Predicting the attention of others.

As social animals, people are highly sensitive to the attention of others. Seeing someone else gaze at an object automatically draws one's own attention to that object. Monitoring the attention of others aids in reconstructing their emotions, beliefs, and intentions and may play a crucial role in social alignment. Recently, however, it has been suggested that the human brain constructs a predictive model of other people's attention that is far more involved than a moment-by-moment monitoring of gaze direction. The hypothesized model learns the statistical patterns in other people's attention and extrapolates how attention is likely to move. Here, we tested the hypothesis of a predictive model of attention. Subjects saw movies of attention displayed as a bright spot shifting around a scene. Subjects were able to correctly distinguish natural attention sequences (based on eye tracking of prior participants) from altered sequences (e.g., played backward or in a scrambled order). Even when the attention spot moved around a blank background, subjects could distinguish natural from scrambled sequences, suggesting a sensitivity to the spatial-temporal statistics of attention. Subjects also showed an ability to recognize the attention patterns of different individuals. These results suggest that people possess a sophisticated model of the normal statistics of attention and can identify deviations from the model. Monitoring attention is therefore more than simply registering where someone else's eyes are pointing. It involves predictive modeling, which may contribute to our remarkable social ability to predict the mind states and behavior of others.

A conceptual framework for consciousness.

This article argues that consciousness has a logically sound, explanatory framework, different from typical accounts that suffer from hidden mysticism. The article has three main parts. The first describes background principles concerning information processing in the brain, from which one can deduce a general, rational framework for explaining consciousness. The second part describes a specific theory that embodies those background principles, the Attention Schema Theory. In the past several years, a growing body of experimental evidence-behavioral evidence, brain imaging evidence, and computational modeling-has addressed aspects of the theory. The final part discusses the evolution of consciousness. By emphasizing the specific role of consciousness in cognition and behavior, the present approach leads to a proposed account of how consciousness may have evolved over millions of years, from fish to humans. The goal of this article is to present a comprehensive, overarching framework in which we can understand scientifically what consciousness is and what key adaptive roles it plays in brain function.

The attention schema theory in a neural network agent: Controlling visuospatial attention using a descriptive model of attention.

In the attention schema theory (AST), the brain constructs a model of attention, the attention schema, to aid in the endogenous control of attention. Growing behavioral evidence appears to support the presence of a model of attention. However, a central question remains: does a controller of attention actually benefit by having access to an attention schema? We constructed an artificial deep Q-learning neural network agent that was trained to control a simple form of visuospatial attention, tracking a stimulus with an attention spotlight in order to solve a catch task. The agent was tested with and without access to an attention schema. In both conditions, the agent received sufficient information such that it should, theoretically, be able to learn the task. We found that with an attention schema present, the agent learned to control its attention spotlight and learned the catch task. Once the agent learned, if the attention schema was then disabled, the agent's performance was greatly reduced. If the attention schema was removed before learning began, the agent was impaired at learning. The results show how the presence of even a simple attention schema can provide a profound benefit to a controller of attention. We interpret these results as supporting the central argument of AST: the brain contains an attention schema because of its practical benefit in the endogenous control of attention.

Attention, awareness, and the right temporoparietal junction.

The attention schema theory posits a specific relationship between subjective awareness and attention, in which awareness is the control model that the brain uses to aid in the endogenous control of attention. In previous experiments, we developed a behavioral paradigm in human subjects to manipulate awareness and attention. The paradigm involved a visual cue that could be used to guide attention to a target stimulus. In task 1, subjects were aware of the cue, but not aware that it provided information about the target. The cue measurably drew exogenous attention to itself. In addition, implicitly, the subjects' endogenous attention mechanism used the cue to help shift attention to the target. In task 2, subjects were no longer aware of the cue. The cue still measurably drew exogenous attention to itself, yet without awareness of the cue, the subjects' endogenous control mechanism was no longer able to use the cue to control attention. Thus, the control of attention depended on awareness. Here, we tested the two tasks while scanning brain activity in human volunteers. We predicted that the right temporoparietal junction (TPJ) would be active in relation to the process in which awareness helps control attention. This prediction was confirmed. The right TPJ was active in relation to the effect of the cue on attention in task 1; it was not measurably active in task 2. The difference was significant. In our interpretation, the right TPJ is involved in an interaction in which awareness permits the control of attention.

