Abstract The ‘default mode network’ (DMN), a collection of brain regions including the posterior cingulate cortex (PCC), shows reliable inter-regional functional connectivity at rest. It has been ...implicated in rumination and other negative affective states, but its role in suicidal ideation is not well understood. We employed seed based functional connectivity methods to analyze resting state fMRI data in 34 suicidal ideators and 40 healthy control participants. Whole-brain connectivity with dorsal PCC or ventral PCC was broadly intact between the two groups, but while the control participants showed greater coupling between the dorsal anterior cingulate cortex (dACC) and dorsal PCC, compared to the dACC and ventral PCC, this difference was reversed in the ideators. Furthermore, ongoing low frequency BOLD signal in these three regions (dorsal, ventral PCC, dACC) was reduced in the ideators. The structural integrity of the cingulum bundle, as measured using diffusion tensor imaging (DTI), also explained variation in the functional connectivity measures but did not abolish the group differences. Together, these findings provide evidence of abnormalities in the DMN underlying the tendency towards suicidal ideation.
Thiopeptide antibiotics are a group of highly modified peptide metabolites. The defining scaffold for the thiopeptides is a macrocycle containing a dehydropiperidine or pyridine ring, dehydrated ...amino acids, and multiple thiazole or oxazole rings. Some members of the thiopeptides, such as thiostrepton, also contain either a quinaldic acid or indolic acid substituent derived from tryptophan. Although the amino acid precursors of these metabolites are well-established, the biogenesis of these complex peptides has remained elusive. Whole-genome scanning of Streptomyces laurentii permitted identification of a thiostrepton prepeptide, TsrA, and involvement of TsrA in thiostrepton biosynthesis was confirmed by mutagenesis. A gene cluster responsible for thiostrepton biosynthesis is reported, and the encoded gene products are discussed. The disruption of a gene encoding an amidotransferase, tsrT, led to the loss of thiostrepton production and the detection of a new metabolite, contributing further support to the identification of the tsr cluster. The tsr locus also appears to possess the gene products needed to convert tryptophan to the quinaldic acid moiety, and an aminotransferase was found to catalyze an early step in this pathway. This work establishes that the thiopeptides are a type of bacteriocin, a family of genetically encoded antimicrobial peptides, and are subjected to extensive posttranslational modification during maturation of the prepeptide.
The extent to which observed differences in emotion processing and regulation neural circuitry in adolescents with a history of suicide attempt are paralleled by structural differences is unknown. We ...measured brain cortical thickness and grey- and white-matter volumes in 100 adolescents: 28 with a history of suicide attempt and major depressive disorder (MDD); 31 with a history of MDD but no suicide attempt; and a healthy control group (n = 41). The first group compared with controls showed reduction in grey-matter volume in the right superior temporal gyrus (BA38), a region important for social emotion processing.
Impaired attentional control and behavioral control are implicated in adult suicidal behavior. Little is known about the functional integrity of neural circuitry supporting these processes in ...suicidal behavior in adolescence.
Functional magnetic resonance imaging was used in 15 adolescent suicide attempters with a history of major depressive disorder (ATTs), 15 adolescents with a history of depressive disorder but no suicide attempt (NATs), and 14 healthy controls (HCs) during the performance of a well-validated go-no-go response inhibition and motor control task that measures attentional and behavioral control and has been shown to activate prefrontal, anterior cingulate, and parietal cortical circuitries. Questionnaires assessed symptoms and standardized interviews characterized suicide attempts.
A 3 group by 2 condition (go-no-go response inhibition versus go motor control blocks) block-design whole-brain analysis (p < .05, corrected) showed that NATs showed greater activity than ATTs in the right anterior cingulate gyrus (p = .008), and that NATs, but not ATTs, showed significantly greater activity than HCs in the left insula (p = .004) to go-no-go response inhibition blocks.
Although ATTs did not show differential patterns of neural activity from HCs during the go-no-go response inhibition blocks, ATTs and NATs showed differential activation of the right anterior cingulate gyrus during response inhibition. These findings indicate that suicide attempts during adolescence are not associated with abnormal activity in response inhibition neural circuitry. The differential patterns of activity in response inhibition neural circuitry in ATTs and NATs, however, suggest different neural mechanisms for suicide attempt versus major depressive disorder in general in adolescence that should be a focus of further study.
Treatment-refractory depression is a devastating condition with significant morbidity, mortality, and societal cost. At least 15% of cases of major depressive disorder remain refractory to treatment. ...The authors previously identified a young adult with treatment-refractory depression and multiple suicide attempts with an associated severe deficiency of CSF tetrahydrobiopterin, a critical cofactor for monoamine neurotransmitter synthesis. Treatment with sapropterin, a tetrahydrobiopterin analogue, led to dramatic and long-lasting remission of depression. This sentinel case led the authors to hypothesize that the incidence of metabolic abnormalities contributing to treatment-refractory depression is underrecognized.
The authors conducted a case-control, targeted, metabolomic evaluation of 33 adolescent and young adult patients with well-characterized histories of treatment-refractory depression (at least three maximum-dose, adequate-duration medication treatments), and 16 healthy comparison subjects. Plasma, urine, and CSF metabolic profiling were performed by coupled gas chromatography/mass spectrometry and high-performance liquid chromatography electrospray ionization tandem mass spectrometry.
CSF metabolite abnormalities were identified in 21 of the 33 participants with treatment-refractory depression. Cerebral folate deficiency (N=12) was most common, with normal serum folate levels and low CSF 5-methyltetrahydrofolate (5-MTHF) levels. All patients with cerebral folate deficiency, including one with low CSF levels of 5-MTHF and tetrahydrobiopterin intermediates, showed improvement in depression symptom inventories after treatment with folinic acid; the patient with low tetrahydrobiopterin also received sapropterin. None of the healthy comparison subjects had a metabolite abnormality.
