Microstructure of Human Corpus Callosum across the Lifespan: Regional Variations in Axon Caliber, Density, and Myelin Content.

The myeloarchitecture of the corpus callosum (CC) is characterized as a mosaic of distinct differences in fiber density of small- and large-diameter axons along the anterior-posterior axis; however, regional and age differences across the lifespan are not fully understood. Using multiecho T2 magnetic resonance imaging combined with multi-T2 fitting, the myelin water fraction (MWF) and geometric-mean of the intra-/extracellular water T2 (geomT2IEW) in 395 individuals (7-85 years; 41% males) were examined. The approach was validated where regional patterns along the CC closely resembled the histology; MWF matched mean axon diameter and geomT2IEW mirrored the density of large-caliber axons. Across the lifespan, MWF exhibited a quadratic association with age in all 10 CC regions with evidence of a positive linear MWF-age relationship among younger participants and minimal age differences in the remainder of the lifespan. Regarding geomT2IEW, a significant linear age × region interaction reflected positive linear age dependence mostly prominent in the regions with the highest density of small-caliber fibers-genu and splenium. In all, these two indicators characterize distinct attributes that are consistent with histology, which is a first. In addition, these results conform to rapid developmental progression of CC myelination leveling in middle age as well as age-related degradation of axon sheaths in older adults.

Screening for Pediatric Obsessive-Compulsive Disorder Using the Obsessive-Compulsive Inventory-Child Version.

The study assessed the ability of the Obsessive-Compulsive Inventory-Child Version (OCI-CV) to detect pediatric obsessive-compulsive disorder (OCD) using receiver operating characteristic analyses. The sample consisted of 114 cases with current OCD, 340 cases with other psychiatric disorders (OPD), and 301 healthy controls (HC) ages 7 to 18 years. All 755 participants were assessed with two semi-structured interviews and seven rating scales. In a comparison of current OCD cases and all other participants, the optimal OCI-CV cut-score was 11 with an area under the curve (AUC) of .88. In a comparison of current OCD cases and OPD cases, the optimal OCI-CV cut-score was 11 with an AUC of .82. In a comparison of current OCD cases and HC, the optimal OCI-CV cut-score was 10 with an AUC of .94. The results indicate that the OCI-CV provides an effective screen for pediatric OCD using empirically derived cut-scores.

From nodes to networks: How methods for defining nodes influence inferences regarding network interactions.

Functional connectivity (FC) analysis of fMRI data typically rests on prior identification of network nodes from activation profiles. We compared Activation Likelihood Estimate (ALE) and the Experimentally Derived Estimate (EDE) approaches to network node identification and functional inference for both verbal and visual forms of working memory. ALE arrives at canonical activation maxima that are assumed to reliably represent peaks of brain activity underlying a psychological process (e.g., working memory). By comparison, EDEs of activation maxima are typically derived from individual participant data, and are thus sensitive to individual participant activation profiles. Here, nodes were localized by both ALE and EDE methods for each participant, and subsequently extracted time series were compared using connectivity analysis. Two sets of significance tests were performed: (1) correlations computed between nodal time series of each method were compared, and (2) correlations computed between network edges (functional connections) of each network node pair were compared. Large proportions of edge correlations significantly differed between methods. ALE effectively summarizes working memory network node locations across studies and subjects, but the sensitivity to individual functional loci suggest that EDE methods provide individualized estimates of network connectivity. We suggest that a hybrid method incorporating both ALE and EDE is optimal for network inference.

Response Hand and Motor Set Differentially Modulate the Connectivity of Brain Pathways During Simple Uni-manual Motor Behavior.

