| 1. |
- Austin, C, et al.
(author)
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Dynamical properties of elemental metabolism distinguish attention deficit hyperactivity disorder from autism spectrum disorder
- 2019
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In: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 9:1, s. 238-
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Journal article (peer-reviewed)abstract
- Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are neurodevelopmental conditions of overlapping etiologies and phenotypes. For ASD, we recently reported altered elemental metabolic patterns in the form of short and irregular zinc and copper cycles. Here, we extend the application of these biomarkers of prenatal and early postnatal elemental metabolism to distinguish between individuals diagnosed with ADHD and/or ASD and neurotypical controls. We recruited twins discordant for ADHD, ASD and other neurodevelopmental diagnoses from national twin studies in Sweden (N = 74) diagnosed according to DSM-5 clinical consensus and standardized psychiatric instruments. Detailed temporal profiles of exposure to 10 metals over the prenatal and early childhood periods were measured using tooth biomarkers. We used recurrence quantification analysis (RQA) to characterize properties of cyclical metabolic patterns of these metals. Regularity (determinism) and complexity (entropy) of elemental cycles was consistently reduced in ADHD for cobalt, lead, and vanadium (determinism: cobalt, β = −0.03, P = 0.017; lead, β = −0.03, P = 0.016; and vanadium, β = −0.03, P = 0.01. Entropy: cobalt, β = −0.13, P = 0.017; lead, β = −0.18, P = 0.016; and vanadium, β = −0.15, P = 0.008). Further, we found elemental pathways and dynamical features specific to ADHD vs ASD, and unique characteristics associated with ADHD/ASD combined presentation. Dysregulation of cyclical processes in elemental metabolism during prenatal and early postnatal development not only encompasses pathways shared by ADHD and ASD, but also comprise features specific to either condition.
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| 2. |
- Bazov, Igor, 1973-, et al.
(author)
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Downregulation of the neuronal opioid gene expression concomitantly with neuronal decline in dorsolateral prefrontal cortex of human alcoholics
- 2018
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In: Translational Psychiatry. - : NATURE PUBLISHING GROUP. - 2158-3188. ; 8
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Journal article (peer-reviewed)abstract
- Molecular changes in cortical areas of addicted brain may underlie cognitive impairment and loss of control over intake of addictive substances and alcohol. Prodynorphin (PDYN) gives rise to dynorphin (DYNs) opioid peptides which target kappa-opioid receptor (KOR). DYNs mediate alcohol-induced impairment of learning and memory, while KOR antagonists block excessive, compulsive-like drug and alcohol self-administration in animal models. In human brain, the DYN/KOR system may undergo adaptive changes, which along with neuronal loss, may contribute to alcohol-associated cognitive deficit. We addressed this hypothesis by comparing the expression levels and co-expression (transcriptionally coordinated) patterns of PDYN and KOR (OPRK1) genes in dorsolateral prefrontal cortex (dlPFC) between human alcoholics and controls. Postmortem brain specimens of 53 alcoholics and 55 controls were analyzed. PDYN was found to be downregulated in dlPFC of alcoholics, while OPRK1 transcription was not altered. PDYN downregulation was confined to subgroup of subjects carrying C, a high-risk allele of PDYN promoter SNP rs1997794 associated with alcoholism. Changes in PDYN expression did not depend on the decline in neuronal proportion in alcoholics, and thereby may be attributed to transcriptional adaptations in alcoholic brain. Absolute expression levels of PDYN were lower compared to those of OPRK1, suggesting that PDYN expression is a limiting factor in the DYN/KOR signaling, and that the PDYN downregulation diminishes efficacy of DYN/KOR signaling in dlPFC of human alcoholics. The overall outcome of the DYN/KOR downregulation may be disinhibition of neurotransmission, which when overactivated could contribute to formation of alcohol-related behavior.
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| 3. |
- Bendre, Megha, et al.
