Brain free water alterations in first-episode psychosis: a longitudinal analysis of diagnosis, course of illness, and medication effects.

BACKGROUND: Multiple lines of evidence suggest the presence of altered neuroimmune processes in patients with schizophrenia (Sz) and severe mood disorders. Recent studies using a novel free water diffusion tensor imaging (FW DTI) approach, proposed as a putative biomarker of neuroinflammation, atrophy, or edema, have shown significantly increased FW in patients with Sz. However no studies to date have investigated the longitudinal stability of FW alterations during the early course of psychosis, nor have studies focused separately on FE psychosis patients with Sz or bipolar disorder (BD) with psychotic features. METHODS: The current study included 188 participants who underwent diffusion magnetic resonance imaging scanning at baseline. Sixty-four participants underwent follow-up rescanning after 12 months. DTI-based alterations in patients were calculated using voxelwise tract-based spatial statistics and region of interest analyses. RESULTS: Patients with FE psychosis, both Sz and BD, exhibited increased FW at illness onset which remained unchanged over the 12-month follow-up period. Preliminary analyses suggested that antipsychotic medication exposure was associated with higher FW in gray matter that reached significance in the BD group. Higher FW in white matter correlated with negative symptom severity. CONCLUSIONS: Our results support the presence of elevated FW at the onset of psychosis in both Sz and BD, which remains stable during the early course of the illness, with no evidence of either progression or remission.

Disrupted GABAergic facilitation of working memory performance in people with schizophrenia.

OBJECTIVES: Gamma-Amiobutyric acid (GABA) is a primary inhibitory neurotransmitter that facilitates neural oscillations that coordinate neural activity between brain networks to facilitate cognition. The present magnetic resonance spectroscopy (MRS) study tests the hypothesis that GABAergic facilitation of working memory is disrupted in people with schizophrenia (PSZ). METHODS: 51 healthy participants and 40 PSZ from the UC Davis Early Psychosis Program performed an item and temporal order working memory (WM) task and underwent resting MRS to measure GABA and glutamate concentrations in dorsolateral prefrontal (DLPFC) and anterior cingulate (ACC) regions of interest. MRS was acquired on a 3 Tesla Siemens scanner and GABA and glutamate concentrations were referenced to creatine. Percent correct on the WM task indexed performance and correlation coefficients examined GABAergic or Glutamatergic facilitation of WM, with Fisher's Z transformation testing for group differences. RESULTS: There were no group differences in GABA or glutamate concentrations, but WM correlations were reversed between groups. In patients, higher DLPFC GABA was associated with worse rather than better WM performance. This pattern was not observed for glutamate or in the ACC. Although under-powered, there was no indication of medication effects. CONCLUSIONS AND RELEVANCE: Results cannot be explained by group differences in DLPFC GABA or glutamate concentrations but, instead, indicate that schizophrenia disrupts the GABAergic facilitation of WM seen in healthy individuals. Results appear to parallel post mortem findings in suggesting that schizophrenia alters the distribution of different classes of GABAergic interneurons rather than producing a general deficit across the total population of neurons.

Memory and cognition in schizophrenia.

Episodic memory deficits are consistently documented as a core aspect of cognitive dysfunction in schizophrenia patients, present from the onset of the illness and strongly associated with functional disability. Over the past decade, research using approaches from experimental cognitive neuroscience revealed disproportionate episodic memory impairments in schizophrenia (Sz) under high cognitive demand relational encoding conditions and relatively unimpaired performance under item-specific encoding conditions. These specific deficits in component processes of episodic memory reflect impaired activation and connectivity within specific elements of frontal-medial temporal lobe circuits, with a central role for the dorsolateral prefrontal cortex (DLPFC), relatively intact function of ventrolateral prefrontal cortex and variable results in the hippocampus. We propose that memory deficits can be understood within the broader context of cognitive deficits in Sz, where impaired DLPFC-related cognitive control has a broad impact across multiple cognitive domains. The therapeutic implications of these findings are discussed.

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.

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.

Effect of retrieval effort and switching demand on fMRI activation during semantic word generation in schizophrenia.

