Is depression modulating brain metabolism in migraine? Insights from proton magnetic resonance spectroscopy of the left dorsolateral prefrontal cortex

INTRODUCTION

Migraine is increasingly recognized as a complex cerebral network disorder with a strong genetic basis. It involves cortical, subcortical, and brainstem regions responsible for pain and a broad spectrum of associated symptoms.^[1] Among its comorbidities, depression is notably prevalent, affecting 8.6–47.9% of migraineurs^[2] and is 2.2–4 times more common than in the general population.^[3,4] Studies have shown that migraine and depression are interrelated, each increasing the risk of the other,^[4,5] and both involve altered neuronal function and brain metabolites.

Magnetic resonance spectroscopy (MRS), especially proton MRS (1H-MRS), is a non-invasive tool for evaluating brain metabolite profiles. It detects key metabolites such as N-acetyl aspartate (NAA), total creatine (tCr), choline (Cho), and myoinositol (mI), reflecting cellular integrity, membrane turnover, and glial activity.^[6] These are often reported as ratios to tCr. Prior studies have shown metabolite changes in regions such as the thalamus, cerebellum, and occipital lobe.^[7,8] For example, reduced NAA has been found in the occipital cortex of migraine patients with aura,^[7] and elevated mI levels in the cerebellum suggest glial proliferation.^[8] Other implicated regions include the basal ganglia and anterior cingulate cortex.^[9]

Recent work has emphasized the dorsolateral prefrontal cortex (DLPFC) due to its role in cognitive processing and pain regulation. Neuropsychological studies indicate prefrontal dysfunction in chronic migraine,^[10] and repetitive transcranial magnetic stimulation (rTMS) over the left DLPFC has been shown to reduce pain^[11] with further support from trials across pain conditions, including migraine.^[12] MRS studies in chronic pain patients also report reduced NAA in the DLPFC, suggesting impaired neuronal integrity.^[13] These findings support the role of the DLPFC in pain-cognition interactions.^[12,14-17] The left DLPFC is also critically involved in major depressive disorder (MDD).^[18,19] MRS studies in MDD show changes in NAA, Cho, and mI,^[18,20,21] and high-frequency rTMS targeting this region is FDA approved for MDD.^[22] Despite such evidence, the metabolic profile of the left DLPFC in migraine, particularly with comorbid depression, is underexplored. Only one study (Lirng et al.) has examined this using MRS, finding elevated mI/tCr in the depression group, indicating gliosis.^[23] These findings suggest that the left DLPFC may be a key to understanding the shared pathophysiology of migraine and depression.

Given the limited replication of these findings across different populations, this study aimed to explore left DLPFC metabolic changes using 1H-MRS in migraineurs with and without depression in a larger sample. We hypothesized that the patients with migraine and comorbid depression would show greater deviations in brain metabolite levels, particularly NAA, Cho, and mI, compared to those with migraine alone. By quantifying these metabolites, this study seeks to contribute to the growing body of evidence on the neurobiological interplay between these disorders and identify potential biomarkers for diagnosis or treatment.

MATERIALS AND METHODS

In this cross-sectional observational study, migraine patients aged >18 years, with or without aura, diagnosed according to the International Classification of Headache Disorders, 3^rd edition (ICHD-3),^[24] and attending the neurology or psychiatry departments of a tertiary care hospital, were screened by qualified clinicians. Only patients with a confirmed diagnosis of primary migraine were included. Neuroimaging was performed in patients who, in addition to migraine, also had at least one red-flag indication for imaging such as abrupt/recent onset, nocturnal, incapacitating, worsening, posterior, postural, positional, pattern change, atypical headache, or features associated with seizures, suspected raised or low intracranial pressure, prolonged aura, papilledema, phacomatosis, periodic strabismus, personality changes, pheochromocytoma, Valsalva- or exertion-induced headaches, or chronic daily headaches unresponsive to treatment. These red flags warranted imaging, but only those who fulfilled the ICHD-3 diagnostic criteria for migraine were enrolled. Patients were excluded if they had psychiatric comorbidities other than MDD, other types of headache (non-migraine), known or clinically diagnosable neurodegenerative conditions, had been on prophylactic migraine medications for >1 week, were pregnant/lactating, or had contraindications for MRS. The diagnosis of depression was established using the International Classification of Diseases, Tenth Revision clinical criteria by qualified psychiatrists. The clinicians screening the subjects for the study were blind to the group allocations and further assessment on different tools.