We investigated the flexible modulation of undirected functional connectivity (uFC) of brain pathways during simple uni-manual responding. Two questions were central to our interests: (1) does response hand (dominant vs. non-dominant) differentially modulate connectivity and (2) are these effects related to responding under varying motor sets. fMRI data were acquired in twenty right-handed volunteers who responded with their right (dominant) or left (non-dominant) hand (blocked across acquisitions). Within acquisitions, the task oscillated between periodic responses (promoting the emergence of motor sets) or randomly induced responses (disrupting the emergence of motor sets). Conjunction analyses revealed eight shared nodes across response hand and condition, time series from which were analyzed. For right hand responses connectivity of the M1 ←→ Thalamus and SMA ←→ Parietal pathways was more significantly modulated during periodic responding. By comparison, for left hand responses, connectivity between five network pairs (including M1 and SMA, insula, basal ganglia, premotor cortex, parietal cortex, thalamus) was more significantly modulated during random responding. uFC analyses were complemented by directed FC based on multivariate autoregressive models of times series from the nodes. These results were complementary and highlighted significant modulation of dFC for SMA → Thalamus, SMA → M1, basal ganglia → Insula and basal ganglia → Thalamus. The results demonstrate complex effects of motor organization and task demand and response hand on different connectivity classes of fMRI data. The brain's sub-networks are flexibly modulated by factors related to motor organization and/or task demand, and our results have implications for assessment of medical conditions associated with motor dysfunction.

Topological Data Analysis Captures Task-Driven fMRI Profiles in Individual Participants: A Classification Pipeline Based on Persistence.

BOLD-based fMRI is the most widely used method for studying brain function. The BOLD signal while valuable, is beset with unique vulnerabilities. The most notable of these is the modest signal to noise ratio, and the relatively low temporal and spatial resolution. However, the high dimensional complexity of the BOLD signal also presents unique opportunities for functional discovery. Topological Data Analyses (TDA), a branch of mathematics optimized to search for specific classes of structure within high dimensional data may provide particularly valuable applications. In this investigation, we acquired fMRI data in the anterior cingulate cortex (ACC) using a basic motor control paradigm. Then, for each participant and each of three task conditions, fMRI signals in the ACC were summarized using two methods: a) TDA based methods of persistent homology and persistence landscapes and b) non-TDA based methods using a standard vectorization scheme. Finally, using machine learning (with support vector classifiers), classification accuracy of TDA and non-TDA vectorized data was tested across participants. In each participant, TDA-based classification out-performed the non-TDA based counterpart, suggesting that our TDA analytic pipeline better characterized task- and condition-induced structure in fMRI data in the ACC. Our results emphasize the value of TDA in characterizing task- and condition-induced structure in regional fMRI signals. In addition to providing our analytical tools for other users to emulate, we also discuss the unique role that TDA-based methods can play in the study of individual differences in the structure of functional brain signals in the healthy and the clinical brain.

Genetic depletion of brain 5HT reveals a common molecular pathway mediating compulsivity and impulsivity.

Neuropsychiatric disorders characterized by behavioral disinhibition, including disorders of compulsivity (e.g. obsessive-compulsive disorder; OCD) and impulse-control (e.g. impulsive aggression), are severe, highly prevalent and chronically disabling. Treatment options for these diseases are extremely limited. The pathophysiological bases of disorders of behavioral disinhibition are poorly understood but it has been suggested that serotonin dysfunction may play a role. Mice lacking the gene encoding brain tryptophan hydroxylase 2 (Tph2-/-), the initial and rate-limiting enzyme in the synthesis of serotonin, were tested in numerous behavioral assays that are well known for their utility in modeling human neuropsychiatric diseases. Mice lacking Tph2 (and brain 5HT) show intense compulsive and impulsive behaviors to include extreme aggression. The impulsivity is motor in form and not cognitive because Tph2-/- mice show normal acquisition and reversal learning on a spatial learning task. Restoration of 5HT levels by treatment of Tph2-/- mice with its immediate precursor 5-hydroxytryptophan attenuated compulsive and impulsive-aggressive behaviors. Surprisingly, in Tph2-/- mice, the lack of 5HT was not associated with anxiety-like behaviors. The results indicate that 5HT mediates behavioral disinhibition in the mammalian brain independent of anxiogenesis.

Sustained attention induces altered effective connectivity of the ascending thalamo-cortical relay in obsessive-compulsive disorder.

