Multi-echo fMRI, resting-state connectivity, and high psychometric schizotypy

Disrupted striatal functional connectivity is proposed to play a critical role in the development of psychotic symptoms. Previous resting-state functional magnetic resonance imaging (rs-fMRI) studies typically reported disrupted striatal connectivity in patients with psychosis and in individuals at clinical and genetic high risk of the disorder relative to healthy controls. This has not been widely studied in healthy individuals with subclinical psychotic-like experiences (schizotypy). Here we applied the emerging technology of multi-echo rs-fMRI to examine corticostriatal connectivity in this group, which is thought to drastically maximize physiological noise removal and increase BOLD contrast-to-noise ratio. Multi-echo rs-fMRI data (echo times, 12, 28, 44, 60 ms) were acquired from healthy individuals with low (LS, n = 20) and high (HS, n = 19) positive schizotypy as determined with the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE). After preprocessing to ensure optimal contrast and removal of non-BOLD signal components, whole-brain functional connectivity from six striatal seeds was compared between the HS and LS groups. Effects were considered significant at cluster-level p < .05 family-wise error correction. Compared to LS, HS subjects showed lower rs-fMRI connectivity between ventromedial prefrontal regions and ventral striatal regions. Lower connectivity was also observed between the dorsal putamen and the hippocampus, occipital regions, as well as the cerebellum. These results demonstrate that subclinical positive psychotic-like experiences in healthy individuals are associated with striatal hypoconnectivity as detected using multi-echo rs-fMRI. Further application of this approach may aid in characterizing functional connectivity abnormalities across the extended psychosis phenotype.

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title: The dysconnection hypothesis (2016)
abstract: Twenty years have passed since the dysconnection hypothesis was first proposed (Friston and Frith, 1995; Weinberger, 1993). In that time, neuroscience has witnessed tremendous advances: we now live in a world of non-invasive neuroanatomy, computational neuroimaging and the Bayesian brain. The genomics era has come and gone. Connectomics and large-scale neuroinformatics initiatives are emerging everywhere. So where is the dysconnection hypothesis now? This article considers how the notion of schizophrenia as a dysconnection syndrome has developed – and how it has been enriched by recent advances in clinical neuroscience. In particular, we examine the dysconnection hypothesis in the context of (i) theoretical neurobiology and computational psychiatry; (ii) the empirical insights afforded by neuroimaging and associated connectomics – and (iii) how bottom-up (molecular biology and genetics) and top-down (systems biology) perspectives are converging on the mechanisms and nature of dysconnections in schizophrenia.

title: Schizophrenia: a disconnection syndrome?
abstract: We review the evidence of pathophysiological changes in the prefrontal and temporal cortices of schizophrenic subjects and of abnormal integration of the physiological dynamics in these two regions. The argument we develop is that some schizophrenic phenomena are best understood in terms of abnormal interactions between different areas, not only at the levels of physiology and functional anatomy, but at the level of cognitive and sensorimotor functioning. We discuss recent functional imaging evidence suggesting abnormal prefronto-temporal interactions in relation to a psychological analysis of experiential symptoms in schizophrenia. Cortico-cortical interactions have been assessed in terms of functional connectivity and eigenimages, using time series of neurophysiological data obtained with positron emission tomography. The results of these analyses suggest that there is a profound disruption of large-scale prefronto-temporal interactions in schizophrenia. These disruptions are particularly relevant if one considers that many positive symptoms of schizophrenia reflect a failure to integrate intrinsically generated behaviour and concurrent perception.

title: Disordered functional connectivity in schizophrenia.
abstract: Psychological Medicine / Volume 26 / Issue 04 / July 1996, pp 663 667 DOI: 10.1017/S0033291700037673,  2009 Link to this article: http://journals.cambridge.org/abstract_S0033291700037673 How to cite this article: P. K. McGuire and C. D. Frith (1996). Disordered functional connectivity in schizophrenia. Psychological Medicine, 26, pp 663-667  Click here

title: Resting Hyperperfusion of the Hippocampus, Midbrain, and Basal Ganglia in People at High Risk for Psychosis.
abstract: Animal models suggest that the development of psychosis involves hyperactivity in the hippocampus that drives increased activity in the midbrain and basal ganglia. The authors examined this hypothesis by measuring resting perfusion in the hippocampus, basal ganglia, and midbrain in people at high risk of psychosis.



Pseudo-continuous arterial spin labeling imaging was used to measure resting regional cerebral blood flow (rCBF) in 52 individuals at ultra-high risk for psychosis and in 27 healthy volunteers. The severity of psychotic symptoms was assessed using the Comprehensive Assessment of At-Risk Mental States. The ultra-high-risk subjects were reassessed after a mean of 17 months, using the same measures as at baseline.



At baseline, relative to healthy volunteers, ultra-high-risk subjects showed elevated rCBF in the hippocampus, basal ganglia, and midbrain. In the ultra-high-risk sample overall, at follow-up, symptomatic improvement and reduced rCBF in the hippocampus and ventral striatum were observed. Subjects whose symptoms had resolved such that they no longer met ultra-high-risk criteria showed a longitudinal reduction in left hippocampal rCBF that was not evident in subjects who remained in a high-risk state or had become psychotic.



A high risk for psychosis was associated with increased resting activity in the hippocampus, midbrain, and basal ganglia. Subsequent resolution of the high-risk state was linked to a normalization of activity in these regions. These findings are consistent with animal models that propose that psychotic symptoms may be generated when hippocampal hyperactivity drives hyperactivity in regions involved in subcortical dopamine signaling.

title: Increased Striatal and Reduced Prefrontal Cerebral Blood Flow in Clinical High Risk for Psychosis
abstract: Increased striatal dopaminergic activity and decreased prefrontal functioning have been reported in individuals at clinical high risk (CHR) for psychosis. Abnormal metabolic rate might affect resting-state cerebral blood flow (rCBF) in the respective regions. Here, we examined if striatal and prefrontal rCBF differ between patients with CHR, first-episode psychosis (FEP), chronic schizophrenia-spectrum disorder (SZ) and controls. Two cohorts with a total of 122 participants were included and analyzed separately: 32 patients with SZ and 31 healthy controls (HC) from the University Hospital of Psychiatry, and 59 patients from the Bern Early Recognition and Intervention Center (29 with CHR, 12 with FEP, and 18 clinical controls [CC]). Ultra-high risk criteria were assessed with the Structured Interview for Psychosis-Risk Syndromes, basic symptom criteria with the Schizophrenia Proneness Instrument. rCBF was measured with pseudo-continuous arterial spin labeling 3T-Magnetic Resonance Imaging. Striatal rCBF was significantly increased and prefrontal rCBF significantly decreased in the SZ group compared to HC group and in the CHR and FEP groups compared to CC group. Striatal rCBF correlated significantly with positive symptom scores in SZ and CHR. An inverse correlation between striatal and frontal rCBF was found in controls (HC, CC), but not in patient groups (SZ, FEP, CHR). This is the first study to demonstrate increased neuronal activity within the striatum, but reduced prefrontal activity in patients with CHR, FEP, and SZ compared to the respective controls. Our results indicate that alterations in striatal and prefrontal rCBF are reflecting metabolic abnormalities preceding the onset of frank psychosis.

title: Increased Intrinsic Brain Activity in the Striatum Reflects Symptom Dimensions in Schizophrenia
abstract: Striatal dysfunction is thought to be a fundamental element in schizophrenia. Striatal dopamine dysfunction impacts on reward processing and learning and is present even at rest. Here, we addressed the question whether and how spontaneous neuronal activity in the striatum is altered in schizophrenia. We therefore assessed intrinsic striatal activity and its relation with disorder states and symptom dimensions in patients with schizophrenia. We performed resting-state functional (rs-fMRI) and structural magnetic resonance imaging as well as psychometric assessment in 21 schizophrenic patients during psychosis. On average 9 months later, we acquired follow-up data during psychotic remission and with comparable levels of antipsychotic medication. Twenty-one age- and sex-matched healthy controls were included in the study. Independent component analysis of fMRI data yielded spatial maps and time-courses of coherent ongoing blood-oxygen-level-dependent signal fluctuations, which were used for group comparisons and correlation analyses with scores of the positive and negative syndrome scale. During psychosis, coherent intrinsic activity of the striatum was increased in the dorsal part and correlated with positive symptoms such as delusion and hallucination. In psychotic remission of the same patients, activity of the ventral striatum was increased and correlated with negative symptoms such as emotional withdrawal and blunted affect. Results were controlled for volumetric and medication effects. These data provide first evidence that in schizophrenia intrinsic activity is changed in the striatum and corresponds to disorder states and symptom dimensions.

title: Aberrant Salience Is Related to Reduced Reinforcement Learning Signals and Elevated Dopamine Synthesis Capacity in Healthy Adults
abstract: The striatum is known to play a key role in reinforcement learning, specifically in the encoding of teaching signals such as reward prediction errors (RPEs). It has been proposed that aberrant salience attribution is associated with impaired coding of RPE and heightened dopamine turnover in the striatum, and might be linked to the development of psychotic symptoms. However, the relationship of aberrant salience attribution, RPE coding, and dopamine synthesis capacity has not been directly investigated. Here we assessed the association between a behavioral measure of aberrant salience attribution, the salience attribution test, to neural correlates of RPEs measured via functional magnetic resonance imaging while healthy participants (n = 58) performed an instrumental learning task. A subset of participants (n = 27) also underwent positron emission tomography with the radiotracer [18F]fluoro-l-DOPA to quantify striatal presynaptic dopamine synthesis capacity. Individual variability in aberrant salience measures related negatively to ventral striatal and prefrontal RPE signals and in an exploratory analysis was found to be positively associated with ventral striatal presynaptic dopamine levels. These data provide the first evidence for a specific link between the constructs of aberrant salience attribution, reduced RPE processing, and potentially increased presynaptic dopamine function.

title: Aberrant Effective Connectivity in Schizophrenia Patients during Appetitive Conditioning
abstract: It has recently been suggested that schizophrenia involves dysfunction in brain connectivity at a neural level, and a dysfunction in reward processing at a behavioral level. The purpose of the present study was to link these two levels of analyses by examining effective connectivity patterns between brain regions mediating reward learning in patients with schizophrenia and healthy, age-matched controls. To this aim, we used functional magnetic resonance imaging and galvanic skin recordings (GSR) while patients and controls performed an appetitive conditioning experiment with visual cues as the conditioned (CS) stimuli, and monetary reward as the appetitive unconditioned stimulus (US). Based on explicit stimulus contingency ratings, conditioning occurred in both groups; however, based on implicit, physiological GSR measures, patients failed to show differences between CS+ and CS− conditions. Healthy controls exhibited increased blood-oxygen-level dependent (BOLD) activity across striatal, hippocampal, and prefrontal regions and increased effective connectivity from the ventral striatum to the orbitofrontal cortex (OFC BA 11) in the CS+ compared to the CS− condition. Compared to controls, patients showed increased BOLD activity across a similar network of brain regions, and increased effective connectivity from the striatum to hippocampus and prefrontal regions in the CS− compared to the CS+ condition. The findings of increased BOLD activity and effective connectivity in response to the CS− in patients with schizophrenia offer insight into the aberrant assignment of motivational salience to non-reinforced stimuli during conditioning that is thought to accompany schizophrenia.

title: Aberrant Salience Is Related to Dysfunctional Self-Referential Processing in Psychosis.
abstract: A dysfunctional differentiation between self-relevant and irrelevant information may affect the perception of environmental stimuli as abnormally salient. The aberrant salience hypothesis assumes that positive symptoms arise from an attribution of salience to irrelevant stimuli accompanied by the feeling of self-relevance. Self-referential processing relies on the activation of cortical midline structures which was demonstrated to be impaired in psychosis. We investigated the neural correlates of self-referential processing, aberrant salience attribution, and the relationship between these 2 measures across the psychosis continuum.



