The organization of frontostriatal brain wiring in non-affective early psychosis compared with healthy subjects using a novel diffusion imaging fiber cluster analysis.

BACKGROUND: Alterations in brain connectivity may underlie neuropsychiatric conditions such as schizophrenia. We here assessed the degree of convergence of frontostriatal fiber projections in 56 young adult healthy controls (HCs) and 108 matched Early Psychosis-Non-Affective patients (EP-NAs) using our novel fiber cluster analysis of whole brain diffusion magnetic resonance imaging tractography. METHODS: Using whole brain tractography and our fiber clustering methodology on harmonized diffusion magnetic resonance imaging data from the Human Connectome Project for Early Psychosis we identified 17 white matter fiber clusters that connect frontal cortex (FCtx) and caudate (Cd) per hemisphere in each group. To quantify the degree of convergence and, hence, topographical relationship of these fiber clusters, we measured the inter-cluster mean distances between the endpoints of the fiber clusters at the level of the FCtx and of the Cd, respectively. RESULTS: We found (1) in both groups, bilaterally, a non-linear relationship, yielding convex curves, between FCtx and Cd distances for FCtx-Cd connecting fiber clusters, driven by a cluster projecting from inferior frontal gyrus; however, in the right hemisphere, the convex curve was more flattened in EP-NAs; (2) that cluster pairs in the right (p = 0.03), but not left (p = 0.13), hemisphere were significantly more convergent in HCs vs EP-NAs; (3) in both groups, bilaterally, similar clusters projected significantly convergently to the Cd; and, (4) a significant group by fiber cluster pair interaction for 2 right hemisphere fiber clusters (numbers 5, 11; p = .00023; p = .00023) originating in selective PFC subregions. CONCLUSIONS: In both groups, we found the FCtx-Cd wiring pattern deviated from a strictly topographic relationship and that similar clusters projected significantly more convergently to the Cd. Interestingly, we also found a significantly more convergent pattern of connectivity in HCs in the right hemisphere and that 2 clusters from PFC subregions in the right hemisphere significantly differed in their pattern of connectivity between groups.

The Organization of Frontostriatal Brain Wiring in Healthy Subjects Using a Novel Diffusion Imaging Fiber Cluster Analysis.

To assess normal organization of frontostriatal brain wiring, we analyzed diffusion magnetic resonance imaging (dMRI) scans in 100 young adult healthy subjects (HSs). We identified fiber clusters intersecting the frontal cortex and caudate, a core component of associative striatum, and quantified their degree of deviation from a strictly topographic pattern. Using whole brain dMRI tractography and an automated tract parcellation clustering method, we extracted 17 white matter fiber clusters per hemisphere connecting the frontal cortex and caudate. In a novel approach to quantify the geometric relationship among clusters, we measured intercluster endpoint distances between corresponding cluster pairs in the frontal cortex and caudate. We show first, the overall frontal cortex wiring pattern of the caudate deviates from a strictly topographic organization due to significantly greater convergence in regionally specific clusters; second, these significantly convergent clusters originate in subregions of ventrolateral, dorsolateral, and orbitofrontal prefrontal cortex (PFC); and, third, a similar organization in both hemispheres. Using a novel tractography method, we find PFC-caudate brain wiring in HSs deviates from a strictly topographic organization due to a regionally specific pattern of cluster convergence. We conjecture cortical subregions projecting to the caudate with greater convergence subserve functions that benefit from greater circuit integration.

Sensory-based and higher-order operations contribute to abnormal emotional prosody processing in schizophrenia: an electrophysiological investigation.

