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BackgroundDopamine D1 receptor signaling plays key roles in core domains of neural function, including cognition and reward processing; however, many questions remain about the functions of circuits modulated by dopamine D1 receptor, largely because clinically viable, selective agonists have yet to be tested in humans.MethodsUsing a novel, exploratory neurofunctional domains study design, we assessed the safety, tolerability, pharmacodynamics, and pharmacokinetics of PF-06412562, a selective D1/D5R partial agonist, in healthy male volunteers who met prespecified criteria for low working memory capacity. Functional magnetic resonance imaging, electrophysiologic endpoints, and behavioral paradigms were used to assess working memory, executive function, and motivation/reward processing following multiple-dose administration of PF-06412562. A total of 77 patients were assigned PF-06412562 (3 mg twice daily and 15 mg twice daily) or placebo administered for 5 to 7 days. Due to the exploratory nature of the study, it was neither powered for any specific treatment effect nor corrected for multiple comparisons.ResultsNominally significant improvements from baseline in cognitive endpoints were observed in all 3 groups; however, improvements in PF-06412562–treated patients were less than in placebo-treated participants. Motivation/reward processing endpoints were variable. PF-06412562 was safe and well tolerated, with no serious adverse events, severe adverse events, or adverse events leading to dose reduction or temporary discontinuation except for 1 permanent discontinuation due to increased orthostatic heart rate.ConclusionsPF-06412562, in the dose range and patient population explored in this study, did not improve cognitive function or motivation/reward processing more than placebo over the 5- to 7-day treatment period.ClinicalTrials.gov IdentifierNCT02306876

Attention Deficit and Hyperactive Disorder (ADHD) and Autism Spectrum Disorders (ASD) are frequent comorbid neurodevelopmental conditions and the overlap between both disorders remains to be delineated. A more complete understanding of the shared genetic and environmental factors is needed. Using a family-based method, we evaluated the risk of ADHD in a group of relatives with an ASD proband (ASD-) and a group of relatives with an ASD and ADHD proband (ASD+). We enrolled 1245 individuals in the study: 499 probands, their 746 first-degree relatives and 140 controls. We used a multivariate generalized estimating equation (GEE) model, in which the dependent variable was the ADHD diagnosis in the relatives and the independent variable the ASD+ or ASD- in probands. We adjusted for sociodemographic factors (age, sex, IQ) and for the nature of the familial relationship with the affected proband (parent or sibling). Among the probands, there were 287 ASD- and 212 ASD+ individuals. ADHD was more frequent in relatives (19%) than in the control group (7%) (p = 0.001). The risk of ADHD was higher in the ASD+ relatives group than in the ASD- relatives group (GEE model OR 1.58 [95% CI 1.04-2.38], p = 0.032). This result was found in parents (OR 1.96 [95% CI 1.14-3.36], but not in siblings (OR 1.28 [95% CI 0.84-1.94], p = 0.434). Our study provides a representative estimate of the family distribution of ADHD in relatives of ASD probands but supports the modest effect of shared genetic and environmental factors between both disorders.

Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans.

While dopamine systems have been implicated in the pathophysiology of schizophrenia and psychosis for many years, how dopamine dysfunction generates psychotic symptoms remains unknown. Recent theoretical interest has been directed at relating the known role of midbrain dopamine neurons in reinforcement learning, motivational salience and prediction error to explain the abnormal mental experience of psychosis. However, this theoretical model has yet to be explored empirically. To examine a link between psychotic experience, reward learning and dysfunction of the dopaminergic midbrain and associated target regions, we asked a group of first episode psychosis patients suffering from active positive symptoms and a group of healthy control participants to perform an instrumental reward conditioning experiment. We characterized neural responses using functional magnetic resonance imaging. We observed that patients with psychosis exhibit abnormal physiological responses associated with reward prediction error in the dopaminergic midbrain, striatum and limbic system, and we demonstrated subtle abnormalities in the ability of psychosis patients to discriminate between motivationally salient and neutral stimuli. This study provides the first evidence linking abnormal mesolimbic activity, reward learning and psychosis.

