Alternative Brain Connectivity Underscores Age-Related Differences in the Processing of Interactive Biological Motion.

Rapidly recognizing and understanding others' social interactions is an important ability that relies on deciphering multiple sources of information, for example, perceiving body information and inferring others' intentions. Despite recent advances in characterizing the brain basis of this ability in adults, its developmental underpinnings are virtually unknown. Here, we used fMRI to investigate which sources of social information support superior temporal sulcus responses to interactive biological motion (i.e., 2 interacting point-light human figures) at different developmental intervals in human participants (of either sex): Children show supportive functional connectivity with key nodes of the mentalizing network, while adults show stronger reliance on regions associated with body- and dynamic social interaction/biological motion processing. We suggest that adults use efficient action-intention understanding via body and biological motion information, while children show a stronger reliance on hidden mental state inferences as a potential means of learning to better understand others' interactive behavior.SIGNIFICANCE STATEMENT Recognizing others' interactive behavior is a critical human skill that depends on different sources of social information (e.g., observable body-action information, inferring others' hidden mental states, etc.). Understanding the brain-basis of this ability and characterizing how it emerges across development are important goals in social neuroscience. Here, we used fMRI to investigate which sources of social information support interactive biological motion processing in children (6-12 years) and adults. These results reveal a striking developmental difference in terms of how wider-brain connectivity shapes functional responses to interactive biological motion that suggests a reliance on distinct neuro-cognitive strategies in service of interaction understanding (i.e., children and adults show a greater reliance on explicit and implicit intentional inference, respectively).

Neuroplastic changes in functional wiring in sensory cortices of the congenitally deaf: A network analysis.

Congenital sensory deprivation induces significant changes in the structural and functional organisation of the brain. These are well-characterised by cross-modal plasticity, in which deprived cortical areas are recruited to process information from non-affected sensory modalities, as well as by other neuroplastic alterations within regions dedicated to the remaining senses. Here, we analysed visual and auditory networks of congenitally deaf and hearing individuals during different visual tasks to assess changes in network community structure and connectivity patterns due to congenital deafness. In the hearing group, the nodes are clearly divided into three communities (visual, auditory and subcortical), whereas in the deaf group a fourth community consisting mainly of bilateral superior temporal sulcus and temporo-insular regions is present. Perhaps more importantly, the right lateral geniculate body, as well as bilateral thalamus and pulvinar joined the auditory community of the deaf. Moreover, there is stronger connectivity between bilateral thalamic and pulvinar and auditory areas in the deaf group, when compared to the hearing group. No differences were found in the number of connections of these nodes to visual areas. Our findings reveal substantial neuroplastic changes occurring within the auditory and visual networks caused by deafness, emphasising the dynamic nature of the sensory systems in response to congenital deafness. Specifically, these results indicate that in the deaf but not the hearing group, subcortical thalamic nuclei are highly connected to auditory areas during processing of visual information, suggesting that these relay areas may be responsible for rerouting visual information to the auditory cortex under congenital deafness.

Semantic feature production norms for manipulable objects.

Feature generation tasks and feature databases are important for understanding how knowledge is organized in semantic memory, as they reflect not only the kinds of information that individuals hold about objects but also how objects are conceptually represented. Traditionally, semantic norms focus on a variety of object categories and, as a result, have a small number of concepts per semantic category. Here, our main goal is to create a more fine-grained feature database exclusively for one category of objects-manipulable objects. This database contributes to the understanding of within-category, content-specific processing. To achieve this, we asked 130 participants to freely generate features for 80 manipulable objects and another group of 32 participants to generate action features for the same objects. We then compared our databases with other published semantic norms and found high similarity between them. In our databases, we calculated the similarity between objects in terms of visual, functional, encyclopaedic, and action feature types using Spearman correlation, Baker's gamma index, and cophenetic correlation. We discovered that objects were grouped in a distinctive and meaningful way according to feature type. Finally, we tested the validity of our databases by asking three groups of participants to perform a feature verification experiment while manipulating production frequency. Our results demonstrate that participants can recognize and associate the features of our databases with specific manipulable objects. Participants were faster to verify high-frequency features than low-frequency features. Overall, our data provide important insights into how we process manipulable objects and can be used to further inform cognitive and neural theories of object processing and identification.

Clinical and Pathophysiologic Insights of Free triiodothyronine/Free thyroxine Ratio in Patients with Heart Failure with Preserved Ejection Fraction: Data from the NETDiamond Cohort.