BACKGROUND: Schizophrenia is characterized by deficits in emotional prosody (EP) perception. However, it is not clear which stages of processing prosody are abnormal and whether the presence of semantic content contributes to the abnormality. This study aimed to examine event-related potential (ERP) correlates of EP processing in 15 chronic schizophrenia individuals and 15 healthy controls. METHOD: A total of 114 sentences with neutral semantic content [sentences with semantic content (SSC) condition] were generated by a female speaker (38 with happy, 38 with angry, and 38 with neutral intonation). The same sentences were synthesized and presented in the 'pure prosody' sentences (PPS) condition where semantic content was unintelligible. RESULTS: Group differences were observed for N100 and P200 amplitude: patients were characterized by more negative N100 for SSC, and more positive P200 for angry and happy SSC and happy PPS. Correlations were found between delusions and P200 amplitude for happy SSC and PPS. Higher error rates in the recognition of EP were also observed in schizophrenia: higher error rates in neutral SSC were associated with reduced N100, and higher error rates in angry SSC were associated with reduced P200. CONCLUSIONS: These results indicate that abnormalities in prosody processing occur at the three stages of EP processing, and are enhanced in SSC. Correlations between P200 amplitude for happy prosody and delusions suggest a role that abnormalities in the processing of emotionally salient acoustic cues may play in schizophrenia symptomatology. Correlations between ERP and behavioral data point to a relationship between early sensory abnormalities and prosody recognition in schizophrenia.

Abnormal inhibitory processes in semantic networks in schizophrenia.

Abnormal language in schizophrenia has been regarded as a hallmark of this disorder. Language abnormalities include loose and unusual associations, tangentiality, and inability to maintain a topic. Recent theories of language dysfunction have invoked working memory abnormalities, as well as abnormal processes within semantic memory in schizophrenia. Two views, often construed as opposing, have been offered to account for language peculiarities in schizophrenia: one holds that initial processes of activation are abnormal while the other holds that late processes of context utilization might be disturbed. We suggest that these views may be complementary rather than mutually exclusive. Given the relative paucity of data on the early processes within semantic networks, we present new evidence using ERP short SOA paradigm that these processes are abnormal in schizophrenia. Furthermore, reduced N400 in the unrelated condition found in this study suggests that the abnormality was related to inefficient early inhibitory processes.

Diffusion tractography of the fornix in schizophrenia.

BACKGROUND: White matter fiber tracts, especially those interconnecting the frontal and temporal lobes, are likely implicated in pathophysiology of schizophrenia. Very few studies, however, have focused on the fornix, a compact bundle of white matter fibers, projecting from the hippocampus to the septum, anterior nucleus of the thalamus and the mamillary bodies. Diffusion Tensor Imaging (DTI), and a new post-processing method, fiber tractography, provides a unique opportunity to visualize and to quantify entire trajectories of fiber bundles, such as the fornix, in vivo. We applied these techniques to quantify fornix diffusion anisotropy in schizophrenia. METHODS: DTI images were used to evaluate the left and the right fornix in 36 male patients diagnosed with chronic schizophrenia and 35 male healthy individuals, group matched on age, parental socioeconomic status, and handedness. Regions of interest were drawn manually, blind to group membership, to guide tractography, and fractional anisotropy (FA), a measure of fiber integrity, was calculated and averaged over the entire tract for each subject. The Doors and People test (DPT) was used to evaluate visual and verbal memory, combined recall and combined recognition. RESULTS: Analysis of variance was performed and findings demonstrated a difference between patients with schizophrenia and controls for fornix FA (p=0.006). Protected post-hoc independent sample t-tests demonstrated a bilateral FA decrease in schizophrenia, compared with control subjects (left side: p=0.048; right side p=0.006). Higher fornix FA was statistically significantly correlated with DPT and measures of combined visual memory (r=0.554, p=0.026), combined verbal memory (r=0.647, p=0.007), combined recall (r=0.516, p=0.041), and combined recognition (r=0.710, p=0.002) for the control group. No such statistically significant correlations were found in the patient group. CONCLUSIONS: Our findings show the utility of applying DTI and tractography to study white matter fiber tracts in vivo in schizophrenia. Specifically, we observed a bilateral disruption in fornix integrity in schizophrenia, thus broadening our understanding of the pathophysiology of this disease.

DTI and MTR abnormalities in schizophrenia: analysis of white matter integrity.

