CiteULike: nishiokov's library [138 articles]

Neural repetition suppression reflects fulfilled perceptual expectations.

Christopher Summerfield — 2008-08-07T08:44:32-00:00

Nature neuroscience (1 August 2008)

Stimulus-evoked neural activity is attenuated on stimulus repetition (repetition suppression), a phenomenon that is attributed to largely automatic processes in sensory neurons. By manipulating the likelihood of stimulus repetition, we found that repetition suppression in the human brain was reduced when stimulus repetitions were improbable (and thus, unexpected). Our data suggest that repetition suppression reflects a relative reduction in top-down perceptual 'prediction error' when processing an expected, compared with an unexpected, stimulus.

From sensation to cognition.

MM Mesulam — 2007-01-03T23:42:30-00:00

Brain, Vol. 121 ( Pt 6) (June 1998), pp. 1013-1052.

Sensory information undergoes extensive associative elaboration and attentional modulation as it becomes incorporated into the texture of cognition. This process occurs along a core synaptic hierarchy which includes the primary sensory, upstream unimodal, downstream unimodal, heteromodal, paralimbic and limbic zones of the cerebral cortex. Connections from one zone to another are reciprocal and allow higher synaptic levels to exert a feedback (top-down) influence upon earlier levels of processing. Each cortical area provides a nexus for the convergence of afferents and divergence of efferents. The resultant synaptic organization supports parallel as well as serial processing, and allows each sensory event to initiate multiple cognitive and behavioural outcomes. Upstream sectors of unimodal association areas encode basic features of sensation such as colour, motion, form and pitch. More complex contents of sensory experience such as objects, faces, word-forms, spatial locations and sound sequences become encoded within downstream sectors of unimodal areas by groups of coarsely tuned neurons. The highest synaptic levels of sensory-fugal processing are occupied by heteromodal, paralimbic and limbic cortices, collectively known as transmodal areas. The unique role of these areas is to bind multiple unimodal and other transmodal areas into distributed but integrated multimodal representations. Transmodal areas in the midtemporal cortex, Wernicke's area, the hippocampal-entorhinal complex and the posterior parietal cortex provide critical gateways for transforming perception into recognition, word-forms into meaning, scenes and events into experiences, and spatial locations into targets for exploration. All cognitive processes arise from analogous associative transformations of similar sets of sensory inputs. The differences in the resultant cognitive operation are determined by the anatomical and physiological properties of the transmodal node that acts as the critical gateway for the dominant transformation. Interconnected sets of transmodal nodes provide anatomical and computational epicentres for large-scale neurocognitive networks. In keeping with the principles of selectively distributed processing, each epicentre of a large-scale network displays a relative specialization for a specific behavioural component of its principal neurospychological domain. The destruction of transmodal epicentres causes global impairments such as multimodal anomia, neglect and amnesia, whereas their selective disconnection from relevant unimodal areas elicits modality-specific impairments such as prosopagnosia, pure word blindness and category-specific anomias. The human brain contains at least five anatomically distinct networks. The network for spatial awareness is based on transmodal epicentres in the posterior parietal cortex and the frontal eye fields; the language network on epicentres in Wernicke's and Broca's areas; the explicit memory/emotion network on epicentres in the hippocampal-entorhinal complex and the amygdala; the face-object recognition network on epicentres in the midtemporal and temporopolar cortices; and the working memory-executive function network on epicentres in the lateral prefrontal cortex and perhaps the posterior parietal cortex. Individual sensory modalities give rise to streams of processing directed to transmodal nodes belonging to each of these networks. The fidelity of sensory channels is actively protected through approximately four synaptic levels of sensory-fugal processing. The modality-specific cortices at these four synaptic levels encode the most veridical representations of experience. Attentional, motivational and emotional modulations, including those related to working memory, novelty-seeking and mental imagery, become increasingly more pronounced within downstream components of unimodal areas, where they help to create a highly edited subjective version of the world. (ABSTRACT TRUNCATED)

A Neural Representation of Prior Information during Perceptual Inference

Christopher Summerfield — 2008-07-31T12:46:28-00:00

Neuron, Vol. 59, No. 2. (31 July 2008), pp. 336-347.

Summary Perceptual inference is biased by foreknowledge about what is probable or possible. How prior expectations are neurally represented during visual perception, however, remains unknown. We used functional magnetic resonance imaging to measure brain activity in humans judging simple visual stimuli. Perceptual decisions were either biased in favor of a single alternative (A/~A decisions) or taken without bias toward either choice (A/B decisions). Extrastriate and anterior temporal lobe regions were more active during A/~A than A/B decisions, suggesting multiple representations of prior expectations within the visual hierarchy. Forward connectivity was increased when expected and observed perception diverged ("prediction error" signals), whereas prior expectations fed backward from higher to lower regions. Finally, the coincidence between expected and observed perception activated orbital prefrontal regions, perhaps reflecting the reinforcement of prior expectations. These data support computational and quantitative models proposing that a visual percept emerges from converging bottom-up and top-down signals.

Neural Coding of Distinct Statistical Properties of Reward Information in Humans.

Jean-Claude Dreher — 2005-09-12T15:00:31-00:00

Cereb Cortex (20 July 2005)

Brain processing of reward information is essential for complex functions such as learning and motivation. Recent primate electrophysiological studies using concepts from information, economic and learning theories indicate that the midbrain may code two statistical parameters of reward information: a transient reward error prediction signal that varies linearly with reward probability and a sustained signal that varies highly non-linearly with reward probability and that is highest with maximal reward uncertainty (reward probability = 0.5). Here, using event-related functional magnetic resonance imaging, we disentangled these two signals in humans using a novel paradigm that systematically varied monetary reward probability, magnitude and expected reward value. The midbrain was activated both transiently with the error prediction signal and in a sustained fashion with reward uncertainty. Moreover, distinct activity dynamics were observed in post-synaptic midbrain projection sites: the prefrontal cortex responded to the transient error prediction signal while the ventral striatum covaried with the sustained reward uncertainty signal. These data suggest that the prefrontal cortex may generate the reward prediction while the ventral striatum may be involved in motivational processes that are useful when an organism needs to obtain more information about its environment. Our results indicate that distinct functional brain networks code different aspects of the statistical properties of reward information in humans.

Menstrual cycle phase modulates reward-related neural function in women

Jean-Claude Dreher — 2007-12-28T02:55:06-00:00

Proceedings of the National Academy of Sciences, Vol. 104, No. 7. (13 February 2007), pp. 2465-2470.

