Background: Attention-deficit/hyperactivity disorder (ADHD) is highly prevalent among youth with or at familial risk for bipolar-I disorder (BD-I), and ADHD symptoms commonly precede and may increase ...the risk for BD-I; however, associated neuropathophysiological mechanisms are not known. In this cross-sectional study, we sought to investigate brain structural network topology among youth with ADHD, with and without familial risk of BD-I. Methods: We recruited 3 groups of psychostimulant-free youth (aged 10-18 yr), namely youth with ADHD and at least 1 biological parent or sibling with BD-I (high-risk group), youth with ADHD who did not have a first- or second-degree relative with a mood or psychotic disorder (low-risk group) and healthy controls. We used graph- based network analysis of structural magnetic resonance imaging data to investigate topological properties of brain networks. We also evaluated relationships between topological metrics and mood and ADHD symptom ratings. Results: A total of 149 youth were included in the analysis (49 healthy controls, 50 low-risk youth, 50 high-risk youth). Low-risk and high-risk ADHD groups exhibited similar differences from healthy controls, mainly in the default mode network and central executive network. We found topological alterations in the salience network of the high-risk group, relative to both low-risk and control groups. We found significant abnormalities in global network properties in the high-risk group only, compared with healthy controls. Among both low-risk and high-risk ADHD groups, nodal metrics in the right triangular inferior frontal gyrus correlated positively with ADHD total and hyperactivity/impulsivity subscale scores. Limitations: The crosssectional design of this study could not determine the relevance of these findings to BD-I risk progression. Conclusion: Youth with ADHD, with and without familial risk for BD-I, exhibit common regional abnormalities in the brain connectome compared with healthy youth, whereas alterations in the salience network distinguish these groups and may represent a prodromal feature relevant to BD-I risk.
Spermatogenesis, the complex process of male germ cell proliferation, differentiation, and maturation, is the basis of male fertility. In the seminiferous tubules of the testes, spermatozoa are ...constantly generated from spermatogonial stem cells through a stereotyped sequence of mitotic and meiotic divisions. The basic physiological principles, however, that control both maturation and luminal transport of the still immotile spermatozoa within the seminiferous tubules remain poorly, if at all, defined. Here, we show that coordinated contractions of smooth muscle-like testicular peritubular cells provide the propulsive force for luminal sperm transport toward the rete testis. Using a mouse model for in vivo imaging, we describe and quantify spontaneous tubular contractions and show a causal relationship between peritubular Ca
waves and peristaltic transport. Moreover, we identify P2 receptor-dependent purinergic signaling pathways as physiological triggers of tubular contractions both in vitro and in vivo. When challenged with extracellular ATP, transport of luminal content inside the seminiferous tubules displays stage-dependent directionality. We thus suggest that paracrine purinergic signaling coordinates peristaltic recurrent contractions of the mouse seminiferous tubules to propel immotile spermatozoa to the rete testis.
In most mammals, conspecific chemosensory communication relies on semiochemical release within complex bodily secretions and subsequent stimulus detection by the vomeronasal organ (VNO). Urine, a ...rich source of ethologically relevant chemosignals, conveys detailed information about sex, social hierarchy, health, and reproductive state, which becomes accessible to a conspecific via vomeronasal sampling. So far, however, numerous aspects of social chemosignaling along the vomeronasal pathway remain unclear. Moreover, since virtually all research on vomeronasal physiology is based on secretions derived from inbred laboratory mice, it remains uncertain whether such stimuli provide a true representation of potentially more relevant cues found in the wild. Here, we combine a robust low-noise VNO activity assay with comparative molecular profiling of sex- and strain-specific mouse urine samples from two inbred laboratory strains as well as from wild mice. With comprehensive molecular portraits of these secretions, VNO activity analysis now enables us to (i) assess whether and, if so, how much sex/strain-selective 'raw' chemical information in urine is accessible via vomeronasal sampling; (ii) identify which chemicals exhibit sufficient discriminatory power to signal an animal's sex, strain, or both; (iii) determine the extent to which wild mouse secretions are unique; and (iv) analyze whether vomeronasal response profiles differ between strains. We report both sex- and, in particular, strain-selective VNO representations of chemical information. Within the urinary 'secretome', both volatile compounds and proteins exhibit sufficient discriminative power to provide sex- and strain-specific molecular fingerprints. While total protein amount is substantially enriched in male urine, females secrete a larger variety at overall comparatively low concentrations. Surprisingly, the molecular spectrum of wild mouse urine does not dramatically exceed that of inbred strains. Finally, vomeronasal response profiles differ between C57BL/6 and BALB/c animals, with particularly disparate representations of female semiochemicals.