In recent years, there has been renewed interest in ketamine, because of growing evidence that surgical patients may benefit from low-dose intraoperative infusions. Potential benefits include neuroprotection,1 pre-emptive analgesia, and attenuation of postoperative hyperalgesia.2 The influence of low-dose ketamine on postoperative analgesia was the subject of a recent Cochrane review.3 Target-controlled infusion (TCI) technology has been employed for ketamine administration in several settings, including critical care,4,5 the operating theatre,6–8 and neuroscience studies.9,10 In our institution, ketamine infusions are being used to investigate the glutaminergic hypofunction theory of schizophrenia. Four studies have been performed, seeking to compare ketamine-induced cognitive changes in healthy volunteers with those observed in schizophrenic patients and also to examine the correlation between performance in different cognitive tasks/tests with the patterns of neural activation detected by functional magnetic resonance imaging (fMRI).11–17 The cognitive function tests used in these psychiatric studies vary in duration between tests, and also between subjects. During all the tests, and particularly during tests examining memory and learning processes, stable blood and effect-site drug concentrations are desirable for pharmacodynamic analyses. Access to the subject is not possible during tests and, with a large number of tests being performed during each scanning session, it was impractical to obtain blood samples before and after each test. TCI technology provides a convenient and user-friendly means of administering stable blood concentrations.18–20 Volunteers in our studies thus received TCI ketamine, implemented using the Domino model,21 chosen because it is commonly used for low-dose TCI administration of ketamine in the experimental setting.8–10,22 Our group has funding to perform two further series of investigations of the influence of ketamine on cognitive function. We plan to continue using TCIs, but first wanted to determine if the Domino model is fit for this purpose. Thus, the aim of the current study was to assess the predictive performance of the Domino model during the four cognitive studies we have conducted so far. We were particularly interested in determining how well steady-state concentrations were maintained at constant target concentrations, and whether performance was similar across the different studies. A secondary goal was to compare the predictions of the Domino model with those of other published models, in order to identify or exclude possible candidate models for future studies. We chose for comparison three bicompartmental models (see Methods for rationale): a model derived by Clements using data from five healthy volunteers who received a single 125 μg kg−1 i.v. bolus (hereafter referred to as the ‘Clements 125′ model),23 a model derived by Clements using data from the same five volunteers after receiving a 250 μg kg−1 i.v. bolus (hereafter referred to as the ‘Clements 250′ model),23 and the Hijazi model (derived from data from a group of 12 critically ill patients who received a 2 mg kg−1 bolus followed by a 2 mg kg−1 h−1 infusion).5 The model parameters for these models are summarized in Table 1. Table 1 Model parameters for the Domino, Clements 125, Clements 250, and Hijazi models. V1, central compartment volume; k10, metabolic clearance rate constant; k12, k21, rate constants for rapid distribution clearance (from compartment 1 to 2 and vice versa); ...

BackgroundThe psychosis-inducing effect of ketamine is important evidence supporting the glutamate hypothesis of schizophrenia. However, the symptoms the drug produces have not been described systematically.AimTo examine the effects of ketamine in healthy people using a structured psychiatric interview.MethodKetamine (200 ng/ml) or placebo was administered by continuous infusion to 15 healthy volunteers. Symptoms were rated using the Present State Examination, the Thought, Language and Communication Scale and the Scale for Assessment of Negative Symptoms.ResultsKetamine induced a range of perceptual distortions, but not hallucinations. Referential ideas were seen in nearly half the sample. There were only mild and infrequent ratings on the thought disorder scale. Affective flattening and alogia were seen in some volunteers.ConclusionsKetamine does not reproduce the full picture of schizophrenia. The main point of similarity concerns referential thinking. Phenomena resembling negative symptoms are also seen, but the distinction of these from the drug's sedative effects requires further elucidation.

