Intermittent theta-burst stimulation moderates interaction between increment of N-Acetyl-Aspartate in anterior cingulate and improvement of unipolar depression

Abstract

a b s t r a c tBackground: Intermittent theta-burst stimulation (iTBS), a novel repetitive transcranial magnetic stimulation (rTMS) technique, appears to have antidepressant effects when applied over left dorsolateral prefrontal cortex (DLPFC). However, its underlying neurobiological mechanisms are unclear. Proton magnetic resonance spectroscopy ( 1 H-MRS) provides in vivo measurements of cerebral metabolites altered in major depressive disorder (MDD) like N-acetyl-aspartate (NAA) and choline-containing compounds (Cho). We used MRS to analyse effects of iTBS on the associations between the shifts in the NAA and Cho levels during therapy and MDD improvement. Methods: In-patients with unipolar MDD (N ¼ 57), in addition to treatment as usual, were randomized to receive 20 iTBS or sham stimulations applied over left DLPFC over four weeks. Single-voxel 1 H-MRS of the anterior cingulate cortex (ACC) was performed at baseline and follow-up. Increments of concentrations, as well as MDD improvement, were defined as endpoints. We tested a moderated mediation model of effects using the PROCESS macro (an observed variable ordinary least squares and logistic regression path analysis modeling tool) for SPSS. Results: Improvement of depressive symptoms was significantly associated with decrease of Cho/NAA ratio, mediated by NAA. iTBS had a significant moderating effect enhancing the relationship between NAA change and depression improvement. Conclusions: Our findings suggest a potential neurochemical pathway and mechanisms of antidepressant action of iTBS, which may moderate the improvement of metabolic markers of neuronal viability. iTBS might increase neuroplasticity, thus facilitating normalization of neuronal circuit function.

Abnormal Reginal Homogeneity in Left Anterior Cingulum Cortex and Precentral Gyrus as a Potential Neuroimaging Biomarker for First-Episode Major Depressive Disorder

“…When ACC is damaged, it will produce many clinical symptoms, including inattention, dysfunction of autonomic function regulation, emotional instability ( 35 , 36 ). Studies have found that the ACC is prone to damage in depression ( 37 , 38 ). Structural magnetic resonance study found that the anterior cingulum white matter fibrosis of the ACC recovered after 8 weeks of antidepressant treatment ( 39 , 40 ).…”

Repetitive Transcranial Magnetic Stimulation-Associated Changes in Neocortical Metabolites in Major Depression: A Systematic Review

“…Participants’ mean age ranged from 15.5 to 53 years across studies, with an overall mean ± SD age of 36.8 ± 11.3. Age composition varied and included studies of adolescents (ages 13–17 ( Croarkin et al, 2016 )), adolescents to young adults (ages 15–21 ( Yang et al, 2014 )); and young adults (ages 18–40 ( Zheng et al, 2015 , Zheng et al, 2010 )), with most studies (8/12) focusing on adult patients (ages 20–70 ( Baeken et al, 2017 , Dubin et al, 2016 , Luborzewski et al, 2007 , Erbay et al, 2019 , Zavorotnyy et al, 2020 , Godfrey et al, 2021 , Levitt et al, 2019 , Bhattacharyya et al, 2021 ).…”

“…With the exception of two studies which included a small number of participants with a primary diagnosis of bipolar II or bipolar I disorder ( n = 3) ( Dubin et al, 2016 , Godfrey et al, 2021 ), participants had a primary diagnosis of current MDD using standard Diagnostic and Statistical Manual of Mental Disorders (DSM) DSM-IV, DSM-IV-TR or DSM 5 criteria ( American Psychiatric Association, 2013 , American Psychiatric Association, 2000 ). Some level of pharmacoresistance characterized the participants in nine studies; one study did not specify participants’ past treatment history or pharmacoresistance ( Zavorotnyy et al, 2020 ), and two did not require treatment resistance ( Luborzewski et al, 2007 , Erbay et al, 2019 ). Information on psychiatric comorbidities was available in five studies and included secondary diagnoses of attention deficit hyperactivity disorder, obsessive compulsive disorder, generalized anxiety disorder, social phobia, and post-traumatic stress disorder ( Croarkin et al, 2016 , Yang et al, 2014 , Dubin et al, 2016 , Erbay et al, 2019 , Godfrey et al, 2021 ).…”

Enhancement of Fear Extinction Memory and Resistance to Age-Related Cognitive Decline in Butyrylcholinesterase Knockout Mice and (R)-Bambuterol Treated Mice

“…Moreover, DESI-MSI showed that the N-acetyl aspartic acid ( m / z = 174.04) and L-glutamine ( m / z = 145.06) levels were increased in the brain of 10-month-old BChE KO mice ( Figure 9 A–E). N-acetyl aspartic acid is synthesized in neuronal mitochondria and transported via axons, its cerebral level correlates with the number of neurons, and is as a putative marker for health, viability, and/or number of neurons [ 50 ]. The level of N-acetyl aspartic acid is reduced in the brain of AD patients [ 51 ].…”

“…An increased of L-glutamine in the brain of BChE KO mice in this study is consistent with our previous publication in which BChE inhibition restored the decreased of L-glutamine in Aβ-42-induced astrocytes [ 30 ], and the glutamate–glutamine cycle has a pivotal role in the etiology of AD [ 53 ]. Studies also have found that the increase of L-glutamine and N-acetyl aspartic acid can reduce the risk of depression [ 50 , 54 ].…”