John D. Ragland

Brain Activity during Simulated Deception: An Event-Related Functional Magnetic Resonance Study

TheGuilty Knowledge Test (GKT) has been used extensively to model deception. An association between the brain evoked response potentials and lying on the GKT suggests that deception may be associated with changes in other measures of brain activity such as regional blood flow that could be anatomically localized with event-related functional magnetic resonance imaging (fMRI). Blood oxygenation level-dependent fMRI contrasts between deceptive and truthful responses were measured with a 4 Tesla scanner in 18 participants performing the GKT and analyzed using statistical parametric mapping. Increased activity in the anterior cingulate cortex (ACC), the superior frontal gyrus (SFG), and the left premotor, motor, and anterior parietal cortex was specifically associated with deceptive responses. The results indicate that: (a) cognitive differences between deception and truth have neural correlates detectable by fMRI, (b) inhibition of the truthful response may be a basic component of intentional deception, and (c) ACC and SFG are components of the basic neural circuitry for deception.

Neuroimaging of cognitive disability in schizophrenia: Search for a pathophysiological mechanism

This article reviews how functional neuroimaging research of cognitive dysfunction in schizophrenia has resulted in a progression of influential pathophysiological models of the disorder. The review begins with discussion of the ‘hypofrontality’ model, moving from resting studies examining anterior to posterior gradients of cerebral blood flow (CBF), to cognitive activation studies employing the Wisconsin Card Sorting Test, and current functional magnetic resonance imaging (fMRI) studies of working memory and cognitive control utilizing parametric task designs and event-related procedures. A similar progression is described for development of the temporal lobe model of schizophrenia, moving from research on the temporal cortex and language processing to the hippocampal formation and long-term memory (LTM). These LTM studies found that hippocampal dysfunction was often accompanied by disrupted prefrontal function, supporting a hybrid model of impaired fronto-temporal connectivity. Developments in image analysis procedures are described that allow assessment of these distributed network models. However, given limitations in temporal and spatial resolution, current methods do not provide ‘real-time’ imaging of network activity, making arrival at a definitive pathophysiologic mechanism difficult. Dorsolateral prefrontal cortex (DLPFC) dysfunction and disrupted fronto-temporal integration appear to be equally viable current models. The article concludes with a discussion of how fMRI can help facilitate development of novel psychosocial and pharmacological interventions designed to improve cognition and functional outcome in patients with schizophrenia.

Optimization of a Goal Maintenance Task for Use in Clinical Applications

BACKGROUND We sought to develop a Dot Pattern Expectancy task (DPX) to assess goal maintenance for use in clinical trials. Altering the standard task created 5 versions of the DPX to compare-a standard version and 4 others. Alterations in the interstimulus interval (ISI) length and the strength of a learned prepotent response distinguished the different tasks. These adjustments were designed to decrease administration time and/or improve reliability of the data. METHODS We determined participant eligibility in an initial session (the first of 3) using clinical interviewing tools. The initial session also included a demographic assessment and assessments of community functioning and symptom severity. All versions of the DPX were administered, across 3 sessions. Specific deficits on the context processing compared with difficulty control condition were evaluated using mixed-effects logistic regression within a hierarchical linear model. RESULTS We analyzed the data from 136 control participants and 138 participants with schizophrenia. Relative to a difficulty control condition, patients performed worse than controls on context processing conditions that required goal maintenance. ISI did not predict errors. Stronger prepotency was associated with increased errors in the difficulty control relative to context processing condition for controls, which improved the interpretability of findings for patients. Reliability was acceptable for a version of the task with a 10-minute running time. CONCLUSIONS The best compromise between task duration and interpretability occurred on a version with a short ISI and a strong prepotency.

Neural correlates of relational and item-specific encoding during working and long-term memory in schizophrenia.

Successful long-term memory (LTM) depends upon effective control of information in working memory (WM), and there is evidence that both WM and LTM are impaired by schizophrenia. This study tests the hypothesis that LTM deficits in schizophrenia may result from impaired control of relational processing in WM due to dorsolateral prefrontal cortex (DLPFC) dysfunction. fMRI was performed on 19 healthy controls and 20 patients with schizophrenia during WM tasks emphasizing relational (reorder trials) versus item-specific (rehearse trials) processing. WM activity was also examined with respect to LTM recognition on a task administered outside the scanner. Receiver operator characteristic analysis assessed familiarity and recollection components of LTM. Patients showed a disproportionate familiarity deficit for reorder versus rehearse trials against a background of generalized LTM impairments. Relational processing during WM led to DLPFC activation in both groups. However, this activation was less focal in patients than in controls, and patients with more severe negative symptoms showed less of a DLPFC increase. fMRI analysis of subsequent recognition performance revealed a group by condition interaction. High LTM for reorder versus rehearse trials was associated with bilateral DLPFC activation in controls, but not in patients who activated the left middle temporal and inferior occipital gyrus. Results indicate that although patients can activate the DLPFC on a structured relational WM task, this activation is less focal and does not translate to high retrieval success, suggesting a disruption in the interaction between WM and LTM processes in schizophrenia.

