Neuronal Computation Underlying Inferential Reasoning in Humans and Mice.

Every day we make decisions critical for adaptation and survival. We repeat actions with known consequences. But we also draw on loosely related events to infer and imagine the outcome of entirely novel choices. These inferential decisions are thought to engage a number of brain regions; however, the underlying neuronal computation remains unknown. Here, we use a multi-day cross-species approach in humans and mice to report the functional anatomy and neuronal computation underlying inferential decisions. We show that during successful inference, the mammalian brain uses a hippocampal prospective code to forecast temporally structured learned associations. Moreover, during resting behavior, coactivation of hippocampal cells in sharp-wave/ripples represent inferred relationships that include reward, thereby "joining-the-dots" between events that have not been observed together but lead to profitable outcomes. Computing mnemonic links in this manner may provide an important mechanism to build a cognitive map that stretches beyond direct experience, thus supporting flexible behavior.

Think You Know How Smell Works? Sniff Again.

The sense of smell is mediated by GPCRs in the odorant receptor (OR) family. Greer et al. report a new family of odor detectors, MS4As, that have similar cellular localization and chemodetection ability as ORs but are not GPCRs and follow a strikingly different logic of odor coding at the periphery.

Language is primarily a tool for communication rather than thought.

Language is a defining characteristic of our species, but the function, or functions, that it serves has been debated for centuries. Here we bring recent evidence from neuroscience and allied disciplines to argue that in modern humans, language is a tool for communication, contrary to a prominent view that we use language for thinking. We begin by introducing the brain network that supports linguistic ability in humans. We then review evidence for a double dissociation between language and thought, and discuss several properties of language that suggest that it is optimized for communication. We conclude that although the emergence of language has unquestionably transformed human culture, language does not appear to be a prerequisite for complex thought, including symbolic thought. Instead, language is a powerful tool for the transmission of cultural knowledge; it plausibly co-evolved with our thinking and reasoning capacities, and only reflects, rather than gives rise to, the signature sophistication of human cognition.

Preserved neural dynamics across animals performing similar behaviour.

Animals of the same species exhibit similar behaviours that are advantageously adapted to their body and environment. These behaviours are shaped at the species level by selection pressures over evolutionary timescales. Yet, it remains unclear how these common behavioural adaptations emerge from the idiosyncratic neural circuitry of each individual. The overall organization of neural circuits is preserved across individuals1 because of their common evolutionarily specified developmental programme2-4. Such organization at the circuit level may constrain neural activity5-8, leading to low-dimensional latent dynamics across the neural population9-11. Accordingly, here we suggested that the shared circuit-level constraints within a species would lead to suitably preserved latent dynamics across individuals. We analysed recordings of neural populations from monkey and mouse motor cortex to demonstrate that neural dynamics in individuals from the same species are surprisingly preserved when they perform similar behaviour. Neural population dynamics were also preserved when animals consciously planned future movements without overt behaviour12 and enabled the decoding of planned and ongoing movement across different individuals. Furthermore, we found that preserved neural dynamics extend beyond cortical regions to the dorsal striatum, an evolutionarily older structure13,14. Finally, we used neural network models to demonstrate that behavioural similarity is necessary but not sufficient for this preservation. We posit that these emergent dynamics result from evolutionary constraints on brain development and thus reflect fundamental properties of the neural basis of behaviour.

Single-neuronal predictions of others' beliefs in humans.

Human social behaviour crucially depends on our ability to reason about others. This capacity for theory of mind has a vital role in social cognition because it enables us not only to form a detailed understanding of the hidden thoughts and beliefs of other individuals but also to understand that they may differ from our own1-3. Although a number of areas in the human brain have been linked to social reasoning4,5 and its disruption across a variety of psychosocial disorders6-8, the basic cellular mechanisms that underlie human theory of mind remain undefined. Here, using recordings from single cells in the human dorsomedial prefrontal cortex, we identify neurons that reliably encode information about others' beliefs across richly varying scenarios and that distinguish self- from other-belief-related representations. By further following their encoding dynamics, we show how these cells represent the contents of the others' beliefs and accurately predict whether they are true or false. We also show how they track inferred beliefs from another's specific perspective and how their activities relate to behavioural performance. Together, these findings reveal a detailed cellular process in the human dorsomedial prefrontal cortex for representing another's beliefs and identify candidate neurons that could support theory of mind.

