Pathology Of Bipolar Disorder Research Articles

Deficits in prefrontal metabotropic glutamate receptor 5 are associated with functional alterations during emotional processing in bipolar disorder

BackgroundElucidating biological mechanisms contributing to bipolar disorder (BD) is key to improved diagnosis and treatment development. With converging evidence implicating the metabotropic glutamate receptor 5 (mGlu5) in the pathology of BD, here, we therefore test the hypothesis that recently identified deficits in mGlu5 are associated with functional brain differences during emotion processing in BD. MethodsPositron emission tomography (PET) with [18F]FPEB was used to measure mGlu5 receptor availability and functional imaging (fMRI) was performed while participants completed an emotion processing task. Data were analyzed from 62 individuals (33 ± 12 years, 45 % female) who completed both PET and fMRI, including individuals with BD (n = 18), major depressive disorder (MDD: n = 20), and psychiatrically healthy comparisons (HC: n = 25). ResultsConsistent with some prior reports, the BD group displayed greater activation during fear processing relative to MDD and HC, notably in right lateralized frontal and parietal brain regions. In BD, (but not MDD or HC) lower prefrontal mGlu5 availability was associated with greater activation in bilateral pre/postcentral gyri and cuneus during fear processing. Furthermore, greater prefrontal mGlu5-related brain activity in BD was associated with difficulties in psychomotor function (r≥0.904, p≤0.005) and attention (r≥0.809, p≤0.028). LimitationsThe modest sample size is the primary limitation. ConclusionsDeficits in prefrontal mGlu5 in BD were linked to increased cortical activation during fear processing, which in turn was associated with impulsivity and attentional difficulties. These data further implicate an mGlu5-related mechanism unique to BD. More generally these data suggest integrating PET and fMRI can provide novel mechanistic insights.

Inflammation Markers in Patients with Bipolar Disorder Who Have Committed Offenses and Their Relationship with Criminal Behavior.

Background and Objectives: This study aimed to examine the function of various inflammation parameters and their interactions in the pathology of Bipolar disorder (BD) and to assess whether they could be biomarkers in the relationship between criminal behavior and BD. Materials and Methods: Overall, 1029 participants, including 343 patients with BD who have committed offenses, 343 nonoffending patients with BD, and 343 healthy controls, were included in this retrospective study. Neutrophil, lymphocyte, monocyte, and platelet counts; high-density lipoprotein (HDL-c) levels; systemic immune-inflammatory index (SII), systemic inflammatory response index (SIRI), neutrophil to high-density lipoprotein ratio (NHR), lymphocyte to high-density lipoprotein ratio (LHR), monocyte to high-density lipoprotein ratio (MHR), platelet to high-density lipoprotein ratio (PHR) were measured. Results: Significant differences were observed between the groups in terms of SII, SIRI, NHR, LHR, MHR, PHR, neutrophil, and monocyte values (p < 0.001). The lymphocyte counts were significantly higher in the patients with BD who committed offenses (p = 0.04). The platelet counts were significantly lower in the patients with BD who committed offenses compared to nonoffending patients with BD (p = 0.015). The HDL-c levels were significantly lower in the patients with BD who have committed offenses than those of nonoffending patients with BD (p < 0.001). Bipolar disorder, not receiving active psychiatric treatment, having a diagnosis of bipolar manic episodes, and having low platelet and HDL values constitute a risk of involvement in crime. Conclusions: The present study emphasizes the role of systemic inflammation in the pathophysiology of patients with BD with and without criminal offenses and the relationship between inflammation and criminal behavior.

Circadian variability of objective sleep measures predicts the relapse of a mood episode in bipolar disorder: findings from the APPLE cohort.