Use of eye movement monitoring to examine item and relational memory in schizophrenia

BACKGROUND Patients with schizophrenia may be impaired at remembering interitem and item-context relationships (relational memory), even when memory for items is intact. Here, we applied the novel approach of using eye movements to assess integrity of item and relational memory in schizophrenia. This method does not rely on introspection and may be more readily translated to animal models than traditional behavioral methods. METHODS Sixteen healthy control subjects and 16 patients were administered a scene memory task while eye movements were monitored. During testing, participants indicated whether the scenes were unchanged, contained a new item (item manipulation), had a change in item location (relational manipulation), or were new. It was predicted that memory would be disproportionately impaired when relational changes were made. RESULTS Results confirmed that tasks were equally difficult and showed that patients were impaired identifying all scene types. These behavioral impairments were associated with more severe disorganization and negative symptoms. Eye movement results were more specific. Both groups looked disproportionately at critical regions of repeated versus novel scenes-an effect of scene repetition. However, in contrast with predictions, patients showed equivalent eye-movement-based memory impairment whether changes were relational or item-based. CONCLUSIONS This is the first experiment to demonstrate that eye movements can be used to investigate item and relational memory in schizophrenia. The eye movement procedure was well tolerated and was more specific than behavioral measures with respect to memory impairment. Results suggest that eye movements may be of use in clinical trials and translational studies employing animal models.

Cognition in schizophrenia and schizo-affective disorder: impairments that are more similar than different.

BACKGROUND Cognition is increasingly being recognized as an important aspect of psychotic disorders and a key contributor to functional outcome. In the past, comparative studies have been performed in schizophrenia and schizo-affective disorder with regard to cognitive performance, but the results have been mixed and the cognitive measures used have not always assessed the cognitive deficits found to be specific to psychosis. A set of optimized cognitive paradigms designed by the Cognitive Neuroscience Test Reliability and Clinical Applications for Schizophrenia (CNTRACS) Consortium to assess deficits specific to schizophrenia was used to measure cognition in a large group of individuals with schizophrenia and schizo-affective disorder. METHOD A total of 519 participants (188 with schizophrenia, 63 with schizo-affective disorder and 268 controls) were administered three cognitive paradigms assessing the domains of goal maintenance in working memory, relational encoding and retrieval in episodic memory and visual integration. RESULTS Across the three domains, the results showed no major quantitative differences between patient groups, with both groups uniformly performing worse than healthy subjects. CONCLUSIONS The findings of this study suggests that, with regard to deficits in cognition, considered a major aspect of psychotic disorder, schizophrenia and schizo-affective disorder do not demonstrate major significant distinctions. These results have important implications for our understanding of the nosological structure of major psychopathology, providing evidence consistent with the hypothesis that there is no natural distinction between cognitive functioning in schizophrenia and schizo-affective disorder.

Utility of Imaging-Based Biomarkers for Glutamate-Targeted Drug Development in Psychotic Disorders: A Randomized Clinical Trial

Importance Despite strong theoretical rationale and preclinical evidence, several glutamate-targeted treatments for schizophrenia have failed in recent pivotal trials, prompting questions as to target validity, compound inadequacy, or lack of target engagement. A key limitation for glutamate-based treatment development is the lack of functional target-engagement biomarkers for translation between preclinical and early-stage clinical studies. We evaluated the utility of 3 potential biomarkers—ketamine-evoked changes in the functional magnetic imaging (fMRI) blood oxygen level–dependent response (pharmacoBOLD), glutamate proton magnetic resonance spectroscopy (1H MRS), and task-based fMRI—for detecting ketamine-related alterations in brain glutamate. Objective To identify measures with sufficient effect size and cross-site reliability to serve as glutamatergic target engagement biomarkers within early-phase clinical studies. Design, Setting, and Participants This randomized clinical trial was conducted at an academic research institution between May 2014 and October 2015 as part of the National Institute of Mental Health–funded Fast-Fail Trial for Psychotic Spectrum Disorders project. All raters were blinded to study group. Healthy volunteers aged 18 to 55 years of either sex and free of significant medical or psychiatric history were recruited from 3 sites. Data were analyzed between November 2015 and December 2016. Interventions Volunteers received either sequential ketamine (0.23 mg/kg infusion over 1 minute followed by 0.58 mg/kg/h infusion over 30 minutes and then 0.29 mg/kg/h infusion over 29 minutes) or placebo infusions. Main Outcomes and Measures Ketamine-induced changes in pharmacoBOLD, 1H MRS, and task-based fMRI measures, along with symptom ratings. Measures were prespecified prior to data collection. Results Of the 65 volunteers, 41 (63%) were male, and the mean (SD) age was 31.1 (9.6) years; 59 (91%) had at least 1 valid scan. A total of 53 volunteers (82%) completed both ketamine infusions. In pharmacoBOLD, a highly robust increase (Cohen d = 5.4; P < .001) in fMRI response was observed, with a consistent response across sites. A smaller but significant signal (Cohen d = 0.64; P = .04) was also observed in 1H MRS–determined levels of glutamate+glutamine immediately following ketamine infusion. By contrast, no significant differences in task-activated fMRI responses were found between groups. Conclusions and Relevance These findings demonstrate robust effects of ketamine on pharmacoBOLD across sites, supporting its utility for definitive assessment of functional target engagement. Other measures, while sensitive to ketamine effects, were not sufficiently robust for use as cross-site target engagement measures. Trial Registration clinicaltrials.gov Identifier: NCT02134951

