A Review of MR Spectroscopy Studies of Pediatric Bipolar Disorder

D.G. Kondo; T.L. Hellem; X.-F. Shi; Y.H. Sung; A.P. Prescot; T.S. Kim; R.S. Huber; L.N. Forrest; P.F. Renshaw

doi:10.3174/ajnr.A3844

Article Figures & Data

Figures

Tables

Download figure
Open in new tab
Download powerpoint
Fig 1.
Representative proton-1 MR spectroscopy (¹H-MRS) spectrum acquired with parameters TR/TE = 2000/31 ms on a 3T MR imaging scanner.
Download figure
Open in new tab
Download powerpoint
Fig 2.
Representative phosphorus 31 MR spectroscopy (³¹P-MRS) spectrum acquired without proton decoupling on a 3T MR imaging scanner.

Tables

Figures

View popup

Table 1:

Cross-sectional MRS studies of pediatric bipolar disorder

Study	Sample	Methods (Device/FS/TR/TE/Sequence)	Region-of-Interest Voxel Size and Location	Findings
Castillo et al, 2000⁶⁶	10 Patients with BD, mood state not reported, unmedicated, (mean age, 8 yr), 10 non-aged-matched healthy volunteers	Not stated/1.5T/3000/30/PRESS	8 mL or 27 mL in the left and right frontal lobe, 8 mL or 27 mL in the left and right temporal lobe	↑ Glx/tCre in BD in the frontal lobe and basal ganglia; No significant difference in NAA/tCre or tChol/tCre
Davanzo et al, 2001⁷⁸	11 Patients with BD, mixed state (n = 9), manic state (n = 2), medicated (n = 9), unmedicated (n = 2), (mean age, 11.4 yr), 11 age- and gender-matched healthy volunteers	Signa^{^a}/1.5T/1500/135/PRESS	8 mL in the anterior cingulate cortex	Trend (P = .054) toward ↑ mIns/tCre in BD
Moore and Galloway, 2002⁵⁰	9 Youth with BD with mean serum lithium level = −0.87 mEq/L, mood state not reported, (mean age, 13.4 yr),	Signa^{^a}/1.5T/25,000/not stated/1D-ISIS	60-mm axial section centered on the superior edge of the ventricles	Mean brain lithium concentration = 0.52 mEq/L in pediatric patients with BD;
		Lithium-7 MRS was used to measure brain lithium concentrations in vivo		mean brain lithium concentration = 0.92 mEq/L in adult patients with BD;
	18 adults with BD with mean serum lithium level = 0.78 mEq/L, mood state not reported, (mean age, 37.3 yr)			lower brain-to-serum concentration ratios^{^b} in youth with BD compared with adults: 0.58 vs 0.92 (P < .02);
				brain-to-serum concentration ratio correlated positively with age (r = 0.44; P < .02);
				formula for brain-to-serum lithium concentration ratio^{^b};
				(brain lithium in mEq/L) / (serum lithium in mEq/L)
Chang et al, 2003⁷⁰	15 Patients with BD with at least 1 parent with BD, mood state euthymic (n = 15), medicated (n = 14), unmedicated (n = 1), (mean age, 12.6 yr), 11 healthy volunteers (mean age, 12.6 yr)	Signa^{^a}/3T/2000/35/PRESS	8 mL in left and right dorsolateral prefrontal cortices	↓ NAA/tCre in BD in the right dorsolateral prefrontal cortex (P < .02)
Davanzo et al, 2003⁷⁵	10 Patients with BD, mood state manic (n = 2), mood state mixed (n = 8), medicated (n = 7), unmedicated (n = 3), (mean age, 9.8 yr),	Signa^{^a}/1.5T/3000/30/PRESS	8 mL in the anterior cingulate cortex,	↑ mIns and mIns/tCre in anterior cingulate in BD compared with both intermittent explosive disorder and healthy volunteers (P <0.02);
	10 patients with intermittent explosive disorder, (mean age, 9.6 yr),		8 mL in the occipital cortex	↓ tChol/tCre in anterior cingulate in BD compared with healthy volunteers (P = .05);
	13 healthy volunteers, (mean age, 11.7 yr)		8 mL in the occipital cortex	no significant group differences in occipital cortex mIns, mIns/tCre, or tChol/tCre
Sassi et al, 2005⁷¹	14 Patients with BD, mood state euthymic (n = 13), mood state depressed (n = 1), medicated (n = 13), unmedicated (n = 1), (mean age, 15.5 yr),	Signa^{^a}/1.5T/1500/20/STEAM	8 mL in the left dorsolateral prefrontal cortex	↓NAA in BD (P = .03);
Sassi et al, 2005⁷¹	18 healthy volunteers, (mean age, 17.3 yr)	Signa^{^a}/1.5T/1500/20/STEAM	8 mL in the left dorsolateral prefrontal cortex	tChol was negatively correlated with the number of previous BD episodes (r = −0.86; P =.0001)
Moore et al, 2007⁶⁷	10 Unmedicated patients with BD mania, (mean age, 11.1 yr),	Signa^{^a}/1.5T/2000/30/Probe-P(PRESS) and MRSI; TR/TE not stated	4.8 mL in the anterior cingulate cortex	↓ Glx/tCre in BD mania compared with BD risperidone-treatment responders (P < .05)
