MCF2 is linked to a complex perisylvian syndrome and affects cortical lamination.

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.

Altered Electroencephalographic Resting-State Large-Scale Brain Network Dynamics in Euthymic Bipolar Disorder Patients.

Background: Neuroimaging studies provided evidence for disrupted resting-state functional brain network activity in bipolar disorder (BD). Electroencephalographic (EEG) studies found altered temporal characteristics of functional EEG microstates during depressive episode within different affective disorders. Here we investigated whether euthymic patients with BD show deviant resting-state large-scale brain network dynamics as reflected by altered temporal characteristics of EEG microstates. Methods: We used high-density EEG to explore between-group differences in duration, coverage, and occurrence of the resting-state functional EEG microstates in 17 euthymic adults with BD in on-medication state and 17 age- and gender-matched healthy controls. Two types of anxiety, state and trait, were assessed separately with scores ranging from 20 to 80. Results: Microstate analysis revealed five microstates (A-E) in global clustering across all subjects. In patients compared to controls, we found increased occurrence and coverage of microstate A that did not significantly correlate with anxiety scores. Conclusion: Our results provide neurophysiological evidence for altered large-scale brain network dynamics in BD patients and suggest the increased presence of A microstate to be an electrophysiological trait characteristic of BD.

Eye-gaze processing in the broader bipolar phenotype revealed by electrical neuroimaging.

Previous studies have documented atypical brain responses to faces in individuals with bipolar disorder (BD) and in their relatives. In view of previous findings of atypical face processing in youths at risk for BD, the aim of this study was to examine whether BD patients and offspring would show differential activation in networks of the social brain when processing eye-gaze. Data from 18 euthymic BD patients and 18 offspring, as well as 36 age-matched healthy controls, were collected using a delayed face-matching paradigm, event related potentials and electrical neuroimaging methods. The P200 component, which is implicated in facial cues decoding, differentiated the BD groups from their age-matched controls. P200 source reconstruction indicates impairments conveyed by eye-contact in a network involved in experiencing others' social intentions in BD patients (supplementary motor cortex, precentral gyrus, inferior parietal lobe), and the engagement of compensatory prefrontal mechanisms for modulating these functions in BD offspring. When viewing faces that had an averted gaze, BD patients and offspring showed a hypo-activation, compared to controls, particularly in regions involved in experiencing others' feelings (post-central gyrus in BD patients / ventral premotor cortex in offspring). Therefore, the neural mechanism for decoding shifts in eye-gaze may be a familial characteristic of BD.

Dysfunctional gaze processing in bipolar disorder.

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.

Maternal PTSD and corresponding neural activity mediate effects of child exposure to violence on child PTSD symptoms.

The aim of this study was to examine the relationship of maternal interpersonal violence-related posttraumatic stress disorder (IPV-PTSD), associated neural activity in response to mother-child relational stimuli, and child psychopathology indicators at child ages 12-42 months and one year later. The study tested the hypothesis that decreased maternal neural activity in regions that subserve emotion regulation would be associated with child symptoms associated with emotional dysregulation at both time points. Functional magnetic resonance imaging of 42 mothers with or without violence-exposure and associated IPV-PTSD were assessed. Their child's life-events and symptoms/behaviors indicative of high-risk subsequent PTSD diagnosis on a maternal-report questionnaire were measured one year later. Maternal IPV-PTSD severity was significantly associated with decreased ventromedial prefrontal cortex (vmPFC) activation in response to mother-child relational stimuli. Maternal IPV-PTSD severity and decreased vmPFC activation were then significantly associated with a child attachment disturbance at 12-42 months and symptoms/behaviors one year later, that were correlated with emotional dysregulation and risk for child PTSD. Maternal IPV-PTSD and child exposure to IPV were both predictive of child PTSD symptoms with maternal IPV-PTSD likely mediating the effects of child IPV exposure on child PTSD symptoms. These findings suggest that maternal IPV-PTSD severity and associated decreased vmPFC activity in response to mother-child relational stimuli are predictors of child psychopathology by age 12-42 months and one-year later. Significant findings in this paper may well be useful in understanding how maternal top-down cortico-limbic dysregulation promotes intergenerational transmission of IPV and related psychopathology and, thus should be targeted in treatment.

