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Abstract

Background

Although the comorbidity between migraine and major depressive disorder (MDD) has been recognized, the pathophysiology remains unclear. The dorsolateral prefrontal cortex (DLPFC) is a well-known neural substrate for MDD. We investigated the relationship between brain metabolites in DLPFC and comorbid MDD in migraine patients.

Methods

We recruited migraine patients from a tertiary headache clinic. A board-certified psychiatrist conducted a structured interview for MDD diagnosis. The severity of depression was evaluated by the Beck Depression Inventory (BDI). Thirty migraine patients (five men, 25 women; mean age: 40.4 ± 12.4 years) completed the study, and 16 of them were diagnosed with MDD. All patients underwent a magnetic resonance spectroscopy (MRS) examination focusing on bilateral DLPFC. The ratios of N-acetylaspartate (NAA), choline (Cho), and myo-inositol (mI) to total creatine (tCr) were compared between migraine patients with and without MDD, and were correlated with BDI scores.

Results

Relative to patients without MDD, migraine patients with MDD had higher mI/tCr ratios in the bilateral DLPFC (p = 0.02, left; p = 0.02, right, Mann-Whitney U test). The mI/tCr ratios in the right DLPFC were positively correlated with BDI scores (r = 0.52, p = 0.003). The NAA/tCr and Cho/tCr ratios did not differ between migraine patients with and without MDD.

Conclusion

Increased mI/tCr within the DLPFC might be associated with the presence of MDD in migraine patients.

Keywords

Migraine psychiatric comorbidity major depressive disorder (MDD)magnetic resonance spectroscopy (MRS)dorsolateral prefrontal cortex (DLPFC)

Introduction

Migraine is frequently comorbid with psychiatric disorders, particularly major depressive disorder (MDD) (1). Comorbidity with MDD may increase the risk of progression from episodic to chronic migraine (1), impair a patient’s function and quality of life (2), and increase dependence on medications and medical expenses (3). Diagnosis of MDD in migraine patients is important because these patients are usually more intractable to treatment (4).

In vivo proton magnetic resonance spectroscopy (¹H-MRS) is a noninvasive method for measuring brain metabolite concentrations. Major compounds that are measured by ¹H-MRS include the neuronal marker N-acetylaspartate (NAA) (5), the membrane phospholipid product choline (Cho) (6,7), the second messenger metabolite and gliosis marker myo-inositol (mI), and the total creatine (tCr), which contains creatine and phosphocreatine, and is usually used as an internal standard (8). Metabolite concentrations measured by ¹H-MRS are often presented as a ratio to brain tCr levels (5 –8). Decreased NAA/tCr levels, elevated Cho/tCr levels, and elevated mI/tCr levels usually represent decreased neuronal function, increased membrane turnover rate, and increased gliosis, respectively. Loss of glial cell volume can be detected as a reduction of the mI/tCr level (9).

In patients with MDD, ¹H-MRS has been used to detect changes of metabolite ratios, such as NAA/tCt, Cho/tCr, and mI/tCr, in different brain regions, including the dorsolateral prefrontal cortex (DLPFC), basal ganglia, thalamus, amygdala, hippocampus, anterior cingulated cortex, and occipital cortex (8 –15). The DLPFC, also known as Brodmann’s areas 9 and 46, modulates cognitive and executive functions. It plays a critical role in MDD (16). Studies in patients with MDD have reported that the right, left, or bilateral DLPFC exhibits increased (12,14) or decreased (9) mI/tCr ratio, decreased NAA/tCr ratio (15), or increased Cho/tCr ratio (12). One study demonstrated that repetitive transcranial magnetic stimulation (rTMS) could increase the mI/tCr ratio in the DLPFC and improve depressive symptoms in MDD patients (17). By contrast,¹H-MRS findings revealed that patients with migraine had elevated lactate/NAA, as well as reduced NAA/tCr, Cho/tCr, mI/tCr, and glutamate (Glu), mainly in the occipital, temporoparietal, and cerebellar regions (18).