Moore et al, 2007⁶⁷	8 patients with BD on risperidone; mean dose = 2.09 mg; mean duration = 101 weeks (mean age, 10.9 yr)		4.8 mL in the anterior cingulate cortex
Moore et al, 2007⁶⁸	22 Patients with BD, euthymic state (n = 2), depressed state (n = 1), manic state (n = 10), mixed state (n = 9), medicated (n = 15), unmedicated (n = 7), (mean age, 12.6 yr),	Varian^{^c} 4T/2000/30/PRESS	8 mL in the anterior cingulate cortex	↓ Gln in unmedicated BD (n = 7; mean age, 12.9 yr) compared with both medicated BD (P = .003) and healthy volunteers (P = .027);
Moore et al, 2007⁶⁸	10 healthy volunteers, (mean age, 12.3 yr)	Varian^{^c} 4T/2000/30/PRESS	8 mL in the anterior cingulate cortex	no significant difference in Glu among the 3 groups
Olvera et al, 2007⁷²	35 Patients with BD, (mean age, 13.2 yr), mood state not reported, medicated (n = 24), unmedicated (n = 11),	Intera^{^b}/1.5T/6000/30/PRESS	8 mL in the left dorsolateral prefrontal cortex	↓ NAA in BD (P = .04);
Olvera et al, 2007⁷²	36 healthy volunteers, (mean age, 13.7 yr)	Intera^{^b}/1.5T/6000/30/PRESS	8 mL in the left dorsolateral prefrontal cortex	no significant difference in Glu, tCre, tChol, or mIns
Patel et al, 2008⁷⁴	28 Unmedicated depressed patients with BD, (mean age, 15.5 yr),	Signa^{^a}/1.5T/2000/35/Probe-P(PRESS)	8 mL in the anterior cingulate cortex, and the left and right ventral lateral prefrontal cortices	↑ NAA in BD in the anterior cingulate cortex, (P = .0002) and the left (P = .0008) and right (P = .002) ventral lateral prefrontal cortices;
	10 healthy volunteers, (mean age, 14.6 yr)			↑ tChol in BD in the left (P = .001) and right (P = .01) ventral lateral prefrontal cortices;
				↑ mIns in BD in the right (P = .002) ventral lateral prefrontal cortex;
				in general, patients with BD had higher neurometabolite concentrations than healthy volunteers
Caetano et al, 2011⁷³	43 Patients with BD, euthymic state (n = 8), depressed state (n = 11), manic state (n = 12), mixed state (n = 12), medicated (n = 31), unmedicated (n = 12), (mean age, 13.2 yr),	Inter^{^b}/1.5T/1500/272/MRSI	8 mL in bilateral medial prefrontal cortex, dorsolateral prefrontal cortex, anterior and posterior cingulate cortices, and occipital lobe	↓ NAA in BD in the left (P = .002) and right (P = .004) medial prefrontal cortices;
				↓ GPC+PC in BD in left (P = .006) and right (P = .002) right) medial prefrontal cortices;
				↓ PCr+Cr in BD in the left medial prefrontal cortex (P = .005);
	38 healthy volunteers, (mean age, 13.9 yr)			↓ NAA in BD in the left dorsolateral prefrontal cortex (P = .013);
	38 healthy volunteers, (mean age, 13.9 yr)			↓ PCr+Cr in BD (P = .011) in the left dorsolateral prefrontal cortex
Shi et al, 2012⁵³	14 Depressed patients with BD, medicated (n = 6), unmedicated (n = 8), (mean age, 15.6 yr),	Trio^{^d}/3T/3000/2.3/³¹P-MRSI; No ¹H decoupling; dual-tuned ¹H and ³¹P head coil	15.625 mL in the frontal lobe	↓ Pi/TP in unmedicated BD vs healthy controls;
Shi et al, 2012⁵³	24 healthy volunteers, (mean age, 15.7 yr)		15.625 mL in the frontal lobe	↑ PCr/Pi ratio in unmedicated BD compared with healthy volunteers (24%; P = .013) and with medicated BD (39%; P = .002)
Sikoglu et al, 2013⁵⁴	8 Patients with BD, mood state euthymic (n = 3), mood state mixed, manic, or depressed (n = 5), medicated (n = 8), unmedicated (n = 0), (mean age, 16.9 yr),	Varian^{^c}/4T/3000/1.2/³¹P-MRSI; no ¹H decoupling; dual-tuned ¹H and ³¹P head coil	540 mL global sagittal whole-brain slab,	↓ Global Pi/TP in BD (P= .021);
	8 healthy volunteers, (mean age, 15.5 yr)		108 mL in the frontal lobe	↑ PCr/Pi global ratio in BD (P= .05);
	8 healthy volunteers, (mean age, 15.5 yr)		108 mL in the frontal lobe	Frontal pHi increased with age in BD (Spearman ρ = 0.64)
Weber et al, 2013⁵⁵	19 Unmedicated patients with manic BD,	Varian^{^c}/4T/500/not stated/³¹P-MRSI	11-mL effective voxel size in the anterior cingulate cortex	↓ pHi in manic BD vs HC (P = .03);
	(mean age, 15.5 yr),	and		↓ ADP in manic BD vs HC (P = .01)
	14 unmedicated patients with euthymic BD,	Varian^{^c}/4T/2000/23/PRESS;
	(mean age, 16.1 yr),	no ¹H decoupling; dual-tuned ¹H and ³¹P head coil
	20 healthy volunteers,
	(mean age, 15.4 yr)

