Resting-state thalamic dysconnectivity in schizophrenia and relationships with symptoms.

BACKGROUND: Schizophrenia (SZ) is a severe neuropsychiatric disorder associated with disrupted connectivity within the thalamic-cortico-cerebellar network. Resting-state functional connectivity studies have reported thalamic hypoconnectivity with the cerebellum and prefrontal cortex as well as thalamic hyperconnectivity with sensory cortical regions in SZ patients compared with healthy comparison participants (HCs). However, fundamental questions remain regarding the clinical significance of these connectivity abnormalities. METHOD: Resting state seed-based functional connectivity was used to investigate thalamus to whole brain connectivity using multi-site data including 183 SZ patients and 178 matched HCs. Statistical significance was based on a voxel-level FWE-corrected height threshold of p < 0.001. The relationships between positive and negative symptoms of SZ and regions of the brain demonstrating group differences in thalamic connectivity were examined. RESULTS: HC and SZ participants both demonstrated widespread positive connectivity between the thalamus and cortical regions. Compared with HCs, SZ patients had reduced thalamic connectivity with bilateral cerebellum and anterior cingulate cortex. In contrast, SZ patients had greater thalamic connectivity with multiple sensory-motor regions, including bilateral pre- and post-central gyrus, middle/inferior occipital gyrus, and middle/superior temporal gyrus. Thalamus to middle temporal gyrus connectivity was positively correlated with hallucinations and delusions, while thalamus to cerebellar connectivity was negatively correlated with delusions and bizarre behavior. CONCLUSIONS: Thalamic hyperconnectivity with sensory regions and hypoconnectivity with cerebellar regions in combination with their relationship to clinical features of SZ suggest that thalamic dysconnectivity may be a core neurobiological feature of SZ that underpins positive symptoms.

fMRI activity correlated with auditory hallucinations during performance of a working memory task: data from the FBIRN consortium study.

INTRODUCTION: Auditory hallucinations are a hallmark symptom of schizophrenia. The neural basis of auditory hallucinations was examined using data from a working memory task. Data were acquired within a multisite consortium and this unique dataset provided the opportunity to analyze data from a large number of subjects who had been tested on the same procedures across sites. We hypothesized that regions involved in verbal working memory and language processing would show activity that was associated with levels of hallucinations during a condition where subjects were rehearsing the stimuli. METHODS: Data from the Sternberg Item Recognition Paradigm, a working memory task, were acquired during functional magnetic resonance imaging procedures. The data were collected and preprocessed by the functional imaging biomedical informatics research network consortium. Schizophrenic subjects were split into nonhallucinating and hallucinating subgroups and activity during the probe condition (in which subjects rehearsed stimuli) was examined. Levels of activation from contrast images for the probe phase (collapsed over levels of memory load) of the working memory task were also correlated with levels of auditory hallucinations from the Scale for the Assessment of Positive Symptoms scores. RESULTS: Patients with auditory hallucinations (relative to nonhallucinating subjects) showed decreased activity during the probe condition in verbal working memory/language processing regions, including the superior temporal and inferior parietal regions. These regions also showed associations between activity and levels of hallucinations in a correlation analysis. DISCUSSION: The association between activation and hallucinations scores in the left hemisphere language/working memory regions replicates the findings of previous studies and provides converging evidence for the association between superior temporal abnormalities and auditory hallucinations.

Working memory and DLPFC inefficiency in schizophrenia: the FBIRN study.

