Angus W. MacDonald

Altered Functional and Anatomical Connectivity in Schizophrenia

BACKGROUND 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. METHODS 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 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. DISCUSSION 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.

Prevalence of ADHD and comorbid disorders among elementary school children screened for disruptive behavior

In the context of a school-based prevention of conduct disorder program, 7,231 first- through fourth-grade children were screened for cross-setting disruptive behavior. Frequencies of DSM-III-R psychiatric disorders and patterns of comorbidity were assessed. We also examined the association of psychiatric diagnosis with child and parent characteristics to determine differential risk based on diagnostic subgroups. Attention deficit hyperactivity disorder (ADHD) and oppositional-defiant disorder (ODD) were the most frequent diagnoses. Mood and anxiety disorders were infrequent as single diagnoses. Patterns of comorbidity demonstrated that both externalizing and internalizing disorders commonly cooccurred with ADHD. More severe degrees of psychopathology and psychosocial risk accrued to the subgroup of youths with ADHD plus a comorbid externalizing disorder.

Context-processing deficits in schizophrenia: Diagnostic specificity, 4-week course, and relationships to clinical symptoms

Previous research on schizophrenia suggests that context-processing disturbances are one of the core cognitive deficits present in schizophia. However, it is not clear whether such deficits are specific to schizophrenia as compared with other psychotic disorders. To address this question, the authors administered a version of the AX Continuous Performance Test designed to assess context processing in a sample of healthy controls, patients with schizophrenia, and patients with other psychotic disorders. Participants were tested at index (when medication naive and experiencing their first contact with psychiatric services) and 4 weeks later, following medication treatment. At index, patients with schizophrenia and the psychotic comparison group demonstrated similar impairments in context processing. However, context-processing deficits improved in the psychotic comparison group at 4 weeks but did not improve in patients with schizophrenia.

Event-related fMRI study of context processing in dorsolateral prefrontal cortex of patients with schizophrenia

Context processing is conceptualized as an executive function involved in voluntary, complex actions such as overcoming automatic responses. The present study tested the hypothesis that context-processing deficits in patients with schizophrenia are associated with a dysfunction of left dorsolateral prefrontal cortex (DLPFC). Using event-related functional magnetic resonance imaging (fMRI), 17 controls and 17 medicated patients performed a version of the AX task in which a learned, automatic response had to be inhibited. In controls, left DLPFC activity increased when preparing to overcome an automatic response, whereas patients with schizophrenia showed no differential activation. In controls, context processing appeared to be associated with the differential representation of cues associated with the need to provide top-down support for overcoming automatic responses. This mechanism appeared to be impaired in patients with schizophrenia.

The functional neuroanatomy of symptom dimensions in schizophrenia: A qualitative and quantitative review of a persistent question

One of the fundamental goals in understanding schizophrenia is linking the observable symptoms to the underlying unobservable pathophysiology. Given recent advances in medical imaging, researchers are increasingly investigating brain-behavior relationships to better understand the neural substrates of negative, positive, and disorganization symptoms in schizophrenia. This review focused on 25 task-related functional magnetic resonance imaging studies and found meaningful small to moderate associations between specific symptom dimensions and regional brain activity. Negative symptoms were related to the functioning of the ventrolateral prefrontal cortex and ventral striatum. Positive symptoms, particularly persecutory ideation, were related to functioning of the medial prefrontal cortex, amygdala, and hippocampus/parahippocampal region. Disorganization symptoms, although less frequently evaluated, were related to functioning of the dorsolateral prefrontal cortex. Surprisingly, no symptom domain had a consistent relationship with the middle or superior temporal regions. While a number of adaptations in experimental design and reporting standards can facilitate this work, current neuroimaging approaches appear to provide a number of consistent links between the manifest symptoms of schizophrenia and brain dysfunction.

