)	60	53	Treatment-naive (unmedicated)	NA	AFNI	3.0 T	p<0.005 Corrected	11
Blair et al^Citation22	SAD/GAD	17	18	35.7 (9.54)	33.4 (9.65)	71	56	Treatment-naive (unmedicated)	100	AFNI	1.5 T	p<0.05 Corrected	10.5
Ball et al^Citation44	PD	18	22	29 (7)	27 (9)	83	50	6 week washout before scan (medicated)	28	AFNI	3.0 T	p<0.05 Corrected	12
Reinecke et al^Citation42	PD	18	18	36.5 (13.8)	32.3 (12.1)	78	78	3 patients had 48 hour washout before scan (medicated)	17	FSL	3.0 T	p<0.05 Corrected	11
Fitzgerald et al^Citation43	GAD	30	30	27.20 (7.57)	25.43 (10.02)	60	77	17 patients treatment-naive; 13 patients had 4 weeks washout before scan (medicated)	60	SPM 8	3.0 T	p<0.05 Corrected	12
Ball et al^Citation44	GAD	23	22	35 (11)	27 (9)	74	50	6 week washout before scan (medicated)	52	AFNI	3.0 T	p<0.05 Corrected	12
Blair et al^Citation22	GAD	17	18	36.1 (11.75)	33.4 (9.65)	76	56	Treatment-naive (unmedicated)	Pure SAD	AFNI	1.5 T	p<0.05 Corrected	10.5

Abbreviations: AFNI, Analysis of Functional NeuroImages; fMRI, functional magnetic resonance imaging; FSL, Functional MRI of the brain Software Libraries package; GAD, generalized anxiety disorder; HC, healthy control; NA, not available; PD, panic disorder; PTSD, posttraumatic stress disorder; SAD, social anxiety disorder; SPM, statistical parametric mapping.

Figure 2 Regions of decreased (blue) activation in individuals with anxiety disorder compared with HC during cognitive reappraisal and subgroup analysis of medication naive group, 3 T MRI group, AFNI software group, SAD group and GAD and SAD group.

Abbreviations: AFNI, Analysis of Functional NeuroImages; dACC, dorsal anterior cingulate cortex; dmPFC, dorsomedial prefrontal cortex; GAD, generalized anxiety disorder; HC, healthy control; L, left; R, right; SAD, social anxiety disorder; SMA, supplementary motor area; vmPFC, ventromedial prefrontal cortex.

Table 2 Altered regional differences in activation during cognitive reappraisal in patients with anxiety disorder compared to healthy controls

Brain regions	MNI coordinates			SDM z score	p-value	Voxels, n	Cluster breakdown	Heterogeneity	Jackknife sensitivity
AD < HC	X	Y	Z
Left superior frontal gyrus, medial, BA 32	−2	28	38	−2.667	~0	2,489	Left superior frontal gyrus, medial, BA 8, 9, 24, 32 (464) Left anterior cingulate/paracingulate gyri, BA 32, 24 (473) Left median cingulate/paracingulate gyri, BA 24, 23, 32 (407) Left supplementary motor area, BA 6, 8, 24, 32 (212) Right median cingulate/paracingulate gyri, BA 24, 23, 32 (483) Right anterior cingulate/paracingulate gyri, BA 24, 32 (229) Right superior frontal gyrus, medial, BA 8, 9, 32 (114) Right supplementary motor area, BA 6, 8, 24, 32 (107)	ns	11 out of 11
Left inferior parietal (excluding supramarginal and angular) gyri, BA 3	−48	−28	46	−2.329	0.000002563	1,138	Left inferior parietal gyri, BA 2, 3, 40 (290) Left postcentral gyrus, BA 1, 2, 3, 4, 6, 40 (561) Left supramarginal gyrus, BA 2, 3, 40, 48 (187) Left precentral gyrus, BA 3, 4, 6 (100)	ns	11 out of 11
Left amygdala	−28	−10	−12	−1.767	0.000503182	216	Left amygdala, BA 20, 28, 34, 36 (139) Anterior commissure (41) Left inferior network (36)	Significant	9 out of 11
Left fusiform gyrus, BA 18	−26	−72	−12	−1.483	0.002632022	69	Left fusiform gyrus, BA 18, 19 (56) Left lingual gyrus, BA 18, 19 (13)	Significant	9 out of 11
Right superior parietal gyrus, BA 7	26	−74	56	−1.696	0.000781834	39	Right superior parietal gyrus, BA 7 (39)	ns	8 out of 11
Left middle frontal gyrus, orbital part, BA 11	−24	34	−16	−1.478	0.002699077	27	Left middle frontal gyrus, orbital part, BA 11 (27)	Significant	9 out of 11

Abbreviations: AD, anxiety disorder; BA, Brodmann area; HC, healthy control; MNI, Montreal Neurological Institute; ns, non-significant; SDM Z, signed differential mapping Z-value.

Table 3 Subgroup analyses of the included studies

Subgroups	Bilateral superior frontal gyrus (dmPFC, dACC and SMA)	Left inferior parietal gyri	Left amygdala	Left fusiform gyrus	Left middle frontal gyrus (vmPFC)	Right superior parietal gyrus
Data sets using 3T MRI (n=8)	Y (except SMA)	Y	Y	Y	Y	N
The medication-naive patient (n=6)	Y	Y	N	Y	N	Y
Social anxiety disorder (n=5)	Y	N	Y	N	N	Y
Data sets using AFNI software (n=7)	Y	Y	N	Y	N	Y
Generalized anxiety disorder and social anxiety disorder (n=8)	Y	Y	Y	Y	N	Y

Abbreviations: AFNI, Analysis of Functional NeuroImages; dACC, dorsal anterior cingulate cortex; dmPFC, dorsomedial prefrontal cortex; N, no; SMA, supplementary motor area; vmPFC, ventromedial prefrontal cortex; Y, yes.

