J. Daniel Ragland

Beyond hypofrontality: A quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia

Although there is considerable evidence that patients with schizophrenia fail to activate the dorsolateral prefrontal cortex (DLPFC) to the degree seen in normal comparison subjects when performing working memory or executive tasks, hypofrontality may be coupled with relatively increased activity in other brain regions. However, most imaging studies of working memory in schizophrenia have focused on DLPFC activity. The goal of this work is to review functional neuroimaging studies that contrasted patients with schizophrenia and healthy comparison subjects during a prototypical working memory task, the n‐back paradigm, to highlight areas of hyper‐ and hypoactivation in schizophrenia. We utilize a quantitative meta‐analysis method to review 12 imaging studies where patients with schizophrenia were contrasted with healthy comparison subjects while performing the n‐back paradigm. Although we find clear support for hypofrontality, we also document consistently increased activation in anterior cingulate and left frontal pole regions in patients with schizophrenia compared to that in controls. These data suggest that whereas reduced DLPFC activation is reported consistently in patients with schizophrenia relative to healthy subjects, abnormal activation patterns are not restricted to this region, raising questions as to whether the pathophysiological dysfunction in schizophrenia is specific to the DLPFC and about the relationship between impaired performance and aberrant activation patterns. The complex pattern of hyper‐ and hypoactivation consistently found across studies implies that rather than focusing on DLPFC dysregulation, researchers should consider the entire network of regions involved in a given task when making inferences about the biological mechanisms of schizophrenia. Hum Brain Mapp 25:60–69, 2005.

Images of desire: Food-craving activation during fMRI

Food craving (defined as an intense desire to eat a specific food) is of interest because it is extremely common and because it influences obesity or nutritional status. It has also been suggested that food craving may be the evolutionary source for cravings of all kinds including cravings for drugs and alcohol. Yet, little is known about the functional neuroanatomy of food craving. We report here the first functional magnetic resonance imaging (fMRI) study to explicitly examine food craving. A two-part technique was used to produce the food cravings. Threshold was reduced through a diet manipulation (monotonous diet) and cravings were triggered during blood oxygenation level-dependent (BOLD) fMRI sessions by having subjects imagine the sensory properties of favorite foods (a cue-induction technique). Subjects were also asked to imagine the monotonous diet (which they did not crave). Diet condition had an activating effect on both behavioral (reports of craving) and fMRI measures. Craving-related changes in fMRI signal were identified in the hippocampus, insula, and caudate, three areas reported to be involved in drug craving. Thus, this work supports the common substrate hypothesis for food and drug cravings.

Neuropsychological evidence supporting a neurodevelopmental model of schizophrenia: a longitudinal study

The stability of neuropsychological performance in schizophrenia and its relationship to clinical change was contrasted between 60 patients with schizophrenia (30 first-episode, 30 previously treated) and 38 healthy controls using a comprehensive neuropsychological battery and clinical scales administered at intake and at a 19-month follow-up. Consistent with the neurodevelopmental model of schizophrenia, patients demonstrated deficits in cognitive performance at initial testing and did not show decline at follow-up. There were no differences in neuropsychological performance over time between first-episode and previously treated patients, nor between male and female patients or controls. As expected, patients improved clinically with treatment with respect to both positive and negative symptoms. First-episode patients improved more on the positive symptoms of hallucination and delusion; male and female patients showed equivalent clinical improvement. Clinical improvement correlated positively with neuropsychological change, with improved negative symptomatology accounting for most of the significant correlations.

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.

GABA Concentration Is Reduced in Visual Cortex in Schizophrenia and Correlates with Orientation-Specific Surround Suppression