The underlying pathophysiology of migraine with comorbid MDD remains unclear. Because of the involvement of the DLPFC in MDD, we hypothesized that the DLPFC may contribute to the comorbidity of MDD in migraine patients. We also hypothesized that metabolite-related changes in the DLPFC may exist in migraine patients with MDD, as they do in patients with MDD. Therefore, we used ¹H-MRS to investigate the relationship between brain metabolites in the DLPFC and MDD in migraine patients. Because the results of prior studies on MDD patients were inconsistent, we were unable to predict whether the metabolites would be elevated or decreased.

Methods

Participants

Migraine patients were recruited from the Taipei Veterans General Hospital tertiary headache clinic. Migraine was diagnosed according to the criteria of the International Classification of Headache Disorders, second edition (19). All patients completed a headache questionnaire, which included questions about migraine characteristics, disease duration, and migraine frequency. To determine comorbidity of MDD, the same board-certified psychiatrist evaluated migraine patients using a semi-structured diagnostic interview based on the Mini-International Neuropsychiatric Interview (MINI) (20). The MINI screens for 17 Axis I disorders and follows the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (21) and the International Classification of Diseases, 10th revision (22) criteria for psychiatric disorder diagnoses. All patients also self-rated their depression levels by completing the Beck Depression Inventory (BDI) (23). The BDI consists of 21 items, each scored from 0 to 3, resulting in total scores ranging from 0 to 63. At the time of the interview, the psychiatrist was blinded with respect to BDI scores.

Thirty migraine patients (25 women, five men; mean age 40.4 ± 12.4 years, range: 18–62 years) were recruited. Among them, 16 migraine patients (14 women, two men) met the diagnostic criteria for MDD, and the other 14 (11 women, three men) did not. None of the patients were on migraine-prophylactic agents. In the 16 MDD patients, six were currently on antidepressants.

All patients underwent both brain magnetic resonance (MR) imaging (MRI) and ¹H-MRS. MRI was performed with a 1.5 T MR scanner (Signa EXCITE, GE Medical System, Milwaukee, WI, USA). MRI sequences included axial T1-weighted three-dimensional (3D) fast-spoiled gradient recalled acquisition in steady-state images (SPGR; repetition time (TR)/echo time (TE)/inversion time (TI) = 8.58/3.62/400 ms, and voxel resolution = 0.75 × 0.75 × 1.5 mm³) and an axial T2-weighted fast spin-echo sequence (TR/TE = 4000/256.5 ms, and voxel resolution = 348 × 512 mm²).

For the ¹H-MRS study, we used the fully automated quantification of metabolite levels by the United States Food and Drug Administration (FDA)-approved PROBE/SVQ algorithm, provided by the vendor (GE Medical Systems). Single-voxel ¹HMRS was performed with point-resolved spectroscopy (PRESS), with TR/TE = 1500/35 ms, number of repetitions (NEX) = 128, number of data points = 1024, flip angles = 90−180−180, and bandwidth = 2.5 KHz. Spectral water saturation was optimized by automated water suppression (AWS; Control Variable 17). The region of interest (ROI) edge saturation mask bitmap 7 was used (control variable 18, SI + AP + RL, sat-bands for voxel shape), with no outer volume suppression. A 2 × 2 × 2 cm³ volume of interest (VOI) was placed on a 1-mm thick axial 3DSPGR image covering the right and left DLPFC, respectively. The scan time of each voxel was about 3 minutes and 48 seconds. The same neuroradiologist placed the VOIs for each subject. Patients with structural lesions were excluded from the study.

Each voxel of ¹H-MRS was automatically pre-scanned for a preset water suppression threshold level of at least 97%. To ensure high-quality spectra and to minimize quantification errors, spectra with a full width at half maximum (FWHM) greater than 6 Hz were excluded from ¹H-MRS analyses. If this threshold/criterion was not met, the voxel place was fine-adjusted once by the same neuroradiologist and tried again. If the threshold/criteria were still not met, the patient had to be excluded.

