Genome-wide association with bone mass and geometry in the Framingham Heart Study

BACKGROUND:Osteoporosis is characterized by low bone mass and compromised bone structure, heritable traits that contribute to fracture risk. There have been no genome-wide association and linkage studies for these traits using high-density genotyping platforms.METHODS:We used the Affymetrix 100K SNP GeneChip marker set in the Framingham Heart Study (FHS) to examine genetic associations with ten primary quantitative traits: bone mineral density (BMD), calcaneal ultrasound, and geometric indices of the hip. To test associations with multivariable-adjusted residual trait values, we used additive generalized estimating equation (GEE) and family-based association tests (FBAT) models within each sex as well as sexes combined. We evaluated 70,987 autosomal SNPs with genotypic call rates [greater than or equal to]80%, HWE p [greater than or equal to] 0.001, and MAF [greater than or equal to]10% in up to 1141 phenotyped individuals (495 men and 646 women, mean age 62.5 yrs). Variance component linkage analysis was performed using 11,200 markers.RESULTS:Heritability estimates for all bone phenotypes were 30-66%. LOD scores [greater than or equal to]3.0 were found on chromosomes 15 (1.5 LOD confidence interval: 51,336,679-58,934,236 bp) and 22 (35,890,398-48,603,847 bp) for femoral shaft section modulus. The ten primary phenotypes had 12 associations with 100K SNPs in GEE models at p < 0.000001 and 2 associations in FBAT models at p < 0.000001. The 25 most significant p-values for GEE and FBAT were all less than 3.5 x 10-6 and 2.5 x 10-5, respectively. Of the 40 top SNPs with the greatest numbers of significantly associated BMD traits (including femoral neck, trochanter, and lumbar spine), one half to two-thirds were in or near genes that have not previously been studied for osteoporosis. Notably, pleiotropic associations between BMD and bone geometric traits were uncommon. Evidence for association (FBAT or GEE p < 0.05) was observed for several SNPs in candidate genes for osteoporosis, such as rs1801133 in MTHFR; rs1884052 and rs3778099 in ESR1; rs4988300 in LRP5; rs2189480 in VDR; rs2075555 in COLIA1; rs10519297 and rs2008691 in CYP19, as well as SNPs in PPARG (rs10510418 and rs2938392) and ANKH (rs2454873 and rs379016). All GEE, FBAT and linkage results are provided as an open-access results resource at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.CONCLUSION:The FHS 100K SNP project offers an unbiased genome-wide strategy to identify new candidate loci and to replicate previously suggested candidate genes for osteoporosis.

A Laminar Cortical Model for 3D Perception of Slanted and Curved Surfaces and of 2D Images: Developement, attention, and Bistability

A model of laminar visual cortical dynamics proposes how 3D boundary and surface representations of slated and curved 3D objects and 2D images arise. The 3D boundary representations emerge from interactions between non-classical horizontal receptive field interactions with intracorticcal and intercortical feedback circuits. Such non-classical interactions contextually disambiguate classical receptive field responses to ambiguous visual cues using cells that are sensitive to angles and disparity gradients with cortical areas V1 and V2. These cells are all variants of bipole grouping cells. Model simulations show how horizontal connections can develop selectively to angles, how slanted surfaces can activate 3D boundary representations that are sensitive to angles and disparity gradients, how 3D filling-in occurs across slanted surfaces, how a 2D Necker cube image can be represented in 3D, and how bistable Necker cuber percepts occur. The model also explains data about slant aftereffects and 3D neon color spreading. It shows how habituative transmitters that help to control developement also help to trigger bistable 3D percepts and slant aftereffects, and how attention can influence which of these percepts is perceived by propogating along some object boundaries.