The neural mechanisms underlying cognitive deficits in schizophrenia remain essentially unknown. The GABA hypothesis proposes that reduced neuronal GABA concentration and neurotransmission results in cognitive impairments in schizophrenia. However, few in vivo studies have directly examined this hypothesis. We used magnetic resonance spectroscopy (MRS) at high field to measure visual cortical GABA levels in 13 subjects with schizophrenia and 13 demographically matched healthy control subjects. We found that the schizophrenia group had an ∼10% reduction in GABA concentration. We further tested the GABA hypothesis by examining the relationship between visual cortical GABA levels and orientation-specific surround suppression (OSSS), a behavioral measure of visual inhibition thought to be dependent on GABAergic synaptic transmission. Previous work has shown that subjects with schizophrenia exhibit reduced OSSS of contrast discrimination (Yoon et al., 2009). For subjects with both MRS and OSSS data (n = 16), we found a highly significant positive correlation (r = 0.76) between these variables. GABA concentration was not correlated with overall contrast discrimination performance for stimuli without a surround (r = −0.10). These results suggest that a neocortical GABA deficit in subjects with schizophrenia leads to impaired cortical inhibition and that GABAergic synaptic transmission in visual cortex plays a critical role in OSSS.

Neurocognitive Endophenotypes in a Multiplex Multigenerational Family Study of Schizophrenia

OBJECTIVE Genetic factors contribute to the development of schizophrenia where cognitive dysfunction is a hallmark. The purpose of this article was to examine computerized neurocognitive measures as candidate endophenotypic markers of liability for schizophrenia in a genetically informative cohort. METHOD European Americans from 35 multiplex multigenerational families (N=349) and healthy participants (N=154) underwent clinical assessments and neurocognitive measurements and provided blood samples. The neurocognitive measures included performance (accuracy and speed) from a computerized battery that assessed abstraction/mental flexibility; attention; verbal, face, and spatial memory; spatial processing; sensorimotor processing; and emotion intensity discrimination. RESULTS Probands, relatives, and comparison subjects differed from each other in performance. Probands demonstrated greatest impairment relative to comparison subjects, followed by family members. Liability for schizophrenia affected the speed-accuracy tradeoff differently for specific neurocognitive domains. Significant heritability estimates were obtained for accuracy of verbal, facial, and spatial memory and spatial and emotion processing. For speed, estimates of heritability were significant for abstraction/mental flexibility, attention, face memory, and spatial and sensorimotor processing. CONCLUSIONS In a multigenerational multiplex design, the authors demonstrated that neurocognitive measures are associated with schizophrenia, differentiate unaffected relatives from comparison subjects, and may have significant presumed heritability. Therefore, they are endophenotypes suitable for genetic studies. Accuracy and speed can be differentially sensitive to presumed genetic liability.

General and Specific Cognitive Deficits in Schizophrenia: Goliath Defeats David?

BACKGROUND Our earlier work suggested that the cognitive performance impairment in individuals with schizophrenia relative to healthy control subjects was generalized, cutting across narrower cognitive ability dimensions. Current analyses sought to extend these findings. METHODS Seventeen neuropsychological variables, available for 148 schizophrenia subjects and 157 control subjects, were subjected to structural equation modeling. Analyses incorporated a hierarchical model, grouping the variables into six familiar cognitive domains and linking these to a higher-order, general cognitive ability factor. We added diagnosis to the model as a grouping factor and estimated loadings from diagnosis to the general cognitive factor and, separately, to the domain factors. RESULTS The fit of the final model was good (e.g., Non-Normed Fit Index [NNFI] = .988). Approximately 63.6% of the diagnosis-related variance in cognitive performance was mediated through the general factor, with smaller direct effects on verbal memory (13.8%) and processing speed (9.1%). CONCLUSIONS The schizophrenia cognitive deficit is largely generalized across performance domains, with small, direct effects of diagnostic group confined to selected domains. This generalized deficit sometimes has been seen as a function of the psychometric limitations of traditional cognitive test batteries. Alternatively, it may be a fundamental manifestation of schizophrenia, with similarly general neurobiological underpinnings.

Working memory for complex figures: An fMRI comparison of letter and fractal n-back tasks

n-back letter and fractal tasks were administered to 11 participants during functional magnetic resonance imaging to test process specificity theories of prefrontal cortex (PFC) function and assess task validity. Tasks were matched on accuracy, but fractal n-back responses were slower and more conservative. Maintenance (1-back minus 0-back) activated inferior parietal and dorsolateral PFC, with additional activation in right ventrolateral PFC during letter n-back and left lingual gyrus during fractal n-back. Maintenance plus manipulation (2-back minus 0-back) activated inferior parietal, Brocas area, insula, and dorsolateral and ventral PFC, with greater right dorsolateral PFC activation for letter n-back. Manipulation only (2-back minus 1-back) produced additional and equivalent dorsolateral PFC and anterior cingulate activation in both tasks. Results support fractal n-back validity and indicate substantial overlap in working memory functions of dorsal and ventral PFC.

