Search

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P =  5.87 × 10 -  9; odds ratio (OR) = 1.12) and markers within ERBB2 (rs2517959, P =  4.53 × 10 -  9; OR = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.

ObjectivesTo estimate the risk of fatal and non-fatal myocardial infarction (MI) and stroke in patients with bipolar I disorder compared to people without bipolar I disorder.MethodUtilizing a records-linkage system spanning 30 years (1966-1996), a population-based cohort of 334 subjects with bipolar I disorder and 334 age and sex-matched referents from Olmsted County, Minnesota, U.S. was identified. Longitudinal follow-up continued until incident MI or stroke (confirmed by board-certified cardiologist/neurologist), death, or study end date (December 31, 2013). Cox proportional hazards models assessed the hazard ratio (HR) for MI or stroke, adjusting for potential confounders.ResultsThere was an increased risk of fatal or non-fatal MI or stroke (as a composite outcome) in patients with bipolar I disorder [HR 1.54, 95% confidence interval (CI) 1.02, 2.33; p=0.04]. However, after adjusting for baseline cardiovascular risk factors (alcoholism, hypertension, diabetes, and smoking), the risk was no longer significantly increased (HR 1.19, 95% CI 0.76, 1.86; p=0.46).LimitationsSmall sample size for the study design. Findings were not retained after adjustment for cardiovascular disease risk factors. Psychotropic medication use during the follow-up was not ascertained and was not included in the analyses.ConclusionThis study in a geographically defined region in the U.S. demonstrated a significant increased risk of MI or stroke in bipolar I disorder, which was no longer significant after adjustment for cardiovascular risk factors.

A new study reveals an unanticipated role for social context in driving group behavior of a solitary species to a sensory stimulus and is mediated by mechanosensory neurons signaling touch interactions among individuals.

ObjectivesThe aim of the present study was to examine N-acetylaspartate (NAA), a general marker of neuronal viability, and total NAA (tNAA), the combined signal of NAA and N-acetylaspartylglutamate, in bipolar depression before and after lamotrigine treatment. Given that NAA is synthesized through direct acetylation of aspartate by acetyl-coenzyme A-l-aspartate-N-acetyltransferase, we hypothesized that treatment with lamotrigine would be associated with an increase in NAA level.MethodsPatients with bipolar depression underwent two-dimensional proton magnetic resonance spectroscopy of the anterior cingulate at baseline (n = 15) and after 12 weeks of lamotrigine treatment (n = 10). A group of age-matched healthy controls (n = 9) underwent scanning at baseline for comparison.ResultsAt baseline, patients with bipolar depression had significantly lower NAA [mean standard deviation (SD) = 1.13 (0.21); p = 0.02] than controls [mean (SD) = 1.37 (0.27)]. Significant increases in NAA [mean (SD) = 1.39 (0.21); p = 0.01] and tNAA [mean (SD) = 1.61 (0.25); p = 0.02] levels were found after 12 weeks of lamotrigine treatment.ConclusionsThese data suggest an NAA deficit in bipolar depression that is normalized after lamotrigine treatment. Future research is warranted to evaluate whether baseline NAA level is a potential biomarker for identifying lamotrigine response patterns and whether this functional brain change has an associated clinical response.

Many animals rely on visual figure-ground discrimination to aid in navigation, and to draw attention to salient features like conspecifics or predators. Even figures that are similar in pattern and luminance to the visual surroundings can be distinguished by the optical disparity generated by their relative motion against the ground, and yet the neural mechanisms underlying these visual discriminations are not well understood. We show in flies that a diverse array of figure-ground stimuli containing a motion-defined edge elicit statistically similar behavioral responses to one another, and statistically distinct behavioral responses from ground motion alone. From studies in larger flies and other insect species, we hypothesized that the circuitry of the lobula--one of the four, primary neuropiles of the fly optic lobe--performs this visual discrimination. Using calcium imaging of input dendrites, we then show that information encoded in cells projecting from the lobula to discrete optic glomeruli in the central brain group these sets of figure-ground stimuli in a homologous manner to the behavior; "figure-like" stimuli are coded similar to one another and "ground-like" stimuli are encoded differently. One cell class responds to the leading edge of a figure and is suppressed by ground motion. Two other classes cluster any figure-like stimuli, including a figure moving opposite the ground, distinctly from ground alone. This evidence demonstrates that lobula outputs provide a diverse basis set encoding visual features necessary for figure detection.

