Barry E. Stein

In this viewpoint article, Florencia Iacaruso, Benjamin A. Rowland and Barry E. Stein examine the principles and open questions surrounding single-neuron dynamics in multisensory integration. Drawing on decades of work, they emphasize that individual neurons, particularly in structures such as the superior colliculus, exhibit rapid, nonlinear interactions when combining inputs from different sensory modalities. These dynamics are shaped by experience, circuit architecture, and the precise timing and balance of converging inputs, rather than reflecting fixed or purely feedforward processes. The authors highlight that single-neuron responses provide a critical bridge between cellular mechanisms and behaviour, revealing how multisensory signals are integrated in real time to support detection, localization, and decision-making. Recent methodological advances, including high-density electrophysiology, calcium imaging, and computational modelling, are enabling more detailed characterization of these dynamics within distributed and context-dependent networks. Key open questions focus on the origin of multisensory effects observed at the single-neuron level, including whether they arise from local circuit computations or reflect inputs inherited from broader network interactions. The variability of neuronal responses across contexts, such as changes in attention, behavioural state, and task demands, further complicates the identification of general principles. Looking forward, the authors argue that integrating large-scale functional data with anatomical connectivity and artificial intelligence approaches will be essential for linking single-neuron dynamics to system-level function. They conclude that understanding multisensory processing at the level of individual neurons remains central to explaining how the brain constructs coherent perception from diverse sensory inputs.

Hemianopia (unilateral blindness), a common consequence of stroke and trauma to visual cortex, is a debilitating disorder for which there are few treatments. Research in an animal model has suggested that visual-auditory stimulation therapy, which exploits the multisensory architecture of the brain, may be effective in restoring visual sensitivity in hemianopia. It was tested in two male human patients who were hemianopic for at least 8 months following a stroke. The patients were repeatedly exposed to congruent visual-auditory stimuli within their blinded hemifield during 2 h sessions over several weeks. The results were dramatic. Both recovered the ability to detect and describe visual stimuli throughout their formerly blind field within a few weeks. They could also localize these stimuli, identify some of their features, and perceive multiple visual stimuli simultaneously in both fields. These results indicate that the multisensory therapy is a rapid and effective method for restoring visual function in hemianopia.SIGNIFICANCE STATEMENTHemianopia (blindness on one side of space) is widely considered to be a permanent disorder. Here, we show that a simple multisensory training paradigm can ameliorate this disorder in human patients.

Hemianopia induced by unilateral visual cortex lesions can be resolved by repeatedly exposing the blinded hemifield to auditory–visual stimuli. This rehabilitative “training” paradigm depends on mechanisms of multisensory plasticity that restore the lost visual responsiveness of multisensory neurons in the ipsilesional superior colliculus (SC) so that they can once again support vision in the blinded hemifield. These changes are thought to operate via the convergent visual and auditory signals relayed to the SC from association cortex (the anterior ectosylvian sulcus [AES], in cat). The present study tested this assumption by cryogenically deactivating ipsilesional AES in hemianopic, anesthetized cats during weekly multisensory training sessions. No signs of visual recovery were evident in this condition, even after providing animals with up to twice the number of training sessions required for effective rehabilitation. Subsequent training under the same conditions, but with AES active, reversed the hemianopia within the normal timeframe. These results indicate that the corticotectal circuit that is normally engaged in SC multisensory plasticity has to be operational for the brain to use visual–auditory experience to resolve hemianopia.

The operation of our multiple and distinct sensory systems has long captured the interest of researchers from multiple disciplines. When the Society was founded 50 years ago to bring neuroscience research under a common banner, sensory research was largely divided along modality-specific lines. At the time, there were only a few physiological and anatomical observations of the multisensory interactions that powerfully influence our everyday perception. Since then, the neuroscientific study of multisensory integration has increased exponentially in both volume and diversity. From initial studies identifying the overlapping receptive fields of multisensory neurons, to subsequent studies of the spatial and temporal principles that govern the integration of multiple sensory cues, our understanding of this phenomenon at the single-neuron level has expanded to include a variety of dimensions. We now can appreciate how multisensory integration can alter patterns of neural activity in time, and even coordinate activity among populations of neurons across different brain areas. There is now a growing battery of sophisticated empirical and computational techniques that are being used to study this process in a number of models. These advancements have not only enhanced our understanding of this remarkable process in the normal adult brain, but also its underlying circuitry, requirements for development, susceptibility to malfunction, and how its principles may be used to mitigate malfunction.

