Representations of pleasant and painful touch in the human orbitofrontal and cingulate cortices

The cortical areas that represent affectively positive and negative aspects of touch were investigated using functional magnetic resonance imaging (fMRI) by comparing activations produced by pleasant touch, painful touch produced by a stylus, and neutral touch, to the left hand. It was found that regions of the orbitofrontal cortex were activated more by pleasant touch and by painful stimuli than by neutral touch and that different areas of the orbitofrontal cortex were activated by the pleasant and painful touches. The orbitofrontal cortex activation was related to the affective aspects of the touch, in that the somatosensory cortex (SI) was less activated by the pleasant and painful stimuli than by the neutral stimuli. This dissociation was highly significant for both the pleasant touch (P < 0.006) and for the painful stimulus (P < 0.02). Further, it was found that a rostral part of the anterior cingulate cortex was activated by the pleasant stimulus and that a more posterior and dorsal part was activated by the painful stimulus. Regions of the somatosensory cortex, including SI and part of SII in the mid-insula, were activated more by the neutral touch than by the pleasant and painful stimuli. Part of the posterior insula was activated only in the pain condition and different parts of the brainstem, including the central grey, were activated in the pain, pleasant and neutral touch conditions. The results provide evidence that different areas of the human orbitofrontal cortex are involved in representing both pleasant touch and pain, and that dissociable parts of the cingulate cortex are involved in representing pleasant touch and pain.     

Differential contributions of dopamine and serotonin to orbitofrontal cortex function in the marmoset

We have shown previously that the inhibitory control functions of the orbitofrontal cortex (OFC) are disrupted by serotonin, but not dopamine depletions. However, both dopamine and serotonin terminals and receptors are present within the OFC and thus the aim of the present study was to determine the differential contributions of these neurotransmitters to orbitofrontal function. OFC and dopamine are involved in the process by which neutral stimuli take on reinforcing properties, by virtue of their prior association with reward, and guide behavior. Thus, we compared the performance of marmosets with dopaminergic or serotoninergic OFC depletions on a test of conditioned reinforcement. To further our understanding of serotonin in behavioral flexibility, the effect of these depletions was also compared on the extinction of a visual discrimination. Monkeys with serotonin depletions of the OFC displayed stimulus-bound responding on both tests of conditioned reinforcement and discrimination extinction suggesting that orbitofrontal serotonin plays a specific role in preventing competing, task irrelevant, salient stimuli from biasing responding. In contrast, monkeys with dopamine depletion were insensitive to conditioned reinforcers and displayed persistent responding in the absence of reward in extinction, a pattern of deficits that may reflect basic deficits in the associative processing of reward.     

Reading salt activates gustatory brain regions: FMRI evidence for semantic grounding in a novel sensory modality

Because many words are typically used in the context of their referent objects and actions, distributed cortical circuits for these words may bind information about their form with perceptual and motor aspects of their meaning. Previous work has demonstrated such semantic grounding for sensorimotor, visual, auditory, and olfactory knowledge linked to words, which is manifest in activation of the corresponding areas of the cortex. Here, we explore the brain basis of gustatory semantic links of words whose meaning is primarily related to taste. In a blocked functional magnetic resonance imaging design, Spanish taste words and control words matched for a range of factors (including valence, arousal, imageability, frequency of use, number of letters and syllables) were presented to 59 right-handed participants in a passive reading task. Whereas all the words activated the left inferior frontal (BA44/45) and the posterior middle and superior temporal gyri (BA21/22), taste-related words produced a significantly stronger activation in these same areas and also in the anterior insula, frontal operculum, lateral orbitofrontal gyrus, and thalamus among others. As these areas comprise primary and secondary gustatory cortices, we conclude that the meaning of taste words is grounded in distributed cortical circuits reaching into areas that process taste sensations.     

Estimating receptive field size from fMRI data in human striate and extrastriate visual cortex.

Functional magnetic resonance imaging (fMRI) was used to estimate the average receptive field sizes of neurons in each of several striate and extrastriate visual areas of the human cerebral cortex. The boundaries of the visual areas were determined by retinotopic mapping procedures and were visualized on flattened representations of the occipital cortex. Estimates of receptive field size were derived from the temporal duration of the functional activation at each cortical location as a visual stimulus passed through the receptive fields represented at that location. Receptive fields are smallest in the primary visual cortex (V1). They are larger in V2, larger again in V3/VP and largest of all in areas V3A and V4. In all these areas, receptive fields increase in size with increasing stimulus eccentricity. The results are qualitatively in line with those obtained by others in macaque monkeys using neurophysiological methods.     

