Biology subjects

Freiwald, W. A.

Publications and source records attributed to Freiwald, W. A..

13 recordsLinked to original sources

bioRxiv2026

A neural circuit algorithm for action grammar

How does the brain generate sequences of discrete elements, such as actions or words, that follow an abstract rule (a grammar)? Motivated by an experiment in which monkeys learned to draw multi-object images according to grammatical rules, we trained a recurrent neural network to generate sequences Am Bn: producing shape A m times, then B n times, or vice versa. Our findings are threefold. First, the network plans the sequence by moving to an initial state encoding m and n along orthogonal directions for upcoming execution. Second, the network repeats each shape by progressing along a shape-specific manifold. Third, transitions from Am to Bn follow parallel trajectories between manifolds across values of n, thus preserving n. Each of these is an experimentally testable prediction. The network generalizes to longer novel sequences by starting further along the same orthogonal directions. These results reveal a neural circuit implementation of a symbolic algorithm for generating rule-based action sequences.

neuroscience↗

bioRxiv2026

Large-scale volumetric two-photon calcium imaging enables cellular-resolution mesoscopic mapping of marmoset cortical areas

Primate neocortex is organized into functionally defined domains. Understanding how the functional organization within each domain emerges from single-cell tuning properties has been hampered by the lack of imaging tools that can capture large-scale activity at different depths of the scattering primate brain at cellular resolution and physiological timescales. Here, we demonstrate mesoscopic and volumetric cellular-resolution calcium imaging of entire cortical areas in the marmoset brain at multi-Hertz rates by combining fluorescence lifetime-limited temporally multiplexed two-photon recording based on Light Beads Microscopy (LBM) with optimized calcium indicator targeting. Using this approach, we perform volumetric recording of neuronal population activity within cortical volumes spanning up to 4 x 4 x 0.3 mm3 capturing the simultaneous activity of over 96,000 cells, including more than 46,000 stimulus-responsive neurons. In auditory cortex, we found fine-grain heterogeneous tuning of individual neurons to frequencies within broader tonotopic gradients. In the middle temporal area (MT) we found direction tuning along functional continua rather than discrete categories, encompassing uni-, bi-, and pandirectional tuning, where cells with similar tuning tend to cluster. Tuning direction follows a columnar organization with a lateral periodicity of [~]500 {micro}m and low variability across depth. Columns are organized by a pinwheel structure. Noise correlations between cells, revealing functional interactions, decay isotropically and monotonically with distance but remain significant even at lateral distances exceeding 3 mm and thus the scale of multiple columns. Together, these discoveries reveal the need for neurotechnologies bridging scales from single cells to multi-columnar systems. The technological advancements open the door for future large-scale, cellular-resolution investigations of functional organization and population dynamics across entire cortical areas in the primate brain.

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bioRxiv2026

Neural representation of action grammar structure in primate frontal cortex

Humans and other animals can solve new problems, even on the first attempt. This capacity to generate novel problem-solving behavior has been hypothesized to depend on brain mechanisms for recombining units of knowledge using systems of procedural rules, or grammars. Yet, whether and how the brain represents and implements grammars remains unclear, in large part due to the lack of neural recordings (typically performed in animal models) during grammar-based problem solving (typically studied in humans). Here, we address that gap, and in turn identify an underlying neural basis of grammatical behavior. We designed a visual-motor construction task in which macaque monkeys trace complex, often novel, geometric figures by generating a sequence of strokes, each a distinct shape, like a circle, dash, or chevron (action symbols1). Critically, sequencing was guided by a learned hierarchical action grammar AnBmCk, meaning "repeat shape A, then repeat shape B, then repeat shape C", where the number of repetitions (n, m, and k) varied across problems. Behavior was internally generated (no cues guiding stroke order), problem-directed (to construct a specific image), and exhibited zero-shot generalization (successful on the first trial for novel problems, including harder ones)--key hallmarks of grammar use. To identify underlying neural substrates, we recorded from multiple frontal cortical areas previously implicated in rule use or action sequencing. Activity during drawing encoded key structural properties of the action grammar: (i) shape index (A, B, C), (ii) abstract role (e.g., the role A independent of the specific shape), and (iii) ordinal position within a shape repeat. Moreover, all three properties were strongest in a single region, the pre-supplementary motor area (preSMA). We suggest the possibility that this conjunction of representations is a signature of an implementation of an iterative algorithm resembling a "for-loop" program: internally tracking how many repetitions remain for each shape index and switching to the next when complete. Our study establishes a paradigm for studying the neural basis of grammar-guided novel behavior and identifies in preSMA a dynamic representation of grammatical structure supporting such behavior.