Sleep disturbance, a core feature of bipolar disorder, is closely associated with mood symptoms. We examined the association between actigraphy sleep parameters and mood episode relapses in patients with bipolar disorder. This prospective cohort study analyzed 193 outpatients with bipolar disorder who participated in the Association between the Pathology of Bipolar Disorder and Light Exposure in Daily Life (APPLE) cohort study. The participants' sleep was objectively evaluated via actigraphy over seven consecutive days for the baseline assessment and then at the 2-year follow-up appointment for mood episode relapses. The actigraphy sleep parameters were presented using the mean and variability (standard deviation) of each sleep parameter for 7 days. Of the 193 participants, 110 (57%) experienced mood episodes during follow-up. The participants with higher variability in total sleep time had a significantly shorter mean estimated time to mood episode relapses than those with lower variability (12.5 vs. 16.8 months; P < 0.001). The Cox proportional hazards model, when adjusted for potential confounders, demonstrated that variability in total sleep time was significantly associated with an increase in the mood episode relapses (per hour; hazard ratio [HR], 1.407; 95% confidence interval (CI), 1.057-1.873), mainly in the depressive episodes (per hour; HR, 1.477; 95% CI, 1.088-2.006). Our findings suggest that consistency in sleep time might be useful, as an adjunct therapy, in preventing the recurrence or relapse of mood episodes in bipolar disorder.

Abnormal features of human self-domestication in bipolar disorder.

Bipolar disorder (BD) is a severe mental condition characterized by episodes of elevated mood and depression. Being a heritable condition, it features a complex genetic architecture, although it is not still clear how genes contribute to the onset and course of the disease. In this paper, we adopted an evolutionary-genomic approach to this condition, focusing on changes occurred during human evolution as a source of our distinctive cognitive and behavioural phenotype. We show clinical evidence that the BD phenotype can be construed as an abnormal presentation of the human self-domestication phenotype. We further demonstrate that candidate genes for BD significantly overlap with candidates for mammal domestication and that this common set of genes is enriched in functions that are important for the BD phenotype, especially neurotransmitter homeostasis. Finally, we show that candidates for domestication are differentially expressed in brain regions involved in BD pathology, particularly, the hippocampus and the prefrontal cortex, which have been subject to recent changes in our species. Overall, this link between human self-domestication and BD should facilitate a better understanding of the BD etiopathology.

Habitual light exposure and circadian activity rhythms in bipolar disorder: A cross-sectional analysis of the APPLE cohort

BackgroundCircadian activity rhythm disruption is a core feature in bipolar disorder. We investigated whether light exposure in daily life is associated with circadian activity rhythms in patients with bipolar disorder. MethodsIn a cross-sectional study, we enrolled 194 outpatients with bipolar disorder who were participants of the Association between Pathology of Bipolar Disorder and Light Exposure in Daily Life (APPLE) cohort study. The participants' physical activity and daytime illuminance were measured using an actigraph over 7 consecutive days. Nighttime illuminance in the bedroom was measured using a portable photometer. Circadian activity rhythm parameters were calculated using cosinor analysis and a nonparametric circadian rhythm analysis. ResultsThe median daytime illuminance and nighttime illuminance were 224.5 lx (interquartile range, 154.5–307.5 lx) and 2.3 lx (0.3–9.4 lx), respectively. Multivariable linear regression analysis, adjusted for potential confounding factors, showed that higher daytime illuminance was significantly associated with higher amplitude and most active continuous 10-hour period, advanced acrophase, higher interdaily stability, and lower intradaily variability. Higher nighttime illuminance was significantly associated with lower relative amplitude, delayed onset of the least active continuous 5-hour period, and higher intradaily variability. LimitationsAs this was a cross-sectional study, the results do not necessarily imply that light exposure alters circadian activity rhythms. ConclusionsDaytime light exposure was associated with a positive effect and nighttime light exposure with a negative effect on circadian activity rhythms in bipolar disorder.

Astrocytes in the Neuropathology of Bipolar Disorder: Review of Current Evidence.