There is considerable evidence from animal studies that the mesolimbic and mesocortical dopamine systems are sensitive to circulating gonadal steroid hormones. Less is known about the influence of estrogen and progesterone on the human reward system. To investigate this directly, we used functional MRI and an event-related monetary reward paradigm to study women with a repeated-measures, counterbalanced design across the menstrual cycle. Here we show that during the midfollicular phase (days 4-8 after onset of menses) women anticipating uncertain rewards activated the orbitofrontal cortex and amygdala more than during the luteal phase (6-10 days after luteinizing hormone surge). At the time of reward delivery, women in the follicular phase activated the midbrain, striatum, and left fronto-polar cortex more than during the luteal phase. These data demonstrate augmented reactivity of the reward system in women during the midfollicular phase when estrogen is unopposed by progesterone. Moreover, investigation of between-sex differences revealed that men activated ventral putamen more than women during anticipation of uncertain rewards, whereas women more strongly activated the anterior medial prefrontal cortex at the time of reward delivery. Correlation between brain activity and gonadal steroid levels also revealed that the amygdalo-hippocampal complex was positively correlated with estradiol level, regardless of menstrual cycle phase. Together, our findings provide evidence of neurofunctional modulation of the reward system by gonadal steroid hormones in humans and establish a neurobiological foundation for understanding their impact on vulnerability to drug abuse, neuropsychiatric diseases with differential expression across males and females, and hormonally mediated mood disorders. 10.1073/pnas.0605569104

The role of context in object recognition.

Aude Oliva — 2007-12-03T09:34:19-00:00

Trends Cogn Sci (15 November 2007)

In the real world, objects never occur in isolation; they co-vary with other objects and particular environments, providing a rich source of contextual associations to be exploited by the visual system. A natural way of representing the context of an object is in terms of its relationship to other objects. Alternately, recent work has shown that a statistical summary of the scene provides a complementary and effective source of information for contextual inference, which enables humans to quickly guide their attention and eyes to regions of interest in natural scenes. A better understanding of how humans build such scene representations, and of the mechanisms of contextual analysis, will lead to a new generation of computer vision systems.

Task-demands can immediately reverse the effects of sensory-driven saliency in complex visual stimuli.

W Einhäuser — 2008-07-31T01:27:37-00:00

Journal of vision, Vol. 8, No. 2. (2008)

In natural vision both stimulus features and task-demands affect an observer's attention. However, the relationship between sensory-driven ("bottom-up") and task-dependent ("top-down") factors remains controversial: Can task-demands counteract strong sensory signals fully, quickly, and irrespective of bottom-up features? To measure attention under naturalistic conditions, we recorded eye-movements in human observers, while they viewed photographs of outdoor scenes. In the first experiment, smooth modulations of contrast biased the stimuli's sensory-driven saliency towards one side. In free-viewing, observers' eye-positions were immediately biased toward the high-contrast, i.e., high-saliency, side. However, this sensory-driven bias disappeared entirely when observers searched for a bull's-eye target embedded with equal probability to either side of the stimulus. When the target always occurred in the low-contrast side, observers' eye-positions were immediately biased towards this low-saliency side, i.e., the sensory-driven bias reversed. Hence, task-demands do not only override sensory-driven saliency but also actively countermand it. In a second experiment, a 5-Hz flicker replaced the contrast gradient. Whereas the bias was less persistent in free viewing, the overriding and reversal took longer to deploy. Hence, insufficient sensory-driven saliency cannot account for the bias reversal. In a third experiment, subjects searched for a spot of locally increased contrast ("oddity") instead of the bull's-eye ("template"). In contrast to the other conditions, a slight sensory-driven free-viewing bias prevails in this condition. In a fourth experiment, we demonstrate that at known locations template targets are detected faster than oddity targets, suggesting that the former induce a stronger top-down drive when used as search targets. Taken together, task-demands can override sensory-driven saliency in complex visual stimuli almost immediately, and the extent of overriding depends on the search target and the overridden feature, but not on the latter's free-viewing saliency.

The neural correlates of consciousness: an update.

G Tononi — 2008-04-11T13:29:18-00:00

Annals of the New York Academy of Sciences, Vol. 1124 (March 2008), pp. 239-261.

This review examines recent advances in the study of brain correlates of consciousness. First, we briefly discuss some useful distinctions between consciousness and other brain functions. We then examine what has been learned by studying global changes in the level of consciousness, such as sleep, anesthesia, and seizures. Next we consider some of the most common paradigms used to study the neural correlates for specific conscious percepts and examine what recent findings say about the role of different brain regions in giving rise to consciousness for that percept. Then we discuss dynamic aspects of neural activity, such as sustained versus phasic activity, feedforward versus reentrant activity, and the role of neural synchronization. Finally, we briefly consider how a theoretical analysis of the fundamental properties of consciousness can usefully complement neurobiological studies.

Neuronal Diversity and Temporal Dynamics: The Unity of Hippocampal Circuit Operations

Thomas Klausberger — 2008-07-07T16:45:00-00:00

Science, Vol. 321, No. 5885. (4 July 2008), pp. 53-57.

In the cerebral cortex, diverse types of neurons form intricate circuits and cooperate in time for the processing and storage of information. Recent advances reveal a spatiotemporal division of labor in cortical circuits, as exemplified in the CA1 hippocampal area. In particular, distinct GABAergic (gamma-aminobutyric acid-releasing) cell types subdivide the surface of pyramidal cells and act in discrete time windows, either on the same or on different subcellular compartments. They also interact with glutamatergic pyramidal cell inputs in a domain-specific manner and support synaptic temporal dynamics, network oscillations, selection of cell assemblies, and the implementation of brain states. The spatiotemporal specializations in cortical circuits reveal that cellular diversity and temporal dynamics coemerged during evolution, providing a basis for cognitive behavior. 10.1126/science.1149381

Where in the brain is the self?

TE Feinberg — 2006-02-20T05:18:28-00:00

Conscious Cogn, Vol. 14, No. 4. (December 2005), pp. 661-678.

Localizing the self in the brain has been the goal of consciousness research for centuries. Recently, there has been an increase in attention to the localization of the self. Here we present data from patients suffering from a loss of self in an attempt to understand the neural correlates of consciousness. Focusing on delusional misidentification syndrome (DMS), we find that frontal regions, as well as the right hemisphere appear to play a significant role in DMS and DMS related disorders. These data are placed in the context of neuroimaging findings.

Do patients with schizophrenia exhibit aberrant salience?

J P Roiser — 2008-07-25T13:38:06-00:00

Psychological medicine (30 June 2008), pp. 1-11.

BACKGROUND: It has been suggested that some psychotic symptoms reflect 'aberrant salience', related to dysfunctional reward learning. To test this hypothesis we investigated whether patients with schizophrenia showed impaired learning of task-relevant stimulus-reinforcement associations in the presence of distracting task-irrelevant cues.MethodWe tested 20 medicated patients with schizophrenia and 17 controls on a reaction time game, the Salience Attribution Test. In this game, participants made a speeded response to earn money in the presence of conditioned stimuli (CSs). Each CS comprised two visual dimensions, colour and form. Probability of reinforcement varied over one of these dimensions (task-relevant), but not the other (task-irrelevant). Measures of adaptive and aberrant motivational salience were calculated on the basis of latency and subjective reinforcement probability rating differences over the task-relevant and task-irrelevant dimensions respectively. RESULTS: Participants rated reinforcement significantly more likely and responded significantly faster on high-probability-reinforced relative to low-probability-reinforced trials, representing adaptive motivational salience. Patients exhibited reduced adaptive salience relative to controls, but the two groups did not differ in terms of aberrant salience. Patients with delusions exhibited significantly greater aberrant salience than those without delusions, and aberrant salience also correlated with negative symptoms. In the controls, aberrant salience correlated significantly with 'introvertive anhedonia' schizotypy. CONCLUSIONS: These data support the hypothesis that aberrant salience is related to the presence of delusions in medicated patients with schizophrenia, but are also suggestive of a link with negative symptoms. The relationship between aberrant salience and psychotic symptoms warrants further investigation in unmedicated patients.