The following MRS data were from the in-line spectral analysis of General Electric (SAGE) and were calculated through the reconstruction processes of PROBE/SVQ, which included a quantitative analysis of the spectrum for the signal intensities of metabolites and the signal-to-noise ratio (SNR) of total creatine. The creatine at the 3.02 ppm was set as the ratio base, with the default display from 0.20 to 4.90 ppm. The peak height ratios of three major metabolites, NAA (2.02 ppm), choline (3.21 ppm), and myo-inositol (3.58 ppm), with tCr were shown automatically on the screen of the scanner (24,25). To regard tCr as internal reference, water reference spectra acquired as part of the acquisition are employed in the reconstruction to determine and apply phase, residual eddy current, and artifact corrections to the water-suppressed data.

The institutional review board of Taipei Veterans General Hospital approved this study. All patients provided written informed consent prior to study participation.

Statistical analysis

Data were analyzed using the statistical program SPSS for Windows, version 18 (IBM Inc, Armonk, NY, USA). The Kolmogorov-Smirnov test was used to verify the normal distribution of the continuous variables. Data for the NAA/tCr ratios in the right DLPFC and the BDI scores did not fit normal distribution; therefore, the nonparametric Mann-Whitney U test was used to analyze the continuous variables. Fisher’s exact test was used for nominal variables. The relationship of BDI scores and metabolite ratios was assessed by Pearson’s correlation coefficients. All tests were two tailed and the level of statistical significance was set at p < 0.05.

Results

The demographics of our participants are shown in Table 1. Migraine patients with or without MDD did not differ in terms of age, sex, migraine frequency, disease duration or percentages of different migraine subtypes, that is, chronic migraine, and migraine with and without aura. The BDI scores were significantly higher in the depression group (p < 0.001).

Table 1.

Patient demographics and headache profiles.

	Migraine patients with MDD	Migraine patients without MDD	p
Number	16	14
Mean age (years old) (Mean ± SD, range)	40.5 ± 11.7 (18 ∼ 55)	40.3 ± 14.0 (23 ∼ 62)	0.54^a
Sex (F:M)	14:2	11:3	0.31^b
Mean frequency of migraine (days/month) (Mean ± SD)	9.2 ± 10.2	8.6 ± 9.4	0.87^a
Mean duration of headache history (years) (Mean ± SD)	16.7 ± 12.1	12.8 ± 8.5	0.31^a
Mean headache intensity (scale 0–10) (Mean ± SD)	7.1 ± 1.9	6.5 ± 1.5	0.58^a
Migraine subtypes
Chronic migraine: number (%)	7 (43.8)	6 (42.9)
Migraine without aura: number (%)	7 (43.8)	6 (42.9)	0.12^b
Migraine with aura: number (%)	2 (12.5)	2 (14.3)
BDI scores (Mean ± SD)	23.3 ± 11.8	8.1 ± 3.8	<0.001^a

MDD: major depressive disorder; F: female; M: male; BDI: Beck Depression Inventory. ^aMann-Whitney U test. ^bFisher’s exact test.

Migraine patients with MDD had higher mean mI/tCr ratios than those without MDD in both the left (0.66 vs. 0.58, p = 0.02) and the right DLPFC (0.65 vs. 0.58, p = 0.02; Table 2 and Figure 1). However, the mean NAA/tCr or Cho/tCr ratios did not differ in the bilateral DLPFC between migraine patients with and without MDD.

Figure 1.

¹H-MRS of the DLPFC in migraine patients with and without MDD. (a) Volume of interest of the right DLPFC. Higher mI/tCr ratios were found in migraine patients with MDD (b) than in those without (c). There were no significant differences between the two groups in the NAA/tCr or Cho/tCr ratios.

Table 2.

Bilateral DLPFC ¹H-MRS results in migraine patients with and without MDD.