A Cortical and Cerebellar Parcellation System for Speech Studies

A neuroanatomical parcellation system is described which encompasses the entire cerebral cortex and the cerebellum. The cortical system modified version of the scheme described by Caviness et al. (1996) and is designed particularly for studies of speech processing. The cerebellum is parcellated into 6 cortical regions of interest (ROIs) and an ROI representing the deep cerebellar nuclei in each hemisphere. The boundaries of each ROI are based on individual anatomical markers that are clearly visible from standard structural MRI acquistions. The system permits averaginh of functional imaging data sets from multiple sujects while accounting for individual anatomical variability. Used in conjuction with region-of-interest analysis techniques such as that described by Nieto-Castanon et al. (2003), the parcellation system provides a more powerful means of analyzing functional data.

Laminar Cortical Dynamics of 3D Surface Perception: Stratification, transparency, and Neon Color Spreading

How does the laminar organization of cortical circuitry in areas VI and V2 give rise to 3D percepts of stratification, transparency, and neon color spreading in response to 2D pictures and 3D scenes? Psychophysical experiments have shown that such 3D percepts are sensitive to whether contiguous image regions have the same relative contrast polarity (dark-light or lightdark), yet long-range perceptual grouping is known to pool over opposite contrast polarities. The ocularity of contiguous regions is also critical for neon color spreading: Having different ocularity despite the contrast relationship that favors neon spreading blocks the spread. In addition, half visible points in a stereogram can induce near-depth transparency if the contrast relationship favors transparency in the half visible areas. It thus seems critical to have the whole contrast relationship in a monocular configuration, since splitting it between two stereogram images cancels the effect. What adaptive functions of perceptual grouping enable it to both preserve sensitivity to monocular contrast and also to pool over opposite contrasts? Aspects of cortical development, grouping, attention, perceptual learning, stereopsis and 3D planar surface perception have previously been analyzed using a 3D LAMINART model of cortical areas VI, V2, and V4. The present work consistently extends this model to show how like-polarity competition between VI simple cells in layer 4 may be combined with other LAMINART grouping mechanisms, such as cooperative pooling of opposite polarities at layer 2/3 complex cells. The model also explains how the Metelli Rules can lead to transparent percepts, how bistable transparency percepts can arise in which either surface can be perceived as transparent, and how such a transparency reversal can be facilitated by an attention shift. The like-polarity inhibition prediction is consistent with lateral masking experiments in which two f1anking Gabor patches with the same contrast polarity as the target increase the target detection threshold when they approach the target. It is also consistent with LAMINART simulations of cortical development. Other model explanations and testable predictions will also be presented.

Fast Synchronization of Perpetual Grouping in Laminar Visual Cortical Circuits

Perceptual grouping is well-known to be a fundamental process during visual perception, notably grouping across scenic regions that do not receive contrastive visual inputs. Illusory contours are a classical example of such groupings. Recent psychophysical and neurophysiological evidence have shown that the grouping process can facilitate rapid synchronization of the cells that are bound together by a grouping, even when the grouping must be completed across regions that receive no contrastive inputs. Synchronous grouping can hereby bind together different object parts that may have become desynchronized due to a variety of factors, and can enhance the efficiency of cortical transmission. Neural models of perceptual grouping have clarified how such fast synchronization may occur by using bipole grouping cells, whose predicted properties have been supported by psychophysical, anatomical, and neurophysiological experiments. These models have not, however, incorporated some of the realistic constraints on which groupings in the brain are conditioned, notably the measured spatial extent of long-range interactions in layer 2/3 of a grouping network, and realistic synaptic and axonal signaling delays within and across cells in different cortical layers. This work addresses the question: Can long-range interactions that obey the bipole constraint achieve fast synchronization under realistic anatomical and neurophysiological constraints that initially desynchronize grouping signals? Can the cells that synchronize retain their analog sensitivity to changing input amplitudes? Can the grouping process complete and synchronize illusory contours across gaps in bottom-up inputs? Our simulations show that the answer to these questions is Yes.

