Assessing neural tuning for object perception in schizophrenia and bipolar disorder with multivariate pattern analysis of fMRI data.

IntroductionDeficits in visual perception are well-established in schizophrenia and are linked to abnormal activity in the lateral occipital complex (LOC). Related deficits may exist in bipolar disorder. LOC contains neurons tuned to object features. It is unknown whether neural tuning in LOC or other visual areas is abnormal in patients, contributing to abnormal perception during visual tasks. This study used multivariate pattern analysis (MVPA) to investigate perceptual tuning for objects in schizophrenia and bipolar disorder.MethodsFifty schizophrenia participants, 51 bipolar disorder participants, and 47 matched healthy controls completed five functional magnetic resonance imaging (fMRI) runs of a perceptual task in which they viewed pictures of four different objects and an outdoor scene. We performed classification analyses designed to assess the distinctiveness of activity corresponding to perception of each stimulus in LOC (a functionally localized region of interest). We also performed similar classification analyses throughout the brain using a searchlight technique. We compared classification accuracy and patterns of classification errors across groups.ResultsStimulus classification accuracy was significantly above chance in all groups in LOC and throughout visual cortex. Classification errors were mostly within-category confusions (e.g., misclassifying one chair as another chair). There were no group differences in classification accuracy or patterns of confusion.ConclusionsThe results show for the first time MVPA can be used successfully to classify individual perceptual stimuli in schizophrenia and bipolar disorder. However, the results do not provide evidence of abnormal neural tuning in schizophrenia and bipolar disorder

More illness in offspring of bipolar patients from the U.S. compared to Europe.

Background Evidence suggests that patients with bipolar disorder from the United States have an earlier age of onset and a more difficult course of illness than those from Germany and the Netherlands. These characteristics were related to a greater family burden of psychiatric illness and the experience of more psychosocial adversity in childhood. We hypothesized that this greater illness burden would extend to the offspring of the US patients. Methods 968 outpatients (average age 41) with bipolar illness gave informed consent for participation in a treatment outcome network and filled out a detailed questionnaire about their illness and family history of illness, including whether their offspring had a diagnosis of depression, bipolar disorder, alcohol or substance abuse, suicide attempt or “other” illness. Of those with children, 356 were from the US and 132 were from Europe. Results Compared to the Europeans, offspring of patients from the US had significantly (p\u3c0.001) more depression, bipolar disorder, drug abuse, and “other” illnesses. The number of illnesses in the offspring was related to the bipolar parent being from the US, having had childhood adversity, more than 20 prior episodes, and more parental psychiatric illness. Conclusions While the findings are limited by their basis on self report, the distribution of the percentages in the US offspring are similar to those of Axelson et al. (2015) who used direct interviews. The higher burden of illness in the offspring and their in directprogenitors from the US compared to Europe warrant new attempts at better treatment and prevention

Relationship of comorbid personality disorders to prospective outcome in bipolar disorder

Introduction There is a high incidence of Axis II personality disorders (PDs) in patients with bipolar illness, but their influence on the prospectively measured course of bipolar disorder has been less well explicated. Methods 392 outpatients with bipolar disorder gave informed consent, completed the PDQ4 99 item personality disorder rating, and where clinically rated during at least one year of prospective naturalistic treatment. They were classified as Well on admission (N = 64) or Responders (N = 146) or Non-responders (N = 182) to treatment for at least six months. Results Patients who were positive for PDs were very infrequently represented in the category of Well on admission. In addition, patients with borderline, depressive, and schizoid PDs were significantly more likely to be Non-responders compared to Responders upon prospective naturalistic treatment in the network. Conclusions Patients with bipolar disorder and comorbid PDs were in general less likely to be Well from treatment in the community at network entry or to be a Responder to prospective treatment in the network. Therapeutic approaches to patients with PDs deserve specific study in an attempt to achieve a better long-term course of bipolar disorder

25 Years of the International Bipolar Collaborative Network (BCN)

Background The Stanley Foundation Bipolar Treatment Outcome Network (SFBN) recruited more than 900 outpatients from 1995 to 2002 from 4 sites in the United States (US) and 3 in the Netherlands and Germany (abbreviated as Europe). When funding was discontinued, the international group of investigators continued to work together as the Bipolar Collaborative Network (BCN), publishing so far 87 peer-reviewed manuscripts. On the 25th year anniversary of its founding, publication of a brief summary of some of the major findings appeared appropriate. Important insights into the course and treatment of adult outpatients with bipolar disorder were revealed and some methodological issues and lessons learned will be discussed. Results The illness is recurrent and pernicious and difficult to bring to a long-term remission. Virtually all aspects of the illness were more prevalent in the US compared to Europe. This included vastly more patients with early onset illness and those with more psychosocial adversity in childhood; more genetic vulnerability; more anxiety and substance abuse comorbidity; more episodes and rapid cycling; and more treatment non-responsiveness. Conclusions The findings provide a road map for a new round of much needed clinical treatment research studies. They also emphasize the need for the formation of a new network focusing on child and youth onset of mood disorders with a goal to achieve early precision diagnostics for intervention and prevention in attempting to make the course of bipolar illness more benign