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). Highdose 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.

Ketamine is increasingly used to model the cognitive deficits and symptoms of schizophrenia. We investigated the extent to which ketamine administration in healthy volunteers reproduces the deficits in episodic recognition memory and agency source monitoring reported in schizophrenia. Intravenous infusions of placebo or 100 ng/ml ketamine were administered to 12 healthy volunteers in a double-blind, placebo-controlled, randomized, within-subjects study. In response to presented words, the subject or experimenter performed a deep or shallow encoding task, providing a 2(drug) × 2(depth of processing) × 2(agency) factorial design. At test, subjects discriminated old/new words, and recalled the sources (task and agent). Data were analyzed using multinomial modelling to identify item recognition, source memory for agency and task, and guessing biases. Under ketamine, item recognition and cued recall of deeply encoded items were impaired, replicating previous findings. In contrast to schizophrenia, there was a reduced tendency to externalize agency source guessing biases under ketamine. While the recognition memory deficit observed with ketamine is consistent with previous work and with schizophrenia, the changes in source memory differ from those reported in schizophrenic patients. This difference may account for the pattern of psychopathology induced by ketamine.

Background. There is considerable variability between patients in their expression of the diverse range of symptoms encompassed by the syndrome of schizophrenia, which may modulate functional activation to cognitive processing.Method. Here we investigate associations between schizophrenic subsyndrome scores, identified by factor analysis, and experimentally controlled brain activation. Five factors were defined by rotated principal components analysis of PANSS rating scale measurements in 100 patients with schizophrenia. A subsample of 30 patients and a group of 27 comparison subjects were studied using functional magnetic resonance imaging (fMRI) during the performance of two periodically designed cognitive activation experiments: verbal working memory and psychomotor sequencing.Results. Factor analysis replicated the five dimensions consistently reported. Within the patient group, power of activation by working memory was negatively associated with global symptom severity in left lingual and temporo-parietal cortices; negatively associated with positive subsyndrome scores in left inferior frontal and superior temporal cortices and basal ganglia; and positively associated with negative subsyndrome scores in lateral and medial premotor cortex. No relationship was observed between subsyndrome scores and functional activation during the motor task. Between-group comparisons demonstrated reduced power of response to the working memory task by patients in bilateral dorsolateral prefrontal and left pre- and post-central cortices.Conclusions. In this study we observed task-specific modulation of functional response associated with symptom expression in schizophrenia. Our findings are compatible with previous empirical findings and theoretical conceptualization of human brain function, in terms of capacity constraints on activation in the face of competing demands from pathological and task-related cognitive activity.

Procedural learning (PL) is a type of rule-based learning in which performance facilitation occurs with practice on task without the need for conscious awareness. Schizophrenic patients have often (though not invariably) been found to show impaired PL. We performed functional magnetic resonance imaging (fMRI) during a blocked, periodic sequence-learning task with groups of: (i) healthy subjects, and (ii) schizophrenic patients on conventional antipsychotics. Healthy subjects showed significant PL, but patients did not. In healthy subjects, PL was associated with increased activation in the striatum, thalamus, cerebellum, precuneus, medial frontal lobe, and cingulate gyrus. The power of activation in the thalamus, striatum, precuneus, cingulate gyrus and BA 6 was related to the magnitude of PL in these subjects. No regions, except the anterior inferior gyrus, were significantly activated in patients. The caudate nucleus, thalamus, precuneus, and sensorimotor regions were activated significantly differently between the two groups. The findings demonstrate the involvement of the striatum, cerebellum, thalamus, cingulate gyrus, precuneus, and sensorimotor regions in PL. Further fMRI studies of PL in normal subjects treated with conventional antipsychotics, drug naïve patients, and patients given atypical antipsychotics would help to clarify the roles of schizophrenic disease processes and antipsychotic medication in impaired PL and associated brain abnormalities in schizophrenia.