Examination of metabolic disorders in treatment-refractory depression identified an unexpectedly large proportion of patients with potentially treatable abnormalities. The etiology of these abnormalities remains to be determined.
Peripheral blood metabolomics was used to gain chemical insight into the biology of treatment-refractory Major Depressive Disorder with suicidal ideation, and to identify individualized differences ...for personalized care. The study cohort consisted of 99 patients with treatment-refractory major depressive disorder and suicidal ideation (trMDD-SI n = 52 females and 47 males) and 94 age- and sex-matched healthy controls (n = 48 females and 46 males). The median age was 29 years (IQR 22-42). Targeted, broad-spectrum metabolomics measured 448 metabolites. Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) were measured as biomarkers of mitochondrial dysfunction. The diagnostic accuracy of plasma metabolomics was over 90% (95%CI: 0.80-1.0) by area under the receiver operator characteristic (AUROC) curve analysis. Over 55% of the metabolic impact in males and 75% in females came from abnormalities in lipids. Modified purines and pyrimidines from tRNA, rRNA, and mRNA turnover were increased in the trMDD-SI group. FGF21 was increased in both males and females. Increased lactate, glutamate, and saccharopine, and decreased cystine provided evidence of reductive stress. Seventy-five percent of the metabolomic abnormalities found were individualized. Personalized deficiencies in CoQ10, flavin adenine dinucleotide (FAD), citrulline, lutein, carnitine, or folate were found. Pathways regulated by mitochondrial function dominated the metabolic signature. Peripheral blood metabolomics identified mitochondrial dysfunction and reductive stress as common denominators in suicidal ideation associated with treatment-refractory major depressive disorder. Individualized metabolic differences were found that may help with personalized management.
Underlying genetic influences may affect perinatal pain, depression, or both. We investigated the role of 59 single-nucleotide polymorphisms on 20 quantitative traits measured in perinatal women. ...Moreover, 183 pregnant women (28–37 weeks’ gestation) were prospectively genotyped for single-nucleotide polymorphisms with known prior associations with either pain or depression in nonpregnant populations. Prenatal saliva samples were collected. Phenotypic data were gathered during prenatal, labor and delivery, and postpartum (six weeks and three months) periods, capturing labor pain, Edinburgh Postnatal Depression Score, and Brief Pain Inventories. Following quality control, genotypes were used as predictors and phenotypes as dependent variables in multiple linear regression analyses to detect associations. Three statistical models were tested: additive allele effects, deviation from dominant allele effects, and the joint test of both. rs4633 (a synonymous single-nucleotide polymorphism in COMT) associated with “pain right now” scores at six weeks postpartum. Single-nucleotide polymorphisms rs1135349 (a single-nucleotide polymorphism within a small noncoding RNA that has many prior associations for depression) and rs7548151 (intronic in ASTN1) were associated with the maximum pain unpleasantness score experienced during labor (a measure of the emotional valence of labor pain), controlling for the Holm–Bonferroni family-wise error rate. Sensory dimensions of labor pain (i.e., pain intensity) and postpartum depression scores were not associated with genotyped single-nucleotide polymorphisms. Identifying genomic components of these perinatal complex disorders may produce insights into relevant pathways or novel treatment options.
More than 36,000 people in the United States die from suicide annually, and suicide is the third leading cause of death in adolescence. Adolescence is a time of high risk for suicidal behavior, as ...well as a time that intervention and treatment may have the greatest impact because of structural brain changes and significant psychosocial development during this period. Functional and structural neuroimaging studies in adults who have attempted suicide suggest distinct gray matter volume abnormalities in cortical regions, as well as prefrontal cortical and dorsal anterior cingulate gyrus neural circuitry differences compared with affective and healthy adult controls. Recent functional neuroimaging studies in adolescents with a history of suicide attempt suggest differences in the attention and salience networks compared with adolescents with depression and no history of suicide attempt and healthy controls when viewing angry faces. In contrast, no abnormalities are seen in these areas in the absence of emotional stimuli. These networks may represent promising targets for future neuroimaging studies to identify markers of risk for future suicide attempt in adolescents.
Abstract Impairment in decision-making is frequently observed in suicide attempters. Little is known, however, about neural circuitry underlying decision-making in adolescent attempters. Functional ...magnetic resonance imaging (fMRI) was used to assess decision-making and learning-related neural activity during Iowa Gambling Task (IGT) performance in adolescents with depression and suicide attempt (ATT, n =15), non-attempters with depression (NAT, n =14), and healthy controls (HC, n =13). ATT performed best on the IGT. A three group by two condition (high-risk versus low-risk) by three IGT block (each of 20 cards) whole-brain analysis ( p <0.05, corrected) interaction was found in the left hippocampal, frontal and temporal cortical, striatal and thalamic regions. Post-hoc analyses revealed that during low-risk decisions in blocks 2 and 3, NAT, but not ATT, showed greater left hippocampal activation versus HC ( p =0.0004, p =0.003); in block 2, during low-risk decisions NAT showed greater left middle temporal gyral activation versus HC ( p =0.003); in block 3, during high-risk decisions ATT showed less activation in the right thalamus versus NAT ( p =0.001) and during low risk decisions ATT showed greater activation than HC in the left caudate ( p =0.002). NAT, but not ATT are differentiated from HC during performance of the IGT. Functional abnormalities in neural circuitry implicated in learning in the context of risk may underlie risk for MDD, but not risk for suicide attempt, in adolescence.
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