Pavlovian reward prediction and receipt in schizophrenia: relationship to anhedonia

Reward processing abnormalities have been implicated in the pathophysiology of negative symptoms such as anhedonia and avolition in schizophrenia. However, studies examining neural responses to reward anticipation and receipt have largely relied on instrumental tasks, which may confound reward processing abnormalities with deficits in response selection and execution. 25 chronic, medicated outpatients with schizophrenia and 20 healthy controls underwent functional magnetic resonance imaging using a pavlovian reward prediction paradigm with no response requirements. Subjects passively viewed cues that predicted subsequent receipt of monetary reward or non-reward, and blood-oxygen-level-dependent signal was measured at the time of cue presentation and receipt. At the group level, neural responses to both reward anticipation and receipt were largely similar between groups. At the time of cue presentation, striatal anticipatory responses did not differ between patients and controls. Right anterior insula demonstrated greater activation for nonreward than reward cues in controls, and for reward than nonreward cues in patients. At the time of receipt, robust responses to receipt of reward vs. nonreward were seen in striatum, midbrain, and frontal cortex in both groups. Furthermore, both groups demonstrated responses to unexpected versus expected outcomes in cortical areas including bilateral dorsolateral prefrontal cortex. Individual difference analyses in patients revealed an association between physical anhedonia and activity in ventral striatum and ventromedial prefrontal cortex during anticipation of reward, in which greater anhedonia severity was associated with reduced activation to money versus no-money cues. In ventromedial prefrontal cortex, this relationship held among both controls and patients, suggesting a relationship between anticipatory activity and anhedonia irrespective of diagnosis. These findings suggest that in the absence of response requirements, brain responses to reward receipt are largely intact in medicated individuals with chronic schizophrenia, while reward anticipation responses in left ventral striatum are reduced in those patients with greater anhedonia severity.     

Unit activity of the prefrontal cortex during delayed alternation performance in monkey.

Unit activity in the dorsolateral regions of the prefrontal cortex (s. principalis) of the monkey was analysed by multineuronal recording technique. The sequence during delayed-response alternation included anticipatory stimulus, non-specific expectancy, conditioned cue, delay, trigger stimulus and alternation performance. Food reward completed the sequence. Unit activity in s. principalis was found to be involved in such learning processes as integration of behavioural acts into an accomplished programme and storage of traces in short-term memory. The latter can be observed in successive involvement of neuronal populations during a 10 sec delay as well as in rearrangements of unit activity, the maximum of which shifts to the latest part of the delay period. Unit activity in s. principalis reflects the level of correct response, corresponding correlates of which depend on the level of attention. The dorsolateral prefrontal cortex has structural and functional characteristics for short-term storage of external signals in its neuronal nets according to the level of attention.     

Increased Amygdala and Visual Cortex Activity and Functional Connectivity towards Stimulus Novelty Is Associated with State Anxiety

Novel stimuli often require a rapid reallocation of sensory processing resources to determine the significance of the event, and the appropriate behavioral response. Both the amygdala and the visual cortex are central elements of the neural circuitry responding to novelty, demonstrating increased activity to new as compared to highly familiarized stimuli. Further, these brain areas are intimately connected, and thus the amygdala may be a key region for directing sensory processing resources to novel events. Although knowledge regarding the neurocircuit of novelty detection is gradually increasing, we still lack a basic understanding of the conditions that are necessary and sufficient for novelty-specific responses in human amygdala and the visual cortices, and if these brain areas interact during detection of novelty. In the present study, we investigated the response of amygdala and the visual cortex to novelty, by comparing functional MRI activity between 1^st and 2^nd time presentation of a series of emotional faces in an event-related task. We observed a significant decrease in amygdala and visual cortex activity already after a single stimulus exposure. Interestingly, this decrease in responsiveness was less for subjects with a high score on state anxiety. Further, novel faces stimuli were associated with a relative increase in the functional coupling between the amygdala and the inferior occipital gyrus (BA 18). Thus, we suggest that amygdala is involved in fast sensory boosting that may be important for attention reallocation to novel events, and that the strength of this response depends on individual state anxiety.     