Diffusion tensor imaging (DTI) studies in schizophrenia demonstrate lower anisotropic diffusion within white matter due either to loss of coherence of white matter fiber tracts, to changes in the number and/or density of interconnecting fiber tracts, or to changes in myelination, although methodology as well as localization of such changes differ between studies. The aim of this study is to localize and to specify further DTI abnormalities in schizophrenia by combining DTI with magnetization transfer imaging (MTI), a technique sensitive to myelin and axonal alterations in order to increase specificity of DTI findings. 21 chronic schizophrenics and 26 controls were scanned using Line-Scan-Diffusion-Imaging and T1-weighted techniques with and without a saturation pulse (MT). Diffusion information was used to normalize co-registered maps of fractional anisotropy (FA) and magnetization transfer ratio (MTR) to a study-specific template, using the multi-channel daemon algorithm, designed specifically to deal with multidirectional tensor information. Diffusion anisotropy was decreased in schizophrenia in the following brain regions: the fornix, the corpus callosum, bilaterally in the cingulum bundle, bilaterally in the superior occipito-frontal fasciculus, bilaterally in the internal capsule, in the right inferior occipito-frontal fasciculus and the left arcuate fasciculus. MTR maps demonstrated changes in the corpus callosum, fornix, right internal capsule, and the superior occipito-frontal fasciculus bilaterally; however, no changes were noted in the anterior cingulum bundle, the left internal capsule, the arcuate fasciculus, or inferior occipito-frontal fasciculus. In addition, the right posterior cingulum bundle showed MTR but not FA changes in schizophrenia. These findings suggest that, while some of the diffusion abnormalities in schizophrenia are likely due to abnormal coherence, or organization of the fiber tracts, some of these abnormalities may, in fact, be attributed to or coincide with myelin/axonal disruption.

An fMRI study of semantic processing in men with schizophrenia.

As a means toward understanding the neural bases of schizophrenic thought disturbance, we examined brain activation patterns in response to semantically and superficially encoded words in patients with schizophrenia. Nine male schizophrenic and 9 male control subjects were tested in a visual levels of processing (LOP) task first outside the magnet and then during the fMRI scanning procedures (using a different set of words). During the experiments visual words were presented under two conditions. Under the deep, semantic encoding condition, subjects made semantic judgments as to whether the words were abstract or concrete. Under the shallow, nonsemantic encoding condition, subjects made perceptual judgments of the font size (uppercase/lowercase) of the presented words. After performance of the behavioral task, a recognition test was used to assess the depth of processing effect, defined as better performance for semantically encoded words than for perceptually encoded words. For the scanned version only, the words for both conditions were repeated in order to assess repetition-priming effects. Reaction times were assessed in both testing scenarios. Both groups showed the expected depth of processing effect for recognition, and control subjects showed the expected increased activation of the left inferior prefrontal cortex (LIPC) under semantic encoding relative to perceptual encoding conditions as well as repetition priming for semantic conditions only. In contrast, schizophrenics showed similar patterns of fMRI activation regardless of condition. Most striking in relation to controls, patients showed decreased LIFC activation concurrent with increased left superior temporal gyrus activation for semantic encoding versus shallow encoding. Furthermore, schizophrenia subjects did not show the repetition priming effect, either behaviorally or as a decrease in LIPC activity. In patients with schizophrenia, LIFC underactivation and left superior temporal gyrus overactivation for semantically encoded words may reflect a disease-related disruption of a distributed frontal temporal network that is engaged in the representation and processing of meaning of words, text, and discourse and which may underlie schizophrenic thought disturbance.

Perceptual asymmetries in schizophrenia: subtype differences in left hemisphere dominance for dichotic fused words.

OBJECTIVE: Dichotic listening techniques have been used to study hemispheric dominance for language in schizophrenia. The authors' goal was to compare subjects with paranoid and undifferentiated subtypes of schizophrenia. METHOD: The Fused Rhymed Words Test was used to compare perceptual asymmetries in 16 patients with paranoid schizophrenia, 28 patients with undifferentiated schizophrenia, and 29 healthy comparison subjects. RESULTS: Patients with paranoid schizophrenia had the largest left hemisphere advantage and patients with undifferentiated schizophrenia had the smallest. The asymmetry of healthy subjects was intermediate. Hemisphere advantage varied as a function of gender only in the patients with undifferentiated schizophrenia. CONCLUSIONS: The findings support the hypotheses that undifferentiated schizophrenia is associated with underactivation of left hemisphere resources for verbal processing and that paranoid schizophrenia is characterized by preserved left hemisphere processing.