BACKGROUND: Thyroid dysfunction is common in patients with heart failure (HF). Impaired conversion of free T4 (FT4) into free T3 (FT3) is thought to occur in these patients, decreasing the availability of FT3 and contributing to HF progression. In HF with preserved ejection fraction (HFpEF), it is not known whether changes in conversion of thyroid hormones (THs) are associated with clinical status and outcomes. OBJECTIVES: The objective of this study was to evaluate the association of FT3/FT4 ratio and TH with clinical, analytical, and echocardiographic parameters, as well as their prognostic impact in individuals with stable HFpEF. METHODS: We evaluated 74 HFpEF participants of the NETDiamond cohort without known thyroid disease. We performed regression modeling to study the associations of TH and FT3/FT4 ratio with clinical, anthropometric, analytical, and echocardiographic parameters, and survival analysis to evaluate associations with the composite of diuretic intensification, urgent HF visit, HF hospitalization, or cardiovascular death over a median follow-up of 2.8 years. RESULTS: The mean age was 73.7 years and 62% were men. The mean FT3/FT4 ratio was 2.63 (standard deviation: 0.43). Subjects with lower FT3/FT4 ratio were more likely to be obese and have atrial fibrillation. Lower FT3/FT4 ratio was associated with higher body fat (ß = -5.60 kg per FT3/FT4 unit, p = 0.034), higher pulmonary arterial systolic pressure (PASP) (ß = -10.26 mm Hg per FT3/FT4 unit, p = 0.002), and lower left ventricular ejection fraction (LVEF) (ß = 3.60% per FT3/FT4 unit, p = 0.008). Lower FT3/FT4 ratio was associated with higher risk for the composite HF outcome (HR = 2.50, 95% CI: 1.04-5.88, per 1-unit decrease in FT3/FT4, p = 0.041). CONCLUSIONS: In patients with HFpEF, lower FT3/FT4 ratio was associated with higher body fat, higher PASP, and lower LVEF. Lower FT3/FT4 predicted a higher risk of diuretic intensification, urgent HF visits, HF hospitalization, or cardiovascular death. These findings suggest that decreased FT4 to FT3 conversion might be a mechanism associated with HFpEF progression.

High-Level Representations in Human Occipito-Temporal Cortex Are Indexed by Distal Connectivity.

Human object recognition is dependent on occipito-temporal cortex (OTC), but a complete understanding of the complex functional architecture of this area must account for how it is connected to the wider brain. Converging functional magnetic resonance imaging evidence shows that univariate responses to different categories of information (e.g., faces, bodies, and nonhuman objects) are strongly related to, and potentially shaped by, functional and structural connectivity to the wider brain. However, to date, there have been no systematic attempts to determine how distal connectivity and complex local high-level responses in occipito-temporal cortex (i.e., multivoxel response patterns) are related. Here, we show that distal functional connectivity is related to, and can reliably index, high-level representations for several visual categories (i.e., tools, faces, and places) within occipito-temporal cortex; that is, voxel sets that are strongly connected to distal brain areas show higher pattern discriminability than less well-connected sets do. We further show that in several cases, pattern discriminability is higher in sets of well-connected voxels than sets defined by local activation (e.g., strong amplitude responses to faces in fusiform face area). Together, these findings demonstrate the important relationship between the complex functional organization of occipito-temporal cortex and wider brain connectivity.SIGNIFICANCE STATEMENT Human object recognition relies strongly on OTC, yet responses in this broad area are often considered in relative isolation to the rest of the brain. We employ a novel connectivity-guided voxel selection approach with functional magnetic resonance imaging data to show higher sensitivity to information (i.e., higher multivoxel pattern discriminability) in voxel sets that share strong connectivity to distal brain areas, relative to (1) voxel sets that are less strongly connected, and in several cases, (2) voxel sets that are defined by strong local response amplitude. These findings underscore the importance of distal contributions to local processing in OTC.

Clonotypic architecture of a Gag-specific CD8+ T-cell response in chronic human HIV-2 infection.