Verbal fluency deficits in schizophrenia are difficult to interpret because the tasks are multi-factorial and groups differ in total words generated. We manipulated retrieval and switching demands by requiring alternation between over-learned sequences in which retrieval is relatively automatic (OS) and semantic categories requiring increased retrieval effort (SC). Controlled processing was also manipulated by including switching and non-switching conditions, and formal thought disorder (FTD) was assessed with the communication disorders index (CDI). The OS/SC semantic fluency paradigm was administered during fMRI to 13 patients with schizophrenia and 14 matched controls. Images were acquired on a 3 Tesla Siemens scanner using compressed image acquisition to allow for cued overt word production. Subjects alternated between OS, SC, OS-switch, SC-switch, and baseline blocks. Images were pre-processed in SPM-2, and a two-stage random effects analysis tested within and between group contrasts. There were no group performance differences. fMRI analysis did not reveal any group differences during the OS non-switching condition. Both groups produced expected activation in bilateral prefrontal and inferior parietal regions. However, during the SC condition patients had greater activation than controls in left prefrontal, right anterior cingulate, right superior temporal, bilateral thalamus, and left parietal regions. There was also evidence of patient over-activation in prefrontal, superior temporal, superior parietal, and visual association areas when a switching component was added. FTD was negatively correlated with BOLD response in the right anterior cingulate, cuneus and superior frontal gyrus during increased retrieval demand, and positively correlated with fMRI activation in the left lingual gyrus, right fusiform gyrus and left superior parietal lobule during increased switching demand. These results indicate that patients are able to successfully perform effortful semantic fluency tasks during non-speeded conditions. When retrieval is relatively automatic there does not appear to be an effect of schizophrenia on fMRI response. However, when retrieval and controlled processing demands increase, patients have greater activation than controls despite unimpaired task performance. This inefficient BOLD response may explain why patients are slower and less accurate on standard self-paced fluency tasks.

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.

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.

Computerized neurocognitive scanning: I. Methodology and validation in healthy people.

Neuropsychological testing batteries are applied in neurobehavioral evaluations of brain disorders, including neuropsychiatric populations. They are lengthy, require expert administrators and professional scorers, and are prone to data handling errors. We describe a brief computerized neurocognitive "scan" that assesses similar domains with adequate reliability. The scan and a traditional battery were administered to a sample of 92 healthy individuals (44 men, 48 women) in a counterbalanced order. Both approaches showed a significant "sex-typical" gradient, with women outperforming men in verbal memory relative to spatial tasks. Both methods also yielded similar profiles of sex differences, with the additional computerized measure of face memory showing better performance in women. Age effects were evident for both methods, but the computerized scan isolated the effects to speed rather than accuracy. Therefore, the computerized scan has favorable reliability and construct validity and can be applied efficiently to study healthy variability related to age and gender.

Computerized neurocognitive scanning: II. The profile of schizophrenia.

Cognitive dysfunction in schizophrenia is well established with neuropsychological batteries, which have assessed multiple domains indicating diffuse deficits especially in processing related to frontotemporal systems. Two studies are reported examining the feasibility of the computerized neurocognitive scan to assess differential deficits in schizophrenia. In Study 1, we tested 53 patients and 71 controls with the traditional and computerized assessments counterbalanced in order. Both showed comparable generalized impairment in schizophrenia with differential deficits in executive functions and memory. The profile was replicated in Study 2 in a new sample of 68 patients and 37 controls, receiving only the computerized scan. The combined sample showed robust correlations between performance on both speed and accuracy measures of the neurocognitive scan and clinical variables, including premorbid adjustment, onset age, illness duration, quality of life, and severity of negative symptoms. These correlations were higher and more prevalent in women than men, who showed correlations predominantly for speed rather than accuracy. Neuroleptic exposure was associated with poorer performance only for speed of memory processing, and in men, this association was seen only for typical neuroleptics. We conclude that the computerized neurocognitive scan can be applied reliably in people with schizophrenia, yielding data that support its construct and criterion validity.

Effect of schizophrenia on frontotemporal activity during word encoding and recognition: a PET cerebral blood flow study.

OBJECTIVE: Neuropsychological studies have shown that deficits in verbal episodic memory in schizophrenia occur primarily during encoding and retrieval stages of information processing. The current study used positron emission tomography to examine the effect of schizophrenia on change in cerebral blood flow (CBF) during these memory stages. METHOD: CBF was measured in 23 healthy comparison subjects and 23 patients with schizophrenia during four conditions: resting baseline, motor baseline, word encoding, and word recognition. The motor baseline was used as a reference that was subtracted from encoding and recognition conditions by using statistical parametric mapping. RESULTS: Patients' performance was similar to that of healthy comparison subjects. During word encoding, patients showed reduced activation of left prefrontal and superior temporal regions. Reduced left prefrontal activation in patients was also seen during word recognition, and additional differences were found in the left anterior cingulate, left mesial temporal lobe, and right thalamus. Although patients' performance was similar to that of healthy comparison subjects, left inferior prefrontal activation was associated with better performance only in the comparison subjects. CONCLUSIONS: Left frontotemporal activation during episodic encoding and retrieval, which is associated with better recognition in healthy people, is disrupted in schizophrenia despite relatively intact recognition performance and right prefrontal function. This may reflect impaired strategic use of semantic information to organize encoding and facilitate retrieval.

Comparison of the continuous performance test with and without working memory demands in healthy controls and patients with schizophrenia.