Retinotopic organization in human visual cortex and the spatial precision of functional MRI

A method of using functional magnetic resonance imaging (fMRI) to measure retinotopic organization within human cortex is described. The method is based on a visual stimulus that creates a traveling wave of neural activity within retinotopically organized visual areas. We measured the fMRI signal caused by this stimulus in visual cortex and represented the results on images of the flattened cortical sheet. We used the method to locate visual areas and to evaluate the spatial precision of fMRI. Specifically, we: (i) identified the borders between several retinotopically organized visual areas in the posterior occipital lobe; (ii) measured the function relating cortical position to visual field eccentricity within area V1; (iii) localized activity to within 1.1 mm of visual cortex; and (iv) estimated the spatial resolution of the fMRI signal and found that signal amplitude falls to 60% at a spatial frequency of 1 cycle per 9 mm of visual cortex. This spatial resolution is consistent with a linespread whose full width at half maximum spreads across 3.5 mm of visual cortex.      

Modulation of the C1 visual event-related component by conditioned stimuli: evidence for sensory plasticity in early affective perception

Previous research has demonstrated optimized processing of motivationally significant stimuli early in perception. In the present study, the time course and underlying mechanisms for such fast differentiation are of interest. We investigated the involvement of the primary visual cortex in affective evaluation of conditioned stimuli (CSs). In order to elicit learning within the visual system we chose affective pictures as unconditioned stimuli and used laterally presented gratings as CSs. Using high-density electroencephalography, we demonstrated modulation of the C1 visual event-related component for threat-related stimuli versus neutral stimuli, which increased with continuing acquisition of affective meaning. The differentiation between aversive and neutral visual stimuli occurred as early as 65-90 ms after stimulus onset and suggested involvement of the primary visual areas in affective evaluation. As an underlying mechanism, we discuss short-term reorganization in visual cortex, enabling sensory amplification of specific visual features that are related to motivationally relevant information.     

Acquisition and performance of delayed-response tasks: a neural network model

We study the time evolution of a neural network model as it learns the three stages of a visual delayed-matching-to-sample (DMS) task: identification of the sample, retention during delay, and matching of sample and target, ignoring distractors. We introduce a neurobiologically plausible, uncommitted architecture, comprising an "executive" subnetwork gating connections to and from a "working" layer. The network learns DMS by reinforcement: reward-dependent synaptic plasticity generates task-dependent behaviour. During learning, working layer cells exhibit stimulus specialization and increased tuning of their firing. The emergence of top-down activity is observed, reproducing aspects of prefrontal cortex control on activity in the visual areas of inferior temporal cortex. We observe a lability of neural systems during learning, with a tendency to encode spurious associations. Executive areas are instrumental during learning to prevent such associations; they are also fundamental for the "mature" network to keep passing DMS. In the mature model, the working layer functions as a short-term memory. The mature system is remarkably robust against cell damage and its performance degrades gracefully as damage increases. The model underlines that executive systems, which regulate the flow of information between working memory and sensory areas, are required for passing tests such as DMS. At the behavioural level, the model makes testable predictions about the errors expected from subjects learning the DMS.     

Activation of the human orbitofrontal cortex to a liquid food stimulus is correlated with its subjective pleasantness

Single-neuron recording studies in non-human primates indicate that orbitofrontal cortex neurons represent the reward value of the sight, smell and taste of food, and even changes in the relative reward value, but provide no direct evidence on brain activity that is correlated with subjective reports of the pleasantness of food. In this fMRI investigation we report a significant correlation between the activation of a region of the human orbitofrontal cortex and the decrease in subjective pleasantness when a liquid food is eaten to satiety. Moreover, a cluster of voxels in the orbitofrontal cortex showed a decrease in its activation that was specific to the particular liquid food consumed in a meal, providing a neural correlate of sensory-specific satiety to a liquid whole food in humans. This sensory-specific reduction in activation of the orbitofrontal cortex correlating with subjective pleasantness is consistent with an important role for the orbitofrontal cortex in human emotion and motivation, and associated subjective states.     