Reduced Frontoparietal Activity in Schizophrenia Is Linked to a Specific Deficit in Goal Maintenance: A Multisite Functional Imaging Study

Patients with schizophrenia (SZ) previously demonstrated specific deficits in an executive function known as goal maintenance, associated with reduced middle frontal gyrus (MFG) activity. This study aimed to validate a new tool-the Dot Pattern Expectancy (DPX) task-developed to facilitate multisite imaging studies of goal maintenance deficits in SZ or other disorders. Additionally, it sought to arrive at recommendations for scan length for future studies using the DPX. Forty-seven SZ and 56 healthy controls (HC) performed the DPX in 3-Tesla functional magnetic resonance imaging (fMRI) scanners at 5 sites. Group differences in DPX-related activity were examined with whole brain voxelwise analyses. SZs showed the hypothesized specific performance deficits with as little as 1 block of data. Reduced activity in SZ compared with HC was observed in bilateral frontal pole/MFG, as well as left posterior parietal lobe. Efficiency analyses found significant group differences in activity using 18 minutes of scan data but not 12 minutes. Several behavioral and imaging findings from the goal maintenance literature were robustly replicated despite the use of different scanners at different sites. We did not replicate a previous correlation with disorganization symptoms among patients. Results were consistent with an executive/attention network dysfunction in the higher levels of a cascading executive system responsible for goal maintenance. Finally, efficiency analyses found that 18 minutes of scanning during the DPX task is sufficient to detect group differences with a similar sample size.

Cognitive control of episodic memory in schizophrenia: Differential role of dorsolateral and ventrolateral prefrontal cortex

Background: Dorsal (DLPFC) and ventral (VLPFC) subregions in lateral prefrontal cortex play distinct roles in episodic memory, and both are implicated in schizophrenia. We test the hypothesis that schizophrenia differentially impairs DLPFC versus VLPFC control of episodic encoding. Methods: Cognitive control was manipulated by requiring participants to encode targets and avoid encoding non-targets based upon stimulus properties of test stimuli. The more automatic encoding response (target versus non-target) was predicted to engage VLPFC in both groups. Conversely, having to overcome the prepotent encoding response (non-targets versus targets) was predicted to produce greater DLPFC activation in controls than in patients. Encoding occurred during event-related fMRI in a sample of 21 individuals with schizophrenia and 30 healthy participants. Scanning was followed by recognition testing outside the scanner. Results: Patients were less successful differentially remembering target versus non-target stimuli, and retrieval difficulties correlated with more severe disorganized symptoms. As predicted, the target versus non-target contrast activated the VLPFC and correlated with retrieval success in both groups. Conversely, the non-target versus target contrast produced greater DLPFC activation in controls than in patients, and DLPFC activation correlated with performance only in controls. Conclusion: Individuals with schizophrenia can successfully engage the VLPFC to provide control over semantic encoding of individual items, but are specifically impaired at engaging the DLPFC to main context for task-appropriate encoding and thereby generate improved memory for target versus non-target items. This extends previous cognitive control models based on response selection tasks to the memory domain.

Impact of schizophrenia on anterior and posterior hippocampus during memory for complex scenes

Objectives Hippocampal dysfunction has been proposed as a mechanism for memory deficits in schizophrenia. Available evidence suggests that the anterior and posterior hippocampus could be differentially affected. Accordingly, we used fMRI to test the hypothesis that activity in posterior hippocampus is disproportionately reduced in schizophrenia, particularly during spatial memory retrieval. Methods 26 healthy participants and 24 patients with schizophrenia from the UC Davis Early Psychosis Program were studied while fMRI was acquired on a 3 Tesla Siemens scanner. During encoding, participants were oriented to critical items through questions about item features (e.g., “Does the lamp have a square shade?”) or spatial location (e.g., “Is the lamp on the table next to the couch?”). At test, participants determined whether scenes were changed or unchanged. fMRI analyses contrasted activation in a priori regions of interest (ROI) in anterior and posterior hippocampus during correct recognition of item changes and spatial changes. Results As predicted, patients with schizophrenia exhibited reduced activation in the posterior hippocampus during detection of spatial changes but not during detection of item changes. Unexpectedly, patients exhibited increased activation of anterior hippocampus during detection of item changes. Whole brain analyses revealed reduced fronto-parietal and striatal activation in patients for spatial but not for item change trials. Conclusions Results suggest a gradient of hippocampal dysfunction in which posterior hippocampus – which is necessary for processing fine-grained spatial relationships – is underactive, and anterior hippocampus – which may process context more globally - is overactive.