Zou Y, Wu YQ, Han YJ, He XM, Zhao J. Application of proton magnetic resonance spectroscopy in metabolic alterations of prefrontal white and gray matter in depression adolescents. World J Psychiatry 2024; 14(11): 1652-1660 [PMID: 39564168 DOI: 10.5498/wjp.v14.i11.1652]
Corresponding Author of This Article
Jiang Zhao, BMed, Doctor, Department of Radiology, Hangzhou Cancer Hospital, No. 34 Yanguan Lane, Zhongshan South Road, Shangcheng District, Hangzhou 310002, Zhejiang Province, China. hzzhaojiang@163.com
Research Domain of This Article
Psychology
Article-Type of This Article
Retrospective Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Ying Zou, Yao-Jing Han, Department of Clinical Psychology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310005, Zhejiang Province, China
Yu-Qin Wu, Xiao-Ming He, Department of Endocrine and Metabolic Diseases, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310005, Zhejiang Province, China
Jiang Zhao, Department of Radiology, Hangzhou Cancer Hospital, Hangzhou 310002, Zhejiang Province, China
Author contributions: Zou Y wrote the manuscript; Zhao J reviewed the manuscript; Zou Y, Wu YQ, Han YJ, He XM and Zhao J collected the data; all authors annotated the manuscript.
Supported bythe General Scientific Research Project of Zhejiang Provincial Department of Education, No. Y202248840 and No. Y201942374.
Institutional review board statement: This study was approved by the Ethic Committee of The Second Affiliated Hospital of Zhejiang Chinese Medical University (Approval No. 2024 Research No. 035-01).
Informed consent statement: The Institutional Review Board waived the requirement for informed consent.
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jiang Zhao, BMed, Doctor, Department of Radiology, Hangzhou Cancer Hospital, No. 34 Yanguan Lane, Zhongshan South Road, Shangcheng District, Hangzhou 310002, Zhejiang Province, China. hzzhaojiang@163.com
Received: July 10, 2024 Revised: July 30, 2024 Accepted: August 1, 2024 Published online: November 19, 2024 Processing time: 119 Days and 21.1 Hours
Abstract
BACKGROUND
Cases of depression among adolescents are gradually increasing. The study of the physiological basis of cognitive function from a biochemical perspective has therefore been garnering increasing attention. Depression has been hypothesized to be associated with the brain biochemical metabolism of the anterior cingulate gyrus, frontal lobe white matter, and the thalamus.
AIM
To explore the application of proton magnetic resonance spectroscopy (1H-MRS) in the metabolic alterations in the prefrontal white matter (PWM) and gray matter (GM) in adolescents with depression.
METHODS
1H-MRS was performed for semi-quantitative analysis of the biochemical metabolites N-acetylaspartate (NAA), choline (Cho) complexes, creatine (Cr), and myo-inositol (mI) in bilateral PWM, anterior cingulate GM, and thalami of 31 adolescent patients with depression (research group) and 35 healthy adolescents (control group), and the NAA/Cr, Cho/Cr, and mI/Cr ratios were calculated. Meanwhile, Hamilton Depression Scale (HAMD) and Wechsler Memory Scale were used to assess the degree of depression and memory function in all adolescents. The correlation of brain metabolite levels with scale scores was also analyzed.
RESULTS
The research group had markedly higher HAMD-24 scores and lower memory quotient (MQ) compared with the control group (P < 0.05). Adolescents with depression were found to have lower bilateral PWM NAA/Cr and Cho/Cr ratios compared with healthy adolescents (P < 0.05). The mI/Cr ratios were found to be similar in both groups (P > 0.05). The bilateral anterior cingulate GM NAA/Cr, Cho/Cr, and mI/Cr also did not demonstrate marked differences (P > 0.05). No statistical inter-group difference was determined in NAA/Cr of the bilateral thalami (P > 0.05), while bilateral thalamic Cho/Cr and mI/Cr were reduced in teenagers with depression compared with healthy adolescents (P < 0.05). A significant negative correlation was observed between the HAMD-24 scores in adolescents with depression with bilateral PWM NAA/Cr and Cho/Cr and were inversely linked to bilateral thalamic Cho/Cr and mI/Cr (P < 0.05). In adolescents with depressions, MQ positively correlated with right PWH NAA/Cr, left PWH Cho/Cr, and bilateral thalamic Cho/Cr and mI/Cr.