Mania and bipolar depression:complementing not opposing poles—a post-hoc analysis of mixed features in manic and hypomanic episodes

BACKGROUND: Depending on the classification system used, 5–40% of manic subjects present with concomitant depressive symptoms. This post-hoc analysis evaluates the hypothesis that (hypo)manic subjects have a higher burden of depression than non-(hypo)manic subjects. METHODS: Data from 806 Bipolar I or II participants of the Stanley Foundation Bipolar Network (SFBN) were analyzed, comprising 17,937 visits. A split data approach was used to separate evaluation and verification in independent samples. For verification of our hypotheses, we compared mean IDS-C scores ratings of non-manic, hypomanic and manic patients. Data were stored on an SQL-server and extracted using standard SQL functions. Linear correlation coefficients and pivotal tables were used to characterize patient groups. RESULTS: Mean age of participants was 40 ± 12 years (range 18–81). 460 patients (57.1%) were female and 624 were diagnosed as having bipolar I disorder (77.4%) and 182 with bipolar II (22.6%). Data of 17,937 visits were available for analyses, split into odd and even patient numbers and stratified into three groups by YMRS-scores: not manic < 12, hypomanic < 21, manic < 30. Average IDS-C sum scores in manic or hypomanic states were significantly higher (p < .001) than for non-manic states. (Hypo)manic female patients were likely to show more depressive symptoms than males (p < .001). Similar results were obtained when only the core items of the YMRS or only the number of depressive symptoms were considered. Analyzing the frequency of (hypo)manic mixed states applying a proxy of the DSM-5 mixed features specifier extracted from the IDS-C, we found that almost 50% of the (hypo)manic group visits fulfilled DSM-5 mixed features specifier criteria. CONCLUSION: Subjects with a higher manic symptom load are also significantly more likely to experience a higher number of depressive symptoms. Mania and depression are not opposing poles of bipolarity but complement each other. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40345-021-00241-5

Are personality disorders in bipolar patients more frequent in the US than Europe?

Objective: Bipolar patients in the United States (US) compared to those from the Netherlands and Germany (here abbrev. as “Europe”) have more Axis I comorbidities and more poor prognosis factors such as early onset and psychosocial adversity in childhood. We wished to examine whether these differences also extended to Axis II personality disorders (PDs). Methods: 793 outpatients with bipolar disorder diagnosed by SCID gave informed consent for participating in a prospective longitudinal follow up study with clinician ratings at each visit. They completed detailed patient questionnaires and a 99 item personality disorder inventory (PDQ-4). US versus European differences in PDs were examined in univariate analyses and then logistic regressions, controlling for severity of depression, age, gender, and other poor prognosis factors. Results: In the univariate analysis, 7 PDs were more prevalent in the US than in Europe, including antisocial, avoidant, borderline, depressive, histrionic, obsessive compulsive, and schizoid PDs. In the multivariate analysis, the last 4 of these PDs remained independently greater in the US than Europe. Conclusions: Although limited by use of self report and other potentially confounding factors, multiple PDs were more prevalent in the US than in Europe, but these preliminary findings need to be confirmed using other methodologies. Other poor prognosis factors are prevalent in the US, including early age of onset, more childhood adversity, anxiety and substance abuse comorbidity, and more episodes and rapid cycling. The interactions among these variables in relationship to the more adverse course of illness in the US than in Europe require further study

The relationship between self-reported borderline personality features and prospective illness course in bipolar disorder

