Explore functional brain changes in bipolar disorder: A whole brain ALE meta-analysis

Hui, Yang; Qing, Qin; Jize, Jiang; Hui, Xiang; Zhenggui, Yang; Yu, Zhou; Yong, Wu; Maolan, Zhang

doi:10.15761/0101-60830000000309

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Original Article • Arc. Clin. Psychiatr. 48 (4) • 2021 • https://doi.org/10.15761/0101-60830000000309 copy

Explore functional brain changes in bipolar disorder: A whole brain ALE meta-analysis

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Background:

Previous functional magnetic resonance imaging (fMRI) studies showed inconsistent results for comparison between bipolar disorder (BD) and healthy controls (HC).

Methods:

An anatomic likelihood estimation (ALE) meta-analysis was used to explore the key regions of brain pathology in BD with different current mood states.

Results:

Depressed BD patients showed reduced regional homogeneity (ReHo) in the left claustrum and the left middle frontal gyrus (MFG), compared to HC. BD patients with mixed mood status showed decreased fractional amplitude of low frequency fluctuations (fALFF) in the right cerebellar tonsil, the bilateral MFG and the right superior frontal gyrus, compared to HC. Additionally, BD patients with mixed mood status showed increased fALFF in the right inferior occipital gyrus, the right culmen and the left lentiform nucleus, compared to HC. BD patients with mixed mood status showed decreased functional connectivity (FC) in the bilateral cerebellar tonsil, compared to HC.

Conclusion:

In the present study, key regions undergoing functional deficits in BD patients with different current mood states were obtained with the ALE meta-analysis. In addition, deficits in these regions in fMRI studies might work as biomarkers for early diagnosis of BD.

Keywords:
activation likelihood estimation; bipolar disorder; functional magnetic resonance imaging; meta-analysis

