Oded Gonen, PhD

Major depressive disorder (MDD) in pediatric populations represents a significant public health concern. Rates of MDD rise dramatically in adolescence, with an estimated lifetime prevalence of 15% in adolescents aged 15 to 18.

MDD is associated with severe consequences, including deterioration in academic functioning, increased risk of substance use and other mental disorders, and most critically, attempted and completed suicides-the third leading cause of death in this age group. Furthermore, adolescent MDD is a strong predictor of MDD in adulthood, which carries its own burden of disadvantage.

The importance of specific neurobiological research in pediatric MDD has been recognized in the past decade. Recent studies of the pathophysiology of MDD have suggested that alteration of both neuroplasticity and cellular resilience play a critical role in the pathogenesis of MDD.

 This notion is supported by neuroimages showing significant reductions in regional CNS volume and number and/or size of neurons and glia, along with abnormalities in metabolic rate in specific brain regions. Complex mechanisms involving stress, the hypothalamic-pituitary-adrenal axis, excessive glutamatergic neurotransmission, and decreased expression of neurotrophic factors (such as brain-derived neurotrophic factor and Bcl-2 proteins) are believed to result in cell atrophy and cell death.

H-MRS) allows for the assessment of certain brain chemicals that reflect neuronal activity and integrity, thus providing a noninvasive "window" into neuroplasticity. This article briefly reviews new research and presents current scientific data on the neurochemistry of pediatric MDD.

Safety concerns regarding radiation exposure in pediatric populations have limited the use of imaging techniques such as computed tomography, positron emission tomography, or single-photon emission computed tomography. Fortunately, MR imaging technology does not involve radiation exposure, thus alleviating safety concerns. MRS is a technique that provides metabolic assays of neuronal cells, cell energetics, density, membrane turnover, gliosis, and glycolysis through their respective surrogate markers, 

-acetyl-l-aspartate (NAA), creatine, choline, 

H-MRS is frequently used to map the tissue-specific distribution of metabolites with 1-, 2-, or 3-dimensional localized spectra. These molecular images can be overlaid for reference on the anatomy from the structural MRI.

NAA is the second most abundant amino acid in the CNS, and it is almost exclusively present in neuronal cell bodies and axons and is considered a putative marker of neuronal integrity and density.

 Its decrease may reflect axonal impairment (white matter abnormalities) or damage secondary to reduced glial support.

 Because oligodendrocytes play a crucial role in axonal myelination, NAA decline may reflect oligodendrocyte loss or dysfunction.

Choline is an essential component of membrane lipids, phosphatidylcholine, and sphingomyelin.

 The contribution of free choline to the signal is less than 5% and the contribution of acetylcholine is negligible.

 Elevated choline is attributed to abnormal cell membrane metabolism, myelin breakdown, or change in glial density.

 Choline also involves the second messenger system.

The creatine resonance is a composite peak comprising overlapping creatine and phosphocreatine resonances, representing the high-energy phosphate reserves in the cytosol of neurons and glia.

 Its elevation has been attributed to synergetic effects of oligodendrocytic remyelination and astrocytic microgliosis. It is believed to be relatively stable throughout the brain and therefore is used as a reference to gauge changes in other metabolites. However, not all MRS laboratories have followed this approach.

 Inositol is presumed to play a role in cerebral metabolism, but its precise mechanism remains unclear. mI is a precursor of the phosphatidyl-inositol second messenger system and has been implicated in MDD. Also, the mood-stabilizing agent lithium inhibits the enzyme inositol monophosphatase, which is involved in the catalytic conversion of inositol monophosphate into mI.

g-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS and is integral in managing brain excitability. Glutamate, on the other hand, is an excitatory neurotransmitter that has been implicated in the pathogenesis of MDD. The resonances arising from glutamate, glutamine, and GABA are overlapping at 2.3 ppm and are often indistinguishable; this is referred to as Glx.

MRS research in MDD is still in its infancy and inconsistencies are rife. The discrepant findings may be attributed, in part, to methodology; for example, use of single voxel localization, which is susceptible to partial volume effects, given the small size and irregular shape of the striatum and thalamus; ratios to creatine instead of absolute quantification, which increase variability; and a lower, 1.5 Tesla magnetic field of lower sensitivity, spatial, and spectral resolutions. The variations may also reflect differing subject selection criteria (eg, age range, depression severity, medication status, and family history). Nonetheless, 

H-MRS studies in pediatric MDD have revealed new information about the neurochemistry of the disorder.

Accumulating evidence shows that MDD is associated with disturbances in pathways linking cortical, subcortical, and limbic sites. These regions include the anterior cingulate cortex, orbital cortex, striatum, amygdala, and hippocampus.

 These brain regions are linked and are believed to be critical in modulating emotional responses. 

In general, MRS studies in pediatric MDD tend to confirm findings in adults implicating these regions. Seven studies have focused on the frontal cortex, 2 focused on the striatum, 1 focused on the thalamus, and 1 focused on the amygdala.

Several regions have been examined within the frontal lobe. These are regions that have been highly implicated in adult depression and include the anterior cingulate cortex, the dorsolateral prefrontal cortex, the left orbitofrontal cortex, and the prefrontal cortex.

