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1.  Deficient Suppression of Default Mode Regions during Working Memory in Individuals with Early Psychosis and at Clinical High-Risk for Psychosis 
Background: The default mode network (DMN) is a set of brain regions typically activated at rest and suppressed during extrinsic cognition. Schizophrenia has been associated with deficient DMN suppression, though the extent to which DMN dysfunction predates psychosis onset is unclear. This study examined DMN suppression during working memory (WM) performance in youth at clinical high-risk (CHR) for psychosis, early schizophrenia (ESZ) patients, and healthy controls (HC). We hypothesized that the DMN would show load-dependent suppression during WM retrieval in HC but not in ESZ, with CHR participants showing an intermediate pattern.
Methods: fMRI data were collected from CHR (n = 32), ESZ (n = 22), and HC (n = 54) participants, ages 12–30. DMN regions were defined via seed-based connectivity analysis of resting-state fMRI data from an independent HC sample. Load-dependent deactivations of these DMN regions in response to WM probes were interrogated.
Results: Healthy controls showed linear load-dependent increases in DMN deactivation. Significant Group-by-Load interactions were observed in DMN regions including medial prefrontal and lateral posterior parietal cortices. Group-by-Load effects in posterior DMN nodes resulted from less suppression at higher WM loads in ESZ relative to HC, with CHR differing from neither group. In medial prefrontal cortex, suppression of activity at higher WM loads was significantly diminished in both CHR and ESZ groups, relative to HC. In addition, investigation of dorsolateral prefrontal cortex (DLPFC) activations revealed that ESZ activated right DLPFC significantly more than HC, with CHR differing from neither group.
Conclusion: While HC showed WM load-dependent modulation of DMN suppression, CHR individuals had deficient higher-load DMN suppression that was similar to, but less pronounced than, the distributed suppression deficits evident in ESZ patients. These results suggest that DMN dysregulation associated with schizophrenia predates psychosis onset.
doi:10.3389/fpsyt.2013.00092
PMCID: PMC3768116  PMID: 24032017
schizophrenia prodrome; ultra-high-risk youth; dorsolateral prefrontal cortex; fMRI task-induced deactivation; adolescent mental health
2.  Altered Age-Related Trajectories of Amygdala-Prefrontal Circuitry in Adolescents at Clinical High Risk for Psychosis: A Preliminary Study 
Schizophrenia research  2011;134(1):1-9.
Emotion processing deficits are prominent in schizophrenia and exist prior to the onset of overt psychosis. However, developmental trajectories of neural circuitry subserving emotion regulation and the role that they may play in illness onset have not yet been examined in patients at risk for psychosis. The present study employed a cross-sectional analysis to examine age-related functional activation in amygdala and prefrontal cortex, as well as functional connectivity between these regions, in adolescents at clinical high risk (CHR) for psychosis relative to typically developing adolescents. Participants (n=34) performed an emotion processing fMRI task, including emotion labeling, emotion matching, and non-emotional control conditions. Regression analyses were used to predict activation in the amygdala and ventrolateral prefrontal cortex (vlPFC) based on age, group, sex, and the interaction of age by group. CHR adolescents exhibited altered age-related variation in amygdala and vlPFC activation, relative to controls. Controls displayed decreased amygdala and increased vlPFC activation with age, while patients exhibited the opposite pattern (increased amygdala and decreased vlPFC activation), suggesting a failure of prefrontal cortex to regulate amygdala reactivity. Moreover, a psychophysiological interaction analysis revealed decreased amygdala-prefrontal functional connectivity among CHR adolescents, consistent with disrupted brain connectivity as a vulnerability factor in schizophrenia. These results suggest that the at-risk syndrome is marked by abnormal development and functional connectivity of neural systems subserving emotion regulation. Longitudinal data are needed to confirm aberrant developmental trajectories intra-individually and to examine whether these abnormalities are predictive of conversion to psychosis, and of later deficits in socioemotional functioning.
doi:10.1016/j.schres.2011.10.005
PMCID: PMC3245800  PMID: 22056201
psychosis; brain development; emotion; amygdala; prefrontal cortex; fMRI
3.  Neuropsychological Profiles in Individuals at Clinical High Risk for Psychosis: Relationship to Psychosis and Intelligence 
Schizophrenia research  2010;123(2-3):188-198.
Background
Characterizing neuropsychological (NP) functioning of individuals at clinical high risk (CHR) for psychosis may be useful for prediction of psychosis and understanding functional outcome. The degree to which NP impairments are associated with general cognitive ability and/or later emergence of full psychosis in CHR samples requires study with well-matched controls.
Methods
We assessed NP functioning across eight cognitive domains in a sample of 73 CHR youth, 13 of whom developed psychotic-level symptoms after baseline assessment, and 34 healthy comparison (HC) subjects. Groups were matched on age, sex, ethnicity, handedness, subject and parent grade attainment, and median family income, and were comparable on WRAT-3 Reading, an estimate of premorbid IQ. Profile analysis was used to examine group differences and the role of IQ in profile shape.
Results
The CHR sample demonstrated a significant difference in overall magnitude of NP impairment but only a small and nearly significant difference in profile shape, primarily due to a large impairment in olfactory identification. Individuals who subsequently developed psychotic-level symptoms demonstrated large impairments in verbal IQ, verbal memory and olfactory identification comparable in magnitude to first episode samples.