Study	Imaging modality	Method	N (BD)	N (HC)	Age (SD)	Gender (male%)	Diagnosis	Treatment status	Mood status	Task (s)	Group contrasts	Foci	Correction for multiple comparisons	Covariates
Altshuler et al. (2005) ¹1 Lu X, Zhong Y, Ma Z. Structural imaging biomarkers for bipolar disorder: Meta-analyses of whole-brain voxel-based morphometry studies. Depress Anxiety. 2019;36(4):353-364. doi: 10.1002/da.22866 https://doi.org/10.1002/da.22866...	Task fMRI	–	11	13	36±7.6	36%	DSM-IV BDI	Mixed	Manic	Go-NoGo task	HC >BD	3	p < 0.0001, uncorrected	NR
Chen et al. (2006) ²2 Alústiza I, Radua J, Pla M, Martin R, Ortuño F. Meta-analysis of functional magnetic resonance imaging studies of timing and cognitive control in schizophrenia and bipolar disorder: Evidence of a primary time deficit. Schizophrenia research 2017;188:21-32. doi: 10.1016/j.schres.2017.01.039 https://doi.org/10.1016/j.schres.2017.01...	Task fMRI	–	8	8	39± 13.44	100%	DSM-IV BDI	Medicated	Manic, Depressed	Implicit Facial Affect Recognition	HC >BD	8	p < 0.005 uncorrected	NR
Roth et al. (2006) ³3 Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med. 2009;6(7):e1000097. doi: 10.1371/journal.pmed.1000097 https://doi.org/10.1371/journal.pmed.100...	Task fMRI	–	11	11	37.7±14.4	NR	DSM-IV BDI	Medicated	Mixed	a counting Stroop task	HC >BD	7	p < 0.005 uncorrected	NR
Lagopoulos et al. (2007) ⁴4 Laird AR, Robinson JL, McMillan KM, Tordesillas-Gutierrez D, Moran ST, Gonzales SM, Ray KL, Franklin C, Glahn DC, Fox PT, Lancaster JL. Comparison of the disparity between Talairach and MNI coordinates in functional neuroimaging data: validation of the Lancaster transform. Neuroimage. 2010;51(2):677-83. doi: 10.1016/j.neuroimage.2010.02.048 https://doi.org/10.1016/j.neuroimage.201...	Task fMRI	–	10	10	32.4±10.8	NR	DSM-IV BDI	Medicated	euthymic	working memory task	HC >BD	2	FDR p < 0.05	NR
Altshuler et al. (2008) ⁵5 Lancaster JL, Tordesillas-Gutierrez D, Martinez M, Salinas F, Evans A, Zilles K, Mazziotta JC, Fox PT. Bias between MNI and Talairach coordinates analyzed using the ICBM-152 brain template. Hum Brain Mapp. 2007;28(11):1194-205. doi: 10.1002/hbm.20345 https://doi.org/10.1002/hbm.20345...	Task fMRI	–	11	17	32 ± 7.3	NR	DSM-IV BDI	Mixed	depressive	face-matching paradigm	HC > BD	3	p < 0.01 uncorrected	NR
	Task fMRI	–	11	17	32 ± 7.3	NR	DSM-IV BDI	Mixed	depressive	face-matching paradigm	BD > HC	1	p < 0.01 uncorrected	NR
McIntosh et al. (2008) ⁶6 Turkeltaub PE, Eickhoff SB, Laird AR, Fox M, Wiener M, Fox P. Minimizing within-experiment and within-group effects in Activation Likelihood Estimation meta-analyses. Hum Brain Mapp. 2012;33(1):1-13. doi: 10.1002/hbm.21186 https://doi.org/10.1002/hbm.21186...	Task fMRI	–	42	37	39.3 ± 10.8	55.3%	DSM-IV BD	NR	NR	Hayling Sentence Completion Test	HC > BD	1	p < 0.005 uncorrected	NR
Kaladjian et al. (2009) ⁷7 Achalia RM, Jacob A, Achalia G, Sable A, Venkatasubramanian G, Rao NP. Investigating spontaneous brain activity in bipolar disorder: A resting-state functional magnetic resonance imaging study. Indian J Psychiatry 2019;61(6)630-634. doi: 10.4103/psychiatry.IndianJPsychiatry_391_19 https://doi.org/10.4103/psychiatry.India...	Task fMRI	–	20	20	37.9 ± 11.4	50%	DSM-IV BDI	Unmedicated	Euthymic	a Go–NoGo task	HC >BD	3	p < 0.05 FWE-corrected	NR