Semantic disturbance in schizophrenia and its relationship to the cognitive neuroscience of attention.

We view schizophrenia as producing a failure of attentional modulation that leads to a breakdown in the selective enhancement or inhibition of semantic/lexical representations whose biological substrata are widely distributed across left (dominant) temporal and frontal lobes. Supporting behavioral evidence includes word recall studies that have pointed to a disturbance in connectivity (associative strength) but not network size (number of associates) in patients with schizophrenia. Paralleling these findings are recent neural network simulation studies of the abnormal connectivity effect in schizophrenia through 'lesioning' network connection weights while holding constant network size. Supporting evidence at the level of biology are in vitro studies examining N-methyl-D-aspartate (NMDA) receptor antagonists on recurrent inhibition; simulations in neural populations with realistically modeled biophysical properties show NMDA antagonists produce a schizophrenia-like disturbance in pattern association. We propose a similar failure of NMDA-mediated recurrent inhibition as a candidate biological substrate for attention and semantic anomalies of schizophrenia.

The P3 auditory event-related brain potential indexes major personality traits.

BACKGROUND: The amplitude of the auditory P3 event-related potential is reduced in patients with axes I and II disorders. Data regarding P3 amplitude and normal personality traits in healthy individuals have been inconsistent, however, although more extreme variants of dimensional traits such as neuroticism and extraversion are associated with psychiatric morbidity. METHODS: Male subjects (n = 18) recruited from the community completed the NEO Five-Factor Inventory, which consists of five scales: Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness. P3 potentials were generated using an auditory discrimination paradigm to which a third, novel stimulus was added. Partial least squares analysis, a multivariate statistical procedure, was used to test the relationship, in both stimulus conditions, between P3 amplitude at six electrode sites and the five personality dimensions. RESULTS: P3 amplitude across conditions and sites was positively related to Extraversion, Openness, Agreeableness, and Conscientiousness and negatively related to Neuroticism. CONCLUSIONS: Previous studies have shown that both reduced P3 amplitude and a high Neuroticism/low Extraversion-Openness-Agreeableness-Conscientiousness trait pattern are associated with the presence of, and risk for, substantial psychiatric morbidity. Our results suggest that processes indexed by auditory P3 amplitude are related to these broad personality dimensions in healthy individuals.

Event-related potentials elicited during a context-free homograph task in normal versus schizophrenic subjects.

Thought disorder in schizophrenia may involve abnormal semantic activation or faulty working memory maintenance. Event-related potentials (ERPs) were recorded while sentences reading "THE NOUN WAS ADJECTIVE/VERB" were presented to 34 schizophrenic and 34 control subjects. Some nouns were homographs with dominant and subordinate meanings. Their sentence ending presented information crucial for interpretation (e.g., The bank was [closed, steep]). Greatest N400 activity to subordinate homograph-meaning sentence endings in schizophrenia would reflect a semantic bias to strong associates. N400 to all endings would reflect faulty verbal working memory maintenance. Schizophrenic subjects showed N400 activity to all endings, suggesting problems in contextual maintenance independent of content, but slightly greater N400 activity to subordinate endings that correlated with the severity of psychosis. Future research should help determine whether a semantic activation bias in schizophrenia toward strong associates is reflected in ERP activity or whether this effect is overshadowed by faulty verbal working memory maintenance of context.

Abnormal angular gyrus asymmetry in schizophrenia.