Twenty-nine schizophrenia patients, 24 healthy individuals with subclinical delusional ideation, and 50 healthy individuals participated in this study. Aberrant salience was assessed behaviorally in terms of reaction times to task irrelevant cues. Participants performed a self-reference task during fMRI in which they had to apply neutral trait words to them or to a public figure. The correlation between self-referential processing and aberrant salience attribution was tested.



Schizophrenia patients displayed increased aberrant salience attribution compared with healthy controls and individuals with subclinical delusional ideation, while the latter exhibited intermediate aberrant salience scores. In the self-reference task, schizophrenia patients showed reduced activation in the ventromedial prefrontal cortex (vmPFC), but individuals with subclinical delusional ideation did not differ from healthy controls. In schizophrenia patients, vmPFC activation correlated negatively with implicit aberrant salience attribution.



Higher aberrant salience attribution in schizophrenia patients is related to reduced vmPFC activation during self-referential judgments suggesting that aberrant relevance coding is reflected in decreased neural self-referential processing as well as in aberrant salience attribution.

title: Neural and Behavioral Correlates of Aberrant Salience in Individuals at Risk for Psychosis
abstract: The “aberrant salience” model proposes that psychotic symptoms first emerge when chaotic brain dopamine transmission leads to the attribution of significance to stimuli that would normally be considered irrelevant. This is thought to occur during the prodromal phase of psychotic disorders, but this prediction has not been tested previously. In the present study, we tested this model in 18 healthy volunteers and 18 unmedicated individuals at ultra-high risk of psychosis. Subjects performed the Salience Attribution Test, which provides behavioral measures of adaptive and aberrant motivational salience, during functional magnetic resonance imaging to assess neural responses to relevant and irrelevant stimulus features. On a separate occasion, the same subjects were also studied with [18F]fluorodopa positron emission tomography to measure dopamine synthesis capacity. Individuals at ultra-high risk of psychosis were more likely to attribute motivational salience to irrelevant stimulus features (t(26.7) = 2.8, P = .008), and this bias was related to the severity of their delusion-like symptoms (r = .62, P = .008). Ventral striatal responses to irrelevant stimulus features were also correlated with delusion-like symptoms in the ultra-high risk group (r = .59, P = .017). Striatal dopamine synthesis capacity correlated negatively with hippocampal responses to irrelevant stimulus features in ultra-high risk individuals, but this relationship was positive in controls. These data are consistent with the hypothesis that aberrant salience processing underlies psychotic symptoms and involves functional alterations in the striatum, hippocampus, and the subcortical dopamine system.

title: Reward Feedback Alterations in Unmedicated Schizophrenia Patients: Relevance for Delusions
abstract: Increased attribution of incentive salience to neutral or aversive stimuli might be associated with dysfunction of neuronal processing of positive and negative reinforcement and contribute to the formation of delusions in schizophrenia.



Fifteen unmedicated patients with schizophrenia (8 drug-naive and 7 drug-free for at least 3 months) and 15 age- and gender-matched healthy control participants underwent functional magnetic resonance imaging to investigate neural responses to feedback of (successful vs. unsuccessful) monetary gain or avoidance of loss. Functional connectivity was assessed between the medial prefrontal cortex (MPFC) and ventral striatum (VS), brain areas known to be activated by feedback of reward and loss.



Responses to negative outcome in reward trials (omission of expected reward) were exaggerated in the MPFC of patients with schizophrenia. In contrast, schizophrenia patients showed reduced neural responses to successful versus unsuccessful avoidance of loss in the VS. Increased severity of delusions in schizophrenia patients was associated with a decrease in MPFC activation elicited by successful versus unsuccessful avoidance of loss. Functional connectivity between the MPFC and the VS was reduced in patients with schizophrenia compared with healthy control subjects.



These findings demonstrate a differential impairment of-and reduced connectivity between--VS and MPFC during processing of reward and loss-avoidance in drug-free patients with schizophrenia. Moreover, our results provide a link between the formation of delusions and the neural processing of aversive outcomes.

title: Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia.
abstract: Substantial evidence suggests that psychosis in schizophrenia is associated with dysregulation of subcortical dopamine system function. Here we examine evidence that this dysregulation is secondary to hyperactivity within hippocampal subfields. Enhanced hippocampal activity has been reported in preclinical models and in schizophrenia patients. Moreover, this hippocampal hyperactivity is correlated with enhanced dopamine neuron activity and positive symptoms, respectively. Thus, restoration of hippocampal function could provide a more effective therapeutic approach than current therapeutics based on blockade of dopamine D2 receptors. Indeed, initial studies demonstrate that allosteric modulation of the α5GABA(A) receptor can decrease aberrant dopamine signaling and associated behaviors in a verified rodent model of psychosis.

title: Prefrontal Cortex Dysfunction Increases Susceptibility to Schizophrenia-Like Changes Induced by Adolescent Stress Exposure
abstract: Stress during adolescence is a risk factor for schizophrenia, and medial prefrontal cortex (mPFC) dysfunction is proposed to interfere with stress control, increasing the susceptibility to stress. We evaluated the impact of different stressful events during adolescence (restraint stress [RS], footshock [FS], or the combination of FS and RS) on behaviors correlated with schizophrenia in rats as adults. At adulthood, animals were tested for anxiety responses (elevated plus-maze), cognitive function (novel-object recognition test) and dopamine (DA) system responsivity (locomotor response to amphetamine and DA neuron activity in the ventral tegmental area (VTA) using in vivo electrophysiology). All adolescent stressors impaired weight gain and induced anxiety-like responses in adults. FS and FS + RS also disrupted cognitive function. Interestingly, only the combination of FS and RS induced a DA hyper-responsivity as indicated by augmented locomotor response to amphetamine and increased number of spontaneously active DA neurons which was confined to the lateral VTA. Additionally, prelimbic (pl) mPFC lesions triggered a DA hyper-responsivity in animals exposed to FS alone during adolescence. Our results are consistent with previous studies showing long-lasting changes induced by stressful events during adolescence. The impact on DA system activity, however, seems to depend on intense multiple stressors. Our data also suggest that plPFC dysfunction increases the vulnerability to stress in terms of changes in the DA system. Hence, stress during adolescence could be a precipitating factor for the transition to schizophrenia, and stress control at this vulnerable period may circumvent these changes to prevent the emergence of psychosis.

title: Altered striatal functional connectivity in subjects with an at-risk mental state for psychosis.
abstract: Recent functional imaging work in individuals experiencing an at-risk mental state (ARMS) for psychosis has implicated dorsal striatal abnormalities in the emergence of psychotic symptoms, contrasting with earlier findings implicating the ventral striatum. Our aims here were to characterize putative dorsal and ventral striatal circuit-level abnormalities in ARMS individuals using resting-state functional magnetic resonance imaging (fMRI) and to investigate their relationship to positive psychotic symptoms. Resting-state fMRI was acquired in 74 ARMS subjects and 35 matched healthy controls. An established method for mapping ventral and dorsal striatal functional connectivity was used to examine corticostriatal functional integrity. Positive psychotic symptoms were assessed using the Comprehensive Assessment of At-Risk Mental State and the Positive and Negative Syndrome Scale. Compared with healthy controls, ARMS subjects showed reductions in functional connectivity between the dorsal caudate and right dorsolateral prefrontal cortex, left rostral medial prefrontal cortex, and thalamus, and between the dorsal putamen and left thalamic and lenticular nuclei. ARMS subjects also showed increased functional connectivity between the ventral putamen and the insula, frontal operculum, and superior temporal gyrus bilaterally. No differences in ventral striatal (ie, nucleus accumbens) functional connectivity were found. Altered functional connectivity in corticostriatal circuits were significantly correlated with positive psychotic symptoms. Together, these results suggest that risk for psychosis is mediated by a complex interplay of alterations in both dorsal and ventral corticostriatal systems.

title: Functional dysconnectivity of corticostriatal circuitry as a risk phenotype for psychosis.
abstract: Dysregulation of corticostriatal circuitry has long been thought to be critical in the etiology of psychotic disorders, although the differential roles played by dorsal and ventral systems in mediating risk for psychosis have been contentious.



To use resting-state functional magnetic resonance imaging to characterize disease-related, risk-related, and symptom-related changes of corticostriatal functional circuitry in patients with first-episode psychosis and their unaffected first-degree relatives.



This case-control cross-sectional study was conducted at a specialist early psychosis clinic, GlaxoSmithKline Clinical Unit, and magnetic resonance imaging facility. Nineteen patients with first-episode psychosis, 25 of their unaffected first-degree relatives, and 26 healthy control subjects were included in this study.



Voxelwise statistical parametric maps testing differences in the strength of functional connectivity between 6 striatal seed regions of interest (3 caudate and 3 putamen) per hemisphere and all other brain regions.



Disease-related changes, reflecting differences between patients and control subjects, involved widespread dysregulation of corticostriatal systems characterized most prominently by a dorsal-to-ventral gradient of hypoconnectivity to hyperconnectivity between striatal and prefrontal regions. A similar gradient was evident in comparisons between relatives and control subjects, identifying it as a genetically inherited risk phenotype. In patients, functional connectivity in risk-affected and disease-affected dorsal frontostriatal circuitry correlated with the severity of both positive and negative symptoms.