Working memory dysfunction is considered to be fundamental to the cognitive and clinical features evident in schizophrenia. Functional neuroimaging studies have begun to elucidate the neurobiological basis of such deficits, however, interpretation of these studies may be confounded by performance impairment, when the cognitive load exceeds the limited response capacity of patients with schizophrenia. In this study, patients were pre-selected on the basis of intact performance on a relatively low-load verbal working memory task, in order to mitigate against performance confounds. Subjects included 20 right-handed male subjects with chronic schizophrenia, and 20 right-handed, age-matched, male healthy controls, without personal or familial psychiatric history. All subjects underwent fMRI scanning whilst performing a verbal n-back task. There were no significant between-group differences in target identification; the patient group showed a significantly increased mean response latency. Both groups demonstrated robust fronto-parietal activation. In the control subjects, the power of functional response was positively correlated with reaction time in bilateral posterior parietal cortex, however, this coupling of behavioural performance and cerebral response was not evident in the patients. This deficit, apparent within the performance capacity of the patients, may represent a fundamental abnormality in schizophrenia, and may compromise performance at higher cognitive loads.

We used multislice functional magnetic resonance imaging (fMRI) to investigate the association between behavioral and neurophysiological measures of working memory task performance in 20 right-handed male healthy volunteers. Images were acquired over a 5-min period at 1.5 Tesla. We used a periodic design, alternating 30-s blocks of the "n-back" working memory task with 30-s blocks of a sensorimotor control task to activate verbal working memory systems. The power of functional response to the task was estimated by sinusoidal regression at each voxel. The relationship between power of fMRI response and mean reaction time over all 11 working memory trials was explored by multiple regression, with age and mean reaction time to the control task as covariates, at voxel and regional levels of analysis. All subjects were able to perform the n-back task accurately. A spatially distributed network was activated, including dorsolateral prefrontal cortex, inferior frontal gyrus, lateral premotor cortex, and supplementary motor area (SMA) in the frontal lobes. More posteriorly, there were major foci of activation in parietal and occipitoparietal cortex, precuneus, lingual, and fusiform gyri of the ventral occipital lobe, inferior temporal gyrus, and cerebellum. The power of functional response was positively correlated with reaction time in bilateral posterior parietal cortex (Talairach coordinates in x, y, z (mm) 35, -44, 37 and -32, -56, 42), indicating that subjects who found the task difficult, and responded with a slower reaction time, tended to activate these regions more powerfully. One interpretation of this regionally specific relationship between prolonged reaction time and increased power of posterior parietal activation is consistent with prior studies identifying similar areas of parietal cortex as the site of the phonological storage function in verbal working memory.

This paper is concerned with the problem of evaluating goodness-of-fit of a path analytic model to an interregional correlation matrix derived from functional magnetic resonance imaging (fMRI) data. We argue that model evaluation based on testing the null hypothesis that the correlation matrix predicted by the model equals the population correlation matrix is problematic because P values are conditional on asymptotic distributional results (which may not be valid for fMRI data acquired in less than 10 min), as well as arbitrary specification of residual variances and effective degrees of freedom in each regional fMRI time series. We introduce an alternative approach based on an algorithm for automatic identification of the best fitting model that can be found to account for the data. The algorithm starts from the null model, in which all path coefficients are zero, and iteratively unconstrains the coefficient which has the largest Lagrangian multiplier at each step until a model is identified which has maximum goodness by a parsimonious fit index. Repeating this process after bootstrapping the data generates a confidence interval for goodness-of-fit of the best model. If the goodness of the theoretically preferred model is within this confidence interval we can empirically say that the theoretical model could be the best model. This relativistic and data-based strategy for model evaluation is illustrated by analysis of functional MR images acquired from 20 normal volunteers during periodic performance (for 5 min) of a task demanding semantic decision and subvocal rehearsal. A model including unidirectional connections from frontal to parietal cortex, designed to represent sequential engagement of rehearsal and monitoring components of the articulatory loop, is found to be irrefutable by hypothesis-testing and within confidence limits for the best model that could be fitted to the data.