The Penn Continuous Performance Test (PCPT), a measure of sustained visual attention developed for use in functional neuroimaging studies, was compared with a standard CPT developed by Gordon Diagnostic Systems (GDS; Vigilance subtest). The PCPT and the GDS CPT were administered with a standard neuropsychological battery to 68 healthy adults to assess reliability and construct validity. The test had adequate internal consistency, and convergent validity was established through significant correlations between measures of efficiency on the PCPT and the GDS CPT. With the exception of a significant correlation between efficiency measures on the GDS CPT and a measure of auditory sustained attention, neither version of the CPT correlated significantly with other measures in the battery. Factor analysis showed that the PCPT loaded with the GDS CPT. In 39 patients with schizophrenia and 39 matched, healthy controls, equivalent impairment was evident on the two CPT tasks. Neither version correlated significantly with symptom measurements. These results support previous conclusions that sustained visual attention in schizophrenia is a core information processing deficit, not directly related to symptomatology.

Neuropsychological differences among empirically derived clinical subtypes of schizophrenia.

Neuropsychological profile differences between empirically derived clinical subtypes of schizophrenia were examined. Two hundred five patients and 209 demographically matched controls were administered a neuropsychological battery examining 8 domains. Subtypes included negative, disorganized, paranoid, Schneiderian, and mild. All subtypes displayed a neuropsychological profile of generalized impairment with greater deficits in learning, memory, and attention. Results were suggestive of diffuse cognitive dysfunction in schizophrenia with more severe deficits in learning and memory relative to executive skills. This pattern of greater learning and memory impairment was pronounced for disorganized patients. In contrast, paranoid patients outperformed disorganized and negative patients in several domains. These findings reflect bilateral frontal-temporal dysfunction, particularly in disorganized and negative patients. Subtype differences highlight the importance of conceptualizing schizophrenia as a multifocal disorder.

Controlled and automatic processing during animal word list generation in schizophrenia.

Controlled and automatic aspects of semantic-associative functioning in schizophrenia were investigated by evaluating performance on animal word list generation (WLG). Responses from control (n = 47) and patient (n = 38) participants were subjected to multidimensional scaling (MDS), cluster analysis (CA), and indices on the basis of number of shared attributes (SA) between consecutive responses. Patient MDS results accounted for less variance and contained more error than control data. CA results yielded fewer and less clear animal-response subgroups among patients yet demonstrated intact associations among strongly related exemplars. The SA indices revealed better clustering and more effective switching among response clusters in controls than patients. Results suggest that animal WLG in schizophrenia is compromised both by aberrant automatic semantic-associative network activation and by controlled processes such as search, access, and selection. This pattern is consistent with prominent frontotemporal pathology evident in the disorder.

Hemispheric activation of anterior and inferior prefrontal cortex during verbal encoding and recognition: a PET study of healthy volunteers.

Evidence of bilateral prefrontal activation during memory encoding and retrieval has increased attention given to anatomical subdivisions within the prefrontal cortex. The current study examined anterior and inferior aspects of the prefrontal cortex to determine their degree of functional and hemispheric overlap during encoding and recognition. Cerebral blood flow of 25 healthy volunteers was measured using PET (15)O-water methods during four conditions: resting baseline, sequential finger movement, word encoding, and word recognition. Resting and motor images were averaged to provide a single reference that was subtracted from encoding and recognition using statistical parametric mapping (SPM96). Memory conditions were also subtracted from each other to identify differences in regional activity. Subjects performed well (86% correct) and had a slightly conservative response bias. Baseline subtraction from encoding revealed focal activation of left inferior prefrontal cortex (area 45) without significant contralateral activation. Recognition minus baseline subtraction produced a focal right anterior prefrontal activation (areas 9 and 10) that was not present in the left hemisphere. Bilateral effects were seen in area 45 during recognition. Subtraction of memory tasks from each other did not reveal any areas of greater activity during encoding. However, the recognition task produced greater activation in right area 9 extending into the anterior cingulate. Greater activity during recognition was also observed in left insula and bilateral visual integration areas. These results are discussed in relation to the prevailing model of prefrontal hemispheric asymmetry during episodic memory.

Sex differences in brain-behavior relationships between verbal episodic memory and resting regional cerebral blood flow.

Women have better verbal memory, and higher rates of resting regional cerebral blood flow (rCBF). This study examined whether there are also sex differences in the relationship between verbal episodic memory and resting rCBF. Twenty eight healthy right-handed volunteers (14 male, 14 female) underwent a neuropsychological evaluation and a Positron Emission Tomography (PET) (15)O-water study. Immediate and delayed recall was measured on the logical memory subtest of the Wechsler Memory Scale - Revised (WMS-R), and on the California Verbal Learning Test (CVLT). Resting rCBF (ml/100 g/min) was calculated for four frontal, four temporal, and four limbic regions of interest (ROIs). Women had better immediate recall on both WMS-R and CVLT tasks. Sex differences in rCBF were found for temporal lobe regions. Women had greater bilateral blood flow in a mid-temporal brain region. There were also sex differences in rCBF correlations with performance. Women produced positive correlations with rCBF laterality in the temporal pole. Greater relative CBF in the left temporal pole was associated with better WMS-R immediate and delayed recall in women only. These results suggest that trait differences in temporal pole brain-behavior relationships may relate to sex differences in verbal episodic memory.