It is well established that perception is largely multisensory; often served by modalities such as touch, vision, and hearing that detect stimuli emanating from a common point in space; and processed by brain tissue maps that are spatially aligned. However, the neural interactions among modalities that share no spatial stimulus domain yet are essential for robust perception within noisy environments remain uncharacterized. Drosophila melanogaster makes its living navigating food odor plumes. Odor acts to increase the strength of gaze-stabilizing optomotor reflexes to keep the animal aligned within an invisible plume, facilitating odor localization in free flight. Here, we investigate the cellular mechanism for cross-modal behavioral interactions. We characterize a wide-field motion-selective interneuron of the lobula plate that shares anatomical and physiological similarities with the "Hx" neuron identified in larger flies. Drosophila Hx exhibits cross-modal enhancement of visual responses by paired odor, and presynaptic inputs to the lobula plate are required for behavioral odor tracking but are not themselves the target of odor modulation, nor is the neighboring wide-field "HSE" neuron. Octopaminergic neurons mediating increased visual responses upon flight initiation also show odor-evoked calcium modulations and form connections with Hx dendrites. Finally, restoring synaptic vesicle trafficking within the octopaminergic neurons of animals carrying a null mutation for all aminergic signaling is sufficient to restore odor-tracking behavior. These results are the first to demonstrate cellular mechanisms underlying visual-olfactory integration required for odor localization in fruit flies, which may be representative of adaptive multisensory interactions across taxa.

The behavioral algorithms and neural subsystems for visual figure-ground discrimination are not sufficiently described in any model system. The fly visual system shares structural and functional similarity with that of vertebrates and, like vertebrates, flies robustly track visual figures in the face of ground motion. This computation is crucial for animals that pursue salient objects under the high performance requirements imposed by flight behavior. Flies smoothly track small objects and use wide-field optic flow to maintain flight-stabilizing optomotor reflexes. The spatial and temporal properties of visual figure tracking and wide-field stabilization have been characterized in flies, but how the two systems interact spatially to allow flies to actively track figures against a moving ground has not. We took a systems identification approach in flying Drosophila and measured wing-steering responses to velocity impulses of figure and ground motion independently. We constructed a spatiotemporal action field (STAF) - the behavioral analog of a spatiotemporal receptive field - revealing how the behavioral impulse responses to figure tracking and concurrent ground stabilization vary for figure motion centered at each location across the visual azimuth. The figure tracking and ground stabilization STAFs show distinct spatial tuning and temporal dynamics, confirming the independence of the two systems. When the figure tracking system is activated by a narrow vertical bar moving within the frontal field of view, ground motion is essentially ignored despite comprising over 90% of the total visual input.

Visual identification of small moving targets is a challenge for all moving animals. Their own motion generates displacement of the visual surroundings, inducing wide-field optic flow across the retina. Wide-field optic flow is used to sense perturbations in the flight course. Both ego-motion and corrective optomotor responses confound any attempt to track a salient target moving independently of the visual surroundings. What are the strategies that flying animals use to discriminate small-field figure motion from superimposed wide-field background motion? We examined how fruit flies adjust their gaze in response to a compound visual stimulus comprising a small moving figure against an independently moving wide-field ground, which they do by re-orienting their head or their flight trajectory. We found that fixing the head in place impairs object fixation in the presence of ground motion, and that head movements are necessary for stabilizing wing steering responses to wide-field ground motion when a figure is present. When a figure is moving relative to a moving ground, wing steering responses follow components of both the figure and ground trajectories, but head movements follow only the ground motion. To our knowledge, this is the first demonstration that wing responses can be uncoupled from head responses and that the two follow distinct trajectories in the case of simultaneous figure and ground motion. These results suggest that whereas figure tracking by wing kinematics is independent of head movements, head movements are important for stabilizing ground motion during active figure tracking.