Drop that pipette: science by design.

An unexpected collaboration between a synthetic biology lab at UCSF and a Palo Alto-based design firm is stirring up the way that research is conceived and conducted, by integrating innovation and "design thinking" into the scientific method.

Differences in the neural correlates of schizophrenia with positive and negative formal thought disorder in patients with schizophrenia in the ENIGMA dataset.

Formal thought disorder (FTD) is a clinical key factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, the relationship between FTD symptom dimensions and patterns of regional brain volume loss in schizophrenia remains to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles by enrolling a large multi-site cohort acquired by the ENIGMA Schizophrenia Working Group (752 schizophrenia patients and 1256 controls), to unravel the neuroanatomy of FTD in schizophrenia and using virtual histology tools on implicated brain regions to investigate the cellular basis. Based on the findings of previous clinical and neuroimaging studies, we decided to separately explore positive, negative and total formal thought disorder. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but positive and negative FTD demonstrated a dissociation: negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD also showed associations with microglial cell types. These results provide an important step towards linking FTD to brain structural changes and their cellular underpinnings, providing an avenue for a better mechanistic understanding of this syndrome.

Default mode network electrophysiological dynamics and causal role in creative thinking.

The default mode network (DMN) is a widely distributed, intrinsic brain network thought to play a crucial role in internally directed cognition. The present study employs stereo-EEG in 13 human patients, obtaining high resolution neural recordings across multiple canonical DMN regions during two processes that have been associated with creative thinking: spontaneous and divergent thought. We probe these two DMN-associated higher cognitive functions through mind wandering and alternate uses tasks, respectively. Our results reveal DMN recruitment during both tasks, as well as a task-specific dissociation in spatiotemporal response dynamics. When compared to the fronto-parietal network, DMN activity was characterized by a stronger increase in gamma band power (30-70 Hz) coupled with lower theta band power (4-8 Hz). The difference in activity between the two networks was especially strong during the mind wandering task. Within the DMN, we found that the tasks showed different dynamics, with the alternate uses task engaging the DMN more during the initial stage of the task, and mind wandering in the later stage. Gamma power changes were mainly driven by lateral DMN sites, while theta power displayed task-specific effects. During alternate uses task, theta changes did not show spatial differences within the DMN, while mind wandering was associated to an early lateral and late dorsomedial DMN engagement. Furthermore, causal manipulations of DMN regions using direct cortical stimulation preferentially decreased the originality of responses in the alternative uses task, without affecting fluency or mind wandering. Our results suggest that DMN activity is flexibly modulated as a function of specific cognitive processes and supports its causal role in divergent thinking. These findings shed light on the neural constructs supporting different forms of cognition and provide causal evidence for the role of DMN in the generation of original connections among concepts.

Effect of cognitive load on time spent offline during wakefulness.

Humans continuously alternate between online attention to the current environment and offline attention to internally generated thought and imagery. This may be a fundamental feature of the waking brain, but remains poorly understood. Here, we took a data-driven approach to defining online and offline states of wakefulness, using machine learning methods applied to measures of sensory responsiveness, subjective report, electroencephalogram (EEG), and pupil diameter. We tested the effect of cognitive load on the structure and prevalence of online and offline states, hypothesizing that time spent offline would increase as cognitive load of an ongoing task decreased. We also expected that alternation between online and offline states would persist even in the absence of a cognitive task. As in prior studies, we arrived at a three-state model comprised of one online state and two offline states. As predicted, when cognitive load was high, more time was spent online. Also as predicted, the same three states were present even when participants were not performing a task. These observations confirm our method is successful at isolating seconds-long periods of offline time. Varying cognitive load may be a useful way to manipulate time spent in at least one of these offline states in future experimental studies.