Linke et al. (2012) ⁸8 Gao W, Jiao Q, Lu S, Zhong Y, Qi R, Lu D, Xiao Q, Yang F, Lu G, Su L. Alterations of regional homogeneity in pediatric bipolar depression: a resting-state fMRI study. BMC Psychiatry 2014;14:222. doi: 10.1186/s12888-014-0222-y. https://doi.org/10.1186/s12888-014-0222-...	Task fMRI	–	19	22	45 ±10	42%	DSM-IV BDI	Unmedicated	Euthymic	a probabilistic reversal learning task	HC >BD	8	p < 0.05 FWE-corrected	NR
Liu et al. (2012) ⁹9 Liang MJ, Zhou Q, Yang KR, Yang XL, Fang J, Chen WL, Huang Z. Identify changes of brain regional homogeneity in bipolar disorder and unipolar depression using resting-state FMRI. PLoS One. 2013;8(12):e79999. doi: 10.1371/journal.pone.0079999 https://doi.org/10.1371/journal.pone.007...	Rs-fMRI	ALFF	26	26	32.35 ±11.31	34.6%	DSM-IV BD	Medicated	depressive	–	HC > BD	4	p < 0.01 uncorrected	NR
	Rs-fMRI	ALFF	26	26	32.35 ±11.31	34.6%	DSM-IV BD	Medicated	depressive	–	BD > HC	10	p < 0.01 uncorrected	NR
Townsen d et al. (2012) ¹⁰10 Liu CH, Li F, Li SF, Wang YJ, Tie CL, Wu HY, Zhou Z, Zhang D, Dong J, Yang Z, Wang CY. Abnormal baseline brain activity in bipolar depression: a resting state functional magnetic resonance imaging study. Psychiatry Res. 2012;203(2-3):175-9. doi: 10.1016/j.pscychresns.2012.02.007 https://doi.org/10.1016/j.pscychresns.20...	Task fMRI	–	32	30	37 ± 13	65.6%	DSM-IV BDI	Unmedicated	euthymic	a Go–NoGo task	HC > BD	17
Vizueta et al. (2012) ¹¹11 Lu D, Jiao Q, Zhong Y, Gao W, Xiao Q, Liu X, Lin X, Cheng W, Luo L, Xu C, Lu G, Su L. Altered baseline brain activity in children with bipolar disorder during mania state: a resting-state study. Neuropsychiatr Dis Treat. 2014;10:317-23. doi: 10.2147/NDT.S54663 https://doi.org/10.2147/NDT.S54663...	Task fMRI	–	21	21	NR	52.4%	DSM-IV BDII	Mixed	depressive	an emotional face-matching task	HC > BD	5	p < 0.005 uncorrected	NR
	Task fMRI	–	21	21	NR	52.4%	DSM-IV BDII	Mixed	depressive	an emotional face-matching task	BD > HC	7	p < 0.005 uncorrected	NR
Liang et al. (2013) ¹²12 Qiu M, Zhang H, Mellor D, Shi J, Wu C, Huang Y, Zhang J, Shen T, Peng D. Aberrant Neural Activity in Patients With Bipolar Depressive Disorder Distinguishing to the Unipolar Depressive Disorder: A Resting-State Functional Magnetic Resonance Imaging Study. Front Psychiatry. 2018;9:238. doi: 10.3389/fpsyt.2018.00238 https://doi.org/10.3389/fpsyt.2018.00238...	Rs-fMRI	ReHo	17	16	34.47 ± 9.77	52.9%	DSM-IV BD	Unmedicated	depressive	–	HC > BD	13	p < 0.05 uncorrected	NR
	Rs-fMRI	ReHo	17	16	34.47 ± 9.77	52.9%	DSM-IV BD	Unmedicated	depressive	–	BD > HC	9	p < 0.05 uncorrected	NR
Sagar et al. (2013) ¹³13 Qiu S, Chen F, Chen G, Jia Y, Gong J, Luo X, Zhong S, Zhao L, Lai S, Qi Z, Huang L, Wang Y. Abnormal resting-state regional homogeneity in unmedicated bipolar II disorder. J Affect Disord. 2019;256:604-610. doi: 10.1016/j.jad.2019.06.037 https://doi.org/10.1016/j.jad.2019.06.03...	Task fMRI	–	23	18	26.65 ± 6.65	NR	DSM-IV BDI	Medicated	NR	a backward-masked affect paradigm	HC > BD	12	p < 0.05 uncorrected	NR
