Predicting lithium response prior to treatment could both expedite therapy and avoid exposure to side effects. Since lithium responsiveness may be heritable, its predictability based on genomic data ...is of interest. We thus evaluate the degree to which lithium response can be predicted with a machine learning (ML) approach using genomic data. Using the largest existing genomic dataset in the lithium response literature (n = 2210 across 14 international sites; 29% responders), we evaluated the degree to which lithium response could be predicted based on 47,465 genotyped single nucleotide polymorphisms using a supervised ML approach. Under appropriate cross-validation procedures, lithium response could be predicted to above-chance levels in two constituent sites (Halifax, Cohen's kappa 0.15, 95% confidence interval, CI 0.07, 0.24; and Würzburg, kappa 0.2 0.1, 0.3). Variants with shared importance in these models showed over-representation of postsynaptic membrane related genes. Lithium response was not predictable in the pooled dataset (kappa 0.02 - 0.01, 0.04), although non-trivial performance was achieved within a restricted dataset including only those patients followed prospectively (kappa 0.09 0.04, 0.14). Genomic classification of lithium response remains a promising but difficult task. Classification performance could potentially be improved by further harmonization of data collection procedures.
The anterior cingulate cortex (ACC) plays a crucial role in encoding, consolidating and retrieving memories related to emotionally salient experiences, such as aversive and rewarding events. Various ...studies have highlighted its importance for fear memory processing, but its circuit mechanisms are still poorly understood. Cortical layer 1 (L1) of the ACC might be a particularly important site of signal integration, since it is a major entry point for long-range inputs, which is tightly controlled by local inhibition. Many L1 interneurons express the ionotropic serotonin receptor 3a (5HT3aR), which has been implicated in post-traumatic stress disorder and in models of anxiety. Hence, unraveling the response dynamics of L1 interneurons and subtypes thereof during fear memory processing may provide important insights into the microcircuit organization regulating this process. Here, using 2-photon laser scanning microscopy of genetically encoded calcium indicators through microprisms in awake mice, we longitudinally monitored over days the activity of L1 interneurons in the ACC in a tone-cued fear conditioning paradigm. We observed that tones elicited responses in a substantial fraction of the imaged neurons, which were significantly modulated in a bidirectional manner after the tone was associated to an aversive stimulus. A subpopulation of these neurons, the neurogliaform cells (NGCs), displayed a net increase in tone-evoked responses following fear conditioning. Together, these results suggest that different subpopulations of L1 interneurons may exert distinct functions in the ACC circuitry regulating fear learning and memory.
Stimulation of endogenous neurogenesis and recruitment of neural progenitors from the subventricular zone (SVZ) neurogenic site may represent a useful strategy to improve regeneration in the ischemic ...cortex. Here, we tested whether transgenic overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN), the regulator of matrix metalloproteinases (MMPs) expression, in endogenous neural progenitor cells (NPCs) in the subventricular zone (SVZ) could increase migration towards ischemic injury. For this purpose, we applied a lentivector-mediated gene transfer system. We found that EMMPRIN-transduced progenitors exhibited enhanced MMP-2 activity in vitro and showed improved motility in 3D collagen gel as well as in cortical slices. Using a rat model of neonatal ischemia, we showed that EMMPRIN overexpressing SVZ cells invade the injured cortical tissue more efficiently than controls. Our results suggest that EMMPRIN overexpression could be suitable approach to improve capacities of endogenous or transplanted progenitors to invade the injured cortex.
•SVZ-derived NPCs express MMPs and their physiological inducer, EMMPRIN.•Transgenic overexpression of EMMPRIN enhances the enzymatic activity of MMP-2.•EMMPRIN overexpression increases NPCs invasive capacities.•NPCs overexpressing EMMPRIN migrate rapidly into cortical injury.