(1) Background: Approximately one-third of patients with bipolar disorder (BD) do not experience sustained remission with current treatments. Presently, astrocytes, i.e., glial cells that act as key regulators of neuroinflammation, have been a target for therapeutic development. Research regarding their role in the neuropathology of BD is limited. We conducted a scoping review on evidence linking astrocytes to the pathology of BD. (2) Methods: The search was conducted in MEDLINE for studies published from inception to August 2022. Studies of interest were data-extracted and reported based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocols. (3) Results: Overall, 650 publications were identified, of which 122 full texts were evaluated and 12 included. Four were in vitro, seven were ex vivo, and one study was both in vitro and in vivo. In vitro investigations focused on plasma levels of neuroinflammatory biomarkers S100B and glial fibrillary acidic protein (GFAP). Ex vivo investigations were post-mortem brain studies assessing astrocytes in regions of interest (i.e., anterior cingulate cortex, dorsolateral prefrontal cortex) using phosphorylated GFAP and ASCT-1. The in vivo and in vitro study evaluated morphological and chemical variations of YKL-40 between cohorts. (4) Conclusions: Reports indicate an association between astrocyte dysfunction and BD although larger studies are required to validate this association.

Differential Relationships Among C-Reactive Protein, Attention Functioning, and Brain Structure in Bipolar Offspring With and Without Subthreshold Mood Symptoms.

Background: Bipolar disorder (BD) is a highly heritable mood disorder. Activated low-grade inflammation may not only play an adverse role in the pathophysiology of BD, but also contribute to a resilience process. The neuroinflammatory processes may underlie the attention deficit and alteration of gray matter volume (GMV) in the early stage and premorbid period of BD. Also, the differential inflammation-brain relationship may be identified as biological markers for BD pathology or resilience.Methods: The present data were collected between March 2013 and June 2016. Sixty-four offspring of BD patients were recruited and subdivided into asymptomatic (n = 33, mean age = 17.8 years) and symptomatic (n = 31, mean age = 16.2 years) groups according to whether they manifested subthreshold mood symptoms. The diagnosis of BD was confirmed according to DSM-IV criteria. C-reactive protein (CRP) level, attention functioning, and GMV data were measured by ELISA, the Continuous Performance Test-Identical Pair test (CPT-IP), and 3.0 T magnetic resonance imaging, respectively. Their relationships were examined with mediation and moderation analyses.Results: We observed a higher level of CRP and poorer attention in the symptomatic group than the asymptomatic group and found a significant group × CRP interactive effect on GMV in regions spanning right precentral and postcentral gyri (P = .043). CRP levels negatively mediated the relationship between the group and CPT-IP scores, and the group marginally moderated the relationship between pre/postcentral gyri volumes and CPT-IP scores (P = .05).Conclusions: Symptomatic and asymptomatic bipolar offspring manifested differential inflammation-GMV-attention relationships, which may represent, respectively, an endophenotype or a resilience process for BD.

Effect of nighttime bedroom light exposure on mood episode relapses in bipolar disorder.

A previous cross-sectional study reported that nighttime light is associated with increased occurrence of manic symptoms in bipolar disorder; however, the longitudinal association between nighttime light and subsequent mood episode relapses remains unclear. We determined whether bedroom nighttime light was associated with mood episode relapses in patients with bipolar disorder. This prospective cohort study included 172 outpatients with bipolar disorder who participated in an Association between the Pathology of Bipolar Disorder and Light Exposure in Daily Life (APPLE) cohort study. A portable photometer was used to measure illuminance in the bedroom from bedtime to rising time during 7 consecutive nights for baseline assessment. Then, the participants were assessed at a 2-year follow-up for mood episode relapses. Of the 172 participants, 157 (91%) completed the 2-year follow-up, and 39 (22%) experienced manic or hypomanic episodes (with or without mixed features), during that time. In the Cox proportional-hazards model, the hazard ratio (HR) for manic/hypomanic episode relapses was significantly higher when the average nighttime illuminance was ≥3lux (n=71) than when it was <3lux (n=101; HR, 2.54; 95% confidence interval (CI), 1.33-4.84). In the multivariable model adjusted for a propensity score in relation to nighttime light, the relationship remained significant (HR, 2.17; 95% CI, 1.04-4.52). The association between nighttime light and depressive episode relapses was not significantly different. Keeping the bedroom dark at night may prevent hypomanic and manic episodes.

Amygdala and anterior cingulate transcriptomes from individuals with bipolar disorder reveal downregulated neuroimmune and synaptic pathways.