Context: Recent theories have suggested that the inappropriate activation of limbic motivational systems in response to neutral stimuli may underlie the development of delusions in schizophrenia. Objective: To investigate the activation of the amygdala, midbrain, and ventral striatum during an aversive pavlovian conditioning task in patients with schizophrenia and healthy control participants using functional magnetic resonance imaging. Design: Cross-sectional case-control functional neuroimaging study. Setting: Academic medical center. Participants: Twenty patients with DSM-IV–diagnosed schizophrenia or schizoaffective disorder and 20 healthy control participants. Main Outcome Measures: Regional brain activation as assessed by functional magnetic resonance imaging blood oxygen level–dependent responses, and delusional symptom severity on the Positive and Negative Syndrome Scale. Results: Patients with schizophrenia showed abnormal activation of the amygdala, midbrain, and ventral striatum during conditioning. Activation of the midbrain in response to neutral rather than aversive cues during conditioning was correlated with the severity of delusional symptoms in the patient group (corrected P = .04). Conclusion: Inappropriate activation of the midbrain in response to neutral stimuli during conditioning is associated with the severity of delusional symptoms in patients with schizophrenia.

The symptoms of major psychotic illness are diverse and vary widely across individuals. Furthermore, the prepsychotic phase is indistinct, providing little indication of the precise pattern of symptoms that may subsequently emerge. Likewise, although in some individuals who have affected family members the occurrence of disease may be predicted, the specific symptom profile may not. An important question, therefore, is whether predictive physiological markers of symptom expression can be identified. We conducted a placebo-controlled, within-subjects study in healthy individuals to investigate whether individual variability in baseline physiology, as assessed using functional magnetic resonance imaging, predicted psychosis elicited by the psychotomimetic drug ketamine and whether physiological change under drug reproduced those reported in patients. Here we show that brain responses to cognitive task demands under placebo predict the expression of psychotic phenomena after drug administration. Frontothalamic responses to a working memory task were associated with the tendency of subjects to experience negative symptoms under ketamine. Bilateral frontal responses to an attention task were also predictive of negative symptoms. Frontotemporal activations during language processing tasks were predictive of thought disorder and auditory illusory experiences. A subpsychotic dose of ketamine administered during a second scanning session resulted in increased basal ganglia and thalamic activation during the working memory task, paralleling previous reports in patients with schizophrenia. These results demonstrate precise and predictive brain markers for individual profiles of vulnerability to drug-induced psychosis.

It is not known whether there is a core abnormality that occurs in all cases of schizophrenia. The cognitive dysmetria hypothesis proposes that there is such an abnormality which is characterized cognitively by a disruption in control and coordination processes, and functionally by abnormal inter-regional connectivity within the cortico-cerebellar-thalamo-cortical circuit (CCTCC). In the current study, we used functional MRI (fMRI) to investigate these two key aspects of the hypothesis. Since patients with schizophrenia show deficits in attention which have been characterized extensively using the continuous performance task (CPT) and since functional imaging studies have also demonstrated that this task engages the CCTCC, we used this task to investigate whether two patient groups with distinct symptom profiles would show functional dysconnectivity within this network. Three groups of subjects participated in the study: healthy volunteers (n = 12), schizophrenia patients with both negative and positive symptoms (n = 11) and schizophrenia patients with primarily positive symptoms (n = 11). Patient groups were matched for age of illness onset and medication, and to the control group for age, gender and handedness. Subjects were scanned using fMRI whilst they performed a modified version of the CPT, involving both degraded and non-degraded stimuli. Stimulus degradation has been shown to produce decrements in sensitivity, which is thought to reflect increased demands on the limited capacity of visual attention. Between-group comparisons revealed that patients with schizophrenia, irrespective of symptomatology, showed attenuation of the anterior cingulate and cerebellar response to stimulus degradation in comparison with control subjects. We also observed disruptions of inter-regional brain integration in schizophrenia. A task-specific relationship between the medial superior frontal gyrus and both anterior cingulate and the cerebellum was disrupted in both patient groups in comparison with controls. In addition, patients with negative symptoms showed impaired behavioural performance, and abnormal task-related connectivity between anterior cingulate and supplementary motor area. These findings are consistent with theoretical accounts of schizophrenia as a disorder of functional integration, and with the cognitive dysmetria hypothesis, which posits a disconnection within the CCTCC as a fundamental abnormality in schizophrenia, independent of diagnostic subtype. Furthermore, these data show evidence of additional functional deficits in patients with negative symptoms, deficits which may explain the accompanying attentional impairment.