neuroscience↗

bioRxiv2025

Functional organizational principle evaluated by microstimulation in the cortical facial motor areas

Facial gestures are crucial for social interactions among all primates. Since these actions are performed in the absence of direct visual feedback, their effectiveness relies on their stereotypical, almost reflexive patterns. One efficient mechanism for controlling ethological actions could involve motor cortical action maps (Graziano et al., 2002; 2016). Here, we studied whether stereotypical socio-communicative facial expressions are organized into discrete cortical zones by applying long-duration, supra-threshold microstimulation to fMRI-identified cortical areas of the facial motor system. Our findings revealed that these stimulation parameters produced complex facial responses by engaging multiple facial regions but did not elicit social-communicative facial behavior. The effects of long-duration stimulation appeared to be an amplified (both spatially and temporally) version of the responses seen with short-duration stimulation. The stimulation-evoked neural activity extended across the facial motor system, suggesting that these cortical regions function as part of a large-scale network designed to generate coherent, context-specific, and socially relevant motor outputs.

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bioRxiv2025

Neural representation of action symbols in primate frontal cortex

A hallmark of intelligence is proficiency in solving new problems, including those that differ dramatically from problems seen before. Problem-solving, in turn, depends on goal-directed generation of novel ideas and behaviors1, which has been proposed to rely on internal representations of discrete units, or symbols, and processes that recombine these units into a large set of possible composite representations1-9. Although this view has been influential in formulating cognitive-level explanations of behavior, definitive evidence for a neuronal substrate of symbols has remained elusive. Here, we identify a neural population encoding action symbols--recombinable representations of discrete units of motor behavior--localized to a specific area of frontal cortex. In macaque monkeys performing a drawing-like task, we found behavioral evidence that action elements (strokes) exhibit three critical features indicating an underlying symbolic representation: (i) invariance over low-level motor parameters; (ii) categorical structure, reflecting discrete types of action; and (iii) recombination into novel sequences. In simultaneous neural recordings across motor, premotor, and prefrontal cortex, we found that planning-related population activity in ventral premotor cortex (PMv) encodes actions in a manner that, like behavior, reflects motor invariance, categorical structure, and recombination. Activity in no other recorded area exhibited these three properties of symbols. These findings reveal a neural representation of action symbols localized to PMv, and therefore identify a putative neural substrate for symbolic cognitive operations.

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bioRxiv2024

Neural correlates of individual facial recognition in a social wasp

Individual recognition is critical for social behavior across species. Whether recognition is mediated by circuits specialized for social information processing has been a matter of debate. Here we examine the neurobiological underpinning of individual visual facial recognition in Polistes fuscatus paper wasps. Front-facing images of conspecific wasps broadly increase activity across many brain regions relative to other stimuli. Notably, we identify a localized subpopulation of neurons in the protocerebrum which show specialized selectivity for front-facing wasp images, which we term wasp cells. These wasp cells encode information regarding the facial patterns, with ensemble activity correlating with facial identity. Wasp cells are strikingly analogous to face cells in primates, indicating that specialized circuits are likely an adaptive feature of neural architecture to support visual recognition. One-Sentence SummaryWe identify a localized population of neurons specifically tuned to wasp faces in a social wasp that has independently evolved individual facial recognition analogous to the face cells of primates.

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bioRxiv2024

The control of overt and covert attention across two nodes of the attention-control network