OBJECTIVE: Few studies have evaluated the parietal lobe in schizophrenia despite the fact that it has an important role in attention, memory, and language-all functions that have been reported to be abnormal in schizophrenia. The inferior parietal lobule, in particular, is of interest because it is not only part of the heteromodal association cortex but also is part of the semantic-lexical network, which also includes the planum temporale. Both the inferior parietal lobule, particularly the angular gyrus of the inferior parietal lobule, and the planum temporale are brain regions that play a critical role as biological substrates of language and thought. The authors compared volume and asymmetry measures of the individual gyri of the parietal lobe by means of magnetic resonance imaging (MRI) scans. METHOD: MRI scans with a 1. 5-Tesla magnet were obtained from 15 male chronic schizophrenic and 15 comparison subjects matched for age, gender, and parental socioeconomic status. RESULTS: Inferior parietal lobule volumes showed a leftward asymmetry (left 7.0% larger than right) in comparison subjects and a reversed asymmetry (left 6.3% smaller than right) in schizophrenic subjects. The angular gyrus accounted for this difference in asymmetry, with the left angular gyrus being significantly larger (18.7%) than the right in comparison subjects, a finding that was not observed in schizophrenic patients. A further test of angular gyrus asymmetry showed a reversal of the normal left-greater-than-right asymmetry in the schizophrenic patients. CONCLUSIONS: Patients with schizophrenia showed a reversed asymmetry in the inferior parietal lobule that was localized to the angular gyrus, a structure belonging to the heteromodal association cortex as well as being part of the semantic-lexical network. This finding contributes to a more comprehensive understanding of the neural substrates of language and thought disorder in schizophrenia.

Personality traits in schizophrenia: comparison with a community sample.

The objective of this study was to compare personality trait profiles in patients with schizophrenia and healthy controls. Male outpatients with schizophrenia (N = 24) and a male nonpsychiatric community sample (N = 46) completed the NEO-FFI personality questionnaire. Multivariate analyses were used to compare mean scale scores and scale profiles for each group. The overall personality profile of clinically stable patients with schizophrenia differed significantly from that of a community sample. On individual scales, patients scored significantly higher on neuroticism and significantly lower on conscientiousness. These results confirm and extend those of previous studies that used normative data for comparison and a much longer version of the same personality questionnaire. Prospective studies of populations at risk are needed to determine whether group differences reflect a premorbid diathesis for schizophrenia or a secondary effect of serious mental illness.

Gamma frequency-range abnormalities to auditory stimulation in schizophrenia.

BACKGROUND: Basic science studies at the neuronal systems level have indicated that gamma-range (30-50 Hz) neural synchronization may be a key mechanism of information processing in neural networks, reflecting integration of various features of an object. Furthermore, gamma-range synchronization is thought to depend on the glutamatergically mediated interplay between excitatory projection neurons and inhibitory neurons utilizing gamma-aminobutyric acid (GABA), which postmortem studies suggest may be abnormal in schizophrenia. We therefore tested whether auditory neural networks in patients with schizophrenia could support gamma-range synchronization. METHODS: Synchronization of the electroencephalogram (EEG) to different rates (20-40 Hz) of auditory stimulation was recorded from 15 patients with schizophrenia and 15 sex-, age-, and handedness-matched control subjects. The EEG power at each stimulation frequency was compared between groups. The time course of the phase relationship between each stimulus and EEG peak was also evaluated for gamma-range (40 Hz) stimulation. RESULTS: Schizophrenic patients showed reduced EEG power at 40 Hz, but not at lower frequencies of stimulation. In addition, schizophrenic patients showed delayed onset of phase synchronization and delayed desynchronization to the click train. CONCLUSIONS: These data provide new information on selective deficits in early-stage sensory processing in schizophrenia, a failure to support the entrainment of intrinsic gamma-frequency oscillators. The reduced EEG power at 40 Hz in schizophrenic patients may reflect a dysfunction of the recurrent inhibitory drive on auditory neural networks.

Competence to stand trial: a neuropsychological inquiry.

How might the deconstruction of the legal theory of competence be related to modern neuropsychological models of cognition? To address this question, we examined retrospectively the relationship between clinical judgments of competence of defendants committed to a maximum security psychiatric facility and their neuropsychological test scores on measures of intelligence, memory, attention, academics, and executive function. In addition, based on both neuropsychological and legal theory, we examined whether subtypes of memory, namely episodic and semantic, and intelligence, specifically social intelligence, would have special relevance to these clinical judgements of competence. Results indicated that in relation to the defendants recommended as incompetent to stand trial (IST), defendants recommended as competent to stand trial (CST) scored significantly higher on summary indexes of psychometric intelligence, attention, and memory, especially verbal memory, but not significantly higher on tests of academics or executive function. Moreover, CST defendants scored significantly higher than did IST defendants on selective tests of episodic memory and social intelligence, but not on measures of semantic memory. Partial correlation also revealed a significant relationship between the likelihood of an IST recommendation and lower scores on tests of episodic memory and social intelligence, but not on measures of semantic memory. These findings illustrate the theoretical import of neuropsychological methods and concepts to the burgeoning nomological net known as competence.

