Tara A. Niendam

Meta-analytic evidence for a superordinate cognitive control network subserving diverse executive functions

Classic cognitive theory conceptualizes executive functions as involving multiple specific domains, including initiation, inhibition, working memory, flexibility, planning, and vigilance. Lesion and neuroimaging experiments over the past two decades have suggested that both common and unique processes contribute to executive functions during higher cognition. It has been suggested that a superordinate fronto–cingulo–parietal network supporting cognitive control may also underlie a range of distinct executive functions. To test this hypothesis in the largest sample to date, we used quantitative meta-analytic methods to analyze 193 functional neuroimaging studies of 2,832 healthy individuals, ages 18–60, in which performance on executive function measures was contrasted with an active control condition. A common pattern of activation was observed in the prefrontal, dorsal anterior cingulate, and parietal cortices across executive function domains, supporting the idea that executive functions are supported by a superordinate cognitive control network. However, domain-specific analyses showed some variation in the recruitment of anterior prefrontal cortex, anterior and midcingulate regions, and unique subcortical regions such as the basal ganglia and cerebellum. These results are consistent with the existence of a superordinate cognitive control network in the brain, involving dorsolateral prefrontal, anterior cingulate, and parietal cortices, that supports a broad range of executive functions.

Cognitive Control Deficits in Schizophrenia: Mechanisms and Meaning

Although schizophrenia is an illness that has been historically characterized by the presence of positive symptomatology, decades of research highlight the importance of cognitive deficits in this disorder. This review proposes that the theoretical model of cognitive control, which is based on contemporary cognitive neuroscience, provides a unifying theory for the cognitive and neural abnormalities underlying higher cognitive dysfunction in schizophrenia. To support this model, we outline converging evidence from multiple modalities (eg, structural and functional neuroimaging, pharmacological data, and animal models) and samples (eg, clinical high risk, genetic high risk, first episode, and chronic subjects) to emphasize how dysfunction in cognitive control mechanisms supported by the prefrontal cortex contribute to the pathophysiology of higher cognitive deficits in schizophrenia. Our model provides a theoretical link between cellular abnormalities (eg, reductions in dentritic spines, interneuronal dysfunction), functional disturbances in local circuit function (eg, gamma abnormalities), altered inter-regional cortical connectivity, a range of higher cognitive deficits, and symptom presentation (eg, disorganization) in the disorder. Finally, we discuss recent advances in the neuropharmacology of cognition and how they can inform a targeted approach to the development of effective therapies for this disabling aspect of schizophrenia.

Neurocognitive performance and functional disability in the psychosis prodrome

OBJECTIVE This study evaluates the pattern of neuropsychological deficits and their association with clinical symptomatology and social functioning in individuals identified as ultra-high-risk (UHR) for psychosis. METHODS A sample of 45 UHR individuals was identified using the Structured Interview for Prodromal Syndromes (SIPS) from consecutive referrals to the Staglin Music Festival Center for the Assessment and Prevention of Prodromal States (CAPPS) at UCLA. Participants were administered a neurocognitive test battery, as well as measures of global (Strauss-Carpenter Outcome Scale) and social functioning (UCLA Social Attainment Survey). RESULTS Participants showed significant deficits in speed of processing, verbal learning and memory, and motor speed. Poorer verbal learning and memory performance was significantly associated with poorer social functioning, and there was a trend for poorer performance on reasoning and problem solving to be associated with poorer global functioning. Verbal memory independently predicted social functioning over and above severity of negative symptoms. Cognitive deficits were not associated with severity of clinical symptomatology. CONCLUSIONS Despite the absence of fully psychotic symptoms, UHR individuals experience significant cognitive deficits, particularly on tasks requiring speeded information-processing and efficient recall from memory, and these deficits appear to be associated with functional disability in a manner parallel to that observed in patients with established psychotic illness.

White Matter Integrity and Prediction of Social and Role Functioning in Subjects at Ultra-High Risk for Psychosis

BACKGROUND White matter microstructural disruptions have been observed in patients with schizophrenia. However, whether changes exist prior to disease onset or in high-risk individuals is unclear. Here, we investigated white matter integrity, as assessed by diffusion tensor imaging (DTI), in individuals at ultra-high risk for psychosis (UHR) relative to healthy control subjects (HC) and the relationship between baseline DTI measures and functional outcome over time. METHODS Thirty-six UHR participants and 25 HCs completed baseline DTI scans. Subjects also completed clinical follow-up assessments approximately 6 months (26 subjects) and 15 months (13 subjects) later. We used a rigorous registration approach (Tract-Based Spatial Statistics [TBSS]) to examine fractional anisotropy (FA) in six major white matter tracts. RESULTS Relative to the HC group, UHR subjects showed lower baseline FA in the superior longitudinal fasciculus, the major frontoparietal white matter connection. Cross-sectional analyses demonstrated that UHR youth failed to show the same age-associated increases in FA in the medial temporal lobe (MTL) and inferior longitudinal fasciculus as HCs. Finally, lower baseline FA in the MTL and inferior longitudinal fasciculus predicted deterioration in social and role functioning in UHR participants at 15-month follow-up. CONCLUSIONS This is the first investigation of white matter microstructural alterations in a clinical high-risk sample. Our findings indicate that white matter development may be altered in youth at risk for psychosis, possibly due to disrupted developmental mechanisms, and further, that white matter integrity may be predictive of functional outcome.

Obsessive compulsive symptoms in the psychosis prodrome: correlates of clinical and functional outcome.