The paradoxical brain: paradoxes impact conflict perspectives through increased neural alignment.

Mental perspectives can sometimes be changed by psychological interventions. For instance, when applied in the context of intergroup conflicts, interventions, such as the paradoxical thinking intervention, may unfreeze ingrained negative outgroup attitudes and thereby promote progress toward peacemaking. Yet, at present, the evaluation of interventions' impact relies almost exclusively on self-reported and behavioral measures that are informative, but are also prone to social desirability and self-presentational biases. In the present study, magnetoencephalography tracked neural alignment, before and after the paradoxical thinking intervention, during the processing of auditory narratives over the Israeli-Palestinian conflict and thereby evaluated the intervention's potential to change individuals' (n = 80) mental perspectives over the conflict. Compared to baseline, the conflict-targeted intervention yielded a specific significant increased neural alignment in the posterior superior temporal sulcus while processing incongruent as well as congruent political narratives of the conflict. This may be interpreted as a possible change in perspective over the conflict. The results and their interpretations are discussed in view of the critical added value of neuroimaging when assessing interventions to potentially reveal changes in mental perspectives or the way in which they are processed, even in contexts of entrenched resistance to reconsider one's ideological stance.

The neural signature of an erroneous thought.

The human brain detects errors in overt behavior fast and efficiently. However, little is known about how errors are monitored that emerge on a mental level. We investigate whether neural correlates of error monitoring can be found during inner speech and whether the involved neural processes differ between these non-motor responses and behavioral motor responses. Therefore, electroencephalographic data were collected while participants performed two versions of a decision task that only differed between these response modalities. Erroneous responses were identified based on participants' metacognitive judgments. Correlates of error monitoring in event-related potentials were analyzed by applying residue iteration decomposition on stimulus-locked activity. Non-motor responses elicited the same cascade of early error-related negativity and late error positivity as motor responses. An analysis of oscillatory brain activity showed a similar theta response for both error types. A multivariate pattern classifier trained on theta from the motor condition could decode theta from the non-motor condition, demonstrating the similarity of both neural responses. These results show that errors in inner speech are monitored and detected utilizing the same neural processes as behavioral errors, suggesting that goal-directed cognition and behavior are supported by a generic error-monitoring system.

Mind blanking is a distinct mental state linked to a recurrent brain profile of globally positive connectivity during ongoing mentation.

Mind blanking (MB) is a waking state during which we do not report any mental content. The phenomenology of MB challenges the view of a constantly thinking mind. Here, we comprehensively characterize the MB's neurobehavioral profile with the aim to delineate its role during ongoing mentation. Using functional MRI experience sampling, we show that the reportability of MB is less frequent, faster, and with lower transitional dynamics than other mental states, pointing to its role as a transient mental relay. Regarding its neural underpinnings, we observed higher global signal amplitude during MB reports, indicating a distinct physiological state. Using the time-varying functional connectome, we show that MB reports can be classified with high accuracy, suggesting that MB has a unique neural composition. Indeed, a pattern of global positive-phase coherence shows the highest similarity to the connectivity patterns associated with MB reports. We interpret this pattern's rigid signal architecture as hindering content reportability due to the brain's inability to differentiate signals in an informative way. Collectively, we show that MB has a unique neurobehavioral profile, indicating that nonreportable mental events can happen during wakefulness. Our results add to the characterization of spontaneous mentation and pave the way for more mechanistic investigations of MB's phenomenology.

Visual object categorization in infancy.