Fear Conditioning in an Abdominal Pain Model: Neural Responses during Associative Learning and Extinction in Healthy Subjects

Fear conditioning is relevant for elucidating the pathophysiology of anxiety, but may also be useful in the context of chronic pain syndromes which often overlap with anxiety. Thus far, no fear conditioning studies have employed aversive visceral stimuli from the lower gastrointestinal tract. Therefore, we implemented a fear conditioning paradigm to analyze the conditioned response to rectal pain stimuli using fMRI during associative learning, extinction and reinstatement.In N = 21 healthy humans, visual conditioned stimuli (CS⁺) were paired with painful rectal distensions as unconditioned stimuli (US), while different visual stimuli (CS⁻) were presented without US. During extinction, all CSs were presented without US, whereas during reinstatement, a single, unpaired US was presented. In region-of-interest analyses, conditioned anticipatory neural activation was assessed along with perceived CS-US contingency and CS unpleasantness.Fear conditioning resulted in significant contingency awareness and valence change, i.e., learned unpleasantness of a previously neutral stimulus. This was paralleled by anticipatory activation of the anterior cingulate cortex, the somatosensory cortex and precuneus (all during early acquisition) and the amygdala (late acquisition) in response to the CS⁺. During extinction, anticipatory activation of the dorsolateral prefrontal cortex to the CS⁻ was observed. In the reinstatement phase, a tendency for parahippocampal activation was found.Fear conditioning with rectal pain stimuli is feasible and leads to learned unpleasantness of previously neutral stimuli. Within the brain, conditioned anticipatory activations are seen in core areas of the central fear network including the amygdala and the anterior cingulate cortex. During extinction, conditioned responses quickly disappear, and learning of new predictive cue properties is paralleled by prefrontal activation. A tendency for parahippocampal activation during reinstatement could indicate a reactivation of the old memory trace. Together, these findings contribute to our understanding of aversive visceral learning and memory processes relevant to the pathophysiology of chronic abdominal pain.     

Competing neural responses for auditory and visual decisions

Why is it hard to divide attention between dissimilar activities, such as reading and listening to a conversation? We used functional magnetic resonance imaging (fMRI) to study interference between simple auditory and visual decisions, independently of motor competition. Overlapping activity for auditory and visual tasks performed in isolation was found in lateral prefrontal regions, middle temporal cortex and parietal cortex. When the visual stimulus occurred during the processing of the tone, its activation in prefrontal and middle temporal cortex was suppressed. Additionally, reduced activity was seen in modality-specific visual cortex. These results paralleled impaired awareness of the visual event. Even without competing motor responses, a simple auditory decision interferes with visual processing on different neural levels, including prefrontal cortex, middle temporal cortex and visual regions.     

A neural network model of attention-modulated neurodynamics

Visual attention appears to modulate cortical neurodynamics and synchronization through various cholinergic mechanisms. In order to study these mechanisms, we have developed a neural network model of visual cortex area V4, based on psychophysical, anatomical and physiological data. With this model, we want to link selective visual information processing to neural circuits within V4, bottom-up sensory input pathways, top-down attention input pathways, and to cholinergic modulation from the prefrontal lobe. We investigate cellular and network mechanisms underlying some recent analytical results from visual attention experimental data. Our model can reproduce the experimental findings that attention to a stimulus causes increased gamma-frequency synchronization in the superficial layers. Computer simulations and STA power analysis also demonstrate different effects of the different cholinergic attention modulation action mechanisms.     

Characteristics of Human Luminance Discrimination and Modeling a Neural Network Based on the Response Properties of the Visual Cortex

Reaction time (RT) and error rate that depend on stimulus duration were measured in a luminance-discrimination reaction time task. Two patches of light with different luminance were presented to participants for ‘short’ (150 ms) or ‘long’ (1 s) period on each trial. When the stimulus duration was ‘short’, the participants responded more rapidly with poorer discrimination performance than they did in the longer duration. The results suggested that different sensory responses in the visual cortices were responsible for the dependence of response speed and accuracy on the stimulus duration during the luminance-discrimination reaction time task. It was shown that the simple winner-take-all-type neural network model receiving transient and sustained stimulus information from the primary visual cortex successfully reproduced RT distributions for correct responses and error rates. Moreover, temporal spike sequences obtained from the model network closely resembled to the neural activity in the monkey prefrontal or parietal area during other visual decision tasks such as motion discrimination and oddball detection tasks.     