First-episode psychosis is associated with pronounced dysregulation of corticostriatal systems, characterized most prominently by hypoconnectivity of dorsal and hyperconnectivity of ventral frontostriatal circuits. These changes correlate with symptom severity and are also apparent in unaffected first-degree relatives, suggesting that they represent a putative risk phenotype for psychotic illness.

title: Changes in extra-striatal functional connectivity in patients with schizophrenia in a psychotic episode
abstract: In patients with schizophrenia in a psychotic episode, intra-striatal intrinsic connectivity is increased in the putamen but not ventral striatum. Furthermore, multimodal changes have been observed in the anterior insula that interact extensively with the putamen.  We hypothesised that during psychosis, putamen extra-striatal functional connectivity is altered with both the anterior insula and areas normally connected with the ventral striatum (i.e. altered functional connectivity distinctiveness of putamen and ventral striatum).  We acquired resting-state functional magnetic resonance images from 21 patients with schizophrenia in a psychotic episode and 42 controls.  Patients had decreased functional connectivity: the putamen with right anterior insula and dorsal prefrontal cortex, the ventral striatum with left anterior insula. Decreased functional connectivity between putamen and right anterior insula was specifically associated with patients' hallucinations. Functional connectivity distinctiveness was impaired only for the putamen.  Results indicate aberrant extra-striatal connectivity during psychosis and a relationship between reduced putamen–right anterior insula connectivity and hallucinations. Data suggest that altered intrinsic connectivity links striatal and insular pathophysiology in psychosis.

title: Dopamine-Related Disruption of Functional Topography of Striatal Connections in Unmedicated Patients With Schizophrenia.
abstract: Despite the well-established role of striatal dopamine in psychosis, current views generally agree that cortical dysfunction is likely necessary for the emergence of psychotic symptoms. The topographic organization of striatal-cortical connections is central to gating and integration of higher-order information, so a disruption of such topography via dysregulated dopamine could lead to cortical dysfunction in schizophrenia. However, this hypothesis remains to be tested using multivariate methods ascertaining the global pattern of striatal connectivity and without the confounding effects of antidopaminergic medication.



To examine whether the pattern of brain connectivity across striatal subregions is abnormal in unmedicated patients with schizophrenia and whether this abnormality relates to psychotic symptoms and extrastriatal dopaminergic transmission.



In this multimodal, case-control study, we obtained resting-state functional magnetic resonance imaging data from 18 unmedicated patients with schizophrenia and 24 matched healthy controls from the New York State Psychiatric Institute. A subset of these (12 and 17, respectively) underwent positron emission tomography with the dopamine D2 receptor radiotracer carbon 11-labeled FLB457 before and after amphetamine administration. Data were acquired between June 16, 2011, and February 25, 2014. Data analysis was performed from September 1, 2014, to January 11, 2016.



Group differences in the striatal connectivity pattern (assessed via multivariable logistic regression) across striatal subregions, the association between the multivariate striatal connectivity pattern and extrastriatal baseline D2 receptor binding potential and its change after amphetamine administration, and the association between the multivariate connectivity pattern and the severity of positive symptoms evaluated with the Positive and Negative Syndrome Scale.



Of the patients with schizophrenia (mean [SEM] age, 35.6 [11.8] years), 9 (50%) were male and 9 (50%) were female. Of the controls (mean [SEM] age, 33.7 [8.8] years), 10 (42%) were male and 14 (58%) were female. Patients had an abnormal pattern of striatal connectivity, which included abnormal caudate connections with a distributed set of associative cortex regions (χ229 = 53.55, P = .004). In patients, more deviation from the multivariate pattern of striatal connectivity found in controls correlated specifically with more severe positive symptoms (ρ = -0.77, P = .002). Striatal connectivity also correlated with baseline binding potential across cortical and extrastriatal subcortical regions (t25 = 3.01, P = .01, Bonferroni corrected) but not with its change after amphetamine administration.



Using a multimodal, circuit-level interrogation of striatal-cortical connections, it was demonstrated that the functional topography of these connections is globally disrupted in unmedicated patients with schizophrenia. These findings suggest that striatal-cortical dysconnectivity may underlie the effects of dopamine dysregulation on the pathophysiologic mechanism of psychotic symptoms.

title: Functional dysconnectivity of the limbic loop of frontostriatal circuits in first‐episode, treatment‐naive schizophrenia
abstract: Frontostriatal circuits dysfunction has been implicated in the etiology and psychopathology of patients with schizophrenia (SZ). However, few studies have investigated SZ‐related functional connectivity (FC) alterations in discrete frontostriatal circuits and their relationship with pathopsychology in first‐episode schizophrenia (FESZ). The goal of this study was to identify dysfunctions in discrete frontostriatal circuits that are associated with key features of FESZ. To this end, a case–control, cross‐sectional study was conducted, wherein resting‐state (RS) functional magnetic resonance (fMRI) data were collected from 37 treatment‐naïve FESZ patients and 29 healthy control (HC) subjects. Seed‐based FC analyses were performed by placing six bilateral pairs of seeds within a priori defined subdivisions of the striatum. We observed significantly decreased FC for the FESZ group relative to the HC group [p < .05, family‐wise error (FWE)‐corrected] in the limbic loop, but not in the sensorimotor or associative loops, of frontostriatal circuitry. Moreover, bilaterally decreased inferior ventral striatum/nucleus accumbens (VSi)‐dorsal anterior cingulate cortex (dACC) FC within the limbic loop correlated inversely with overall FESZ symptom severity and the disorganization factor score of PANSS. These findings provide new insight into the role of frontostriatal limbic loop hypoconnectivity in early‐stage schizophrenia pathology and suggest potential novel therapeutic targets.

title: Cortico-striatal disconnection within the cingulo-opercular network in schizophrenia revealed by intrinsic functional connectivity analysis: A resting fMRI study
abstract: The cingulo-opercular network (CON) is a newly defined control network responsible for various cognitive processes that have been consistently found to be impaired in schizophrenia. The aim of this study was to use functional connectivity magnetic resonance imaging (fcMRI) to test the hypothesis that schizophrenia is associated with functional disconnection within the CON. Thirty subjects with schizophrenia and thirty healthy controls were enrolled in the study. Each subject received resting fMRI scanning, clinical evaluations and cognitive examinations. The CON of each subject was derived by calculating the functional connectivity map of a seed in the dorsal anterior cingulate (dACC). A between-group comparison was performed using a random effect analysis. Further network analyses with multiple regions of interest (ROIs) were performed to characterize the pattern of functional disconnection within the entire CON. Using the dACC seed in healthy controls, we derived the CON, which includes the following anatomical structures: the dACC; the bilateral anterior prefrontal, inferior parietal and anterior insular cortices; the putamen; the thalamus; and the cerebellum. Compared with healthy controls, schizophrenic patients showed significantly reduced functional connectivity in the bilateral putamens. Further network analysis demonstrated widespread cortico-striatal disconnection within the CON of schizophrenic patients. The disconnections correlated with negative symptom severity. Behavioral regression revealed that cortico-striatal functional connectivity predicted 2-back working memory performance in healthy controls, but not in schizophrenic patients. Our findings suggest that schizophrenia is associated with cortical-striatal disconnection within the CON. The result provides a network basis for the cortico-striatal disconnection hypothesis of schizophrenia.

title: An updated and conservative systematic review and meta-analysis of epidemiological evidence on psychotic experiences in children and adults: on the pathway from proneness to persistence to dimensional expression across mental disorders
abstract: The psychosis-proneness–persistence–impairment model of psychotic disorder incorporates notions of both phenomenological and temporal continuity (persistence) of psychotic experiences (PE), but not structural continuity. Specific testable propositions of phenomenological continuity and persistence are identified.  Propositions are tested by systematic reviews of the epidemiology of PE, persistence of PE and disorder outcomes, and meta-analyses (including Monte Carlo permutation sampling, MCPS) of reported rates and odds ratios (ORs).  Estimates of the incidence and prevalence of PE obtained from 61 cohorts revealed a median annual incidence of 2.5% and a prevalence of 7.2%. Meta-analysis of risk factors identified age, minority or migrant status, income, education, employment, marital status, alcohol use, cannabis use, stress, urbanicity and family history of mental illness as important predictors of PE. The mode of assessment accounted for significant variance in the observed rates. Across cohorts, the probability of persistence was very strongly related to the rate of PE at baseline. Of those who report PE, ∼20% go on to experience persistent PE whereas for ∼80%, PE remit over time. Of those with baseline PE, 7.4% develop a psychotic disorder outcome.  Compelling support is found for the phenomenological and temporal continuity between PE and psychotic disorder and for the fundamental proposition that this relationship is probabilistic. However, imprecision in epidemiological research design, measurement limitations and the epiphenomenological nature of PE invite further robust scrutiny of the continuity theory.

title: Evidence of a dimensional relationship between schizotypy and schizophrenia: A systematic review
abstract: The personality dimension of schizotypy is well established, and schizotypal traits can be taken to represent a proneness toward developing psychosis. Yet, there are competing theories about the latent structure of schizotypy. More specifically, there is controversy over the extent to which this propensity toward psychosis is present only in a small proportion of the population, or whether it is spread dimensionally throughout the general community. On the basis of accumulating research findings the present article argues for a fully dimensional model of schizotypy. It describes recent neurobiological, neuropsychological, social and environmental evidence supporting the idea that schizotypy in healthy populations, and disorders on the schizophrenia spectrum are fundamentally linked. Directions for further research are also considered.

title: Schizotypal Traits are Linked to Dopamine-Induced Striato-Cortical Decoupling: A Randomized Double-Blind Placebo-Controlled Study
abstract: The dopamine hypothesis of schizophrenia implies that alterations in the dopamine system cause functional abnormalities in the brain that may converge to aberrant salience attribution and eventually lead to psychosis. Indeed, widespread brain disconnectivity across the psychotic spectrum has been revealed by resting-state functional magnetic resonance imaging (rs-fMRI). However, the dopaminergic involvement in intrinsic functional connectivity (iFC) and its putative relationship to the development of psychotic spectrum disorders remains partly unclear-in particular at the low-end of the psychosis continuum. Therefore, we investigated dopamine-induced changes in striatal iFC and their modulation by psychometrically assessed schizotypy. Our randomized, double-blind placebo-controlled study design included 54 healthy, right-handed male participants. Each participant was assessed with the Schizotypal Personality Questionnaire (SPQ) and underwent 10 minutes of rs-fMRI scanning. Participants then received either a placebo or 200 mg of L-DOPA, a dopamine precursor. We analyzed iFC of 6 striatal seeds that are known to evoke modulation of dopamine-related networks. The main effect of L-DOPA was a significant functional decoupling from the right ventral caudate to both occipital fusiform gyri. This dopamine-induced decoupling emerged primarily in participants with low SPQ scores, while participants with high positive SPQ scores showed decoupling indifferently of the L-DOPA challenge. Taken together, these findings demonstrate that schizotypal traits may be the result of dopamine-induced striato-occipital decoupling.