Figure 3 Results of the meta-regression analysis showing the percentage of female patients with a positive relationship with activation in the right fusiform gyrus. In the graphs, AES-SDM values needed to create this plot were extracted from the peak of maximum slope significance, and each study is represented as a dot, whose size reflects sample size. The regression line (meta-regression signed differential mapping slope) is shown.

Abbreviations: AES, anisotropic effect-size; SDM, signed differential mapping.

Table S1 Imaging methodology quality assessment checklist (when criteria were partially met, 0.5 points were assigned)

Category 1: subjects	Score (0/0.5/1)
1. Patients were evaluated prospectively, specific diagnostic criteria were applied, and demographic data were reported
2. Healthy comparison subjects were evaluated prospectively, psychiatric and medical illnesses were excluded
3. Important variables (eg, age, gender, illness duration, onset time, medication status, comorbidity, severity of illness) were checked, either by stratification or statistically
4. Sample size per group >10
Category 2: methods for image acquisition and analysis
5. Magnet strength at least 1.5 T
6. MRI slice-thickness ≤3 mm
7. Whole brain analysis was automated with no a priori regional selection
8. Coordinates reported in a standard space
9. The imaging technique used was clearly described so that it could be reproduced
10. Measurements were clearly described so that they could be reproduced
Category 3: results and conclusions
11. Statistical parameters for significant, and important non-significant, differences were provided
12. Conclusions were consistent with the results obtained and the limitations were discussed
Total  /12

Table S2 Sensitivity analyses of task-based fMRI studies of regional differences in activation in patients with anxiety disorder compared with healthy controls

Study	Bilateral superior frontal gyrus (dmPFC, dACC and SMA)	Left inferior parietal gyri	Left amygdala	Left fusiform gyrus	Right superior parietal gyrus	Left vmPFC
New et al^Citation1 (PTSD)	Y	Y	Y	Y	Y	N
Gaebler et al^Citation2 (SAD)	Y	Y	Y	Y	Y	Y
Ziv et al^Citation3 (SAD)	Y	Y	N	N	Y	Y
Blair et al^Citation4 (SAD)	Y	Y	Y	Y	N	Y
Goldin et al^Citation5 (SAD)	Y	Y	Y	N	Y	Y
Blair et al^Citation4 (SAD/GAD)	Y	Y	Y	Y	N	Y
Ball et al^Citation6 (PD)	Y	Y	Y	Y	Y	Y
Reinecke et al^Citation7 (PD)	Y	Y	Y	Y	Y	Y
Fitzgerald et al^Citation8 (PD)	Y	Y	N	Y	Y	N
Ball et al^Citation6 (GAD)	Y	Y	Y	Y	Y	Y
Blair et al^Citation4 (GAD)	Y	Y	Y	Y	N	Y

Abbreviations: dACC, dorsal anterior cingulate cortex; dmPFC, dorsomedial prefrontal cortex; fMRI, functional magnetic resonance imaging; GAD, generalized anxiety disorder; N, no; PD, panic disorder; PTSD, post-traumatic stress disorder; SAD, social anxiety disorder; SMA, supplementary motor area; vmPFC, ventromedial prefrontal cortex; Y, yes.

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ReineckeAFilippiniNBernaCEffective emotion regulation strategies improve fMRI and ECG markers of psychopathology in panic disorder: implications for psychological treatment actionTransl Psychiatry20155e67326529426

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FitzgeraldJMPhanKLKennedyAEShankmanSALangeneckerSAKlumppHPrefrontal and amygdala engagement during emotional reactivity and regulation in generalized anxiety disorderJ Affect Disord201721839840628501740

 PubMed Web of Science ®Google Scholar

NewASFanJMurroughJWA functional magnetic resonance imaging study of deliberate emotion regulation in resilience and post-traumatic stress disorderBiol Psychiatry200966765666419589502

 PubMed Web of Science ®Google Scholar

GaeblerMDanielsJKLamkeJPFydrichTWalterHBehavioural and neural correlates of self-focused emotion regulation in social anxiety disorderJ Psychiatry Neurosci201439424925824690369

 PubMed Web of Science ®Google Scholar

ZivMGoldinPRJazaieriHHahnKSGrossJJEmotion regulation in social anxiety disorder: behavioral and neural responses to three socio-emotional tasksBiol Mood Anxiety Disord2013312024517388

 PubMedGoogle Scholar

BlairKSGeraciMSmithBWReduced 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 disorderBiol Psychiatry201272647648222592057

 PubMed Web of Science ®Google Scholar

GoldinPRManberTHakimiSCanliTGrossJJNeural bases of social anxiety disorder: emotional reactivity and cognitive regulation during social and physical threatArch Gen Psychiatry200966217018019188539

 PubMed Web of Science ®Google Scholar

BallTMRamsawhHJCampbellsillsLPaulusMPSteinMBPrefrontal dysfunction during emotion regulation in generalized anxiety and panic disordersPsychol Med20134371475148623111120

 PubMed Web of Science ®Google Scholar

ReineckeAFilippiniNBernaCEffective emotion regulation strategies improve fMRI and ECG markers of psychopathology in panic disorder: implications for psychological treatment actionTransl Psychiatry20155e67326529426

 PubMed Web of Science ®Google Scholar

FitzgeraldJMPhanKLKennedyAEShankmanSALangeneckerSAKlumppHPrefrontal and amygdala engagement during emotional reactivity and regulation in generalized anxiety disorderJ Affect Disord201721839840628501740

 PubMed Web of Science ®Google Scholar