Verbal fluency is a classic neuropsychological measure of language production. Phonological verbal fluency involves the generation of words beginning with a specified letter, and its functional neuroanatomy is comprised of a distributed network of regions which is modulated by cognitive load. In order to investigate the functional relationship of these regions, the effective connectivity was analyzed with covariance structural equation modeling under conditions of varying cognitive load. Significant path coefficients were evident between the anterior cingulate, left middle frontal gyrus, and precuneus. The left middle frontal gyrus showed a facilitory projection to the precuneus which had a suppressive influence on anterior cingulate activation. With increasing cognitive demand, the left middle frontal projection to the precuneus became suppressive, and the path coefficient from the precuneus to the anterior cingulate showed a marked diminution in strength. The path analysis suggests that the lead-in process for letter verbal fluency may primarily involve an orthographic visual strategy. The marked changes in path coefficients with the increased cognitive load may reflect the greater demands placed on executive function. The significant changes in path coefficient values with increased cognitive demand indicate the importance of accounting for task difficulty not only in the interpretation of brain activation maps but also for effective connectivity measurements.

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine produces episodic memory deficits. We used functional magnetic resonance imaging to characterize the effects of ketamine on frontal and hippocampal responses to memory encoding and retrieval in healthy volunteers using a double-blind, placebo-controlled, randomized, within-subjects comparison of two doses of intravenous ketamine. Dissociation of the effects of ketamine on encoding and retrieval processes was achieved using two study-test cycles: in the first, items were encoded prior to drug infusion and retrieval tested, during scanning, on drug; in the second, encoding was scanned on drug, and retrieval tested once ketamine plasma levels had declined. We additionally determined the interaction of ketamine with the depth of processing that occurred at encoding. A number of effects upon task-dependent activations were seen. Overall, our results suggest that left frontal activation is augmented by ketamine when elaborative semantic processing is required at encoding. In addition, successful encoding on ketamine is supplemented by additional non-verbal processing that is incidental to task demands. The effects of ketamine at retrieval are consistent with impaired access to accompanying contextual features of studied items. Our findings show that, even when overt behaviour is unimpaired, ketamine has an impact upon the recruitment of key regions in episodic memory task performance.

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.

We have used functional MRI to determine the effects of ketamine on brain systems activated in association with a working memory task. Healthy volunteers received intravenous infusions of placebo, ketamine at 50 ng/ml plasma concentration, and ketamine at 100 ng/ml. They were scanned while carrying out a verbal working memory task in which we varied the executive requirements (manipulation vs maintenance processes) and the mnemonic load (three vs five presented letters). We previously showed that ketamine produces a specific behavioral impairment in the manipulation task. In the current study, we modified tasks in order to match performance across drug and placebo conditions, and used an event-related fMRI design, allowing us to remove unsuccessful trials from the analysis. Our results suggest a task-specific effect of ketamine on working memory in a brain system comprising frontal cortex, parietal cortex, and putamen. When subjects are required to manipulate presented letters into alphabetical order, as opposed to maintaining them in the order in which they were presented, ketamine is associated with significantly greater activity in this system, even under these performance-matched conditions. No significant effect of ketamine was seen in association with increasing load. This suggests that our findings are not explicable in terms of a nonspecific effect of ketamine when task difficulty is increased. Rather, our findings provide evidence that the predominant effects of low, subdissociative doses of ketamine are upon the control processes engaged by the manipulation task. Furthermore, we have shown that ketamine's effects may be elucidated by fMRI even when overt behavioral measures show no evidence of impairment.

