Propagation of activity through the cortical hierarchy and perception are determined by neural variability

Brains are composed of anatomically and functionally distinct regions performing specialized tasks, but regions do not operate in isolation. Orchestration of complex behaviors requires communication between brain regions, but how neural dynamics are organized to facilitate reliable transmission is not well understood. Here we studied this process directly by generating neural activity that propagates between brain regions and drives behavior, assessing how neural populations in sensory cortex cooperate to transmit information. We achieved this by imaging two densely interconnected regions—the primary and secondary somatosensory cortex (S1 and S2)—in mice while performing two-photon photostimulation of S1 neurons and assigning behavioral salience to the photostimulation. We found that the probability of perception is determined not only by the strength of the photostimulation but also by the variability of S1 neural activity. Therefore, maximizing the signal-to-noise ratio of the stimulus representation in cortex relative to the noise or variability is critical to facilitate activity propagation and perception

Shared neural representations of tactile roughness intensities by somatosensation and touch observation using an associative learning method

Previous human fMRI studies have reported activation of somatosensory areas not only during actual touch, but also during touch observation. However, it has remained unclear how the brain encodes visually evoked tactile intensities. Using an associative learning method, we investigated neural representations of roughness intensities evoked by (a) tactile explorations and (b) visual observation of tactile explorations. Moreover, we explored (c) modality-independent neural representations of roughness intensities using a cross-modal classification method. Case (a) showed significant decoding performance in the anterior cingulate cortex (ACC) and the supramarginal gyrus (SMG), while in the case (b), the bilateral posterior parietal cortices, the inferior occipital gyrus, and the primary motor cortex were identified. Case (c) observed shared neural activity patterns in the bilateral insula, the SMG, and the ACC. Interestingly, the insular cortices were identified only from the cross-modal classification, suggesting their potential role in modality-independent tactile processing. We further examined correlations of confusion patterns between behavioral and neural similarity matrices for each region. Significant correlations were found solely in the SMG, reflecting a close relationship between neural activities of SMG and roughness intensity perception. The present findings may deepen our understanding of the brain mechanisms underlying intensity perception of tactile roughness

Neuronal correlates of tactile working memory in rat barrel cortex and prefrontal cortex

The neuronal mechanisms of parametric working memory \u2013 the short-term storage of graded stimuli to guide behavior \u2013 are not fully elucidated. We have designed a working memory task where rats compare two sequential vibrations, S1 and S2, delivered to their whiskers (Fassihi et al, 2014). Vibrations are a series of velocities sampled from a zero-mean normal distribution. Rats must judge which stimulus had greater velocity standard deviation, \u3c3 (e.g. \u3c31 > \u3c32 turn left, \u3c31 < \u3c32 turn right). A critical operation in this task is to hold S1 information in working memory for subsequent comparison. In an earlier work we uncovered this cognitive capacity in rats (Fassihi et al, 2014), an ability previously ascribed only to primates. Where in the brain is such a memory kept and what is the nature of its representation? To address these questions, we performed simultaneous multi-electrode recordings from barrel cortex \u2013 the entryway of whisker sensory information into neocortex \u2013 and prelimbic area of medial prefrontal cortex (mPFC) which is involved in higher order cognitive functioning in rodents. During the presentation of S1 and S2, a majority of neurons in barrel cortex encoded the ongoing stimulus by monotonically modulating their firing rate as a function of \u3c3; i.e. 42% increased and 11% decreased their firing rate for progressively larger \u3c3 values. During the 2 second delay interval between the two stimuli, neuronal populations in barrel cortex kept a graded representation of S1 in their firing rate; 30% at early delay and 15% at the end. In mPFC, neurons expressed divers coding characteristics yet more than one-fourth of them varied their discharge rate according to the ongoing stimulus. Interestingly, a similar proportion carried the stimulus signal up to early parts of delay period. A smaller but considerable proportion (10%) kept the memory until the end of delay interval. We implemented novel information theoretic measures to quantify the stimulus and decision signals in neuronal responses in different stages of the task. By these measures, a decision signal was present in barrel cortex neurons during the S2 period and during the post stimulus delay, when the animal needed to postpone its action. Medial PFC units also represented animal choice, but later in the trial in comparison to barrel cortex. Decision signals started to build up in this area after the termination of S2. We implemented a regularized linear discriminant algorithm (RDA) to decode stimulus and decision signals in the population activity of barrel cortex and mPFC neurons. The RDA outperformed individual clusters and the standard linear discriminant analysis (LDA). The stimulus and animal\u2019s decision could be extracted from population activity simply by linearly weighting the responses of neuronal clusters. The population signal was present even in epochs of trial where no single cluster was informative. We predicted that coherent oscillations between brain areas might optimize the flow of information within the networks engaged by this task. Therefore, we quantified the phase synchronization of local field potentials in barrel cortex and mPFC. The two signals were coherent at theta range during S1 and S2 and, interestingly, prior to S1. We interpret the pre-stimulus coherence as reflecting top-down preparatory and expectation mechanisms. We showed, for the first time to our knowledge, the neuronal correlates of parametric working memory in rodents. The existence of both positive and negative codes in barrel cortex, besides the representation of stimulus memory and decision signals suggests that multiple functions might be folded into single modules. The mPFC also appears to be part of parametric working memory and decision making network in rats