title: The Role of Schizotypy in the Study of the Etiology of Schizophrenia Spectrum Disorders
abstract: Schizotypy provides a useful construct for understanding the development of schizophrenia spectrum disorders. As research on the epidemiology of psychotic symptoms and clinical risk for psychosis has expanded, conceptual challenges have emerged to comprehend the nature and borders of the space comprised between personality variation and psychosis. Schizotypy is considered in light of these more recent constructs. It is suggested that rather than being superseded by them due to their higher specificity and predictive power for transition to psychosis, schizotypy integrates them as it constitutes a dynamic continuum ranging from personality to psychosis. The advantages of schizotypy for studying schizophrenia etiology are discussed (eg, it facilitates a developmental approach and the identification of causal, resilience, and compensating factors and offers a multidimensional structure that captures etiological heterogeneity). An overview of putative genetic, biological, and psychosocial risk factors is presented, focusing on communalities and differences between schizotypy and schizophrenia spectrum disorders. The found notable overlap supports etiological continuity, and, simultaneously, differential findings appear that are critical to understanding resilience to schizophrenia. For example, discrepant findings in genetic studies might be interpreted as suggestive of sets of independent genetic factors playing a differential role in schizotypy and schizophrenia: some would influence variation specifically on schizotypy dimensions (ie, high vs low schizotypy, thereby increasing proneness to psychosis), some would confer unspecific liability to disease by impacting neural properties and susceptibility to environmental factors (ie, high vs low resilience to disorder) and some might contribute to disease–specific characteristics. Finally, schizotypy’s promise for studying gene-environment interactions is considered.

title: Do measures of schizotypal personality provide non-clinical analogues of schizophrenic symptomatology?
abstract: This study tested the assumption that measures of schizotypal personality provide non-clinical analogues of the heterogeneous symptomatology found in the schizophrenic disorder. The Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE) was administered to schizophrenic patients and healthy controls, and measures of symptomatology from the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS) were assessed in the patient group. Schizophrenic patients scored significantly higher than controls on O-LIFE measures of positive, negative and disorganised schizotypy, while no difference in Impulsive Nonconformity was observed. In the patient group, SAPS positive symptomatology was significantly correlated with O-LIFE positive schizotypy (Unusual Experiences) and Cognitive Disorganisation. However, there was no significant relationship between SAPS/SANS disorganisation and O-LIFE Cognitive Disorganisation, or between the SANS negative factor score and O-LIFE Introvertive Anhedonia. The results suggest that the O-LIFE is a valid tool for assessing schizotypal personality in both schizophrenic patients and healthy controls. However, while the O-LIFE measure of positive schizotypy may correspond with SAPS/SANS positive schizophrenic symptomatology, the negative and disorganised subscales may not be analogous to their SAPS/SANS counterparts. There is also evidence to question the acceptability of Impulsive Nonconformity as a true schizophrenia-like construct.

title: Relationship between Duration of Untreated Psychosis and Intrinsic Corticostriatal Connectivity in Patients with Early Phase Schizophrenia
abstract: Patients with first-episode psychosis experience psychotic symptoms for a mean of up to 2 years prior to initiation of treatment, and long duration of untreated psychosis (DUP) is associated with poor clinical outcomes. Meanwhile, evidence compiled from numerous studies suggests that longer DUP is not associated with structural brain abnormalities. To date, few studies have examined the relationship between DUP and functional neuroimaging measures. In the present study, we used seed-based resting-state functional connectivity to examine the impact of DUP on corticostriatal circuitry. We included 83 patients with early phase schizophrenia and minimal exposure to antipsychotic drugs (<2 years), who underwent resting state scanning while entering 12 weeks of prospective treatment with second-generation antipsychotic drugs. Functional connectivity maps of the striatum were generated and examined in relation to DUP as a covariate. Mediation analyses were performed on a composite measure of corticostriatal connectivity derived from the significant results of our DUP analysis. We found that longer DUP correlated with worse response to treatment as well as overall decreased functional connectivity between striatal nodes and specific regions within frontal and parietal cortices. Moreover, the relationship between DUP and treatment response was significantly mediated by corticostriatal connectivity. Our results indicate that variation in corticostriatal circuitry may play a role in the relationship between longer DUP and worsened response to treatment. Future prospective studies are necessary to further characterize potential causal links between DUP, striatal circuitry and clinical outcomes.

title: Antipsychotic treatment and functional connectivity of the striatum in first-episode schizophrenia.
abstract: Previous evidence has implicated corticostriatal abnormalities in the pathophysiology of psychosis. Although the striatum is the primary target of all efficacious antipsychotics, the relationship between its functional connectivity and symptomatic reduction remains unknown.



To explore the longitudinal effect of treatment with second-generation antipsychotics on functional connectivity of the striatum during the resting state in patients experiencing a first episode of psychosis.



This prospective controlled study took place at a clinical research center and included 24 patients with first-episode psychosis and 24 healthy participants matched for age, sex, education, and handedness. Medications were administered in a double-blind randomized manner.



Patients were scanned at baseline and after 12 weeks of treatment with either risperidone or aripiprazole. Their symptoms were evaluated with the Brief Psychiatric Rating Scale at baseline and follow-up. Healthy participants were scanned twice within a 12-week interval.



Functional connectivity of striatal regions was examined via functional magnetic resonance imaging using a seed-based approach. Changes in functional connectivity of these seeds were compared with reductions in ratings of psychotic symptoms.



Patients had a median exposure of 1 day to antipsychotic medication prior to being scanned (mean [SD] = 4.5 [6.1]). Eleven patients were treated with aripiprazole and 13 patients were treated with risperidone. As psychosis improved, we observed an increase in functional connectivity between striatal seed regions and the anterior cingulate, dorsolateral prefrontal cortex, and limbic regions such as the hippocampus and anterior insula (P < .05, corrected for multiple comparisons). Conversely, a negative relationship was observed between reduction in psychosis and functional connectivity of striatal regions with structures within the parietal lobe (P < .05, corrected for multiple comparisons).



Our results indicated that corticostriatal functional dysconnectivity in psychosis is a state-dependent phenomenon. Increased functional connectivity of the striatum with prefrontal and limbic regions may be a biomarker for improvement in symptoms associated with antipsychotic treatment.

title: Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion
abstract: Here, we demonstrate that subject motion produces substantial changes in the timecourses of resting state functional connectivity MRI (rs-fcMRI) data despite compensatory spatial registration and regression of motion estimates from the data. These changes cause systematic but spurious correlation structures throughout the brain. Specifically, many long-distance correlations are decreased by subject motion, whereas many short-distance correlations are increased. These changes in rs-fcMRI correlations do not arise from, nor are they adequately countered by, some common functional connectivity processing steps. Two indices of data quality are proposed, and a simple method to reduce motion-related effects in rs-fcMRI analyses is demonstrated that should be flexibly implementable across a variety of software platforms. We demonstrate how application of this technique impacts our own data, modifying previous conclusions about brain development. These results suggest the need for greater care in dealing with subject motion, and the need to critically revisit previous rs-fcMRI work that may not have adequately controlled for effects of transient subject movements.

title: Low-frequency fluctuations in the cardiac rate as a source of variance in the resting-state fMRI BOLD signal
abstract: Heart rate fluctuations occur in the low-frequency range (<0.1 Hz) probed in functional magnetic resonance imaging (fMRI) studies of resting-state functional connectivity and most fMRI block paradigms and may be related to low-frequency blood-oxygenation-level-dependent (BOLD) signal fluctuations. To investigate this hypothesis, temporal correlations between cardiac rate and resting-state fMRI signal timecourses were assessed at 3 T. Resting-state BOLD fMRI and accompanying physiological data were acquired and analyzed using cross-correlation and regression. Time-shifted cardiac rate timecourses were included as regressors in addition to established physiological regressors (RETROICOR (Glover, G.H., Li, T.Q., Ress, D., 2000. Image-based method for retrospective correction of physiological motion effects in fMRI: RETROICOR. Magn Reson Med 44, 162-167) and respiration volume per unit time (Birn, R.M., Diamond, J.B., Smith, M.A., Bandettini, P.A., 2006b. Separating respiratory-variation-related fluctuations from neuronal-activity-related fluctuations in fMRI. NeuroImage 31, 1536-1548). Significant correlations between the cardiac rate and BOLD signal timecourses were revealed, particularly negative correlations in gray matter at time shifts of 6-12 s and positive correlations at time shifts of 30-42 s (TR=6 s). Regressors consisting of cardiac rate timecourses shifted by delays of between 0 and 24 s explained an additional 1% of the BOLD signal variance on average over the whole brain across 9 subjects, a similar additional variance to that explained by respiration volume per unit time and RETROICOR regressors, even when used in combination with these other physiological regressors. This suggests that including such time-shifted cardiac rate regressors will be beneficial for explaining physiological noise variance and will thereby improve the statistical power in future task-based and resting-state fMRI studies.

title: Differentiating BOLD and non-BOLD signals in fMRI time series using multi-echo EPI
abstract: A central challenge in the fMRI based study of functional connectivity is distinguishing neuronally related signal fluctuations from the effects of motion, physiology, and other nuisance sources. Conventional techniques for removing nuisance effects include modeling of noise time courses based on external measurements followed by temporal filtering. These techniques have limited effectiveness. Previous studies have shown using multi-echo fMRI that neuronally related fluctuations are Blood Oxygen Level Dependent (BOLD) signals that can be characterized in terms of changes in R(2)* and initial signal intensity (S(0)) based on the analysis of echo-time (TE) dependence. We hypothesized that if TE-dependence could be used to differentiate BOLD and non-BOLD signals, non-BOLD signal could be removed to denoise data without conventional noise modeling. To test this hypothesis, whole brain multi-echo data were acquired at 3 TEs and decomposed with Independent Components Analysis (ICA) after spatially concatenating data across space and TE. Components were analyzed for the degree to which their signal changes fit models for R(2)* and S(0) change, and summary scores were developed to characterize each component as BOLD-like or not BOLD-like. These scores clearly differentiated BOLD-like "functional network" components from non BOLD-like components related to motion, pulsatility, and other nuisance effects. Using non BOLD-like component time courses as noise regressors dramatically improved seed-based correlation mapping by reducing the effects of high and low frequency non-BOLD fluctuations. A comparison with seed-based correlation mapping using conventional noise regressors demonstrated the superiority of the proposed technique for both individual and group level seed-based connectivity analysis, especially in mapping subcortical-cortical connectivity. The differentiation of BOLD and non-BOLD components based on TE-dependence was highly robust, which allowed for the identification of BOLD-like components and the removal of non BOLD-like components to be implemented as a fully automated procedure.

