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We hypothesized that neuropsychological disturbance in schizophrenia (SZ) may reflect faulty interactions of executive attention and episodic memory, emanating, in part, from reduced prefrontal cortex (PFC) gray matter volume. Participants with SZ (n = 84) and age-matched (n = 77) controls completed both the Wisconsin Card Sorting Test (WCST) and the Wechsler Memory Scale–Third Edition (WMS-III), used, respectively, as measures of executive attention and episodic memory. A subset of SZ (n = 27) and control (n = 17) groups also had available 3-T magnetic resonance imaging (MRI) studies of the PFC. For SZ, but not control groups, neuropsychological results indicated that executive attention interacted significantly with episodic memory, with failures of executive attention, as reflected by increased WCST perseverative errors, directly linked to poor performance on the WMS-III measure of delayed visual recall of action scenes. MRI results indicated reduced left PFC gray matter volume for SZ group, which in turn correlated significantly with their deficits in visual memory but not in executive attention. Results showed that 61% of the variance in neuropsychological performance in the SZ group was attributed to gray matter volume of left inferior prefrontal gyrus gray matter volume. PFC-mediated failure of executive attention-episodic memory interactions may represent an important mechanism in neuropsychological disturbance in SZ.

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders defines internet gaming disorder without differentiating games from their respective genres, such as first-person shooter versus real-time strategy versus online gaming. Our review of the literature on massively multiplayer online role-playing games (MMORPGs) suggests that MMORPGs are different from other games because they are the most addictive, and therefore deserve to be looked at separately. MMORPGs are internet platforms for online users to interact with each other in a virtual story line. The overview of the existing literature delineates the positive and negative aspects of MMORPGs and also the available evidence on neuroscientific and neuroanatomical correlates between internet gaming disorder and other addictions. Evidence shows that a player's characteristics and motivations can determine his or her risk of developing problematic play. Problematic MMORPG use may lead to mental disorders such as depression and addiction, and can negatively affect quality of life, and vice versa. Conversely, some players may benefit from being part of a social community and from using it as a learning platform or as a safe space to explore gender-identity issues. Brain circuitry and metabolism are changed through problematic MMORPG use, with the affected areas including the ventral striatum and left angular gyrus.

In schizophrenia, abnormalities in structural connectivity between brain regions known to contain mirror neurons and their relationship to negative symptoms related to a domain of social cognition are not well understood. Diffusion tensor imaging (DTI) scans were acquired in 16 patients with first episode schizophrenia and 16 matched healthy controls. FA and Trace of the tracts interconnecting regions known to be rich in mirror neurons, i.e., anterior cingulate cortex (ACC), inferior parietal lobe (IPL) and premotor cortex (PMC) were evaluated. A significant group effect for Trace was observed in IPL-PMC white matter fiber tract (F (1, 28) = 7.13, p = .012), as well as in the PMC-ACC white matter fiber tract (F (1, 28) = 4.64, p = .040). There were no group differences in FA. In addition, patients with schizophrenia showed a significant positive correlation between the Trace of the left IPL-PMC white matter fiber tract, and the Ability to Feel Intimacy and Closeness score (rho = .57, p = 0.034), and a negative correlation between the Trace of the left PMC-ACC and the Relationships with Friends and Peers score (rho = remove -.54, p = 0.049). We have demonstrated disrupted white mater microstructure within the white matter tracts subserving brain regions containing mirror neurons. We further showed that such structural disruptions might impact negative symptoms and, more specifically, contribute to the inability to feel intimacy (a measure conceptually related to theory of mind) in first episode schizophrenia. Further studies are needed to understand the potential of our results for diagnosis, prognosis and therapeutic interventions.