Recent genetic studies have identified variants associated with bipolar disorder (BD), but it remains unclear how brain gene expression is altered in BD, and how genetic risk for BD may contribute to these alterations. Here, we obtained transcriptomes from subgenual anterior cingulate cortex and amygdala samples from post-mortem brains of individuals with BD and neurotypical controls, including 511 total samples from 295 unique donors. We examined differential gene expression between cases and controls, and the transcriptional effects of BD-associated genetic variants. We found two co-expressed modules that were associated with transcriptional changes in BD: one enriched for immune and inflammatory genes and the other with genes related to the post-synaptic membrane. Over 50% of BD genome-wide significant loci contained significant expression quantitative trait loci (eQTLs), and these data converged on several individual genes, including SCN2A and GRIN2A. Thus, these data implicate specific genes and pathways that may contribute to the pathology of bipolar disorder.

Association between circadian activity rhythms and mood episode relapse in bipolar disorder: a 12-month prospective cohort study

A significant proportion of patients with bipolar disorder experience mood episode relapses. We examined whether circadian activity rhythms were associated with mood episode relapses in patients with bipolar disorder. This prospective cohort study included outpatients with bipolar disorder who participated in a study titled “Association between the Pathology of Bipolar Disorder and Light Exposure in Daily Life (APPLE) cohort study.” The participants’ physical activity was objectively assessed using a wrist-worn accelerometer over 7 consecutive days for the baseline assessment and then at the 12-month follow-up for mood episode relapses. The levels and timing of the circadian activity rhythms were estimated using a cosinor analysis and a nonparametric circadian rhythm analysis. Of the 189 participants, 88 (46%) experienced mood episodes during follow-up. The Cox proportional hazards model adjusting for potential confounders showed that a robust circadian activity rhythm, including midline-estimating statistic of rhythm (MESOR) and amplitude by cosinor analysis and 10 consecutive hours with the highest amplitude values (M10) by the nonparametric circadian rhythm analysis, was significantly associated with a decrease in mood episode relapses (per counts/min, hazard ratio [95% confidence interval]: MESOR, 0.993 [0.988–0.997]; amplitude, 0.994 [0.988–0.999]; and M10, 0.996 [0.993–0.999]). A later timing of the circadian activity rhythm (M10 onset time) was significantly associated with an increase in the depressive episode relapses (per hour; 1.109 [1.001–1.215]). We observed significant associations between circadian activity rhythms and mood episode relapses in bipolar disorder.

The Role of the UPR Pathway in the Pathophysiology and Treatment of Bipolar Disorder.

Bipolar disorder (BD) is a mood disorder that affects millions worldwide and is associated with severe mood swings between mania and depression. The mood stabilizers valproate (VPA) and lithium (Li) are among the main drugs that are used to treat BD patients. However, these drugs are not effective for all patients and cause serious side effects. Therefore, better drugs are needed to treat BD patients. The main barrier to developing new drugs is the lack of knowledge about the therapeutic mechanism of currently available drugs. Several hypotheses have been proposed for the mechanism of action of mood stabilizers. However, it is still not known how they act to alleviate both mania and depression. The pathology of BD is characterized by mitochondrial dysfunction, oxidative stress, and abnormalities in calcium signaling. A deficiency in the unfolded protein response (UPR) pathway may be a shared mechanism that leads to these cellular dysfunctions. This is supported by reported abnormalities in the UPR pathway in lymphoblasts from BD patients. Additionally, studies have demonstrated that mood stabilizers alter the expression of several UPR target genes in mouse and human neuronal cells. In this review, we outline a new perspective wherein mood stabilizers exert their therapeutic mechanism by activating the UPR. Furthermore, we discuss UPR abnormalities in BD patients and suggest future research directions to resolve discrepancies in the literature.