After obtaining ethics approval and written informed consent, participants were enrolled through convenient sampling. Based on the presence or absence of depression, subjects were assigned to Group A (migraine only, n = 27) or Group B (migraine with depression, n = 30). In addition, migraine patients with depression were assessed on the Inventory of Depressive Symptomatology - Clinician Rated (IDS-C), for the severity of depression.^[25] A cut-off score of ≥14 on the IDS-C was used to categorize patients as having depression. No patient was on antidepressants or any migraine prophylaxis for at least 1 week before 1H-MRS.

MRS was done using a 3.0 Tesla magnetic resonance (MR) scanner (GE Discovery MR750w 3.0T) to measure the brain metabolites in the left DLPFC using the point resolved spectroscopy sequence. A single voxel study was done with a 2 × 2 × 2 cm³ volume of interest (VOI) applied to an axial image covering the left DLPFC. No subject was required to be excluded from the study due to structural brain lesions.

RESULTS

Table 1 represents the sociodemographic and clinical characteristics of the study participants in the two groups, i.e., migraine (group A; n = 27) and migraine with comorbid depression (group B; n = 30). The mean age of migraine patients without depression was 31.1 ± 10.31 years, and of migraine patients with comorbid depression was 36.5 ± 9.5 years. For age, the Shapiro–Wilk statistic was significant, indicating that the normality assumption was not violated. Levene’s test was also non-significant; thus, equal variances were assumed. No significant difference was noted between the two groups for age (t[55] = −1.95, P = 0.58, 95% confidence interval [CI] [−10.68, 0.14]), gender (χ² = 0.026, P = 0.119), marital status (χ² = 2.27, P = 0.58), residence (χ² = 3.05, P = 0.07), education (χ² = 0.674, P = 0.995), and occupation (χ² = 0.09, P = 0.764).

1H-MRS was used to obtain the brain metabolites’ values in the subjects’ left DLPFC (single voxel), as illustrated in Figure 1. The Proton MRS produced a graph demonstrating the values, the absolute values, and their ratios, which are shown in Figure 2. The figures’ labels represent the software’s cursor or voxel pointer only and do not reflect the actual size of the spectroscopy voxel. As described in the Methods section, each spectroscopy voxel had a volume of 2 × 2 × 2 cm³ (8 cm³).

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Figure 1:

Left DLPFC as the VOI on proton magnetic resonance spectroscopy. The figure only shows the cursor position, not the full extent of the VOI, i.e., 8 cm³ (2 × 2 × 2 cm³). Ch: Choline, Cr: Creatine, NAA: N-acetyl aspartate, MI: Myo-inositol, VOI: Volume of interest, DLPFC: Dorsolateral prefrontal cortex.

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Figure 2:

Findings of brain metabolites in the left dorsolateral prefrontal cortex on proton magnetic resonance spectroscopy in a patient with migraine and comorbid depression. Figure only shows the cursor position, not the full extent of the volume of interest, i.e., 8 cm³ (2 × 2 × 2 cm³). Ch: Choline, Cr: Creatine, NAA: N-acetyl aspartate, MI: Myo-inositol, LL: Lipid and/or Lactate. X-axis represents values in parts per million (ppm), and Y-axis represents magnetic resonance units.

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Table 2 compares the values of the two groups of brain metabolites in the left DLPFC. The Shapiro–Wilk test for the assumption of normality was found to be non-significant for NAA/tCr within the groups. However, the normality assumption was violated for Cho/tCr and mI/tCr in the groups. We did not find a significant difference between the groups for NAA/tCr (t[55] = 0.22, P = 0.983, 95% CI [−0.26, 0.27], d = 0.05), Cho/tCr (W = 686, P = 0.121, r = 0.56), and mI/tCr (W = 854, P = 0.79, r = 0.95) between the groups.