EMMPRIN overexpression in SVZ neural progenitor cells increases their migration towards ischemic cortex.

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.

Effects of interpersonal violence-related post-traumatic stress disorder (PTSD) on mother and child diurnal cortisol rhythm and cortisol reactivity to a laboratory stressor involving separation.

Women who have experienced interpersonal violence (IPV) are at a higher risk to develop posttraumatic stress disorder (PTSD), with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and impaired social behavior. Previously, we had reported impaired maternal sensitivity and increased difficulty in identifying emotions (i.e. alexithymia) among IPV-PTSD mothers. One of the aims of the present study was to examine maternal IPV-PTSD salivary cortisol levels diurnally and reactive to their child's distress in relation to maternal alexithymia. Given that mother-child interaction during infancy and early childhood has important long-term consequences on the stress response system, toddlers' cortisol levels were assessed during the day and in response to a laboratory stressor. Mothers collected their own and their 12-48month-old toddlers' salivary samples at home three times: 30min after waking up, between 2-3pm and at bedtime. Moreover, mother-child dyads participated in a 120-min laboratory session, consisting of 3 phases: baseline, stress situation (involving mother-child separation and exposure to novelty) and a 60-min regulation phase. Compared to non-PTSD controls, IPV-PTSD mothers - but not their toddlers, had lower morning cortisol and higher bedtime cortisol levels. As expected, IPV-PTSD mothers and their children showed blunted cortisol reactivity to the laboratory stressor. Maternal cortisol levels were negatively correlated to difficulty in identifying emotions. Our data highlights PTSD-IPV-related alterations in the HPA system and its relevance to maternal behavior. Toddlers of IPV-PTSD mothers also showed an altered pattern of cortisol reactivity to stress that potentially may predispose them to later psychological disorders.

The association of serotonin receptor 3A methylation with maternal violence exposure, neural activity, and child aggression.

BACKGROUND: Methylation of the serotonin 3A receptor gene (HTR3A) has been linked to child maltreatment and adult psychopathology. The present study examined whether HTR3A methylation might be associated with mothers' lifetime exposure to interpersonal violence (IPV), IPV-related psychopathology, child disturbance of attachment, and maternal neural activity. METHODS: Number of maternal lifetime IPV exposures and measures of maternal psychopathology including posttraumatic stress disorder (PTSD), major depression and aggressive behavior (AgB), and a measure of child attachment disturbance known as "secure base distortion" (SBD) were assessed in a sample of 35 mothers and children aged 12-42 months. Brain fMRI activation was assessed in mothers using 30-s silent film excerpts depicting menacing adult male-female interactions versus prosocial and neutral interactions. Group and continuous analyses were performed to test for associations between clinical and fMRI variables with DNA methylation. RESULTS: Maternal IPV exposure-frequency was associated with maternal PTSD; and maternal IPV-PTSD was in turn associated with child SBD. Methylation status of several CpG sites in the HTR3A gene was associated with maternal IPV and IPV-PTSD severity, AgB and child SBD, in particular, self-endangering behavior. Methylation status at a specific CpG site (CpG2_III) was associated with decreased medial prefrontal cortical (mPFC) activity in response to film-stimuli of adult male-female interactions evocative of violence as compared to prosocial and neutral interactions. CONCLUSIONS: Methylation status of the HTR3A gene in mothers is linked to maternal IPV-related psychopathology, trauma-induced brain activation patterns, and child attachment disturbance in the form of SBD during a sensitive period in the development of self-regulation.

Early averted gaze processing in the right Fusiform Gyrus: An EEG source imaging study.