Evaluation of postmortem microarray data in bipolar disorder using traditional data comparison and artificial intelligence reveals novel gene targets

Large-scale microarray studies on post-mortem brain tissues have been utilized to investigate the complex molecular pathology of bipolar disorder. However, a major challenge in characterizing the dysregulation of gene expression in patients with bipolar disorder includes the lack of convergence between different studies, limiting comprehensive understanding from individual results. In this study, we aimed to identify genes that are both validated in published literature and are important classification features of unsupervised machine learning analysis of Stanley Brain Bank microarray database, followed by augmented intelligence method to identify distinct patient molecular subgroups. Through combining traditional literature approaches and machine learning, we identified TBL1XR1, SMARCA2, and CHMP5 to be replicated in 3 of the 4 studies included our analysis. The expression of these genes segregated unique subgroups of patients with bipolar disorder. Our study suggests the involvement of PPARγ pathway regulation in patients with bipolar disorder.

Dysregulation of Myt1 expression acts as a potential peripheral biomarker for major depressive disorder and bipolar disorder

Major depressive disorder (MDD) and bipolar disorder (BPD) are among the most debilitating mental conditions. Diagnostic criteria for MDD include psychological and physical symptoms, such as low mood and changes in appetite or sleep, respectively. BPD in addition to periods of depression represents episodes of mania or hypomania, and elevation in mood and energy levels are associated with this condition. Dysregulation in adult neurogenesis and myelination have been reported in psychiatric disorders. As a key factor in neurogenesis, it was hypothesized that Myt1 gene expression may be altered in these conditions. Using Real-time PCR, Myt1 expression level in 100 MDD patients and 100 BPD patients, compared with healthy control (HC) individuals was evaluated. Results demonstrate significant downregulation of Myt1 in MDD and BPD. Logistic regression analysis and binary classification evaluation reveal potential risk factor and biomarker characteristics of Myt1, respectively. Moreover, forward and backward digit span results denote a significant reduction in the function of working memory (WM) of MDD and BPD subjects. Correlation analysis revealed a significant association between Myt1 downregulation and WM disruption in the affected individuals. In conclusion, due to its altered role in neurogenesis, downregulation of Myt1 can be associated with the pathology of MDD and BPD.

Fractional amplitude of low-frequency fluctuations and gray matter volume alterations in patients with bipolar depression

PurposeWe used fractional amplitude of low-frequency fluctuations (fALFF) and gray matter volume (GMV) jointly to explore the mechanism of brain function and structure in unmedicated patients with bipolar disorder (BD). MethodsThirty first episode drug-naive patients with and thirty healthy controls (HCs) were recruited in this study; All the subjects underwent Magnetic Resonance Imaging (MRI) scanning and performed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), all the patients with MDD finished the 17-item Hamilton Depression Rating Scale (HAMD17). Data Processing and Analysis for Brain Imaging (DPABI) and SPM8 were used to find potential differences in fALFF and GMV between the two groups. A Pearson correlation model was used to analyze associations of functional and morphometric changes with clinical symptoms and cognitive tests. ResultsCompared to healthy controls, the BD group had significantly reduced fALFF values in the lingual gyrus and increased fALFF values in the bilateral superior frontal gyrus and superior frontal gyrus. With regards to VBM, patients with BD showed significant GMV decreases in the bilateral superior temporal gyrus, bilateral superior frontal gyrus, right superior frontal gyrus, right parahippocampal gyrus and precuneus. Additionally, we found an overlap of brain regions focused on the left SFG. Significant negative correlations were observed between abnormal GMV values in the left SFG and vocabulary memory. ConclusionThe superior frontal gyrus was the site of the most robust and reliable abnormality, with an overlap of abnormal structural and functional MRI features that play an important role in pathology in BD.

CACNA1C Risk Variant and Mood Stabilizers Effects in the Prefrontal Cortical Thickness of Mexican Patients with Bipolar Disorder.