Conclusions
CHR status may be associated with moderate generalized cognitive impairments marked by some degree of selective impairment in olfaction and verbal memory. Impairments were greatest in those who later developed psychotic symptoms. Future study of olfaction in CHR samples may enhance early detection and specification of neurodevelopmental mechanisms of risk.
doi:10.1016/j.schres.2010.06.021
PMCID: PMC2964352  PMID: 20692125
Schizophrenia; Prodrome; Cognition; Ultra High Risk; Neurocognitive Functioning; IQ
4.  Neuropsychology of the Prodrome to Psychosis in the NAPLS Consortium: Relationship to Family History and Conversion to Psychosis 
Archives of General Psychiatry  2010;67(6):578-588.
Context
Early detection and prospective evaluation of clinical high-risk (CHR) individuals who may develop schizophrenia or other psychotic disorders is critical for predicting psychosis onset and for testing preventive interventions.
Objective
To elucidate the neuropsychology of the CHR syndrome, to determine the association of neuropsychological function with conversion to psychosis and family history (FH) of psychosis, and to examine whether baseline neuropsychological functioning predicts subsequent psychosis.
Design, Setting, and Participants
Longitudinal study with 2 1/2 years follow-up of 304 prospectively identified CHR individuals meeting Structured Interview for Prodromal Syndromes (SIPS) criteria, 52 non-CHR persons with a FH of psychosis in first- or second-degree relatives (“family HR”/FHR), and 193 normal controls with neither a FH of psychosis nor a CHR syndrome, all of whom had baseline neuropsychological evaluations, recruited across eight centers as part of the North American Prodrome Longitudinal Study (NAPLS).
Main Measures
A neurocognitive composite score, eight individual neuropsychological measures, an IQ estimate, and HR status.
Results
Global (“composite”) neuropsychological functioning was comparably impaired in CHR and FHR groups compared to controls, but profiles differed significantly between groups. Neuropsychological functioning in the CHR group was significantly lower in persons who progressed to psychosis than in those who did not, and worst in the subgroup with a FH of psychosis. Tests of processing speed and verbal learning and memory were most sensitive in discriminating CHR from controls, although reductions were less severe than in established schizophrenia. Neuropsychological functioning did not contribute uniquely to the prediction of psychosis beyond clinical criteria, but worse verbal memory predicted more rapid conversion.
Conclusion
These findings document that CHR individuals have significant neuropsychological difficulties, particularly those who later develop psychosis. This dysfunction is generally of moderate severity but less than in first episode schizophrenia, suggesting that a further decline may occur after baseline CHR assessment.
doi:10.1001/archgenpsychiatry.2010.66
PMCID: PMC3332118  PMID: 20530007
5.  Exploring Predictors of Outcome in the Psychosis Prodrome: Implications for Early Identification and Intervention 
Neuropsychology Review  2009;19(3):280-293.
Functional disability is a key component of many psychiatric illnesses, particularly schizophrenia. Impairments in social and role functioning are linked to cognitive deficits, a core feature of psychosis. Retrospective analyses demonstrate that substantial functional decline precedes the onset of psychosis. Recent investigations reveal that individuals at clinical-high-risk (CHR) for psychosis show impairments in social relationships, work/school functioning and daily living skills. CHR youth also demonstrate a pattern of impairment across a range of cognitive domains, including social cognition, which is qualitatively similar to that of individuals with schizophrenia. While many studies have sought to elucidate predictors of clinical deterioration, specifically the development of schizophrenia, in such CHR samples, few have investigated factors relevant to psychosocial outcome. This review integrates recent findings regarding cognitive and social-cognitive predictors of outcome in CHR individuals, and proposes potential directions for future research that will contribute to targeted interventions and improved outcome for at-risk youth.
doi:10.1007/s11065-009-9108-z
PMCID: PMC2745530  PMID: 19597747
Schizophrenia; Prodrome; Ultra-high-risk; Social cognition; Clinical high-risk; Psychosocial functioning; Functional outcome; Neurocognition
6.  Prospective Study of Cannabis Use in Adolescents at Clinical High-Risk for Psychosis: Impact on Conversion to Psychosis and Functional Outcome 
Psychological medicine  2012;42(12):2485-2497.
Background
Clinical and epidemiological studies suggest an association between cannabis use and psychosis, but this relationship remains controversial.
Methods
Clinical High-Risk (CHR) subjects (age 12–22) with attenuated positive symptoms of psychosis (CHR+, n=101) were compared to healthy controls (HC, n=59) on rates of substance use, including cannabis. CHR+ subjects with and without lifetime cannabis use (and abuse) were compared on prodromal symptoms and social/role functioning at baseline. Participants were followed an average of 2.97 years to determine psychosis conversion status and functional outcome.
Results
At baseline, CHR+ subjects had significantly higher rates of lifetime cannabis use than HC subjects. CHR+ lifetime cannabis users (N=35) were older (p=0.015, trend), more likely Caucasian (p=0.002), less socially anhedonic (p<0.001), and had higher Global Functioning (GF):Social scores (p<0.001) than non-users (N=61). CHR+ cannabis users continued to have higher social functioning than non-users at follow-up (p<0.001), but no differences on role functioning. A small sample of CHR+ cannabis abusers (N=10) showed similar results in that abusers were older (p=0.008), less socially anhedonic (p=0.017, trend), and had higher baseline GF:Social scores (p=0.006) than non-abusers. Logistic regression analyses revealed that conversion to psychosis in CHR+ subjects (N=15) was not related to lifetime cannabis use or abuse.