Mature multisensory superior colliculus (SC) neurons integrate information across the senses to enhance their responses to spatiotemporally congruent cross-modal stimuli. The development of this neurotypic feature of SC neurons requires experience with cross-modal cues. In the absence of such experience the response of an SC neuron to congruent cross-modal cues is no more robust than its response to the most effective component cue. This “default” or “naive” state is believed to be one in which cross-modal signals do not interact. The present results challenge this characterization by identifying interactions between visual-auditory signals in male and female cats reared without visual-auditory experience. By manipulating the relative effectiveness of the visual and auditory cross-modal cues that were presented to each of these naive neurons, an active competition between cross-modal signals was revealed. Although contrary to current expectations, this result is explained by a neuro-computational model in which the default interaction is mutual inhibition. These findings suggest that multisensory neurons at all maturational stages are capable of some form of multisensory integration, and use experience with cross-modal stimuli to transition from their initial state of competition to their mature state of cooperation. By doing so, they develop the ability to enhance the physiological salience of cross-modal events thereby increasing their impact on the sensorimotor circuitry of the SC, and the likelihood that biologically significant events will elicit SC-mediated overt behaviors.SIGNIFICANCE STATEMENTThe present results demonstrate that the default mode of multisensory processing in the superior colliculus is competition, not non-integration as previously characterized. A neuro-computational model explains how these competitive dynamics can be implemented via mutual inhibition, and how this default mode is superseded by the emergence of cooperative interactions during development.

Neurons in the superior colliculus (SC) integrate cross-modal inputs to generate responses that are more robust than to either input alone, and are frequently greater than their sum (superadditive enhancement). Previously, the principles of a real-time multisensory transform were identified and used to accurately predict a neuron's responses to combinations of brief flashes and noise bursts. However, environmental stimuli frequently have more complex temporal structures that elicit very different response dynamics than previously examined. The present study tested whether such stimuli (i.e., pulsed) would be treated similarly by the multisensory transform. Pulsing visual and auditory stimuli elicited responses composed of higher discharge rates that had multiple peaks temporally aligned to the stimulus pulses. Combinations pulsed cues elicited multiple peaks of superadditive enhancement within the response window. Measured over the entire response, this resulted in larger enhancements than expected given enhancements elicited by non-pulsed (“sustained”) stimuli. However, as with sustained stimuli, the dynamics of multisensory responses to pulsed stimuli were highly related to the temporal dynamics of the unisensory inputs. This suggests that the specific characteristics of the multisensory transform are not determined by the external features of the cross-modal stimulus configuration; rather the temporal structure and alignment of the unisensory inputs is the dominant driving factor in the magnitudes of the multisensory product.

Multisensory neurons in animals whose cross-modal experiences are compromised during early life fail to develop the ability to integrate information across those senses. Consequently, they lack the ability to increase the physiological salience of the events that provide the convergent cross-modal inputs. The present study demonstrates that superior colliculus (SC) neurons in animals whose visual-auditory experience is compromised early in life by noise-rearing can develop visual-auditory multisensory integration capabilities rapidly when periodically exposed to a single set of visual-auditory stimuli in a controlled laboratory paradigm. However, they remain compromised if their experiences are limited to a normal housing environment. These observations seem counterintuitive given that multisensory integrative capabilities ordinarily develop during early life in normal environments, in which a wide variety of sensory stimuli facilitate the functional organization of complex neural circuits at multiple levels of the neuraxis. However, the very richness and inherent variability of sensory stimuli in normal environments will lead to a less regular coupling of any given set of cross-modal cues than does the otherwise “impoverished” laboratory exposure paradigm. That this poses no significant problem for the neonate, but does for the adult, indicates a maturational shift in the requirements for the development of multisensory integration capabilities.

The manner in which the brain integrates different sensory inputs to facilitate perception and behavior has been the subject of numerous speculations. By examining multisensory neurons in cat superior colliculus, the present study demonstrated that two operational principles are sufficient to understand how this remarkable result is achieved: (1) unisensory signals are integrated continuously and in real time as soon as they arrive at their common target neuron and (2) the resultant multisensory computation is modified in shape and timing by a delayed, calibrating inhibition. These principles were tested for descriptive sufficiency by embedding them in a neurocomputational model and using it to predict a neuron's moment-by-moment multisensory response given only knowledge of its responses to the individual modality-specific component cues. The predictions proved to be highly accurate, reliable, and unbiased and were, in most cases, not statistically distinguishable from the neuron's actual instantaneous multisensory response at any phase throughout its entire duration. The model was also able to explain why different multisensory products are often observed in different neurons at different time points, as well as the higher-order properties of multisensory integration, such as the dependency of multisensory products on the temporal alignment of crossmodal cues. These observations not only reveal this fundamental integrative operation, but also identify quantitatively the multisensory transform used by each neuron. As a result, they provide a means of comparing the integrative profiles among neurons and evaluating how they are affected by changes in intrinsic or extrinsic factors.SIGNIFICANCE STATEMENTMultisensory integration is the process by which the brain combines information from multiple sensory sources (e.g., vision and audition) to maximize an organism's ability to identify and respond to environmental stimuli. The actual transformative process by which the neural products of multisensory integration are achieved is poorly understood. By focusing on the millisecond-by-millisecond differences between a neuron's unisensory component responses and its integrated multisensory response, it was found that this multisensory transform can be described by two basic principles: unisensory information is integrated in real time and the multisensory response is shaped by calibrating inhibition. It is now possible to use these principles to predict a neuron's multisensory response accurately armed only with knowledge of its unisensory responses.