Abnormal function of the thalamo-cortical relay is considered a hallmark of obsessive-compulsive disorder (OCD) and aberrant network interactions may underpin many of the clinical and cognitive symptoms that characterize the disorder. Several statistical approaches have been applied to in vivo fMRI data to support the general loss of thalamo-cortical connectivity in OCD. However, (a) few studies have assessed the contextual constraints under which abnormal network interactions arise or (b) have used methods of effective connectivity to understand abnormal network interactions. Effective connectivity is a particularly valuable method as it describes the putative causal influences that brain regions exert over each other, as opposed to the largely statistical consistencies captured in functional connectivity techniques. Here, using dynamic causal modeling (DCM), we evaluated how attention demand induced inter-group differences (HC ≠ OCD) in effective connectivity within a motivated thalamo-cortical network. Of interest was whether these effects were observed on the ascending thalamo-cortical relay, essential for the sensory innervation of the cortex. fMRI time series data from sixty-two participants (OCD, 30; HC, 32) collected using an established sustained attention task were submitted to a space of 162 competing models. Across the space, models distinguished between competing hypotheses of thalamo-cortical interactions. Bayesian model selection (BMS) identified marginally differing likely generative model architectures in OCD and HC groups. Bayesian model averaging (BMA), was used to weight connectivity parameter estimates across all models, with each parameter weighted by each model's posterior probability, thus providing more stable estimates of effective connectivity. Inferential statistical analyses of estimated parameters revealed two principal results: (1) Significantly reduced intrinsic connectivity of the V1 → SPC pathway in OCD, suggested connective weakness in the early constituents of the dorsal visual pathway; (2) More pertinent with the discovery possibilities afforded by DCM, sustained attention in OCD patients induced significantly reduced contextual modulation of the ascending relay from the thalamus to the prefrontal cortex. These results form an important complement to our understanding of the contextual bases of thalamo-cortical network deficits in OCD, emphasizing vulnerability of the ascending relay.

The OCI-CV-R: A Revision of the Obsessive-Compulsive Inventory - Child Version.

BACKGROUND: The Obsessive-Compulsive Inventory-Children's Version (OCI-CV) was developed to assess obsessive-compulsive symptoms in youth. Recent changes in the Diagnostic and Statistical Manual (DSM-5) exclude hoarding from inclusion in the diagnosis of obsessive-compulsive disorder (OCD). Accordingly, the present study examined the reliability, validity, factorial structure, and diagnostic sensitivity of a revised version of the scale - the OCI-CV-R- that excludes items assessing hoarding. METHODS: Participant were 1047 youth, including 489 meeting DSM criteria for primary OCD, 298 clinical controls, and 260 nonclinical controls, who completed the OCI-CV and measures of obsessive-compulsive symptom severity, depression, and anxiety at various treatment and research centers. RESULTS: Findings support a five-factor structure (doubting/checking, obsessing, washing, ordering, and neutralizing), with a higher order factor. Factorial invariance was found for older (12-17 years) and younger (7-11 years) children. Internal consistency of the OCI-CV-R was acceptable, and discriminant and convergent validity were adequate and akin to that of its progenitor. Diagnostic sensitivity and specificity were found for a total score of 8 and higher. CONCLUSION: It is recommended that the OCI-CV-R replace the former version, and that this measure serve as part of a comprehensive clinical assessment of youth with OCD. Recommendations for further research with ethnically and racially diverse samples, as well as the need to establish benchmark scores are discussed.

An ultra-brief screening scale for pediatric obsessive-compulsive disorder: The OCI-CV-5.

BACKGROUND: Obsessive-compulsive disorder (OCD) is an often disabling and chronic condition that is normally assessed using diagnostic interviews or lengthy self-report questionnaires. This makes routine screening in general health settings impractical, and as a result OCD is often under-(or mis-)recognized. The present study reports on the development of an ultra-brief version of the Obsessive-Compulsive Inventory-Child Version (OCI-CV) which may be administered routinely as a screener for pediatric OCD. METHOD: A total of 489 youth diagnosed with OCD, 259 non-clinical controls, and 299 youth with other disorders completed the OCI-CV and other indices of psychopathology. Using item analyses, we extracted five items and examined the measure's factor structure, sensitivity and specificity, and convergent and discriminant validity. RESULTS: We extracted five items that assess different dimensions of OCD (washing, checking, ordering, obsessing, neutralizing/counting), termed the OCI-CV-5. Results revealed that the measure possesses good to excellent psychometric properties, and a cutoff off (≥2) yielded optimal sensitivity and specificity. LIMITATIONS: Participants were predominantly White. In addition, more research is needed to examine the OCI-CV-5's test-retest reliability and sensitivity to treatment. CONCLUSIONS: The OCI-CV-5 shows promise as an ultra-brief self-report screener for identifying OCD in youth when in-depth assessment is unfeasible.