Conclusions
The current data do not support low to moderate lifetime cannabis use to be a major contributor to psychosis or poor social and role functioning in high-risk youth.
doi:10.1017/S0033291712000803
PMCID: PMC3459073  PMID: 22716931
Cannabis use; high-risk; prodrome; social functioning; conversion; psychosis
7.  Social Functioning in Individuals at Clinical High Risk for Psychosis 
Schizophrenia research  2007;99(1-3):119-124.
Poor social functioning is a hallmark of schizophrenia. The purpose of this study was to examine social functioning in individuals at clinical high risk for psychosis. Social functioning was assessed in a sample of 86 clinical high risk (CHR) individuals and compared to that of 50 first-episode of psychosis (FE) subjects, 53 multi-episode schizophrenia subjects (ME) and 55 non-psychiatric controls (NPC). Subjects were assessed on the Social Functioning Scale (SFS), the Role Functioning subscale of the Quality of Life Scale (QLS-role), and the premorbid functioning scale. On the SFS, the CHR group did not differ significantly from the FE and ME groups and all were impaired relative to the NPCs. On QLS-role, the CHR group performed significantly better than the ME patients and significantly worse than NPCs. CHR subjects did not differ from patients in terms of premorbid functioning. This study demonstrates that even at the pre-psychotic phase of the illness, these young people are demonstrating significant deficits in social functioning, supporting that social deficits are present long before the onset of psychotic symptoms.
doi:10.1016/j.schres.2007.10.001
PMCID: PMC2292799  PMID: 18023329
clinical high risk; prodrome; early psychosis; schizophrenia; social functioning; role functioning
8.  Thought Disorder and Communication Deviance as Predictors of Outcome in Youth at Clinical High Risk for Psychosis 
Objective
Given the fundamental role of thought disorder in schizophrenia, subtle communication disturbance may be a valuable predictor of subsequent development of psychosis. Here we examined the contribution of thought and communication disturbance to the prediction of outcome in adolescents identified as putatively prodromal for psychosis.
Method
Transcribed speech samples were elicited from 105 adolescents (54 identified as being at clinical high risk for a first episode of psychosis (CHR) and 51 demographically comparable comparison subjects) and coded for formal thought disorder (FTD) and linguistic cohesion. We then examined the association of baseline FTD/cohesion with conversion to psychosis and social and role outcome at follow-up, approximately one year later.
Results
At baseline, CHR patients who subsequently converted to psychosis (CHR+) showed an elevated rate of illogical thinking and poverty of content (POC) in their speech, relative to both typically developing controls and non-converters (CHR−). CHR+ youth also used significantly less referential cohesion at baseline, indicating that they provide fewer references to people, objects, or events mentioned in preceding utterances. Multiple regression models indicated that, among measures of FTD/cohesion, illogical thinking was uniquely predictive of subsequent conversion to psychosis, whereas POC and referential cohesion were significant predictors of social and role functioning, respectively.
Conclusions
Despite the absence of fully psychotic symptoms, putatively prodromal individuals evidence signs of communication disturbance that are qualitatively similar to those seen in schizophrenia, and are predictive of both conversion to psychosis and psychosocial outcome. These findings suggest that FTD measures have prognostic significance for at-risk youth.
doi:10.1016/j.jaac.2011.03.021
PMCID: PMC3124656  PMID: 21703494
thought disorder; psychosis prodrome; schizophrenia; language; psychosocial outcome
9.  Theory of Mind in Patients at Clinical High Risk for Psychosis 
Schizophrenia research  2011;131(1-3):11-17.
Background
Patients with schizophrenia have a decreased ability to interpret the intentions of other individuals, called Theory of Mind (ToM). As capacity for ToM normally advances with brain maturation, research on ToM in individuals at heightened clinical risk for psychosis may reveal developmental differences independent of disease based differences.
Methods
We examined ToM in at clinical high risk and schizophrenia patients as well as healthy controls: 1) 63 clinical high risk (CHR) patients and 24 normal youths ascertained by a CHR program; and 2) in 13 schizophrenia cases and 14 normal adults recruited through a schizophrenia program. ToM measures included first- and second-order false belief cartoon tasks (FBT) and two “higher order” tasks (“Strange Stories Task” (SST) and the “Reading the Mind in the Eyes” task). In the first study, CHR patients and normal youths were also assessed for cognition, “prodromal” symptoms and social function.
Results
Errors on first- and second-order false belief tasks were made primarily by patients. CHR patients and their young comparison group had equivalent performance on higher order ToM, which was not significantly different from the worse ToM performance of schizophrenia patients and the higher performance of normal adult controls. In the combined dataset from both studies, all levels of ToM were associated with IQ, controlling for age and sex. ToM bore no relation to explicit memory, prodromal symptoms, social function, or later transition to psychosis.
Conclusions
Higher order ToM capacity was equally undeveloped in high risk cases and younger controls, suggesting performance on these tasks is not fully achieved until adulthood. This study also replicates the association of IQ with ToM performance described in previous studies of schizophrenia.
doi:10.1016/j.schres.2011.06.005
PMCID: PMC3159813  PMID: 21757324
psychosis; theory of mind; IQ; risk; prodrome
10.  Affect Recognition in People at Clinical High Risk of Psychosis 
Schizophrenia research  2012;140(1-3):87-92.