Attention is a central cognitive capability whose focus is thought to be directed by a spatial map coding behavioral priority. Here we tested the three defining properties of priority map theory with electrophysiological recordings from two attentional control areas. Both areas, lateral intraparietal area LIP and dorsal posterior inferotemporal cortex PITd, selected behaviorally relevant locations even in the absence of visual stimuli (cognitive sustainment principle). Second, priority signals are thought to arise from the summation of multiple spatial signals (superposition principle). LIP approximated linear summation for visual stimuli, spatial attention, and eye movements, while PITd did not. Third, the same priority signal should guide different behaviors (agnosticity principle). LIP, instead, used separable processing channels for representing attentional focus and eye position, while PITd coded attentional focus only. Thus primate attentional control circuits implement multiple priority maps, whose functional diversity and dimensionality increase the computational capacity of attentional selection. SIGNIFICANCE STATEMENTA central theory of attention poses that the brain computes a priority map to highlight spatial locations of relevance for behavior. Here we tested the hypothesis and its key predictions about how priority signals are assembled and used, through electrophysiological single-unit recordings from two nodes of the attention control network, localized by functional magnetic resonance imaging. We found both areas to highlight locations even in the absence of a stimulus, and that each assembled spatial signals differently and provided spatial information in different forms. These findings force a revision of how and where spatial attention is controlled in the brain.

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bioRxiv2023

A familiar face and person processing area in the human temporal pole

How does the brain process the faces of familiar people? Neuropsychological studies have argued for an area of the temporal pole (TP) linking faces with person identities, but magnetic susceptibility artifacts in this region have hampered its study with fMRI. Using data acquisition and analysis methods optimized to overcome this artifact, we identify a familiar face response in TP, reliably observed in individual brains. This area responds strongly to visual images of familiar faces over images of unfamiliar faces, objects, and scenes. However, TP did not just respond to images of faces, but also to a variety of high-level cognitive tasks that involve thinking about people, including semantic, episodic, and theory of mind tasks. The response profile of TP contrasted from a nearby region of perirhinal cortex that responded specifically to faces, but not to social cognition tasks. TP was functionally connected with a distributed network in association cortex associated with social cognition, while PR was functionally connected with face-preferring areas of ventral visual cortex. This work identifies a missing link in the human familiar face processing system that specifically processes familiar faces, and is well placed to integrate visual information about faces with higher-order conceptual information about other people. The results suggest that separate streams for person and face processing reach anterior temporal areas positioned at the top of the cortical hierarchy.

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bioRxiv2023

Mixed Multi-Level Visual, Reward, and Motor Signals in Dorsomedial Frontal Cortex Area F7 during Active Naturalistic Video Exploration

In the primate brain the frontal lobes support complex functions, including social cognition. Understanding the functional organization of these regions requires an approach for rich functional characterization. Here we used a novel paradigm, the visual exploration of dynamic social and non-social video scenes, to characterize diverse functions in area F7 of dorsomedial premotor cortex in the macaque monkey (Macaca mulatta) previously suggested to be involved in the representation of social interactions. We found that neural populations within this area carry information about both visual events in the videos, like head turning, and higher-level social categories, like grooming. In addition to signaling visual events, the population also encoded the delivery of juice reward. Our novel free viewing paradigm and naturalistic stimuli elicited active visual exploration, and we found that a large fraction of F7 neurons responded to the subjects own saccadic eye movements. Information from these three different domains were not separated across distinct neural sub-populations, but distributed, such that many neurons carried sensory, reward, and motor information in a mixed format. Thus we uncover a hitherto unappreciated diversity of functions in region F7 within dorsomedial frontal cortex.

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bioRxiv2022

Encoding of Dynamic Facial Information in the Middle Dorsal Face Area

Faces in motion reveal a plethora of information through visual dynamics. Faces can move in complex patterns while transforming facial shape, e.g. during the generation of different emotional expressions. While motion and shape processing have been studied extensively in separate research enterprises, much less is known about their conjunction during biological motion. Here we took advantage of the discovery in brain-imaging studies of an area in the dorsal portion of the macaque monkey superior temporal sulcus (STS), the middle dorsal face area (MD), with selectivity for naturalistic face motion. To gain mechanistic insights into the coding of facial motion, we recorded single-unit activity from MD, testing whether and how MD cells encode face motion. The MD population was highly sensitive to naturalistic facial motion and facial shape. Some MD cells responded only to the conjunction of facial shape and motion, others were selective for facial shape even without movement, and yet others were suppressed by facial motion. We found that this heterogeneous MD population transforms face motion into a higher-dimensional activity space, a representation that would allow for high sensitivity to relevant small-scale movements. Indeed we show that many MD cells carry such sensitivity for eye movements. We further found that MD cells encode motion of head, mouth, and eyes in a separable manner, requiring the use of multiple reference frames. Thus, MD is a bona-fide face-motion area that uses highly heterogeneous cell populations to create codes capturing even complex facial motion trajectories.