The dynamics of T-cell receptor (TCR)selection in chronic HIV-1 infection, and its association with clinical outcome, is well documented for an array of MHC-peptide complexes and disease stages. However, the factors that may contribute to the selection and expansion of CD8+ T-cells in chronic HIV-2 infection, especially at the clonal level remain unclear. To address this question, we undertook a detailed molecular characterization of the clonotypic architecture of an HLA-B*3501 restricted Gag-specific CD8+ T-cell response in donors chronically infected with HIV-2 using a combination of flow cytometry, tetramer-specific CD8+ TCR clonotyping, and in vitro assays. We show that the response to the NY9 epitope is hierarchical and narrow in terms of T-cell receptor-alpha (TCRA) and -beta (TCRB) gene usage yet clonotypically diverse. Furthermore, clonotypic dominance in shared origin CTL clones was associated with a greater magnitude of cytokine production and antigen sensitivity at limiting antigen dilution as well as enhanced cross-reactivity for known HIV-2 variants. Hence, our data suggest that effector mobilization and expansion in human chronic HIV-2 infection may be linked to the qualitative features of specific CD8+ T-cell clonotypes, which could have implications for viral control and disease outcome.

What we learn about bipolar disorder from large-scale neuroimaging: Findings and future directions from the ENIGMA Bipolar Disorder Working Group.

MRI-derived brain measures offer a link between genes, the environment and behavior and have been widely studied in bipolar disorder (BD). However, many neuroimaging studies of BD have been underpowered, leading to varied results and uncertainty regarding effects. The Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Bipolar Disorder Working Group was formed in 2012 to empower discoveries, generate consensus findings and inform future hypothesis-driven studies of BD. Through this effort, over 150 researchers from 20 countries and 55 institutions pool data and resources to produce the largest neuroimaging studies of BD ever conducted. The ENIGMA Bipolar Disorder Working Group applies standardized processing and analysis techniques to empower large-scale meta- and mega-analyses of multimodal brain MRI and improve the replicability of studies relating brain variation to clinical and genetic data. Initial BD Working Group studies reveal widespread patterns of lower cortical thickness, subcortical volume and disrupted white matter integrity associated with BD. Findings also include mapping brain alterations of common medications like lithium, symptom patterns and clinical risk profiles and have provided further insights into the pathophysiological mechanisms of BD. Here we discuss key findings from the BD working group, its ongoing projects and future directions for large-scale, collaborative studies of mental illness.

Presence and clinical impact of human herpesvirus-6 infection in patients with moderate to critical coronavirus disease-19.

Human herpesvirus-6 (HHV-6) may cause serious diseases in immunocompromised individuals. SARS-CoV-2/HHV-6 coinfection has been emphasized in previous works, mostly case reports, small series, or epidemiological studies, but few are known about its real clinical outcomes. Here we present a real-world pilot study aiming to understand the frequency and the clinical impact of HHV-6 coinfection in moderate to critically ill patients hospitalized due to COVID-19. SARS-CoV-2 and HHV-6 were evaluated in nasopharyngeal samples at the hospital admission of suspected COVID-19 patients. From 173 consecutive cases, 60 were SARS-CoV-2 positive and 13/60 (21.7%) were HHV-6 positive after identified as the HHV-6B species by a Sanger sequencing. The SARS-CoV-2+/HHV-6+ group was younger but not significant for cardiovascular diseases, diabetes, obesity, and cancer, but significant among therapeutic immunosuppressed patients (as systemic lupus erythematosus and kidney transplant patients). In the medical records, only sparse data on cutaneous or neurological manifestations were found. Biochemical and hematological data showed only a trend towards hyperferritinemic status and lymphopenia. In conclusion, despite the impressive high frequency of HHV-6 coinfection in SARS-CoV-2 positive cases, it did not impact general mortality. We suggest larger future prospective studies to better elucidate the influence of HHV-6 reactivation in cases of COVID-19, designed to specific assessment of clinical outcomes and viral reactivation mechanisms.

Acute kidney injury associated to COVID-19 leads to a strong unbalance of circulant immune mediators.

BACKGROUND: Severe cases of coronavirus disease 2019 (COVID-19) have increased risk for acute kidney injury (AKI). The exacerbation of the immune response seems to contribute to AKI development, but the immunopathological process is not completely understood. OBJECTIVES: To analyze levels of circulant immune mediators in COVID-19 patients evolving with or without AKI. We have also investigated possible associations of these mediators with viral load and clinical outcomes. METHODS: This is a longitudinal study performed with hospitalized patients with moderate to severe COVID-19. Serum levels of 27 immune mediators were measured by a multiplex immunoassay. Data were analyzed at two timepoints during the follow-up: within the first 13 days of the disease onset (early sample) and from the 14th day to death or hospital discharge (follow-up sample). RESULTS: We studied 82 COVID-19 patients (59.5 ± 17.5 years, 54.9% male). Of these, 34 (41.5%) developed AKI. These patients presented higher SARS-CoV-2 viral load (P = 0.03), higher frequency of diabetes (P = 0.01) and death (P = 0.0004). Overall, AKI patients presented significantly higher and sustained levels (P < 0.05) of CCL-2, CCL-3, CCL-4, CXCL-8, CXCL-10, IFN-γ, IL-2, IL-6, TNF-α, IL-1Ra, IL-10 and VEGF. Importantly, higher levels of CCL-2, CXCL-10, IL-2, TNF-α, IL-10, FGFb, and VEGF were observed in AKI patients independently of death. ROC curves demonstrated that early alterations in CCL-2, CXCL-8, CXCL-10, IFN-γ, IL-6, IL-1Ra and IL-10 show a good predictive value regarding AKI development. Lastly, immune mediators were significantly associated with each other and with SARS-CoV-2 viral load in AKI patients. CONCLUSIONS: COVID-19 associated AKI is accompanied by substantial alterations in circulant levels of immune mediators, which could significantly contribute to the establishment of kidney injury.

Interleukin-6, infection and cardiovascular outcomes in acute heart failure: Findings from the EDIFICA registry.

AIMS: Interleukin-6 (IL-6) is upregulated in response to infectious and inflammatory triggers and independently predicts all-cause mortality in acute heart failure (AHF). However, the association of IL-6 with cardiovascular outcomes and its interplay with C-reactive protein and infection, a major precipitating factor in AHF, remains poorly understood. METHODS AND RESULTS: The association between IL-6 and clinical outcomes (180 days) in AHF was evaluated using a cohort of 164 patients from the EDIFICA registry. Median IL-6 levels at admission were 17.4 pg/mL. Patients in the higher admission IL-6 tertile presented with lower blood pressure and more congestion, were diagnosed more frequently with infection, and had a longer hospital stay. Higher IL-6 levels were associated with increased risk of HF rehospitalization (hazard ratio per log2 3.69, 95% confidence interval (CI) 1.26-10.8, p =.017) and the composite of HF rehospitalization or cardiovascular death (hazard ratio per log2 3.50; 95% CI 1.28-9.57; p =.014), independently of major AHF prognosticators, including B-type natriuretic peptide and renal function. However, no independent associations were found for all-cause rehospitalization or mortality. Despite a moderate correlation of IL-6 with C-reactive protein (CRP) levels (R = .51), the latter were not associated with clinical outcomes in this population. CONCLUSIONS: IL-6 levels associate with higher rate of cardiovascular events in AHF, independently of classical prognosticators and evidence of infection, outperforming CRP as an inflammatory outcome biomarker.

A molecular basis for the control of preimmune escape variants by HIV-specific CD8+ T cells.

The capacity of the immune system to adapt to rapidly evolving viruses is a primary feature of effective immunity, yet its molecular basis is unclear. Here, we investigated protective HIV-1-specific CD8+ T cell responses directed against the immunodominant p24 Gag-derived epitope KK10 (KRWIILGLNK263-272) presented by human leukocyte antigen (HLA)-B∗2705. We found that cross-reactive CD8+ T cell clonotypes were mobilized to counter the rapid emergence of HIV-1 variants that can directly affect T cell receptor (TCR) recognition. These newly recruited clonotypes expressed TCRs that engaged wild-type and mutant KK10 antigens with similar affinities and almost identical docking modes, thereby accounting for their antiviral efficacy in HLA-B∗2705+ individuals. A protective CD8+ T cell repertoire therefore encompasses the capacity to control TCR-accessible mutations, ultimately driving the development of more complex viral escape variants that disrupt antigen presentation.

Distinguishing between depression in bipolar disorder and unipolar depression using magnetic resonance imaging: a systematic review.

OBJECTIVES: Magnetic resonance imaging (MRI) studies comparing bipolar and unipolar depression characterize pathophysiological differences between these conditions. However, it is difficult to interpret the current literature due to differences in MRI modalities, analysis methods, and study designs. METHODS: We conducted a systematic review of publications using MRI to compare individuals with bipolar and unipolar depression. We grouped studies according to MRI modality and task design. Within the discussion, we critically evaluated and summarized the functional MRI research and then further complemented these findings by reviewing the structural MRI literature. RESULTS: We identified 88 MRI publications comparing participants with bipolar depression and unipolar depressive disorder. Compared to individuals with unipolar depression, participants with bipolar disorder exhibited heightened function, increased within network connectivity, and reduced grey matter volume in salience and central executive network brain regions. Group differences in default mode network function were less consistent but more closely associated with depressive symptoms in participants with unipolar depression but distractibility in bipolar depression. CONCLUSIONS: When comparing mood disorder groups, the neuroimaging evidence suggests that individuals with bipolar disorder are more influenced by emotional and sensory processing when responding to their environment. In contrast, depressive symptoms and neurofunctional response to emotional stimuli were more closely associated with reduced central executive function and less adaptive cognitive control of emotionally oriented brain regions in unipolar depression. Researchers now need to replicate and refine network-level trends in these heterogeneous mood disorders and further characterize MRI markers associated with early disease onset, progression, and recovery.

Offline tDCS modulates prefrontal-cortical-subcortical-cerebellar fear pathways in delayed fear extinction.

Transcranial direct current stimulation (tDCS) has been studied to enhance extinction-based treatments for anxiety disorders. However, the field shows conflicting results about its anxiolytic effect and only a few studies have observed the extinction of consolidated memories. We looked to study the effect of offline 1 mA tDCS over the right dorsolateral pre-frontal cortex across the fear pathways, in consolidated fear response during delayed extinction. Participants (N = 34 women) underwent in a two-day fear conditioning procedure. On day 1, participants were assigned to the control group (N = 18) or the tDCS group (N = 16) and went through a fear acquisition procedure. On day 2, the tDCS group received 20 min tDCS before extinction and while inside the MRI scanner. The control group completed the extinction procedure only. The tDCS session (for the tDCS group) and the fMRI scan (for both groups) were completed just on the second day. Univariate fMRI analysis showed stimulation-dependent activity during late extinction with the tDCS group showing decreased neural activity during the processing of threat cues (CS +) and increased activity during the processing of safety cues (CS -), in prefrontal, postcentral and paracentral regions, during late extinction. ROI to whole-brain psychophysiological interaction (PPI) analysis showed the tDCS effect on the connectivity between the left dorsolateral prefrontal cortex three cortical-amygdalo-hippocampal-cerebellar pathway clusters during the processing of the CS + in late extinction (TFCE corrected; p < 0.05). Increased neuronal activity during the processing of safety cues and stronger coupling during the processing of threat cues might be the mechanisms by which tDCS contributes to stimuli discrimination.

The European Portuguese version of the Oxford Cognitive Screening (OCS-Pt): a screening test for acute stroke patients.

In Portugal, there is no gold standard test to assess acute stroke patients in the hospital context. However, cognitive deficits are common after a stroke episode and are followed by a negative impact on a patient's quality of life and rehabilitation. Here, we first aimed to adapt the Oxford Cognitive Screening to European Portuguese speakers (OCS-Pt), develop normative data cut-offs, and report the psychometric properties of the OCS-Pt. The second aim was to test the incidence of impairments in acute stroke patients. We tested 137 healthy participants aged between 25 and 92 years old, and we report normative cut-offs based on the 5th and 95th percentile, and on the patterns for age and education level. Our results are similar to other European OCS versions, and results using convergent and divergent validity show satisfactory values ranged between moderate to high. Additionally, 146 acute stroke patients, in the first week after the stroke episode, performed the OCS-Pt. Results show that this is an inclusive test and allows to discriminate between impaired and preserved functions. In conclusion, OCS-Pt is a promising cognitive screening tool to assess acute stroke survivors to be used in stroke care in Portugal.

Size constancy affects the perception and parietal neural representation of object size.