Humans make sense of the world by organizing things into categories. When and how does this process begin? We investigated whether real-world object categories that spontaneously emerge in the first months of life match categorical representations of objects in the human visual cortex. Using eye tracking, we measured the differential looking time of 4-, 10-, and 19-mo-olds as they looked at pairs of pictures belonging to eight animate or inanimate categories (human/nonhuman, faces/bodies, real-world size big/small, natural/artificial). Taking infants' looking times as a measure of similarity, for each age group, we defined a representational space where each object was defined in relation to others of the same or of a different category. This space was compared with hypothesis-based and functional MRI-based models of visual object categorization in the adults' visual cortex. Analyses across different age groups showed that, as infants grow older, their looking behavior matches neural representations in ever-larger portions of the adult visual cortex, suggesting progressive recruitment and integration of more and more feature spaces distributed over the visual cortex. Moreover, the results characterize infants' visual categorization as an incremental process with two milestones. Between 4 and 10 mo, visual exploration guided by saliency gives way to an organization according to the animate-inanimate distinction. Between 10 and 19 mo, a category spurt leads toward a mature organization. We propose that these changes underlie the coupling between seeing and thinking in the developing mind.

Mapping the neural mechanism that distinguishes between holistic thinking and analytic thinking.

Holistic and analytic thinking are two distinct modes of thinking used to interpret the world with relative preferences varying across cultures. While most research on these thinking styles has focused on behavioral and cognitive aspects, a few studies have utilized functional magnetic resonance imaging (fMRI) to explore the correlations between brain metrics and self-reported scale scores. Other fMRI studies used single holistic and analytic thinking tasks. As a single task may involve processing in spurious low-level regions, we used two different holistic and analytic thinking tasks, namely the frame-line task and the triad task, to seek convergent brain regions to distinguish holistic and analytic thinking using multivariate pattern analysis (MVPA). Results showed that brain regions fundamental to distinguish holistic and analytic thinking include the bilateral frontal lobes, bilateral parietal lobes, bilateral precentral and postcentral gyrus, bilateral supplementary motor areas, bilateral fusiform, bilateral insula, bilateral angular gyrus, left cuneus, and precuneus, left olfactory cortex, cingulate gyrus, right caudate and putamen. Our study maps brain regions that distinguish between holistic and analytic thinking and provides a new approach to explore the neural representation of cultural constructs. We provide initial evidence connecting culture-related brain regions with language function to explain the origins of cultural differences in cognitive styles.

Perceived plausibility modulates hippocampal activity in episodic counterfactual thinking.

Episodic counterfactual thinking (ECT) consists of imagining alternative outcomes to past personal events. Previous research has shown that ECT shares common neural substrates with episodic future thinking (EFT): our ability to imagine possible future events. Both ECT and EFT have been shown to critically depend on the hippocampus, and past research has explored hippocampal engagement as a function of the perceived plausibility of an imagined future event. However, the extent to which the hippocampus is modulated by perceived plausibility during ECT is unknown. In this study, we combine two functional magnetic resonance imaging datasets to investigate whether perceived plausibility modulates hippocampal activity during ECT. Our results indicate that plausibility parametrically modulates hippocampal activity during ECT, and that such modulation is confined to the left anterior portion of the hippocampus. Moreover, our results indicate that this modulation is positive, such that increased activity in the left anterior hippocampus is associated with higher ratings of ECT plausibility. We suggest that neither effort nor difficulty alone can account for these results, and instead suggest possible alternatives to explain the role of the hippocampus during the construction of plausible and implausible ECT.

Conscious but not thinking-Mind-blanks during visuomotor tracking: An fMRI study of endogenous attention lapses.