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bioRxiv2021

Parallel systems for social and spatial reasoning within the cortical apex

What is the cognitive and neural architecture for high-level reasoning? We hypothesize that systems for understanding people and places remain separate throughout the brain, but share a parallel organization. We test this hypothesis using deep neuroimaging of individual human brains on diverse tasks involving reasoning and memory about familiar people, places, and objects. We find that thinking about people and places elicits responses in distinct areas of high-level association cortex, spanning the frontal, parietal, and temporal lobes. Person- and place-preferring brain regions are systematically yoked across cortical zones. These areas have strongly domain-specific response profiles across visual, semantic, and episodic tasks, and are specifically functionally connected to other parts of association cortex with like category preference. Social and spatial networks are anatomically separated even at the top of the cortical hierarchy, and include parts of cortex with anatomical connections to the hippocampal formation. These results demonstrate parallel, domain-specific networks within the cortical apex. They suggest that domain-specific systems for reasoning constitute components of a broader cortico-hippocampal system for long-term memory.

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bioRxiv2020

Face selective patches in marmoset frontal cortex

Primates have evolved the ability transmit important social information through facial expression. In humans and macaque monkeys, socially relevant face processing is accomplished via a distributed cortical and subcortical functional network that includes specialized patches in anterior cingulate cortex and lateral prefrontal cortex, regions usually associated with high-level cognition. It is unclear whether a similar network exists in New World primates, who diverged ~35 million years from Old World primates and have a less elaborated frontal cortex. The common marmoset (Callithrix jacchus) is a small New World primate that is ideally placed to address this question given the complex social repertoire inherent to this species (e.g., observational social learning; imitation; cooperative antiphonal calling). Here, we investigated the existence of a putative high-level face processing network in marmosets by employing ultra-high field (9.4 Tesla) task-based functional MRI (fMRI). We demonstrated that, like Old World primates, marmosets show differential activation in anterior cingulate cortex and lateral prefrontal cortex while they view socially relevant videos of marmoset faces. We corroborate the locations of these frontal regions by demonstrating both functional (via resting-state fMRI) and structural (via cellular-level tracing) connectivity between these regions and temporal lobe face patches. Given the evolutionary separation between macaques and marmosets, our results suggest this frontal network specialized for social face processing predates the separation between Platyrrhini and Catarrhine. These results give further credence to the marmoset as a viable preclinical modelling species for studying human social disorders.

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bioRxiv2018

Resting state functional connectivity patterns associated with pharmacological treatment resistance in temporal lobe epilepsy

There are no functional imaging based biomarkers for pharmacological treatment response in temporal lobe epilepsy (TLE). In this study, we investigated whether there is an association between resting state functional brain connectivity (RsFC) and seizure control in TLE. We screened a large database containing resting state functional magnetic resonance imaging (Rs-fMRI) data from 286 epilepsy patients. Patient medical records were screened for seizure characterization, EEG reports for lateralization and location of seizure foci to establish uniformity of seizure localization within patient groups. Rs-fMRI data from patients with well-controlled left TLE, patients with treatment-resistant left TLE, and healthy controls were analyzed. Healthy controls and cTLE showed similar functional connectivity patterns, whereas trTLE exhibited a significant bilateral decrease in thalamo-hippocampal functional connectivity. This work is the first to demonstrate differences in neural network connectivity between well-controlled and treatment-resistant TLE. These differences are spatially highly focused and suggest sites for the etiology and possibly treatment of TLE. Altered thalamo-hippocampal RsFC thus is a potential new biomarker for TLE treatment resistance.\n\nSummaryResting State functional magnetic resonance imaging (Rs-fMRI), previously utilized to predict lateralization of seizure foci in temporal lobe epilepsy (TLE), is utilized to determine potential mechanisms and biomarkers for treatment-resistant and well-controlled unilateral TLE. We found significant differences in thalamo-hippocampal functional connectivity between treatment-resistant and well-controlled TLE patients. Differences in functional connectivity were focused to thalamo-hippocampal connections and more pronounced in the hemisphere ipsilateral to seizure foci. Aberrant functional connectivity patterns as measured by Rs-fMRI could thus serve as biomarkers for treatment response in TLE.

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