Quantitative volumetric MRI study of the cerebellum and vermis in schizophrenia: clinical and cognitive correlates.

OBJECTIVE: Recent evidence suggests that the cerebellum may play a role in higher cognitive functions and, therefore, may play an important role in schizophrenia. METHOD: The authors used magnetic resonance imaging to measure cerebellum and vermis volume in 15 patients with schizophrenia and 15 normal comparison subjects. RESULTS: They found that 1) vermis volume was greater in patients with schizophrenia than in normal subjects, 2) greater vermis white matter volume in the patients with schizophrenia significantly correlated with severity of positive symptoms and thought disorder and with impairment in verbal logical memory, and 3) patients with schizophrenia showed a trend for more cerebellar hemispheric volume asymmetry (left greater than right). CONCLUSIONS: These data suggest that an abnormality in the vermis may contribute to the pathophysiology of schizophrenia.

Identification of neural circuits underlying P300 abnormalities in schizophrenia.

Event-related potentials (ERPs) provide a noninvasive method to evaluate neural activation and cognitive processes in schizophrenia. The pathophysiological significance of these findings would be greatly enhanced if scalp-recorded ERP abnormalities could be related to specific neural circuits and/or regions of the brain. Using quantitative approaches in which scalp-recorded ERP components are correlated with underlying neuroanatomy in schizophrenia, we focused on biophysical and statistical procedures (partial least squares) to relate the auditory P300 component to anatomic measures obtained from quantitative magnetic resonance imaging. These findings are consistent with other evidence that temporal lobe structures contribute to the generation of the scalp-recorded P300 component and that P300 amplitude asymmetry over temporal recording sites on the scalp may reflect anatomic asymmetries in the volume of the superior temporal gyrus in schizophrenia.

Cognitive dysfunction in schizophrenia: unifying basic research and clinical aspects.

Seeking to unite psychological and biological approaches, this paper links cognitive and cellular hypotheses and data about thought and language abnormalities in schizophrenia. The common thread, it is proposed, is a dysregulated suppression of associations (at the behavioral and functional neural systems level), paralleled by abnormalities of inhibition at the cellular and molecular level, and by an abnormal anatomical substrate (reduced MRI gray matter volume) in areas subserving language. At the level of behavioral experiments and connectionist modeling, data suggest an abnormal semantic network connectivity (strength of associations) in schizophrenia, but not an abnormality of network size (number of associates). This connectivity abnormality is likely to be a preferential processing of the dominant (strongest) association, with the neglect of preceding contextual information. At the level of functional neural systems, the N400 event-related potential amplitude is used to index the extent of "search" for a semantic match to a word. In a short stimulus-onset-asynchrony condition, both schizophrenic and schizotypal personality disorder subjects showed, compared with controls, a reduced N400 amplitude to the target words that were related to cues, e.g. cat-dog, a result compatible with behavioral data. Other N400 data strongly and directly suggest that schizophrenics do not efficiently utilize context.

Multimodal imaging in psychiatry: the electroencephalogram as a complement to other modalities.

The use of different imaging modalities provides the clinician and researcher with different views of anatomy and physiology at unprecedented levels of detail. Multimodal imaging allows for noninvasive measurement of structure and function in humans during complex behavior, and thus provides information about the inner workings of the brain previously unavailable. The present paper examines the various imaging techniques available, and describes their application to the clinic-in the case of epilepsy-and to research-in the case of schizophrenia. Because the electroencephalogram has a dynamic response in milliseconds, it provides the best temporal sensitivity of functional measures of brain activity. When coupled with high-resolution magnetic resonance imaging measures of brain structure, this multimodal approach provides a powerful tool for understanding brain activity. Clinically, the use of multimodal imaging has provided greater precision in localization of the epileptogenic focus. For researchers attempting to determine the underlying causes of schizophrenia, the use of multimodal imaging has helped lead the field away from a specific lesion view to a more distributed system abnormality view of this disorder.