title: Multi-echo fMRI: A review of applications in fMRI denoising and analysis of BOLD signals
abstract: &NA; In recent years the field of fMRI research has enjoyed expanded technical abilities related to resolution, as well as use across many fields of brain research. At the same time, the field has also dealt with uncertainty related to many known and unknown effects of artifact in fMRI data. In this review we discuss an emerging fMRI technology, called multi‐echo (ME)‐fMRI, which focuses on improving the fidelity and interpretability of fMRI. Where the essential problem of standard single‐echo fMRI is the indeterminacy of sources of signals, whether BOLD or artifact, this is not the case for ME‐fMRI. By acquiring multiple echo images per slice, the ME approach allows T2* decay to be modeled at every voxel at every time point. Since BOLD signals arise by changes in T2* over time, an fMRI experiment sampling the T2* signal decay can be analyzed to distinguish BOLD from artifact signal constituents. While the ME approach has a long history of use in theoretical and validation studies, modern MRI systems enable whole‐brain multi‐echo fMRI at high resolution. This review covers recent multi‐echo fMRI acquisition methods, and the analysis steps for this data to make fMRI at once more principled, straightforward, and powerful. After a brief overview of history and theory, T2* modeling and applications will be discussed. These applications include T2* mapping and combining echoes from ME data to increase BOLD contrast and mitigate dropout artifacts. Next, the modeling of fMRI signal changes to detect signal origins in BOLD‐related T2* versus artifact‐related S0 changes will be reviewed. A focus is on the use of ME‐fMRI data to extract and classify components from spatial ICA, called multi‐echo ICA (ME‐ICA). After describing how ME‐fMRI and ME‐ICA lead to a general model for analysis of fMRI signals, applications in animal and human imaging will be discussed. Applications include removing motion artifacts in resting state data at subject and group level. New imaging methods such as multi‐band multi‐echo fMRI and imaging at 7 T are demonstrated throughout the review, and a practical analysis pipeline is described. The review culminates with evidence from recent studies of major boosts in statistical power from using multi‐echo fMRI for detecting activation and connectivity in healthy individuals and patients with neuropsychiatric disease. In conclusion, the review shows evidence that the multi‐echo approach expands the range of experiments that is practicable using fMRI. These findings suggest a compelling future role of the multi‐echo approach in subject‐level and clinical fMRI. HighlightsAn emerging fMRI technology, multi‐echo (ME)‐fMRI, makes fMRI more interpretable by enabling the detection of BOLD or artifact origins of acquired signals.This review covers recent multi‐echo fMRI acquisition methods, and the analysis steps for this data that make fMRI at once more principled, straightforward, and powerful.After an overview of history and theory of ME‐fMRI, T2* modeling and applications is discussed.A focus is on the use of ME‐fMRI data to extract and classify components from spatial ICA, called multi‐echo ICA (ME‐ICA).New imaging methods such as multi‐band multi‐echo fMRI and imaging at 7 T are demonstrated throughout the review, and a practical analysis pipeline is described.

title: Resting-state fMRI confounds and cleanup
abstract: The goal of resting-state functional magnetic resonance imaging (fMRI) is to investigate the brain's functional connections by using the temporal similarity between blood oxygenation level dependent (BOLD) signals in different regions of the brain "at rest" as an indicator of synchronous neural activity. Since this measure relies on the temporal correlation of fMRI signal changes between different parts of the brain, any non-neural activity-related process that affects the signals will influence the measure of functional connectivity, yielding spurious results. To understand the sources of these resting-state fMRI confounds, this article describes the origins of the BOLD signal in terms of MR physics and cerebral physiology. Potential confounds arising from motion, cardiac and respiratory cycles, arterial CO₂ concentration, blood pressure/cerebral autoregulation, and vasomotion are discussed. Two classes of techniques to remove confounds from resting-state BOLD time series are reviewed: 1) those utilising external recordings of physiology and 2) data-based cleanup methods that only use the resting-state fMRI data itself. Further methods that remove noise from functional connectivity measures at a group level are also discussed. For successful interpretation of resting-state fMRI comparisons and results, noise cleanup is an often over-looked but essential step in the analysis pipeline.

title: Integrated strategy for improving functional connectivity mapping using multiecho fMRI
abstract: Functional connectivity analysis of resting state blood oxygen level–dependent (BOLD) functional MRI is widely used for noninvasively studying brain functional networks. Recent findings have indicated, however, that even small (≤1 mm) amounts of head movement during scanning can disproportionately bias connectivity estimates, despite various preprocessing efforts. Further complications for interregional connectivity estimation from time domain signals include the unaccounted reduction in BOLD degrees of freedom related to sensitivity losses from high subject motion. To address these issues, we describe an integrated strategy for data acquisition, denoising, and connectivity estimation. This strategy builds on our previously published technique combining data acquisition with multiecho (ME) echo planar imaging and analysis with spatial independent component analysis (ICA), called ME-ICA, which distinguishes BOLD (neuronal) and non-BOLD (artifactual) components based on linear echo-time dependence of signals—a characteristic property of BOLD signal changes. Here we show for 32 control subjects that this method provides a physically principled and nearly operator-independent way of removing complex artifacts such as motion from resting state data. We then describe a robust estimator of functional connectivity based on interregional correlation of BOLD-independent component coefficients. This estimator, called independent components regression, considerably simplifies statistical inference for functional connectivity because degrees of freedom equals the number of independent coefficients. Compared with traditional connectivity estimation methods, the proposed strategy results in fourfold improvements in signal-to-noise ratio, functional connectivity analysis with improved specificity, and valid statistical inference with nominal control of type 1 error in contrasts of connectivity between groups with different levels of subject motion.

title: Association of schizotypy with striatocortical functional connectivity and its asymmetry in healthy adults
abstract: Altered striatocortical functional connectivity has been suggested to be a trait marker of schizophrenia spectrum disorders, including schizotypal personality. In the present study, we examined the association between schizotypal personality traits and striatocortical functional connectivity in a sample of healthy adults. The German version of the Schizotypal Personality Questionnaire was obtained from N = 111 participants recruited from the general public. Resting‐state functional magnetic resonance imaging scans were acquired at 3T. Six striatal seed regions in each hemisphere were defined and striatocortical resting‐state functional connectivity (rsFC) as well as its lateralization indices was calculated. Regression analysis showed that schizotypy scores, especially from the positive dimension, were positively correlated with rsFC between ventral striatum and frontal cortex and negatively associated with rsFC between dorsal striatum and posterior cingulate. No significant associations were found between negative dimension schizotypy and striatocortical rsFC. We also found positive correlations between schizotypy total scores and lateralization index of right dorsal caudate and right rostral putamen. In conclusion, the present study extends previous evidence of altered striatocortical rsFC in the schizophrenia spectrum. The observed associations resemble in part the alterations observed in psychotic patients and their relatives, providing support for dimensionality from schizotypal personality to the clinical disorder.

title: The Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE): Further description and extended norms
abstract: The Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE) was introduced in 1995 as a four-scale questionnaire for measuring psychosis-proneness, principally schizotypy. Its items were deliberately chosen to make it suitable for tapping psychotic characteristics in healthy individuals. Since its inception the O-LIFE has been used in a wide variety of experimental and clinical studies, establishing its reliability and validity.



Data was pooled from 1926 participants together with available demographic information from several research institutions.



Extensive norms are presented by age and gender. Inter-correlations and regression equations based on age and gender are also presented.



The theoretical background and implications of work on using the O-LIFE are briefly discussed.

title: Neural processing of social rejection: The role of schizotypal personality traits
abstract: A fear of being rejected can cause perceptions of more insecurity and stress in close relationships. Healthy individuals activate the dorsal anterior cingulate cortex (dACC) when experiencing social rejection, while those who are vulnerable to depression deactivate the dACC presumably to downregulate salience of rejection cues and minimize distress. Schizotypal individuals, characterized by unusual perceptual experiences and/or odd beliefs, are more rejection sensitive than normal. We tested the hypothesis, for the first time, that individuals with high schizotypy also have an altered dACC response to rejection stimuli. Twenty‐six healthy individuals, 14 with low schizotypy (LS) and 12 with high schizotypy (HS), viewed depictions of rejection and acceptance and neutral scenes while undergoing functional MRI. Activation maps in LS and HS groups during each image type were compared using SPM5, and their relation to participant mood and subjective ratings of the images was examined. During rejection relative to neutral scenes, LS activated and HS deactivated the bilateral dACC, right superior frontal gyrus, and left ventral prefrontal cortex. Across both groups, a temporo‐occipito‐parieto‐cerebellar network was active during rejection, and a left fronto‐parietal network during acceptance, relative to neutral scenes, and the bilateral lingual gyrus during rejection relative to acceptance scenes. Our finding of dACC‐dorso‐ventral PFC activation in LS, but deactivation in HS individuals when perceiving social rejection scenes suggests that HS individuals attach less salience to and distance themselves from such stimuli. This may enable them to cope with their higher‐than‐normal sensitivity to rejection.

title: The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10.
abstract: The Mini-International Neuropsychiatric Interview (M.I.N.I.) is a short structured diagnostic interview, developed jointly by psychiatrists and clinicians in the United States and Europe, for DSM-IV and ICD-10 psychiatric disorders. With an administration time of approximately 15 minutes, it was designed to meet the need for a short but accurate structured psychiatric interview for multicenter clinical trials and epidemiology studies and to be used as a first step in outcome tracking in nonresearch clinical settings. The authors describe the development of the M.I.N.I. and its family of interviews: the M.I.N.I.-Screen, the M.I.N.I.-Plus, and the M.I.N.I.-Kid. They report on validation of the M.I.N.I. in relation to the Structured Clinical Interview for DSM-III-R, Patient Version, the Composite International Diagnostic Interview, and expert professional opinion, and they comment on potential applications for this interview.