Pictures of appetizing foods activate gustatory cortices for taste and reward

Increasing research indicates that concepts are represented as distributed circuits of property information across the brain's modality-specific areas. The current study examines the distributed representation of an important but under-explored category, foods. Participants viewed pictures of appetizing foods (along with pictures of locations for comparison) during event-related fMRI. Compared to location pictures, food pictures activated the right insula/operculum and the left orbitofrontal cortex, both gustatory processing areas. Food pictures also activated regions of visual cortex that represent object shape. Together these areas contribute to a distributed neural circuit that represents food knowledge. Not only does this circuit become active during the tasting of actual foods, it also becomes active while viewing food pictures. Via the process of pattern completion, food pictures activate gustatory regions of the circuit to produce conceptual inferences about taste. Consistent with theories that ground knowledge in the modalities, these inferences arise as reenactments of modality-specific processing.     

Functional magnetic resonance imaging measures of the effects of morphine on central nervous system circuitry in opioid-naive healthy volunteers

In this pilot study, we used functional magnetic resonance imaging (fMRI) to study the effects of morphine in 8 healthy, opioid-na?ve volunteers. Intravenous small-dose morphine (4 mg/70 kg) or saline was administered to volunteers undergoing a fMRI scan. Infusion of morphine, but not saline, elicited mild euphoria without aversive symptoms and resulted in positive signal changes in reward structures including the nucleus accumbens, sublenticular extended amygdala, orbitofrontal cortex, and hippocampus. The positive signal in the accumbens was opposite to the signal previously reported for noxious stimuli. Morphine produces a decreased signal in cortical areas in a similar manner to sedative-hypnotic drugs such as propofol or midazolam. Activation in endogenous analgesic regions was observed in the periaqueductal gray, the anterior cingulate gyrus (decreased signal), and hypothalamus (increased signals). The pattern of activation in reward circuitry was similar to that reported for euphoric drugs of abuse, providing a model to evaluate the initial effects of morphine on the central nervous system components of the circuitry involved in addiction. The segregation of fMRI response that was observed in cortical versus subcortical regions suggests a dissociation of reward from sensory-motor and cognitive functions. Activation patterns were opposite to those previously observed for the mu antagonist, naloxone.     

Perinatal-lesion-induced reorganization of cerebral functions revealed using reversible cooling deactivation and attentional tasks

We tested the concept that lesions of primary visual cortical areas 17 and 18 sustained on the day of birth induce a redistribution of cerebral operations underlying the ability to disengage visual attention and then redirect it to a new location. In cats, these operations are normally highly localizable to posterior middle suprasylvian (pMS) cortex. Three stimulation paradigms were used: (i) movement of a high contrast visual stimulus into the visual field; (ii) illumination of a static light-emitting diode (LED) stimulus; and (iii) a control static auditory stimulus. To test for the redistribution of critical neural operations, cryoloops were implanted bilaterally in the pMS sulcus and in contact with ventral posterior suprasylvian (vPS) cortex. Separate and combined deactivations of pMS and vPS cortices in cats with early lesions of primary visual cortex showed that full, unilateral deactivation of pMS cortex only partially impaired the ability to detect and orient to stimuli moved into the contracooled hemifield. Much more complete impairment required the additional deactivation of ipsilateral vPS cortex. Bilateral pMS deactivation alone, or in combination with bilateral vPS deactivation, largely reversed the unilateral contracooled neglect. For the orienting to static, illuminated LED stimuli, unilateral deactivation of pMS cortex was sufficient to fully impair orienting to stimuli presented in the contracooled hemifield. Bilateral pMS deactivation induced an almost complete visual-field-wide neglect of stimuli. On its own, unilateral deactivation of vPS cortex was without effect on either task, although bilateral vPS deactivations introduced inconsistencies into the performance. Termination of cooling reversed all deficits. Finally, neither the initial lesion of areas 17 and 18 nor cooling of either the MS or vPS cortex alone, or in combination, interfered with orienting to sound stimuli. Overall, our results provide evidence that at least one highly localizable visual function of normal cerebral cortex is remapped across the cortical surface following the early lesion of primary visual cortical areas 17 and 18. Moreover, the redistribution has spread the essential neural operations from the visual parietal cortex to a normally functionally distinct type of cortex in the visual temporal system.     

An integrate-and-fire model of prefrontal cortex neuronal activity during performance of goal-directed decision making

The orbital frontal cortex appears to be involved in learning the rules of goal-directed behavior necessary to perform the correct actions based on perception to accomplish different tasks. The activity of orbitofrontal neurons changes dependent upon the specific task or goal involved, but the functional role of this activity in performance of specific tasks has not been fully determined. Here we present a model of prefrontal cortex function using networks of integrate-and-fire neurons arranged in minicolumns. This network model forms associations between representations of sensory input and motor actions, and uses these associations to guide goal-directed behavior. The selection of goal-directed actions involves convergence of the spread of activity from the goal representation with the spread of activity from the current state. This spiking network model provides a biological implementation of the action selection process used in reinforcement learning theory. The spiking activity shows properties similar to recordings of orbitofrontal neurons during task performance.     