Visual motion assists in social cognition.

Recent evidence suggests a link between visual motion processing and social cognition. When person A watches person B, the brain of A apparently generates a fictitious, subthreshold motion signal streaming from B to the object of B's attention. These previous studies, being correlative, were unable to establish any functional role for the false motion signals. Here, we directly tested whether subthreshold motion processing plays a role in judging the attention of others. We asked, if we contaminate people's visual input with a subthreshold motion signal streaming from an agent to an object, can we manipulate people's judgments about that agent's attention? Participants viewed a display including faces, objects, and a subthreshold motion hidden in the background. Participants' judgments of the attentional state of the faces was significantly altered by the hidden motion signal. Faces from which subthreshold motion was streaming toward an object were judged as paying more attention to the object. Control experiments showed the effect was specific to the agent-to-object motion direction and to judging attention, not action or spatial orientation. These results suggest that when the brain models other minds, it uses a subthreshold motion signal, streaming from an individual to an object, to help represent attentional state. This type of social-cognitive model, tapping perceptual mechanisms that evolved to process physical events in the real world, may help to explain the extraordinary cultural persistence of beliefs in mind processes having physical manifestation. These findings, therefore, may have larger implications for human psychology and cultural belief.

Other people's gaze encoded as implied motion in the human brain.

Keeping track of other people's gaze is an essential task in social cognition and key for successfully reading other people's intentions and beliefs (theory of mind). Recent behavioral evidence suggests that we construct an implicit model of other people's gaze, which may incorporate physically incoherent attributes such as a construct of force-carrying beams that emanate from the eyes. Here, we used functional magnetic resonance imaging and multivoxel pattern analysis to test the prediction that the brain encodes gaze as implied motion streaming from an agent toward a gazed-upon object. We found that a classifier, trained to discriminate the direction of visual motion, significantly decoded the gaze direction in static images depicting a sighted face, but not a blindfolded one, from brain activity patterns in the human motion-sensitive middle temporal complex (MT+) and temporo-parietal junction (TPJ). Our results demonstrate a link between the visual motion system and social brain mechanisms, in which the TPJ, a key node in theory of mind, works in concert with MT+ to encode gaze as implied motion. This model may be a fundamental aspect of social cognition that allows us to efficiently connect agents with the objects of their attention. It is as if the brain draws a quick visual sketch with moving arrows to help keep track of who is attending to what. This implicit, fluid-flow model of other people's gaze may help explain culturally universal myths about the mind as an energy-like, flowing essence.

Implicit model of other people's visual attention as an invisible, force-carrying beam projecting from the eyes.

As a part of social cognition, people automatically construct rich models of other people's vision. Here we show that when people judge the mechanical forces acting on an object, their judgments are biased by another person gazing at the object. The bias is consistent with an implicit perception that gaze adds a gentle force, pushing on the object. The bias was present even though the participants were not explicitly aware of it and claimed that they did not believe in an extramission view of vision (a common folk view of vision in which the eyes emit an invisible energy). A similar result was not obtained on control trials when participants saw a blindfolded face turned toward the object, or a face with open eyes turned away from the object. The findings suggest that people automatically and implicitly generate a model of other people's vision that uses the simplifying construct of beams coming out of the eyes. This implicit model of active gaze may be a hidden, yet fundamental, part of the rich process of social cognition, contributing to how we perceive visual agency. It may also help explain the extraordinary cultural persistence of the extramission myth of vision.

Consciousness is already solved: The continued debate is not about science.

A logical explanation of consciousness has been known for decades. The brain must construct a specific set of information about conscious feeling (theory-of-mind information), causing people to believe, think, and claim to have consciousness. Theories that propose an actual, intangible feeling are non-explanatory. They add a magical red herring while leaving unexplained the objective phenomena: the believing, thinking, and claiming.

T4-mediated rescue of aortic malformations in hypothyroid rats indicates maternal thyroid status can affect great vessel development.

Pexacerfont is a corticotrophin-releasing factor subtype 1 receptor (CRF-1) antagonist developed for potential treatment of anxiety and stress-related disorders. In male rats, pexacerfont caused hepatic enzyme induction leading to increased thyroxine (T4) clearance. When administered to pregnant rats on gestation day 6 to 15, pexacerfont at 300 mg/kg/day (30× mean AUC in humans at 100 mg/day) produced similar effects on thyroid homeostasis with serum T4 and thyroid-stimulating hormone levels that were 0.3-0.5× and 3.3-3.7× of controls, respectively. At this dose, fetuses of pexacerfont-treated dams presented findings associated with maternal hypothyroidism including growth retardation and increased skeletal alterations. Additionally, there were unexpected great vessel malformations that were mostly derived from the 4th pharyngeal arch artery in 5 (4.3%) fetuses from 3 (15.8%) litters. The etiology was unclear whether the vascular malformations were related to insufficient thyroid hormones or another mechanism. To better understand this relationship, pregnant rats were implanted with a subcutaneous L-thyroxine pellet designed to provide a sustained release of T4 throughout organogenesis in rat embryos (GD 6 to 15; the dosing period of pexacerfont). T4 supplementation produced a near euthyroid state in pexacerfont-treated dams and completely prevented the fetal vascular malformations. These results suggest maternal T4 levels during organogenesis may have a role in great vessel morphogenesis associated with patterning and/or regression of pharyngeal arch arteries. Although previous clinical reports have speculated a potential relationship between thyroid hormone homeostasis and early cardiovascular development, this is the first report to experimentally demonstrate this relationship in great vessel morphogenesis.

Pegbelfermin, a PEGylated FGF21 analogue, has pharmacology without bone toxicity after 1-year dosing in skeletally-mature monkeys.

Pegbelfermin (PGBF) is a PEGylated fibroblast growth factor 21 (FGF21) analogue in development for treatment of nonalcoholic steatohepatitis (NASH). Mouse models highlight potential utility of FGF21 in NASH, but also suggest negative effects on bone, though these findings are confounded by profound FGF21-related decreases in body mass/growth. This study aimed to profile PGBF-related bone effects in adult nonhuman primates after long-term, clinically-relevant exposures. Adult male cynomolgus monkeys received weekly subcutaneous PGBF (0.3, 0.75 mg/kg) or control injections for 1 year (n = 5/group). Assessments included body weight, clinical chemistry, adiponectin levels, bone turnover biomarkers, skeletal radiography, pharmacokinetics, immunogenicity, and histopathology. Bone densitometry and body composition were evaluated in vivo and/or ex vivo with dual-energy x-ray absorptiometry, peripheral quantitative computed tomography, and biomechanical strength testing. After 1 year of PGBF administration, there was clear evidence of sustained PGBF pharmacology in monkeys (peak increase in serum adiponectin of 1.7× and 2.35× pretest at 0.3 and 0.75 mg/kg PGBF, respectively) and decreased body weight compared with control at exposures comparable to those tested in humans. At 0.75 mg/kg PGBF, pharmacologically-mediated reductions in lean mass, lean area, and fat area were observed relative to controls. There were no PGBF-related effects on bone biomarkers, radiography, densitometry, or strength. Together, these data demonstrate that PGBF did not adversely alter bone metabolism, density, or strength following 1 year of dosing at clinically relevant (0.7-2.2× human AUC[0-168 h] at 20 mg once weekly), pharmacologically-active exposures in adult monkeys, suggesting a low potential for negative effects on bone quality in adult humans.

Projecting one's own spatial bias onto others during a theory-of-mind task.

Many people show a left-right bias in visual processing. We measured spatial bias in neurotypical participants using a variant of the line bisection task. In the same participants, we measured performance in a social cognition task. This theory-of-mind task measured whether each participant had a processing-speed bias toward the right of, or left of, a cartoon agent about which the participant was thinking. Crucially, the cartoon was rotated such that what was left and right with respect to the cartoon was up and down with respect to the participant. Thus, a person's own left-right bias could not align directly onto left and right with respect to the cartoon head. Performance on the two tasks was significantly correlated. People who had a natural bias toward processing their own left side of space were quicker to process how the cartoon might think about objects to the left side of its face, and likewise for a rightward bias. One possible interpretation of these results is that the act of processing one's own personal space shares some of the same underlying mechanisms as the social cognitive act of reconstructing someone else's processing of their space.

Decreased immune response in monkeys administered a human T-effector cell agonist (OX40) antibody.

The OX40 receptor plays a crucial co-stimulatory role in T effector cell survival, expansion, cytokine production, and cytotoxicity to tumor cells; therefore, OX40 agonists are being evaluated as anti-cancer immunotherapies, especially in combination with checkpoint inhibitors. To support clinical development of BMS-986178 (an OX40 agonist antibody), two repeat-dose toxicity studies were conducted in cynomolgus monkeys. In the first study, BMS-986178 was administered intravenously (IV) once weekly for one month at doses from 30 to 120 mg/kg. BMS-986178 was well tolerated; surprisingly, immune function was suppressed rather than increased based on pharmacodynamic (PD) and flow cytometry readouts (e.g. T-cell dependent antibody response [TDAR]). To determine whether immune suppression was due to a bi-phasic response, a follow-up study was conducted at lower doses (1 and 10 mg/kg). Although receptor engagement was confirmed, immune function was still suppressed at both doses. In addition, treatment-emergent anti-drug antibodies (ADAs) at 1 mg/kg resulted in hypersensitivity reactions and reduced BMS-986178 exposure after repeated dosing, which precluded a full PD assessment at this dose. In conclusion, BMS-986178 was clinically well-tolerated by monkeys at weekly IV doses from 10 to 120 mg/kg (AUC[0-168] ≤ 712,000 µg●h/mL). However, despite target engagement, PD assays and other immune endpoints demonstrated immune suppression, not stimulation. Due to the inverted immune response at higher doses and the onset of ADAs, additional repeat-dose toxicity studies of BMS-986178 in monkeys (that would typically be required to support Phase 3 clinical trials and registration) would not add value for human safety assessment.

Consciousness and the attention schema: Why it has to be right.

This article describes some aspects of the underlying logic of the attention schema theory (AST) of subjective consciousness. It is a theory that distinguishes between what the brain actually, physically has, what is represented by information models constructed in the brain, what higher cognition thinks based on access to those models and what speech machinery claims based on the information within higher cognition. It is a theory of how we claim to have an essentially magical, subjective mind, based on the impoverishment and reduction of information along that pathway. While the article can stand on its own as a brief account of some critical aspects of AST, it specifically addresses questions and concerns raised by a set of commentaries on a target article.

Toward a standard model of consciousness: Reconciling the attention schema, global workspace, higher-order thought, and illusionist theories.

Here we examine how people's understanding of consciousness may have been shaped by an implicit theory of mind. This social cognition approach may help to make sense of an apparent divide between the physically incoherent consciousness we think we have and the complex, rich, but mechanistic consciousness we may actually have. We suggest this approach helps reconcile some of the current cognitive neuroscience theories of consciousness. We argue that a single, coherent explanation of consciousness is available and has been for some time, encompassing the views of many researchers, but is not yet recognized. It is obscured partly by terminological differences, and partly because researchers view isolated pieces of it as rival theories. It may be time to recognize that a deeper, coherent pool of ideas, a kind of standard model, is available to explain multiple layers of consciousness and how they relate to specific networks within the brain.

Intermittent dosing of the transforming growth factor beta receptor 1 inhibitor, BMS-986260, mitigates class-based cardiovascular toxicity in dogs but not rats.

Small-molecule inhibitors of transforming growth factor beta receptor 1 (TGFßRI) have a history of significant class-based toxicities (eg, cardiac valvulopathy) in preclinical species that have limited their development as new medicines. Nevertheless, some TGFßRI inhibitors have entered into clinical trials using intermittent-dosing schedules and exposure limits in an attempt to avoid these toxicities. This report describes the toxicity profile of the small-molecule TGFßRI inhibitor, BMS-986260, in rats and dogs. Daily oral dosing for 10 days resulted in valvulopathy and/or aortic pathology at systemic exposures that would have been targeted clinically, preventing further development with this dosing schedule. These toxicities were not observed in either species in 1-month studies using the same doses on an intermittent-dosing schedule of 3 days on and 4 days off (QDx3 once weekly). Subsequently, 3-month studies were conducted (QDx3 once weekly), and while there were no cardiovascular findings in dogs, valvulopathy and mortality occurred early in rats. The only difference compared to the 1-month study was that the rats in the 3-month study were 2 weeks younger at the start of dosing. Therefore, a follow-up 1-month study was conducted to evaluate whether the age of rats influences sensitivity to target-mediated toxicity. Using the same dosing schedule and similar doses as in the 3-month study, there was no difference in the toxicity of BMS-986260 in young (8 weeks) or adult (8 months) rats. In summary, an intermittent-dosing schedule mitigated target-based cardiovascular toxicity in dogs but did not prevent valvulopathy in rats, and thus the development of BMS-986260 was terminated.

Cortical networks involved in visual awareness independent of visual attention.

It is now well established that visual attention, as measured with standard spatial attention tasks, and visual awareness, as measured by report, can be dissociated. It is possible to attend to a stimulus with no reported awareness of the stimulus. We used a behavioral paradigm in which people were aware of a stimulus in one condition and unaware of it in another condition, but the stimulus drew a similar amount of spatial attention in both conditions. The paradigm allowed us to test for brain regions active in association with awareness independent of level of attention. Participants performed the task in an MRI scanner. We looked for brain regions that were more active in the aware than the unaware trials. The largest cluster of activity was obtained in the temporoparietal junction (TPJ) bilaterally. Local independent component analysis (ICA) revealed that this activity contained three distinct, but overlapping, components: a bilateral, anterior component; a left dorsal component; and a right dorsal component. These components had brain-wide functional connectivity that partially overlapped the ventral attention network and the frontoparietal control network. In contrast, no significant activity in association with awareness was found in the banks of the intraparietal sulcus, a region connected to the dorsal attention network and traditionally associated with attention control. These results show the importance of separating awareness and attention when testing for cortical substrates. They are also consistent with a recent proposal that awareness is associated with ventral attention areas, especially in the TPJ.

Toxicity of Pexacerfont, a Corticotropin-Releasing Factor Type 1 Receptor Antagonist, in Rats and Dogs.

Pexacerfont is a corticotropin-releasing factor subtype 1 receptor antagonist that was developed for the treatment of anxiety- and stress-related disorders. This report describes the results of repeat-dose oral toxicity studies in rats (3 and 6 months) and dogs (3 months and 1 year). Pexacerfont was well tolerated in all of these studies at exposures equal to or greater than areas under the curve in humans (clinical dose of 100 mg). Microscopic changes in the liver (hepatocellular hypertrophy), thyroid glands (hypertrophy/hyperplasia and adenomas of follicular cells), and pituitary (hypertrophy/hyperplasia and vacuolation of thyrotrophs) were only observed in rats and were considered adaptive changes in response to hepatic enzyme induction and subsequent alterations in serum thyroid hormone levels. Evidence for hepatic enzyme induction in dogs was limited to increased liver weights and reduced thyroxine (T4) levels. Mammary gland hyperplasia and altered female estrous cycling were only observed in rats, whereas adverse testicular effects (consistent with minimal to moderate degeneration of the germinal epithelium) were only noted following chronic dosing in dogs. The testicular effects were reversible changes with exposure margins of 8× at the no observed adverse effect level. It is not clear whether the changes in mammary gland, estrous cycling, and testes represent secondary hormonal changes due to perturbation of the hypothalamic-pituitary-adrenal axis or are off-target effects. In conclusion, the results of chronic toxicity studies in rats and dogs show that pexacerfont has an acceptable safety profile to support further clinical testing.