Individuals with schizophrenia demonstrate stable deficits in affect recognition. Similar deficits in affect recognition have been observed in those who are at clinical high risk (CHR) of developing psychosis. The current project aimed to longitudinally examine affect processing in CHR individuals, to determine if affect processing predicted later conversion to psychosis and if affect processing deficits were unique to those who met established criteria for prodromal syndromes. The sample consisted of 172 CHR and 100 help-seeking individuals (HS) who were followed for up to 24 months. All CHR individuals met the Criteria of Prodromal States (COPS) based on the Structured Interview for Prodromal Symptoms (SIPS). The SIPS was used to determine conversion to psychosis. Affect recognition was assessed using two facial affect recognition tasks and a measure of affective prosody. In comparison to previously published data from non-psychiatric controls, both CHR and HS groups demonstrated deficits on affect recognition. By 2 years 25 CHR participants converted to psychosis. Interestingly, there were no differences between converters and non-converters on any affect recognition tasks. This is one of the first studies to longitudinally examine affect processing and its relationship to later conversion to psychosis in individuals at-risk for psychosis. While poorer affect recognition may be associated with vulnerability for psychosis, the current results suggest that it may not be a marker of developing a psychotic illness.
doi:10.1016/j.schres.2012.06.012
PMCID: PMC3460803  PMID: 22763425
psychosis prodrome; social cognition; affect recognition; facial affect; affective prosody
11.  Error Monitoring Dysfunction Across the Illness Course of Schizophrenia 
Journal of Abnormal Psychology  2011;121(2):372-387.
Response monitoring abnormalities have been reported in chronic schizophrenia patients, but it is unknown whether they predate the onset of psychosis, are present in early stages of illness, or are late-developing abnormalities associated with illness progression. Response-synchronized event-related potentials (ERP) recorded during a picture-word matching task yielded error-related negativity (ERN), correct-response negativity (CRN), and error positivity (Pe) from 84 schizophrenia patients (SZ), 48 clinical high risk patients (CHR), and their age-matched healthy controls (HC; n = 110 and 88, respectively). A sub-sample of 35 early illness schizophrenia patients (ESZ) was compared to 93 age-matched HC and the CHR patients (after statistically removing the effects of normal aging). Relative to HC, 1) SZ, ESZ, and CHR had smaller ERNs, and 2) SZ and ESZ had larger CRNs and smaller Pes. Within the SZ, longer illness duration was associated with larger CRNs but was unrelated to ERN or Pe. CHR and ESZ did not differ on ERN or CRN, although Pe was smaller in ESZ than CHR. These results indicate that while ERN, CRN, and Pe abnormalities are present early in the illness, only the ERN abnormality is evident prior to psychosis onset, and only the CRN abnormality appears to worsen progressively over the illness course. Brain regions subserving response monitoring may be compromised early in the illness and possibly during its clinical prodrome.
doi:10.1037/a0025487
PMCID: PMC3358508  PMID: 22060947
schizophrenia; prodrome; at-risk; error-related negativity; performance monitoring
12.  From lumping to splitting and back again: Atypical social and language development in individuals with clinical-high-risk for psychosis, first episode schizophrenia, and autism spectrum disorders 
Schizophrenia research  2011;131(1-3):146-151.
Objective
Individuals with autism and schizophrenia exhibit atypical language and social symptoms. The extent to which these symptoms are evident during development and in current functioning is unclear.
Method
Three groups of patients aged 11–20 diagnosed as clinical-high-risk for psychosis (CHR; n = 15), first episode psychosis (FEP; n = 16), and autism spectrum disorders (ASD; n = 20), plus typically developing individuals (TYP; n = 20) were compared on common autism parent-report questionnaires assessing social and language development and current functioning including the Social Communication Questionnaire, the Children’s Communication Checklist, and the Social Reciprocity Scale.
Results
All clinical groups demonstrated atypical social and language development, with social impairment highest in ASD. Twenty percent of participants with CHR and FEP met diagnostic criteria for ASD as assessed by parent-report. ASD exhibited greater current syntactic, and pragmatic language symptoms including delayed echolalia, pedantic speech, and deficits in appreciating irony and sarcasm. All clinical groups exhibited current deficits in social functioning. CHR and FE had similar and intermediate levels of functioning relative to ASD and TYP, with CHR generally scoring closer to TYP, providing construct validity for the CHR diagnostic label.
Conclusions
The results of this study suggest that ASDs, CHR, and FEP share common features of atypical neurodevelopment of language and social function. Evidence of impaired social reciprocity across both disorders and distinct language symptoms in ASDs provides important information for differential diagnosis and psychosis prevention, as well as leads for future investigations of comparative genetics and pathophysiology.
doi:10.1016/j.schres.2011.03.005
PMCID: PMC3143216  PMID: 21458242
language; social; neurodevelopment; schizophrenia; autism; thought disorder
13.  Abnormal responses to monetary outcomes in cortex, but not in the basal ganglia, in schizophrenia 
Psychosis has been associated with aberrant brain activity concurrent with both the anticipation and integration of monetary outcomes. The extent to which abnormal reward-related neural signals can be observed in chronic, medicated patients with schizophrenia (SZ), however, is not clear.
In an fMRI study involving 17 chronic outpatients with SZ and 17 matched controls, we used a monetary incentive delay (MID) task, in which different-colored shapes predicted gains, losses, or neutral outcomes. Subjects needed to respond to a target within a time window in order to receive the indicated gain, or avoid the indicated loss. Group differences in BOLD responses to cues and outcomes were assessed through voxel-wise whole-brain analyses and regions-of-interest analyses in the neostriatum and prefrontal cortex (PFC).