Humans and animals rely on accurate object size perception to guide behavior. Object size is judged from visual input, but the relationship between an object's retinal size and its real-world size varies with distance. Humans perceive object sizes to be relatively constant when retinal size changes. Such size constancy compensates for the variable relationship between retinal size and real-world size, using the context of recent retinal sizes of the same object to bias perception towards its likely real-world size. We therefore hypothesized that object size perception may be affected by the range of recently viewed object sizes, attracting perceived object sizes towards recently viewed sizes. We demonstrate two systematic biases: a central tendency attracting perceived size towards the average size across all trials, and a serial dependence attracting perceived size towards the size presented on the previous trial. We recently described topographic object size maps in the human parietal cortex. We therefore hypothesized that neural representations of object size here would be attracted towards recently viewed sizes. We used ultra-high-field (7T) functional MRI and population receptive field modeling to compare object size representations measured with small (0.05-1.4°diameter) and large objects sizes (0.1-2.8°). We found that parietal object size preferences and tuning widths follow this presented range, but change less than presented object sizes. Therefore, perception and neural representation of object size are attracted towards recently viewed sizes. This context-dependent object size representation reveals effects on neural response preferences that may underlie context dependence of object size perception.

Discovery and replication of cerebral blood flow differences in major depressive disorder.

Major depressive disorder (MDD) is a serious, heterogeneous disorder accompanied by brain-related changes, many of which are still to be discovered or refined. Arterial spin labeling (ASL) is a neuroimaging technique used to measure cerebral blood flow (CBF; perfusion) to understand brain function and detect differences among groups. CBF differences have been detected in MDD, and may reveal biosignatures of disease-state. The current work aimed to discover and replicate differences in CBF between MDD participants and healthy controls (HC) as part of the EMBARC study. Participants underwent neuroimaging at baseline, prior to starting study medication, to investigate biosignatures in MDD. Relative CBF (rCBF) was calculated and compared between 106 MDD and 36 HC EMBARC participants (whole-brain Discovery); and 58 MDD EMBARC participants and 58 HC from the DLBS study (region-of-interest Replication). Both analyses revealed reduced rCBF in the right parahippocampus, thalamus, fusiform and middle temporal gyri, as well as the left and right insula, for those with MDD relative to HC. Both samples also revealed increased rCBF in MDD relative to HC in both the left and right inferior parietal lobule, including the supramarginal and angular gyri. Cingulate and prefrontal regions did not fully replicate. Lastly, significant associations were detected between rCBF in replicated regions and clinical measures of MDD chronicity. These results (1) provide reliable evidence for ASL in detecting differences in perfusion for multiple brain regions thought to be important in MDD, and (2) highlight the potential role of using perfusion as a biosignature of MDD.

Reward related ventral striatal activity and differential response to sertraline versus placebo in depressed individuals.

Medications to treat major depressive disorder (MDD) are not equally effective across patients. Given that neural response to rewards is altered in MDD and given that reward-related circuitry is modulated by dopamine and serotonin, we examined, for the first time, whether reward-related neural activity moderated response to sertraline, an antidepressant medication that targets these neurotransmitters. A total of 222 unmedicated adults with MDD randomized to receive sertraline (n = 110) or placebo (n = 112) in the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study completed demographic and clinical assessments, and pretreatment functional magnetic resonance imaging while performing a reward task. We tested whether an index of reward system function in the ventral striatum (VS), a key reward circuitry region, moderated differential response to sertraline versus placebo, assessed with the Hamilton Rating Scale for Depression (HSRD) over 8 weeks. We observed a significant moderation effect of the reward index, reflecting the temporal dynamics of VS activity, on week-8 depression levels (Fs ≥ 9.67, ps ≤ 0.002). Specifically, VS responses that were abnormal with respect to predictions from reinforcement learning theory were associated with lower week-8 depression symptoms in the sertraline versus placebo arms. Thus, a more abnormal pattern of pretreatment VS dynamic response to reward expectancy (expected outcome value) and prediction error (difference between expected and actual outcome), likely reflecting serotonergic and dopaminergic deficits, was associated with better response to sertraline than placebo. Pretreatment measures of reward-related VS activity may serve as objective neural markers to advance efforts to personalize interventions by guiding individual-level choice of antidepressant treatment.

Variation in rostral anterior cingulate functional connectivity with amygdala and caudate during first manic episode distinguish bipolar young adults who do not remit following treatment.