(author)
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Effect of voluntary alcohol consumption on Maoa expression in the mesocorticolimbic brain of adult male rats previously exposed to prolonged maternal separation. : Maoa,ELS and alcohol
- 2015
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In: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 5
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Journal article (peer-reviewed)abstract
- Discordant associations between monoamine oxidase A (MAOA) genotype and high alcohol drinking have been reported in human and non-human primates. Environmental influences likely moderate genetic susceptibility. The biological basis for this interplay remains elusive, and inconsistencies call for translational studies in which conditions can be controlled and brain tissue is accessible. The present study investigated whether early life stress and subsequent adult episodic alcohol consumption affect Maoa expression in stress- and reward-related brain regions in the rat. Outbred Wistar rats were exposed to rearing conditions associated with stress (prolonged maternal separation) or no stress during early life, and given free choice between alcohol and/or water in adulthood. Transcript levels of Maoa were assessed in the ventral tegmental area, nucleus accumbens (NAc), medial prefrontal cortex, cingulate cortex, amygdala and dorsal striatum (DS). Blood was collected to assess corticosterone levels. After alcohol consumption, lower blood corticosterone and Maoa expression in the NAc and DS were found in rats exposed to early life stress compared with control rats. An interaction between early life stress and voluntary alcohol intake was found in the NAc. Alcohol intake before death correlated negatively with Maoa expression in DS in high alcohol-drinking rats exposed to early life stress. Maoa expression is sensitive to adulthood voluntary alcohol consumption in the presence of early life stress in outbred rats. These findings add knowledge of the molecular basis of the previously reported associations between early life stress, MAOA and susceptibility to alcohol misuse.
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| 4. |
- Bergman, Olle, 1978, et al.
(author)
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Association between amygdala reactivity and a dopamine transporter gene polymorphism.
- 2014
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In: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 4
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Journal article (peer-reviewed)abstract
- Essential for detection of relevant external stimuli and for fear processing, the amygdala is under modulatory influence of dopamine (DA). The DA transporter (DAT) is of fundamental importance for the regulation of DA transmission by mediating reuptake inactivation of extracellular DA. This study examined if a common functional variable number tandem repeat polymorphism in the 3' untranslated region of the DAT gene (SLC6A3) influences amygdala function during the processing of aversive emotional stimuli. Amygdala reactivity was examined by comparing regional cerebral blood flow, measured with positron emission tomography and [(15)O]water, during exposure to angry and neutral faces, respectively, in a Swedish sample comprising 32 patients with social anxiety disorder and 17 healthy volunteers. In a separate US sample, comprising 85 healthy volunteers studied with blood oxygen level-dependent functional magnetic resonance imaging, amygdala reactivity was assessed by comparing the activity during exposure to threatening faces and neutral geometric shapes, respectively. In both the Swedish and the US sample, 9-repeat carriers displayed higher amygdala reactivity than 10-repeat homozygotes. The results suggest that this polymorphism contributes to individual variability in amygdala reactivity.
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| 5. |
- Bernabe, Beatriz Penalver, et al.
(author)
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Interactions between perceived stress and microbial-host immune components : two demographically and geographically distinct pregnancy cohorts
- 2023
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In: Translational Psychiatry. - : Springer Nature. - 2158-3188. ; 13
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Journal article (peer-reviewed)abstract
- Higher stress during pregnancy associates with negative outcomes and elevated inflammation. The gut microbiota, reflecting environment and social interactions, alongside host immune responses have the potential to better understand perceived stress and identify when stress is excessive in pregnancy. Two U.S. cohorts of 84 pregnant individuals, composed of urban women of color and suburban white women, completed the Perceived Stress Scale-10 (PSS-10) and provided fecal and blood samples at two time points. Confirmatory Factor Analysis assessed the robustness of a two-factor PSS-10 model (Emotional Distress/ED and Self-Efficacy/SE). Gut microbiota composition was measured by 16 S rRNA amplicon sequencing and the immune system activity was assessed with a panel of 21 T-cell related cytokines and chemokines. ED levels were higher in the suburban compared to the urban cohort, but levels of SE were similar. ED and SE levels were associated with distinct taxonomical signatures and the gut microbiota data improved the prediction of SE levels compared with models based on socio-demographic characteristics alone. Integration of self-reported symptoms, microbial and immune information revealed a possible mediation effect of Bacteroides uniformis between the immune system (through CXCL11) and SE. The study identified links between distinct taxonomical and immunological signatures with perceived stress. The data are congruent with a model where gut microbiome and immune factors, both impacting and reflecting factors such as close social relationships and dietary fiber, may modulate neural plasticity resulting in increased SE during pregnancy. The predictive value of these peripheral markers merit further study.
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| 6. |
- Björkstrand, Johannes, et al.
(author)
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Decrease in amygdala activity during repeated exposure to spider images predicts avoidance behavior in spider fearful individuals.