Associative fear learning enhances sparse network coding in primary sensory cortex

Several models of associative learning predict that stimulus processing changes during association formation. How associative learning reconfigures neural circuits in primary sensory cortex to "learn" associative attributes of a stimulus remains unknown. Using 2-photon in vivo calcium imaging to measure responses of networks of neurons in primary somatosensory cortex, we discovered that associative fear learning, in which whisker stimulation is paired with foot shock, enhances sparse population coding and robustness of the conditional stimulus, yet decreases total network activity. Fewer cortical neurons responded to stimulation of the trained whisker than in controls, yet their response strength was enhanced. These responses were not observed in mice exposed to a nonassociative learning procedure. Our results define how the cortical representation of a sensory stimulus is shaped by associative fear learning. These changes are proposed to enhance efficient sensory processing after associative learning.     

Scene segmentation by spike synchronization in reciprocally connected visual areas. I. Local effects of cortical feedback

 To investigate scene segmentation in the visual system we present a model of two reciprocally connected visual areas using spiking neurons. Area P corresponds to the orientation-selective subsystem of the primary visual cortex, while the central visual area C is modeled as associative memory representing stimulus objects according to Hebbian learning. Without feedback from area C, a single stimulus results in relatively slow and irregular activity, synchronized only for neighboring patches (slow state), while in the complete model activity is faster with an enlarged synchronization range (fast state). When presenting a superposition of several stimulus objects, scene segmentation happens on a time scale of hundreds of milliseconds by alternating epochs of the slow and fast states, where neurons representing the same object are simultaneously in the fast state. Correlation analysis reveals synchronization on different time scales as found in experiments (designated as tower, castle, and hill peaks). On the fast time scale (tower peaks, gamma frequency range), recordings from two sites coding either different or the same object lead to correlograms that are either flat or exhibit oscillatory modulations with a central peak. This is in agreement with experimental findings, whereas standard phase-coding models would predict shifted peaks in the case of different objects. Received: 22 August 2001 / Accepted in revised form: 8 April 2002     

Brain mechanisms associated with top-down processes in perception.

Perception arises through an interaction between sensory input and prior knowledge. We propose that at least two brain areas are required for such an interaction: the ''site'' where analysis of afferent signals occurs and the ''source'' which applies the relevant prior knowledge. In the human brain, functional imaging studies have demonstrated that selective attention modifies activity in early visual processing areas specific to the attended feature. Early processing areas are also modified when prior knowledge permits a percept to emerge from an otherwise meaningless stimulus. Sources of this modification have been identified in parietal cortex and in prefrontal cortex. Modification of early processing areas also occurs on the basis of prior knowledge about the predicted sensory effects of the subject''s own actions. Activity associated with mental imagery resembles that associated with response preparation (for motor imagery) and selective attention (for sensory imagery) suggesting that mental imagery reflects the effects of prior knowledge on sensory processing areas in the absence of sensory input. Damage to sensory processing areas can lead to a form of sensory hallucination which seems to arise from the interaction of prior knowledge with random sensory activity. In contrast, hallucinations associated with schizophrenia may arise from a failure of prior knowledge about motor intentions to modify activity in relevant sensory areas. When functioning normally, this mechanism permits us to distinguish our own actions from those of independent agents in the outside world. Failure to make this distinction correctly may account for the strong association between hallucinations and paranoid delusions in schizophrenia; the patient not only hears voices, but attributes (usually hostile) intentions to these voices.     