	Migraine patients with MDD		Migraine patients without MDD
DLPFC	Mean	SD	Mean	SD	p ^a
Left
NAA/tCr	1.68	0.13	1.70	0.19	0.79
Cho/tCr	0.74	0.07	0.74	0.12	0.64
mI/tCr	0.66	0.08	0.58	0.07	0.02
Right
NAA/tCr	1.67	0.12	1.64	0.12	0.38
Cho/tCr	0.75	0.09	0.74	0.07	0.80
mI/tCr	0.65	0.06	0.58	0.07	0.02

DLPFC: dorsolateral prefrontal cortex; ¹H-MRS: proton magnetic resonance spectroscopy; MDD: major depressive disorder; NAA: N-acetylaspartate; tCr: total creatine; Cho: choline; mI: myo-inositol. ^aMann-Whitney U test.

A significant correlation existed between the BDI scores and the mI/tCr ratio in the right DLPFC (r = 0.52, p = 0.003; Figure 2(a)), but not in the left DLPFC (r = 0.29, p = 0.12; Figure 2(b)).

Figure 2.

Correlations between mI/tCr and BDI scores in the right DLPFC (a) and in the left DLPFC (b).

Discussion

Migraine patients with MDD had increased mI/tCr ratios in bilateral DLPFC compared to migraine patients without MDD. Within the right DLPFC of all patients, the mI/tCr ratio was also positively correlated with depression severity. Migraine frequencies, disease durations, and percentages of patients with different migraine subtypes (e.g. chronic migraine and migraine with aura) were comparable between the migraine with and without MDD groups. To avoid bias, the same psychiatrist used a valid diagnostic instrument (i.e. the MINI) to diagnose MDD, and all patients also filled out a depression questionnaire (i.e. the BDI) to evaluate their depression severity.

Previous studies reported that in MDD patients, the DLPFC has been found to display abnormal metabolism (14), decreased blood flow (26,27), and reduced gray-matter volume (28). In post-mortem MDD patients, the neuronal and glial densities in the DLPFC were reduced (29). Thus, the DLPFC is considered a crucial region in the neuronal circuitry underlying MDD pathophysiology. Our study suggested that the DLPFC might also be involved in the comorbidity of MDD in migraine patients.

Myo-inositol is the product of inositol monophosphate hydroxyldephosphorylation by inositol monophosphatase (IMP). It is stored in glial cells, but is trafficked to neurons, where it becomes a precursor of phosphatidylinositol-4,5-biphosphate (PIP2) and participates in the PIP2 secondary messenger system (8,30). Therefore, it can be used as a marker of glial function or the extent of gliosis. The mood-stabilizing agent lithium, which is an IMP inhibitor, could limit signal transduction in pathogenic neurons by reducing mI levels (31). Kumar et al. (12) found that mean mI/tCr ratios were elevated about 20% in elderly patients with MDD compared to elderly subjects without (0.90 ± 0.25 vs. 0.75 ± 0.16). High mI levels in these patients were proposed to result from either increased uptake/retention of mI in the cellular/extracellular matrix, or from perturbation of receptor coupling with the secondary messenger system. Alternatively, increased reactive gliosis has been suggested to underlie the elevated mI levels in depressed elderly patients (9). However, children suffering from depression also showed elevated absolute mI levels (14). After antidepressive treatment, the mI/tCr levels were decreased about 11% compared to controls (0.40 ± 0.05 vs. 0.45 ± 0.06); therefore, researchers concluded that the decreased mI levels were associated with loss of glial density and post-treatment changes (8,15). By contrast, Coupland et al. found decreased mean mI/tCr levels in treatment-naïve adults (9) compared to controls (0.94 ± 0.23 vs. 1.32 ± 0.37).

In our study, the mI/tCr ratios of migraine patients with or without MDD were lower than those of MDD patients or controls in the studies by Kumar et al. (12) and Coupland et al. (9). This difference might be due to the influence of comorbidity with migraine or the relatively younger age of our patients compared to those in the study by Kumar et al. However, we observed that the mI/tCr ratios were increased by 13.8% and 12.0% in the left and right DLPFC, respectively, of migraine patients with MDD compared to those without MDD. These results were of the same direction but slightly lower that (20% elevation) found by Kumar et al. (12) in the elderly depressed patients with the mean age of 70. Although the findings of the mI/tCr changes in the DLPFC of MDD patients and healthy controls are not consistent (8,9,12,14,15), these studies suggest that glial and synaptic function play important roles in mood modulation (8,9,12,31). It is likely that the increased PIP2 catabolism in MDD patients also may occur in migraine patients with MDD (32), possibly associated with elevated mI/tCr ratios in the DLPFC.