BACKGROUND: The Functional Imaging Biomedical Informatics Network is a consortium developing methods for multisite functional imaging studies. Both prefrontal hyper- or hypoactivity in chronic schizophrenia have been found in previous studies of working memory. METHODS: In this functional magnetic resonance imaging (fMRI) study of working memory, 128 subjects with chronic schizophrenia and 128 age- and gender-matched controls were recruited from 10 universities around the United States. Subjects performed the Sternberg Item Recognition Paradigm1,2 with memory loads of 1, 3, or 5 items. A region of interest analysis examined the mean BOLD signal change in an atlas-based demarcation of the dorsolateral prefrontal cortex (DLPFC), in both groups, during both the encoding and retrieval phases of the experiment over the various memory loads. RESULTS: Subjects with schizophrenia performed slightly but significantly worse than the healthy volunteers and showed a greater decrease in accuracy and increase in reaction time with increasing memory load. The mean BOLD signal in the DLPFC was significantly greater in the schizophrenic group than the healthy group, particularly in the intermediate load condition. A secondary analysis matched subjects for mean accuracy and found the same BOLD signal hyperresponse in schizophrenics. CONCLUSIONS: The increase in BOLD signal change from minimal to moderate memory loads was greater in the schizophrenic subjects than in controls. This effect remained when age, gender, run, hemisphere, and performance were considered, consistent with inefficient DLPFC function during working memory. These findings from a large multisite sample support the concept not of hyper- or hypofrontality in schizophrenia, but rather DLPFC inefficiency that may be manifested in either direction depending on task demands. This redirects the focus of research from direction of difference to neural mechanisms of inefficiency.

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.

Prefrontal cortex, negative symptoms, and schizophrenia: an MRI study.

The present study measured prefrontal cortical gray and white matter volume in chronic, male schizophrenic subjects who were characterized by a higher proportion of mixed or negative symptoms than previous patients that we have evaluated. Seventeen chronic male schizophrenic subjects and 17 male control subjects were matched on age and handedness. Regions of interest (ROI) were measured using high-resolution magnetic resonance (MR) acquisitions consisting of contiguous 1.5-mm slices of the entire brain. No significant differences were found between schizophrenic and control subjects in mean values for prefrontal gray matter volume in either hemisphere. However, right prefrontal white matter was significantly reduced in the schizophrenic group. In addition, right prefrontal gray matter volume was significantly correlated with right hippocampal volume in the schizophrenic, but not in the control group. Furthermore, an analysis in which the current data were combined with those from a previous study showed that schizophrenic subjects with high negative symptom scores had significantly smaller bilateral white matter volumes than those with low negative symptom scores. White matter was significantly reduced in the right hemisphere in this group of schizophrenic subjects. Prefrontal volumes were also associated with negative symptom severity and with volumes of medial-temporal lobe regions - two results that were also found previously in schizophrenic subjects with mostly positive symptoms. These results underscore the importance of temporal-prefrontal pathways in the symptomatology of schizophrenia, and they suggest an association between prefrontal abnormalities and negative symptoms.

A functional magnetic resonance imaging study of auditory mismatch in schizophrenia.

OBJECTIVE: Previous research has noted functional and structural temporal lobe abnormalities in schizophrenia that relate to symptoms such as auditory hallucinations and thought disorder. The goal of the study was to determine whether the functional abnormalities are present in schizophrenia at early stages of auditory processing. METHOD: Functional magnetic resonance imaging activity was examined during the presentation of the mismatch stimuli, which are deviant tones embedded in a series of standard tones. The mismatch stimuli are used to elicit the mismatch negativity, an early auditory event-related potential. Ten patients with schizophrenia and 10 comparison subjects were presented the mismatch stimuli condition and a control condition in which only one tone was presented repeatedly. RESULTS: The superior temporal gyrus showed the most prevalent and consistent activation. The superior temporal gyrus showed less activation in the schizophrenic subjects than in the comparison subjects only during the mismatch stimuli condition. CONCLUSIONS: This result is consistent with those of mismatch negativity event-related potential studies and suggests that early auditory processing is abnormal in chronic schizophrenia.

Superior temporal gyrus volume abnormalities and thought disorder in left-handed schizophrenic men.