PurposeBipolar disorder (BD) is a condition associated with structural alterations in the prefrontal cortex (PFC); some genetic variants and mood stabilizer medications like lithium or valproate are associated with these changes. CACNA1C is a gene involved in BD pathology and brain function; carriers of the A allele of rs1006737 are reported to have increased risk for BD and increased cortical thickness (CT) in the PFC compared to non-carriers. Lithium is also associated with increased CT in the PFC of BD subjects compared to the ones on valproate. The influence of these treatments and gene variants over the PFC structure of Mexican subjects has not been explored. Therefore, we evaluate the effects of mood stabilizers and risk A allele of CACNA1C rs1006737 on the prefrontal cortical thickness of Mexican BD patients treated with lithium or valproate.Patients and MethodsA cross-sectional study of 40 BD type I euthymic adult outpatients (20 treated with lithium and 20 with valproate) who underwent a 3T T1-weighted 3D brain scan and genotyping for CACNA1C risk allele rs1006737 was conducted. We performed a cortical thickness analysis of the dorsolateral and orbitofrontal regions of the prefrontal cortex with BrainVoyager 20.6. The effects of treatment and gene variants were analyzed with a two-way multivariate analysis of covariance.ResultsThere was no association of CACNA1C risk allele rs1006737 with CT measures of both PFCs nor significant interaction between the genetic variant and treatment. Mood stabilizers reported the main effect on the CT measures of the right PFC of our sample. Patients on treatment with lithium showed higher mean CT on the right orbitofrontal cortex.ConclusionWe did not find any association between the prefrontal CT and CACNA1C risk A allele rs1006737 in BD Mexican patients treated with lithium or valproate. Our results suggest that mood stabilizers had the main effect in the CT of the right PFC.

Mitochondrial DNA content and oxidation in bipolar disorder and its role across brain regions

The underlying pathology of bipolar disorder remains unknown, though evidence is accumulating to support a role of mitochondrial dysfunction. In this study, we aim to investigate electron transport chain complex I subunit NDUFS7 protein expression; mtDNA content; common deletion; and oxidation in the Broadmann area 24 (BA24), cerebellum, hippocampus, and prefrontal cortex from patients with bipolar disorder, schizophrenia, and non-psychiatric controls. Here, we demonstrate no changes in NDUFS7 in BA24, cerebellum or hippocampus, increases in mtDNA content in hippocampus of patients with bipolar disorder, and decreases in mtDNA oxidation in patients with bipolar disorder and schizophrenia, respectively. Paired analysis between BA24 and cerebellum reveal increases within NDUFS7 levels and mtDNA content in cerebellum of patients with bipolar disorder or schizophrenia. We found a positive correlation between NDUFS7 and mtDNA content (ND4 and ND5) when combining brain regions. Our study supports the involvement of mitochondrial dysfunction in bipolar disorder and schizophrenia.

P2X7 Purinergic Receptor Is Involved in the Pathophysiology of Mania: a Preclinical Study.

The pathophysiology of bipolar disorder remains incompletely elucidated. The purinergic receptor, P2X7 (P2X7R), plays a central role in neuroinflammation, the establishment, and maintenance of microglial activation and neuronal damage/death, all characteristics of bipolar disorder pathology. The present study aims to explore the participation of the P2X7R in a preclinical pharmacological model of mania. We analyzed the modulatory effects of the P2X7R antagonist, brilliant blue, on behavior, monoamines, gene expression, serum purine levels, and cell typing in a pharmacological model of mania induced by D-amphetamine (AMPH) in mice. Our results corroborate an association between the P2X7 receptor and the preclinical animal model of mania, as demonstrated by the decreased responsiveness to AMPH in animals with pharmacologically blocked P2X7R. This study further suggests a possible dopaminergic mechanism for the action of P2X7 receptor antagonism. Additionally, we observed increased peripheral levels of adenosine, a neuroprotective molecule, and increased central expression of Entpd3 and Entpd1 leading to the hydrolysis of ATP, a danger signal, possibly as an attempt to compensate for the damage induced by AMPH. Lastly, P2X7R antagonism in the AMPH model was found to potentially modulate astrogliosis. Our results support the hypothesis that P2X7R plays a vital role in the pathophysiology of mania, possibly by modulating the dopaminergic pathway and astrogliosis, as reflected in the behavioral changes observed. Taken together, this study suggests that a purinergic system imbalance is associated with the AMPH-induced preclinical animal model of mania. P2X7R may represent a promising molecular therapeutic target for bipolar disorder.

Abnormal brain activation during emotion processing of euthymic bipolar patients taking different mood stabilizers.