The precise nature of the impact of the N-methyl-d-aspartate antagonist, ketamine, upon human episodic memory, has yet to be elucidated fully. This study sought to assess the effects of ketamine on the sub-processes facilitating memory encoding and retrieval. We evaluated the effects of the drug on a series of memory performance measures depending upon whether it was administered at the encoding or retrieval stage and on the nature of the encoding task used. Twelve healthy volunteers participated in a double-blind, placebo-controlled, randomized, within-subjects study. Intravenous infusions of placebo, 50 ng/ml ketamine or 100 ng/ml ketamine were administered. We investigated the effects of ketamine on three key aspects of episodic memory: encoding vs retrieval processes, source memory, and depth of processing. Data were analysed using both multinomial modelling and standard measures of item discrimination and response bias. Deleterious effects of ketamine on episodic memory were primarily attributable to its effects on encoding, rather than retrieval processes. Recognition memory was impaired for items encoded at an intermediate level of processing, but preserved for shallowly and deeply encoded items. Increased source guessing bias was also observed when encoding took place under ketamine. The effects of ketamine upon episodic memory seem, therefore, to predominate at encoding. Furthermore, our results are also consistent with a specific impairment of encoding processes that result in subsequent recollective, as opposed to familiarity-based, retrieval. The observed effects are compatible with memory deficits seen in schizophrenia and thus provide some support for the ketamine model of the disease.

We investigated the effects of subdissociative dose ketamine on executive processes during a working memory task. A total of 11 healthy volunteers participated in a double-blind, placebo-controlled, randomized, within-subjects study. They attended on three occasions, receiving intravenous infusions of placebo, a lower ketamine dose, and a higher ketamine dose. On each occasion, they underwent a series of tasks engaging working memory function in verbal and visuo-spatial domains. Further tasks explored aspects of long-term memory, planning, attention, and perceptual processing. With respect to working memory/executive function, a highly specific pattern of impairment was observed. Impairments were seen only at the higher dose of ketamine and restricted to a subgroup of the verbal working memory tasks: While visuo-spatial working memory showed no evidence of impairment, and while simple maintenance processes during verbal working memory were also unimpaired, higher dose ketamine produced a significant impairment in the manipulation of information within working memory. This process-specific effect of ketamine was reflected in a drug-by-task interaction. The specificity of this ketamine effect suggests that the earliest effect of NMDA receptor blockade is in higher order control of executive function rather than in more basic maintenance processes.

Multidimensional scaling (MDS) is a multivariate statistical technique that can be used to define subsystems of functionally connected brain regions based on the analysis of functional magnetic resonance imaging (fMRI) data. Here we introduce three-way multidimensional scaling as a method for the analysis of a group of fMRI data, which yields both a generic interregional configuration in low-dimensional space and a measure of each individual's deviation from the generic configuration. The distance between two generic interregional configurations obtained by MDS of two groups of data can be minimized by generalized Procrustes analysis, and the probability under the null hypothesis (that the two groups are sampled from the same population) of any residual group difference in interregional configurations can be assessed by a permutation test. These methods are developed and applied to activated fMRI time series acquired from 19 patients with schizophrenia and 20 normal comparison subjects during the performance of a semantic categorization and subvocal rehearsal task. The first three scaling dimensions are interpretable in terms of the major anatomical or functional subsystems of the activated system: "left-right," "input processing-other," and "subvocal output-other". We found no significant global or local differences between groups in interregional configurations in this 3D space. However, there was significantly greater variability of interregional configurations within the group of patients with schizophrenia. The implications for schizophrenia as a disconnexion disorder are discussed.