Note:—TR and TE are expressed in milliseconds. FS indicates field strength; 1D-ISIS, adiabatic 1D image-selected in vivo spectroscopy; PRESS, point-resolved spectroscopic sequence; Probe-P(PRESS), proton brain examination single-voxel PRESS; MRSI, multivoxel MRS imaging; ³¹P-MRSI, multivoxel phosphorus MRS imaging; ↓, decreased; ↑, increased; ³¹P-MRS, phosphorus 31 MRS; ADP, adenosine diphosphate; GPC, glycerophosphocholine; PC, phosphocholine; pHi, intracellular pH; tCre, total creatine; TP, total ³¹P signal.
↵a GE Healthcare, Milwaukee, Wisconsin.
↵b Philips Healthcare, Best, the Netherlands.
↵c Varian, Palo Alto, California.
↵d Siemens, Erlangen, Germany.

View popup

Table 2:

Longitudinal MRS studies of pediatric bipolar disorder and youth at risk for bipolar disorder

Study	Sample	Methods (Device/FS/TR/TE/Sequence)	Region-of-Interest Voxel Size and Location	Findings
Davanzo et al, 2001⁷⁸	11 Patients with BD mania, medicated (n = 9), unmedicated (n = 2), (mean age, 11.4 yr),	Signa^{^a}/1.5T/3000/30/PRESS	8 mL in the anterior cingulate cortex	↓ mIns/tCre was associated with acute lithium treatment (P = .047);
				↓ mIns/tCre in lithium responders (P < .012);
				mIns/tCre was not significantly different in lithium nonresponders (P < .655);
				NAA/tCre was the metabolite least affected by lithium
	Treatment with lithium for 1 week (mean lithium level = 0.64 mEq/L),
	Scans obtained at baseline and day 7
DelBello et al, 2006⁸¹	19 Unmedicated manic or mixed patients with BD treated with olanzapine, 10–20 mg/day for 4 weeks,	Signa/1.5T/2000/35/PRESS	8 mL in the medial ventral prefrontal cortex,	↑ tChol in medial ventral prefrontal cortex (P = .0001) associated with olanzapine treatment;
	(mean age, 14.7 yr),		8 mL in the left and right ventral lateral prefrontal cortices,	↑ baseline tChol in the medial ventral prefrontal cortex associated with remission at 4 weeks (P = .001);
	10 healthy volunteers, (mean age, 15 yr),		Scans obtained at baseline, day 7, and day 28	↑ NAA for 4 weeks in the medial ventral prefrontal cortex in olanzapine remitters (n = 11) vs ↓ NAA in nonremitters (n = 8) (P = .006);
	10 healthy volunteers, (mean age, 15 yr),		Scans obtained at baseline, day 7, and day 28	↑ NAA for 4 weeks was associated with reduction in YMRS scores (r = 0.68; P = .004)
Patel et al, 2006⁷⁹	28 Unmedicated depressed patients with BD, (mean age, 15.5 yr),	Signa/1.5T/2000/35/PRESS	8 mL in the medial prefrontal cortex,	mIns in medial prefrontal cortex did not significantly differ among baseline, day 7, or day 42;
			8 mL in the left and right lateral prefrontal cortices,	↓ baseline mIns in medial prefrontal cortex in lithium remitters (n = 8) vs non-remitters (n = 20) (P = .003)
	Treatment with lithium for 42 days, titrated to serum levels of 1.0–1.2 mEq/L		Scans obtained at baseline, day 7, and day 42
Chang et al, 2009⁸³	10 Offspring of BD parents with mood symptoms but not BD, medicated (n = 3), unmedicated (n = 7), (mean age, 11.3 yr),	Signa/3T/2000/35/ PRESS	8 mL in the left and right dorsolateral prefrontal cortices,	No significant difference in NAA in the left (P = .88) or right (P = .13) dorsolateral prefrontal cortex associated with 12 weeks of divalproex treatment;
			Scans obtained at baseline and 12 weeks	Effect size for decreased NAA = 0.94 for the right dorsolateral prefrontal cortex;
				Exploratory analyses showed no significant differences in tChol or mIns
	Treatment with divalproex for 12 weeks; mean serum VPA level = 82 μg/mL
Strawn et al, 2012⁷⁶	25 Unmedicated manic or mixed patients with BD (mean age, 14.5),	Varian^{^b}/4T/3000/23/PRESS	8 mL in the anterior cingulate cortex (gray matter),	↓ Glx at baseline in the left ventrolateral prefrontal cortex in treatment remitters (P = .01);
			8 mL in left and right ventrolateral prefrontal cortices (white matter),	In divalproex treatment remitters, change in Glu in the left ventrolateral prefrontal cortex correlated with change in YMRS score (r = 0.82; P = .03)
	Treatment with divalproex for 28 days, titrated to a serum VPA level of 85–125 μg/mL		Scans obtained at baseline, day 7, and day 28
Chang et al, 2012⁸²	26 Unmedicated depressed patients with BD,	Signa/3T/2000/26/ PRESS	8 mL in the anterior cingulate cortex,	↓ Posttreatment mIns in the ACC in quetiapine responders (5 of 16 patients);
	Treatment with either quetiapine (n = 16) or placebo (n = 10) for 8 weeks,	and	8 mL in the left dorsolateral prefrontal cortex,	no significant change in NAA between the quetiapine and placebo groups
	(mean age, 15.6 yr)	Varian/4T/2000/26/PRESS	8 mL in the right dorsolateral prefrontal cortex

Note:—TR and TE are expressed in milliseconds. FS indicates field strength; PRESS, point-resolved spectroscopic sequence; ↓, decreased; ↑, increased; tCre, total creatine; VPA, valproic acid; YMRS, Young Mania Rating Scale.
↵a GE Healthcare, Milwaukee, Wisconsin.
↵b Varian, Palo Alto, California.

View popup

Table 3:

Cross-sectional MRS studies of youth at risk for bipolar disorder

Study	Sample	Methods (Device/FS/TR/TE/Sequence)	Region-of-Interest Voxel Size and Location	Findings
Cecil et al, 2003⁶⁹	9 Patients with euthymic mood disorder with at least 1 parent with BD, medicated (n = 1), unmedicated (n = 8), (mean age, 9.9 yr),	Signa^{^a}/1.5T/2000/35/PRESS	8 mL in the cerebellar vermis,	↑ mIns/tCre levels in patients with mood disorder in the medial frontal cortex (16%);
			8 mL in the medial frontal cortex,	↓ NAA/tCre in patients with mood disorder in the cerebellar vermis (8%);
	10 healthy volunteers, (mean age, 10.6 yr)		8 mL in frontal lobe white matter	no significant differences in NAA/tCre, tChol/tCre, or mIns/tCre in frontal lobe white matter
Gallelli et al, 2005⁸⁴	60 Offspring of parents with BD, 32 patients with BD, medicated (n = 28), unmedicated (n = 4), (mean age, 14.1 yr),	Signa/3T/2000/35/ PRESS	8 mL in the left and right dorsolateral prefrontal cortices	No significant group difference in NAA/tCre in the left (P = .99) or right (P = .75) dorsolateral prefrontal cortex;
Gallelli et al, 2005⁸⁴	28 patients with subsyndromal BD symptoms, medicated (n = 20), unmedicated (n = 8), (mean age, 12.2 yr), mood state not reported, though “most subjects were not experiencing a manic or depressive episode at the time of scan,” 26 unaffected controls, (mean age, 14.2 yr)	Signa/3T/2000/35/ PRESS	8 mL in the left and right dorsolateral prefrontal cortices	no significant group difference in mIns/tCre in the left (P = .15) or right (P = .19) dorsolateral prefrontal cortex; no significant group difference in tChol/tCre in the left (P = .31) or right (P = .46) dorsolateral prefrontal cortex
Singh et al, 2010⁸⁵	20 Patients with euthymic BD, medicated (n = 17), unmedicated (n = 3), (mean age, 15.9 yr),	Signa/3T/2000/35/ PRESS	8 mL in the anterior cingulate cortex	↓ Glu in BD compared with both healthy volunteers (P < .04) and subsyndromal BD (P < .04);
	20 euthymic patients with subsyndromal BD, medicated (n = 17), unmedicated (n = 3), (mean age, 12.9),			no significant group differences in NAA or mIns
	20 healthy volunteers, (mean age, 15.1 yr)			no significant group differences in NAA or mIns
Singh et al, 2011⁸⁶	22 Euthymic youth at risk for BD with a parent with BD, medicated (n = 17), unmedicated (n = 5), psychostimulants discontinued 24 hours prior to scan, (mean age, 13.3 yr),	Signa/3T/2000/35/PRESS	8 mL in the cerebellar vermis	↓ mIns in children at risk for BD (P < .01);
Singh et al, 2011⁸⁶	25 healthy volunteers, (mean age, 13.5 yr)	Signa/3T/2000/35/PRESS	8 mL in the cerebellar vermis	↓ tChol in children at risk for BD (P < .01)
