Inflammation, anxiety, and stress in bipolar disorder and borderline personality disorder: A narrative review.

Bipolar disorder (BD) and borderline personality disorder (BPD) are serious and prevalent psychiatric diseases that share common phenomenological characteristics: symptoms (such as anxiety, affective lability or emotion dysregulation), neuroimaging features, risk factors and comorbidities. While several studies have focused on the link between stress and peripheral inflammation in other affective disorders such as anxiety or depression, fewer have explored this relationship in BD and BPD. This review reports on evidence showing an interplay between immune dysregulation, anxiety and stress, and how an altered acute neuroendocrine stress response may exist in these disorders. Moreover, we highlight limitations and confounding factors of these existing studies and discuss multidirectional hypotheses that either suggest inflammation or stress and anxiety as the primum movens in BD and BPD pathophysiology, or inflammation as a consequence of the pathophysiology of these diseases. Untangling these associations and implementing a transdiagnostic approach will have diagnostic, therapeutic and prognostic implications for BD and BPD patients

New GABAergic interneurons in the adult neocortex and striatum are generated from different precursors

Ongoing neurogenesis in the adult mammalian dentate gyrus and olfactory bulb is generally accepted, but its existence in other adult brain regions is highly controversial. We labeled newly born cells in adult rats with the S-phase marker bromodeoxyuridine (BrdU) and used neuronal markers to characterize new cells at different time points after cell division. In the neocortex and striatum, we found BrdU-labeled cells that expressed each of the eight neuronal markers. Their size as well as staining for γ-aminobutyric acid (GABA), glutamic acid decarboxylase 67, calretinin and/or calbindin, suggest that new neurons in both regions are GABAergic interneurons. BrdU and doublecortin-immunoreactive (BrdU+/DCX+) cells were seen within the striatum, suggesting migration of immature neurons from the subventricular zone. Surprisingly, no DCX+ cells were found within the neocortex. NG2 immunoreactivity in some new neocortical neurons suggested that they may instead be generated from the NG2+ precursors that reside within the cortex itself

Neural correlates of generation and inhibition of verbal association patterns in mood disorders

Objectives: Thought disorders such as rumination or flight of ideas are frequent in patients with mood disorders, and not systematically linked to mood state. These symptoms point to anomalies in cognitive processes mediating the generation and control of thoughts; for example, associative thinking and inhibition. However, their neural substrates are not known. Method: To obtain an ecological measure of neural processes underlying the generation and suppression of spontaneous thoughts, we designed a free word association task during fMRI allowing us to explore verbal associative patterns in patients with mood disorders and matched controls. Participants were presented with emotionally negative, positive or neutral words, and asked to produce two words either related or unrelated to these stimuli. Results: Relative to controls, patients produced a reverse pattern of answer typicality for the related vs unrelated conditions. Controls activated larger semantic and executive control networks, as well as basal ganglia, precuneus and middle frontal gyrus. Unlike controls, patients activated fusiform gyrus, parahippocampal gyrus and medial prefrontal cortex for emotional stimuli. Conclusions: Mood disorder patients are impaired in automated associative processes, but prone to produce more unique/personal associations through activation of memory and self-related area

CBT/DBT SKILLS TRAINING FOR ADULTS WITH ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)

Background: Attention deficit hyperactivity disorder (ADHD) is associated with marked impairments in familial, social, and professional functioning. Although stimulant treatments can be effective in adult ADHD, some patients will respond poorly or not at all to medication. Previous studies demonstrated that cognitive behavioural therapy- (CBT) and dialectical behavior therapy- (DBT) oriented interventions are effective in reducing the burden of the disease, which is mainly marked by depression, interpersonal difficulties, low self-esteem, and low quality of life. In order to determine the effectiveness of this intervention, we assessed the benefits of a CBT/DBT programme to reduce residual symptoms and help patients improve their quality of life. Subjects and methods: 49 ADHD-patients, poor responders to medication, were enrolled in a one-year programme where they received individual therapy, associated with weekly sessions of group therapy with different modules: Mindfulness, Emotion Regulation, Interpersonal Effectiveness and Distress Tolerance, Impulsivity/Hyperactivity and Attention. Each subject was assessed at baseline, at months 3 and 6, and at the end of the treatment for ADHD severity (ASRS v1.1), depression severity (BDI-II), hopelessness (BHS), mindfulness skills (KIMS), anger expression and control (STAXI), impulsivity (BIS-11), quality of life (WHOQOL-BREF), and social functioning (QFS). The 49 ADHD patients were compared with 13 ADHD subjects on a waiting list. Linear mixed models were used to measure response to treatment. Results: Overall, the psychotherapeutic treatment was associated with significant improvements in almost all dimensions. The most significant changes were observed for BDI-II (b=-0.30; p<0.0001), ASRS total score (b=-0.16; p<0.0001), and KIMS AwA (b=0.21; p<0.0001), with moderate to large effect sizes. Compared with the waiting list controls, ADHD patients showed a better, albeit non-significant, pattern of response. Conclusions: Individual and structured psycho-educational DBT/CBT groups support existing data suggesting that a structured psychotherapeutic approach is useful for patients who respond partially or not at all to drug therapy

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 corte

Anesthetics Rapidly Promote Synaptogenesis during a Critical Period of Brain Development

Experience-driven activity plays an essential role in the development of brain circuitry during critical periods of early postnatal life, a process that depends upon a dynamic balance between excitatory and inhibitory signals. Since general anesthetics are powerful pharmacological modulators of neuronal activity, an important question is whether and how these drugs can affect the development of synaptic networks. To address this issue, we examined here the impact of anesthetics on synapse growth and dynamics. We show that exposure of young rodents to anesthetics that either enhance GABAergic inhibition or block NMDA receptors rapidly induce a significant increase in dendritic spine density in the somatosensory cortex and hippocampus. This effect is developmentally regulated; it is transient but lasts for several days and is also reproduced by selective antagonists of excitatory receptors. Analyses of spine dynamics in hippocampal slice cultures reveals that this effect is mediated through an increased rate of protrusions formation, a better stabilization of newly formed spines, and leads to the formation of functional synapses. Altogether, these findings point to anesthesia as an important modulator of spine dynamics in the developing brain and suggest the existence of a homeostatic process regulating spine formation as a function of neural activity. Importantly, they also raise concern about the potential impact of these drugs on human practice, when applied during critical periods of development in infants

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 corte

Bimodal modulation of L1 interneuron activity in anterior cingulate cortex during fear conditioning

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

Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients

Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium's therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD