ICH S1 prospective evaluation study and weight of evidence assessments: commentary from industry representatives.

Industry representatives on the ICH S1B(R1) Expert Working Group (EWG) worked closely with colleagues from the Drug Regulatory Authorities to develop an addendum to the ICH S1B guideline on carcinogenicity studies that allows for a weight-of-evidence (WoE) carcinogenicity assessment in some cases, rather than conducting a 2-year rat carcinogenicity study. A subgroup of the EWG composed of regulators have published in this issue a detailed analysis of the Prospective Evaluation Study (PES) conducted under the auspices of the ICH S1B(R1) EWG. Based on the experience gained through the Prospective Evaluation Study (PES) process, industry members of the EWG have prepared the following commentary to aid sponsors in assessing the standard WoE factors, considering how novel investigative approaches may be used to support a WoE assessment, and preparing appropriate documentation of the WoE assessment for presentation to regulatory authorities. The commentary also reviews some of the implementation challenges sponsors must consider in developing a carcinogenicity assessment strategy. Finally, case examples drawn from previously marketed products are provided as a supplement to this commentary to provide additional examples of how WoE criteria may be applied. The information and opinions expressed in this commentary are aimed at increasing the quality of WoE assessments to ensure the successful implementation of this approach.

Testing theory of mind in large language models and humans.

At the core of what defines us as humans is the concept of theory of mind: the ability to track other people's mental states. The recent development of large language models (LLMs) such as ChatGPT has led to intense debate about the possibility that these models exhibit behaviour that is indistinguishable from human behaviour in theory of mind tasks. Here we compare human and LLM performance on a comprehensive battery of measurements that aim to measure different theory of mind abilities, from understanding false beliefs to interpreting indirect requests and recognizing irony and faux pas. We tested two families of LLMs (GPT and LLaMA2) repeatedly against these measures and compared their performance with those from a sample of 1,907 human participants. Across the battery of theory of mind tests, we found that GPT-4 models performed at, or even sometimes above, human levels at identifying indirect requests, false beliefs and misdirection, but struggled with detecting faux pas. Faux pas, however, was the only test where LLaMA2 outperformed humans. Follow-up manipulations of the belief likelihood revealed that the superiority of LLaMA2 was illusory, possibly reflecting a bias towards attributing ignorance. By contrast, the poor performance of GPT originated from a hyperconservative approach towards committing to conclusions rather than from a genuine failure of inference. These findings not only demonstrate that LLMs exhibit behaviour that is consistent with the outputs of mentalistic inference in humans but also highlight the importance of systematic testing to ensure a non-superficial comparison between human and artificial intelligences.

Ascribing consciousness to artificial intelligence: human-AI interaction and its carry-over effects on human-human interaction.

The question of whether artificial intelligence (AI) can be considered conscious and therefore should be evaluated through a moral lens has surfaced in recent years. In this paper, we argue that whether AI is conscious is less of a concern than the fact that AI can be considered conscious by users during human-AI interaction, because this ascription of consciousness can lead to carry-over effects on human-human interaction. When AI is viewed as conscious like a human, then how people treat AI appears to carry over into how they treat other people due to activating schemas that are congruent to those activated during interactions with humans. In light of this potential, we might consider regulating how we treat AI, or how we build AI to evoke certain kinds of treatment from users, but not because AI is inherently sentient. This argument focuses on humanlike, social actor AI such as chatbots, digital voice assistants, and social robots. In the first part of the paper, we provide evidence for carry-over effects between perceptions of AI consciousness and behavior toward humans through literature on human-computer interaction, human-AI interaction, and the psychology of artificial agents. In the second part of the paper, we detail how the mechanism of schema activation can allow us to test consciousness perception as a driver of carry-over effects between human-AI interaction and human-human interaction. In essence, perceiving AI as conscious like a human, thereby activating congruent mind schemas during interaction, is a driver for behaviors and perceptions of AI that can carry over into how we treat humans. Therefore, the fact that people can ascribe humanlike consciousness to AI is worth considering, and moral protection for AI is also worth considering, regardless of AI's inherent conscious or moral status.

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.

Human engineered cardiac tissue model of hypertrophic cardiomyopathy recapitulates key hallmarks of the disease and the effect of chronic mavacamten treatment.

Introduction: The development of patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offers an opportunity to study genotype-phenotype correlation of hypertrophic cardiomyopathy (HCM), one of the most common inherited cardiac diseases. However, immaturity of the iPSC-CMs and the lack of a multicellular composition pose concerns over its faithfulness in disease modeling and its utility in developing mechanism-specific treatment. Methods: The Biowire platform was used to generate 3D engineered cardiac tissues (ECTs) using HCM patient-derived iPSC-CMs carrying a ß-myosin mutation (MYH7-R403Q) and its isogenic control (WT), withal ECTs contained healthy human cardiac fibroblasts. ECTs were subjected to electro-mechanical maturation for 6 weeks before being used in HCM phenotype studies. Results: Both WT and R403Q ECTs exhibited mature cardiac phenotypes, including a lack of automaticity and a ventricular-like action potential (AP) with a resting membrane potential < -75 mV. Compared to WT, R403Q ECTs demonstrated many HCM-associated pathological changes including increased tissue size and cell volume, shortened sarcomere length and disorganized sarcomere structure. In functional assays, R403Q ECTs showed increased twitch amplitude, slower contractile kinetics, a less pronounced force-frequency relationship, a smaller post-rest potentiation, prolonged AP durations, and slower Ca2+ transient decay time. Finally, we observed downregulation of calcium handling genes and upregulation of NPPB in R403Q vs. WT ECTs. In an HCM phenotype prevention experiment, ECTs were treated for 5-weeks with 250 nM mavacamten or a vehicle control. We found that chronic mavacamten treatment of R403Q ECTs: (i) shortened relaxation time, (ii) reduced APD90 prolongation, (iii) upregulated ADRB2, ATP2A2, RYR2, and CACNA1C, (iv) decreased B-type natriuretic peptide (BNP) mRNA and protein expression levels, and (v) increased sarcomere length and reduced sarcomere disarray. Discussion: Taken together, we demonstrated R403Q ECTs generated in the Biowire platform recapitulated many cardiac hypertrophy phenotypes and that chronic mavacamten treatment prevented much of the pathology. This demonstrates that the Biowire ECTs are well-suited to phenotypic-based drug discovery in a human-relevant disease model.

Fundamental principles of cortical organization reflected in a new study.

In an exciting new finding by Gordon et al., the human motor cortex does not show a traditional body map. Instead, body-part-specific zones are separated by integrative zones, possibly reflecting the statistical structure of the human motor repertoire.

Acute effects of cardiac contractility modulation stimulation in conventional 2D and 3D human induced pluripotent stem cell-derived cardiomyocyte models.

Cardiac contractility modulation (CCM) is a medical device therapy whereby non-excitatory electrical stimulations are delivered to the myocardium during the absolute refractory period to enhance cardiac function. We previously evaluated the effects of the standard CCM pulse parameters in isolated rabbit ventricular cardiomyocytes and 2D human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) monolayers, on flexible substrate. In the present study, we sought to extend these results to human 3D microphysiological systems to develop a robust model to evaluate various clinical CCM pulse parameters in vitro. HiPSC-CMs were studied in conventional 2D monolayer format, on stiff substrate (i.e., glass), and as 3D human engineered cardiac tissues (ECTs). Cardiac contractile properties were evaluated by video (i.e., pixel) and force-based analysis. CCM pulses were assessed at varying electrical 'doses' using a commercial pulse generator. A robust CCM contractile response was observed for 3D ECTs. Under comparable conditions, conventional 2D monolayer hiPSC-CMs, on stiff substrate, displayed no contractile response. 3D ECTs displayed enhanced contractile properties including increased contraction amplitude (i.e., force), and accelerated contraction and relaxation slopes under standard acute CCM stimulation. Moreover, 3D ECTs displayed enhanced contractility in a CCM pulse parameter-dependent manner by adjustment of CCM pulse delay, duration, amplitude, and number relative to baseline. The observed acute effects subsided when the CCM stimulation was stopped and gradually returned to baseline. These data represent the first study of CCM in 3D hiPSC-CM models and provide a nonclinical tool to assess various CCM device signals in 3D human cardiac tissues prior to in vivo animal studies. Moreover, this work provides a foundation to evaluate the effects of additional cardiac medical devices in 3D ECTs.