OBJECTIVE: Studies of schizophrenia have not clearly defined handedness as a differentiating variable. Moreover, the relationship between thought disorder and anatomical anomalies has not been studied extensively in left-handed schizophrenic men. The twofold purpose of this study was to investigate gray matter volumes in the superior temporal gyrus of the temporal lobe (left and right hemispheres) in left-handed schizophrenic men and left-handed comparison men, in order to determine whether thought disorder in the left-handed schizophrenic men correlated with tissue volume abnormalities. METHOD: Left-handed male patients (N = 8) with DSM-III-R diagnoses of schizophrenia were compared with left-handed comparison men (N = 10) matched for age, socioeconomic status, and IQ. Magnetic resonance imaging (MRI) with a 1.5-T magnet was used to obtain scans, which consisted of contiguous 1.5-mm slices of the whole brain. MRI analyses (as previously defined by the authors) included the anterior, posterior, and total superior temporal gyrus in both the left and right hemispheres. RESULTS: There were three significant findings regarding the left-handed schizophrenic men: 1) bilaterally smaller gray matter volumes in the posterior superior temporal gyrus (16% smaller on the right, 15% smaller on the left); 2) a smaller volume on the right side of the total superior temporal gyrus; and 3) a positive correlation between thought disorder and tissue volume in the right anterior superior temporal gyrus. CONCLUSIONS: These results suggest that expression of brain pathology differs between left-handed and right-handed schizophrenic men and that the pathology is related to cognitive disturbance.

Subgenual cingulate cortex volume in first-episode psychosis.

OBJECTIVE: Gray matter volume and glucose utilization have been reported to be reduced in the left subgenual cingulate of subjects with familial bipolar or unipolar depression. It is unclear whether these findings are secondary to recurrent illness or are part of a familial/genetic syndrome. The authors' goal was to clarify these findings. METHOD: Volumetric analyses were performed by using magnetic resonance imaging in 41 patients experiencing their first episode of affective disorder or schizophrenia and in 20 normal comparison subjects. RESULTS: The left subgenual cingulate volume of the patients with affective disorder who had a family history of affective disorder was smaller than that of patients with affective disorder with no family history of the illness and the normal comparison subjects. Patients with schizophrenia did not differ from comparison subjects in left subgenual cingulate volume. CONCLUSIONS: Left subgenual cingulate abnormalities are present at first hospitalization for psychotic affective disorder in patients who have a family history of affective disorder.

MRI anatomy of schizophrenia.

Structural magnetic resonance imaging (MRI) data have provided much evidence in support of our current view that schizophrenia is a brain disorder with altered brain structure, and consequently involving more than a simple disturbance in neurotransmission. This review surveys 118 peer-reviewed studies with control group from 1987 to May 1998. Most studies (81%) do not find abnormalities of whole brain/intracranial contents, while lateral ventricle enlargement is reported in 77%, and third ventricle enlargement in 67%. The temporal lobe was the brain parenchymal region with the most consistently documented abnormalities. Volume decreases were found in 62% of 37 studies of whole temporal lobe, and in 81% of 16 studies of the superior temporal gyrus (and in 100% with gray matter separately evaluated). Fully 77% of the 30 studies of the medial temporal lobe reported volume reduction in one or more of its constituent structures (hippocampus, amygdala, parahippocampal gyrus). Despite evidence for frontal lobe functional abnormalities, structural MRI investigations less consistently found abnormalities, with 55% describing volume reduction. It may be that frontal lobe volume changes are small, and near the threshold for MRI detection. The parietal and occipital lobes were much less studied; about half of the studies showed positive findings. Most studies of cortical gray matter (86%) found volume reductions were not diffuse, but more pronounced in certain areas. About two thirds of the studies of subcortical structures of thalamus, corpus callosum and basal ganglia (which tend to increase volume with typical neuroleptics), show positive findings, as do almost all (91%) studies of cavum septi pellucidi (CSP). Most data were consistent with a developmental model, but growing evidence was compatible also with progressive, neurodegenerative features, suggesting a "two-hit" model of schizophrenia, for which a cellular hypothesis is discussed. The relationship of clinical symptoms to MRI findings is reviewed, as is the growing evidence suggesting structural abnormalities differ in affective (bipolar) psychosis and schizophrenia.