Large-scale visuomotor integration in the cerebral cortex

Efficient visuomotor behavior depends on integrated processing by the visual and motor systems of the cerebral cortex. Yet, many previous cortical neurophysiology studies have examined the visual and motor modalities in isolation, largely ignoring questions of large-scale cross-modal integration. To address this issue, we analyzed event-related local field potentials simultaneously recorded from multiple visual, motor, and executive cortical sites in monkeys performing a visuomotor pattern discrimination task. The timing and cortical location of four aspects of event-related activities were examined: stimulus-evoked activation onset, stimulus-specific processing, stimulus category-specific processing, and response-specific processing. Activations appeared earliest in striate cortex and rapidly thereafter in other visual areas. Stimulus-specific processing began early in most visual cortical areas, some at activation onset. Early onset latencies were also observed in motor, premotor, and prefrontal areas, some as early as in striate cortex, but these early-activating frontal sites did not show early stimulus-specific processing. Response-specific processing began around 150 ms poststimulus in widespread cortical areas, suggesting that perceptual decision formation and response selection arose through concurrent processes of visual, motor, and executive areas. The occurrence of stimulus-specific and stimulus category-specific differences after the onset of response-specific processing suggests that sensory and motor stages of visuomotor processing overlapped in time.     

Visual modulation of neurons in auditory cortex

Our brain integrates the information provided by the different sensory modalities into a coherent percept, and recent studies suggest that this process is not restricted to higher association areas. Here we evaluate the hypothesis that auditory cortical fields are involved in cross-modal processing by probing individual neurons for audiovisual interactions. We find that visual stimuli modulate auditory processing both at the level of field potentials and single-unit activity and already in primary and secondary auditory fields. These interactions strongly depend on a stimulus' efficacy in driving the neurons but occur independently of stimulus category and for naturalistic as well as artificial stimuli. In addition, interactions are sensitive to the relative timing of audiovisual stimuli and are strongest when visual stimuli lead by 20-80 msec. Exploring the underlying mechanisms, we find that enhancement correlates with the resetting of slow (approximately 10 Hz) oscillations to a phase angle of optimal excitability. These results demonstrate that visual stimuli can modulate the firing of neurons in auditory cortex in a manner that depends on stimulus efficacy and timing. These neurons thus meet the criteria for sensory integration and provide the auditory modality with multisensory contextual information about co-occurring environmental events.     

A dual role for prediction error in associative learning

Confronted with a rich sensory environment, the brain must learn statistical regularities across sensory domains to construct causal models of the world. Here, we used functional magnetic resonance imaging and dynamic causal modeling (DCM) to furnish neurophysiological evidence that statistical associations are learnt, even when task-irrelevant. Subjects performed an audio-visual target-detection task while being exposed to distractor stimuli. Unknown to them, auditory distractors predicted the presence or absence of subsequent visual distractors. We modeled incidental learning of these associations using a Rescorla-Wagner (RW) model. Activity in primary visual cortex and putamen reflected learning-dependent surprise: these areas responded progressively more to unpredicted, and progressively less to predicted visual stimuli. Critically, this prediction-error response was observed even when the absence of a visual stimulus was surprising. We investigated the underlying mechanism by embedding the RW model into a DCM to show that auditory to visual connectivity changed significantly over time as a function of prediction error. Thus, consistent with predictive coding models of perception, associative learning is mediated by prediction-error dependent changes in connectivity. These results posit a dual role for prediction-error in encoding surprise and driving associative plasticity.     

Physiological and anatomical evidence for multisensory interactions in auditory cortex