CONCLUSION
PWM and thalamic metabolic abnormalities might influence teen depression, and the reduction in bilateral PWM NAA/Cr and Cho/Cr could be related to the neuropathology of adolescents with depression suffering from memory impairment. There exists a possibility of dysfunction of nerve cell membrane phospholipids in the thalami of adolescent patients with depression.
Core Tip: The prefrontal cortex and anterior cingulate gyrus are the key regions that play a significant role in emotional processing and modulation, and the thalamus is closely related to emotional activities. In this study, multi-voxel proton magnetic resonance spectroscopy scans were performed on the frontal white matter, anterior cingulate gray matter, and thalami in adolescents with depression, to explore the biochemical basis of the pathogenesis of teen depression.
Citation: Zou Y, Wu YQ, Han YJ, He XM, Zhao J. Application of proton magnetic resonance spectroscopy in metabolic alterations of prefrontal white and gray matter in depression adolescents. World J Psychiatry 2024; 14(11): 1652-1660
Mood disorder is characterized by low mood, lack of interest, and insufficient willpower; similarly, depression has been associated with high prevalence and recurrence rates, and rising disability and suicide rates in recent years[1,2]. Depression ranks tenth among the leading causes of increased global burden and sixth among the primary causes of disability-adjusted life years in the 10–24 age group according to the Global Burden of Diseases, Injuries, and Risk Factors Study, 2019 (GBD 2019)[3]. Early-onset depression is a common occurrence globally, with a lifetime prevalence estimated to be 15% in late adolescence. Women experience depressive symptoms and disorders more frequently, compared with men[4,5]. The rate of depression among adolescents has gradually increased in the recent years. Adult depression mostly initiates during adolescence, and teen depression is associated with recurrent episodes and other mental disorders in adulthood[6,7]. Depression can lead to cognitive dysfunction, particularly memory impairment, which can adversely affect the study and life of teenagers. However, the increase in neuroplasticity occurs before adulthood, and investigating the neural circuits of adolescents with depression is important for understanding the trajectory of neural development[8]. Although several studies have indicated the presence of brain abnormalities in patients with depression[9,10], the underlying pathophysiological mechanisms remain unclear. There is a lack of effective biomarkers that can not only help to distinguish between healthy and depressed adolescents but also identify potential targets for accurate risk assessment and effective intervention strategies.
Recent advances in medical imaging, especially functional magnetic resonance imaging (MRI), enables the identification of structural, functional, and metabolic abnormalities in depressive patients, which facilitates the study of the etiology and pathogenesis of depression. Magnetic resonance spectroscopy (MRS) is a nuclear magnetic resonance technology that facilitates the non-invasive detection of metabolite concentrations in vivo along with the characteristics of the biochemical changes in the brain. The biochemical and metabolic data obtained using MRS provides more complementary research information for studying structural and functional alterations in the depressed brain[11]. Due to the abundance of hydrogen in living organisms and its easy spectral identification, proton MRS (1H-MRS) is currently the most commonly employed technique in clinical practice. MRS can indirectly reflect the functional status of the brain by detecting the concentration of intracellular metabolites in the brain neurons[12]. The study of the physiological basis of cognitive function from a biochemical perspective has attracted increasing attention, with research in this area focused on dementia, epilepsy, and schizophrenia, both at domestic and international levels[13,14]. Yet, studies investigating the changes in brain metabolites in patients with depression are scarce, particularly in adolescents with depression; and these studies offer mixed conclusions. MRS studies of depression have revealed abnormalities in biochemical metabolism in the frontal cortex, amygdala, hippocampus, anterior cingulate cortex and thalamus[15,16]. Among these regions, the prefrontal cortex and anterior cingulate gyrus play a vital role in emotional processing and modulation, while the thalamus is closely related to emotional activities. Hence, depression is thought to be linked to the brain biochemical metabolism of the anterior cingulate gyrus, frontal lobe white matter, and thalamus.
In this study, multi-voxel 1H-MRS scans were performed on the frontal white matter, anterior cingulate gray matter (GM), and thalami in adolescents with depression, to determine N-acetylaspartate (NAA), choline (Cho), creatine (Cr), and myo-inositol (mI) contents, so as to explore the biochemical basis of the pathogenesis of teen depression.