OBJECTIVES Obsessive-Compulsive Disorder (OCD) is a common co-morbid condition in schizophrenia, associated with poor prognosis. However, the prevalence of obsessive compulsive symptomatology (OCS) and its relationship to outcome has not been evaluated in adolescents at ultra high-risk for psychosis (UHR). METHODS Sixty-four UHR and 26 non-prodromal comparison (NPC) youth were ascertained using the Structured Interview for Prodromal Syndromes (SIPS). Participants completed diagnostic interviews and the Padua Inventory (Sanavio, E., 1988. Obsessions and compulsions: the Padua Inventory. Behav. Res. Ther. 26, 169-177.), a self-report measure of OCS. RESULTS UHR youth reported significantly higher rates of OCS on the Padua Inventory compared to NPC youth. Clinical diagnosis of OCD (20% of sample) was associated with lower risk of conversion to psychosis over the follow-up period, but was unrelated to clinical severity or psychosocial functioning. However, dimensional ratings of OCS were significantly associated with positive symptom severity, self-reported depression, and a trend toward increased suicidal ideation within the UHR sample. CONCLUSIONS OCS rates in UHR youth are well above estimated prevalence rates in normal populations, and commensurate with rates of comorbidity observed in schizophrenia. Although clinical diagnosis of OCD was not associated with later conversion to psychosis, OCS severity in UHR youth was associated with more acute symptomatic presentation, including more severe depression and suicidality.

Neuroplasticity-Based Auditory Training Via Laptop Computer Improves Cognition in Young Individuals With Recent Onset Schizophrenia

OBJECTIVE Cognitive deficits that characterize schizophrenia are present in the prodrome, worsen with illness onset, and predict functional outcome. Cognitive dysfunction is thus a critical target for early intervention in young individuals with recent onset schizophrenia. METHOD This 2-site double-blind randomized controlled trial investigated cognitive training of auditory processing/verbal learning in 86 subjects with recent onset schizophrenia (mean age of 21 years). Subjects were given laptop computers to take home and were asked to perform 40 hours of training or 40 hours of commercial computer games over 8 weeks. We examined cognitive measures recommended by the Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative (MATRICS), symptoms, and functioning. We also assessed baseline reward anticipation to index motivational system functioning and measured changes in auditory processing speed after 20 hours of training to assess target engagement. RESULTS Auditory training subjects demonstrated significant improvements in global cognition, verbal memory, and problem solving compared with those of computer games control subjects. Both groups showed a slight but significant decrease in symptoms and no change in functional outcome measures. Training-induced cognitive gains at posttraining showed significant associations with reward anticipation at baseline and with improvement in auditory processing speed at 20 hours. CONCLUSION Neuroscience-informed cognitive training via laptop computer represents a promising treatment approach for cognitive dysfunction in early schizophrenia. An individuals baseline motivational system functioning (reward anticipation), and ability to engage in auditory processing speed improvement, may represent important predictors of treatment outcome. Future studies must investigate whether cognitive training improves functioning and how best to integrate it into critical psychosocial interventions.

Gender differences in symptoms, functioning and social support in patients at ultra-high risk for developing a psychotic disorder

Gender differences have been widely observed in the clinical presentation, psychosocial functioning and course of illness in first-episode and chronic patients suffering from schizophrenia. However, little is known about gender differences in the psychosis prodrome. This study investigated gender differences in symptoms, functioning and social support in individuals at ultra-high-risk for developing a psychotic disorder. Sixty-eight ultra-high-risk patients were assessed at baseline, and twenty-seven returned for follow-up assessments approximately 6 and 12 months later. Clinical symptoms and functioning were assessed by clinical interview; social support was measured using a self-report questionnaire. There were no gender differences in demographic variables, symptoms or functioning at baseline. Males were found to have significantly higher levels of negative symptoms and marginally lower levels of functioning when baseline and follow-up time points were considered collectively. Additionally, females reported higher levels of social support at baseline. Differences in negative symptoms were found to mediate differences in functioning between male and female patients. This study suggests that gender based differences in symptom presentation and functional outcome may predate conversion to psychosis. Follow-up studies should examine the relationship between symptoms, functioning and social support in this population.

Exploring Predictors of Outcome in the Psychosis Prodrome: Implications for Early Identification and Intervention

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.

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

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 Childrens 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.

Clinical and Functional Outcomes After 2 Years in the Early Detection and Intervention for the Prevention of Psychosis Multisite Effectiveness Trial

Objective: To test effectiveness of the Early Detection, Intervention, and Prevention of Psychosis Program in preventing the onset of severe psychosis and improving functioning in a national sample of at-risk youth. Methods: In a risk-based allocation study design, 337 youth (age 12–25) at risk of psychosis were assigned to treatment groups based on severity of positive symptoms. Those at clinically higher risk (CHR) or having an early first episode of psychosis (EFEP) were assigned to receive Family-aided Assertive Community Treatment (FACT); those at clinically lower risk (CLR) were assigned to receive community care. Between-groups differences on outcome variables were adjusted statistically according to regression-discontinuity procedures and evaluated using the Global Test Procedure that combined all symptom and functional measures. Results: A total of 337 young people (mean age: 16.6) were assigned to the treatment group (CHR + EFEP, n = 250) or comparison group (CLR, n = 87). On the primary variable, positive symptoms, after 2 years FACT, were superior to community care (2 df, p < .0001) for both CHR (p = .0034) and EFEP (p < .0001) subgroups. Rates of conversion (6.3% CHR vs 2.3% CLR) and first negative event (25% CHR vs 22% CLR) were low but did not differ. FACT was superior in the Global Test (p = .0007; p = .024 for CHR and p = .0002 for EFEP, vs CLR) and in improvement in participation in work and school (p = .025). Conclusion: FACT is effective in improving positive, negative, disorganized and general symptoms, Global Assessment of Functioning, work and school participation and global outcome in youth at risk for, or experiencing very early, psychosis.