Wozniak et al, 2012⁸⁷	24 Euthymic youth at risk for BD, with a parent with BD, medicated (n = 11), unmedicated (n = 13), (mean age, 11.8 yr),	Varian^{^b}/4T/2000/30/PRESS	8 mL in the anterior cingulate cortex	Positive correlation between emotional dysregulation score and Glu (Pearson correlation = 0.659; P < .02)
Wozniak et al, 2012⁸⁷	13 healthy volunteers (mean age, 11.5 yr)	Varian^{^b}/4T/2000/30/PRESS

Note:—TR and TE are expressed in milliseconds. FS indicates field strength; PRESS, point-resolved spectroscopic sequence; ↓, decreased; ↑, increased; tCre, total creatine.
↵a GE Healthcare, Milwaukee, Wisconsin.
↵b Varian, Palo Alto, California.

View popup

Table 4:

Cross-sectional and repeated-measures MRS studies of severe mood dysregulation

Study	Sample	Methods (Device/FS/TR/TE/Sequence)	Region-of-Interest Voxel Size and Location	Findings
Dickstein et al, 2008⁹³	36 Euthymic unmedicated patients with severe mood dysregulation, (mean age, 12.2 yr),	Signa^{^a}/1.5T/2000/30/PRESS	8 mL in the right frontal cortex,	↓ mIns/tCre in severe mood dysregulation in the left temporal lobe (P = .03);
			8 mL in the left temporal cortex,	no significant group differences in mIns/tCre, NAA/tCre, or Glx/tCre in the other regions of interest;
	43 healthy volunteers, (mean age, 12.9 yr)		8 mL in the central parieto-occipital lobe,	females with severe mood dysregulation showed trends toward
			8 mL in the left parietal lobe	↓ mIns/tCre in the left temporal cortex (P = .07),
				↑ tCre in the left temporal cortex (P = .08), and
				↑ Glx/tCre in the left parietal lobe (P = .08)
Dickstein et al, 2009⁹⁴	25 Euthymic unmedicated patients with severe mood dysregulation, randomized to 6 weeks of treatment with	Signa/1.5T/2000/30/PRESS	8 mL in the right frontal cortex,	There was a significant Group × Time interaction for Glx/tCre in the parieto-occipital lobe (P = .01), with ↑ Glx/tCre in the lithium group and ↓ Glx/tCre in the placebo group;
	lithium (n = 14; mean age, 10.8 yr; mean serum lithium level = 0.82 mmol/L)		8 mL in the left temporal cortex,	Group × Time interactions for mIns/tCre, NAA/tCre, and Glx/tCre in the other regions of interest were nonsignificant
	or		8 mL in the central parieto-occipital lobe,
	placebo (n = 11; mean age, 12.1 yr)		8 mL in the left parietal lobe,
			scans obtained at baseline and 6 weeks

Note:—TR and TE are expressed in milliseconds. FS indicates field strength; PRESS, point-resolved spectroscopic sequence; ↓, decreased; ↑, increased; tCre, total creatine.
↵a GE Healthcare, Milwaukee, Wisconsin.