MATERIALS AND METHODS
Study subjects
This study involved the retrospective analysis of the clinical data of adolescent patients experiencing their first episode of depression who visited our hospital for treatment from January 2020 to September 2023. Inclusion criteria were as follows: (1) Age 13–19 years; (2) Patients younger than 18 years, who met the depression diagnostic criteria described by the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL)[17]; patients above the age of 18 years, who met the depression diagnostic criteria described by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)[18]; (3) Patients with first onset depression; (4) 24-item Hamilton Depression Rating Scale (HAMD-24) score ≥ 20 points; (5) No previous use of psychotropic drugs (including antidepressants, benzodiazepines and other sedatives/sleeping pills), electroconvulsive therapy, or psychotherapy; (6) Patients who were right-handed; (7) Those who had previously undergone an MRI examination; and (8) Patients with complete clinical data. Exclusion criteria: (1) Diagnosis of attention deficit hyperactivity, oppositional defiance, behavioral, pervasive developmental, post-traumatic stress, obsessive-compulsive, or bipolar affective disorders, Tourette’s syndrome, psychosis, etc. in accordance with DSM-IV; (2) Currently using antipsychotic drugs; (3) History of neurological disease or head trauma; (4) Post-traumatic stress disorder; (5) Left-handed individuals; and (6) Patients with general MRI limitations (e.g., metal implants and claustrophobia). A total of 31 eligible patients were selected after screening. In addition, 35 healthy adolescent volunteers who matched in age and education with the research group, underwent MRI examinations. These individuals had a total Hamilton Depression Scale (HAMD) score of less than 7, and were screened. Healthy volunteers were included and excluded based on the same criteria as the study group, with normal scores and no personal or family history of depression or anxiety, brain injury or organic brain disease. This research was ratified by the hospital’s ethics committee.
Scale evaluation
The severity of depression in all participants was evaluated using the HAMD scale. The researchers used interviews and observations to check and evaluate the patients, and calculated the final scores based on the interview results. Most of the items in the scale adopted a 5-point Likert scale of 0–4 points, and a few adopted a 3-point Likert scale of 0–2 points. A 24-item version was used in this study. A total score of ≥ 20 indicates definite depression, while a total score of < 7 suggests absence of depressive symptoms.
The Wechsler Memory Scale (WMS) was used for evaluating memory function of the subjects. The WMS consists of 10 sub-tests, specifically questions judging the subject’s long-term (personal experience, time and space, and relationships in numerical order), short-term (visual recognition, picture memory, visual regeneration, associative learning, tactile testing, comprehension, and memory), and immediate memory (memorization and reciting). The subject’s memory quotient (MQ) was obtained and graded based on the score of each subtest and age: ≤ 69: Memory impairment; 70–79: Critical value; 80–89: Lower than usual; 90–109: Normal; 110–119: Higher than normal; 120–129: Exceptional; ≥ 130: Very exceptional.
1H-MRS
The Siemens Skyra 3.0T MRI system, Germany was used to conduct the 1H-MRS examination. Signals were transmitted and received using an 8-channel standard head and neck coil. The subject was positioned in a supine position, with the positioning line perpendicular to the nasal root, and earplugs and foam pads were provided to reduce noise. First, the presence of brain lesions and any structural and signal abnormalities was ruled out by performing MRI scans with SE sequences and 1H-MRS was located, using triaxial positioning. The regions of interest (ROIs) were selected after positioning, avoiding structures such as the skull, fat, air cavity, and cerebrospinal fluid, and saturated bandshapes were used to avoid the influence of the surrounding tissues on the examination results. Scanning was performed after automatic shimming. The volumes of interest were the bilateral dorsolateral prefrontal cortex white matter and anterior cingulate GM. Scanning parameters were as follows: Repetition time = 1700 ms, echo time = 135 ms, number of averages = 192, and acquisition time = 4 minutes and 48 seconds. Spectral signals were calculated and processed using the workstation, and were then converted into corresponding data and spectrogram to represent relative NAA, Cho, Cr, and mI levels. The phase and frequency coding and the baseline correction of the spectra was performed automatically by the software to determine the area under the peak of NAA, Cho, Cr, and mI in the ROIs and calculate the NAA/Cr, Cho/Cr, and mI/Cr ratios.
Statistical analyses
Statistical processing and analyses were performed using SPSS 25.0. First, normality test and variance homogeneity test were performed on the data, and all the measures were represented by mean ± SD. χ2 tests and t-tests were used to identify the differences in clinical and demographic characteristics between depressed adolescents and healthy controls. The independent sample t-test was used for the comparative analysis of the brain biochemical and metabolic indices, and Spearman correlation coefficients were used to determine the correlation of clinical variables with the scale scores. P values < 0.05 were considered statistically significant.