Numerous functional magnetic resonance imaging studies have been conducted to elucidate emotion processing of patients with bipolar disorder (BD), but due to different inclusion criteria used, especially for the history of medication use, the results for euthymic BD patients are inconsistent. For this reason, brain functional effects of psychopharmacological treatments on BD patients have been investigated by numerous fMRI studies, but there is no existing report for brain functional effects of different mood stabilizers. In this study, we compared the emotion processing in BD patients treated by two popularly used mood stabilizer, lithium (N = 13; 30 ± 9years) and valproate (N = 16; 33 ± 8years), as well as healthy controls (HC; N = 16; 29 ± 7years). Two emotional tasks were applied in this study: one used emotional pictures of everyday objects and scenes, and another used emotional facial expression pictures. The main findings were that BD on lithium showed increased fMRI activation in the right dorsal anterior cingulate cortex and bilateral lingual gyrus in response to the positive pictures relative to neutral pictures compared with BD on valproate and HC. Besides, no abnormal activation was observed in the amygdala. Limitations of this study comprise the small sample size and the cross-sectional design. Therefore, the results were suggestive of a different effect of lithium and valproate on brain activities during emotion processing but no causal role can be proposed. The enduring impairments in euthymic state could provide clues to the brain regions involved in the primary pathology of BD.

Modeling Complex Neurological Diseases with Stem Cells: A Study of Bipolar Disorder.

The pathogenesis of bipolar disorder (BPD) is unknown. Using human-induced pluripotent stem cells (hiPSCs) to unravel pathological mechanisms in polygenic diseases is challenging, with few successful studies to date. However, hiPSCs from BPD patients responsive to lithium have offered unique opportunities to discern lithium's mechanism of action and hence gain insight into BPD pathology. By profiling the proteomics of BPD-hiPSC-derived neurons, we found that lithium alters the phosphorylation state of collapsin response mediator protein-2 (CRMP2). The "set point" for the ratio of pCRMP2:CRMP2 is elevated uniquely in hiPSC-derived neurons from lithium responsive (Li-R) BPD patients, but not other psychiatric and neurological disorders. Utilizing neurons differentiated from human patient stem cells as an in vitro platform, we were abletoelucidate the mechanism driving the pathogenesis and pathophysiology of lithium-responsive BPD, heretofore unknown.Importantly, the findings in culture werevalidated in human postmortemmaterial as well as in animal models of BPD behavior. These data suggest that the "lithium response pathway" in BPD governs CRMP2's phosphorylation, which regulates cytoskeletal organization, particularly in dendritic spines, leading to modulated neural networks that may underlie Li-R BPD pathogenesis. This chapter reviews the methodology of leveraging a functional agent, lithium, to identify unknown pathophysiological pathways with hiPSCs and how to translate this disease modeling approach to other neurological disorders.

Unraveling the biology of bipolar disorder using induced pluripotent stem-derived neurons.

Bipolar disorder has been studied from numerous angles, from pathological studies to large-scale genomic studies, overall making moderate gains toward an understanding of the disorder. With the advancement of induced pluripotent stem (iPS) cell technology, in vitro models based on patient samples are now available that inherently incorporate the complex genetic variants that largely are the basis for this disorder. A number of groups are starting to apply iPS technology to the study of bipolar disorder. We selectively reviewed the literature related to understanding bipolar disorder based on using neurons derived from iPS cells. So far, most work has used the prototypical iPS cells. However, others have been able to transdifferentiate fibroblasts directly to neurons. Others still have utilized olfactory epithelium tissue as a source of neural-like cells that do not need reprogramming. In general, iPS and related cells can be used for studies of disease pathology, drug discovery, or stem cell therapy. Published studies have primarily focused on understanding bipolar disorder pathology, but initial work is also being done to use iPS technology for drug discovery. In terms of disease pathology, some evidence is pointing toward a differentiation defect with more ventral cell types being prominent. Additionally, there is evidence for a calcium signaling defect, a finding that builds on the genome-wide association study results. Continued work with iPS cells will certainly help us understand bipolar disorder and provide a way forward for improved treatments.