Editorial: Neurobiological Substrates of Subclinical Obsessive-Compulsive Disorder in Children.

"I'm a little bit OCD" is a common refrain on social media, usually referring to a benign tendency toward cleanliness, order, and "keeping one's eye on the prize." In truth, obsessive-compulsive disorder (OCD) is a debilitating disorder of ritual and doubt that carries a significant burden on functioning for those affected. Even subclinical OCD, which is 2-8 times more common than OCD in children, can engender considerable suffering, including social withdrawal, anxiety, depressed mood, and excess somatic complaints.1,2 It has been suggested that subclinical OCD symptoms during childhood may be precursors to developing the full disorder in adolescence and adulthood. However, the neurobiological underpinnings of subclinical OCD and their development and correlation to child functioning have not yet been well elucidated.

Interaction between Different Implant Surfaces and Liquid Fibrinogen: A Pilot In Vitro Experiment.

BACKGROUND: Platelet concentrates like leucocyte- and platelet-rich fibrin (L-PRF) have been widely evaluated in different oral surgical procedures to promote the healing process. However, liquid L-PRF products such as liquid fibrinogen have been poorly explored, especially in the biomimetic functionalization of dental implants. The aim of this in vitro study is to evaluate the interaction between 5 different dental implant surfaces and liquid fibrinogen. METHODS: Five commercially available dental implants with different surfaces (Osseospeed™, TiUnite™, SLActive®, Ossean®, and Plenum®) were immersed for 60 minutes in liquid fibrinogen obtained from healthy donors. After this period, the implants were removed and fixed for scanning electron microscopy (SEM). RESULTS: All dental implants were covered by a fibrin mesh. However, noticeable noncontact areas were observed for the Osseospeed™, TiUnite™, and SLActive® surfaces. On the other hand, Ossean® and Plenum® surfaces showed a dense and uniform layer of fibrin covering almost the entire implant surface. The Osseospeed™, TiUnite™, and SLActive® surfaces presented with lower blood cell numbers inside the fibrin mesh compared with the others. Moreover, at higher magnification, thicker fibrin fibers were observed in contact with Ossean® and Plenum® surfaces. The Plenum ®surface showed the thickest fibers which also inserted and interconnect to the microroughness. CONCLUSION: The initial contact between an implant surface and the fibrin network differs significantly among different implant brands. Further studies are necessary to explore the clinical impact of these observations in the osseointegration process of dental implants.

Evoking network profiles of the dorsal anterior cingulate in youth with Obsessive-Compulsive Disorder during motor control and working memory.

Interest in the pathology of Obsessive-Compulsive Disorder\has focused on brain network profiles of the dorsal Anterior Cingulate Cortex (dACC), given its role as a principal control region. Both motor control and working memory tasks induce dysfunctional dACC profiles in OCD. H H We contrasted dACC network profiles in OCD and age-comparable controls during both tasks (from data collected in the same participants). The motor task required participants to tap their right forefinger in response to a flashing white probe; the memory task was a standard n-back (2-Back) requiring participants to identify if a current stimulus was identical to the one presented two items before it in the sequence. Network interactions were modeled using Psychophysiological Interactions (PPI), a model of directional functional connectivity. Inter-group analyses indicated a) that the motor control task evoked greater dACC modulation than the working memory task, and b) that the modulatory effect was significantly greater in the OCD group. We also investigated the relationship between OCD symptom dimensions (lifetime obsession and lifetime compulsion measured using the CY-BOCS) and dACC network profiles in OCD. This analysis revealed a dichotomy between Obsessive-Compulsive symptom dimensions and the degree of dACC modulation: primarily increased obsessions predicted increased modulation during the motor control task, but primarily increased compulsions predicted increased modulation during the working memory task. These results re-emphasize the salience of the dACC in OCD, and the primacy of tasks of motor control in evoking dACC pathology in the disorder.