Recent studies, conducted almost exclusively in primates, have shown that several cortical areas usually associated with modality-specific sensory processing are subject to influences from other senses. Here we demonstrate using single-unit recordings and estimates of mutual information that visual stimuli can influence the activity of units in the auditory cortex of anesthetized ferrets. In many cases, these units were also acoustically responsive and frequently transmitted more information in their spike discharge patterns in response to paired visual-auditory stimulation than when either modality was presented by itself. For each stimulus, this information was conveyed by a combination of spike count and spike timing. Even in primary auditory areas (primary auditory cortex [A1] and anterior auditory field [AAF]), approximately 15% of recorded units were found to have nonauditory input. This proportion increased in the higher level fields that lie ventral to A1/AAF and was highest in the anterior ventral field, where nearly 50% of the units were found to be responsive to visual stimuli only and a further quarter to both visual and auditory stimuli. Within each field, the pure-tone response properties of neurons sensitive to visual stimuli did not differ in any systematic way from those of visually unresponsive neurons. Neural tracer injections revealed direct inputs from visual cortex into auditory cortex, indicating a potential source of origin for the visual responses. Primary visual cortex projects sparsely to A1, whereas higher visual areas innervate auditory areas in a field-specific manner. These data indicate that multisensory convergence and integration are features common to all auditory cortical areas but are especially prevalent in higher areas.     

The anatomical connections of the macaque monkey orbitofrontal cortex. A review

The orbitofrontal cortex (OfC) is a heterogeneous prefrontal sector selectively connected with a wide constellation of other prefrontal, limbic, sensory and premotor areas. Among the limbic cortical connections, the ones with the hippocampus and parahippocampal cortex are particularly salient. Sensory cortices connected with the OfC include areas involved in olfactory, gustatory, somatosensory, auditory and visual processing. Subcortical structures with prominent OfC connections include the amygdala, numerous thalamic nuclei, the striatum, hypothalamus, periaqueductal gray matter, and biochemically specific cell groups in the basal forebrain and brainstem. Architectonic and connectional evidence supports parcellation of the OfC. The rostrally placed isocortical sector is mainly connected with isocortical areas, including sensory areas of the auditory, somatic and visual modalities, whereas the caudal non-isocortical sector is principally connected with non-isocortical areas, and, in the sensory domain, with olfactory and gustatory areas. The connections of the isocortical and non-isocortical orbital sectors with the amygdala, thalamus, striatum, hypothalamus and periaqueductal gray matter are also specific. The medial sector of the OfC is selectively connected with the hippocampus, posterior parahippocampal cortex, posterior cingulate and retrosplenial areas, and area prostriata, while the lateral orbitofrontal sector is the most heavily connected with sensory areas of the gustatory, somatic and visual modalities, with premotor regions, and with the amygdala.     

Dynamic changes in representations of preceding and upcoming reward in monkey orbitofrontal cortex

We investigated how orbitofrontal cortex (OFC) contributes to adaptability in the face of changing reward contingencies by examining how reward representations in monkey orbitofrontal neurons change during a visually cued, multi-trial reward schedule task. A large proportion of orbitofrontal neurons were sensitive to events in this task (69/80 neurons in the valid and 48/58 neurons in the random cue context). Neuronal activity depended upon preceding reward, upcoming reward, reward delivery, and schedule state. Preceding reward-dependent activity occurred in both the valid and random cue contexts, whereas upcoming reward-dependent activity was observed only in the valid context. A greater proportion of neurons encoded preceding reward in the random than the valid cue context. The proportion of neurons with preceding reward-dependent activity declined as each trial progressed, whereas the proportion encoding upcoming reward increased. Reward information was represented by ensembles of neurons, the composition of which changed with task context and time. Overall, neuronal activity in OFC adapted to reflect the importance of different types of reward information in different contexts and time periods. This contextual and temporal adaptability is one hallmark of neurons participating in executive functions.     

Modulation of connectivity in visual pathways by attention: cortical interactions evaluated with structural equation modelling and fMRI

Electrophysiological and neuroimaging studies have shown that attention to visual motion can increase the responsiveness of the motion- selective cortical area V5 and the posterior parietal cortex (PP). Increased or decreased activation in a cortical area is often attributed to attentional modulation of the cortical projections to that area. This leads to the notion that attention is associated with changes in connectivity. We have addressed attentional modulation of effective connectivity using functional magnetic resonance imaging (fMRI). Three subjects were scanned under identical stimulus conditions (visual motion) while varying only the attentional component of the task. Haemodynamic responses defined an occipito-parieto-frontal network, including the, primary visual cortex (V1), V5 and PR A structural equation model of the interactions among these dorsal visual pathway areas revealed increased connectivity between V5 and PP related to attention. On the basis of our analysis and the neuroanatomical pattern of projections from the prefrontal cortex to PP we attributed the source of modulatory influences, on the posterior visual pathway, to the prefrontal cortex (PFC). To test this hypothesis we included the PFC in our model as a 'modulator' of the pathway between V5 and PP, using interaction terms in the structural equation model. This analysis revealed a significant modulatory effect of prefrontal regions on V5 afferents to posterior parietal cortex.