Two-photon all-optical interrogation of mouse barrel cortex during sensory discrimination

The neocortex supports a rich repertoire of cognitive and behavioural functions, yet the rules, or neural ‘codes’, that determine how patterns of cortical activity drive perceptual processes remain enigmatic. Experimental neuroscientists study these codes through measuring and manipulating neuronal activity in awake behaving subjects, which allows links to be identified between patterns of neural activity and ongoing behaviour functions. In this thesis, I detail the application of novel optical techniques for simultaneously recording and manipulating neurons with cellular resolution to examine how tactile signals are processed in sparse neuronal ensembles in mouse somatosensory ‘barrel’ cortex. To do this, I designed a whisker-based perceptual decision-making task for head-fixed mice, that allows precise control over sensory input and interpretable readout of perceptual choice. Through several complementary experimental approaches, I show that task performance is exquisitely coupled to barrel cortical activity. Using two- photon calcium imaging to simultaneously record from populations of barrel cortex neurons, I demonstrate that different subpopulations of neurons in layer 2/3 (L2/3) show selectivity for contralateral and ipsilateral whisker input during behaviour. To directly test whether these stimulus-tuned groups of neurons differentially impact perceptual decision-making I performed patterned photostimulation experiments to selectively activate these functionally defined sets of neurons and assessed the resulting impact on behaviour and the local cortical network in layer 2/3. In contrast with the expected results, stimulation of sensory-coding neurons appeared to have little perceptual impact on task performance. However, activation of non- stimulus coding neurons did drive decision biases. These results challenge the conventional view that strongly sensory responsive neurons carry more perceptual weight than non-responsive sensory neurons during perceptual decision-making. Furthermore, patterned photostimulation revealed and imposed potent surround suppression in L2/3, which points to strong lateral inhibition playing a dominant role in shaping spatiotemporally sparse activity patterns. These results showcase the utility of combined patterned photostimulation methods and population calcium imaging for revealing and testing neural circuit function during sensorimotor behaviour and provide new perspectives on sensory coding in barrel cortex

Coordinated population activity underlying texture discrimination in rat barrel cortex

Rodents can robustly distinguish fine differences in texture using their whiskers, a capacity that depends on neuronal activity in primary somatosensory \u201cbarrel\u201d cortex. Here we explore how texture was collectively encoded by populations of three to seven neuronal clusters simultaneously recorded from barrel cortex while a rat performed a discrimination task. Each cluster corresponded to the single-unit or multiunit activity recorded at an individual electrode. To learn how the firing of different clusters combines to represent texture, we computed population activity vectors across moving time windows and extracted the signal available in the optimal linear combination of clusters. We quantified this signal using receiver operating characteristic analysis and compared it to that available in single clusters. Texture encoding was heterogeneous across neuronal clusters, and only a minority of clusters carried signals strong enough to support stimulus discrimination on their own. However, jointly recorded groups of clusters were always able to support texture discrimination at a statistically significant level, even in sessions where no individual cluster represented the stimulus. The discriminative capacity of neuronal activity was degraded when error trials were included in the data, compared to only correct trials, suggesting a link between the neuronal activity and the animal's performance. These analyses indicate that small groups of barrel cortex neurons can robustly represent texture identity through synergistic interactions, and suggest that neurons downstream to barrel cortex could extract texture identity on single trials through simple linear combination of barrel cortex responses