Locally Bayesian learning with applications to retrospective revaluation and highlighting.

JK Kruschke — 2006-11-03T17:46:21-00:00

Psychol Rev, Vol. 113, No. 4. (October 2006), pp. 677-699.

A scheme is described for locally Bayesian parameter updating in models structured as successions of component functions. The essential idea is to back-propagate the target data to interior modules, such that an interior component's target is the input to the next component that maximizes the probability of the next component's target. Each layer then does locally Bayesian learning. The approach assumes online trial-by-trial learning. The resulting parameter updating is not globally Bayesian but can better capture human behavior. The approach is implemented for an associative learning model that first maps inputs to attentionally filtered inputs and then maps attentionally filtered inputs to outputs. The Bayesian updating allows the associative model to exhibit retrospective revaluation effects such as backward blocking and unovershadowing, which have been challenging for associative learning models. The back-propagation of target values to attention allows the model to show trial-order effects, including highlighting and differences in magnitude of forward and backward blocking, which have been challenging for Bayesian learning models.

Delusions: A suitable case for imaging?

Hadyn Ellis — 2008-07-25T13:29:51-00:00

International Journal of Psychophysiology, Vol. 63, No. 2. (February 2007), pp. 146-151.

This review is intended to outline the need/opportunities for imaging research in the area of delusions. In particular, delusions of misidentification are offered as possible examples of how both spatial and temporal brain imaging may throw light upon the theoretical, parallel processes of identification and emotional arousal occurring when a familiar face is encountered. Other types of Delusional Misidentifications are also briefly explored. The review then turns to related phenomena, including the ways imaging may help elucidate different types of covert face recognition; and also further explain the distinctive (but not entirely independent) processes underlying face, voice and object recognition. Throughout the review the aim is to emphasise the potential value to cognitive neuropsychiatry of good imaging techniques.

Capgras delusion: a window on face recognition.

H Ellis — 2008-07-25T13:27:07-00:00

Trends in cognitive sciences, Vol. 5, No. 4. (1 April 2001), pp. 149-156.

Capgras delusion is the belief that significant others have been replaced by impostors, robots or aliens. Although it usually occurs within a psychiatric illness, it can also be the result of brain injury or other obviously organic disorder. In contrast to patients with prosopagnosia, who cannot consciously recognize previously familiar faces but display autonomic or covert recognition (measured by skin conductance responses), people with Capgras delusion do not show differential autonomic activity to familiar compared with unknown faces. This challenges traditional models of the way faces are identified and presents some epistemological questions concerning identity. New data also indicate that, contrary to previous evidence, covert recognition can be fractionated into autonomic and behavioural/cognitive types, which is consistent with a recently proposed modification of the modal face recognition model.

Explaining delusions: a cognitive perspective.

V Bell — 2008-07-25T13:25:58-00:00

Trends in cognitive sciences, Vol. 10, No. 5. (May 2006), pp. 219-226.

There is now considerable evidence for reasoning, attention, metacognition and attribution biases in delusional patients. Recently, these findings have been incorporated into a number of cognitive models that aim to explain delusion formation, maintenance and content. Although delusions are commonly conceptualized as beliefs, not all models make reference to models of normal belief formation. This review considers those models that explain delusions as a breakdown of normal belief formation (belief-positive models), approaches that explain the pathology only (belief-negative models) and approaches that view delusions as one end of a distribution of anomalous mental phenomena (the continuum view). A cognitive theory that includes the 'pragmatic pathology' of delusions will be able to address both the phenomenology and the treatment of delusion-related distress.

Right prefrontal hypometabolism predicts delusions in dementia with Lewy bodies.

Robert Perneczky — 2008-07-25T13:23:26-00:00

Neurobiology of aging (4 February 2008)

Delusions (DEL) are frequent in dementia with Lewy bodies (DLB); however, the neural equivalent is poorly understood. The present study therefore aimed to identify the cerebral metabolic pattern of glucose of a DLB group suffering from DEL (DLB+DEL) as compared to a non-delusional group (DLB-DEL) and a control group (NL); and to determine the predictive value of the regional metabolic deficit for DEL symptomatology in comparison to other clinical variables significantly associated with DEL. Voxel-wise comparisons were conducted between the patient and control groups in SPM2. The most significant regional metabolic deficit of the DLB+DEL group was used a predictor for DEL symptomatology in a logistic regression analysis along with other variables significantly associated with DEL, such as visual hallucinations (VH), and overall cognitive impairment. A significant relative hypometabolism of the right prefrontal cortex was found in the DLB+DEL group, which predicted DEL symptomatology in the regression analysis. VH and overall cognitive dysfunction were no significant predictors. These results underline the significance of right prefrontal damage for DEL in DLB.

Frontal responses during learning predict vulnerability to the psychotogenic effects of ketamine: linking cognition, brain activity, and psychosis.

PR Corlett — 2008-07-25T13:21:12-00:00

Archives of general psychiatry, Vol. 63, No. 6. (June 2006), pp. 611-621.

CONTEXT: Establishing a neurobiological account of delusion formation that links cognitive processes, brain activity, and symptoms is important to furthering our understanding of psychosis. OBJECTIVE: To explore a theoretical model of delusion formation that implicates prediction error-dependent associative learning processes in a pharmacological functional magnetic resonance imaging study using the psychotomimetic drug ketamine. DESIGN: Within-subject, randomized, placebo-controlled study. SETTING: Hospital-based clinical research facility, Addenbrooke's Hospital, Cambridge, England. The work was completed within the Wellcome Trust and Medical Research Council Behavioral and Clinical Neuroscience Institute, Cambridge. PARTICIPANTS: Fifteen healthy, right-handed volunteers (8 of whom were male) with a mean +/- SD age of 29 +/- 7 years and a mean +/- SD predicted full-scale IQ of 113 +/- 4 were recruited from within the local community by advertisement. INTERVENTIONS: Subjects were given low-dose ketamine (100 ng/mL of plasma) or placebo while performing a causal associative learning task during functional magnetic resonance imaging. In a separate session outside the scanner, the dose was increased (to 200 ng/mL of plasma) and subjects underwent a structured clinical interview. MAIN OUTCOME MEASURES: Brain activation, blood plasma levels of ketamine, and scores from psychiatric ratings scales (Brief Psychiatric Ratings Scale, Present State Examination, and Clinician-Administered Dissociative States Scale). RESULTS: Low-dose ketamine perturbs error-dependent learning activity in the right frontal cortex (P = .03). High-dose ketamine produces perceptual aberrations (P = .01) and delusion-like beliefs (P = .007). Critically, subjects showing the highest degree of frontal activation with placebo show the greatest occurrence of drug-induced perceptual aberrations (P = .03) and ideas or delusions of reference (P = .04). CONCLUSIONS: These findings relate aberrant prediction error-dependent associative learning to referential ideas and delusions via a perturbation of frontal cortical function. They are consistent with a model of delusion formation positing disruptions in error-dependent learning.