Searching for host immune-microbiome mechanisms in obsessive-compulsive disorder: A narrative literature review and future directions.

Obsessive-compulsive disorder (OCD) is disabling and often treatment-refractory. Host immunity and gut microbiota have bidirectional communication with each other and with the brain. Perturbations to this axis have been implicated in neuropsychiatric disorders, but immune-microbiome signaling in OCD is relatively underexplored. We review support for further pursuing such investigations in OCD, including: 1) gut microbiota has been associated with OCD, but causal pathogenic mechanisms remain unclear; 2) early environmental risk factors for OCD overlap with critical periods of immune-microbiome development; 3) OCD is associated with increased risk of immune-mediated disorders and changes in immune parameters, which are separately associated with the microbiome; and 4) gut microbiome manipulations in animal models are associated with changes in immunity and some obsessive-compulsive symptoms. Theoretical pathogenic mechanisms could include microbiota programming of cytokine production, promotion of expansion and trafficking of peripheral immune cells to the CNS, and regulation of microglial function. Immune-microbiome signaling in OCD requires further exploration, and may offer novel insights into pathogenic mechanisms and potential treatment targets for this disabling disorder.

ALE meta-analysis, its role in node identification and the effects on estimates of local network organization.

Functional connectivity analyses for task-based fMRI data are generally preceded by methods for identification of network nodes. As there is no general canonical approach to identifying network nodes, different identification techniques may exert different effects on inferences drawn regarding functional network properties. Here, we compared the impact of two different node identification techniques on estimates of local node importance (based on Degree Centrality, DC) in two working memory domains: verbal and visual. The two techniques compared were the commonly used Activation Likelihood Estimate (ALE) technique (with node locations based on data aggregation), against a hybrid technique, Experimentally Derived Estimation (EDE). In the latter, ALE was first used to isolate regions of interest; then participant-specific nodes were identified based on individual-participant local maxima. Time series were extracted at each node for each dataset and subsequently used in functional connectivity analysis to: (1) assess the impact of choice of technique on estimates of DC, and (2) assess the difference between the techniques in the ranking of nodes (based on DC) in the networks they produced. In both domains, we found a significant Technique by Node interaction, signifying that the two techniques yielded networks with different DC estimates. Moreover, for the majority of participants, node rankings were uncorrelated between the two techniques (85% for the verbal working memory task and 92% for the visual working memory task). The latter effect is direct evidence that the identification techniques produced different rankings at the level of individual participants. These results indicate that node choice in task-based fMRI data exerts downstream effects that will impact interpretation and reverse inference regarding brain function.

Serotonin system gene variants and regional brain volume differences in pediatric OCD.

Obsessive-compulsive disorder (OCD) is phenotypically heterogeneous and genetically complex. This study aimed to reduce heterogeneity using structural brain imaging to study putative intermediate phenotypes for OCD. We hypothesized that select serotonin gene variants would differ in their relationship with brain volume in specific regions of the cortico-striato-thalamo-cortical (CSTC) circuits between OCD patients and controls. In a total of 200 pediatric subjects, we genotyped candidate serotonin genes (SLC6A4, HTR2A, HTR1B, and HTR2C) and conducted structural magnetic resonance imaging (sMRI) to measure regional brain volumes within CSTC circuits. In males and females separately, we first tested the association between serotonin gene variants and OCD and the effect of serotonin gene variants on brain volume irrespective of diagnosis. We then carried out a series of analyses to assess the effect of genotype-diagnosis interaction on brain volume. In females, but not in males, we identified a statistically significant genotype-diagnosis interaction for two single nucleotide polymorphisms (SNPs) in HTR2C, rs12860460 (interaction term estimate of 5.45 cc and interaction P value of 9.70e-8) and rs12854485 (interaction term estimate of 4.28 cc and interaction P value of 2.07e-6). The tested allele in each SNP was associated with decreased anterior cingulate cortex (ACC) volume in controls and with increased ACC volume in OCD patients. Our findings suggest that, in females, sequence variation in HTR2C influences ACC volume in pediatric OCD. The variants may contribute to differences in ACC volume and to OCD in a sex-specific manner when acting together with other genetic, biological, and/or environmental factors.