	Task fMRI	–	23	18	26.65 ± 6.65	NR	DSM-IV BDI	Medicated	NR	a backward-masked affect paradigm	BD > HC	30	p < 0.05 uncorrected	NR
Xiao et al. (2013) ¹⁴14 Skatun KC, Kaufmann T, Tonnesen S, Biele G, Melle I, Agartz I, Alnaes D, Andreassen OA, Westlye LT. Global brain connectivity alterations in patients with schizophrenia and bipolar spectrum disorders. J Psychiatry Neurosci. 2016;41(5):331-41. doi: 10.1503/jpn.150159 https://doi.org/10.1503/jpn.150159...	Rs-fMRI	ReHo	15	15	15.0 ± 1.7	40%	DSM-IV Pediatric BD	Medicated	Manic	–	HC > BD	10	p < 0.05 FWE-corrected	NR
	Rs-fMRI	ReHo	15	15	15.0 ± 1.7	40%	DSM-IV Pediatric BD	Medicated	Manic	–	BD > HC	5	p < 0.05 FWE-corrected	NR
Gao et al. (2013) ¹⁵15 Wang Y, Zhong S, Chen G, Liu T, Zhao L, Sun Y, Jia Y, Huang L. Altered cerebellar functional connectivity in remitted bipolar disorder: A resting-state functional magnetic resonance imaging study. Aust N Z J Psychiatry. 2018;52(10):962-971. doi: 10.1177/0004867417745996 https://doi.org/10.1177/0004867417745996...	Rs-fMRI	ReHo	17	18	14.4 ± 1.77	41.2%	DSM-IV Pediatric BD	Mixed	depressive		HC > BD	6	p < 0.05 uncorrected	NR
Lu et al. (2014) ¹⁶16 Wang Y, Zhong S, Jia Y, Zhou Z, Wang B, Pan J, Huang L. Interhemispheric resting state functional connectivity abnormalities in unipolar depression and bipolar depression. Bipolar Disord. 2015;17(5):486-95. doi: 10.1111/bdi.12315 https://doi.org/10.1111/bdi.12315...	Rs-fMRI	ALFF	18	18	15.1 ± 1.81	33.3%	DSM-IV Pediatric BD	Medicated	Manic	–	HC > BD	4	p < 0.001 uncorrected	NR
	Rs-fMRI	ALFF	18	18	15.1 ± 1.81	33.3%	DSM-IV Pediatric BD	Medicated	Manic	–	BD > HC	3	p < 0.001 uncorrected	NR
McKenna et al. (2014) ¹⁷17 Xiao Q, Zhong Y, Lu D, Gao W, Jiao Q, Lu G, Su L. Altered regional homogeneity in pediatric bipolar disorder during manic state: a resting-state fMRI study. PLoS One. 2013;8(3):e57978. doi: 10.1371/journal.pone.0057978 https://doi.org/10.1371/journal.pone.005...	Task fMRI	–	23	23	45.31 ± 9.45	34.9%	DSM-IV BD	Medicated	euthymic	a delayed match-to-sampleWM paradigm	HC > BD	5	p < 0.01 uncorrected	NR
	Task fMRI	–	23	23	45.31 ± 9.45	34.9%	DSM-IV BD	Medicated	euthymic	a delayed match-to-sampleWM paradigm	BD > HC	3	p < 0.01 uncorrected	NR
Rey et al. (2014) ¹⁸18 Yang Y, Liu S, Jiang X, Yu H, Ding S, Lu Y, Li W, Zhang H, Liu B, Cui Y, Fan L, Jiang T, Lv L. Common and Specific Functional Activity Features in Schizophrenia, Major Depressive Disorder, and Bipolar Disorder. Front Psychiatry. 2019;10:52. doi: 10.3389/fpsyt.2019.00052 https://doi.org/10.3389/fpsyt.2019.00052...	Task fMRI	–	12	12	42.6 ± 11.4	66.7%	DSM-IV BD	Medicated	Depressive, euthymic, hypomania		HC > Depressive BD	2	p < 0.001 uncorrected	NR
	Task fMRI	–	12	12	42.6 ± 11.4	66.7%	DSM-IV BD	Medicated	Depressive, euthymic, hypomania		HC > euthymic BD	1	p < 0.001 uncorrected	NR
Favre et al. (2015) ¹⁹19 Yao X, Yin Z, Liu F, Wei S, Zhou Y, Jiang X, Wei Y, Xu K, Wang F, Tang Y. Shared and distinct regional homogeneity changes in bipolar and unipolar depression. Neurosci Lett. 2018;673:28-32. doi: 10.1016/j.neulet.2018.02.033 https://doi.org/10.1016/j.neulet.2018.02...	Task fMRI	–	14	13	44.07 ± 9.63	36%	DSM-IV BD	Mixed	euthymic	a word-face emotional Stroop task	HC > BD	4	p < 0.001 uncorrected	NR