The neural basis of hallucinations and delusions

Chris Frith — 2008-07-25T13:18:15-00:00

Comptes Rendus Biologies, Vol. 328, No. 2. (February 2005), pp. 169-175.

Schizophrenia is a biologically based disorder characterised by false perceptions (hallucinations) and false beliefs (delusions). The underlying physiological cause of these mental abnormalities remains unknown. There is increasing evidence that one class of symptom, the [`]made experiences' including delusions of alien control and thought insertion, is associated with abnormalities in the mechanism that predicts the outcome of intended actions (the forward model). For these patients active movements feel like passive movements. As a result these patients do not feel in control of their actions. However, comparison with various neurological disorders, such as those associated with parietal lobe lesions, suggest that this abnormal experience is not sufficient to explain the feeling that some other agent is controlling is one's actions. Preliminary evidence suggests that patients with schizophrenia have an exaggerated sense of agency. In combination with the feeling of not being in control, this exaggerated sense of agency could explain delusions of alien control in which the patient attributes his own actions to another agent. Little is yet know about the neural basis of the predictive mechanisms that create the feeling that we are in control of our movements. Such prediction requires integration of information about intended movements generated in frontal cortex with sensory processing in posterior regions of the brain. Measures of functional connectivity suggest that long-range interactions between frontal and posterior regions are abnormally reduced in patients with schizophrenia. Further research is needed to explore the precise involvement of long-range connections in the mechanisms of forward modelling. To cite this article: C. Frith, C. R. Biologies 328 (2005).Résumé La schizophrénie est un désordre d'origine biologique, caractérisé par des perceptions fausses (hallucinations) et des croyances erronées (délires). La cause physiologique sous-jacente à ces anomalies mentales demeure inconnue. Il semble de plus en plus établi qu'une classe de symptômes, les « expériences vécues », incluant les délires de contrôle extérieur et d'insertion de pensée, est associée à des anomalies du mécanisme de prédiction de la survenue d'actions intentionnelles (modèle forward). Pour ces patients, les mouvements actifs sont comme les mouvements passifs. Il en résulte qu'ils ne se sentent pas en mesure de contrôler leurs actions. Toutefois, la comparaison avec divers désordres neurologiques, tels ceux associés à des lésions du lobe pariétal, suggère que cette expérience anormale ne suffit pas à expliquer le sentiment que quelque autre agent contrôle ses propres actions. Des données préliminaires indiquent que les patients souffrant de schizophrénie ont un sens exagéré de l'action. Combiné au sentiment de ne pouvoir se contrôler, ce sens exagéré de l'action pourrait expliquer les illusions de contrôle extérieur qui font que le patient attribue ses propres actions à un autre agent. On ne sait toujours que peu de choses quant à la base neurale des mécanismes prédictifs qui créent le sentiment que nous contrôlons nos mouvements. Une telle prédiction exige que les informations sur les mouvements intentionnels engendrées dans le cortex frontal soient intégrées au traitement sensoriel dans les régions postérieures du cerveau. Des mesures de connectivité fonctionnelle suggèrent que des interactions à longue distance entre les régions frontale et postérieure sont anormalement réduites chez les patients souffrant de schizophrénie. Des recherches plus approfondies seront nécessaires pour explorer l'implication précise de ces connections longues dans les mécanismes de modélisation forward. Pour citer cet article : C. Frith, C. R. Biologies 328 (2005).

ATYPICAL ANTIPSYCHOTICS: New Directions and New Challenges in the Treatment of Schizophrenia

Shitij Kapur — 2008-07-22T08:50:15-00:00

Annual Review of Medicine, Vol. 52, No. 1. (2001), pp. 503-517.

Abstract Atypical antipsychotics represent a new generation of antipsychotics with a significantly lower incidence of extrapyramidal side effects (EPS), as well as little or no effect on prolactin elevation. These advantages constitute a major improvement in the treatment of patients with schizophrenia. The exact mechanisms that make these drugs atypical is not clear. However, a preferential action on serotonin 5-HT2 or D4 receptors, or a more rapid dissociation from the dopamine D2 receptor, may account for atypicality. Although the atypical antipsychotics have overcome EPS, other side effects such as weight gain and impaired glucose tolerance/lipid abnormalities have come to the fore. Thus, the challenges are far from over. The current atypicals are much more effective against the psychosis of schizophrenia than against the other, more enduring aspects of this disorder, e.g. negative symptoms and cognitive dysfunction. At present, the atypicals use a pharmacological shotgun strategy to treat aspects of the disease in all patients. A more sophisticated and perhaps effective approach to schizophrenia may lie in independently targeting the pathophysiological mechanisms of each clinical dimension (i.e. positive, negative, cognitive, and affective) with more selective drugs that can be combined and individually titrated to the needs of each patient.

Corollary discharge across the animal kingdom

Trinity Crapse — 2008-07-22T01:01:55-00:00

Nat Rev Neurosci, Vol. 9, No. 8. (2008), pp. 587-600.

Prediction error during retrospective revaluation of causal associations in humans: fMRI evidence in favor of an associative model of learning.

PR Corlett — 2005-10-16T16:50:08-00:00

Neuron, Vol. 44, No. 5. (2 December 2004), pp. 877-888.

Associative learning theory assumes that prediction error is a driving force in learning. A competing view, probabilistic contrast (PC) theory, is that learning and prediction error are unrelated. We tested a learning phenomenon that has proved troublesome for associative theory--retrospective revaluation--to evaluate these two models. We previously showed that activation in right lateral prefrontal cortex (PFC) provides a reliable signature for the presence of prediction error. Thus, if the associative view is correct, retrospective revaluation should be accompanied by right lateral PFC activation. PC theory would be supported by the absence of this activation. Right PFC and ventral striatal activation occurred during retrospective revaluation, supporting the associative account. Activations appeared to reflect the degree of revaluation, predicting later brain responses to revalued cues. Our results support a modified associative account of retrospective revaluation and demonstrate the potential of functional neuroimaging as a tool for evaluating competing learning models.

Disrupted prediction-error signal in psychosis: evidence for an associative account of delusions

PR Corlett — 2008-07-20T11:34:58-00:00

Brain, Vol. 130, No. 9. (1 September 2007), pp. 2387-2400.

Delusions are maladaptive beliefs about the world. Based upon experimental evidence that prediction error--a mismatch between expectancy and outcome--drives belief formation, this study examined the possibility that delusions form because of disrupted prediction-error processing. We used fMRI to determine prediction-error-related brain responses in 12 healthy subjects and 12 individuals (7 males) with delusional beliefs. Frontal cortex responses in the patient group were suggestive of disrupted prediction-error processing. Furthermore, across subjects, the extent of disruption was significantly related to an individual's propensity to delusion formation. Our results support a neurobiological theory of delusion formation that implicates aberrant prediction-error signalling, disrupted attentional allocation and associative learning in the formation of delusional beliefs. 10.1093/brain/awm173

Cost, Benefit, Tonic, Phasic: What Do Response Rates Tell Us about Dopamine and Motivation

Yael Niv — 2007-06-29T02:35:42-00:00

Annals of the New York Academy of Sciences, Vol. 1104, No. 1. (May 2007), pp. 357-376.