A moving visual figure may contain first-order signals defined by variation in mean luminance, as well as second-order signals defined by constant mean luminance and variation in luminance envelope, or higher-order signals that cannot be estimated by taking higher moments of the luminance distribution. Separating these properties of a moving figure to experimentally probe the visual subsystems that encode them is technically challenging and has resulted in debated mechanisms of visual object detection by flies. Our prior work took a white noise systems identification approach using a commercially available electronic display system to characterize the spatial variation in the temporal dynamics of two distinct subsystems for first- and higher-order components of visual figure tracking. The method relied on the use of single pixel displacements of two visual stimuli according to two binary maximum length shift register sequences (m-sequences) and cross-correlation of each m-sequence with time-varying flight steering measurements. The resultant spatio-temporal action fields represent temporal impulse responses parameterized by the azimuthal location of the visual figure, one STAF for first-order and another for higher-order components of compound stimuli. Here we review m-sequence and reverse correlation procedures, then describe our application in detail, provide Matlab code, validate the STAFs, and demonstrate the utility and robustness of STAFs by predicting the results of other published experimental procedures. This method has demonstrated how two relatively modest innovations on classical white noise analysis--the inclusion of space as a way to organize response kernels and the use of linear decoupling to measure the response to two channels of visual information simultaneously--could substantially improve our basic understanding of visual processing in the fly.

Visually-guided animals rely on their ability to stabilize the panorama and simultaneously track salient objects, or figures, that are distinct from the background in order to avoid predators, pursue food resources and mates, and navigate spatially. Visual figures are distinguished by luminance signals that produce coherent motion cues as well as more enigmatic 'higher-order' statistical features. Figure discrimination is thus a complex form of motion vision requiring specialized neural processing. In this minireview, we will highlight recent advances in understanding the perceptual, behavioral, and neurophysiological basis of higher-order figure detection in flies, much of which is grounded in the historical perspective and mechanistic underpinnings of human psychophysics.

The article discusses the importance of measuring the exposome in bipolar disorder research. While bipolar disorder has a genetic component, genetic variants only explain a small portion of the disease's variation and risk. Environmental exposures, both modifiable and non-modifiable, play a significant role in the development of bipolar disorder. The exposome concept, introduced in 2005, emphasizes the need to assess all environmental exposures an individual encounters throughout their life. Measuring the exposome is challenging but can be achieved through emerging technologies and multi-omics investigation. Understanding an individual's exposome composition can provide insights into the gene-environment interplay and lead to breakthrough discoveries in bipolar disorder research. [Extracted from the article]

In response to imposed course deviations, the optomotor reactions of animals reduce motion blur and facilitate the maintenance of stable body posture. In flies, many anatomical and electrophysiological studies suggest that disparate motion cues stimulating the left and right eyes are not processed in isolation but rather are integrated in the brain to produce a cohesive panoramic percept. To investigate the strength of such inter-ocular interactions and their role in compensatory sensory-motor transformations, we utilize a virtual reality flight simulator to record wing and head optomotor reactions by tethered flying flies in response to imposed binocular rotation and monocular front-to-back and back-to-front motion. Within a narrow range of stimulus parameters that generates large contrast insensitive optomotor responses to binocular rotation, we find that responses to monocular front-to-back motion are larger than those to panoramic rotation, but are contrast sensitive. Conversely, responses to monocular back-to-front motion are slower than those to rotation and peak at the lowest tested contrast. Together our results suggest that optomotor responses to binocular rotation result from the influence of non-additive contralateral inhibitory as well as excitatory circuit interactions that serve to confer contrast insensitivity to flight behaviors influenced by rotatory optic flow.