Humans are able to categorize face properties with impressively short latencies. Nevertheless, the latency at which gaze recognition occurs is still a matter of debate. Through spatio-temporal analysis of high-density event-related potentials (ERP), we investigated the brain activity underlying the ability to spontaneously and quickly process gaze. We presented neutral faces with direct and averted gaze in a matching picture paradigm, where subjects had to detect repetition of identical faces and gaze was implicitly manipulated. The results indicate that faces with averted gaze were better discriminated than faces with direct gaze, and evoked stronger P100 amplitudes localized to the right fusiform gyrus. In contrast, direct gaze induced stronger activation in the orbital frontal gyrus at this latency. Later in time, at the beginning of the N170 component, direct gaze induced changes in scalp topography with a stronger activation in the right medial temporal gyrus. The location of these differential activations of direct vs. averted gaze further support the view that faces with averted gaze are perceived as less rewarding than faces with direct gaze. We additionally found differential ERP responses between repeated and novel faces as early as 50ms, thereby replicating earlier studies of very fast detection of mnestic aspects of stimuli. Together, these results suggest an early dissociation between implicit gaze detection and explicit identity processing.

Relationship of Grafted FGF-2-Overexpressing Neural Stem/Progenitor Cells With the Vasculature in the Cerebral Cortex.

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.

BDNF Methylation and Maternal Brain Activity in a Violence-Related Sample.

It is known that increased circulating glucocorticoids in the wake of excessive, chronic, repetitive stress increases anxiety and impairs Brain-Derived Neurotrophic Factor (BDNF) signaling. Recent studies of BDNF gene methylation in relation to maternal care have linked high BDNF methylation levels in the blood of adults to lower quality of received maternal care measured via self-report. Yet the specific mechanisms by which these phenomena occur remain to be established. The present study examines the link between methylation of the BDNF gene promoter region and patterns of neural activity that are associated with maternal response to stressful versus non-stressful child stimuli within a sample that includes mothers with interpersonal violence-related PTSD (IPV-PTSD). 46 mothers underwent fMRI. The contrast of neural activity when watching children-including their own-was then correlated to BDNF methylation. Consistent with the existing literature, the present study found that maternal BDNF methylation was associated with higher levels of maternal anxiety and greater childhood exposure to domestic violence. fMRI results showed a positive correlation of BDNF methylation with maternal brain activity in the anterior cingulate (ACC), and ventromedial prefrontal cortex (vmPFC), regions generally credited with a regulatory function toward brain areas that are generating emotions. Furthermore we found a negative correlation of BDNF methylation with the activity of the right hippocampus. Since our stimuli focus on stressful parenting conditions, these data suggest that the correlation between vmPFC/ACC activity and BDNF methylation may be linked to mothers who are at a disadvantage with respect to emotion regulation when facing stressful parenting situations. Overall, this study provides evidence that epigenetic signatures of stress-related genes can be linked to functional brain regions regulating parenting stress, thus advancing our understanding of mothers at risk for stress-related psychopathology.

Methylation of NR3C1 is related to maternal PTSD, parenting stress and maternal medial prefrontal cortical activity in response to child separation among mothers with histories of violence exposure.

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.

5-HT6 Receptor: A New Player Controlling the Development of Neural Circuits.

5-HT6 receptor (5-HT6R) is a G protein-coupled receptor that has recently emerged as a new regulator of neural development. In addition to the canonical Gs adenylyl cyclase pathway, recent proteomics approaches reveal that 5-HT6R is able to engage key developmental signaling pathways controlling neuronal circuit formation, neuronal connectivity, and psychiatric-relevant behaviors. For example, at early stages of neuronal development, expression of 5-HT6R constitutively regulates the activity of the cyclin-dependent kinase (Cdk)5 and, through this mechanism, controls cellular processes involved in circuit formation, including neuronal migration and neurite outgrowth. In addition to the Cdk5 pathway, 5-HT6R modulates a variety of key developmental targets such as Fyn, Jab1, and mammalian target of rapamycin (mTOR). Engagement of developmental pathways through 5-HT6R pharmacological manipulation has led to interesting new therapeutic perspectives in the field of psychiatric-related disorders. Indeed, 5-HT6R blockade can rescue a pathological overactivation of the mTOR pathway induced by early life insults in rodents and normalizes the associated social and episodic memory deficits. Here, we review recent evidence supporting the notion that 5-HT6R is at the interface of key developmental signaling pathways and a novel actor in the orchestration of neural circuit formation.