Dopaminergic regulation of limbic-striatal interplay.

SB Floresco — 2008-07-20T08:14:13-00:00

Journal of psychiatry & neuroscience : JPN, Vol. 32, No. 6. (November 2007), pp. 400-411.

Neurochemical, electrophysiological and behavioural evidence indicates that certain forms of goal-directed behaviours are mediated by complex and reciprocal interactions between limbic and dopamine (DA) inputs in the nucleus accumbens (NAc). Mesoaccumbens DA transmission appears to be compartmentalized; synaptic DA transmission is mediated by phasic burst firing of DA neurons, whereas extrasynaptic tonic DA levels are regulated by DA neuron population activity and limbic glutamatergic inputs to the NAc. DA release facilitated by limbic inputs and acting on D1 receptors can either potentiate or suppress neural activity driven by separate limbic inputs converging on the same postsynaptic NAc neurons. In turn, D1 receptors in the NAc mediate accuracy of search behaviour regulated by hippocampal-ventral striatal circuitries; D2 receptors appear to mediate motivational aspects of task performance. These findings suggest that dopaminergic modulation of limbic afferents to the NAc may be a cellular mechanism for input selection that governs the smooth coordination of behaviour by permitting information processed by one limbic region to temporarily exert control over the type and intensity of adaptive behavioural responses.

Arousal Mechanisms: Speedy Flies Don't Sleep at Night

Serge Birman — 2008-07-20T08:09:28-00:00

Current Biology, Vol. 15, No. 13. (12 July 2005), pp. R511-R513.

Alertness and behavioral performance depend on an animal's level of arousal. In vertebrates, reinforcement and maintenance of arousal in the cortex are ensured by diffuse inputs from neurons releasing biogenic amine neuromodulators. Fruit flies similarly use dopamine for arousal control, indicating an ancient evolutionary origin of this essential feature of the functioning brain.

The Role of the Lateral Frontal Cortex in Causal Associative Learning: Exploring Preventative and Super-learning

Danielle Turner — 2008-07-20T07:16:00-00:00

Cereb. Cortex, Vol. 14, No. 8. (1 August 2004), pp. 872-880.

Prediction error -- a mismatch between expected and actual outcome -- is critical to associative accounts of inferential learning. However, it has proven difficult to explore the effects of prediction error using functional magnetic resonance imaging (fMRI) while excluding the confounding effects of stimulus novelty and incorrect responses. In this event-related fMRI study we used a three-stage experiment generating preventative- and super-learning conditions. In both cases, it was possible to generate prediction error within a causal associative learning experiment while subtracting the effects of novelty and error. We show that right lateral prefrontal cortex (PFC) activation is sensitive to the magnitude of prediction error. Furthermore, super-learning activation in this region of PFC correlates, across subjects, with the amount learned. We thus provide direct evidence for a brain correlate of the surprise-dependent mechanisms proposed by associative accounts of causal learning. We show that activity in right lateral PFC is sensitive to the magnitude, though not the direction, of the prediction error. Furthermore, its activity is not directly explicable in terms of novelty or response errors and appears directly related to the learning that arises out of prediction error. 10.1093/cercor/bhh046

Responses of human frontal cortex to surprising events are predicted by formal associative learning theory.

PC Fletcher — 2008-07-20T07:14:18-00:00

Nature neuroscience, Vol. 4, No. 10. (October 2001), pp. 1043-1048.

Learning depends on surprise and is not engendered by predictable occurrences. In this functional magnetic resonance imaging (fMRI) study of causal associative learning, we show that dorsolateral prefrontal cortex (DLPFC) is associated specifically with the adjustment of inferential learning on the basis of unpredictability. At the outset, when all associations were unpredictable, DLPFC activation was maximal. This response attenuated with learning but, subsequently, activation here was evoked by surprise violations of the learned association. Furthermore, the magnitude of DLPFC response to a surprise event was sensitive to the relationship that had been learned and was predictive of subsequent behavioral change. In short, the physiological response properties of right DLPFC satisfied specific predictions made by associative learning theory.

A computational substrate for incentive salience.

SM McClure — 2005-03-09T16:57:03-00:00

Trends Neurosci, Vol. 26, No. 8. (August 2003), pp. 423-428.

Theories of dopamine function are at a crossroads. Computational models derived from single-unit recordings capture changes in dopaminergic neuron firing rate as a prediction error signal. These models employ the prediction error signal in two roles: learning to predict future rewarding events and biasing action choice. Conversely, pharmacological inhibition or lesion of dopaminergic neuron function diminishes the ability of an animal to motivate behaviors directed at acquiring rewards. These lesion experiments have raised the possibility that dopamine release encodes a measure of the incentive value of a contemplated behavioral act. The most complete psychological idea that captures this notion frames the dopamine signal as carrying 'incentive salience'. On the surface, these two competing accounts of dopamine function seem incommensurate. To the contrary, we demonstrate that both of these functions can be captured in a single computational model of the involvement of dopamine in reward prediction for the purpose of reward seeking.

Computational roles for dopamine in behavioural control

Read Montague — 2005-10-18T09:12:26-00:00

Nature, Vol. 431, No. 7010. (14 October 2004), pp. 760-767.

Neural Coding of Distinct Statistical Properties of Reward Information in Humans

Jean-Claude Dreher — 2006-03-10T19:10:05-00:00

Cerebral Cortex, Vol. 16, No. 4. (April 2006), pp. 561-573.

Learning and selective attention.

P Dayan — 2006-03-10T19:31:44-00:00

Nat Neurosci, Vol. 3 Suppl (November 2000), pp. 1218-1223.

Selective attention involves the differential processing of different stimuli, and has widespread psychological and neural consequences. Although computational modeling should offer a powerful way of linking observable phenomena at different levels, most work has focused on the relatively narrow issue of constraints on processing resources. By contrast, we consider statistical and informational aspects of selective attention, divorced from resource constraints, which are evident in animal conditioning experiments involving uncertain predictions and unreliable stimuli. Neuromodulatory systems and limbic structures are known to underlie attentional effects in such tasks.

Uncertainty, Neuromodulation, and Attention

Angela Yu — 2006-01-23T11:38:22-00:00

Neuron, Vol. 46, No. 4. (19 May 2005), pp. 681-692.

SummaryUncertainty in various forms plagues our interactions with the environment. In a Bayesian statistical framework, optimal inference and prediction, based on unreliable observations in changing contexts, require the representation and manipulation of different forms of uncertainty. We propose that the neuromodulators acetylcholine and norepinephrine play a major role in the brain's implementation of these uncertainty computations. Acetylcholine signals expected uncertainty, coming from known unreliability of predictive cues within a context. Norepinephrine signals unexpected uncertainty, as when unsignaled context switches produce strongly unexpected observations. These uncertainty signals interact to enable optimal inference and learning in noisy and changeable environments. This formulation is consistent with a wealth of physiological, pharmacological, and behavioral data implicating acetylcholine and norepinephrine in specific aspects of a range of cognitive processes. Moreover, the model suggests a class of attentional cueing tasks that involve both neuromodulators and shows how their interactions may be part-antagonistic, part-synergistic.

Neuronal coding of prediction errors.