title: Increased resting perfusion of the hippocampus in high positive schizotypy: A pseudocontinuous arterial spin labeling study
abstract: Arterial spin labeling (ASL) provides absolute quantification of resting tissue cerebral blood flow (CBF) as an entirely noninvasive approach with good reproducibility. As a result of neurovascular coupling, ASL provides a useful marker of resting neuronal activity. Recent ASL studies in individuals at clinical high risk of psychosis (CHR) have reported increased resting hippocampal perfusion compared with healthy controls. Schizotypy refers to the presence of subclinical psychotic‐like experiences in healthy individuals and represents a robust framework to study neurobiological mechanisms involved in the extended psychosis phenotype while avoiding potentially confounding effects of antipsychotic medications or disease comorbidity. Here we applied pseudo‐continuous ASL to examine differences in resting CBF in 21 subjects with high positive schizotypy (HS) relative to 22 subjects with low positive schizotypy (LS), as determined by the Oxford and Liverpool Inventory of Feelings and Experiences. Based on preclinical evidence that hippocampal hyperactivity leads to increased activity in mesostriatal dopamine projections, CBF in hippocampus, midbrain, and striatum was assessed. Participants with HS showed higher CBF of the right hippocampus compared to those with LS (p = .031, family‐wise error corrected). No differences were detected in the striatum or midbrain. The association between increased hippocampal CBF and HS supports the notion that hippocampal hyperactivity might be a central characteristic of the extended psychosis phenotype, while hyperactivity in subcortical dopamine pathways may only emerge at a higher intensity of psychotic experiences.

title: Corticolimbic hyper-response to emotion and glutamatergic function in people with high schizotypy: a multimodal fMRI-MRS study
abstract: Animal models and human neuroimaging studies suggest that altered levels of glutamatergic metabolites within a corticolimbic circuit have a major role in the pathophysiology of schizophrenia. Rodent models propose that prefrontal glutamate dysfunction could lead to amygdala hyper-response to environmental stress and underlie hippocampal overdrive in schizophrenia. Here we determine whether changes in brain glutamate are present in individuals with high schizotypy (HS), which refers to the presence of schizophrenia-like characteristics in healthy individuals, and whether glutamate levels are related to altered corticolimbic response to emotion. Twenty-one healthy HS subjects and 22 healthy subjects with low schizotypy (LS) were selected based on their Oxford and Liverpool Inventory of Feelings and Experiences rating. Glutamate levels were measured in the anterior cingulate cortex (ACC) using proton magnetic resonance spectroscopy, followed by a functional magnetic resonance imaging (fMRI) scan to measure corticolimbic response during emotional processing. fMRI results and fMRI × glutamate interactions were considered significant after voxel-wise P<0.05 family-wise error correction. While viewing emotional pictures, HS individuals showed greater activation than did subjects with LS in the caudate, and marginally in the ACC, hippocampus, medial prefrontal cortex (MPFC) and putamen. Although no between-group differences were found in glutamate concentrations, within the HS group ACC glutamate was negatively correlated with striatal activation (left: z=4.30, P=0.004 and right: z=4.12 P=0.008 caudate; left putamen: z=3.89, P=0.018) and marginally with MPFC (z=3.55, P=0.052) and amygdala (left: z=2.88, P=0.062; right: z=2.79, P=0.079), correlations that were not present in LS subjects. These findings provide, to our knowledge, the first evidence that brain glutamate levels are associated with hyper-responsivity in brain regions thought to be critical in the pathophysiology of psychosis.

title: The Social Functioning Questionnaire: a rapid and robust measure of perceived functioning.
abstract: The Social Functioning Questionnaire (SFQ), an eight-item self-report scale (score range 0-24), was developed from the Social Functioning Schedule (SFS), a semi-structured interview which has been used primarily with non-psychotic patients and has good test-retest and inter-rater reliability as well as construct validity. The SFQ was developed following the need for a quick assessment of perceived social function.



To give further details of old and new data sets from studies involving over 4000 subjects assessed with the SFQ illustrating its epidemiological and clinical associations.



New data were analysed from a national epidemiological study, a comparison of key-worker and subject versions of the SFQ, and reanalysis of data from three earlier clinical studies, of psychiatric emergencies, general practice psychiatric patients and those with recurrent psychotic illnesses. These data were examined further to determine their range, their relationship to other clinical measures, and change over time in clinical trials.



The population mean score in 4164 subjects was 4.6 and the data from all studies suggested that a score of 10 or more indicated poor social functioning. Those presenting as psychiatric emergencies had the poorest social function (mean 11.4) and psychiatric patients from general practice the best function (mean 7.7) of the clinical populations. The eight item scores had a normal distribution in psychiatric populations and a skewed one in a normal population; scores were relatively stable over the short (weeks) and long-term (months), and were high in the presence of acute mental health disturbance and personality disorder, giving support to the validity of the scale. The results from a UK sample of a randomly selected population specifically weighted for ethnic minorities showed similar social function across groups.

title: To cut a short test even shorter: Reliability and validity of a brief assessment of intellectual ability in Schizophrenia—a control-case family study
abstract: The potential inclusion of cognitive assessments in the DSM-V and large time-consuming assessments drive a need for short tests of cognitive impairments. We examined the reliability and validity of a brief, 15-minute, version of the Wechsler Adult Intelligence Scale–III (WAIS-III).  The sample consisted of patients diagnosed with schizophrenia (n=75), their siblings without schizophrenia (n=74) and unrelated healthy controls (n=84). A short WAIS-III consists of the Digit Symbol Coding subtest, and every second (or third) item of Block Design, Information, and Arithmetic. Psychometric analyses were implemented using item-response theory (IRT) to determine the best minimal item short version, while maintaining the sensitivity and reliability of the IQ score.  The proposed 15-minute WAIS-III gave reliable estimates of the Full Scale IQ (FSIQ) in all three groups in the sample. The 15-minute (select-item) version yielded an overall R of.95 (R2=.92) and IRT yielded an R of .96 (R2=.92). All four subtests performed well in differentiating patients, relatives, and healthy controls. Multivariate analysis showed a significant difference in FSIQ-estimate between patients, relatives, and healthy controls, F(2, 202) = 19.00, p < .0001. Regression modelling showed that the three versions of the WAIS had similar associations with functional outcome after a 3-year follow-up.  Our proposed 15-minute version of the WAIS may serve as a useful screening device for general intellectual ability in research or clinical settings, and is recommended when a quick and accurate IQ estimate is desired.

title: Study-specific EPI template improves group analysis in functional MRI of young and older adults
abstract: Spatial normalization to a common coordinate space, e.g. via the Montreal Neurological Institute (MNI) brain template, is an essential step of analyzing multi-subject functional MRI (fMRI) datasets. The imperfect compensation for individual regional discrepancies during spatial transformation, which could potentially introduce localization errors of the activation foci and/or reduce the detection sensitivity, may be minimized if a template specifically designed for the subjects of a study is applied. In this fMRI study, we proposed and evaluated the use of a study-specific template (SST) based on the mean of individually normalized echo-planar images for group data analysis. A hand flexion and a word generation tasks were performed on young volunteers in experiment 1. Comparing with the MNI template approach, greater t-values of local maxima and activated voxels were detected within volume-of-interests (VOIs) with the SST approach in both tasks. Moreover, the SST approach reduced Euclidean distances between activation foci of individuals and group by 1.52 mm in motor fMRI and 5.84 mm in language fMRI. Similar results were obtained with or without spatial smoothing of the echo-planar images. Experiment 2 further examined these two approaches in older adults, in which volumetric differences between subjects are of great concerns. With a working memory task, the SST approach showed greater t-values of local maxima and activated voxels within the VOI of prefrontal gyrus. This study demonstrated that the SST resulted in more focused activation patterns and effectively improved the fMRI sensitivity, which suggested potentials of reducing number of subjects required for group analysis.

title: Accurate and robust brain image alignment using boundary-based registration
abstract: The fine spatial scales of the structures in the human brain represent an enormous challenge to the successful integration of information from different images for both within- and between-subject analysis. While many algorithms to register image pairs from the same subject exist, visual inspection shows that their accuracy and robustness to be suspect, particularly when there are strong intensity gradients and/or only part of the brain is imaged. This paper introduces a new algorithm called Boundary-Based Registration, or BBR. The novelty of BBR is that it treats the two images very differently. The reference image must be of sufficient resolution and quality to extract surfaces that separate tissue types. The input image is then aligned to the reference by maximizing the intensity gradient across tissue boundaries. Several lower quality images can be aligned through their alignment with the reference. Visual inspection and fMRI results show that BBR is more accurate than correlation ratio or normalized mutual information and is considerably more robust to even strong intensity inhomogeneities. BBR also excels at aligning partial-brain images to whole-brain images, a domain in which existing registration algorithms frequently fail. Even in the limit of registering a single slice, we show the BBR results to be robust and accurate.

title: A global optimisation method for robust affine registration of brain images
abstract: Registration is an important component of medical image analysis and for analysing large amounts of data it is desirable to have fully automatic registration methods. Many different automatic registration methods have been proposed to date, and almost all share a common mathematical framework - one of optimising a cost function. To date little attention has been focused on the optimisation method itself, even though the success of most registration methods hinges on the quality of this optimisation. This paper examines the assumptions underlying the problem of registration for brain images using inter-modal voxel similarity measures. It is demonstrated that the use of local optimisation methods together with the standard multi-resolution approach is not sufficient to reliably find the global minimum. To address this problem, a global optimisation method is proposed that is specifically tailored to this form of registration. A full discussion of all the necessary implementation details is included as this is an important part of any practical method. Furthermore, results are presented for inter-modal, inter-subject registration experiments that show that the proposed method is more reliable at finding the global minimum than several of the currently available registration packages in common usage.

title: Selective Augmentation of Striatal Functional Connectivity Following NMDA Receptor Antagonism: Implications for Psychosis
abstract: The psychotomimetic effect of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine is thought to arise from a functional modulation of the brain’s fronto-striato-thalamic (FST) circuits. Animal models suggest a pronounced effect on ventral ‘limbic’ FST systems, although recent work in patients with psychosis and high-risk individuals suggests specific alterations of dorsal ‘associative’ FST circuits. Here, we used functional magnetic resonance imaging to investigate the effects of a subanesthetic dose of ketamine on measures of functional connectivity as indexed by the temporal coherence of spontaneous neural activity in both dorsal and ventral FST circuits, as well as their symptom correlates. We adopted a placebo-controlled, double-blind, randomized, repeated-measures design in which 19 healthy participants received either an intravenous saline infusion or a racemic mixture of ketamine (100 ng/ml) separated by at least 1 week. Compared with placebo, ketamine increased functional connectivity between the dorsal caudate and both the thalamus and midbrain bilaterally. Ketamine additionally increased functional connectivity of the ventral striatum/nucleus accumbens and ventromedial prefrontal cortex. Both connectivity increases significantly correlated with the psychosis-like and dissociative symptoms under ketamine. Importantly, dorsal caudate connectivity with the ventrolateral thalamus and subthalamic nucleus showed inverse correlation with ketamine-induced symptomatology, pointing to a possible resilience role to disturbances in FST circuits. Although consistent with the role of FST in mediating psychosis, these findings contrast with previous research in clinical samples by suggesting that acute NMDAR antagonism may lead to psychosis-like experiences via a mechanism that is distinct from that implicated in frank psychotic illness.