Glutamate receptor gene (GRIN2B) associated with reduced anterior cingulate glutamatergic concentration in pediatric obsessive-compulsive disorder.

In this preliminary study, 16 psychotropic-naïve pediatric patients with obsessive-compulsive disorder (OCD) were studied using magnetic resonance spectroscopy (MRS) and genotyped for six candidate polymorphisms in two glutamate system genes. A significant association was identified between the rs1019385 polymorphism of the glutamate receptor, ionotropic, N-methyl-d-aspartate 2B (GRIN2B) and decreased anterior cingulate cortex (ACC) glutamatergic concentration (Glx) but not with occipital Glx. These results suggest that GRIN2B may be associated with Glx in the ACC, a region consistently implicated in OCD.

The dysfunctional attitudes scale: psychometric properties in depressed adolescents.

The psychometric properties and factor structure of the Dysfunctional Attitudes Scale were examined in a sample of 422 male and female adolescents (ages 12-17) with current major depressive disorder. The scale demonstrated high internal consistency (alpha = .93) and correlated significantly with self-report and interview-based measures of depression. Confirmatory factor analysis indicated that a correlated 2-factor model, with scales corresponding to perfectionism and need for social approval, provided a satisfactory fit to the data. The goodness-of-fit was equivalent across sexes and age groups. The findings support the use of the Dysfunctional Attitudes Scale and its subscales in the assessment of clinically depressed adolescents.

A large data resource of genomic copy number variation across neurodevelopmental disorders.

Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in <0.1% of 10,851 population control samples. We found clinically relevant CNVs (broadly defined) in 284 (10.5%) of total subjects, including 22 (10.8%) among subjects with SCZ, 209 (11.4%) with ASD, 40 (9.4%) with ADHD, and 13 (5.6%) with OCD. Among all NDD subjects, we identified 17 (0.63%) with aneuploidies and 115 (4.3%) with known genomic disorder variants. We searched further for genes impacted by different CNVs in multiple disorders. Examples of NDD-associated genes linked across more than one disorder (listed in order of occurrence frequency) are NRXN1, SEH1L, LDLRAD4, GNAL, GNG13, MKRN1, DCTN2, KNDC1, PCMTD2, KIF5A, SYNM, and long non-coding RNAs: AK127244 and PTCHD1-AS. We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants.

Gray matter differences between pediatric obsessive-compulsive disorder patients and high-risk siblings: a preliminary voxel-based morphometry study.

Neuroimaging studies have identified alterations in frontostriatal circuitry in obsessive-compulsive disorder (OCD). Voxel-based morphometry (VBM) allows for the assessment of differences in gray matter density across the whole brain. VBM has not previously been used to examine regional gray matter density in pediatric OCD patients and the siblings of pediatric OCD patients. Volumetric magnetic resonance imaging (MRI) studies were conducted in 10 psychotropic naïve pediatric patients with OCD, 10 unaffected siblings of pediatric patients with OCD, and 10 healthy controls. VBM analysis was conducted using SPM2. Statistical comparisons were performed with the general linear model, implementing small volume random field corrections for a priori regions of interest (anterior cingulate cortex or ACC, striatum and thalamus). VBM analysis revealed significantly lower gray matter density in OCD patients compared to healthy in the left ACC and bilateral medial superior frontal gyrus (SFG). Furthermore, a small volume correction was used to identify a significantly greater gray matter density in the right putamen in OCD patients as compared to unaffected siblings of OCD patients. These findings in patients, siblings, and healthy controls, although preliminary, suggest the presence of gray matter structural differences between affected subjects and healthy controls as well as between affected subjects and individuals at risk for OCD.