Volumetric evaluation of the thalamus in schizophrenic male patients using magnetic resonance imaging.

BACKGROUND: The thalamus, an important subcortical brain region connecting limbic and prefrontal cortices, has a significant role in sensory and cortical processing. Although inconsistently, previous studies have demonstrated neuroanatomical abnormalities in the thalamus of schizophrenic patients. METHODS: This structural magnetic resonance imaging study, based on segmentation of contiguous coronal 1.5-mm images, compared thalamic brain volumes of 15 chronic, male schizophrenic patients with 15 normal controls matched on age, sex, handedness, and parental socioeconomic status. RESULTS: There were no significant differences between patients and controls in thalamic volumes, right or left, adjusted for total brain volume; however, there were significantly different correlations of thalamic volumes with prefrontal white matter and lateral ventricles among patients, but not among controls. Thalamic volumes among patients were also significantly correlated with bizarre behavior, hallucinations, and thought disorder. CONCLUSIONS: Findings suggest that connectivity between thalamic nuclei and prefrontal cortical areas are abnormal in chronic male schizophrenic patients. In addition, ventricular enlargement may be, in part, due to subtle reduction in thalamic volume and/or in volume of thalamocortical and corticothalamic fibers secondary to thalamic abnormalities. Finally, correlations with positive symptomatology underscore the role of the thalamus in gating or filtering of sensory information and coordination of cortical processing.

Parcellation of the human prefrontal cortex using MRI.

A methodology was developed for dividing prefrontal cortical gray matter into insular, orbital, inferior, middle, superior, cingulate, and frontal pole regions using anatomical criteria. This methodology was developed as a follow-up to one that measured whole prefrontal gray and white matter volumes in schizophrenic and control subjects. This study showed no overall volume differences in prefrontal cortex between schizophrenic and control subjects. The parcellation of prefrontal cortex was done to increase the probability of detecting abnormalities that were circumscribed to a particular portion of the region. A 1.5 Tesla magnet was used to acquire contiguous 1.5-mm coronal slices of the entire brain. Volumes were then measured in a group of right-handed male (n = 15) subjects. Gray matter was parcellated using criteria that were mainly based on gross anatomy, as visualized in 3-dimensional renderings of the brain. Reliability of the parcellation scheme was very high (r(i) = 0.80 and above). This methodology should be useful in the study of cortical pathology in a number of neurological disorders, including schizophrenia.

Caudate, putamen, and globus pallidus volume in schizophrenia: a quantitative MRI study.

Basal ganglia structures have been reported to be abnormal in schizophrenia. However, while component structures of the basal ganglia are functionally differentiated, there have been no evaluations of their separate magnetic resonance imaging (MRI) volumes with small voxel (1.5 mm3) spoiled gradient-recalled acquisition in steady state techniques and multi-plane assessments. We examined MRI scans from 15 male, right-handed, neuroleptic-medicated schizophrenic patients and 15 age-, handedness-, and gender-matched normal volunteers. Compared with normal subjects, schizophrenic patients showed enlarged volumes: 14.2% for total basal ganglia, 27.4% for globus pallidus, 15.9% for putamen, and 9.5% for caudate. Increased volumes, especially of the caudate, were associated with poorer neuropsychological test performance on finger tapping and Hebb's Recurring Digits. These findings indicate abnormalities throughout all basal ganglia structures in at least a subgroup of schizophrenic patients.

Prefrontal cortex and schizophrenia. A quantitative magnetic resonance imaging study.