RESULTS
General information
Thirty-one adolescents with depression, including 14 males and 17 females aged 15.5 ± 1.6 years were enrolled in the study. The average body mass index (BMI) was 22.3 ± 1.8 kg/m2. Among the 31 subjects, there were 8, 17, and 6 subjects currently receiving primary school education, junior high school education, and high school/vocational high school education, respectively. Thirty-five adolescents including 15 males and 20 females, aged 15.1 ± 1.4 years, with a BMI of 22.9 ± 1.6 kg/m2, were included in the normal control group. In the control group, 6, 19, and 10 adolescents were receiving primary school education, junior high school education, and senior high school/vocational high school education, respectively. No statistical inter-group differences were determined in age, sex, BMI, and education level (P > 0.05; Table 1).
Comparative analysis of the scale evaluation results was performed using the independent sample t-test. Statistical significance was identified between groups in HAMD-24 and MQ scores (P < 0.05), with even higher HAMD-24 scores and lower MQ scores in the research group, as depicted in Figure 1.
Figure 1 Comparison of scale scoring results.
A: Comparison of 24-item Hamilton Depression Rating Scale scoring results; B: Comparison of memory quotient scoring results. aP < 0.0001. HAMD-24: 24-item Hamilton Depression Rating Scale.
Brain biochemical metabolism
The relative contents of various prefrontal white matter (PWM) metabolites were compared between the research group and the control group. The bilateral PWM NAA/Cr and Cho/Cr ratios were markedly lower in the research group compared with the control group (P < 0.05), while the change in mI/Cr was not significant (P > 0.05). The anterior cingulate GM biochemical metabolism results (P > 0.05) did not indicate a marked difference in the anterior cingulate GM NAA/Cr, Cho/Cr and mI/Cr ratios between groups. The inter-group comparison of brain biochemical metabolism of the thalamus indicated no statistical difference in bilateral thalamic NAA/Cr (P > 0.05); however, the bilateral thalamic Cho/Cr and mI/Cr values were significantly reduced in the research group compared to the control group (P < 0.05). Please refer to Tables 2-4 for details.
Table 2 Comparison of brain biochemical metabolism of the prefrontal white matter.
Correlation of 1H-MRS findings with scale scores in the research group
A significant negative correlation was observed in the HAMD-24 scores in adolescents with depression with bilateral PWM NAA/Cr and Cho/Cr. A negative correlation was also observed the HAMD-24 scores in adolescents with depression with bilateral thalamic Cho/Cr and mI/Cr (P < 0.05). A significant positive correlation was observed between MQ and NAA/Cr in the right PWM and Cho/Cr in the left PWM in adolescent depressed patients, and a positive association was observed between MQ and Cho/Cr and mI/Cr in the bilateral thalami (P < 0.05), as demonstrated in Table 5.
Table 5 Correlation analysis between proton magnetic resonance spectroscopy findings and scale scores in the research group.
Current evidence has indicated the presence of hypothalamus-pituitary-adrenal axis abnormalities in patients suffering from depression[19]. 1H-MRS made it possible to obtain sufficient neurochemical information in vivo through non-invasive methods to display the pathophysiological changes taking place in the brain tissue due to depression. This novel research approach enabled examination of the microscopic changes taking place in the brain tissues of adolescent patients suffering from depression. The 1H-MRS technique also enabled the in vivo and non-invasive determination of alterations in the types and quantities of metabolites such as NAA, Cho, and Cr in the ROIs. Since these indicators can indirectly reflect the synthesis of mitochondria in neurons and axons, they can serve as markers for detecting the functional status of neurodensitometers.