A large body of evidence has linked the anterior cingulate cortex to MDD. The anterior cingulate cortex is placed anterior and ventral to the genu of the corpus callosum (termed "pregenual" and "subgenual"). In adults, striking reductions of up to 42% in mean gray matter volume of the subgenual prefrontal cortex were reported in several neuroimaging studies of familial MDD.

 A postmortem study of adults with familial MDD attributed gray matter reduction to reduced glial cell density in the subgenual prefrontal cortex.

 These findings suggest the potential role of 

H-MRS in identifying neurochemical alterations of MDD in this brain region. 

H-MRS studies examined Glx and glutamate levels in the anterior cingulate cortex. In one study of 13 psychotropically naive adolescents with MDD and 13 healthy controls (aged 13 to 18), lower Glx levels in the anterior cingulate cortex of the MDD group were reported.

 Another study reported the same results in 14 children and adolescents with MDD (all medication-naive) and 14 matched comparisons (aged 10 to 19).

 In a later analysis of the same study, reduced Glx was found to contribute to glutamate but not to glutamine.

H-MRS studies focused on the dorsolateral prefrontal cortex in pediatric MDD. These studies reported significant findings in the left dorsolateral prefrontal cortex but with conflicting results. One study reported increased absolute choline concentrations in the left dorsolateral prefrontal cortex,

 while a later study reported decreased choline and increased mI in the same region.

It is important to note that these studies differed in the imaging technique used; 3-dimensional versus single-voxel, 0.8 cm

, respectively. In addition, while in the first study all patients were psychotropically naive, in the second study, treatment with psychotropic agents was allowed at the time of the scan.

 There is only one study identified that focused on the left orbitofrontal cortex.

 Seventeen adolescents with MDD were compared with 28 healthy controls (aged 13 to 17). Patients with MDD were allowed to take psychotropic medications. Significant results showed higher ratios of choline/creatine and choline/NAA in the left orbitofrontal cortex of the group with MDD.

One study examined the prefrontal cortex of 12 children and adolescents who had MDD and 12 control subjects (aged 10 to 18). Patients were psychotropic medication-naive. The group with MDD was found to have increased choline/creatine in the right prefrontal cortex.

 The amygdala, part of the limbic system, is central to activating emotional responses and has been the focus of many imaging studies in MDD. Only one 

H-MRS study of adolescents with MDD (aged 14 to 18) examined this region. Decreased choline/creatine ratios were found in the left amygdala region of the MDD group (n = 11) compared with controls (n = 11).

Thalamus and striatum (caudate and putamen).

 There are few studies that focus on these regions in pediatric MDD. The relationship between the basal ganglia and MDD has been inferred from the high comorbidity between MDD and Parkinson and Huntington disease, both basal ganglia-related disorders. In addition, morphometric and functional neuroimaging studies have documented a smaller caudate, putamen, and thalamus, as well as impaired metabolism and blood flow in the striatum and thalamus of patients with MDD.

No significant metabolic alterations were found in choline and creatine levels of 18 children and adolescents with MDD and 18 controls. All patients were psychotropically naive.

Our group recently completed a study that focused on the striatum and thalamus of adolescents with MDD (n = 13) compared with 10 controls. We identified increased choline and creatine only in the left caudate in patients with MDD.

H-MRS studies provide additional scientific support that impaired neuroplasticity may play a role in pediatric MDD as it does in adult MDD. In addition, findings of several studies reporting chemical changes only in the left hemisphere correlate with mounting evidence that implicates the left hemisphere in depression.

Most studies found choline concentration or ratios to be significantly different between groups with MDD and healthy comparisons. Choline has been consistently implicated in adult MDD as well. Alterations in choline levels most likely reflect accelerated cell membrane turnover caused by glial impairment that has been linked to MDD.

Another possible mechanism for choline elevation involves the second messenger system. Phosphocholine,  which is a major choline signal contributor and a metabolite of phosphatidylcholine, is an important source of the second messenger, diacylglycerol, known to participate in intracellular signal transduction pathways

 that are thought to contribute to MDD pathogenesis.

The findings of impaired Glx levels in the anterior cingulate cortex add neurochemical evidence to the role of impaired neuroplasticity in pediatric and adult patients with MDD. The findings also suggest that pediatric MDD does not entail neuronal loss, because none of the studies documented decreased NAA.

MRS research in pediatric MDD has great potential. It could allow for the early detection of neurochemical alterations, contribute to the identification of at-risk individuals, foster preventive therapeutic options, and provide biological markers for treatment response. Methodological inconsistencies and low statistical power limit current 

H-MRS findings. Future studies should enroll larger cohorts of medication-naive patients, comprise longitudinal follow-up, and strive to focus on specific clinical subgroups such as familial MDD and specific ages at onset (adolescent-onset vs childhood-onset). Such refinements in study design would improve the yield of this powerful, noninvasive neuroimaging technology.

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Oded Gonen, PhD

Articles

The Neurochemistry of Pediatric Major Depressive Disorder