title: Functional connectivity of human striatum: a resting state FMRI study.
abstract: Classically regarded as motor structures, the basal ganglia subserve a wide range of functions, including motor, cognitive, motivational, and emotional processes. Consistent with this broad-reaching involvement in brain function, basal ganglia dysfunction has been implicated in numerous neurological and psychiatric disorders. Despite recent advances in human neuroimaging, models of basal ganglia circuitry continue to rely primarily upon inference from animal studies. Here, we provide a comprehensive functional connectivity analysis of basal ganglia circuitry in humans through a functional magnetic resonance imaging examination during rest. Voxelwise regression analyses substantiated the hypothesized motor, cognitive, and affective divisions among striatal subregions, and provided in vivo evidence of a functional organization consistent with parallel and integrative loop models described in animals. Our findings also revealed subtler distinctions within striatal subregions not previously appreciated by task-based imaging approaches. For instance, the inferior ventral striatum is functionally connected with medial portions of orbitofrontal cortex, whereas a more superior ventral striatal seed is associated with medial and lateral portions. The ability to map multiple distinct striatal circuits in a single study in humans, as opposed to relying on meta-analyses of multiple studies, is a principal strength of resting state functional magnetic resonance imaging. This approach holds promise for studying basal ganglia dysfunction in clinical disorders.

title: Altered corticostriatal functional connectivity in individuals with high social anhedonia
abstract: Dysregulation of the striatum and altered corticostriatal connectivity have been associated with psychotic disorders. Social anhedonia has been identified as a predictor for the development of schizophrenia spectrum disorders. The aim of the present study was to examine corticostriatal functional connectivity in individuals with high social anhedonia.  Twenty-one participants with high social anhedonia score and 30 with low social anhedonia score measured by the Chinese version of the Revised Social Anhedonia Scale were recruited from university undergraduates (age 17–21 years) to undergo resting-state functional MRI scans. Six subdivisions of the striatum in each hemisphere were defined as seeds. Voxel-wise functional connectivity analyses were conducted between each seed and the whole brain voxels, followed by repeated-measures ANOVA for the group effect.  Participants with high social anhedonia showed hyper-connectivity between the ventral striatum and the anterior cingulate cortex and the insula, and between the dorsal striatum and the motor cortex. Hypo-connectivity in participants with high social anhedonia was also observed between the ventral striatum and the posterior cingulate cortex. Partial correlation analyses further showed that the functional connectivity between the ventral striatum and the prefrontal cortex was associated with pleasure experience and emotional suppression.  Our findings suggest that altered corticostriatal connectivity can be found in participants with high levels of social anhedonia. Since social anhedonia has been considered a predictor for schizophrenia spectrum disorders, our results may provide novel evidence on the early changes in brain functional connectivity in at-risk individuals.

title: REST: A Toolkit for Resting-State Functional Magnetic Resonance Imaging Data Processing
abstract: Resting-state fMRI (RS-fMRI) has been drawing more and more attention in recent years. However, a publicly available, systematically integrated and easy-to-use tool for RS-fMRI data processing is still lacking. We developed a toolkit for the analysis of RS-fMRI data, namely the RESting-state fMRI data analysis Toolkit (REST). REST was developed in MATLAB with graphical user interface (GUI). After data preprocessing with SPM or AFNI, a few analytic methods can be performed in REST, including functional connectivity analysis based on linear correlation, regional homogeneity, amplitude of low frequency fluctuation (ALFF), and fractional ALFF. A few additional functions were implemented in REST, including a DICOM sorter, linear trend removal, bandpass filtering, time course extraction, regression of covariates, image calculator, statistical analysis, and slice viewer (for result visualization, multiple comparison correction, etc.). REST is an open-source package and is freely available at http://www.restfmri.net.

title: Regulation of firing of dopaminergic neurons and control of goal-directed behaviors
abstract: There are several brain regions that have been implicated in the control of motivated behavior and whose disruption leads to the pathophysiology observed in major psychiatric disorders. These systems include the ventral hippocampus, which is involved in context and focus on tasks, the amygdala, which mediates emotional behavior, and the prefrontal cortex, which modulates activity throughout the limbic system to enable behavioral flexibility. Each of these systems has overlapping projections to the nucleus accumbens, where these inputs are integrated under the modulatory influence of dopamine. Here, we provide a systems-oriented approach to interpreting the function of the dopamine system, its modulation of limbic-cortical interactions and how disruptions within this system might underlie the pathophysiology of schizophrenia and drug abuse.

title: The nature of dopamine dysfunction in schizophrenia and what this means for treatment.
abstract: Current drug treatments for schizophrenia are inadequate for many patients, and despite 5 decades of drug discovery, all of the treatments rely on the same mechanism: dopamine D(2) receptor blockade. Understanding the pathophysiology of the disorder is thus likely to be critical to the rational development of new treatments for schizophrenia.



To investigate the nature of the dopaminergic dysfunction in schizophrenia using meta-analysis of in vivo studies.



The MEDLINE, EMBASE, and PsycINFO databases were searched for studies from January 1, 1960, to July 1, 2011.



A total of 44 studies were identified that compared 618 patients with schizophrenia with 606 controls, using positron emission tomography or single-photon emission computed tomography to measure in vivo striatal dopaminergic function.



Demographic, clinical, and imaging variables were extracted from each study, and effect sizes were determined for the measures of dopaminergic function. Studies were grouped into those of presynaptic function and those of dopamine transporter and receptor availability. Sensitivity analyses were conducted to explore the consistency of effects and the effect of clinical and imaging variables.



There was a highly significant elevation (P.<001) in presynaptic dopaminergic function in schizophrenia with a large effect size (Cohen d=0.79). There was no evidence of alterations in dopamine transporter availability. There was a small elevation in D(2/3) receptor availability (Cohen d=0.26), but this was not evident in drug-naive patients and was influenced by the imaging approach used.



The locus of the largest dopaminergic abnormality in schizophrenia is presynaptic, which affects dopamine synthesis capacity, baseline synaptic dopamine levels, and dopamine release. Current drug treatments, which primarily act at D(2/3) receptors, fail to target these abnormalities. Future drug development should focus on the control of presynaptic dopamine synthesis and release capacity.

title: Correlation of individual differences in schizotypal personality traits with amphetamine-induced dopamine release in striatal and extrastriatal brain regions.
abstract: Schizotypal personality traits are associated with schizophrenia spectrum disorders, and individuals with schizophrenia spectrum disorders demonstrate increased dopamine transmission in the striatum. The authors sought to determine whether individual differences in normal variation in schizotypal traits are correlated with dopamine transmission in the striatum and in extrastriatal brain regions.



Sixty-three healthy volunteers with no history of psychiatric illness completed the Schizotypal Personality Questionnaire and underwent positron emission tomography imaging with [(18)F]fallypride at baseline and after administration of oral d-amphetamine (0.43 mg/kg). Dopamine release, quantified by subtracting each participant's d-amphetamine scan from his or her baseline scan, was correlated with Schizotypal Personality Questionnaire total and factor scores using region-of-interest and voxel-wise analyses.



Dopamine release in the striatum was positively correlated with overall schizotypal traits. The association was especially robust in the associative subdivision of the striatum. Voxel-wise analyses identified additional correlations between dopamine release and schizotypal traits in the left middle frontal gyrus and left supramarginal gyrus. Exploratory analyses of Schizotypal Personality Questionnaire factor scores revealed correlations between dopamine release and disorganized schizotypal traits in the striatum, thalamus, medial prefrontal cortex, temporal lobe, insula, and inferior frontal cortex.



The association between dopamine signaling and psychosis phenotypes extends to individual differences in normal variation in schizotypal traits and involves dopamine transmission in both striatal and extrastriatal brain regions. Amphetamine-induced dopamine release may be a useful endophenotype for investigating the genetic basis of schizophrenia spectrum disorders.

title: Altered functional and anatomical connectivity in schizophrenia.
abstract: Schizophrenia is characterized by a lack of integration between thought, emotion, and behavior. A disruption in the connectivity between brain processes may underlie this schism. Functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) were used to evaluate functional and anatomical brain connectivity in schizophrenia.



In all, 29 chronic schizophrenia patients (11 females, age: mean=41.3, SD=9.28) and 29 controls (11 females, age: mean=41.1, SD=10.6) were recruited. Schizophrenia patients were assessed for severity of negative and positive symptoms and general cognitive abilities of attention/concentration and memory. Participants underwent a resting-fMRI scan and a DTI scan. For fMRI data, a hybrid independent components analysis was used to extract the group default mode network (DMN) and accompanying time-courses. Voxel-wise whole-brain multiple regressions with corresponding DMN time-courses was conducted for each subject. A t-test was conducted on resulting DMN correlation maps to look between-group differences. For DTI data, voxel-wise statistical analysis of the fractional anisotropy data was carried out to look for between-group differences. Voxel-wise correlations were conducted to investigate the relationship between brain connectivity and behavioral measures.



Results revealed altered functional and anatomical connectivity in medial frontal and anterior cingulate gyri of schizophrenia patients. In addition, frontal connectivity in schizophrenia patients was positively associated with symptoms as well as with general cognitive ability measures.