W Schultz — 2005-04-08T21:47:07-00:00

Annu Rev Neurosci, Vol. 23 (2000), pp. 473-500.

Associative learning enables animals to anticipate the occurrence of important outcomes. Learning occurs when the actual outcome differs from the predicted outcome, resulting in a prediction error. Neurons in several brain structures appear to code prediction errors in relation to rewards, punishments, external stimuli, and behavioral reactions. In one form, dopamine neurons, norepinephrine neurons, and nucleus basalis neurons broadcast prediction errors as global reinforcement or teaching signals to large postsynaptic structures. In other cases, error signals are coded by selected neurons in the cerebellum, superior colliculus, frontal eye fields, parietal cortex, striatum, and visual system, where they influence specific subgroups of neurons. Prediction errors can be used in postsynaptic structures for the immediate selection of behavior or for synaptic changes underlying behavioral learning. The coding of prediction errors may represent a basic mode of brain function that may also contribute to the processing of sensory information and the short-term control of behavior.

The 28th Bartlett Memorial Lecture. Causal learning: an associative analysis.

A Dickinson — 2008-02-12T21:35:55-00:00

Q J Exp Psychol B, Vol. 54, No. 1. (February 2001), pp. 3-25.

The concordance between performance and judgements of the causal effectiveness of an instrumental action suggests that such actions are mediated by causal knowledge. Although causal learning exhibits many associative phenomena--blocking, inhibitory or preventative learning, and super-learning--judgements of the causal status of a cue can be changed retrospectively as a result of learning episodes that do not directly involve the cue. In order to explain retrospective revaluation, a modified associative theory is described in which the learning processes for retrieved cue representations are the opposite to those for presented cues, and this theory is evaluated by studies of the role of within-compound associations in retrospective revaluation and blocking. However, this modified theory only applies when the within-compound association represents a contiguous rather than a causal cue relationship.

DOPAMINE, LEARNING AND MOTIVATION

Roy Wise — 2005-10-12T16:19:08-00:00

Nat Rev Neurosci, Vol. 5, No. 6. (June 2004), pp. 483-494.

A Role for Brain Stress Systems in Addiction

George Koob — 2008-07-17T00:26:09-00:00

Neuron, Vol. 59, No. 1. (10 July 2008), pp. 11-34.

Drug addiction is a chronically relapsing disorder characterized by compulsion to seek and take drugs and has been linked to dysregulation of brain regions that mediate reward and stress. Activation of brain stress systems is hypothesized to be key to the negative emotional state produced by dependence that drives drug seeking through negative reinforcement mechanisms. This review explores the role of brain stress systems (corticotropin-releasing factor, norepinephrine, orexin [hypocretin], vasopressin, dynorphin) and brain antistress systems (neuropeptide Y, nociceptin [orphanin FQ]) in drug dependence, with emphasis on the neuropharmacological function of extrahypothalamic systems in the extended amygdala. The brain stress and antistress systems may play a key role in the transition to and maintenance of drug dependence once initiated. Understanding the role of brain stress and antistress systems in addiction provides novel targets for treatment and prevention of addiction and insights into the organization and function of basic brain emotional circuitry.

Place Cells, Grid Cells, and the Brain's Spatial Representation System

Edvard Moser — 2008-03-20T16:29:23-00:00

Annual Review of Neuroscience, Vol. 31, No. 1. (2008)

More than three decades of research have demonstrated a role for hippocampal place cells in representation of the spatial environment in the brain. New studies have shown that place cells are part of a broader circuit for dynamic representation of self-location. A key component of this network is the entorhinal grid cells, which, by virtue of their tessellating firing fields, may provide the elements of a path integration-based neural map. Here we review how place cells and grid cells may form the basis for quantitative spatiotemporal representation of places, routes, and associated experiences during behavior and in memory. Because these cell types have some of the most conspicuous behavioral correlates among neurons in nonsensory cortical systems, and because their spatial firing structure reflects computations internally in the system, studies of the entorhinal-hippocampal representation system may offer considerable insight into general principles of cortical network dynamics. Expected final online publication date for the Annual Review of Neuroscience Volume 31 is June 16, 2008. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.

Habits, Rituals, and the Evaluative Brain

Ann Graybiel — 2008-07-17T00:19:01-00:00

Annual Review of Neuroscience, Vol. 31, No. 1. (2008), pp. 359-387.

Scientists in many different fields have been attracted to the study of habits because of the power habits have over behavior and because they invoke a dichotomy between the conscious, voluntary control over behavior, considered the essence of higher-order deliberative behavioral control, and lower-order behavioral control that is scarcely available to consciousness. A broad spectrum of behavioral routines and rituals can become habitual and stereotyped through learning. Others have a strong innate basis. Repetitive behaviors can also appear as cardinal symptoms in a broad range of neurological and neuropsychiatric illness and in addictive states. This review suggests that many of these behaviors could emerge as a result of experience-dependent plasticity in basal ganglia-based circuits that can influence not only overt behaviors but also cognitive activity. Culturally based rituals may reflect privileged interactions between the basal ganglia and cortically based circuits that influence social, emotional, and action functions of the brain.

Brain Circuits for the Internal Monitoring of Movements

Marc Sommer — 2008-06-19T15:46:34-00:00

Annual Review of Neuroscience, Vol. 31, No. 1. (2008), pp. 317-338.

Each movement we make activates our own sensory receptors, thus causing a problem for the brain: the spurious, movement-related sensations must be discriminated from the sensory inputs that really matter, those representing our environment. Here we consider circuits for solving this problem in the primate brain. Such circuits convey a copy of each motor command, known as a corollary discharge (CD), to brain regions that use sensory input. In the visual system, CD signals may help to produce a stable visual percept from the jumpy images resulting from our rapid eye movements. A candidate pathway for providing CD for vision ascends from the superior colliculus to the frontal cortex in the primate brain. This circuit conveys warning signals about impending eye movements that are used for planning subsequent movements and analyzing the visual world. Identifying this circuit has provided a model for studying CD in other primate sensory systems and may lead to a better understanding of motor and mental disorders.

Monitoring for target objects: activation of right frontal and parietal cortices with increasing time on task

JT Coull — 2008-07-14T05:26:34-00:00

Neuropsychologia, Vol. 36, No. 12. (1 December 1998), pp. 1325-1334.

The right prefrontal and parietal cortices have been implicated in attentional processing in both neuropsychological and functional neuroimaging literature. However, attention is a heterogeneous collection of processes, each of which may be underpinned by different neural networks. These attentional networks may interact, such that engaging one type of attentional process could influence the efficiency of another via overlapping neural substrates. We investigated the hypothesis that right frontal and parietal cortices provide the neuroanatomical location of the functional interaction between sustained attention and the process of selectively monitoring for target objects. Six healthy volunteers performed one of two tasks which required either selective or non-selective responding. The task lasted continuously for 18 min, during which time 3 Positron Emission Tomography (PET) scans were acquired for each task. This was repeated to obtain 12 PET measurements of regional cerebral blood flow (rCBF) for each subject. The right inferior frontal and parietal cortices were differentially activated by increasing time on task during the selective (S) vs non-selective (NS) task. Specifically, rCBF decreased with increasing time spent performing the NS task but not the S task. This result suggests that the normal deactivation in these areas as time on task increases is counteracted by the extra cognitive demands of selectively responding to target objects. Therefore, we have confirmed our hypothesis that right frontal and parietal cortices provide the neuroanatomical location for the modulation of object selection by sustained attention. We also identified the neuroanatomical correlates of each process separately, and confirmed earlier reports of prefrontal cortex and anterior cingulate activation associated with selective responding, and a fronto-parietal-thalamic network associated with sustained attention.