Significant group by outcome valence interactions were observed in medial and lateral PFC, lateral temporal cortex, and the amygdalae, such that controls, but not patients, showed greater activation for gains, relative to losses. In the striatum, neural activity was modulated by outcome magnitude in both groups. Additionally, we found that ratings of negative symptoms in patients correlated with sensitivity to obtained losses in medial PFC, obtained gains in lateral PFC, and anticipated gains in left ventral striatum. Sensitivity to obtained gains in lateral PFC also correlated with positive symptom scores in patients.
Our findings of systematic relationships between clinical symptoms and neural responses to stimuli associated with rewards and punishments offer promise that reward-related neural responses may provide sensitive probes of the effectiveness of treatments for negative symptoms.
doi:10.1038/npp.2010.126
PMCID: PMC2955756  PMID: 20720534
schizophrenia; dopamine; reinforcement; basal ganglia; ventromedial prefrontal cortex
14.  Research in People with the Psychosis Risk Syndrome: A Review of the Current Evidence and Future Directions 
After decades of research, schizophrenia and related psychotic disorders are still among the most debilitating disorders in medicine. The chronic illness course in most individuals, greater treatment responsiveness during the first episode, progressive grey matter decline during early disease stages, and retrospective accounts of “prodromal” or early illness signs and symptoms formed the basis for research on the psychosis risk syndrome,, known variably as “clinical high risk”(CHR), or “ultra-high risk“ (UHR), or “prodromal”. The pioneering era of research on the psychosis risk syndrome focused on the development and validation of specific assessment tools and the delineation of high risk criteria. This was followed by the examination of conversion rates in psychosis risk cohorts followed naturalistically, identification of predictors of conversion to psychosis, and investigation of interventions able to abort or delay the development of full psychosis. Despite initially encouraging results concerning the predictive validity of the psychosis risk syndrome criteria, recent findings of declining conversion rates demonstrate the need for further investigations. Results from intervention studies, mostly involving second-generation antipsychotics and cognitive behavioral therapy, are encouraging, but are currently still insufficient to make treatment recommendations for this early, relatively non-specific illness phase. The next phase of research on the psychosis risk syndrome just now beginning, has moved to larger, “multi-site” projects to increase generalizability and to ensure that sufficiently large samples at true risk for psychosis are included. Emphasis in these emerging studies is on: 1) identification of biomarkers for conversion to psychosis; 2) examination of non-antipsychotic, neuroprotective and low-risk pharmacologic and non-pharmacologic interventions; 3) testing of potentially phase-specific interventions; 4) examination of the relationship between treatment response during yhre of psychosis risk syundrome and prognosis for the course of illness; 5) follow-up of patients who developed schizophrenia despite early interventions and comparison of illness trajectories with patients who did not receive early interventions; 6) characterization of individuals with outcomes other than schizophrenia spectrum disorders, including bipolar disorder and remission from the psychosis risk syndrome, including false positive cases; 7) assessment of meaningful social and role functioning outcomes. While the research conducted to date has already yielded crucial information, the translation of the concept of a clinically identifiable psychosis risk syndrome into clinical practice does not seem justified at this point.
doi:10.1111/j.1469-7610.2010.02235.x
PMCID: PMC3085111  PMID: 20214698
Schizophrenia; Psychosis; Risk Syndrome; Prodrome; Early Recognition; Early Intervention; Biomarker; DSM-V
15.  Recovery From an At-Risk State: Clinical and Functional Outcomes of Putatively Prodromal Youth Who Do Not Develop Psychosis 
Schizophrenia Bulletin  2011;38(6):1225-1233.
Background: The “clinical high risk” (CHR) construct was developed to identify individuals at imminent risk of developing psychosis. However, most individuals identified as CHR do not convert to psychosis, and it is unknown whether these nonconverting individuals actually recover from an at-risk state.
Methods: Eighty-four prospectively identified patients meeting CHR criteria, and 58 healthy comparison subjects were followed in a 2-year longitudinal study. Analyses examined rates of conversion, clinical, and functional recovery. Proportional cause-specific hazard models were used to examine the effects of baseline and time-varying predictors on conversion and remission. Trajectories of symptoms and psychosocial functioning measures were compared across outcome groups.
Results: Competing risk survival analyses estimated that 30% of CHR subjects convert to psychosis by 2 years, while 36% symptomatically remit and 30% functionally recover by 2 years. Lower levels of negative and mood/anxiety symptoms were related to increased likelihood of both symptomatic and functional recovery. CHR subjects who remitted symptomatically were more similar to healthy controls in terms of both their baseline and longitudinal symptoms and functioning than the other outcome groups.
Conclusions: Nonconverting CHR cases represented a heterogeneous group. Given that nonconverted subjects who remitted symptomatically also presented initially with less severe prodromal symptomatology and showed a distinct normative trajectory of both symptoms and psychosocial functioning over time, it may be possible to refine the CHR criteria to reduce the number of “false positive” cases by eliminating those who present with less severe attenuated positive symptoms or show early improvements in terms of symptoms or functioning.
doi:10.1093/schbul/sbr098
PMCID: PMC3494042  PMID: 21825282
psychosis; prodrome; conversion; at-risk; schizophrenia; functioning
16.  Do Subjects at Clinical High Risk for Psychosis Differ from those with a Genetic High Risk? – A Systematic Review of Structural and Functional Brain Abnormalities 
Current Medicinal Chemistry  2013;20(3):467-481.