Background Bipolar I disorder is defined by the occurrence of mania. The presence of mania, coupled with a course of illness characterized by waxing and waning of affective symptoms, suggests that ...bipolar disorder arises from dysfunction of neural systems that maintain emotional arousal and homeostasis. We used functional magnetic resonance imaging (fMRI) to study manic bipolar subjects as they performed a cognitive task designed to examine the ventrolateral prefrontal emotional arousal network. Methods We used fMRI to study regional brain activation in 40 DSM-IV manic bipolar I patients and 36 healthy subjects while they performed a continuous performance task with emotional and neutral distracters. Event-related region-of-interest analyses were performed to test the primary hypothesis. Voxelwise analyses were also completed. Results Compared with healthy subjects, the manic subjects exhibited blunted activation to emotional and neutral images, but not targets, across most of the predefined regions of interest. Several additional brain regions identified in the voxelwise analysis also exhibited similar differences between groups, including right parahippocampus, right lingual gyrus, and medial thalamus. In addition to these primary findings, the manic subjects also exhibited increased activation in response to targets in a number of brain regions that were primarily associated with managing affective stimuli. Group differences did not appear to be secondary to medication exposure or other confounds. Conclusions Bipolar manic subjects exhibit blunted brain fMRI response to emotional cues throughout the ventrolateral prefrontal emotional arousal network. Disruption of this emotional network may contribute to the mood dysregulation of bipolar disorder.
Objectives
Individualized treatment for bipolar disorder based on neuroimaging treatment targets remains elusive. To address this shortcoming, we developed a linguistic machine learning system based ...on a cascading genetic fuzzy tree (GFT) design called the LITHium Intelligent Agent (LITHIA). Using multiple objectively defined functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy (1H‐MRS) inputs, we tested whether LITHIA could accurately predict the lithium response in participants with first‐episode bipolar mania.
Methods
We identified 20 subjects with first‐episode bipolar mania who received an adequate trial of lithium over 8 weeks and both fMRI and 1H‐MRS scans at baseline pre‐treatment. We trained LITHIA using 18 1H‐MRS and 90 fMRI inputs over four training runs to classify treatment response and predict symptom reductions. Each training run contained a randomly selected 80% of the total sample and was followed by a 20% validation run. Over a different randomly selected distribution of the sample, we then compared LITHIA to eight common classification methods.
Results
LITHIA demonstrated nearly perfect classification accuracy and was able to predict post‐treatment symptom reductions at 8 weeks with at least 88% accuracy in training and 80% accuracy in validation. Moreover, LITHIA exceeded the predictive capacity of the eight comparator methods and showed little tendency towards overfitting.
Conclusions
The results provided proof‐of‐concept that a novel GFT is capable of providing control to a multidimensional bioinformatics problem—namely, prediction of the lithium response—in a pilot data set. Future work on this, and similar machine learning systems, could help assign psychiatric treatments more efficiently, thereby optimizing outcomes and limiting unnecessary treatment.