Perception of the intensity and duration of a stimulus within a unified framework: psychophysics and underlying neuronal processing

Every sensory experience is embedded in time, and is accompanied by the perception of the passage of time. The fact that perception of the content of a sensory event and the perception of the time occupied by that event are generated in parallel raises a number of questions: Do these percepts interact with each other? Do they emerge within separate neural populations? Which neuronal mechanism underlies this divergence? In the work of my thesis I explored how the perception of the intensity of a vibrotactile stimulus, interacts with the perception of its duration, in both humans and rats. I have carried out three main studies. Chapter I works out the details of the interaction between vibration amplitude and duration, revealing a symmetric confound: perceived duration depends on stimulus speed, and perceived intensity depends on stimulus duration. Quantification of this interaction allowed us formulate a testable computational model for the generation of both percepts, which posits that a single sensory drive provides input to two distinct downstream centers, which generate the two percepts in parallel. Chapter II addresses the effect of stimulus history. Systems neuroscience has given considerable attention in recent years to the effects of preceding stimuli on the perception of the current stimulus. We now ask whether the interaction found in Study I extends to an interaction in the memory trace of recent stimuli: are the perceptual priors mixed or separate? Through psychophysical testing, we were able to show that perception of the duration and the intensity of stimuli, are biased toward the perceived features of previously presented stimuli, and not their low-level physical properties, and that separate representations of prior perceived duration and prior perceived intensity exist in the brain. Chapter III begins to look for neuronal correlates of perceived duration, through extracellular recordings in behaving rats in Dorso-Lateral Striatum (DLS), a region which receives direct input from primary somatosensory cortex and has previously shown to be involved in time perception. The delayed comparison task, differently from many common behavioral paradigms, has the advantage of dissociating the first stimulus presented to the animal from any decisional and motor processes. This makes it particularly relevant for the search for the neural basis of stimulus duration perception. Moreover, the bias of stimulus intensity on perceived time found on Study I, posits the principle that the interaction between these two features should be present in the neural population that encodes the perception of stimulus duration in a behaviourally-relevant way. Ongoing recordings are showing that the unfolding of trial time can be decoded from the striatal neural activity, but the confound of stimulus speed is not encoded by the population. This findings points toward a role of striatum in representing temporal sequences of events, while questioning its involvement in encoding the perception of stimulus duration

“Is Butter a Carb?” Neural mechanisms of nutrient-sensing and food reward in the human brain

Sensing the nutrient composition of a food and the processing of this information by the brain’s reward system to regulate food consumption are crucial biological needs. However, dysfunction in neural reward pathways may also lead to overconsumption of certain nutrients, contributing to obesity and comorbid diseases. In the context of fat, the oral sensory mechanism of its detection is disputed, although there is substantial evidence for fat detection through oral textural properties. In this thesis, I investigate the neural correlates related to the specific textural properties of oral food stimuli with defined nutrient contents, as well as their formally measured economic reward values and psychophysical ratings during functional Magnetic Resonance Imaging (fMRI) in healthy human volunteers. These results are then correlated with an ad-libitum naturalistic eating test. The thesis contains the following chapters: Chapter I discusses the key background literature; Chapter II focuses on the optimisation of the design and stimuli; Chapter III provides a detailed analysis of behavioural data, through basic psychophysical ratings of food stimuli and modelling of subjective value data; Chapter IV describes the results of the neuroimaging component of the experiment, and Chapter V discusses the results of the project in the context of current literature. This project investigates the textural contributions to sensory fat detection and reward valuation. Crucially, it is the first time a formal fMRI investigation is done on the oral-lubricative nature of fat, demonstrating encoding of sliding friction in the midposterior insula and the oral somatosensory cortex, which supports the concept that fat detection occurs through texture. Furthermore, our results highlight the unique role of the orbitofrontal cortex in processing food texture parameters, their subjective perception, and integration to subjective value, before subsequent evaluation in the ventromedial prefrontal cortex.Wellcome Trust Henry Dale Fellowship (Fabian Grabenhorst

Short-term memory of temporal aspects of noxious and innocuous thermal sensation : psychophysical and fMRI studies