Introduction:
Pre-psychotic and early psychotic characteristics are investigated in the high-risk (HR) populations for psychosis. There are two different approaches based either on hereditary factors (genetic high risk, G-HR) or on the clinically manifested symptoms (clinical high risk, C-HR). Common features are an increased risk for development of psychosis and similar cognitive as well as structural and functional brain abnormalities.
Methods:
We reviewed the existing literature on longitudinal structural, and on functional imaging studies, which included G-HR and/or C-HR individuals for psychosis, healthy controls (HC) and/or first episode of psychosis (FEP) or schizophrenia patients (SCZ).
Results:
With respect to structural brain abnormalities, vulnerability to psychosis was associated with deficits in frontal, temporal, and cingulate regions in HR, with additional insular and caudate deficits in C-HR population. Furthermore, C-HR had progressive prefrontal deficits related to the transition to psychosis.
With respect to functional brain abnormalities, vulnerability to psychosis was associated with prefrontal, cingulate and middle temporal abnormalities in HR, with additional parietal, superior temporal, and insular abnormalities in C-HR population. Transition-to-psychosis related differences emphasized prefrontal, hippocampal and striatal components, more often detectable in C-HR population.
Multimodal studies directly associated psychotic symptoms displayed in altered prefrontal and hippocampal activations with striatal dopamine and thalamic glutamate functions.
Conclusion:
There is an evidence for similar structural and functional brain abnormalities within the whole HR population, with more pronounced deficits in the C-HR population. The most consistent evidence for abnormality in the prefrontal cortex reported in structural, functional and multimodal studies of HR population may underlie the complexity of higher cognitive functions that are impaired during HR mental state for psychosis.
doi:10.2174/0929867311320030018
PMCID: PMC3580804  PMID: 23157639
Clinical high-risk for psychosis; Genetic high-risk for psychosis; At-risk mental state; functional MRI.
17.  Risk Factors for Psychosis: Impaired Social and Role Functioning 
Schizophrenia Bulletin  2011;38(6):1247-1257.
Objectives: Risk for psychosis is currently defined primarily on the basis of attenuated positive symptoms (APS), with no inclusion of the functional deficits characteristic of schizophrenia. Impaired social and role functioning have been of interest for reflecting poor outcome but far less is known about the developmental impact of these deficits as vulnerability or risk factors. Methods: Age-appropriate social and role functioning were prospectively assessed in 100 individuals at clinical high risk (CHR) for psychosis included in the 8-site North American Prodromal Longitudinal Study database. A nested case-control design was used to compare changes in social and role functioning in 26 individuals converting to psychosis shortly after baseline assessment and 24 converting over a year later. Individuals in each converter subgroup were directly matched to a non-converter at the same site, controlling for time to conversion, age, gender, and severity of baseline symptoms. Results: At baseline, CHR subjects who later became psychotic were significantly more likely to be impaired socially than matched non-converters. Onset of psychosis did not further disrupt social difficulties. Role functioning showed some of the same trends, but the overall pattern was not as consistent as for the social domain. Controlling for neurocognition did not change the pattern of group differences. Conclusions: Early impaired social functioning appears to be a risk factor for psychosis and, added to APS, could potentially contribute to accurate identification of CHR individuals and provide a new direction for early intervention to reduce long-term disability.
doi:10.1093/schbul/sbr136
PMCID: PMC3494064  PMID: 22080497
clinical high risk; functional deficits; prodromal; social risk factors; functional outcome/attenuated positive symptoms
18.  Cognitive Control and Discourse Comprehension in Schizophrenia 
Cognitive deficits across a wide range of domains have been consistently observed in schizophrenia and are linked to poor functional outcome (Green, 1996; Carter, 2006). Language abnormalities are among the most salient and include disorganized speech as well as deficits in comprehension. In this review, we aim to evaluate impairments of language processing in schizophrenia in relation to a domain-general control deficit. We first provide an overview of language comprehension in the healthy human brain, stressing the role of cognitive control processes, especially during discourse comprehension. We then discuss cognitive control deficits in schizophrenia, before turning to evidence suggesting that schizophrenia patients are particularly impaired at processing meaningful discourse as a result of deficits in control functions. We conclude that domain-general control mechanisms are impaired in schizophrenia and that during language comprehension this is most likely to result in difficulties during the processing of discourse-level context, which involves integrating and maintaining multiple levels of meaning. Finally, we predict that language comprehension in schizophrenia patients will be most impaired during discourse processing. We further suggest that discourse comprehension problems in schizophrenia might be mitigated when conflicting information is absent and strong relations amongst individual words are present in the discourse context.