Attention lapses (ALs) are complete lapses of responsiveness in which performance is briefly but completely disrupted and during which, as opposed to microsleeps, the eyes remain open. Although the phenomenon of ALs has been investigated by behavioural and physiological means, the underlying cause of an AL has largely remained elusive. This study aimed to investigate the underlying physiological substrates of behaviourally identified endogenous ALs during a continuous visuomotor task, primarily to answer the question: Were the ALs during this task due to extreme mind-wandering or mind-blanks? The data from two studies were combined, resulting in data from 40 healthy non-sleep-deprived subjects (20M/20F; mean age 27.1 years, 20-45). Only 17 of the 40 subjects were used in the analysis due to a need for a minimum of two ALs per subject. Subjects performed a random 2-D continuous visuomotor tracking task for 50 and 20 min in Studies 1 and 2, respectively. Tracking performance, eye-video, and functional magnetic resonance imaging (fMRI) were recorded simultaneously. A human expert visually inspected the tracking performance and eye-video recordings to identify and categorise lapses of responsiveness as microsleeps or ALs. Changes in neural activity during 85 ALs (17 subjects) relative to responsive tracking were estimated by whole-brain voxel-wise fMRI and by haemodynamic response (HR) analysis in regions of interest (ROIs) from seven key networks to reveal the neural signature of ALs. Changes in functional connectivity (FC) within and between the key ROIs were also estimated. Networks explored were the default mode network, dorsal attention network, frontoparietal network, sensorimotor network, salience network, visual network, and working memory network. Voxel-wise analysis revealed a significant increase in blood-oxygen-level-dependent activity in the overlapping dorsal anterior cingulate cortex and supplementary motor area region but no significant decreases in activity; the increased activity is considered to represent a recovery-of-responsiveness process following an AL. This increased activity was also seen in the HR of the corresponding ROI. Importantly, HR analysis revealed no trend of increased activity in the posterior cingulate of the default mode network, which has been repeatedly demonstrated to be a strong biomarker of mind-wandering. FC analysis showed decoupling of external attention, which supports the involuntary nature of ALs, in addition to the neural recovery processes. Other findings were a decrease in HR in the frontoparietal network before the onset of ALs, and a decrease in FC between default mode network and working memory network. These findings converge to our conclusion that the ALs observed during our task were involuntary mind-blanks. This is further supported behaviourally by the short duration of the ALs (mean 1.7 s), which is considered too brief to be instances of extreme mind-wandering. This is the first study to demonstrate that at least the majority of complete losses of responsiveness on a continuous visuomotor task are, if not due to microsleeps, due to involuntary mind-blanks.

Effects of task context on EEG correlates of mind-wandering.

This study was designed to examine how mind-wandering and its neural correlates vary across tasks with different attentional demands, motivated by the context regulation hypothesis of mind-wandering. Participants (n = 59 undergraduates) completed the sustained attention to response task (SART) and the Stroop selective attention task in counterbalanced order while EEG was recorded. The tasks included experience-sampling probes to identify self-reported episodes of mind-wandering, along with retrospective reports. Participants reported more mind-wandering during the SART than the Stroop and during whichever task was presented second during the session, compared with first. Replicating previous findings, EEG data (n = 37 usable participants) indicated increased alpha oscillations during episodes of mind-wandering, compared with on-task episodes, for both the SART and Stroop tasks. ERP data, focused on the P2 component reflecting perceptual processing, found that mind-wandering was associated with increased P2 amplitudes during the Stroop task, counter to predictions from the perceptual decoupling theory. Overall, the study found that self-report and neural correlates of mind-wandering are sensitive to task context. This line of research can further the understanding of how mechanisms of mind-wandering are adapted to varied tasks and situations.

Thinking computationally in translational psychiatry. A commentary on Neville et al. (2024).

There is a growing focus on the computational aspects of psychiatric disorders in humans. This idea also is gaining traction in nonhuman animal studies. Commenting on a new comprehensive overview of the benefits of applying this approach in translational research by Neville et al. (Cognitive Affective & Behavioral Neuroscience 1-14, 2024), we discuss the implications for translational model validity within this framework. We argue that thinking computationally in translational psychiatry calls for a change in the way that we evaluate animal models of human psychiatric processes, with a shift in focus towards symptom-producing computations rather than the symptoms themselves. Further, in line with Neville et al.'s adoption of the reinforcement learning framework to model animal behaviour, we illustrate how this approach can be applied beyond simple decision-making paradigms to model more naturalistic behaviours.