This report continues our monographic analysis of mammalian diversity and Matses ethnomammalogy in the Yavarí-Ucayali interfluvial region of northeastern Peru. Based primarily on specimens collected ...in the region from 1926 to 2003, interviews with Matses hunters, and published sight surveys of large mammals, we document the local occurrence of 33 species of xenarthrans, carnivores, perissodactyls, artiodactyls (including cetaceans), and sirenians. All of the species in these groups, with the exception of the Amazonian manatee (Trichechus inunguis), are recognized and named by the Matses, from whom we recorded extensive accounts of mammalian natural history. The local xenarthran fauna consists of nine species (Cabassous unicinctus, Priodontes maximus, Dasypus novemcinctus, D. pastasae, Bradypus variegatus, Choloepus hoffmanni, Cyclopes didactylus, Myrmecophaga tridactyla, Tamandua tetradactyla), all of which are represented by examined specimens. Only two xenarthrans (D. pastasae and C. hoffmanni) are primary game species for the Matses, who are familiar with many aspects of their biology that were previously unrecorded in the scientific literature. However, Matses interviews also provide important new information about the behavior of D. novemcinctus (a secondary game species) and M. tridactyla, neither of which has previously been studied in rainforested environments. The local carnivore fauna consists of 16 species (Atelocynus microtis, Speothos venaticus, Leopardus pardalis, L. wiedii, Panthera onca, Puma concolor, Pu. yagouaroundi, Eira barbara, Galictis vittata, Mustela africana, Lontra longicaudis, Pteronura brasiliensis, Bassaricyon alleni, Nasua nasua, Potos flavus, Procyon cancrivorus), most of which are represented by examined specimens; six species without preserved voucher material are known from camera-trap photographs and/or unambiguous sightings by Matses hunters and field biologists. Although the coati (N. nasua) is the only carnivore occasionally hunted by the Matses for food, Matses interviews are richly informative about the natural history of other species, notably including S. venaticus, Leopardus spp., Pa. onca, Puma spp., and E. barbara. All of the local ungulates (Tapirus terrestris, Pecari tajacu, Tayassu pecari, Mazama americana, M. nemorivaga) are hunted by the Matses for food, and the hunters we interviewed are correspondingly well informed about the natural history of most of these species, with the exception of the seldom-encountered gray brocket (M. nemorivaga). Both species of local cetaceans (Inia geoffroyi, Sotalia fluviatilis) are familiar to the Matses, although neither is eaten. The xenarthrans, carnivores, ungulates, and aquatic mammals that inhabit the Yavarí-Ucayali interfluve are all widespread species, so this component of the regional fauna, as currently understood, is not biogeographically distinctive, nor is it extraordinarily diverse (by western Amazonian standards). Although we discuss several noteworthy taxonomic and nomenclatural issues relevant to these taxa, the principal contribution of this report consists in the natural history information compiled from our Matses informants and the resulting overview of local community structure as defined by diurnal activity, locomotion, social behavior, and trophic relationships.
Peritubular myoid cells, which form the walls of seminiferous tubules in the testis, are functionally unexplored. While they transport sperm and contribute to the spermatogonial stem cell niche, ...specifically their emerging role in the immune surveillance of the testis and in male infertility remains to be studied. Recently, cytokine production and activation of Toll-like receptors (TLRs) were uncovered in cultured peritubular cells. We now show that human peritubular cells express purinergic receptors P2RX4 and P2RX7, which are functionally linked to TLRs, with P2RX4 being the prevalent ATP-gated ion channel. Subsequent ATP treatment of cultured peritubular cells resulted in up-regulated (pro-)inflammatory cytokine expression and secretion, while characteristic peritubular proteins, that is smooth muscle cell markers and extracellular matrix molecules, decreased. These findings indicate that extracellular ATP may act as danger molecule on peritubular cells, able to promote inflammatory responses in the testicular environment.
The neurophysiological substrates of cognition and emotion, as seen with fMRI, are generally explained using modular structures. The present study was designed to probe the modular structure of ...cognitive-emotional processing in bipolar and healthy individuals using factor analysis and compare the results with current conceptions of the neurophysiology of bipolar disorder.