Wang et al. (2015) ²⁰20 Altshuler L, Bookheimer S, Townsend J, Proenza MA, Sabb F, Mintz J, Cohen MS. Regional brain changes in bipolar I depression: a functional magnetic resonance imaging study. Bipolar disorders 2008;10(6):708-717. doi: 10.1111/j.1399-5618.2008.00617.x https://doi.org/10.1111/j.1399-5618.2008...	Rs-fMRI	VMHC	26	40	26.12 ± 10.30	57.7%	DSM-IV BDII	Unmedicated	NR	–	HC > BD	2	p < 0.05 uncorrected	NR
Skatun et al. (2016) ²¹21 Altshuler LL, Bookheimer SY, Townsend J, Proenza MA, Eisenberger N, Sabb F, Mintz J, Cohen, MS. Blunted activation in orbitofrontal cortex during mania: a functional magnetic resonance imaging study. Biol psychiatry 2005;58(10):763-769. doi: 10.1016/j.biopsych.2005.09.012 https://doi.org/10.1016/j.biopsych.2005....	Rs-fMRI	FC	43	196	31.3 ± 11.3	43.2%	DSM-IV BD	Mixed	NR	–	HC > BD	6	p < 0.05 uncorrected	NR
King et al. (2018) ²²22 Chen CH, Lennox B, Jacob R, Calder A, Lupson V, Bisbrown-Chippendale R, Suckling J, Bullmore E. Explicit and implicit facial affect recognition in manic and depressed States of bipolar disorder: a functional magnetic resonance imaging study. Biol Psychiatry 2006;59(1):31-9. doi: 10.1016/j.biopsych.2005.06.008 https://doi.org/10.1016/j.biopsych.2005....	Task fMRI	–	35	35	15 ± 2		DSM-IV Pediatric BDI	Unmedicated	euthymic	a self-paced sequential bilateral finger-tapping task	HC > BD	4	FDR p < 0.05	NR
Qiu et al. (2018) ²³23 Favre P, Polosan M, Pichat C, Bougerol T, Baciu M. Cerebral Correlates of Abnormal Emotion Conflict Processing in Euthymic Bipolar Patients: A Functional MRI Study. 2015;10(8):e0134961. doi: 10.1371/journal.pone.0134961. https://doi.org/10.1371/journal.pone.013...	Rs-fMRI	fALFF	28	27	31.79 ± 12.83	50%	DSM-IV BD	Mixed	depressive	–	HC > BD	2	p < 0.001 uncorrected	age, gender and education level
	Rs-fMRI	fALFF	28	27	31.79 ± 12.83	50%	DSM-IV BD	Mixed	depressive	–	BD > HC	1	p < 0.001 uncorrected	age, gender and education level
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Yao et al. (2018) ²⁵25 King JB, Anderson JS, Yurgelun-Todd DA, Subramaniam P, Ehrler MR, Lopez-Larson MP. Decreased anterior cingulate activation in a motor task in youths with bipolar disorder. J Child Psychol Psychiatry. 2018;59(8):900-907. doi: 10.1111/jcpp.12875 https://doi.org/10.1111/jcpp.12875...	Rs-fMRI	ReHo	55	113	27.02 ± 7.706	40%	DSM-IV BDI	Mixed	depressive	–	HC > BD	4	p < 0.005 uncorrected	NR
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Qiu et al. (2019) ²⁷27 Linke J, King AV, Rietschel M, Strohmaier J, Hennerici M, Gass A, Meyer-Lindenberg A, Wessa M. Increased medial orbitofrontal and amygdala activation: evidence for a systems-level endophenotype of bipolar I disorder. Am J Psychiatry. 2012;169(3):316-25. doi: 10.1176/appi.ajp.2011.11050711 https://doi.org/10.1176/appi.ajp.2011.11...	Rs-fMRI	ReHo	100	100	26.37 ± 8.89	55%	DSM-IV BDII	unmedicated	depressive	–	HC > BD	5	p < 0.05 uncorrected	NR
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	Rs-fMRI	fALFF	41	93	32.98 ± 9.41	56%	DSM-IV BD	Mixed	NR	–	BD > HC	3	p < 0.001 uncorrected	Age and sex