Abstract Background Although bipolar disorder (BD) and borderline personality disorder (BPD) share clinical characteristics and frequently co-occur, their interrelationship is controversial. Especially, the differentiation of rapid cycling BD and BPD can be troublesome. This study investigates the relationship between borderline personality features (BPF) and prospective illness course in patients with BD, and explores the effects of current mood state on self-reported BPF profiles. Methods The study included 375 patients who participated in the former Stanley Foundation Bipolar Network. All patients met DSM-IV criteria for bipolar-I disorder (n = 294), bipolar-II disorder (n = 72) or bipolar disorder NOS (n = 9). BPF were assessed with the self-rated Personality Diagnostic Questionnaire. Illness course was based on 1-year clinician rated prospective daily mood ratings with the life chart methodology. Regression analyses were used to estimate the relationships among these variables. Results Although correlations were weak, results showed that having more BPF at baseline is associated with a higher episode frequency during subsequent 1-year follow-up. Of the nine BPF, affective instability, impulsivity, and self-mutilation/suicidality showed a relationship to full-duration as well as brief episode frequency. In contrast all other BPF were not related to episode frequency. Conclusions Having more BPF was associated with an unfavorable illness course of BD. Affective instability, impulsivity, and self-mutilation/suicidality are associated with both rapid cycling BD and BPD. Still, many core features of BPD show no relationship to rapid cycling BD and can help in the differential diagnosis

Blood Lead Levels Among Afghan Children in the United States, 2014-2016

Lead poisoning disproportionately affects children and can result in permanent neurologic damage.1 Although blood lead levels (BLLs) declined among children in the United States over the past several decades, children resettling to the United States from other countries emerged as a population at risk for BLLs that are higher than the United States blood lead reference value of $5 mg/dL at the time of this analysis.2 Among children screened for lead shortly after resettlement, children from Afghanistan have a higher prevalence of BLLs$5 mg/dL compared with children from other countries,3,4 but timely sources of data available for analysis are limited. In 2021, the United States troop withdrawal from Afghanistan prompted the rapid evacuation and resettlement of more than 76 000 Afghans to the United States.5 We analyzed existing data from domestic medical examinations (DMEs) conducted from 2014 to 2016 for refugees and eligible populations #90 days after arrival in multiple states. We described and compared the prevalence of BLL $5 mg/dL among Afghan and non-Afghan refugee children screened and evaluated select characteristics associated with BLL$5 mg/dL among Afghan children

Frontal lobe hypoactivation in medication-free adults with bipolar II depression during response inhibition

In executive function, specifically in response inhibition, numerous studies support the essential role for the inferior frontal cortex (IFC). Hypoactivation of the IFC during response-inhibition tasks has been found consistently in subjects with bipolar disorder during manic and euthymic states. The aim of this study was to examine whether reduced IFC activation also exists in unmedicated subjects with bipolar disorder during the depressed phase of the disorder. Participants comprised 19 medication-free bipolar II (BP II) depressed patients and 20 healthy control subjects who underwent functional magnetic resonance imaging (fMRI) while performing a Go/NoGo response-inhibition task. Whole-brain analyses were conducted to assess activation differences within and between groups. The BP II depressed group, compared with the control group, showed significantly reduced activation in right frontal regions, including the IFC (Brodmann's area (BA) 47), middle frontal gyrus (BA 10), as well as other frontal and temporal regions. IFC hypoactivation may be a persistent deficit in subjects with bipolar disorder in both acute mood states as well as euthymia, thus representing a trait feature of bipolar disorder

Tissue-specific alternative splicing of TCF7L2

Common variants in the transcription factor 7-like 2 (TCF7L2) gene have been identified as the strongest genetic risk factors for type 2 diabetes (T2D). However, the mechanisms by which these non-coding variants increase risk for T2D are not well-established. We used 13 expression assays to survey mRNA expression of multiple TCF7L2 splicing forms in up to 380 samples from eight types of human tissue (pancreas, pancreatic islets, colon, liver, monocytes, skeletal muscle, subcutaneous adipose tissue and lymphoblastoid cell lines) and observed a tissue-specific pattern of alternative splicing. We tested whether the expression of TCF7L2 splicing forms was associated with single nucleotide polymorphisms (SNPs), rs7903146 and rs12255372, located within introns 3 and 4 of the gene and most strongly associated with T2D. Expression of two splicing forms was lower in pancreatic islets with increasing counts of T2D-associated alleles of the SNPs: a ubiquitous splicing form (P = 0.018 for rs7903146 and P = 0.020 for rs12255372) and a splicing form found in pancreatic islets, pancreas and colon but not in other tissues tested here (P = 0.009 for rs12255372 and P = 0.053 for rs7903146). Expression of this form in glucose-stimulated pancreatic islets correlated with expression of proinsulin (r2 = 0.84–0.90, P < 0.00063). In summary, we identified a tissue-specific pattern of alternative splicing of TCF7L2. After adjustment for multiple tests, no association between expression of TCF7L2 in eight types of human tissue samples and T2D-associated genetic variants remained significant. Alternative splicing of TCF7L2 in pancreatic islets warrants future studies. GenBank Accession Numbers: FJ010164–FJ010174