“There is no “centre of Speech” in the brain any more than there is a faculty of Speech in the mind. The entire brain, more or less, is at work in a man who uses language”William JamesFrom The Principles of Psychology, 1890“The mind in dementia praecox is like an orchestra without a conductor”Kraepelin, 1919
doi:10.1155/2012/484502
PMCID: PMC3420642  PMID: 22970364
19.  A Method for High Fidelity Optogenetic Control of Individual Pyramidal Neurons In vivo 
Optogenetic methods have emerged as a powerful tool for elucidating neural circuit activity underlying a diverse set of behaviors across a broad range of species. Optogenetic tools of microbial origin consist of light-sensitive membrane proteins that are able to activate (e.g., channelrhodopsin-2, ChR2) or silence (e.g., halorhodopsin, NpHR) neural activity ingenetically-defined cell types over behaviorally-relevant timescales. We first demonstrate a simple approach for adeno-associated virus-mediated delivery of ChR2 and NpHR transgenes to the dorsal subiculum and prelimbic region of the prefrontal cortex in rat. Because ChR2 and NpHR are genetically targetable, we describe the use of this technology to control the electrical activity of specific populations of neurons (i.e., pyramidal neurons) embedded in heterogeneous tissue with high temporal precision. We describe herein the hardware, custom software user interface, and procedures that allow for simultaneous light delivery and electrical recording from transduced pyramidal neurons in an anesthetized in vivo preparation. These light-responsive tools provide the opportunity for identifying the causal contributions of different cell types to information processing and behavior.
doi:10.3791/50291
PMCID: PMC3857391  PMID: 24022017
Neuroscience; Issue 79; Genetic Techniques; Genetics; Behavioral; Biological Science Disciplines; Neurosciences; genetics (animal and plant); Investigative Techniques; Behavior and Behavior Mechanisms; Behavioral Disciplines and Activities; Natural Science Disciplines; Optogenetics; prefrontal cortex; subiculum; virus injection;  in vivo recording; Neurophysiology; prelimbic; optrode; molecular neurogenetics; Gene targeting
20.  Delivery of continuously-varying stimuli using channelrhodopsin-2 
To study sensory processing, stimuli are delivered to the sensory organs of animals and evoked neural activity is recorded downstream. However, noise and uncontrolled modulatory input can interfere with repeatable delivery of sensory stimuli to higher brain regions. Here we show how channelrhodopsin-2 (ChR2) can be used to deliver continuous, subthreshold, time-varying currents to neurons at any point along the sensory-motor pathway. To do this, we first deduce the frequency response function of ChR2 using a Markov model of channel kinetics. We then confirm ChR2's frequency response characteristics using continuously-varying optical stimulation of neurons that express one of three ChR2 variants. We find that wild-type ChR2 and the E123T/H134R mutant (“ChETA”) can pass continuously-varying subthreshold stimuli with frequencies up to ~70 Hz. Additionally, we find that wild-type ChR2 exhibits a strong resonance at ~6–10 Hz. Together, these results indicate that ChR2-derived optogenetic tools are useful for delivering highly repeatable artificial stimuli that mimic in vivo synaptic bombardment.
doi:10.3389/fncir.2013.00184
PMCID: PMC3853882  PMID: 24367294
channelrhodopsin-2; linear response theory; dynamical systems; neural circuits; networks and dynamical systems; circuit dynamics; optogenetics; electrophysiology methods
21.  The Extended Language Network: A Meta-Analysis of Neuroimaging Studies on Text Comprehension 
Human brain mapping  2008;29(5):581-593.
Language processing in context requires more than merely comprehending words and sentences. Important subprocesses are inferences for bridging successive utterances, the use of background knowledge and discourse context, and pragmatic interpretations. The functional neuroanatomy of these text comprehension processes has only recently been investigated. Although there is evidence for right-hemisphere contributions, reviews have implicated the left lateral prefrontal cortex, left temporal regions beyond Wernicke’s area, and the left dorso-medial prefrontal cortex (dmPFC) for text comprehension. To objectively confirm this extended language network and to evaluate the respective contribution of right hemisphere regions, meta-analyses of 23 neuroimaging studies are reported here. The analyses used replicator dynamics based on activation likelihood estimates. Independent of the baseline, the anterior temporal lobes (aTL) were active bilaterally. In addition, processing of coherent compared with incoherent text engaged the dmPFC and the posterior cingulate cortex. Right hemisphere activations were seen most notably in the analysis of contrasts testing specific subprocesses, such as metaphor comprehension. These results suggest task dependent contributions for the lateral PFC and the right hemisphere. Most importantly, they confirm the role of the aTL and the fronto-medial cortex for language processing in context.
doi:10.1002/hbm.20422
PMCID: PMC2878642  PMID: 17557297
text comprehension; theory-of-mind; pragmatics; language interpretation; anterior temporal lobe; fronto-medial cortex; right hemisphere; metaanalysis; neuroimaging
22.  fMRI Study of Language Activation in Schizophrenia, Schizoaffective Disorder and in Individuals Genetically at High Risk 
Schizophrenia research  2007;96(1-3):14-24.
Background:
Structural and functional abnormalities have been found in language-related brain regions in patients with schizophrenia. We previously reported findings pointing to differences in word processing between people with schizophrenia and individuals who are at high-risk for schizophrenia using a voxel-based (whole brain) fMRI approach. We now extend this finding to specifically examine functional activity in three language related cortical regions using a larger cohort of individuals.
Method:
A visual lexical discrimination task was performed by 36 controls, 21 subjects at high genetic-risk for schizophrenia, and 20 patients with schizophrenia during blood oxygenation level dependent (BOLD) fMRI scanning. Activation in bilateral inferior frontal gyri (Brodmann's area 44-45), bilateral inferior parietal lobe (Brodmann's area 39-40), and bilateral superior temporal gyri (Brodmann's area 22) was investigated. For all subjects, two-tailed Pearson correlations were calculated between the computed laterality index and a series of cognitive test scores determining language functioning.