Activin A directly impairs human cardiomyocyte contractile function indicating a potential role in heart failure development.

Activin A has been linked to cardiac dysfunction in aging and disease, with elevated circulating levels found in patients with hypertension, atherosclerosis, and heart failure. Here, we investigated whether Activin A directly impairs cardiomyocyte (CM) contractile function and kinetics utilizing cell, tissue, and animal models. Hydrodynamic gene delivery-mediated overexpression of Activin A in wild-type mice was sufficient to impair cardiac function, and resulted in increased cardiac stress markers (N-terminal pro-atrial natriuretic peptide) and cardiac atrophy. In human-induced pluripotent stem cell-derived (hiPSC) CMs, Activin A caused increased phosphorylation of SMAD2/3 and significantly upregulated SERPINE1 and FSTL3 (markers of SMAD2/3 activation and activin signaling, respectively). Activin A signaling in hiPSC-CMs resulted in impaired contractility, prolonged relaxation kinetics, and spontaneous beating in a dose-dependent manner. To identify the cardiac cellular source of Activin A, inflammatory cytokines were applied to human cardiac fibroblasts. Interleukin -1ß induced a strong upregulation of Activin A. Mechanistically, we observed that Activin A-treated hiPSC-CMs exhibited impaired diastolic calcium handling with reduced expression of calcium regulatory genes (SERCA2, RYR2, CACNB2). Importantly, when Activin A was inhibited with an anti-Activin A antibody, maladaptive calcium handling and CM contractile dysfunction were abrogated. Therefore, inflammatory cytokines may play a key role by acting on cardiac fibroblasts, causing local upregulation of Activin A that directly acts on CMs to impair contractility. These findings demonstrate that Activin A acts directly on CMs, which may contribute to the cardiac dysfunction seen in aging populations and in patients with heart failure.

Conscious intention: New data on where and how in the brain.

How do we decide to act, and how do those decisions relate to conscious choice? A new study helps dissociate the neuronal mechanisms that choose, prepare, and trigger movement from our explicit reports of conscious intention.

Right temporoparietal junction encodes inferred visual knowledge of others.

When people make inferences about other people's minds, called theory of mind (ToM), a cortical network becomes active. The right temporoparietal junction (TPJ) is one of the most consistently responsive nodes in that network. Here we used a pictorial, reaction-time, ToM task to study brain activity in the TPJ and other cortical areas. Subjects were asked to take the perspective of a cartoon character and judge its knowledge of a visual display in front of it. The right TPJ showed evidence of encoding information about the implied visual knowledge of the cartoon head. When the subject was led to believe that the head could see a visual change take place, activity in the right TPJ significantly reflected that change. When the head could apparently not see the same visual change take place, activity in the right TPJ no longer significantly reflected that change. The subject could see the change in all cases; the critical factor that affected TPJ activity was whether the subject was led to think the cartoon character could see the change. We also found that whether the beliefs attributed to the cartoon head were true or false did not significantly affect activity in the present paradigm. These results suggest that the right TPJ may play a role in modeling the contents of the minds of others, perhaps more than it participates in evaluating the truth or falsity of that content.

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.

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.

Consciousness explained or described?