Prior research has shown that mothers with Interpersonal violence-related posttraumatic stress disorder (IPV-PTSD) report greater difficulty in parenting their toddlers. Relative to their frequent ...early exposure to violence and maltreatment, these mothers display dysregulation of their hypothalamic pituitary adrenal axis (HPA-axis), characterized by hypocortisolism. Considering methylation of the promoter region of the glucocorticoid receptor gene NR3C1 as a marker for HPA-axis functioning, with less methylation likely being associated with less circulating cortisol, the present study tested the hypothesis that the degree of methylation of this gene would be negatively correlated with maternal IPV-PTSD severity and parenting stress, and positively correlated with medial prefrontal cortical (mPFC) activity in response to video-stimuli of stressful versus non-stressful mother-child interactions. Following a mental health assessment, 45 mothers and their children (ages 12-42 months) participated in a behavioral protocol involving free-play and laboratory stressors such as mother-child separation. Maternal DNA was extracted from saliva. Interactive behavior was rated on the CARE-Index. During subsequent fMRI scanning, mothers were shown films of free-play and separation drawn from this protocol. Maternal PTSD severity and parenting stress were negatively correlated with the mean percentage of methylation of NR3C1. Maternal mPFC activity in response to video-stimuli of mother-child separation versus play correlated positively to NR3C1 methylation, and negatively to maternal IPV-PTSD and parenting stress. Among interactive behavior variables, child cooperativeness in play was positively correlated with NR3C1 methylation. Thus, the present study is the first published report to our knowledge, suggesting convergence of behavioral, epigenetic, and neuroimaging data that form a psychobiological signature of parenting-risk in the context of early life stress and PTSD.
The combination of congenital bilateral perisylvian syndrome (CBPS) with lower motor neuron dysfunction remains unusual and suggests a potential common genetic insult affecting basic ...neurodevelopmental processes. Here we identify a putatively pathogenic missense mutation in the MCF2 gene in a boy with CBPS. Using in utero electroporation to genetically manipulate cortical neurons during corticogenesis, we demonstrate that the mouse Mcf2 gene controls the embryonic migration of cortical projection neurons. Strikingly, we find that the CBPS‐associated MCF2 mutation impairs cortical laminar positioning, supporting the hypothesis that alterations in the process of embryonic neuronal migration can lead to rare cases of CBPS.
The initial formation and growth of dendrites is a critical step leading to the integration of newly generated neurons into postnatal functional networks. However, the cellular mechanisms and ...extracellular signals regulating this process remain mostly unknown. By directly observing newborn neurons derived from the subventricular zone in culture as well as in olfactory bulb slices, we show that ambient GABA acting through GABA(A) receptors is essential for the temporal stability of lamellipodial protrusions in dendritic growth cones but did not interfere with filopodia dynamics. Furthermore, we provide direct evidence that ambient GABA is required for the proper initiation and elongation of dendrites by promoting the rapid stabilization of new dendritic segments after their extension. The effects of GABA on the initial formation of dendrites depend on depolarization and Ca2+ influx and are associated with a higher stability of microtubules. Together, our results indicate that ambient GABA is a key regulator of dendritic initiation in postnatally generated olfactory interneurons and offer a mechanism by which this neurotransmitter drives early dendritic growth.
Neural progenitor cells (NPCs) overexpressing fibroblast growth factor 2 (FGF-2) have the distinct tendency to associate with the vasculature and establish multiple proliferative clusters in the ...perivascular environment after transplantation into the cerebral cortex. Strikingly, the vascular clusters of progenitor cells give rise to immature neurons after ischemic injury, raising prospects for the formation of ectopic neurogenic niches for repair. We investigated the spatial relationship of perivascular clusters with the host vascular structures. FGF-2-GFP-transduced NPCs were transplanted into the intact somatosensory rat cortex. Confocal microscopic analysis revealed that grafted cells preferentially contacted venules at sites with aquaporin-4-positive astrocytic endfeet and avoided contacts with desmin-positive pericytes. Electron microscopic analysis confirmed that grafted cells preferentially made contact with astroglial endfeet, and only a minority of them reached the endothelial basal lamina. These results provide new insights into the fine structural and anatomical relationship between grafted FGF-2-transduced NPCs and the host vasculature.