Serotonin homeostasis and serotonin receptors as actors of cortical construction: special attention to the 5-HT3A and 5-HT6 receptor subtypes.

Cortical circuits control higher-order cognitive processes and their function is highly dependent on their structure that emerges during development. The construction of cortical circuits involves the coordinated interplay between different types of cellular processes such as proliferation, migration, and differentiation of neural and glial cell subtypes. Among the multiple factors that regulate the assembly of cortical circuits, 5-HT is an important developmental signal that impacts on a broad diversity of cellular processes. 5-HT is detected at the onset of embryonic telencephalic formation and a variety of serotonergic receptors are dynamically expressed in the embryonic developing cortex in a region and cell-type specific manner. Among these receptors, the ionotropic 5-HT3A receptor and the metabotropic 5-HT6 receptor have recently been identified as novel serotonergic targets regulating different aspects of cortical construction including neuronal migration and dendritic differentiation. In this review, we focus on the developmental impact of serotonergic systems on the construction of cortical circuits and discuss their potential role in programming risk for human psychiatric disorders.

A three-dimensional model of thoughts: insight into depression.

Thought processing and mood regulation are closely linked, but existing classifications of mood disorders fail to recognize the complex interplay between these two clinical dimensions. Furthermore, existing classifications fail to account for the possibility that depression might be associated with an increased frequency of self-referential thoughts that could in some circumstances be related to creativity processes. Based on recent evidence from clinical phenomenology, experimental psychology and affective neuroscience, we propose a novel comprehensive theoretical framework that incorporates thought processing and emotional valence. This new taxonomy provides insights into the clinical understanding of the spectrum of mood disorders and accounts for the possibility of increased creativity in altered mood states.

Early postnatal migration and development of layer II pyramidal neurons in the rodent cingulate/retrosplenial cortex.

The cingulate and retrosplenial regions are major components of the dorsomedial (dm) limbic cortex and have been implicated in a range of cognitive functions such as emotion, attention, and spatial memory. While the structure and connectivity of these cortices are well characterized, little is known about their development. Notably, the timing and mode of migration that govern the appropriate positioning of late-born neurons remain unknown. Here, we analyzed migratory events during the early postnatal period from ventricular/subventricular zone (VZ/SVZ) to the cerebral cortex by transducing neuronal precursors in the VZ/SVZ of newborn rats/mice with Tomato/green fluorescent protein-encoding lentivectors. We have identified a pool of postmitotic pyramidal precursors in the dm part of the neonatal VZ/SVZ that migrate into the medial limbic cortex during the first postnatal week. Time-lapse imaging demonstrates that these cells migrate on radial glial fibers by locomotion and display morphological and behavioral changes as they travel through the white matter and enter into the cortical gray matter. In the granular retrosplenial cortex, these cells give rise to a Satb2+ pyramidal subtype and develop dendritic bundles in layer I. Our observations provide the first insight into the patterns and dynamics of cell migration into the medial limbic cortex.

Fibroblast growth factor-2 overexpression in transplanted neural progenitors promotes perivascular cluster formation with a neurogenic potential.

Stem/progenitor cell-based therapies hold promises for repairing the damaged nervous system. However, the efficiency of these approaches for neuronal replacement remains very limited. A major challenge is to develop pretransplant cell manipulations that may promote the survival, engraftment, and differentiation of transplanted cells. Here, we investigated whether overexpression of fibroblast growth factor-2 (FGF-2) in grafted neural progenitors could improve their integration in the host tissue. We show that FGF-2-transduced progenitors grafted in the early postnatal rat cortex have the distinct tendency to associate with the vasculature and establish multiple proliferative clusters in the perivascular environment. The contact with vessels appears to be critical for maintaining progenitor cells in an undifferentiated and proliferative phenotype in the intact cortex. Strikingly, perivascular clusters of FGF-2 expressing cells seem to supply immature neurons in an ischemic environment. Our data provide evidence that engineering neural progenitors to overexpress FGF-2 may be a suitable strategy to improve the integration of grafted neural progenitor cells with the host vasculature thereby generating neurovascular clusters with a neurogenic potential for brain repair.