As in most prior studies on MDD patients and controls (9 –11), we found similar NAA/tCr and Cho/tCr ratios in the DLPFC between migraine patients with and without MDD. However, not all previous studies are in agreement on the NAA/tCr and Cho/tCr levels in depressed patients. In particular, one previous study found that MDD patients had a decreased NAA/tCr ratio in the DLPFC (15), and two previous studies found that late-life MDD patients had elevated Cho/tCr ratios in the DLPFC and orbitofrontal cortex (12,13). We thought the lack of significance in the comparison of NAA/tCr or Cho/tCr results might be contributed to by the small differences in NAA/tCr and Cho/tCr between MDD and non-MDD groups and also by the under power due to the small sample size of the study. Moreover, we found that the mI/tCr ratios were correlated with BDI scores in the right but not in the left DLPFC; we do not have a good explanation for this finding. Interestingly, however, a previous report in chronic back pain patients with MDD found that the BDI scores were correlated with ¹H-MRS metabolite ratios only in the right DLPFC (33).

Several mechanisms have been proposed for migraine comorbidity with MDD (4). Co-occurrence of migraines and MDD might result from chance, or from common environmental or biological factors. Additionally, some investigators have suggested that migraine actually causes MDD or vice versa (4,34). Ligthart et al. (35) recently found that pure forms of migraine and MDD were genetically distinct from each other; migraine patients with MDD were genetically more similar to MDD patients than to migraine patients. This genetic similarity may contribute to the similar role that the DLPFC plays in migraine patients with MDD and patients with MDD alone (16,18). MDD is a risk factor for migraine progression. Both migraine and depression decrease health-related quality of life; therefore, treatment of migraine patients with MDD is challenging (1,30). One helpful treatment for migraine patients with MDD might be rTMS over the DLPFC; however, further studies are needed to test this hypothesis.

The current study has several limitations. First, our study used a semi-quantitative MRS approach, in which the intensity of each metabolite is normalized to tCr under the assumption that tCr concentration remains relatively constant in different brain diseases. This method is the most frequently used method for clinical use for MRS study (21). However, variations in the concentration of tCr do exist in the presence of tissue destruction (by tumor or infection) or systemic diseases. Second, although most demographics or clinical features were relatively balanced between the two study groups (i.e. age, severity, disease duration, among others), the sample size was rather small, and the migraine subtypes were heterogeneous though compatible between the two study groups. Therefore, these preliminary results need further replication with a large sample size. In addition, the number of male patients in the current study was very small (n = 5); therefore, we should be even more cautious in generalizing our results to male patients even though prior studies did not demonstrate the difference in the frequencies or pathophysiology of comorbid MDD between men and women with migraine (36,37). Subgroup analyses by sex showed the results were significant for female patients only but not for male patients because of the small sample size (online Supplementary Tables S1 and S2). Third, many of our patients had a high frequency of migraine attacks, and approximately 40% suffered from chronic migraine. Therefore, our study might not be representative of patients with infrequent episodic migraine. Fourth, six depression patients were already on antidepressants, and post-treatment effects could have influenced the mI levels (8,15). Fifth, we evaluated the ¹H-MRS metabolite ratios only in the DLFPC. We cannot exclude the possibility that other brain regions involved in MDD might be associated with the comorbidity of MDD in migraine patients. Sixth, we did not recruit patients with MDD only or healthy controls. Future ¹H-MRS studies should focus on additional locations and recruit patients with MDD and healthy controls to help understand the pathophysiology of migraine comorbidity with MDD.

Conclusions

We found an increased mI/tCr ratio in the DLPFC in migraine patients with MDD, which may indicate that a potential glial dysfunction in this region might be associated with co-occurrence of these two disorders. As such, the DLPFC might be a target for novel treatments for migraine patients comorbid with MDD.