OBJECTIVES: Altered activity in the ventrolateral prefrontal and anterior cingulate cortices, as well as subcortical and amygdala projection sites, was previously reported during a first manic episode in youth with bipolar disorder and observed to be associated with treatment response. To extend these findings, we investigated functional connectivity among these regions in first-episode manic participants who remitted after 8 weeks of treatment compared to those who did not. METHODS: Forty-two participants with bipolar disorder (60% female) during their first manic episode were recruited and received 8 weeks of treatment. Twenty-one remitted following treatment. Participants completed fMRI scans, at baseline and following 8 weeks of treatment, while performing a continuous performance task with emotional and neutral distractors. A healthy comparison group (n = 41) received fMRI evaluations at the same intervals. Differences in functional connectivity of the amygdala and caudate with the rostral anterior cingulate and ventrolateral prefrontal cortices at baseline (and changes in functional connectivity following treatment) were modeled between groups. RESULTS: At baseline, non-remitters showed an increase in positive connectivity between right anterior cingulate and caudate and a loss of negative connectivity between right anterior cingulate and amygdala, compared to healthy participants. Individuals who remitted following treatment showed an increase in negative connectivity between amygdala and left anterior cingulate 8 weeks following treatment. CONCLUSIONS: Results provide evidence of alterations in anterior cingulate amygdala and caudate functional connectivity in bipolar disorder non-remitters during a first manic episode and changes in anterior cingulate functional connectivity associated with remission suggesting targets to predict treatment response. Registered at ClinicalTrials.Gov; Functional and Neurochemical Brain Changes in First-episode Bipolar Mania. NCT00609193. URL: https://clinicaltrials.gov/ct2/show/NCT00609193?term=strakowskirank=1.

Consensus on nomenclature for clinical staging models in bipolar disorder: A narrative review from the International Society for Bipolar Disorders (ISBD) Staging Task Force.

OBJECTIVES: Clinical staging is widely used in medicine to map disease progression, inform prognosis, and guide treatment decisions; in psychiatry, however, staging remains a hypothetical construct. To facilitate future research in bipolar disorders (BD), a well-defined nomenclature is needed, especially since diagnosis is often imprecise with blurred boundaries, and a full understanding of pathophysiology is lacking. METHODS: Under the auspices of the International Society of Bipolar Disorders, a Task Force of international experts was convened to review, discuss, and integrate findings from the scientific literature relevant to the development of a consensus staging model and standardize a terminology that could be used to advance future research including staging of BD and related disorders. RESULTS: Consensus opinion and areas of uncertainty or difference were identified in regard to terms referring to staging as it may apply to BD, to at-risk status and subthreshold stages, and to various clinical stages of BD as it is currently diagnosed. CONCLUSION: The use of a standardized nomenclature about the clinical stages of BD will facilitate communication about research on clinical and pathological components of this heterogeneous group of disorders. The concepts presented are based on current evidence, but the template provided allows for further refinements as etiological advances come to light.

Immunogenicity and safety of HBAI20 Hepatitis B vaccine in non-responders: Double-blinded, randomised, controlled phase 2 trial.

BACKGROUND & AIMS: Approximately 5%-10% of the general population respond inadequately to licensed recombinant hepatitis B vaccines. We assessed the immunogenicity and safety of a new HBAI20 vaccine, consisting of a new AI20 adjuvant (20-µg recombinant human IL-2 attached to 20-µg aluminium hydroxide) in combination with HBVaxPro®-10 µg. METHODS: In a double-blinded, randomised, controlled phase 2 trial, 18- to 59-year-old healthy non-responders (titre <10 mIU/ml after three or more doses of hepatitis B vaccine) were assigned (3:1 ratio) to receive either HBAI20 vaccine or HBVaxPro®-10 µg in a 0, 1 and 2-month schedule. The primary outcome was seroprotection (titre ≥ 10 mIU/ml) measured 1-3 months following the third vaccination. RESULTS: A total of 133 participants were randomised to receive either HBAI20 vaccine (n = 101) or HBVaxPro®-10 µg (n = 32). In the modified intention-to-treat analysis, the seroprotection rate after the third vaccination was 92.0% (80/87) in the HBAI20 group and 79.3% (23/29) in the HBVaxPro®-10-µg group, P = .068. Using a generalised linear mixed model to adjust for stratification factors, a higher odds of seroprotection with HBAI20 vaccine was shown (adjusted odds ratio = 3.48, P = .028). Frequency of mild and moderate local adverse events was greater in the HBAI20 group than in the HBVaxPro®-10 µg. Rates of severe local adverse events and systemic adverse events were low and similar in both groups. CONCLUSIONS: In this group of hepatitis B vaccine non-responders, the HBAI20 vaccine demonstrated a higher seroprotection rate when adjusting for stratification factors and a similar safety profile compared to the licensed recombinant HBVaxPro®-10 µg.