OBJECTIVE: To measure prefrontal cortical volume in a group of schizophrenic subjects who presented with mainly positive symptoms and who were previously shown to have volume reductions in left temporal lobe structures. METHOD: Fourteen men with chronic schizophrenia and 15 male control subjects were matched for age, IQ, handedness, and parental socioeconomic status. Magnetic resonance images were obtained by means of a 1.5-T magnet, and contiguous 1.5-mm slices of the entire brain were obtained. RESULTS: No significant differences were found between schizophrenic and control subjects in mean values for prefrontal white or gray matter on either the right or the left side. However, within the schizophrenic group, there was evidence of a relationship between the volumes of left prefrontal gray matter and left temporal lobe structures that was not present in the control group. CONCLUSIONS: At least in this group of schizophrenic subjects with mainly positive symptoms, temporal lobe abnormalities can exist in conjunction with no gross volumetric abnormalities of the prefrontal cortex.

Temporal lobe sulco-gyral pattern anomalies in schizophrenia: an in vivo MR three-dimensional surface rendering study.

Neuroanatomical and histological findings from post-mortem brains, as well as in vivo findings from magnetic resonance imaging (MRI) studies, suggest the presence of morphologic temporal lobe abnormalities in schizophrenia. To determine whether or not sulco-gyral pattern abnormalities in the temporal lobe could be detected in vivo, we applied computerized surface rendering techniques to MR data sets in order to make both qualitative and quantitative analyses of three-dimensional reconstructions of the temporal and frontal cortex in 15 schizophrenic patients and 15 normal controls. The qualitative analysis, based on a visual classification of the temporal lobe sulco-gyral pattern by 4 raters blind to diagnosis, showed that in schizophrenics there was a more vertical orientation to the sulci in the left temporal lobe, with an interrupted course of sulci due to gyri coursing across the sulci. Normal controls, in contrast, showed a more horizontal orientation with no interruptions. These findings were supported by the quantitative analysis, where more sulcal lines, representing an interrupted course of sulci, were observed in the temporal lobes (more pronounced on the left) in schizophrenics than in normal controls. These data suggest that some of the abnormalities observed in schizophrenia may have their origin in alterations occurring during the course of neurodevelopment when the sulco-gyral pattern is determined.

Temporal lobe abnormalities in a patient with schizophrenia who has word-finding difficulty: use of high-resolution magnetic resonance imaging and auditory P300 event-related potentials.

Postmortem, magnetic resonance, and event-related potential studies suggest the presence of temporal lobe abnormalities in schizophrenia. Analyses using convergent measurements of brain structure and function, however, have rarely been done in the same patients. We recently developed a protocol using high-spatial-resolution magnetic resonance scans, auditory P300 event-related potentials, and thought disorder scales to examine temporal lobe structure and function in the same patients. We report a case of schizophrenia that showed left-lateralized volume reduction in the superior temporal gyrus, hippocampus, and parahippocampal gyrus (also on right), with associated P300 amplitude reduction and thought disorder marked by word-finding difficulties and perseverations.

Hippocampus, fimbria-fornix, amygdala, and memory: object discriminations in rats.

Rats with lesions of the fimbria-fornix, hippocampus, or hippocampus and amygdala were tested in object discriminations commonly used with monkeys. Two 1-pair object discriminations were learned preoperatively and tested postoperatively. Additional postoperative testing included acquisition of a third 1-pair object discrimination, an 8-pair concurrent object discrimination, and spatial alternation. All lesions impaired performance in the 8-pair object discrimination and in spatial alternation but not in the 1-pair object discriminations. Data from this study and from previous studies indicate that the hippocampus in both rats and monkeys has an important role in the mnemonic processes required for concurrent object discriminations and that variations of the procedure for concurrent object discriminations can be an effective tool for investigating hippocampal function.

Abnormalities of the left temporal lobe and thought disorder in schizophrenia. A quantitative magnetic resonance imaging study.