DISCUSSION

This study was conducted to measure and compare different brain metabolites in the left DLPFC among migraine patients with and without depression. Left DLPFC is the most evidently promising brain region among patients with depression and has been reported to have a role in migraine with comorbid depression. In this study, we hypothesized that the changes in brain metabolite ratios in left DLPFC among migraineurs with comorbid depression would be differentially higher or lower as compared to migraine-only patients. Our study revealed no significant difference in the ratios of NAA/tCr, Cho/tCr, and mI/tCr in the left DLPFC region among the two groups. Lirng et al. in 2015 compared NAA, Cho, and mI in comparison to tCr between the two similar groups, i.e., patients having migraine with depression and patients having migraine alone.^[23] The VOI in their research was the bilateral DLPFC. The authors did observe a significant difference in the mI/tCr ratio between the two groups, with raised mI/tCr in the group having migraine with depression. It was suggested that the higher mI/CR might indicate more gliosis among the migraineurs with comorbid depression than with migraine-only patients. Moreover, it was proposed that the glial and synaptic dysfunctions within DLPFC play an integral role in the pathophysiology of migraine and comorbid MDD.

Furthermore, it was suggested that the DLPFC plays a crucial role in the executive and cognitive functions of the brain. We did not find any other published study among similar clinical groups with matching VOI during our literature review. Although our study design was modeled closely on the work by Lirng et al.,^[23] our results did not replicate their findings. Differences in sample demographics, clinical profiles of migraine or depression (e.g., episodic vs. chronic migraine, severity of depressive symptoms), voxel placement, or scanner settings may account for this variation. Such inconsistencies highlight the need for further replication in larger, multicenter studies. Notably, our study included a larger sample (n = 57) compared to the Lirng et al. study (n = 30), which may enhance the robustness and generalizability of our findings.^[23]

Among other findings, the duration of illness was significantly higher in patients with migraine and depression than in migraine-only patients. Nausea was substantially more prevalent in the comorbid group. Most subjects (n = 49, 85.9%) were middle-aged married female homemakers. The mean age was 31.1 ± 10.31 years in the migraine-only group and 36.5 ± 9.5 years in the comorbid group. The global burden of disease survey (2015) reported a 2–3 times higher migraine prevalence in females, highest between 30 and 39 years.^[26] Another study by Kahriman and Zhu in 2018 reported similar findings.^[27] Similar results were reported by Kahriman and Zhu (2018)^[27] and an Indian community survey (2017), showing peak prevalence among women aged 30–34 years.^[28] Illness duration was nearly 3 years in migraine-only and 6 years in the comorbid group, consistent with earlier findings linking depression to longer, treatment-resistant illness,^[29] possibly due to delayed depression recognition and poor compliance. Nausea was higher in the comorbid group, potentially from greater chemoreceptor trigger zone sensitivity in depression.^[30] Psychiatric comorbidity may impact migraine prognosis, with more extended illness and more nausea. Discrepancies with earlier elevated mI/tCr findings in bilateral DLPFC may be due to methodological differences such as voxel placement and sample size.

In our study, all participants underwent 1H-MRS during the interictal phase to capture baseline metabolic status. While this minimizes variability due to acute symptoms, it may overlook dynamic changes seen during ictal phases. However, it is also recognized that ictal and peri-ictal phases may reveal more pronounced or dynamic changes in metabolite levels, especially regarding glutamate, lactate or mI. Our findings reflect chronic or trait-level neurochemical characteristics rather than acute state-dependent changes, possibly partially explaining the lack of significant group differences. Future studies combining both ictal and interictal imaging may help clarify the temporal dynamics of metabolic alterations in migraine and depression comorbidity. Furthermore, our use of single-voxel 1H-MRS focused only on the left DLPFC, which may not capture more nuanced or region-specific metabolic alterations. If present, such changes are likely subtle or localized to sub-regions within the DLPFC or other nodes of the pain and mood regulatory networks.

CONCLUSION

This study is among the few to explore brain metabolite differences in the left DLPFC among migraine patients with and without comorbid depression using proton MRS. The findings contribute to the growing literature examining the neurobiological overlap between migraine and depression. Future research using multisite designs, bilateral or multi-voxel MRS, larger and more diverse cohorts, and longitudinal approaches – along with detailed clinical profiling such as ictal versus interictal phase and episodic versus chronic migraine – may help uncover subtle neurometabolic variations and guide targeted interventions for this complex comorbidity.