Gaze conveys emotional information, and humans present sensitivity to its direction from the earliest days of life. Bipolar disorder is a disease characterized by fluctuating states of emotional and ...cognitive dysregulation. To explore the role of attentional control on face processing in bipolar patients (BP) we used gaze direction as an emotion modulation parameter in a two-back Working Memory (WM) task while high-density EEG data were acquired. Since gaze direction influences emotional attributions to faces with neutral expressions as well, we presented neutral faces with direct and averted gaze. Nineteen euthymic BP and a sample of age- and gender-matched controls were examined. In BP we observed diminished P200 and augmented P300 evoked responses, differentially modulated by non-repeated or repeated faces, as well as by gaze direction. BP showed a reduced P200 amplitude, significantly stronger for faces with direct gaze than averted gaze. Source localization of P200 indicated decreased activity in sensory-motor regions and frontal areas suggestive of abnormal affective processing of neutral faces. The present study provides neurophysiological evidence for abnormal gaze processing in BP and suggests dysfunctional processing of direct eye contact as a prominent characteristic of bipolar disorder.
Childhood trauma and self-stigma in mood disorders Hofmann, Michel; Jermann, Françoise; Baggio, Stéphanie ...
Psychiatry Research Communications,
September 2023, 2023-09-00, 2023-09-01, Letnik:
3, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Childhood maltreatment and mood disorders are associated and linked to self-stigma. In this study, we assessed the relationship between childhood trauma and self-stigma in patients with mood ...disorders. Patients with bipolar disorder (n = 69) and unipolar disorder (n = 111) were recruited from the Mood Disorders Unit of the Geneva University Hospitals in Switzerland. All participants underwent a semi-structured interview to assess mood disorder and fulfilled the Internalized Stigma of Mental Illness (ISMI) scale and the Childhood Trauma Questionnaire (CTQ). The results showed that overall self-stigma was not significantly different between the groups. Linear regression modeling revealed that the ISMI total score was significantly associated with the CTQ total score (estimate = 0.01, p = 0.045). Our findings support the assumption that childhood trauma promotes the development of self-stigma in patients with mood disorders. Therefore, this study underscores the importance of assessing childhood trauma in the management of self-stigma in patients with unipolar and bipolar disorder.
•Both childhood trauma and self-stigmatization are frequent in mood disorders.•Childhood traumas foster the emergence of self-stigmatization in mood disorders.•This results is similar in both unipolar and bipolar disorders.•Managing self-stigmatization in mood disorders should address childhood trauma.
Introduction
Mood disorder patients have a tendency to be more internally oriented, with difficulties in switching attentional focus, which might result in the generation of negative thoughts, such ...as rumination. The present study explored self-referential neural activity correlating with rumination tendency and attentional switching capacity in bipolar disorder.
Methods
Twenty euthymic bipolar patients and twenty matched healthy controls underwent a novel introspection task of switching between internally and externally focused attention during a word processing task, while their brain activity was assessed using functional MRI.
Results
During internal focus, higher activity in self-related regions (mPFC, PCC) was found in euthymic bipolar patients as compared to controls, verifying the hypothesis of exaggerated recruitment of self-referential processes in bipolar subjects. Switching from internal to external focus revealed higher parahippocampal activity in patients as compared to controls, additionally more pronounced when switching away from negative as compared to positive self-referential information. Furthermore, rumination traits correlated with activity in PCC, subgenual and pregenual ACC, and bilateral anterior insula during repetition of internal focus, specifically when evaluating negative words. Finally, we used ACC subregions that correlated with tendency to ruminate as seeds for a whole brain connectivity analysis. Patients showed stronger connectivity between sgACC (seed), pgACC, dPFC, and anterior insula during internal focus, whereas pgACC (seed) was more strongly connected to parahippocampal gyrus when switching from internal to external focus.
Conclusions
These findings reveal an overactive rumination-related network whose activity is enhanced by negative information in euthymic bipolar patients, which could possibly contribute to impaired switching of thoughts away from internal attention.
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