The Kraepelinian Dichotomy From the Perspective of Prenatal Infectious and Immunologic Insults

The “Kraepelinian dichotomy” between schizophrenia (SZ) and bipolar disorder (BD) has been a dominant force in our thinking on the classification of these mental disorders. Emerging evidence indicates that these 2 disorders overlap significantly with regard to epidemiology, clinical presentation, genetic susceptibility, structural neuroanatomy, and treatment. Prenatal infection and immunologic dysfunction appear to be risk factors for both SZ and BD; some of these gestational exposures are present in both disorders while others may be specific to 1 or the other of the 2 syndromes. In this paper, we shall review prior studies of prenatal infections and immunologic insults in schizophrenia and BD, including exposures which overlap and which differ between these disorders, discuss the potential utility of maternal infection as one strategy toward developing a more biologically meaningful diagnostic classification system, and propose new recommendations for future research aimed at dissecting these 2 disorders from one another at the etiologic level.Key words: schizophrenia, bipolar disorder, infection, immunology, epidemiology, Kraepelin, prenatal, birth cohort, risk factorThe “Kraepelinian dichotomy” between schizophrenia (SZ) and bipolar disorder (BD) has been a dominant force in our clinical and research discourse for decades. Recent evidence, however, suggests that these 2 disorders overlap significantly with regard to their epidemiologic features, clinical presentation, familial aggregation and susceptibility genes, structural neurobiology, and treatment response.^1–9 Indeed, Kraepelin himself noted “It is becoming increasingly clear that we cannot distinguish satisfactorily between these 2 illnesses (dementia praecox [SZ] and manic depressive psychosis [BD]).¹⁰” In the present article, we aim to: (1) review previous studies of prenatal infections and immunologic insults in SZ and BD; (2) discuss the potential utility of these environmental exposures with regard to development of a new nosology of these disorders; and (3) discuss strategies for future research aimed at dissecting these 2 disorders from one another at the etiologic level.     

White matter abnormalities in bipolar disorder: insights from diffusion tensor imaging studies

Diffusion tensor imaging (DTI) is a neuroimaging technique with the potential to elucidate white matter abnormalities. Recently, it has been applied to help in better understanding of the pathophysiology of bipolar disorder (BD). This review sought to synthesise existing literature on DTI studies in BD, summarise current findings and highlight brain regions that have consistently been implicated in BD, as well as posit possible future directions for DTI research in BD. The extant findings from this review suggest loss of white matter network connectivity as a possible phenomenon associated with bipolar disorder, involving prefrontal and frontal regions, projection, associative and commissural fibres, with sparse and less consistent evidence implicating the subcortical and non-frontal lobes of the brain. There are some differences in the direction of changes observed in white matter indices, and these may be attributed to factors including sample heterogeneity and limitations of DTI techniques. The possible roles of the parietal, temporal and occipital lobes and subcortical regions in BD await further investigation. Studies of bipolar disorder using DTI lag behind other neuropsychiatric diseases such as schizophrenia, but DTI research in BD is fast gaining pace. The emerging trends from these DTI findings underscore the importance of further research to unravel the underlying neural mechanisms and clinico-anatomical correlations involving white matter in BD.     

Orbitofrontal cortex gray matter volumes in bipolar disorder patients: a region‐of‐interest MRI study

Objectives: Functional and postmortem studies suggest that the orbitofrontal cortex (OFC) is involved in the pathophysiology of bipolar disorder (BD). This anatomical magnetic resonance imaging (MRI) study examined whether BD patients have smaller OFC gray matter volumes compared to healthy comparison subjects (HC). Methods: Twenty‐eight BD patients were compared to 28 age‐ and gender‐matched HC. Subjects underwent a 1.5T MRI with 3D spoiled gradient recalled acquisition. Total OFC and medial and lateral subdivisions were manually traced by a blinded examiner. Images were segmented and gray matter volumes were calculated using an automated method. Results: Analysis of covariance, with intracranial volume as covariate, showed that BD patients and HC did not differ in gray matter volumes of total OFC or its subdivisions. However, total OFC gray matter volume was significantly smaller in depressed patients (n = 10) compared to euthymic patients (n = 18). Moreover, total OFC gray matter volumes were inversely correlated with depressive symptom intensity, as assessed by the Hamilton Depression Rating Scale. OFC gray matter volumes were not related to lithium treatment, age at disease onset, number of episodes, or family history of mood disorders. Conclusions: Our results suggest that abnormal OFC gray matter volumes are not a pervasive characteristic of BD, but may be associated with specific clinical features of the disorder.     

A meta-analysis of whole-brain diffusion tensor imaging studies in bipolar disorder

Objectives

White matter abnormalities are one of the most consistently reported findings in neuroimaging studies of bipolar disorder (BD). We conducted an anatomical likelihood estimation meta-analysis of BD whole-brain diffusion tensor imaging (DTI) studies, with the aim of identifying statistically consistent fractional anisotropy (FA) changes reflecting microstructural modifications to white matter in BD.

Methods

We performed online searches of the PUBMED and EMBASE databases in January 2011. Studies were considered for inclusion if they used diffusion tensor MRI, compared a group of subjects with BD with healthy controls and involved whole-brain white matter analysis of FA. The analyses were conducted in Talairach space, using the activation likelihood estimation technique. We carried out a meta-analysis restricted to studies reporting a lower FA in patients with BD than in healthy controls.

Results

Ten studies were included. We identified two significant clusters of decreased FA on the right side of the brain. The first was located in the right white matter, close to the parahippocampal gyrus. Four of the ten studies included contributed to this cluster. The second cluster was located close to the right anterior and subgenual cingulate cortex. These two clusters of decreased FA in BD are crossed by several white matter tracts.

Conclusions

These two clusters of altered FA may underlie the abnormal emotional processing and altered functional limbic connectivity in BD. Explorations based on DTI-based tractography are required to identify the tracts involved in the pathophysiology of BD.     

Structural connectivity associated with familial risk for mental illness: A meta‐analysis of diffusion tensor imaging studies in relatives of patients with severe mental disorders

Schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) are heritable conditions with overlapping genetic liability. Transdiagnostic and disorder‐specific brain changes associated with familial risk for developing these disorders remain poorly understood. We carried out a meta‐analysis of diffusion tensor imaging (DTI) studies to investigate white matter microstructure abnormalities in relatives that might correspond to shared and discrete biomarkers of familial risk for psychotic or mood disorders. A systematic search of PubMed and Embase was performed to identify DTI studies in relatives of SCZ, BD, and MDD patients. Seed‐based d Mapping software was used to investigate global differences in fractional anisotropy (FA) between overall and disorder‐specific relatives and healthy controls (HC). Our search identified 25 studies that met full inclusion criteria. A total of 1,144 relatives and 1,238 HC were included in the meta‐analysis. The overall relatives exhibited decreased FA in the genu and splenium of corpus callosum (CC) compared with HC. This finding was found highly replicable in jack‐knife analysis and subgroup analyses. In disorder‐specific analysis, compared to HC, relatives of SCZ patients exhibited the same changes while those of BD showed reduced FA in the left inferior longitudinal fasciculus (ILF). The present study showed decreased FA in the genu and splenium of CC in relatives of SCZ, BD, and MDD patients, which might represent a shared familial vulnerability marker of severe mental illness. The white matter abnormalities in the left ILF might represent a specific familial risk for bipolar disorder.     

Trait and state corticostriatal dysfunction in bipolar disorder during emotional face processing

Liu J, Blond BN, van Dyck LI, Spencer L, Wang F, Blumberg HP. Trait and state corticostriatal dysfunction in bipolar disorder during emotional face processing.
Bipolar Disord 2012: 14: 432–441. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: Convergent evidence supports limbic, anterior paralimbic, and prefrontal cortex (PFC) abnormalities in emotional processing in bipolar disorder (BD) and suggests that some abnormalities are mood‐state dependent and others persist into euthymia. However, few studies have assessed elevated, depressed, and euthymic mood states while individuals processed emotional stimuli of varying valence to investigate trait‐ and state‐related neural system responses. Here, regional brain responses to positive, negative, and neutral emotional stimuli were assessed in individuals with BD during elevated, depressed, and euthymic mood states. Methods: One hundred and thirty‐four subjects participated in functional magnetic resonance imaging scanning while processing faces depicting happy, fearful, and neutral expressions: 76 with BD (18 in elevated mood states, 19 depressed, 39 euthymic) and 58 healthy comparison (HC) individuals. Analyses were performed for BD trait‐ and mood state‐related features. Results: Ventral anterior cingulate cortex (VACC), orbitofrontal cortex (OFC), and ventral striatum responses to happy and neutral faces were decreased in the BD group, compared to the HC group, and were not influenced by mood state. Elevated mood states were associated with decreased right rostral PFC activation to fearful and neutral faces, and depression was associated with increased left OFC activation to fearful faces. Conclusions: The findings suggest that abnormal VACC, OFC, and ventral striatum responses to happy and neutral stimuli are trait features of BD. Acute mood states may be associated with additional lateralized abnormalities of diminished right rostral PFC responses to fearful and neutral stimuli in elevated states and increased left OFC responses to fearful stimuli in depressed states.     

White matter abnormalities in bipolar disorder: a voxel-based diffusion tensor imaging study

Objectives:  In bipolar disorder (BD), dysregulation of mood may result from white matter abnormalities that disrupt fronto-subcortical circuits. In this study, we explore such abnormalities using diffusion tensor imaging (DTI), an imaging technique capable of detecting subtle changes not visible with conventional magnetic resonance imaging (MRI), and voxel-based analysis.
Methods:  Thirty-six patients with BD, all but two receiving antidepressants or mood stabilizers, and 28 healthy controls matched for age and gender were studied. Diffusion-weighted echoplanar images (DW-EPI) were obtained using a 1.5T scanner. Voxel-based analysis was performed using SPM 2. Differences between the groups in mean diffusivity and fractional anisotropy (FA) were explored.
Results:  In the patient group, mean diffusivity was increased in the right posterior frontal and bilateral prefrontal white matter, while FA was increased in the inferior, middle temporal and middle occipital regions. The areas of increased mean diffusivity overlapped with those previously found to be abnormal using volumetric MRI and magnetization transfer imaging (MTI) in the same group of patients.
Conclusions:  White matter abnormalities, predominantly in the fronto-temporal regions, can be detected in patients with BD using DTI. The neuropathology of these abnormalities is uncertain, but neuronal and axonal loss, myelin abnormalities and alterations in axonal packing density are likely to be relevant. The neuroprotective effects of some antidepressants and mood stabilizers make it unlikely that medication effects could explain the abnormalities described here, although minor effects cannot be excluded.     

A Comparative Multimodal Meta-analysis of Anisotropy and Volume Abnormalities in White Matter in People Suffering From Bipolar Disorder or Schizophrenia

Schizophrenia (SZ) and bipolar disorder (BD) share some similarities in terms of genetic-risk genes and abnormalities of gray-matter structure in the brain, but white matter (WM) abnormalities have not been studied in depth. We undertook a comparative multimodal meta-analysis to identify common and disorder-specific abnormalities in WM structure between SZ and BD. Anisotropic effect size-signed differential mapping software was used to conduct a comparative meta-analysis of 68 diffusion tensor imaging (DTI) and 34 voxel-based morphometry (VBM) studies comparing fractional anisotropy (FA) and white matter volume (WMV), respectively, between patients with SZ (DTI: N = 1543; VBM: N = 1068) and BD (DTI: N = 983; VBM: N = 518) and healthy controls (HCs). The bilateral corpus callosum (extending to the anterior and superior corona radiata) showed shared decreased WMV and FA in SZ and BD. Compared with BD patients, SZ patients showed remarkable disorder-specific WM abnormalities: decreased FA and increased WMV in the left cingulum, and increased FA plus decreased WMV in the right anterior limb of the internal capsule. SZ patients showed more extensive alterations in WM than BD cases, which may be the pathophysiological basis for the clinical continuity of both disorders. The disorder-specific regions in the left cingulum and right anterior limb of the internal capsule provided novel insights into both disorders. Our study adds value to further understanding of the pathophysiology, classification, and differential diagnosis of SZ and BD.     

ENIGMA‐DTI: Translating reproducible white matter deficits into personalized vulnerability metrics in cross‐diagnostic psychiatric research

The ENIGMA‐DTI (diffusion tensor imaging) workgroup supports analyses that examine the effects of psychiatric, neurological, and developmental disorders on the white matter pathways of the human brain, as well as the effects of normal variation and its genetic associations. The seven ENIGMA disorder‐oriented working groups used the ENIGMA‐DTI workflow to derive patterns of deficits using coherent and coordinated analyses that model the disease effects across cohorts worldwide. This yielded the largest studies detailing patterns of white matter deficits in schizophrenia spectrum disorder (SSD), bipolar disorder (BD), major depressive disorder (MDD), obsessive–compulsive disorder (OCD), posttraumatic stress disorder (PTSD), traumatic brain injury (TBI), and 22q11 deletion syndrome. These deficit patterns are informative of the underlying neurobiology and reproducible in independent cohorts. We reviewed these findings, demonstrated their reproducibility in independent cohorts, and compared the deficit patterns across illnesses. We discussed translating ENIGMA‐defined deficit patterns on the level of individual subjects using a metric called the regional vulnerability index (RVI), a correlation of an individual''s brain metrics with the expected pattern for a disorder. We discussed the similarity in white matter deficit patterns among SSD, BD, MDD, and OCD and provided a rationale for using this index in cross‐diagnostic neuropsychiatric research. We also discussed the difference in deficit patterns between idiopathic schizophrenia and 22q11 deletion syndrome, which is used as a developmental and genetic model of schizophrenia. Together, these findings highlight the importance of collaborative large‐scale research to provide robust and reproducible effects that offer insights into individual vulnerability and cross‐diagnosis features.     

Association between white matter microstructure and cognitive function in patients with methamphetamine use disorder

Methamphetamine use disorder (MUD) has been associated with broad neurocognitive impairments. While the cognitive impairments of MUD have been demonstrated, the neuropathological underpinnings remain inadequately understood. To date, the published human diffusion tensor imaging (DTI) studies involving the correlation between diffusion parameters and neurocognitive function in MUD are limited. Hence, the present study aimed to examine the association between cognitive performance and white matter microstructure in patients with MUD. Forty‐five patients with MUD and 43 healthy controls (HCs) completed their demographic information collection, cognitive assessments, and DTI imaging. DTI images were preprocessed to extract fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) of various fiber tracts. Univariate tests were used to examine group differences in cognitive assessments and DTI metrics. Linear regression was used to examine the relationship between these two metrics. The results revealed that patients with MUD had lower subset scores of the MATRICS Consensus Cognitive Battery (MCCB), which reflects five cognitive domains: processing speed, attention, verbal learning, visual learning, problem‐solving. Patients with MUD also had significantly higher AD, MD, and RD values of the left superior longitudinal fasciculus than HCs. Furthermore, the RD value of the left superior longitudinal fasciculus was a significant predictor of processing speed and problem‐solving ability, as shown by the digit‐symbol coding test and NAB‐Mazes scores, respectively. Findings extended our understanding of white matter microstructure that is related to neurocognitive deficits in MUD and provided potential targets for the prevention and treatment of this chronic disorder.     

Spatial Representations in Rat Orbitofrontal Cortex

The orbitofrontal cortex (OFC) and hippocampus share striking cognitive and functional similarities. As a result, both structures have been proposed to encode “cognitive maps” that provide useful scaffolds for planning complex behaviors. However, while this function has been exemplified by spatial coding in neurons of hippocampal regions—particularly place and grid cells—spatial representations in the OFC have been investigated far less. Here we sought to address this by recording OFC neurons from male rats engaged in an open-field foraging task like that originally developed to characterize place fields in rodent hippocampal neurons. Single-unit activity was recorded as rats searched for food pellets scattered randomly throughout a large enclosure. In some sessions, particular flavors of food occurred more frequently in particular parts of the enclosure; in others, only a single flavor was used. OFC neurons showed spatially localized firing fields in both conditions, and representations changed between flavored and unflavored foraging periods in a manner reminiscent of remapping in the hippocampus. Compared with hippocampal recordings taken under similar behavioral conditions, OFC spatial representations were less temporally reliable, and there was no significant evidence of grid tuning in OFC neurons. These data confirm that OFC neurons show spatial firing fields in a large, two-dimensional environment in a manner similar to hippocampus. Consistent with the focus of the OFC on biological meaning and goals, spatial coding was weaker than in hippocampus and influenced by outcome identity.SIGNIFICANCE STATEMENT The orbitofrontal cortex (OFC) and hippocampus have both been proposed to encode “cognitive maps” that provide useful scaffolds for planning complex behaviors. This function is exemplified by place and grid cells identified in hippocampus, the activity of which maps spatial environments. The current study directly demonstrates very similar, though not identical, spatial representatives in OFC neurons, confirming that OFC—like hippocampus—can represent a spatial map under the appropriate experimental conditions.     

Anterior cingulate volumes associated with trait impulsivity in individuals with bipolar disorder

Objective:  Impulsivity is associated with the clinical outcome and likelihood of risky behaviors among bipolar disorder (BD) patients. Our previous study showed an inverse relationship between impulsivity and orbitofrontal cortex (OFC) volume in healthy subjects. We hypothesized that BD patients would show an inverse relationship between impulsivity and volumes of the OFC, anterior cingulate cortex (ACC), medial prefrontal cortex, and amygdala, which have been implicated in the pathophysiology of BD.
Methods:  Sixty-three BD patients were studied (mean ± SD age = 38.2 ± 11.5 years; 79% female). The Barratt Impulsiveness Scale (BIS), version 11A, was used to assess trait impulsivity. Images were processed using SPM2 and an optimized voxel-based morphometry protocol. We examined the correlations between BIS scores and the gray matter (GM) and white matter (WM) volumes of the prespecified regions.
Results:  Left rostral ACC GM volume was inversely correlated with the BIS total score ( t  =   3.95, p_corrected = 0.003) and the BIS motor score ( t  =   5.22, p_corrected < 0.001). In contrast to our hypothesis, OFC volumes were not significantly associated with impulsivity in BD. No WM volume of any structure was significantly correlated with impulsivity. No statistical association between any clinical variable and the rostral ACC GM volumes reached significance.
Conclusions:  Based on our previous findings and the current results, impulsivity may have a different neural representation in BD and healthy subjects, and the ACC may be involved in the pathophysiology of abnormal impulsivity regulation in BD patients.     

Response to Lithium in Bipolar Disorder: Clinical and Genetic Findings

相似文献   

Effects of medication on neuroimaging findings in bipolar disorder: an updated review

Hafeman DM, Chang KD, Garrett AS, Sanders EM, Phillips ML. Effects of medication on neuroimaging findings in bipolar disorder: an updated review.
Bipolar Disord 2012: 14: 375–410. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective: Neuroimaging is an important tool for better understanding the neurobiological underpinnings of bipolar disorder (BD). However, potential study participants are often receiving psychotropic medications which can possibly confound imaging data. To better interpret the results of neuroimaging studies in BD, it is important to understand the impact of medications on structural magnetic resonance imaging (sMRI), functional MRI (fMRI), and diffusion tensor imaging (DTI). Methods: To better understand the impact of medications on imaging data, we conducted a literature review and searched MEDLINE for papers that included the key words bipolar disorder and fMRI, sMRI, or DTI. The search was limited to papers that assessed medication effects and had not been included in a previous review by Phillips et al. (Medication effects in neuroimaging studies of bipolar disorder. Am J Psychiatry 2008; 165: 313–320). This search yielded 74 sMRI studies, 46 fMRI studies, and 15 DTI studies. Results: Medication appeared to influence many sMRI studies, but had limited impact on fMRI and DTI findings. From the structural studies, the most robust finding (20/45 studies) was that lithium was associated with increased volumes in areas important for mood regulation, while antipsychotic agents and anticonvulsants were generally not. Regarding secondary analysis of the medication effects of fMRI and DTI studies, few showed significant effects of medication, although rigorous analyses were typically not possible when the majority of subjects were medicated. Medication effects were more frequently observed in longitudinal studies designed to assess the impact of particular medications on the blood oxygen level‐dependent (BOLD) signal. With a few exceptions, the observed effects were normalizing, meaning that the medicated individuals with BD were more similar than their unmedicated counterparts to healthy subjects. Conclusions: The effects of psychotropic medications, when present, are predominantly normalizing and thus do not seem to provide an alternative explanation for differences in volume, white matter tracts, or BOLD signal between BD participants and healthy subjects. However, the normalizing effects of medication could obfuscate differences between BD and healthy subjects, and thus might lead to type II errors.     

Orbitofrontal State Representations Are Related to Choice Adaptations and Reward Predictions

Animals can categorize the environment into “states,” defined by unique sets of available action-outcome contingencies in different contexts. Doing so helps them choose appropriate actions and make accurate outcome predictions when in each given state. State maps have been hypothesized to be held in the orbitofrontal cortex (OFC), an area implicated in decision-making and encoding information about outcome predictions. Here we recorded neural activity in OFC in 6 male rats to test state representations. Rats were trained on an odor-guided choice task consisting of five trial blocks containing distinct sets of action-outcome contingencies, constituting states, with unsignaled transitions between them. OFC neural ensembles were analyzed using decoding algorithms. Results indicate that the vast majority of OFC neurons contributed to representations of the current state at any point in time, independent of odor cues and reward delivery, even at the level of individual neurons. Across state transitions, these representations gradually integrated evidence for the new state; the rate at which this integration happened in the prechoice part of the trial was related to how quickly the rats'' choices adapted to the new state. Finally, OFC representations of outcome predictions, often thought to be the primary function of OFC, were dependent on the accuracy of OFC state representations.SIGNIFICANCE STATEMENT A prominent hypothesis proposes that orbitofrontal cortex (OFC) tracks current location in a “cognitive map” of state space. Here we tested this idea in detail by analyzing neural activity recorded in OFC of rats performing a task consisting of a series of states, each defined by a set of available action-outcome contingencies. Results show that most OFC neurons contribute to state representations and that these representations are related to the rats'' decision-making and OFC reward predictions. These findings suggest new interpretations of emotional dysregulation in pathologies, such as addiction, which have long been known to be related to OFC dysfunction.     

Abnormal asymmetry of white matter integrity in schizophrenia revealed by voxelwise diffusion tensor imaging

A number of magnetic resonance imaging (MRI) studies have revealed morphological cortical asymmetry in the normal human brain, and reduction or inversion of such hemispheric asymmetry has been reported in schizophrenia. On the other hand, diffusion tensor imaging (DTI) studies have reported inconsistent findings concerning abnormal asymmetry of white matter integrity in schizophrenia. Our aim was to confirm whether there is reduced or inverted asymmetry of white matter integrity in the whole brain in schizophrenia. For this study, 26 right-handed schizophrenia patients, and 32 matched healthy control subjects were investigated. Voxelwise analysis of DTI data was performed using the tract-based spatial statistics. The fractional anisotropy (FA) images were normalized and projected onto the symmetrical white matter skeleton, and the laterality index (LI) of FA, determined by 2 × (left - right)/(left + right), was calculated. The results reveal that schizophrenia patients and healthy controls showed similar patterns of overall FA asymmetries. In the group comparison, patients showed significant reduction of LI in the external capsule (EC), and posterior limb of the internal capsule (PLIC). The EC cluster revealed increased rightward asymmetry, and the PLIC cluster showed reduced leftward asymmetry. Rightward-shift of FA in the EC cluster correlated with negative symptom severity. Considering that the EC cluster includes the uncinate and inferior occipitofrontal fasciculi, which have connections to the orbitofrontal cortex, abnormal asymmetry of white matter integrity in schizophrenia may play a crucial role in the pathogenesis of schizophrenia, through the altered connectivity to the orbitofrontal cortex.     

Geolocation as a Digital Phenotyping Measure of Negative Symptoms and Functional Outcome

ObjectiveNegative symptoms and functional outcome have traditionally been assessed using clinical rating scales, which rely on retrospective self-reports and have several inherent limitations that impact validity. These issues may be addressed with more objective digital phenotyping measures. In the current study, we evaluated the psychometric properties of a novel “passive” digital phenotyping method: geolocation. MethodParticipants included outpatients with schizophrenia or schizoaffective disorder (SZ: n = 44), outpatients with bipolar disorder (BD: n =19), and demographically matched healthy controls (CN: n = 42) who completed 6 days of “active” digital phenotyping assessments (eg, surveys) while geolocation was recorded. ResultsResults indicated that SZ patients show less activity than CN and BD, particularly, in their travel from home. Geolocation variables demonstrated convergent validity by small to medium correlations with negative symptoms and functional outcome measured via clinical rating scales, as well as active digital phenotyping behavioral indices of avolition, asociality, and anhedonia. Discriminant validity was supported by low correlations with positive symptoms, depression, and anxiety. Reliability was supported by good internal consistency and moderate stability across days. ConclusionsThese findings provide preliminary support for the reliability and validity of geolocation as an objective measure of negative symptoms and functional outcome. Geolocation offers enhanced precision and the ability to take a “big data” approach that facilitates sophisticated computational models. Near-continuous recordings and large numbers of samples may make geolocation a novel outcome measure for clinical trials due to enhanced power to detect treatment effects.     

TMS Reveals Dynamic Interaction between Inferior Frontal Gyrus and Posterior Middle Temporal Gyrus in Gesture-Speech Semantic Integration

Semantic processing is an amodal process with modality-specific information integrated in supramodal “convergence zones” or “semantic hub” with executive mechanisms that tailor semantic representation in a task-appropriate way. One unsolved question is how frontal control region dynamically interacts with temporal representation region in semantic integration. The present study addressed this issue by using inhibitory double-pulse transcranial magnetic stimulation over the left inferior frontal gyrus (IFG) or left posterior middle temporal gyrus (pMTG) in one of eight 40 ms time windows (TWs) (3 TWs before and 5 TWs after the identification point of speech), when human participants (12 females, 14 males) were presented with semantically congruent or incongruent gesture-speech pairs but merely identified the gender of speech. We found a TW-selective disruption of gesture-speech integration, indexed by the semantic congruency effect (i.e., a cost of reaction time because of semantic conflict), when stimulating the left pMTG in TW1, TW2, and TW7 but when stimulating the left IFG in TW3 and TW6. Based on the timing relationship, we hypothesize a two-stage gesture-speech integration circuit with a pMTG-to-IFG sequential involvement in the prelexical stage for activating gesture semantics and top-down constraining the phonological processing of speech. In the postlexical stage, an IFG-to-pMTG feedback signal might be implicated for the control of goal-directed representations and multimodal semantic unification. Our findings provide new insights into the dynamic brain network of multimodal semantic processing by causally revealing the temporal dynamics of frontal control and temporal representation regions.SIGNIFICANCE STATEMENT Previous research has identified differential functions of left inferior frontal gyrus (IFG) and posterior middle temporal gyrus (pMTG) in semantic control and semantic representation, respectively, and a causal contribution of both regions in gesture-speech integration. However, it remains largely unclear how the two regions dynamically interact in semantic processing. By using double-pulse transcranial magnetic stimulation to disrupt regional activity at specific time, this study for the first time revealed critical time windows when the two areas were causally involved in integrating gesture and speech semantics. Findings suggest a pMTG-IFG-pMTG neurocircuit loop in gesture-speech integration, which deepens current knowledge and inspires future investigation of the temporal dynamics and cognitive processes of the amodal semantic network.     

Meta-analysis of magnetic resonance imaging studies of the corpus callosum in bipolar disorder

Objective: The corpus callosum (CC) plays a pivotal role in inter‐hemispheric transfer and integration of information and is a relatively understudied structure in bipolar disorder (BD). Magnetic resonance imaging (MRI) studies have reported callosal abnormalities in this condition but findings have been inconsistent. Structural changes affecting the CC may underlie functional abnormalities in BD and could contribute to, or explain the pathophysiology of, the condition. Method: A systematic review was carried out to identify, appraise and summarize MRI studies which compared callosal areas in BD with an unrelated control group. The findings were then synthesized using random effects meta‐analysis. Consideration was given to a number of variables to explain heterogeneity. Results: Five case–control studies were identified. Bipolar patients showed reduced callosal areas in comparison with healthy volunteers with no evidence of heterogeneity or publication bias. Conclusion: Findings from this study indicate that callosal areas are reduced in BD and suggest that a failure to integrate information across the hemispheres may contribute to the pathophysiology of the disorder. Further research is necessary to clarify the underlying cellular changes leading to these morphometric differences.     

Bipolar disorder in children and adolescents: international perspective on epidemiology and phenomenology

OBJECTIVE: There is considerable skepticism outside the US over the prevalence of pediatric bipolar disorder (BD). We wished to evaluate the epidemiology of BD in children and adolescents in non-US samples. METHOD: We reviewed studies on the prevalence of BD in children and adolescents in international samples. We also describe our sample of 27 children with BD at the University of Navarra. RESULTS: There are important and frequently overlooked differences in the definition of BD between the International Classification of Diseases 10th edition (ICD-10) and DSM-IV and methodological differences in epidemiological studies that may partially explain international differences in prevalence of pediatric BD. The prevalence of bipolar spectrum disorder in young adults in Switzerland is 11%. In Holland the 6-month prevalence of mania in adolescents was 1.9% and of hypomania 0.9%. Only 1.2% of hospitalized youth (<15 years) in Denmark and 1.7% of adolescents in Finland had BD. In our clinic, the prevalence of DSM-IV BD in children 5-18 years old is 4%, and of any mood disorders 27%. There are also data from Brazil, India and Turkey with varying results. CONCLUSION: Relative lack of data, ICD-10 and DSM-IV differences in diagnostic criteria, different levels of recognition of Child and Adolescent Psychiatry as a true specialty in Europe, clinician bias against BD, an overdiagnosis of the disorder in USA and/or a true higher prevalence of pediatric BD in USA may explain these results. US-International differences may be a methodological artifact and research is needed in this field.