- 2020
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In: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 10:1
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Journal article (peer-reviewed)abstract
- Spider phobia is characterized by exaggerated fear of situations where spiders could be present, resulting in avoidance of such situations and compromised quality of life. An important component in psychological treatment of spider phobia is exposure to phobic situations that reduces avoidance behaviors. At the neural level, amygdala responses to phobic material are elevated, but normalizes following exposure treatment. To what extent amygdala activity decreases during a session of repeated phobic stimulation, and whether activity decrease is related to subsequent avoidance is not well studied. We hypothesized reduced amygdala activity during the course of repeated exposure to spider pictures, and that the degree of reduction would predict subsequent avoidance of spider pictures. To test our hypothesis, functional magnetic resonance imaging was performed in 45 individuals with spider fear during repeated exposure to spider pictures. Results showed that repeated exposure to spider stimuli attenuated amygdala reactivity and individual differences in activity reductions predicted subsequent avoidance behavior to spider pictures in an incentive-conflict task, with larger attenuations predicting less avoidance. At 6-month follow up, initial reductions in amygdala activation still predicted avoidance. This result demonstrates that reduction in amygdala responses is related to clinically meaningful outcomes in human anxiety, and suggests that within-session reductions in amygdala responses could be an important mechanism explaining the clinical effects of exposure therapy.
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| 7. |
- Bodén, Robert, et al.
(author)
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Striatal phosphodiesterase 10A and medial prefrontal cortical thickness in patients with schizophrenia : a PET and MRI study
- 2017
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In: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 7:3
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Journal article (peer-reviewed)abstract
- The enzyme phosphodiesterase 10A (PDE10A) is abundant in striatal medium spiny neurons and has been implicated in the pathophysiology of schizophrenia in animal models and is investigated as a possible new pharmacological treatment target. A reduction of prefrontal cortical thickness is common in schizophrenia, but how this relates to PDE10A expression is unknown. Our study aim was to compare, we believe for the first time, the striatal non-displaceable binding potential (BPND) of the new validated PDE10A ligand [(11)C]Lu AE92686 between patients with schizophrenia and healthy controls. Furthermore, we aimed to assess the correlation of PDE10A BPND to cortical thickness. Sixteen healthy male controls and 10 male patients with schizophrenia treated with clozapine, olanzapine or quetiapine were investigated with positron emission tomography (PET) and magnetic resonance imaging (MRI). Striatal binding potential (BPND) of [(11)C]Lu AE92686 was acquired through dynamic PET scans and cortical thickness by structural MRI. Clinical assessments of symptoms and cognitive function were performed and the antipsychotic dosage was recorded. Patients with schizophrenia had a significantly lower BPND of [(11)C]Lu AE92686 in striatum (P=0.003) than healthy controls. The striatal BPND significantly correlated to cortical thickness in the medial prefrontal cortex and superior frontal gyrus across patients with schizophrenia and healthy controls. No significant correlation was observed between the BPND for [(11)C]Lu AE92686 in striatum and age, schizophrenia symptoms, antipsychotic dosage, coffee consumption, smoking, duration of illness or cognitive function in the patients. In conclusion, PDE10A may be important for functioning in the striato-cortical interaction and in the pathophysiology of schizophrenia.
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| 8. |
- Boström, Adrian Desai E., et al.
(author)
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Accelerated epigenetic aging in women with emotionally unstable personality disorder and a history of suicide attempts
- 2023
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In: Translational Psychiatry. - : Nature Publishing Group. - 2158-3188. ; 13:1
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Journal article (peer-reviewed)abstract
- Emotional unstable personality disorder (EUPD; previously borderline personality disorder, BPD) is associated with excess natural-cause mortality, comorbid medical conditions, poor health habits and stress related epigenomic alterations. Previous studies demonstrated that GrimAge – a state-of-the-art epigenetic age (EA) estimator – strongly predicts mortality risk and physiological dysregulation. Herein, we utilize the GrimAge algorithm to investigate whether women with EUPD and a history of recent suicide attempts exhibit EA acceleration (EAA) in comparison to healthy controls. Genome-wide methylation patterns were measured using the Illumina Infinum Methylation Epic BeadChip in whole blood from 97 EUPD patients and 32 healthy controls. The control group was significantly older (p < 0.0001) and reported lesser exposure to violent behavior in both youth and adulthood (p < 0.0001). Groups were otherwise comparable regarding gender, BMI, or tobacco usage (p > 0.05). EA estimator DNAmGrimAge exceeded chronological age by 8.8 and 2.3 years in the EUPD and control group, respectively. Similarly, EAA marker AgeAccelGrim was substantially higher in EUPD subjects when compared to controls, in both univariate and multivariate analyzes (p < 0.00001). Tobacco usage conferred substantial within-group effects on the EA-chronological age difference, i.e., 10.74 years (SD = 4.19) compared to 6.00 years (SD = 3.10) in the non-user EUPD group (p < 0.00001). Notably, past alcohol and substance abuse, use of psychotropic medications, global assessment of functioning, self-reported exposure to violent behavior in youth and adulthood, later completed suicide (N = 8) and age at first suicide attempt did not predict EAA in the EUPD group (p > 0.05). These results underscore the importance of addressing medical health conditions along with low-cost preventative interventions aimed at improving somatic health outcomes in EUPD, such as efforts to support cessation of tobacco use. The independency of GrimAge to other EA algorithms in this group of severely impaired EUPD patients, suggest it may have unique characteristics to evaluate risk of adverse health outcomes in context of psychiatric disorders.