Exploratory factor analysis was used to assess patterns of covariation among brain regions-of-interest activated during the Continuous Performance Task with Emotional and Neutral Distractors in healthy and bipolar individuals without a priori constraints on the number or composition of latent factors.
Results indicated a common cognitive-emotional network consisting of prefrontal, medial temporal, limbic, parietal, anterior cingulate and posterior cingulate modules. However, reduced brain activation to emotional stimuli in the frontal, medial temporal and limbic modules was apparent in the bipolar relative to the healthy group, potentially accounting for emotional dysregulation in bipolar disorder.
This study is limited by a relatively small sample size recruited at a single site. The results have yet to be validated on a larger independent sample.
Although the modular structure of cognitive-emotional processing is similar in bipolar and healthy individuals, activation in response to emotional/neutral cues varies. These findings are not only consistent with recent conceptions of mood regulation in bipolar disorder, but also suggest that regional activation can be considered within tighter modular structures without compromising data interpretation. This demonstration may serve as a template for data reduction in future region-of-interest analyses to increase statistical power.
•Brain modularity for CPT-END processing is similar for healthy and bipolar groups.•However, brain activation within modules differs across healthy and bipolar groups.•Conceptions of modularity may allow for more hypothesis-driven neuroimaging analyses.
OBJECTIVES/GOALS: Cognitive dysfunction and/or depressionfollowing ischemic stroke results in loss of independence in daily functioning. The objective of this work is to assess neural correlates of ...post-stroke cognitive deficits and the effect of left frontal transcranial electrical stimulation on cognitive control and associated brain rhythms. METHODS/STUDY POPULATION: We recorded midfrontal scalp EEG from 15 healthy and 13 participants with stroke while they performed a multi-source interference task (MSIT). The stroke cohort also performed additional MSIT sessions where they received active and sham transcranial direct current stimulation (tDCS) on the left prefrontal cortex (PFC). The EEG was pre-processed to get rid of eye movement and other channel noise artifacts and filtered to retain 0.5-55 Hz components. A Morlet wavelet was used to estimate power in theta (4-8 Hz), alpha (8-15 Hz) and gamma (35-50 Hz) frequency bands over a period of 2 seconds following MSIT image presentation. A generalized linear mixed effects model was used to find effect of group on behavior and EEG oscillations. A GLME was also used to find effects of active tDCS on behavior and EEG. RESULTS/ANTICIPATED RESULTS: We found Group (healthy v stroke) as a significant predictor of both response time (behavior) and conflict evoked theta power in the frontal channels (F1-Fz, F2-Fz). We also found that active tDCS significantly improved MSIT performance as compared to sham, after accounting for cognitive load. Active tDCS also induced low frequency oscillations in frontal EEG channels compared to sham. Preliminary results indicate that mid-frontal theta oscillations are a potential neural correlate of post-stroke cognitive deficit and tDCS of the left PFC might be a promising therapeutic intervention to ameliorate this. DISCUSSION/SIGNIFICANCE: Current therapeutic approaches often do not alleviate post stroke executive dysfunction, hence a better understanding of the brain network changes underlying such deficit can elucidate neural correlates of post stroke cognitive deficit to inform the development of neuromodulation interventions.
A new species of the nectarivorous bat genus Hsunycteris is described from lowland Amazonian forest in northeastern Peru. The new species, H. dashe, can be distinguished from other congeners by its ...larger size; V-shaped array of dermal chin papillae separated by a wide basal cleft; metacarpal V longer than metacarpal IV; broad rostrum; lateral margin of infraorbital foramen not projecting beyond rostral outline in dorsal view; well-developed sphenoidal crest; large outer upper incisors; weakly developed lingual cusp on P5; and well-developed, labially oriented M1 parastyle. A phylogenetic analysis of cytochrome-b sequence data indicates that H. dashe is sister to a clade that includes all other species of the genus including H. cadenai, Hpattoni, and a paraphyletic H. thomasi. We provide a key based on craniodental and external characters of all four known species of Hsunycteris.
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