Consciousness is an unusual phenomenon to study scientifically. It is defined as a subjective, first-person phenomenon, and science is an objective, third-person endeavor. This misalignment between the means-science-and the end-explaining consciousness-gave rise to what has become a productive workaround: the search for 'neural correlates of consciousness' (NCCs). Science can sidestep trying to explain consciousness and instead focus on characterizing the kind(s) of neural activity that are reliably correlated with consciousness. However, while we have learned a lot about consciousness in the bargain, the NCC approach was not originally intended as the foundation for a true explanation of consciousness. Indeed, it was proposed precisely to sidestep the, arguably futile, attempt to find one. So how can an account, couched in terms of neural correlates, do the work that a theory is supposed to do: explain consciousness? The answer is that it cannot, and in fact most modern accounts of consciousness do not pretend to. Thus, here, we challenge whether or not any modern accounts of consciousness are in fact theories at all. Instead we argue that they are (competing) laws of consciousness. They describe what they cannot explain, just as Newton described gravity long before a true explanation was ever offered. We lay out our argument using a variety of modern accounts as examples and go on to argue that at least one modern account of consciousness, attention schema theory, goes beyond describing consciousness-related brain activity and qualifies as an explanatory theory.

The origin of smiling, laughing, and crying: The defensive mimic theory.

Why do we leak lubricant from the eyes to solicit comfort from others? Why do we bare our teeth and crinkle our faces to express non-aggression? The defensive mimic theory proposes that a broad range of human emotional expressions evolved originally as exaggerated, temporally extended mimics of the fast, defensive reflexes that normally protect the body surface. Defensive reflexes are so important to survival that they cannot be safely suppressed; yet they also broadcast information about an animal's internal state, information that can potentially be exploited by other animals. Once others can observe and exploit an animal's defensive reflexes, it may be advantageous to the animal to run interference by creating mimic defensive actions, thereby manipulating the behaviour of others. Through this interaction over millions of years, many human emotional expressions may have evolved. Here, human social signals including smiling, laughing and crying, are compared component-by-component with the known, well-studied features of primate defensive reflexes. It is suggested that the defensive mimic theory can adequately account for the physical form of not all, but a large range of, human emotional expression.

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.

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.

Thymic Lymphomas in a 6-Month rasH2-Tg Mouse Carcinogenicity Study With the RORγt Inverse Agonist, BMS-986251.

BMS-986251 is a retinoid-related orphan receptor γt (RORγt) inverse agonist that was in development for the treatment of autoimmune diseases. RORγt is a nuclear hormone receptor and transcription factor that is involved in the differentiation and function of T helper 17 cells. RORγt-deficient (constitutive or conditional) mice develop thymic lymphomas with >50% mortality at 4 months, whereas heterozygous mice are normal. A 6-month study was conducted in rasH2-Tg hemizygous mice to assess the potential carcinogenicity of BMS-986251. BMS-986251 was administered once daily by oral gavage to groups of 27 mice/sex at doses of 0 (water control), 0 (vehicle control), 5, 25, or 75 mg/kg. The positive control, N-methyl-N-nitrosourea, was administered by a single intraperitoneal injection to 15 mice/sex at a dose of 75 mg/kg. There were no tumors attributed to BMS-986251 except for thymic lymphomas. Thymic lymphoma was observed in 1 male (3.7%) and 3 females (11.1%) at the mid dose, and 6 females (22.2%) at the high dose. No lymphomas were observed in the negative control groups whereas the incidence of lymphomas in the positive control group was 47-60%. The incidence of thymic lymphomas in the BMS-986251-treated groups was higher than published literature and test facility historical control data. Furthermore, increased thymic lymphoid cellularity (lymphoid hyperplasia) was observed at the mid dose in males and at all doses in females. Since lymphoid hyperplasia may represent a preneoplastic change, a no-effect dose for potential tumor induction was not identified in this study. These results led to the discontinuation of BMS-986251 and underscore the challenges in targeting RORγt for drug development.

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.