Oscillatory Activity in the Medial Prefrontal Cortex and Nucleus Accumbens Correlates with Impulsivity and Reward Outcome

Actions expressed prematurely without regard for their consequences are considered impulsive. Such behaviour is governed by a network of brain regions including the prefrontal cortex (PFC) and nucleus accumbens (NAcb) and is prevalent in disorders including attention deficit hyperactivity disorder (ADHD) and drug addiction. However, little is known of the relationship between neural activity in these regions and specific forms of impulsive behaviour. In the present study we investigated local field potential (LFP) oscillations in distinct sub-regions of the PFC and NAcb on a 5-choice serial reaction time task (5-CSRTT), which measures sustained, spatially-divided visual attention and action restraint. The main findings show that power in gamma frequency (50–60 Hz) LFP oscillations transiently increases in the PFC and NAcb during both the anticipation of a cue signalling the spatial location of a nose-poke response and again following correct responses. Gamma oscillations were coupled to low-frequency delta oscillations in both regions; this coupling strengthened specifically when an error response was made. Theta (7–9 Hz) LFP power in the PFC and NAcb increased during the waiting period and was also related to response outcome. Additionally, both gamma and theta power were significantly affected by upcoming premature responses as rats waited for the visual cue to respond. In a subgroup of rats showing persistently high levels of impulsivity we found that impulsivity was associated with increased error signals following a nose-poke response, as well as reduced signals of previous trial outcome during the waiting period. Collectively, these in-vivo neurophysiological findings further implicate the PFC and NAcb in anticipatory impulsive responses and provide evidence that abnormalities in the encoding of rewarding outcomes may underlie trait-like impulsive behaviour.     

Prefrontal cortex and somatosensory cortex in tactile crossmodal association: an independent component analysis of ERP recordings

Our previous studies on scalp-recorded event-related potentials (ERPs) showed that somatosensory N140 evoked by a tactile vibration in working memory tasks was enhanced when human subjects expected a coming visual stimulus that had been paired with the tactile stimulus. The results suggested that such enhancement represented the cortical activities involved in tactile-visual crossmodal association. In the present study, we further hypothesized that the enhancement represented the neural activities in somatosensory and frontal cortices in the crossmodal association. By applying independent component analysis (ICA) to the ERP data, we found independent components (ICs) located in the medial prefrontal cortex (around the anterior cingulate cortex, ACC) and the primary somatosensory cortex (SI). The activity represented by the IC in SI cortex showed enhancement in expectation of the visual stimulus. Such differential activity thus suggested the participation of SI cortex in the task-related crossmodal association. Further, the coherence analysis and the Granger causality spectral analysis of the ICs showed that SI cortex appeared to cooperate with ACC in attention and perception of the tactile stimulus in crossmodal association. The results of our study support with new evidence an important idea in cortical neurophysiology: higher cognitive operations develop from the modality-specific sensory cortices (in the present study, SI cortex) that are involved in sensation and perception of various stimuli.     

A role of dopamine-dependent activity reorganizations in the cortico-basal ganglia-thalamocortical loops in visual attention (hypothetical mechanism)

A mechanism of attention is proposed according to which its influence on visual processing is switched on by release of dopamine into the striatum. A dopamine release during involuntary attention is promoted by visual activation of striatonigral cells via the thalamus and subsequent disinhibition through the basal ganglia of the superior colliculus. A dopamine release during voluntary attention is promoted by activation of prefrontal cortex. The strengthening of responses of neocortical neurons to attended stimulus, and suppression of responses to other stimuli is the result of opposite modulatory action of dopamine on the efficacy of strong and weak corticostriatal inputs. This leads to changes in the output basal ganglia signals ("attentional filter") that exert disinhibitory and inhibitory influence (via the thalamus) on neocortical cells that initially were strongly and weakly activated by a stimulus, respectively. From proposed mechanism follows, that attention modulates only those components of responses of cortical neurons which latency exceeds the latency of reactions of dopaminergic cells (80-100 ms).     