How antipsychotics work-from receptors to reality.

S Kapur — 2008-07-14T02:48:35-00:00

NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics, Vol. 3, No. 1. (January 2006), pp. 10-21.

How does a small molecule blocking a few receptors change a patients' passionately held paranoid belief that the FBI is out to get him? To address this central puzzle of antipsychotic action, we review a framework linking dopamine neurochemistry to psychosis, and then link this framework to the mechanism of action of antipsychotics. Normal dopamine transmission has a role in predicting novel rewards and in marking and responding to motivationally salient stimuli. Abnormal dopamine transmission alters these processes and results in an aberrant sense of novelty and inappropriate assignment of salience leading to the experience of psychosis. Antipsychotics improve psychosis by diminishing this abnormal transmission by blocking the dopamine D2/3 receptor (not D1 or D4), and although several brain regions may be involved, it is suggested that the ventral striatal regions (analog of the nucleus accumbens in animals) may have a particularly critical role. Contrary to popular belief, the antipsychotic effect is not delayed in its onset, but starts within the first few days. There is more improvement in the first 2 weeks, than in any subsequent 2-week period thereafter. However, a simple organic molecule cannot target the complex phenomenology of the individual psychotic experience. Antipsychotics diminish dopamine transmission and thereby dampen the salience of the pre-occupying symptoms. Therefore, in the initial stage of an antipsychotic response, the patients experience a detachment from symptoms, a relegation of the delusions and hallucinations to the back of their minds, rather than a complete erasure of the symptoms. Only with time, and only in some, via the mediation of new learning and plasticity, is there a complete resolution of symptoms. The implications of these findings for clinical care, animal models, future target discovery and drug development are discussed.

'Jumping to conclusions' and delusions in psychosis: relationship and response to treatment.

M Menon — 2008-07-14T02:47:25-00:00

Schizophrenia research, Vol. 98, No. 1-3. (January 2008), pp. 225-231.

'Jumping to conclusions' (JTC) on probabilistic reasoning tasks has been shown to be related with delusions in schizophrenia. However, whether JTC is merely correlated with, moderate or mediate delusions is not known. Further, it is unclear how antipsychotics affect JTC and its relationship to delusions. We examined the effect of treatment on JTC in a sample of patients (N=19) who were initiated on treatment and followed. Two versions of the task were used--the 'beads' version of the task and an emotionally salient version. Within two weeks of treatment, we found an increase in the number of trials to decision on the emotionally salient version and a reduction in intensity of psychotic symptoms and delusions (measured by the change on P1 and PANSS-P scores). While, these two measures, or changes in these measures, showed no reliable correlation, the baseline performance on the emotionally salient version of the task helped predict patients who would show improvements in their PANSS-P and global PANSS scores in response to medication. The findings suggest that JTC might moderate the effects of treatment on symptomatology, but it does not mediate the treatment induced reduction in delusional intensity.

The selective effect of antipsychotics on the different dimensions of the experience of psychosis in schizophrenia spectrum disorders.

R Mizrahi — 2008-07-14T02:46:40-00:00

Schizophrenia research, Vol. 88, No. 1-3. (December 2006), pp. 111-118.

While most standard symptom scales regard the 'psychotic' or 'positive' dimension of schizophrenia as a single factor, several lines of evidence suggest that psychosis itself is a multidimensional phenomenon. The foregoing literature suggested at least five distinct dimensions to psychosis; to test this, we developed, validated and applied an instrument to measure these dimensions and then applied it to examine the effect of antipsychotics on the different dimensions of the psychotic experience. The Dimensions of Psychosis Instrument (DIPI) was administered to 91 psychotic patients with schizophrenia spectrum disorders and a confirmatory factor analyses (CFA) was carried out to examine the five dimensions: cognitive preoccupation (CP) with the psychotic experience; emotional involvement (EM); behavioural impact (BI) of the experience; conviction (CO) in it; emotional; and external perspective (EP) about the experience. In a separate cohort of 17 prospectively treated patients, the impact of antipsychotics on these dimensions was assessed. BI showed the greatest improvement (32%) at 2 weeks, while CP and emotional improved somewhat less (22% and 14%, respectively). Improvement in CO was limited (6%) while EP showed no change. These results suggest that over the first few weeks of treatment, antipsychotics rapidly reduce the behavioural impact of the principal psychotic symptom and decrease cognitive and emotional preoccupation with it, without greatly altering the patients' conviction in or perspective about their psychotic experience.

Linking Animal Models of Psychosis to Computational Models of Dopamine Function

Andrew Smith — 2006-07-21T19:07:27-00:00

Neuropsychopharmacology, Vol. aop, No. current.

Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia.

S Kapur — 2008-07-14T02:42:06-00:00

The American journal of psychiatry, Vol. 160, No. 1. (January 2003), pp. 13-23.

OBJECTIVE: The clinical hallmark of schizophrenia is psychosis. The objective of this overview is to link the neurobiology (brain), the phenomenological experience (mind), and pharmacological aspects of psychosis-in-schizophrenia into a unitary framework. METHOD: Current ideas regarding the neurobiology and phenomenology of psychosis and schizophrenia, the role of dopamine, and the mechanism of action of antipsychotic medication were integrated to develop this framework. RESULTS: A central role of dopamine is to mediate the "salience" of environmental events and internal representations. It is proposed that a dysregulated, hyperdopaminergic state, at a "brain" level of description and analysis, leads to an aberrant assignment of salience to the elements of one's experience, at a "mind" level. Delusions are a cognitive effort by the patient to make sense of these aberrantly salient experiences, whereas hallucinations reflect a direct experience of the aberrant salience of internal representations. Antipsychotics "dampen the salience" of these abnormal experiences and by doing so permit the resolution of symptoms. The antipsychotics do not erase the symptoms but provide the platform for a process of psychological resolution. However, if antipsychotic treatment is stopped, the dysregulated neurochemistry returns, the dormant ideas and experiences become reinvested with aberrant salience, and a relapse occurs. CONCLUSIONS: The article provides a heuristic framework for linking the psychological and biological in psychosis. Predictions of this hypothesis, particularly regarding the possibility of synergy between psychological and pharmacological therapies, are presented. The author describes how the hypothesis is complementary to other ideas about psychosis and also discusses its limitations.

Half a century of antipsychotics and still a central role for dopamine D2 receptors.

S Kapur — 2008-07-14T02:40:59-00:00

Progress in neuro-psychopharmacology & biological psychiatry, Vol. 27, No. 7. (October 2003), pp. 1081-1090.