Neural Modeling and Imaging of the Cortical Interactions Underlying Syllable Production

This paper describes a neural model of speech acquisition and production that accounts for a wide range of acoustic, kinematic, and neuroimaging data concerning the control of speech movements. The model is a neural network whose components correspond to regions of the cerebral cortex and cerebellum, including premotor, motor, auditory, and somatosensory cortical areas. Computer simulations of the model verify its ability to account for compensation to lip and jaw perturbations during speech. Specific anatomical locations of the model's components are estimated, and these estimates are used to simulate fMRI experiments of simple syllable production with and without jaw perturbations.

Laminar Cortical Dynamics of Visual Form and Motion Interactions During Coherent Object Motion Perception

How do visual form and motion processes cooperate to compute object motion when each process separately is insufficient? A 3D FORMOTION model specifies how 3D boundary representations, which separate figures from backgrounds within cortical area V2, capture motion signals at the appropriate depths in MT; how motion signals in MT disambiguate boundaries in V2 via MT-to-Vl-to-V2 feedback; how sparse feature tracking signals are amplified; and how a spatially anisotropic motion grouping process propagates across perceptual space via MT-MST feedback to integrate feature-tracking and ambiguous motion signals to determine a global object motion percept. Simulated data include: the degree of motion coherence of rotating shapes observed through apertures, the coherent vs. element motion percepts separated in depth during the chopsticks illusion, and the rigid vs. non-rigid appearance of rotating ellipses.

Modeling the Possible Influences of Eye Movements on the Refinement of Cortical Direction Selectivity

The second-order statistics of neural activity was examined in a model of the cat LGN and V1 during free-viewing of natural images. In the model, the specific patterns of thalamocortical activity required for a Bebbian maturation of direction-selective cells in VI were found during the periods of visual fixation, when small eye movements occurred, but not when natural images were examined in the absence of fixational eye movements. In addition, simulations of stroboscopic reming that replicated the abnormal pattern of eye movements observed in kittens chronically exposed to stroboscopic illumination produced results consistent with the reported loss of direction selectivity and preservation of orientation selectivity. These results suggest the involvement of the oculomotor activity of visual fixation in the maturation of cortical direction selectivity.

How Does Binocular Rivalry Emerge from Cortical Mechanisms of 3D Vision?

Under natural viewing conditions, a single depthful percept of the world is consciously seen. When dissimilar images are presented to corresponding regions of the two eyes, binocular rivalyr may occur, during which the brain consciously perceives alternating percepts through time. How do the same brain mechanisms that generate a single depthful percept of the world also cause perceptual bistability, notably binocular rivalry? What properties of brain representations correspond to consciously seen percepts? A laminar cortical model of how cortical areas V1, V2, and V4 generate depthful percepts is developed to explain and quantitatively simulate binocualr rivalry data. The model proposes how mechanisms of cortical developement, perceptual grouping, and figure-ground perception lead to signle and rivalrous percepts. Quantitative model simulations include influences of contrast changes that are synchronized with switches in the dominant eye percept, gamma distribution of dominant phase durations, piecemeal percepts, and coexistence of eye-based and stimulus-based rivalry. The model also quantitatively explains data about multiple brain regions involved in rivalry, effects of object attention on switching between superimposed transparent surfaces, and monocular rivalry. These data explanations are linked to brain mechanisms that assure non-rivalrous conscious percepts. To our knowledge, no existing model can explain all of these phenomena.

Speaker Normalization Using Cortical Strip Maps: A Neural Model for Steady State Vowel Identification

Auditory signals of speech are speaker-dependent, but representations of language meaning are speaker-independent. Such a transformation enables speech to be understood from different speakers. A neural model is presented that performs speaker normalization to generate a pitchindependent representation of speech sounds, while also preserving information about speaker identity. This speaker-invariant representation is categorized into unitized speech items, which input to sequential working memories whose distributed patterns can be categorized, or chunked, into syllable and word representations. The proposed model fits into an emerging model of auditory streaming and speech categorization. The auditory streaming and speaker normalization parts of the model both use multiple strip representations and asymmetric competitive circuits, thereby suggesting that these two circuits arose from similar neural designs. The normalized speech items are rapidly categorized and stably remembered by Adaptive Resonance Theory circuits. Simulations use synthesized steady-state vowels from the Peterson and Barney [J. Acoust. Soc. Am. 24, 175-184 (1952)] vowel database and achieve accuracy rates similar to those achieved by human listeners. These results are compared to behavioral data and other speaker normalization models.