Functional brain organization of global and local visual perception: an ERP study

Adult subjects were asked to recognize a hierarchical visual stimulus (a letter) while their attention was drawn to either the global or local level of the stimulus. Event-related potentials (ERP) and psychophysical indices (reaction time and percentage of correct responses) were measured. An analysis of psychophysical indices showed the global level precedence effect, i.e., the increase in a small letter recognition time when this letter is a part of incongruent stimulus. An analysis of ERP components showed level-related (global vs. local) differences in the timing and topography of the brain organization of perceptual processing and regulatory mechanisms of attention. Visual recognition at the local level was accompanied by (1) stronger activation of the visual associative areas (Pz and T6) at the stage of sensory features analysis (P1 ERP component), (2) involvement mainly of inferior temporal cortices of the right hemisphere (T6) at the stage of sensory categorization (P2 ERP component), and (3) involvement of prefrontal cortex of the right hemisphere at the stage of the selection of the relevant features of the target (N2 ERP component). Visual recognition at the global level was accompanied by (1) pronounced involvement of mechanisms of early sensory selection (N1 ERP component), (2) prevailing activation of parietal cortex of the right hemisphere (P4) at the stage of sensory categorization (P2 ERP component) as well as at the stage of the target stimulus identification (P3 ERP component). It is suggested that perception at the global level of the hierarchical stimulus is related primarily to the analysis of the spatial features of the stimulus in the dorsal visual system whereas the perception at the local level primarily involves an analysis of the object-related features in the ventral visual system.     

Synchronization of neuronal assemblies in reciprocally connected cortical areas

Summary To investigate scene segmentation in the visual system we present a model of two reciprocally connected visual areas comprising spiking neurons. The peripheral area P is modeled similar to the primary visual cortex, while the central area C is modeled as an associative memory representing stimulus objects according to Hebbian learning. Without feedback from area C, spikes corresponding to stimulus representations in P are synchronized only locally (slow state). Feedback from C can induce fast oscillations and an increase of synchronization ranges (fast state). Presenting a superposition of several stimulus objects, scene segmentation happens on a time scale of hundreds of milliseconds by alternating epochs of the slow and fast state, where neurons representing the same object are simultaneously in the fast state. We relate our simulation results to various phenomena observed in neurophysiological experiments, such as stimulus-dependent synchronization of fast oscillations, synchronization on different time scales, ongoing activity, and attention-dependent neural activity.     

Neuronal responses related to long-term recognition memory processes in prefrontal cortex

Much evidence indicates that prefrontal cortex plays an important role in long-term recognition memory processes. Here, we report primate prefrontal neuronal responses carrying information necessary for long-term visual recognition memory. The responses of many neurons signaled stimulus familiarity even when the period over which stimuli had to be remembered extended to 24 hr. Such responses occurred frequently in ventromedial, orbitofrontal, and anterior cingulate but not dorsolateral prefrontal cortex. Prefrontal information processing, as indicated by the response latencies, started after that in inferior temporal cortex and might be related to retrieval processes, as responses were typically larger for familiar than for novel stimuli.     

A hypothetical role of cortico-basal ganglia-thalamocortical loops in visual processing

The goal of the present work was to define the mechanisms underlying the contribution of sensory and limbic cortico-basal ganglia-thalamocortical loops to visual processing and its attentional modulation. We proposed that visual processing is promoted by dopamine-dependent long-term modifications of synaptic transmission in the basal ganglia that favour a selection of neocortical patterns representing a visual stimulus. This selection is the result of the opposite sign of modulation of strong and weak cortico-basal ganglia inputs and subsequent activity reorganization in each loop. Reorganization leads to disinhibition/inhibition of cortical neurons strongly/weakly excited by stimulus during dopamine release. Recruitment of the thalamo-basal ganglia-collicular pathway is proposed to be necessary for stimulus-evoked dopamine release that underlies bottom-up attentional effects. Visual excitation of the prefrontal cortex and hippocampus (via the thalamus), their cooperation in control of the basal ganglia and dopaminergic cell firing, and simultaneous modulation of activity in diverse cortico-basal ganglia-thalamocortical loops is proposed to underlie top-down attentional effects. It follows from our model that only those components of cortical responses can be modulated by attention, whose onset exceeds the latency of visual responses of dopaminergic cells (50-110 ms). This and other consequences of the model are in accordance with known experimental data.     