Clinical implications

By using ¹H-MRS, we demonstrated increased mI/tCr ratios in bilateral DLPFC in migraine patients with MDD than in those without.

The mI/tCr ratios in the right DLPFC were positively correlated with depression severity.

Our study suggests that glial dysfunction within the DLPFC might be associated with comorbid MDD in migraine patients.

DLPFC might be a treatment target for comorbid MDD in patients with migraine in the future.

Footnotes

Funding

This study was supported, in part, by grants from 1) the Taipei Veterans General Hospital (VGHUST102-G7-6-1, V102C-118, V102E9-001, V102B-039), 2) National Science Council (NSC) support for the Center for Dynamical Biomarkers and Translational Medicine, National Central University (NSC 101-2911-I-008-001; NSC 96-2321-B-010-002), 3) the Brain Research Center, National Yang-Ming University, and 4) a grant from the Ministry of Education (Aim for the Top University Plan).

Acknowledgments

We would like to express our appreciation to the “Biostatistics Task Force of Taichung Veterans General Hospital, Taichung, Taiwan, ROC” as a consultant for statistical analysis.

Conflict of interest

None declared.

References

Breslau

Lipton

Stewart

. Comorbidity of migraine and depression: Investigating potential etiology and prognosis. Neurology 2003; 60: 1308–1312.

Hung

Liu

Fuh

. Comorbid migraine is associated with a negative impact on quality of life in patients with major depression. Cephalalgia 2006; 26: 26–32.

Frediani

Villani

. Migraine and depression. Neurol Sci 2007; 28(Suppl 2): S161–S165.

Sheftell

Atlas

. Migraine and psychiatric comorbidity: From theory and hypotheses to clinical application. Headache 2002; 42: 934–944.

Tsai

Coyle

. N-acetylaspartate in neuropsychiatric disorders. Prog Neurobiol 1995; 46: 531–540.

Moore

Galloway

. Magnetic resonance spectroscopy: Neurochemistry and treatment effects in affective disorders. Psychopharmacol Bull 2002; 36: 5–23.

Glitz

Manji

Moore

. Mood disorders: Treatment-induced changes in brain neurochemistry and structure. Semin Clin Neuropsychiatry 2002; 7: 269–280.

Frey

Metzler

Fischer

. Myo-inositol in depressive and healthy subjects determined by frontal 1H-magnetic resonance spectroscopy at 1.5 tesla. J Psychiatr Res 1998; 32: 411–420.

Coupland

Ogilvie

Hegadoren

. Decreased prefrontal myo-inositol in major depressive disorder. Biol Psychiatry 2005; 57: 1526–1534.

10.

Michael

Erfurth

Ohrmann

. Metabolic changes within the left dorsolateral prefrontal cortex occurring with electroconvulsive therapy in patients with treatment resistant unipolar depression. Psychol Med 2003; 33: 1277–1284.

11.

Brambilla

Stanley

Nicoletti

. 1H Magnetic resonance spectroscopy study of dorsolateral prefrontal cortex in unipolar mood disorder patients. Psychiatry Res 2005; 138: 131–139.

12.

Kumar

Thomas

Lavretsky

. Frontal white matter biochemical abnormalities in late-life major depression detected with proton magnetic resonance spectroscopy. Am J Psychiatry 2002; 159: 630–636.

13.

Steingard

Yurgelun-Todd

Hennen

. Increased orbitofrontal cortex levels of choline in depressed adolescents as detected by in vivo proton magnetic resonance spectroscopy. Biol Psychiatry 2000; 48: 1053–1061.

14.

Caetano

Fonseca

Olvera

. Proton spectroscopy study of the left dorsolateral prefrontal cortex in pediatric depressed patients. Neurosci Lett 2005; 384: 321–326.

15.

Gruber

Frey

Mlynárik

. Quantification of metabolic differences in the frontal brain of depressive patients and controls obtained by 1H-MRS at 3 Tesla. Invest Radiol 2003; 38: 403–408.

16.

Koenigs

Grafman

. The functional neuroanatomy of depression: Distinct roles for ventromedial and dorsolateral prefrontal cortex. Behav Brain Res 2009; 201: 239–243.