Cortical Learning of Recognition Categories: A Resolution of the Exemplar Vs. Prototype Debate

Do humans and animals learn exemplars or prototypes when they categorize objects and events in the world? How are different degrees of abstraction realized through learning by neurons in inferotemporal and prefrontal cortex? How do top-down expectations influence the course of learning? Thirty related human cognitive experiments (the 5-4 category structure) have been used to test competing views in the prototype-exemplar debate. In these experiments, during the test phase, subjects unlearn in a characteristic way items that they had learned to categorize perfectly in the training phase. Many cognitive models do not describe how an individual learns or forgets such categories through time. Adaptive Resonance Theory (ART) neural models provide such a description, and also clarify both psychological and neurobiological data. Matching of bottom-up signals with learned top-down expectations plays a key role in ART model learning. Here, an ART model is used to learn incrementally in response to 5-4 category structure stimuli. Simulation results agree with experimental data, achieving perfect categorization in training and a good match to the pattern of errors exhibited by human subjects in the testing phase. These results show how the model learns both prototypes and certain exemplars in the training phase. ART prototypes are, however, unlike the ones posited in the traditional prototype-exemplar debate. Rather, they are critical patterns of features to which a subject learns to pay attention based on past predictive success and the order in which exemplars are experienced. Perturbations of old memories by newly arriving test items generate a performance curve that closely matches the performance pattern of human subjects. The model also clarifies exemplar-based accounts of data concerning amnesia.

Cortical Dynamics of Contextually-Cued Attentive Visual Learning and Search: Spatial and Object Evidence Accumulation

How do humans use predictive contextual information to facilitate visual search? How are consistently paired scenic objects and positions learned and used to more efficiently guide search in familiar scenes? For example, a certain combination of objects can define a context for a kitchen and trigger a more efficient search for a typical object, such as a sink, in that context. A neural model, ARTSCENE Search, is developed to illustrate the neural mechanisms of such memory-based contextual learning and guidance, and to explain challenging behavioral data on positive/negative, spatial/object, and local/distant global cueing effects during visual search. The model proposes how global scene layout at a first glance rapidly forms a hypothesis about the target location. This hypothesis is then incrementally refined by enhancing target-like objects in space as a scene is scanned with saccadic eye movements. The model clarifies the functional roles of neuroanatomical, neurophysiological, and neuroimaging data in visual search for a desired goal object. In particular, the model simulates the interactive dynamics of spatial and object contextual cueing in the cortical What and Where streams starting from early visual areas through medial temporal lobe to prefrontal cortex. After learning, model dorsolateral prefrontal cortical cells (area 46) prime possible target locations in posterior parietal cortex based on goalmodulated percepts of spatial scene gist represented in parahippocampal cortex, whereas model ventral prefrontal cortical cells (area 47/12) prime possible target object representations in inferior temporal cortex based on the history of viewed objects represented in perirhinal cortex. The model hereby predicts how the cortical What and Where streams cooperate during scene perception, learning, and memory to accumulate evidence over time to drive efficient visual search of familiar scenes.

Laminar Cortical Dynamics of Cognitive and Motor Working Memory, Sequence Learning and Performance: Toward a Unified Theory of How the Cerebral Cortex Works

How do the layered circuits of prefrontal and motor cortex carry out working memory storage, sequence learning, and voluntary sequential item selection and performance? A neural model called LIST PARSE is presented to explain and quantitatively simulate cognitive data about both immediate serial recall and free recall, including bowing of the serial position performance curves, error-type distributions, temporal limitations upon recall, and list length effects. The model also qualitatively explains cognitive effects related to attentional modulation, temporal grouping, variable presentation rates, phonemic similarity, presentation of non-words, word frequency/item familiarity and list strength, distracters and modality effects. In addition, the model quantitatively simulates neurophysiological data from the macaque prefrontal cortex obtained during sequential sensory-motor imitation and planned performance. The article further develops a theory concerning how the cerebral cortex works by showing how variations of the laminar circuits that have previously clarified how the visual cortex sees can also support cognitive processing of sequentially organized behaviors.