Adverse effects of methylene blue on the central nervous system.

BACKGROUND: An increasing number of clinical observations suggest adverse neurologic outcome after methylene blue (MB) infusion in the setting of parathyroid surgery. Hence, the aim of the current study was to investigate the potentially neurotoxic effects of MB using a combination of in vivo and in vitro experimental approaches. METHODS: Isoflurane-anesthetized adult rats were used to evaluate the impact of a single bolus intravascular administration of MB on systemic hemodynamic responses and on the minimum alveolar concentration (MAC) of isoflurane using the tail clamp test. In vivo, MB-induced cell death was evaluated 24 h after MB administration using Fluoro-Jade B staining and activated caspase-3 immunohistochemistry. In vitro, neurotoxic effects of MB were examined in hippocampal slice cultures by measuring excitatory field potentials as well as propidium iodide incorporation after MB exposure. The impact of MB on dendritic arbor was evaluated in differentiated single cell neuronal cultures. RESULTS: Bolus injections of MB significantly reduced isoflurane MAC and initiated widespread neuronal apoptosis. Electrophysiologic recordings in hippocampal slices revealed a rapid suppression of evoked excitatory field potentials by MB, and this was associated with a dose-dependent effect of this drug on cell death. Dose-response experiments in single cell neuronal cultures revealed that a 2-h-long exposure to MB at non-cell-death-inducing concentrations could still induce significant retraction of dendritic arbor. CONCLUSIONS: These results suggest that MB exerts neurotoxic effects on the central nervous system and raise questions regarding the safety of using this drug at high doses during parathyroid gland surgery.

New interneurons in the adult neocortex: small, sparse, but significant?

During the last decade, the intense study of adult hippocampal neurogenesis has led to several new lines of inquiry in the field of psychiatry. Although it is generally believed that adult mammalian neurogenesis is restricted to the hippocampus and olfactory bulb, a growing number of studies have described new neurons in the adult neocortex in both rodents and nonhuman primates. Interestingly, all of the new neurons observed in these studies have features of interneurons rather than pyramidal cells, the largest neuronal population of the neocortex. In this review, we discuss features of these interneurons that may explain why cortical neurogenesis has been so difficult to detect. In addition, these features suggest ways that production of even a small numbers of new neurons in the adult cortex could make a significant impact on neocortical function.

Expression of FGF-2 in neural progenitor cells enhances their potential for cellular brain repair in the rodent cortex.

Strategies to enhance the capacity of grafted stem/progenitors cells to generate multipotential, proliferative and migrating pools of cells in the postnatal brain could be crucial for structural repair after brain damage. We investigated whether the over-expression of basic fibroblast growth factor 2 (FGF-2) in neural progenitor cells (NPCs) could provide a robust source of migrating NPCs for tissue repair in the rat cerebral cortex. Using live imaging we provide direct evidence that FGF-2 over-expression significantly enhances the migratory capacity of grafted NPCs in complex 3D structures, such as cortical slices. Furthermore, we show that the migratory as well as proliferative properties of FGF-2 over-expressing NPCs are maintained after in vivo transplantation. Importantly, after transplantation into a neonatal ischaemic cortex, FGF-2 over-expressing NPCs efficiently invade the injured cortex and generate an increased pool of immature neurons available for brain repair. Differentiation of progenitor cells into immature neurons was correlated with a gradual down-regulation of the FGF-2 transgene. These results reveal an important role for FGF-2 in regulating NPCs functions when interacting with the host tissue and offer a potential strategy to generate a robust source of migrating and immature progenitors for repairing a neonatal ischaemic cortex.