A review of the history of antipsychotics reveals that while the therapeutic effects of chlorpromazine and reserpine were discovered and actively researched almost concurrently, subsequent drug development has been restricted to drugs acting on postsynaptic receptors rather than modulation of dopamine release. The fundamental property of atypical antipsychotics is their ability to produce an antipsychotic effect in the absence of extrapyramidal side effects (EPS) or prolactin elevation. Modulation of the dopamine D2 receptor remains both necessary and sufficient for antipsychotic drug action, with affinity to the D2-receptor being the single most important discriminator between a typical and atypical drug profile. Most antipsychotics, including atypical antipsychotics, show a dose-dependent threshold of D2 receptor occupancy for their therapeutic effects, although the precise threshold is different for different drugs. Some atypical antipsychotics do not appear to reach the threshold for EPS and prolactin elevation, possibly accounting for their atypical nature. To link the biological theories of antipsychotics to their psychological effects, a hypothesis is proposed wherein psychosis is a state of aberrant salience of stimuli and ideas, and antipsychotics, via modulation of the mesolimbic dopamine system, dampen the salience of these symptoms. Thus, antipsychotics do not excise psychosis: they provide the neurochemical platform for the resolution of symptoms. Future generations of antipsychotics may need to move away from a "one-size-fits-all polypharmacy-in-a-pill" approach to treat all the different aspects of schizophrenia. At least in theory a preferred approach would be the development of specific treatments for the different dimensions of schizophrenia (e.g., positive, negative, cognitive, and affective) that can be flexibly used and titrated in the service of patients' presenting psychopathology.

How antipsychotics become anti-"psychotic"--from dopamine to salience to psychosis.

S Kapur — 2008-07-14T02:38:09-00:00

Trends in pharmacological sciences, Vol. 25, No. 8. (August 2004), pp. 402-406.

The relationship between dopamine, psychosis and antipsychotics has been challenged by the suggestion that there is a delay, of weeks, between the onset of dopamine receptor blockade and improvement in psychosis. However, recent data show that there is no significant delay. In light of these new findings, it is proposed that dopamine, through its role in reward prediction and motivational salience, provides a link to psychosis. Psychosis results from aberrant reward prediction and aberrant attribution of salience that is caused by disordered dopamine transmission. Antipsychotics become anti-"psychotic" by blocking dopamine transmission and attenuating the motivational salience of the symptoms, leading to the common statement from patients that symptoms "don't bother me as much anymore". This attenuation of salience also impacts on normal motivational drives, providing an explanation for why antipsychotics might induce iatrogenic negative symptoms and dysphoria, often leading to non-compliance by patients. The implications of this framework for relapse and other clinical phenomena, animal models and future studies are discussed.

Cholinergic mediation of attention: contributions of phasic and tonic increases in prefrontal cholinergic activity.

V Parikh — 2008-07-14T02:35:11-00:00

Annals of the New York Academy of Sciences, Vol. 1129 (2008), pp. 225-235.

Contrary to the classic description of acetylcholine (ACh) as a slowly acting neuromodulator that influences arousal states, results from experiments that employed enzyme-selective microelectrodes for the real-time monitoring of ACh release in the cortex of attentional task-performing rats indicate that cholinergic signals manifesting on multiple timescales (seconds, tens of seconds, and minutes) support, and are necessary for, the mediation of defined cognitive operations. Specifically, in the prefrontal cortex, second-based cholinergic signals support the detection of behaviorally significant cues. In contrast to these prefrontal cholinergic transients, performance-associated cholinergic activity that manifested at lower temporal resolution also was observed elsewhere in the cortex. Although tonic cholinergic signal levels were correlated with the amplitudes of cue-evoked cholinergic transients, and the latter with response latencies, the interrelationships and interactions between the multiple cholinergic signaling modes remains unclear. Hypotheses concerning the afferent circuitry contributing to the regulation of second- versus minute-based cholinergic signals are discussed. The discovery of cholinergic transients and their crucial role in cue detection and attentional performance form the basis for new hypotheses about the nature of cholinergic dysfunction in cognitive disorders and offer new targets for the development of treatments for the cognitive symptoms of neuropsychiatric and neurodegenerative disorders.

Modulation of cortical activation and behavioral arousal by cholinergic and orexinergic systems.

BE Jones — 2008-07-14T02:34:05-00:00

Annals of the New York Academy of Sciences, Vol. 1129 (2008), pp. 26-34.

Multiple neuronal systems contribute to the promotion and maintenance of the wake state, which is characterized by cortical activation and behavioral arousal. Using predominantly glutamate as a neurotransmitter, neurons within the reticular formation of the brainstem give rise to either ascending projections into the forebrain or descending projections into the spinal cord to promote through relays fast cortical activity or motor activity with postural muscle tone. Using acetylcholine, cholinergic neurons in the brainstem project to forebrain relays and others in the basal forebrain to the cortex, by which they stimulate fast gamma activity during waking and during rapid eye movement or paradoxical sleep (PS). Other neuromodulatory systems, such as noradrenergic locus coeruleus neurons, give rise to highly diffuse projections through brain and spinal cord and simultaneously stimulate cortical activation and behavioral arousal. Although such neuromodulatory systems were thought to be redundant, a recently discovered peptide called orexin (Orx) or hypocretin, contained in diffusely projecting neurons of the hypothalamus, was found to be essential for the maintenance of waking with muscle tone, since in its absence narcolepsy with cataplexy occurred. Orx neurons discharge during active waking and cease firing during sleep. Since cholinergic neurons discharge during waking and PS, they would stimulate cortical activation in association with muscle tone when orexinergic neurons are also active but would stimulate cortical activation with muscle atonia when orexinergic neurons are silent, as in natural PS, or absent, as in pathological narcolepsy with cataplexy.

Central thalamic contributions to arousal regulation and neurological disorders of consciousness.

ND Schiff — 2008-07-14T02:32:48-00:00

Annals of the New York Academy of Sciences, Vol. 1129 (2008), pp. 105-118.

This review focuses on the contributions of the central thalamus to normal mechanisms of arousal regulation and to neurological disorders of consciousness. Forebrain arousal is regulated by ascending influences from brainstem/basal forebrain neuronal populations ("arousal systems") and control signals descending from frontal cortical systems. These subcortical and cortical systems have converging projections to the central thalamus that emphasize their role in maintaining organized behavior during wakefulness. Central thalamic neurons appear to be specialized both anatomically and physiologically to support distributed network activity that maintains neuronal firing patterns across long-range cortico-cortical pathways and within cortico-striatopallidal-thalamocortical loop connections. Recruitment of central thalamic neurons occurs in response to increasing cognitive demand, stress, fatigue, and other perturbations that reduce behavioral performance. In addition, the central thalamus receives projections from brainstem pathways evolved to rapidly generate brief shifts of arousal associated with the appearance of salient stimuli across different sensory modalities. Through activation of the central thalamus, neurons across the cerebral cortex and striatum can be depolarized and their activity patterns selectively gated by descending or ascending signals related to premotor attention and alerting stimuli. Direct injury to the central thalamus or prominent deafferentation of these neurons as a result of complex, multifocal, brain insults are both associated with severe impairment of forebrain functional integration and arousal regulation. Interventions targeting neurons within the central thalamus may lead to rational therapeutic approaches to the treatment of impaired arousal regulation following nonprogressive brain injuries. A model accounting for present therapeutic strategies is proposed.