Modelling attention in individual cells leads to a system with realistic saccade behaviours

Single cell recordings in monkey inferior temporal cortex (IT) and area V4 during visual search tasks indicate that modulation of responses by the search target object occurs in the late portion of the cell’s sensory response (Chelazzi et al. in J Neurophysiol 80:2918–2940, 1998; Cereb Cortex 11:761–772, 2001) whereas attention to a spatial location influences earlier responses (Luck et al. in J Neurophysiol 77:24–42, 1997). Previous computational models have not captured differences in the latency of these attentional effects and yet the more protracted development of the object-based effect could have implications for behaviour. We present a neurodynamic biased competition model of visual attention in which we aimed to model the timecourse of spatial and object-based attention in order to simulate cellular responses and saccade onset times observed in monkey recordings. In common with other models, a top-down prefrontal signal, related to the search target, biases activity in the ventral visual stream. However, we conclude that this bias signal is more complex than modelled elsewhere: the latency of object-based effects in V4 and IT, and saccade onset, can be accurately simulated when the target object feedback bias consists of a sensory response component in addition to a mnemonic response. These attentional effects in V4 and IT cellular responses lead to a system that is able to produce search scan paths similar to those observed in monkeys and humans, with attention being guided to locations containing behaviourally relevant stimuli. This work demonstrates that accurate modelling of the timecourse of single cell responses can lead to biologically realistic behaviours being demonstrated by the system as a whole.     

The role of prefrontal cortex in working memory: examining the contents of consciousness.

Working memory enables us to hold in our ''mind''s eye'' the contents of our conscious awareness, even in the absence of sensory input, by maintaining an active representation of information for a brief period of time. In this review we consider the functional organization of the prefrontal cortex and its role in this cognitive process. First, we present evidence from brain-imaging studies that prefrontal cortex shows sustained activity during the delay period of visual working memory tasks, indicating that this cortex maintains on-line representations of stimuli after they are removed from view. We then present evidence for domain specificity within frontal cortex based on the type of information, with object working memory mediated by more ventral frontal regions and spatial working memory mediated by more dorsal frontal regions. We also propose that a second dimension for domain specificity within prefrontal cortex might exist for object working memory on the basis of the type of representation, with analytic representations maintained preferentially in the left hemisphere and image-based representations maintained preferentially in the right hemisphere. Furthermore, we discuss the possibility that there are prefrontal areas brought into play during the monitoring and manipulation of information in working memory in addition to those engaged during the maintenance of this information. Finally, we consider the relationship of prefrontal areas important for working memory, both to posterior visual processing areas and to prefrontal areas associated with long-term memory.     

Erratum to: Functional Brain Organization of Global and Local Visual Perception: An Event-Related Potentials Study

Adult subjects were asked to recognize a hierarchical visual stimulus (a letter) while their attention was drawn to either the global or local level of the stimulus. Event-related potentials (ERP) and behavioral indices (reaction time and percentage of correct responses) were measured. An analysis of behavioral indices showed the global level precedence effect, i.e. the increase in a small letter recognition time when this letter is a part of incongruent stimulus. An analysis of ERP components showed level-related (global vs. local) differences in the timing and topography of the brain organization of perceptual processing and regulatory mechanisms of attention. Visual recognition at the local level was accompanied by (1) stronger activation of the visual associative areas (P _z and T ₆) at the stage of sensory features analysis (P1 ERP component), (2) involvement mainly of inferior temporal cortices of the right hemisphere (T ₆) at the stage of sensory categorization (P2 ERP component), and (3) involvement of prefrontal cortex of the right hemisphere at the stage of selection of the relevant features of the target (N2 ERP component). Visual recognition at the global level was accompanied by (1) pronounced involvement of mechanisms of early sensory selection (N1 ERP component), (2) prevailing activation of parietal cortex of the right hemisphere (P ₄) at the stage of sensory categorization (P2 ERP component) as well as at the stage of the target stimulus identification (P3 ERP component). We suggested that perception of the hierarchical stimulus at the global level is related primarily to the analysis of its spatial features in the dorsal visual system whereas the perception at the local level primarily involves an analysis of the object-related features in the ventral visual system.