La douleur peut être considérée comme un système de protection qui signale une menace et qui nous avertit des dégâts imminents aux tissus. En tant que mécanisme de défense, il nécessite l'apprentissage et la mémoire des expériences du passé pour la survie et les comportements liés à la douleur. Par conséquent, notre expérience de la douleur actuelle est fortement influencée par les expériences antérieures et l'apprentissage. Cependant, malgré son importance, notre compréhension actuelle de l'interaction entre le système de la douleur et le système de mémoire est très limitée. La mémoire de la douleur est un sujet de recherche très vaste. Il nécessite une compréhension des mécanismes impliqués à chaque étape du système de mémoire (mémoire immédiate, à court terme et à long terme) et l'interaction entre eux. Parmi les étapes multiples de la mémoire, la mémoire à court terme de la douleur est une zone qui est moins recherchée, alors qu'il existe une énorme quantité de recherche neuroscientifique dans la mémoire à court terme sur d'autres modalités, en particulier la vision. L'étude de la mémoire à court terme de la douleur est particulièrement importante car cette trace de la mémoire à court terme de la douleur est ensuite convertie en mémoire à long terme et affecte ensuite les expériences futures de la douleur. Cette thèse est largement axée sur la mémoire à court terme de la douleur. La complexité et la multi dimensionnalité de la douleur ajoutent encore un autre élément à la recherche sur la mémoire de la douleur. Par exemple, la trace de la mémoire de la douleur peut contenir des traces de mémoire de diverses composantes de la douleur telles que la réponse sensorielle affective, cognitive et motrice et l'interaction entre elles. Par conséquent, une première étape dans l'exploration neuroscientifique de la mémoire de la douleur nécessite la réduction de l'expérience de la douleur tout en englobant tous ces différents composants à un seul composant. Dans la recherche présentée ici, nous avons généralement examiné cela par des instructions d'attention ‘ top-down’ pour assister à la dimension sensorielle de la douleur. La recherche précédente sur la mémoire à court terme de la douleur a également porté principalement sur la dimension sensorielle de la douleur. Cependant, parmi les dimensions sensorielles de la douleur, la mémoire à court terme de l'intensité et de la dimension spatiale de la douleur a fait l'objet de recherches antérieures. Malgré son importance, la dimension temporelle de la douleur est restée complètement inexplorée dans la recherche sur la mémoire de la douleur. La recherche menée dans cette thèse est consacrée à l'exploration de la mémoire à court terme de la durée de la douleur. La durée de la douleur peut être suivie de manière indépendante, mais peut également être suivie conjointement avec la dimension d'intensité telle que le suivi dynamique de l'intensité de la douleur dans le temps. Les études menées dans cette thèse traitent spécifiquement du traitement isolé de la durée de la douleur ainsi que du traitement conjoint de la dimension durée / intensité de la douleur. La première étude psychophysique a exploré la nature de la représentation mentale du modèle de mémoire de la douleur thermique dynamique et a également été conçue pour aborder les différences de la dimension sensorielle et affective de la douleur thermique dans la mémoire à court terme. La deuxième étude psychophysique portait sur les propriétés de la mémoire à court terme de la sensation thermique non douloureux en comparant le suivi dynamique de la sensation et le suivi isolé de la durée d'un événement thermique non douloureux. La troisième étude poursuit l'exploration du traitement dynamique de la durée conjointement avec l'intensité par rapport au traitement isolé de la durée dans la mémoire à court terme en utilisant des stimuli thermiques douloureuse une résonance magnétique fonctionnelle (IRMF). Dans l'ensemble, les résultats des études psychophysiques ont montré une transformation significative de la durée et de la dynamique de la sensation thermique douloureux et non-douloureux dans la mémoire à court terme; comme la perte d'informations somatosensorielles temporelles en mémoire. Nous avons en outre montré une amélioration du rappel de la durée dans le suivi dynamique de la durée, en comparaison avec le suivi de la durée isolée. Nous avons également montré des différences dans les corrélats neuronaux de la mémoire à court terme de la durée de douleur par rapport à la dynamique de douleur. L'étude de l'IRMF a montré des similitudes frappantes dans les corrélats neuronaux sous-jacents à la mémoire à court terme de douleur et d'autres modalités telles que la contribution des coticés fronto-pariétales ainsi que les corticaux sensoriels impliqués dans le traitement perceptuel.Pain can be viewed as a protective system that signals threat and alerts us to impending tissue damage. As a defense mechanism, it necessitates the learning and memory of past painful experiences for survival and pain-related behavior. Therefore our current pain experience is heavily influenced by previous experiences and learning. However, despite its importance, our