This study found a statistical reduction in the bilateral PWM NAA/Cr and Cho/Cr values in adolescents with depression compared with healthy adolescents, while the alteration in mI/Cr values was not significant. Additionally, an inverse association of HAMD-24 scores with bilateral PWM NAA/Cr and Cho/Cr was observed in adolescents with depression. NAA is a marker reflecting the integrity of neurons and mitochondria. It is related to protein and fat synthesis, maintenance of intracellular cation concentration, and excitability of neural membranes. NAA content reflects the functional status or the number and activation degree of neurons[20]. Cho, a potential biomarker of phospholipid metabolism in cell membranes, is associated with the decomposition and transformation of cell membranes or myelin. An increase in the Cho peak primarily indicates enhanced cell membrane metabolism or active cell proliferation[21]. mI is a metabolite of hormone-sensitive neuroreceptors and possibly a precursor of glucuronic acid, which participates in neuronal osmotic pressure modulation, membrane-bound phospholipid metabolism, and the second messenger pathway of phosphatidylinositol[22]. Because of its relatively constant content, Cr often acts as an internal standard for comparison. The findings of this study corroborate with those of a study conducted by Mao et al[23], which reported significantly decreased left dorsolateral PWM NAA/Cr and Cho/Cr and markedly reduced right dorsolateral PWM NAA/Cr in adolescents with depression compared with healthy adolescents. Moreover, a positive correlation was observed between MQ in adolescent depressed patients with NAA/Cr on the right side and Cho/Cr on the left side of the PWM. Lower NAA/Cr indicates a reduction in the count of neurons and their axons in this region or their dysfunction. In addition, no significant inter-group difference was identified in NAA/Cr, Cho/Cr, and mI/Cr of the bilateral anterior cingulate GM. The anterior cingulate gyrus is very important with respect to cognitive function (e.g., rewards, decision-making, and emotions)[24]. Some symptoms of depression such as cognitive dysfunction and apathy, might be related to cingulate gyrus and neural circuit dysfunction[25]. Our results are also in agreement with the results of previous studies investigating changes in the concentration of metabolites in the anterior cingulate gyrus, that indicate no significant differences in Acetyl-CoA carboxylase (ACC) metabolites between the research and control groups[23,26,27]. It is however worth mentioning that ACC has been found to exhibit significant abnormal brain metabolite concentrations in adolescent major depressive disorder (MDD) patients, with research mainly focusing on glutamatergic metabolites and confirming a significant decrease in their concentrations[28]. However, this has not currently been focused upon in this study. Furthermore, no significant inter-group difference was observed in bilateral thalamic NAA/Cr in this study; however, bilateral thalamic Cho/Cr and mI/Cr values were observed to be lower in the research group compared with the control group. The thalamus is the largest oval GM nucleus in the diencephalon, located on either side of the third ventricle. The thalamus is the core component of reward circuits, and its activation could be vital in the pathogenesis of teen depression[29]. However, a study conducted by Gabbay et al[30] indicated no significant difference in thalamic metabolites between adolescents suffering from MDD and healthy adolescents; however, another study has indicated that thalamic stroke can cause impaired emotional regulation[31]. mI, a product of myelin degeneration, is a vital regulator of osmotic pressure and cell volume, and performs the functions of nourishing cells, generating surfactant, and also plays an important role in antioxidation[32]. mI is involved in the signal transduction of the phosphatidylcholine system and the regulation of neuronal osmotic pressure. Elevated mI levels can affect the second messenger binding of phosphoinositide, which is associated with the variations in membrane structure caused by phosphorylation status of cellular proteins or alterations in phospholipid metabolism[33]. Therefore, adolescent patients with depression could possibly have a metabolic disorder of phospholipids in the thalamic nerve cell membrane.
However, this study has some limitations. First limitation is the retrospective nature of this study. A multi-center large sample prospective study is warranted for more rigorous verification of the metabolic alterations in the brains of adolescents with depression. Second, the disturbance in lipid profiling has been recognized in MDD, in animal models of MDD or in depressed patients, which might help to unravel the etiology of the disease and find putative new biomarkers; thus, specific pathways such as phospholipid metabolism in the thalamus could provide deeper insights into neurobiological processes associated with depression. Therefore, a well-designed, randomized, and controlled trial with prospective data collection and sample size calculation is required for further confirmation of the findings of this study.
CONCLUSION
In summary, this paper indicates that the metabolic abnormalities of the PWM and thalamus might play a role in the occurrence of teen depression, and the reduction in bilateral PWM NAA/Cr and Cho/Cr might be related to the neuropathology of depression in adolescent patients with memory impairment. A dysfunction in the phospholipid metabolism of the nerve cell membrane in the thalamus of adolescents with depression is also a possibility. However, this study has some limitations such as the retrospective design of the study, lack of grouping of adolescent depressed patients with or without suicide and self-injury, and lack of comprehensive consideration of the possible impact of medication on the results of MRS. Therefore, it is necessary to conduct a study involving a large sample size on samples with more obvious characteristics and to further verify and improve the previous research results. Multimodal MRI can be used in the future to study various brain regions, so that the results obtained by various types of MRI techniques can be mutually confirmed and supplemented, thereby providing more comprehensive clinical clues and imaging evidence.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Psychiatry
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade C, Grade C
Novelty: Grade B, Grade B
Creativity or Innovation: Grade B, Grade B
Scientific Significance: Grade B, Grade B
P-Reviewer: Birnbaum ML; Citrin DE S-Editor: Lin C L-Editor: A P-Editor: Yu HG
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