The present study shows convergent fMRI and DTI findings that are consistent with the disconnection hypothesis in schizophrenia, particularly in medial frontal regions, while adding some insight of the relationship between brain disconnectivity and behavior.

title: A Review of the Functional and Anatomical Default Mode Network in Schizophrenia
abstract: Schizophrenia is a severe mental disorder characterized by impaired perception, delusions, thought disorder, abnormal emotion regulation, altered motor function, and impaired drive. The default mode network (DMN), since it was first proposed in 2001, has become a central research theme in neuropsychiatric disorders, including schizophrenia. In this review, first we define the DMN and describe its functional activity, functional and anatomical connectivity, heritability, and inverse correlation with the task positive network. Second, we review empirical studies of the anatomical and functional DMN, and anti-correlation between DMN and the task positive network in schizophrenia. Finally, we review preliminary evidence about the relationship between antipsychotic medications and regulation of the DMN, review the role of DMN as a treatment biomarker for this disease, and consider the DMN effects of individualized therapies for schizophrenia.

title: Treatment with Olanzapine is Associated with Modulation of the Default Mode Network in Patients with Schizophrenia
abstract: Earlier studies have shown widespread alterations of functional connectivity of various brain networks in schizophrenia, including the default mode network (DMN). The DMN has also an important role in the performance of cognitive tasks. Furthermore, treatment with second-generation antipsychotic drugs may ameliorate to some degree working memory (WM) deficits and related brain activity. The aim of this study was to evaluate the effects of treatment with olanzapine monotherapy on functional connectivity among brain regions of the DMN during WM. Seventeen patients underwent an 8-week prospective study and completed two functional magnetic resonance imaging (fMRI) scans at 4 and 8 weeks of treatment during the performance of the N-back WM task. To control for potential repetition effects, 19 healthy controls also underwent two fMRI scans at a similar time interval. We used spatial group-independent component analysis (ICA) to analyze fMRI data. Relative to controls, patients with schizophrenia had reduced connectivity strength within the DMN in posterior cingulate, whereas it was greater in precuneus and inferior parietal lobule. Treatment with olanzapine was associated with increases in DMN connectivity with ventromedial prefrontal cortex, but not in posterior regions of DMN. These results suggest that treatment with olanzapine is associated with the modulation of DMN connectivity in schizophrenia. In addition, our findings suggest critical functional differences in the regions of DMN.

title: DRD2 genotype-based variation of default mode network activity and of its relationship with striatal DAT binding.
abstract: The default mode network (DMN) comprises a set of brain regions with "increased" activity during rest relative to cognitive processing. Activity in the DMN is associated with functional connections with the striatum and dopamine (DA) levels in this brain region. A functional single-nucleotide polymorphism within the dopamine D2 receptor gene (DRD2, rs1076560 G > T) shifts splicing of the 2 D2 isoforms, D2 short and D2 long, and has been associated with striatal DA signaling as well as with cognitive processing. However, the effects of this polymorphism on DMN have not been explored. The aim of this study was to evaluate the effects of rs1076560 on DMN and striatal connectivity and on their relationship with striatal DA signaling. Twenty-eight subjects genotyped for rs1076560 underwent functional magnetic resonance imaging during a working memory task and 123 55 I-Fluoropropyl-2-beta-carbomethoxy-3-beta(4-iodophenyl) nortropan Single Photon Emission Computed Tomography ([(123)I]-FP-CIT SPECT) imaging (a measure of dopamine transporter [DAT] binding). Spatial group-independent component (IC) analysis was used to identify DMN and striatal ICs. Within the anterior DMN IC, GG subjects had relatively greater connectivity in medial prefrontal cortex (MPFC), which was directly correlated with striatal DAT binding. Within the posterior DMN IC, GG subjects had reduced connectivity in posterior cingulate relative to T carriers. Additionally, rs1076560 genotype predicted connectivity differences within a striatal network, and these changes were correlated with connectivity in MPFC and posterior cingulate within the DMN. These results suggest that genetically determined D2 receptor signaling is associated with DMN connectivity and that these changes are correlated with striatal function and presynaptic DA signaling.

title: The Infralimbic Cortex Bidirectionally Modulates Mesolimbic Dopamine Neuron Activity via Distinct Neural Pathways
abstract: The ventral tegmental area (VTA) has been implicated in a number of psychiatric disorders, including schizophrenia, depression, and bipolar disorder. One major regulator of the mesolimbic dopaminergic system is the medial prefrontal cortex (mPFC), which makes direct and indirect connections to the hippocampus and amygdala, as well as directly to the VTA. The mPFC is comprised of two subregions: the infralimbic and prelimbic cortices (ilPFC and plPFC). However, the specific roles of these subregions in regulating VTA dopamine activity have remained unclear. In this study, we aim to clarify this role and to examine the divergent neuranatomical circuits by which the mPFC regulates VTA activity. Using in vivo extracellular recordings in rats, we tested the effects of pharmacological activation (with NMDA) and inactivation (with TTX) of the ilPFC and plPFC on dopamine neuron activity, and tested the roles of the ventral subiculum (vSub) and basolateral amygdala in this process. We found that the ilPFC exerts a bidirectional control of VTA dopamine neurons, which are differentially modulated through the vSub and the basolateral amygdala. Specifically, activation or inactivation of the ilPFC attenuated or activated dopamine neuron population activity, respectively. Furthermore, dopamine activation depended on the ventral hippocampus and inactivation on the amygdala. In contrast, only inactivation of the plPFC altered dopamine neuron activity. These data indicate that the mPFC has the ability to uniquely fine-tune dopaminergic activity in the VTA. Furthermore, the data presented here suggest that the ilPFC may have a role in the pathophysiology of psychiatric disorders.

title: The Nucleus Reuniens of the Midline Thalamus Gates Prefrontal-Hippocampal Modulation of Ventral Tegmental Area Dopamine Neuron Activity
abstract: The circuitry mediating top-down control of dopamine (DA) neurons in the ventral tegmental area (VTA) is exceedingly complex. Characterizing these networks will be critical to our understanding of fundamental behaviors, such as motivation and reward processing, as well as several disease states. Previous work suggests that the medial prefrontal cortex (mPFC) exerts a profound influence on VTA DA neuron firing. Recently, our group reported that inhibition of the infralimbic subdivision of the medial prefrontal cortex (ilPFC) increases the proportion of VTA DA neurons that are spontaneously active (i.e., “population activity”) and that this effect depends on activity in the ventral subiculum of the hippocampus (vSub). However, there is no direct projection from the mPFC to the vSub. Anatomical evidence suggests that communication between the two structures is mediated by the nucleus reuniens of the midline thalamus (RE). Here, we used in vivo electrophysiological and behavioral approaches in rats to explore the role of the RE in the circuitry governing VTA DA neuron firing. We show that pharmacological stimulation of the RE enhances VTA DA neuron population activity and amphetamine-induced hyperlocomotion, a behavioral indicator of an over-responsive DA system. Furthermore, the effect of RE stimulation on population activity is prevented if vSub is also inhibited. Finally, pharmacological inhibition of ilPFC enhances VTA DA neuron population activity, but this effect does not occur if RE is also inhibited. These findings suggest that disruption of ilPFC–RE–vSub communication could lead to a dysregulated, hyperdopaminergic state, and may play a role in psychiatric disorders.  Dopamine (DA) neurons in the ventral tegmental area (VTA) are involved in a variety of fundamental brain functions. To understand the neurobiological basis for these functions it is essential to identify regions controlling DA neuron activity. The medial prefrontal cortex (mPFC) is emerging as a key regulator of DA neuron activity, but the circuitry by which it exerts its influence remains poorly described. Here, we show that the nucleus reuniens of the midline thalamus gates mPFC control of VTA DA neuron firing by the hippocampus. These data identify a unique role for this corticothalamic-hippocampal circuit, and suggest that dysfunction in these regions likely influences the pathophysiology of psychiatric disorders.

title: Increased Resting Hippocampal and Basal Ganglia Perfusion in People at Ultra High Risk for Psychosis: Replication in a Second Cohort
abstract: We recently reported that resting hippocampal, basal ganglia and midbrain perfusion is elevated in people at ultra high risk (UHR) for psychosis. The present study sought to replicate our previous finding in an independent UHR cohort, and examined the relationship between resting perfusion in these regions, psychosis and depression symptoms, and traumatic experiences in childhood. Pseudo-Continuous Arterial Spin Labelling (p-CASL) imaging was used to measure resting cerebral blood flow (rCBF) in 77 UHR for psychosis individuals and 25 healthy volunteers in a case-control design. UHR participants were recruited from clinical early detection services at 3 sites in the South of England. Symptoms levels were assessed using the Comprehensive Assessment of At Risk Mental States (CAARMS), the Hamilton Depression Scale (HAM-D), and childhood trauma was assessed retrospectively using the Childhood Trauma Questionnaire (CTQ). Right hippocampal and basal ganglia rCBF were significantly increased in UHR subjects compared to controls, partially replicating our previous finding in an independent cohort. In UHR participants, positive symptoms were positively correlated with rCBF in the right pallidum. CTQ scores were positively correlated with rCBF values in the bilateral hippocampus and negatively associated with rCBF in the left prefrontal cortex. Elevated resting hippocampal and basal ganglia activity appears to be a consistent finding in individuals at high risk for psychosis, consistent with data from preclinical models of the disorder. The association with childhood trauma suggests that its influence on the risk of psychosis may be mediated through an effect on hippocampal function.

title: Imaging Patients with Psychosis and a Mouse Model Establishes a Spreading Pattern of Hippocampal Dysfunction and Implicates Glutamate as a Driver
abstract: VIDEO 
The hippocampus in schizophrenia is characterized by both hypermetabolism and reduced size. It remains unknown whether these abnormalities are mechanistically linked. Here we addressed this question by using MRI tools that can map hippocampal metabolism and structure in patients and mouse models. In at-risk patients, hypermetabolism was found to begin in CA1 and spread to the subiculum after psychosis onset. CA1 hypermetabolism at baseline predicted hippocampal atrophy, which occurred during progression to psychosis, most prominently in similar regions. Next, we used ketamine to model conditions of acute psychosis in mice. Acute ketamine reproduced a similar regional pattern of hypermetabolism, while repeated exposure shifted the hippocampus to a hypermetabolic basal state with concurrent atrophy and pathology in parvalbumin-expressing interneurons. Parallel in vivo experiments using the glutamate-reducing drug LY379268 and direct measurements of extracellular glutamate showed that glutamate drives both neuroimaging abnormalities. These findings show that hippocampal hypermetabolism leads to atrophy in psychotic disorder and suggest glutamate as a pathogenic driver.

title: Prediction of psychopathology and functional impairment by positive and negative schizotypy in the Chapmans' ten-year longitudinal study.
abstract: The present study examined the predictive validity of psychometrically assessed positive and negative schizotypy in the Chapmans' 10-year longitudinal data set. Schizotypy provides a useful construct for understanding the etiology and development of schizophrenia and related disorders. Schizotypy and schizophrenia share a common multidimensional structure that includes positive and negative symptom dimensions. Recent cross-sectional studies have supported the validity of psychometric positive and negative schizotypy; however, the present study is the first to examine the predictive validity of these dimensions. The Chapmans' longitudinal data provided an ideal opportunity because of the large sample size, high reassessment rate, and extended interval between assessments. A total of 534 psychometric high-risk and control participants were initially assessed, and 95% of this sample was reinterviewed 10 years later. As hypothesized, positive and negative schizotypy uniquely predicted the development of schizophrenia-spectrum disorders. At the reassessment, both positive and negative schizotypy predicted psychotic-like, schizotypal, and paranoid symptoms, as well as poorer adjustment. The positive dimension was associated with mood and substance use disorders and mental health treatment. Negative schizotypy was associated with schizoid symptoms and social impairment at the follow-up. The results extend the growing validity findings for psychometrically assessed positive and negative schizotypy by demonstrating that they are associated with the development of differential patterns of symptoms and impairment.