Prefrontal functioning during context processing in schizophrenia and major depression: An event-related fMRI study

Patients with schizophrenia frequently demonstrate hypofrontality in tasks that require executive processing; however questions still remain as to whether prefrontal cortex dysfunctions are specific to schizophrenia, or a general feature of major psychopathology. Context processing is conceptualized as an executive function associated with attention and working memory processes. Impairment in the ability of patients with schizophrenia to represent and maintain context information has been previously reported in a number of studies. To examine the question of the specificity of a context processing deficit to schizophrenia, we used functional MRI and an expectancy AX continuous performance task designed to assess context processing in a group of healthy controls (n=9), depressed patient controls (n=10), and patients with schizophrenia (n=7). The behavioral performance was consistent with a context processing deficit in patients with schizophrenia, but not those with depression. The imaging data replicate previous results in showing abnormal activity in the right middle frontal gyrus (BA9) in schizophrenia patients related to context processing.

Prefrontal cortical changes following cognitive training in patients with chronic schizophrenia: effects of practice, generalization, and specificity.

Cognitive training is increasingly used in the treatment of schizophrenia, but it remains unknown how this training affects functional neuroanatomy. Practice on specific cognitive tasks generally leads to automaticity and decreased prefrontal cortical activity, yet broad-based cognitive training programs may avoid automaticity and increase prefrontal cortex (PFC) activity. This study used quasi-randomized, placebo-control design and pre/post neuroimaging to examine functional plasticity associated with attention and working memory-focused cognitive training in patients with schizophrenia. Twenty-one participants with schizophrenia or schizoaffective disorder split into two demographically and performance matched groups (nine scanned per group) and nine control participants were tested 6–8 weeks apart. Compared with both patient controls and healthy controls, patients receiving cognitive training increased activation significantly more in attention and working memory networks, including dorsolateral prefrontal cortex, anterior cingulate and frontopolar cortex. The extent to which activity increased in a subset of these regions predicted performance improvements. Although this study was not designed to speak to the efficacy of cognitive training as a treatment, it is the first study to show that such training can increase the ability of patients to activate the PFC regions subserving attention and working memory.

Complementary Category Learning Systems Identified Using Event-Related Functional MRI

Event-related fMRI was used to dissociate the neural systems involved in category learning with and without awareness. Ten subjects performed a speeded response category learning task. Functional MR images were acquired during both explicit and implicit learning conditions. Behavioral data showed evidence of learning in both conditions. Functional imaging data showed different activation patterns in implicit and explicit trials. Decreased activation in extrastriate region V3 was found with implicit learning, and increased activation in V3, the medial temporal lobe, and frontal regions were found with explicit learning. These results support the theory that implicit and explicit learning utilize dissociable neural systems. Moreover, in both the implicit and explicit conditions a similar pattern of decreased activation was found in parietal regions. This commonality suggests that these dissociable systems also operate in parallel.

What We Know: Findings That Every Theory of Schizophrenia Should Explain

The article summarizes the process used to distill schizophrenia science into 22 facts. These facts consist of 6 basic facts, 3 etiological facts, 6 pharmacological and treatment facts, 5 pathology facts, and 2 behavioral facts that were critically reviewed by the scholarly community through a special initiative in cooperation with the Schizophrenia Research Forum. A subset of 10 of these facts was selected to form a common set of findings to be explained from the different theoretical perspectives included in this special section of Schizophrenia Bulletin. The rationale for this exercise is to distinguish more precisely the areas of agreement and disagreement between theories of schizophrenia and to highlight where more thought and data can make the greatest impact for understanding this disease.

CNTRICS Final Task Selection: Working Memory

The third meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) was focused on selecting promising measures for each of the cognitive constructs selected in the first CNTRICS meeting. In the domain of working memory, the 2 constructs of interest were goal maintenance and interference control. CNTRICS received 3 task nominations for each of these constructs, and the breakout group for working memory evaluated the degree to which each of these tasks met prespecified criteria. For goal maintenance, the breakout group for working memory recommended the AX-Continuous Performance Task/Dot Pattern Expectancy task for translation for use in clinical trial contexts in schizophrenia research. For interference control, the breakout group recommended the recent probes and operation/symmetry span tasks for translation for use in clinical trials. This article describes the ways in which each of these tasks met the criteria used by the breakout group to recommend tasks for further development.