Evaluation of Uracil, Sodium Ascorbate, and Rosiglitazone as Promoters of Urinary Bladder Transitional Cell Carcinomas in Male Sprague-Dawley Rats.

The purpose of this study was to establish a 2-stage model of urinary bladder carcinogenesis in male Sprague-Dawley rats to identify tumor promoters. In phase 1 of the study, rats ( n = 170) were administered 100 mg/kg of the tumor initiator, N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN), twice weekly by oral gavage (po) for a period of 6 weeks. Phase 2 consisted of dividing rats into 4 groups ( n = 40 per group) and administering one of the following for 26 weeks to identify putative tumor promoters: (1) vehicle po, (2) 25 mg/kg/day rosiglitazone po, (3) 5% dietary sodium l-ascorbate, and (4) 3% dietary uracil. Rats were necropsied after 7.5 months, and urinary bladders were evaluated by histopathology. BBN/vehicle treatments induced the development of urothelial hyperplasia (83%) and papillomas (15%) but no transitional cell carcinomas (TCCs). Rosiglitazone increased the incidence and severity of papillomas (93%) and resulted in TCC in 10% of treated rats. Uracil was the most effective tumor promoter in our study and increased the incidence of papillomas (90%) and TCC (74%). Sodium ascorbate decreased the incidence of urothelial hyperplasia (63%) and did not increase the incidence of urothelial papillomas or TCC. These data confirm the capacity of our 2-stage model to identify urinary bladder tumor promoters.

Functional Connectivity Between the Temporoparietal Cortex and Cerebellum in Autism Spectrum Disorder.

The neural basis of autism spectrum disorder (ASD) is not yet understood. ASD is marked by social deficits and is strongly associated with cerebellar abnormalities. We studied the organization and cerebellar connectivity of the temporoparietal junction (TPJ), an area that plays a crucial role in social cognition. We applied localized independent component analysis to resting-state fMRI data from autistic and neurotypical adolescents to yield an unbiased parcellation of the bilateral TPJ into 11 independent components (ICs). A comparison between neurotypical and autistic adolescents showed that the organization of the TPJ was not significantly altered in ASD. Second, we used the time courses of the TPJ ICs as spatially unbiased "seeds" for a functional connectivity analysis applied to voxels within the cerebellum. We found that the cerebellum contained a fine-grained, lateralized map of the TPJ. The connectivity of the TPJ subdivisions with cerebellar zones showed one striking difference in ASD. The right dorsal TPJ showed markedly less connectivity with the left Crus II. Disturbed cerebellar input to this key region for cognition and multimodal integration may contribute to social deficits in ASD. The findings might also suggest that the right TPJ and/or left Crus II are potential targets for noninvasive brain stimulation therapies.

Safety assessment of propylparaben in juvenile rats.

There are conflicting literature reports that parabens, useful antimicrobial additives in pharmaceuticals, may have estrogenic activity. We conducted a comprehensive study to determine whether propylparaben (PP) administration to juvenile rats is associated with adverse effects on reproductive development and function. PP was administered orally once daily to groups of Crl:CD(SD) rats at doses of 0 (vehicle), 10, 100, or 1,000 mg/kg on Postnatal Days (PNDs) 4-90. In-life observations, clinical pathology, reproductive organ weights and histopathology, landmarks of sexual maturation, estrous cyclicity and functional reproductive competence were assessed. A conventional uterotrophic assay was conducted separately using the same doses. Systemic exposures to PP and 3 metabolites were evaluated on PND 7, 21 and 83. These studies demonstrated that PP was well tolerated when administered from PND 4-90 at all doses (AUC[0-T] on PND 83 = 69.9 ng•h/mL). Para-hydroxybenzoic acid, a non-estrogenic compound, was the predominant metabolite contributing to 95% of the total exposure at 1,000 mg/kg/day on PND 7. There was no evidence of estrogenic activity at any dose, and no effects on reproductive organs or function. The No-Observed-Adverse-Effect-Level (NOAEL) was 1,000 mg/kg/day.