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| 9. |
- Cervenka, Simon, et al.
(author)
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Application of positron emission tomography in psychiatry-methodological developments and future directions
- 2022
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In: Translational Psychiatry. - : Springer Nature. - 2158-3188. ; 12:1
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Journal article (peer-reviewed)abstract
- Mental disorders represent an increasing source of disability and high costs for societies globally. Molecular imaging techniques such as positron emission tomography (PET) represent powerful tools with the potential to advance knowledge regarding disease mechanisms, allowing the development of new treatment approaches. Thus far, most PET research on pathophysiology in psychiatric disorders has focused on the monoaminergic neurotransmission systems, and although a series of discoveries have been made, the results have not led to any material changes in clinical practice. We outline areas of methodological development that can address some of the important obstacles to fruitful progress. First, we point towards new radioligands and targets that can lead to the identification of processes upstream, or parallel to disturbances in monoaminergic systems. Second, we describe the development of new methods of PET data quantification and PET systems that may facilitate research in psychiatric populations. Third, we review the application of multimodal imaging that can link molecular imaging data to other aspects of brain function, thus deepening our understanding of disease processes. Fourth, we highlight the need to develop imaging study protocols to include longitudinal and interventional paradigms, as well as frameworks to assess dimensional symptoms such that the field can move beyond cross-sectional studies within current diagnostic boundaries. Particular effort should be paid to include also the most severely ill patients. Finally, we discuss the importance of harmonizing data collection and promoting data sharing to reach the desired sample sizes needed to fully capture the phenotype of psychiatric conditions.
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| 10. |
- Cervenka, Simon, et al.
(author)
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Changes in dopamine D2-receptor binding are associated to symptom reduction after psychotherapy in social anxiety disorder
- 2012
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In: Translational Psychiatry. - : Springer Nature. - 2158-3188. ; 2
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Journal article (peer-reviewed)abstract
- The dopamine system has been suggested to play a role in social anxiety disorder (SAD), partly based on molecular imaging studies showing reduced levels of striatal dopaminergic markers in patients compared with control subjects. However, the dopamine system has not been examined in frontal and limbic brain regions proposed to be central in the pathophysiology of SAD. In the present study, we hypothesized that extrastriatal dopamine D2-receptor (D2-R) levels measured using positron emission tomography (PET) would predict symptom reduction after cognitive behavior therapy (behavior). Nine SAD patients were examined using high-resolution PET and the high-affinity D2-R antagonist radioligand [C-11]FLB 457, before and after 15 weeks of CBT. Symptom levels were assessed using the anxiety subscale of Liebowitz Social Anxiety Scale (LSAS(anx)). At posttreatment, there was a statistically significant reduction of social anxiety symptoms (Po0.005). Using a repeated measures analysis of covariance, significant effects for time and time x LSAS(anx) change on D2-R-binding potential (BPND) were shown (P<0.05). In a subsequent region-by-region analysis, negative correlations between change in D2-R BPND and LSAS(anx) change were found for medial prefrontal cortex and hippocampus (P<0.05). This is the first study to report a direct relationship between symptom change after psychological treatment and a marker of brain P<0.05. Using an intra-individual comparison design, the study supports a role for the dopamine system in cortical and limbic brain regions in the pathophysiology of SAD. Translational Psychiatry (2012) 2, e120; doi:10.1038/tp.2012.40; published online 22 May 2012
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