Working memory constrains abstraction in schizophrenia.

BACKGROUND: Abstraction has long been considered an area of differential cognitive deficit in schizophrenia, primarily because of patients' poor performance on the Wisconsin Card Sorting Test (WCST). Yet, the complexity and multidimensional nature of the WCST increases the likelihood that several different cognitive processes, perhaps mediated by different neural systems, are being tapped. METHODS: In the current study, the Abstraction and Working Memory (AIM) task was designed to disentangle abstraction and working memory so that the effects of each cognitive domain could be independently analyzed. The AIM task and a battery of neuropsychological tests were administered to 62 patients with schizophrenia and 62 matched healthy volunteers. RESULTS: Whereas patients with schizophrenia demonstrated deficits in simple abstraction, they were disproportionately impaired with the addition of a minimal memory requirement. CONCLUSIONS: Group differences on WCST performance appear to be attributable to patients' inability to maintain information over a short delay, before that information is used for more complex cognitive operations.

Marchiafava-Bignami disease: literature review and case report.

OBJECTIVE: We postulated that disruption of callosal pathways as occurs in Marchiafava-Bignami disease (MBD) is associated with marked impairment in brain functioning as measured by cognitive assessment and neuroimaging. BACKGROUND: MBD is considered to be a rare and severe complication of chronic alcoholism. It is characterized by necrosis and subsequent atrophy of the corpus callosum, which is the major brain structure connecting corresponding areas of both hemispheres. METHODS: We review the existing literature on MBD with respect to conceptualization, theories of pathogenesis, forms of the disease, and neuroimaging and neuropsychological findings. We then present the case of a middle-aged man with MBD who underwent extensive clinical, neuropsychological, and neuroimaging studies. RESULTS: Neuropsychological evaluation revealed a pattern of severe global dementia. Magnetic resonance imaging showed moderate atrophy of anterior callosal regions and severe atrophy of posterior callosal regions in the setting of cortical and subcortical atrophy. Resting metabolism positron emission tomography revealed decreased glucose metabolism most pronounced in subcortical and mesial frontal regions. The differential diagnosis, function of the corpus callosum, and potential limitations of our case study are discussed. CONCLUSIONS: On account of the history, clinical presentation, and results of magnetic resonance imaging of the brain, we diagnosed our patient with chronic MBD.

Neuropsychological laterality indices of schizophrenia: interactions with gender.

Neurobehavioral laterality indices were examined across motor, sensory, language versus spatial, and verbal memory versus spatial memory domains for 75 patients with schizophrenia (45 men, 30 women) and 75 demographically matched healthy controls. Patients were impaired across tasks, and laterality results varied by domain. There was no evidence for diagnosis by hemisphere interactions in motor, sensory, or memory tasks. However, patients were more impaired in language than in spatial domains, which suggests relatively greater left hemisphere dysfunction. This finding was mediated by the sex of the participant. While patients as a group showed greater language than spatial impairment, male patients showed expected superiority in spatial relative to language performance, whereas female patients performed the same on both functions. These results underscore the importance of examining sex differences in laterality effects. The findings also demonstrate that, although the left hemisphere model of schizophrenia may be partially supported by data on higher cognitive functions, this support does not extend to more basic motor and sensory domains.

Frontotemporal cerebral blood flow change during executive and declarative memory tasks in schizophrenia: a positron emission tomography study.

Schizophrenia affects prefrontal and temporal-limbic networks. These regions were examined by contrasting regional cerebral blood flow (rCBF) during executive (Wisconsin Card Sorting Test [WCST]), and declarative memory tasks (Paired Associate Recognition Test [PART]). The tasks, and a resting baseline, were administered to 15 patients with schizophrenia and 15 healthy controls during 10 min positron emission tomography 15O-water measures of rCBF. Patients were worse on both tasks. Controls activated inferior frontal, occipitotemporal, and temporal pole regions for both tasks. Similar results were obtained for controls matched to level of patient performance. Patients showed no activation of hypothesized regions during the WCST and activated the dorsolateral prefrontal cortex during the PART. On the PART, occipitotemporal activation correlated with better performance for controls only. Better WCST performance correlated with CBF increase in prefrontal regions for controls and in the parahippocampal gyrus for patients. Results suggest that schizophrenia may involve a breakdown in the integration of a frontotemporal network that is responsive to executive and declarative memory demands in healthy individuals.