Results:
Regional activation in Brodmann's area 44-45 was left lateralized in normal controls, while high-risk subjects and patients with schizophrenia or schizoaffective disorder showed more bilateral activation. No significant differences among the three diagnostic groups in the other two regions of interest (Brodmann's area 22 or areas 39-40) were found. Furthermore, the apparent reasons for loss of leftward language lateralization differed between groups. In high-risk subjects, the loss of lateralization was based on reduced left hemisphere activation, while in the patient group, it was due to increased right side activation. Language ability related cognitive scores were positively correlations with the laterality indices obtained from Brodmann's areas 44-45 in the high-risk group, and with the laterality indices from Brodmann's areas 22 and 44-45 in the patient group.
Conclusions:
This study reinforces previous language related imaging studies in high-risk subjects and patients with schizophrenia suggesting that reduced functional lateralization in language related frontal cortex may be a vulnerability marker for schizophrenia. Future studies will determine whether it is predictive of who develops illness.
doi:10.1016/j.schres.2007.07.013
PMCID: PMC2212592  PMID: 17719745
fMRI; schizophrenia; High risk, genetic; Language lateralization; ROI based study
23.  Neural Substrates of Interactive Musical Improvisation: An fMRI Study of ‘Trading Fours’ in Jazz 
PLoS ONE  2014;9(2):e88665.
Interactive generative musical performance provides a suitable model for communication because, like natural linguistic discourse, it involves an exchange of ideas that is unpredictable, collaborative, and emergent. Here we show that interactive improvisation between two musicians is characterized by activation of perisylvian language areas linked to processing of syntactic elements in music, including inferior frontal gyrus and posterior superior temporal gyrus, and deactivation of angular gyrus and supramarginal gyrus, brain structures directly implicated in semantic processing of language. These findings support the hypothesis that musical discourse engages language areas of the brain specialized for processing of syntax but in a manner that is not contingent upon semantic processing. Therefore, we argue that neural regions for syntactic processing are not domain-specific for language but instead may be domain-general for communication.
doi:10.1371/journal.pone.0088665
PMCID: PMC3929604  PMID: 24586366
24.  Progressive Brain Structural Changes Mapped as Psychosis Develops in ‘At Risk’ Individuals 
Schizophrenia research  2009;108(1-3):85-92.
Background
Schizophrenia and related psychoses are associated with brain structural abnormalities. Recent findings in ‘at risk’ populations have identified progressive changes in various brain regions preceding illness onset, while changes especially in prefrontal and superior temporal regions have been demonstrated in first-episode schizophrenia patients. However, the timing of the cortical changes and their regional extent, relative to the emergence of psychosis, has not been clarified. We followed individuals at high-risk for psychosis to determine whether structural changes in the cerebral cortex occur with the onset of psychosis. We hypothesized that progressive volume loss occurs in prefrontal regions during the transition to psychosis.
Methods
35 individuals at ultra-high risk (UHR) for developing psychosis, of whom 12 experienced psychotic onset by 1-year follow-up (‘converters’), participated in a longitudinal structural MRI study. Baseline and follow-up T1-weighted MR images were acquired and longitudinal brain surface contractions were assessed using Cortical Pattern Matching.
Results
Significantly greater brain contraction was found in the right prefrontal region in the ‘converters’ compared with UHR cases who did not develop psychosis (‘non-converters’).
Conclusions
These findings show cortical volume loss is associated with the onset of psychosis, indicating ongoing pathological processes during the transition stage to illness. The prefrontal volume loss is in line with structural and functional abnormalities in schizophrenia, suggesting a critical role for this change in the development of psychosis.
doi:10.1016/j.schres.2008.11.026
PMCID: PMC2670732  PMID: 19138834
schizophrenia; MRI; brain mapping; longitudinal; prodrome; ultra-high risk
25.  Identification and Characterization of the Transcriptional Regulator ChrB in the Chromate Resistance Determinant of Ochrobactrum tritici 5bvl1 
PLoS ONE  2013;8(11):e77987.
Ochrobactrum tritici 5bvl1 is able to resist to high concentrations of chromate through the expression of an inducible chromate-resistant determinant, found in a mobile element (TnOtChr), which carries the genes, chrB, chrA, chrC and chrF. The regulation of chr operon present in TnOtChr, which is controlled by a transcriptional regulator, ChrB, was characterized in the current work. Fusions of chr promoter, or chr promoter and chrB gene, upstream of a gfp reporter gene, identified the most probable promoter sequence within the tnpR-chrB intergenic region. This region contains an AT-rich imperfect inverted repeat sequence, which overlaps a part of the −10 sequence. The results of the in vitro DNA-binding assays with purified ChrB (His- or no-tagged) showed that the protein binds directly to the chr promoter region. In order to identify the ChrB functional domain for sensing chromate stress and for DNA-binding, site-directed mutagenesis of ChrB was performed. Among several single amino acid mutants, three mutants (R180; R187 and H229) prevented chromate induction without any modification to the protein’s stability. Interestingly, two ChrB mutants (R18 and R23) were constitutively active, regardless of chromate stress conditions, indicating that the residues most probably belong to the protein-DNA binding site. As such, the ChrB was classified as a transcriptional regulator that recognizes a specific DNA sequence, regulating the expression of a chromate resistance determinant.
doi:10.1371/journal.pone.0077987
PMCID: PMC3817168  PMID: 24223748

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