BACKGROUND: Data from postmortem, CT, and magnetic resonance imaging (MRI) studies indicate that patients with schizophrenia may have anatomical abnormalities of the left temporal lobe, but it is unclear whether these abnormalities are related to the thought disorder characteristic of schizophrenia. METHODS: We used new MRI neuroimaging techniques to derive (without knowledge of the diagnosis) volume measurements and three-dimensional reconstructions of temporal-lobe structures in vivo in 15 right-handed men with chronic schizophrenia and 15 matched controls. RESULTS: As compared with the controls, the patients had significant reductions in the volume of gray matter in the left anterior hippocampus-amygdala (by 19 percent [95 percent confidence interval, 3 to 36 percent]), the left parahippocampal gyrus (by 13 percent [95 percent confidence interval, 3 to 23 percent], vs. 8 percent on the right), and the left superior temporal gyrus (by 15 percent [95 percent confidence interval, 5 to 25 percent]). The volume of the left posterior superior temporal gyrus correlated with the score on the thought-disorder index in the 13 patients evaluated (r = -0.81, P = 0.001). None of these regional volume decreases was accompanied by a decrease in the volume of the overall brain or temporal lobe. The volume of gray matter in a control region (the superior frontal gyrus) was essentially the same in the patients and controls. CONCLUSIONS: Schizophrenia involves localized reductions in the gray matter of the left temporal lobe. The degree of thought disorder is related to the size of the reduction in volume of the left posterior superior temporal gyrus.

Learning-related patterns of CA1 spike trains parallel stimulation parameters optimal for inducing hippocampal long-term potentiation.

Recent studies have revealed 3 stimulation parameters that together comprise the temporal pattern of neuronal activation optimal for the induction of hippocampal LTP: high-frequency bursts, activity 100-200 ms prior to a burst, and burst delivery in phase with the ongoing hippocampal theta rhythm. The present paper reports that these 3 aspects of patterned neural activity, collectively referred to as "theta-bursting," are characteristic of the spike trains of CA1 pyramidal cells in rats during the sampling and analysis of learning cues in an odor discrimination task and during performances of a spatial memory task. In contrast, theta-bursting occurs relatively infrequently during behavioral events less directly related to task-relevant mnemonic processing. These findings suggest that the optimal conditions for the induction of LTP occur naturally in behaving animals, time-locked to behavioral events critical to learning.

Mnemonic theories of hippocampal function.

Although mnemonic interpretations of hippocampal function in people have been readily accepted for many years, similar interpretations of hippocampal function in animals have received a number of challenges. This article reviews two of these challenges, shows how they were resolved in favor of some kind of mnemonic interpretation, and then suggests ways in which these types of interpretations must change in order to encompass new data.

Mnemonic correlates of unit activity in the hippocampus.

The role of the hippocampus in memory processing was examined by recording single unit activity while rats performed two different types of memory tasks. The same apparatus was used for all tasks; it consisted of two goal boxes, side by side, on the end of a runway. One goal box was white, the other was black. Experiment I used a working memory, delayed match-to-sample (DMTS) task. A trial began with a sample phase in which the rat was forced to a goal box containing a reward. The rat was then placed at the beginning of the runway again for the choice phase and allowed to enter either of the two goal boxes. Entering the goal box with the same color as that entered during the sample phase was rewarded. Experiment II used a within-subjects, within-units, design to test rats in two reference memory tasks, a cue task and a spatial task. During the cue task, the rat was rewarded for choosing the same colored goal box on each trial regardless of its spatial location. During the spatial task, the rat was rewarded for choosing the goal box in a specific location on each trial regardless of its color. During all tasks, the location of the goal boxes was changed between trials in a pseudorandom, counterbalanced fashion so that each colored goal box was on the right for half of the trials and on the left for half of the trials. During performance of the DMTS task, activity of most units was correlated with a combination of factors such as color and location, or color and phase. For example, most units showing differential activity in one of the colored goal boxes fired more when that box was in a certain spatial location, or during either the sample or choice phase. During performance of the reference memory tasks, the activity of most units was not correlated with behavior. However, the rate for some units changed between the cue and spatial tasks. When unit activity was correlated with behavior, it was dependent on a combination of dimensions such as color and spatial location. These results demonstrate that units in the hippocampus respond to combinations of stimulus dimensions such as color and spatial location, and to the temporal context necessary to solve a working memory task.