17.

Zheng

Zhang

. High-frequency rTMS treatment increases left prefrontal myo-inositol in young patients with treatment-resistant depression. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34: 1189–1195.

18.

Reyngoudt

Achten

Paemeleire

. Magnetic resonance spectroscopy in migraine: What have we learned so far? Cephalalgia 2012; 32: 845–859.

19.

Olesen

Steiner

. The International classification of headache disorders, 2nd edn (ICDH-II). J Neurol Neurosurg Psychiatry 2004; 75: 808–811.

20.

Sheehan

Lecrubier

Sheehan

. The Mini-International Neuropsychiatric Interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998; 59 (Suppl 20). 22–33; quiz 34–57.

21.

Currie

Hadjivassiliou

Craven

. Magnetic resonance spectroscopy of the brain. Postgrad Med J 2013; 89: 94–106.

22.

Soher

Hurd

Sailasuta

. Quantitation of automated single-voxel proton MRS using cerebral water as an internal reference. Magn Reson Med 1996; 36: 335–339.

23.

Craven

Rodin

Littlefield

. The Beck Depression Inventory as a screening device for major depression in renal dialysis patients. Int J Psychiatry Med 1988; 18: 365–374.

24.

Webb

Sailasuta

Kohler

. Automated single-voxel proton MRS: Technical development and multisite verification. Magn Reson Med 1994; 31: 365–373.

25.

Ohkubo

Kimura

Matsuzawa

. Evaluation of efficacy of an automated single-voxel proton MRS algorithm on a 3T system. Magn Reson Med Sci 2002; 1: 121–124.

26.

Biver

Goldman

Delvenne

. Frontal and parietal metabolic disturbances in unipolar depression. Biol Psychiatry 1994; 36: 381–388.

27.

Baxter

Jr Schwartz

Phelps

. Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatry 1989; 46: 243–250.

28.

Chang

McQuoid

. Reduction of dorsolateral prefrontal cortex gray matter in late-life depression. Psychiatry Res 2011; 193: 1–6.

29.

Miguel-Hidalgo

O’Dwyer

. Age-dependent reductions in the level of glial fibrillary acidic protein in the prefrontal cortex in major depression. Neuropsychopharmacology 2004; 29: 2088–2096.

30.

Strunecká

Patocka

Šárek

. How does lithium mediate its therapeutic effects? J Appl Biomed 2005; 3: 25–35.

31.

Haydon

. GLIA: Listening and talking to the synapse. Nat Rev Neurosci 2001; 2: 185–193.

32.

Karege

Bovier

Rudolph

. Platelet phosphoinositide signaling system: An overstimulated pathway in depression. Biol Psychiatry 1996; 39: 697–702.

33.

Grachev

Ramachandran

Thomas

. Association between dorsolateral prefrontal N-acetyl aspartate and depression in chronic back pain: An in vivo proton magnetic resonance spectroscopy study. J Neural Transm 2003; 110: 287–312.

34.

Binesh

Kumar

Hwang

. Neurochemistry of late-life major depression: A pilot two-dimensional MR spectroscopic study. J Magn Reson Imaging 2004; 20: 1039–1045.

35.

Ligthart

Hottenga

Lewis

. Genetic risk score analysis indicates migraine with and without comorbid depression are genetically different disorders. Hum Genet 2014; 133: 173–186.

36.

Macgregor

Rosenberg

Kurth

. Sex-related differences in epidemiological and clinic-based headache studies. Headache 2011; 51: 843–859.

37.

Jette

Patten

Williams

. Comorbidity of migraine and psychiatric disorders—a national population-based study. Headache 2008; 48: 501–516.

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Increased myo-inositol level in dorsolateral prefrontal cortex in migraine patients with major depression

Abstract

Background

Methods

Results

Conclusion

Keywords

Introduction

Methods

Participants

Statistical analysis

Results

Discussion

Conclusions

Clinical implications

Footnotes

Funding

Acknowledgments

Conflict of interest

References

Supplementary Material