Cluster #	Volume (mm³)	Weighted Center (MNI)			Extrema value	Maximum ALE value (MNI)			Side	BA	Anatomical label
Cluster #	Volume (mm³)	x	y	z	Extrema value	x	y	z	Side	BA	Anatomical label
ALE results for rs-fMRI studies (ReHo) (189 depressed BD patients and 247 HC)
HC >BD (26 foci, 4 experiments)
1	288	-39	-12	3	0.009293	-40	-12	2	Left		Claustrum
2	264	-39	42	-12	0.009703	-38	42	-12	Left	47	Middle Frontal Gyrus
ALE results for rs-fMRI studies (fALFF) (69 BD patients with mixed mood status and 120 HC)
HC > BD (5 foci, 2 experiments)
1	480	40	-57	-36	0.008758	40	-57	-36	Right		Cerebellar Tonsil
2	480	30	42	-15	0.00931	30	42	-15	Right	11	Middle Frontal Gyrus
3	384	-33	42	-9	0.008985	-33	42	-9	Left	47	Middle Frontal Gyrus
4	384	30	57	-9	0.008985	30	57	-9	Right	10	Superior Frontal Gyrus
HC < BD (4 foci, 2 experiments)
1	560	30	-90	-3	0.008563	30	-90	-3	Right	18	Inferior Occipital Gyrus
2	448	15	-69	-3	0.008007	15	-69	-3	Right		Culmen
3	448	-27	-15	-3	0.008007	-27	-15	-3	Left		Lentiform Nucleus
ALE results for rs-fMRI studies (FC) (68 BD patients with mixed mood status and 221 HC)
HC > BD (8 foci, 2 experiments)
1	880	36	-45	-54	0.008563	36	-45	-54	Right		Cerebellar Tonsil
2	880	-30	-42	-45	0.008563	-30	-42	-45	Left		Cerebellar Tonsil
ALE results for WM-related studies (33 euthymic BD and 33 HC)
HC > BD (7 foci, 2 experiments)
1	640	3.6	-61.3	1.5	0.008368	4	-62	2	Right		Culmen of Vermis
2	640	-52.6	-47.1	18.9	0.008139	-52	-48	18	Left	22	Superior Temporal Gyrus
3	536	11.9	47.4	4	0.006559	12	48	4	Right	10	Medial Frontal Gyrus
ALE results for Go-Nogo-related studies (53 euthymic BD and 50 HC)
HC > BD (20 foci, 2 experiments)
1	344	20.3	3.8	-10.2	0.00929	20	4	-10	Right		Lentiform Nucleus
2	336	-21.5	65	-1.5	0.008117	-22	64	-2	Left	10	Middle Frontal Gyrus
3	328	-28.4	-9.2	-14.5	0.008199	-28	-10	-14	Left		Parahippocampal Gyrus
ALE results for face-matching tasks-related studies (32 depressed BD and 38 HC)
HC > BD (8 foci, 2 experiments)
1	272	-50.8	14.3	-2.9	0.006602	-50	14	-2	Left	13	Insula
2	264	40	46	14	0.008508	40	46	14	Right	10	Middle Frontal Gyrus
3	264	26	-68	48	0.008508	26	-68	48	Right	7	Precuneus
4	256	48.4	25	-7.9	0.006669	48	26	-8	Right	47	Inferior Frontal Gyrus
5	248	53.3	19.5	24	0.006725	54	20	24	Right	9	Middle Frontal Gyrus

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[1] Address for correspondence: Hui Yang, Department of psychology, the people’s hospital of Guizhou province, No.83, Zhongshan East Road, Guiyang, Guizhou province, 550001, China. Tel: +86-0851-85607128 Fax: +86-0851-85607128 E-mail: HuiYang20201@126.com