Association of Dorsolateral Prefrontal Cortex Dysfunction With Disrupted Coordinated Brain Activity in Schizophrenia: Relationship With Impaired Cognition, Behavioral Disorganization, and Global Function

OBJECTIVE Although deficits in cognitive control are thought to contribute to the diverse cognitive and behavioral abnormalities in individuals with schizophrenia, the neural mechanisms underlying these deficits remain unclear. In this event-related functional magnetic resonance imaging (fMRI) study, the authors tested the hypothesis that during cognitive control tasks, impaired activation of the dorsolateral prefrontal cortex in schizophrenia patients is associated with disrupted coordinated activity between this prefrontal region and a distributed brain network that supports cognitive control. METHOD Through the use of an event-related design, 25 patients with first-episode schizophrenia and 24 healthy comparison subjects, matched on demographic characteristics, were assessed while performing a version of the AX continuous performance task. Functional neuroimaging data were analyzed using 1) univariate (region-of-interest blood-oxygen-level-dependent [BOLD] time series and whole brain voxel-wise regression) analysis to confirm the presence of dorsolateral prefrontal cortex dysfunction and 2) multivariate analysis to examine dorsolateral prefrontal cortex functional connectivity. In addition, correlations between dorsolateral prefrontal cortex functional connectivity and the following variables were investigated: clinical symptoms, task performance, and coordinated brain activity associated with cognitive control. RESULTS Schizophrenia patients exhibited a specific deficit in cognitive control, with significantly reduced accuracy in the BX condition relative to any other condition. Univariate fMRI revealed dorsolateral prefrontal cortex dysfunction during the high cognitive control condition. Multivariate analysis revealed significant impairment in functional connectivity between the dorsolateral prefrontal cortex and task-relevant brain regions. Significant correlations were also found between dorsolateral prefrontal cortex functional connectivity and cognitive performance, behavioral disorganization, and global functioning. CONCLUSIONS These findings suggest that there is an association between decreased dorsolateral prefrontal cortex activity and connectivity and a task-related neural network. This deficit in coordinated brain activity may result in the disabling disorganization symptoms related to impaired cognition in individuals with schizophrenia.

Differential connectivity of perirhinal and parahippocampal cortices within human hippocampal subregions revealed by high-resolution functional imaging

Numerous studies support the importance of the perirhinal cortex (PRC) and parahippocampal cortex (PHC) in episodic memory. Theories of PRC and PHC function in humans have been informed by neuroanatomical studies of these regions obtained in animal tract-tracing studies, but knowledge of the connectivity of PHC and PRC in humans is limited. To address this issue, we used resting-state functional magnetic resonance imaging to compare the intrinsic functional connectivity profiles associated with the PRC and PHC both across the neocortex and within the subfields of the hippocampus. In Experiment 1, we acquired standard-resolution whole-brain resting-state fMRI data in 15 participants, and in Experiment 2, we acquired high-resolution resting-state fMRI data targeting the hippocampus in an independent sample of 15 participants. Experiment 1 revealed that PRC showed preferential connectivity with the anterior hippocampus, whereas PHC showed preferential connectivity with posterior hippocampus. Experiment 2 indicated that this anterior–posterior functional connectivity dissociation was more evident for subfields CA1 and subiculum than for a combined CA2/CA3/dentate gyrus region. Finally, whole-brain analyses from Experiment 1 revealed preferential PRC connectivity with an anterior temporal and frontal cortical network, and preferential PHC connectivity with a posterior medial temporal, parietal, and occipital network. These results suggest a framework for refining models of the functional organization of the human medial temporal lobes in which the PRC and PHC are associated with distinct neocortical pathways that, in turn, may differentially interact with regions along the anterior–posterior axis of the hippocampus.