Laminar Cortical Dynamics of Visual Form and Motion Interactions During Coherent Object Motion Perception

How do visual form and motion processes cooperate to compute object motion when each process separately is insufficient? Consider, for example, a deer moving behind a bush. Here the partially occluded fragments of motion signals available to an observer must be coherently grouped into the motion of a single object. A 3D FORMOTION model comprises five important functional interactions involving the brain’s form and motion systems that address such situations. Because the model’s stages are analogous to areas of the primate visual system, we refer to the stages by corresponding anatomical names. In one of these functional interactions, 3D boundary representations, in which figures are separated from their backgrounds, are formed in cortical area V2. These depth-selective V2 boundaries select motion signals at the appropriate depths in MT via V2-to-MT signals. In another, motion signals in MT disambiguate locally incomplete or ambiguous boundary signals in V2 via MT-to-V1-to-V2 feedback. The third functional property concerns resolution of the aperture problem along straight moving contours by propagating the influence of unambiguous motion signals generated at contour terminators or corners. Here, sparse “feature tracking signals” from, e.g., line ends, are amplified to overwhelm numerically superior ambiguous motion signals along line segment interiors. In the fourth, a spatially anisotropic motion grouping process takes place across perceptual space via MT-MST feedback to integrate veridical feature-tracking and ambiguous motion signals to determine a global object motion percept. The fifth property uses the MT-MST feedback loop to convey an attentional priming signal from higher brain areas back to V1 and V2. The model's use of mechanisms such as divisive normalization, endstopping, cross-orientation inhibition, and longrange cooperation is described. Simulated data include: the degree of motion coherence of rotating shapes observed through apertures, the coherent vs. element motion percepts separated in depth during the chopsticks illusion, and the rigid vs. non-rigid appearance of rotating ellipses.

Towards a Unified Theory of Neocortex: Laminar Cortical Circuits for Vision and Cognition

A key goal of computational neuroscience is to link brain mechanisms to behavioral functions. The present article describes recent progress towards explaining how laminar neocortical circuits give rise to biological intelligence. These circuits embody two new and revolutionary computational paradigms: Complementary Computing and Laminar Computing. Circuit properties include a novel synthesis of feedforward and feedback processing, of digital and analog processing, and of pre-attentive and attentive processing. This synthesis clarifies the appeal of Bayesian approaches but has a far greater predictive range that naturally extends to self-organizing processes. Examples from vision and cognition are summarized. A LAMINART architecture unifies properties of visual development, learning, perceptual grouping, attention, and 3D vision. A key modeling theme is that the mechanisms which enable development and learning to occur in a stable way imply properties of adult behavior. It is noted how higher-order attentional constraints can influence multiple cortical regions, and how spatial and object attention work together to learn view-invariant object categories. In particular, a form-fitting spatial attentional shroud can allow an emerging view-invariant object category to remain active while multiple view categories are associated with it during sequences of saccadic eye movements. Finally, the chapter summarizes recent work on the LIST PARSE model of cognitive information processing by the laminar circuits of prefrontal cortex. LIST PARSE models the short-term storage of event sequences in working memory, their unitization through learning into sequence, or list, chunks, and their read-out in planned sequential performance that is under volitional control. LIST PARSE provides a laminar embodiment of Item and Order working memories, also called Competitive Queuing models, that have been supported by both psychophysical and neurobiological data. These examples show how variations of a common laminar cortical design can embody properties of visual and cognitive intelligence that seem, at least on the surface, to be mechanistically unrelated.