current understanding of the interaction between the pain system and the memory system is very limited. Pain memory is a very broad topic of research on its own. It requires an understanding of the mechanisms involved at each stage of the memory system (immediate, short-term, and long-term memory), and the interaction among them. Among the multiple stages of memory, the short-term memory of pain is an area that is less researched, while there are enormous amount of neuroscientific research in short-term memory of other modalities, particularly vision. Investigation of the short-term memory of pain is especially important as the short-term memory trace of pain is converted to long-term memory and subsequently affects future pain experiences. This thesis is broadly focused on the short-term memory of pain. The complexity and multi-dimensionality of pain adds yet another element to the research on pain memory. For example, the memory trace of pain may contain memory traces of various components of pain such as sensory, affective, cognitive, and motoric responses, and the interactions among them. Therefore, an initial step in the neuroscientific exploration of pain memory requires narrowing down the pain experience, which encompasses all of these various components, to one single component. In the research presented here, we achieved this using top-down attentional instructions to attend to the sensory component of pain. The previous research on short-term memory of pain also focused mainly on the sensory component of pain. However, within the sensory component of pain the short-term memory of intensity and spatial dimension of pain has been the focus of previous research. Despite its importance, the temporal dimension of pain remained completely unexplored in pain memory research. Thus, the research conducted in this thesis is devoted to the exploration of short-term memory of the duration of pain. Pain duration can be tracked independently, but it can also be tracked conjointly with intensity, such as in dynamic tracking of pain intensity over time. The studies addressed in this thesis examined the isolated processing of pain duration as well as conjoint processing of the duration and intensity of pain. The first psychophysical study explored the nature of the mental representation of the memory template of dynamic thermal pain sensation and, additionally, addressed the differences between the sensory versus affective dimensions of thermal pain sensation in short-term memory. The second psychophysical study focused on properties of the short-term memory of innocuous thermal sensation by comparing dynamic tracking of sensation versus isolated tracking of duration of an innocuous thermal event. The third study explored the dynamic processing of duration conjointly with intensity, versus the isolated processing of duration in short-term memory, using noxious thermal stimuli and functional magnetic resonance imaging (fMRI). Overall, the results of the psychophysical studies showed significant transformation of duration and dynamics information of noxious and innocuous thermal sensation in short-term memory, such as loss of temporal somatosensory information. Additionally, we showed improvement in duration recall during dynamic tracking versus isolated tracking of duration. The fMRI study revealed differences in neural correlates of short-term memory of pain duration versus pain dynamics. Importantly, it also showed striking similarities between neural correlates underlying the short-term memory of pain and those underlying other modalities, such as a contribution of fronto-parietal cortices as well as sensory cortices involved in perceptual processing

Paradigm Shift in Sensorimotor Control Research and Brain Machine Interface Control: The Influence of Context on Sensorimotor Representations

Neural activity in the primary motor cortex (M1) is known to correlate with movement related variables including kinematics and dynamics. Our recent work, which we believe is part of a paradigm shift in sensorimotor research, has shown that in addition to these movement related variables, activity in M1 and the primary somatosensory cortex (S1) are also modulated by context, such as value, during both active movement and movement observation. Here we expand on the investigation of reward modulation in M1, showing that reward level changes the neural tuning function of M1 units to both kinematic as well as dynamic related variables. In addition, we show that this reward-modulated activity is present during brain machine interface (BMI) control. We suggest that by taking into account these context dependencies of M1 modulation, we can produce more robust BMIs. Toward this goal, we demonstrate that we can classify reward expectation from M1 on a movement-by-movement basis under BMI control and use this to gate multiple linear BMI decoders toward improved offline performance. These findings demonstrate that it is possible and meaningful to design a more accurate BMI decoder that takes reward and context into consideration. Our next step in this development will be to incorporate this gating system, or a continuous variant of it, into online BMI performance