Background The association of white matter (WM) abnormalities with clinical variables in schizophrenia (SCZ) is poorly understood. We investigated the clinical correlates of WM impairments using imaging data of 597 patients with SCZ and 490 healthy controls (HC). We focused on lifelong changes of WM (measured by Fractional Anisotropy [FA]) in SCZ and compared it to that of HC. We investigated how age, duration of illness, and medication influence WM trajectories, and examined how structural impairments are related to symptoms and cognition. Last, we tested for the role of sex in structure-function interactions. Methods Diffusion-weighted images and clinical measurements were collected as part of 13 independent studies, and data was harmonized across all sites. We registered images to the IIT Human Brain Atlas and averaged FA for forceps major, forceps minor, cingulum, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus (SLF) and uncinate fasciculus. First, we modeled the FA age trajectory of each tract in HC and used it to regress out the effect of age in patients. The residuals in the FA values were utilized for further analyses. We conducted mediator regression analyses with FA as the dependent variable, sex as a covariate, and age and duration of illness as the independent variables. Next, patients were grouped based on Chlorpromazine equivalent dosage (CPZ) and CPZ group was added to the regression model. To examine the association between structure and function, a structural equation model (SEM) was used, with cognition as a mediator. Last, all analyses were repeated for males and females separately. Results Regression analyses revealed a significant influence of duration of illness on the forceps major (T=3.24, p Adding CPZ to the model displayed a significant effect of medication on forceps major (T=3.93, p For SEM, FA of all tracts was used to represent structural impairment, and symptom scores were used to reflect functional impairment. All data paths were calculated with an asymptotically distribution-free model. The overall model fit was acceptable (RMSEA =.09) with a medium-strong effect of structural impairment on functional impairment (standardized estimate=.44). When separating sexes, males showed a significant association of duration of illness and FA. Females displayed a stronger influence of structural impairment on functional impairment (standardized estimate: males = .29, females =.52), and cognition had an impact on this relationship for females only. Discussion The effect of duration of illness on specific WM tracts suggests a progressive, neurodegenerative pathology, which might contribute to the devastating effects of chronicity. Medication seems to have only a small, localized effect on corpus callosum WM integrity. However, since our analysis used cross-sectional CPZ measures, future studies should include measurements of lifetime dosage. The observed impact of WM abnormalities on function further highlights the importance of WM for SCZ pathology. The association of structure and function seems sex-specific. Men show a stronger effect of chronicity. For females, cognition mediates the effect of structure on function, suggesting the role of cognitive reserve. Our approach provides the first step towards evidence-based medicine, by demonstrating the apparent relationship between structural pathology and functional outcome and suggesting possible mediators of this relationship, including duration of illness, cognition, medication, and sex.

Objective: We combined neuropsychological and structural magnetic resonance imaging (MRI) measures to examine the neural and informational processes underlying episodic memory in healthy participants. Method: The Doors-and-People Test (DPT) provided a detailed assessment of episodic memory, including recall and recognition tasks of matched difficulty for social (e.g., people) and non-social (e.g., shape) content. The Wisconsin Card Sorting (WCS) test provided a measure of category learning that relies heavily on executive control and inhibition. A subset of participants also had available high-resolution, 3-T MRI gray matter volume studies of prefrontal cortex (PFC) parcellated into four regions: 1) frontal pole; 2) superior frontal gyrus; 3) middle frontal gyrus; and 4) inferior frontal gyrus. Results: Bivariate neuropsychological correlations revealed a highly statistically significant relationship of reduced WCS perseverative errors and stronger recall for people but not for shapes. By contrast, WCS perseveration did not correlate with any recognition measures. Hierarchical regression revealed that perseverative errors and people recall test scores combined to account for approximately 29.98% to 57.78% of the variance in left PFC gray matter volume. Conclusions: These results may point to an important role of the PFC in mnemonic process of retrieval inhibition in episodic memory for recall of social content in healthy participants.

Characterization of the default mode network (DMN) as a complex network of functionally interacting dynamic systems has received great interest for the study of DMN neural mechanisms. In particular, understanding the relationship of intrinsic resting-state DMN brain network with cognitive behaviors is an important issue in healthy cognition and mental disorders. However, it is still unclear how DMN functional connectivity links to cognitive behaviors during resting-state. In this study, we hypothesize that static and dynamic DMN nodal topology is associated with upcoming cognitive task performance. We used graph theory analysis in order to understand better the relationship between the DMN functional connectivity and cognitive behavior during resting-state and task performance. Nodal degree of the DMN was calculated as a metric of network topology. We found that the static and dynamic posterior cingulate cortex (PCC) nodal degree within the DMN was associated with task performance (Reaction Time). Our results show that the core node PCC nodal degree within the DMN was significantly correlated with reaction time, which suggests that the PCC plays a key role in supporting cognitive function.

We used the Iowa Gambling Test (IGT) to examine the relationship of reward learning to both neuropsychological functioning and symptom formation in 65 individuals with schizophrenia. Results indicated that compared to controls, participants with schizophrenia showed significantly reduced reward learning, which in turn correlated with reduced intelligence, memory and executive function, and increased negative symptoms. The current findings suggested that a disease-related disturbance in reward learning may underlie both cognitive and motivation deficits, as expressed by neuropsychological impairment and negative symptoms in schizophrenia.

Olfactory processing is thought to be mediated via the frontal and temporolimbic brain regions, both of which, as well as olfactory dysfunction, are implicated in schizophrenia. Likewise, several empirical studies of olfactory dysfunction--in particular, olfactory deficits in identification, odor detection threshold sensitivity, and odor memory, along with associated brain structural changes--have been conducted to illuminate the pathophysiology of schizophrenia. These anomalies have been investigated, more recently, as possible biological markers of that disabling illness. This article summarizes recent research on neuroimaging changes associated with olfactory impairments in schizophrenia patients and on related functional changes in psychophysiological measurements (e.g., odor identification, odor discrimination, odor detection threshold, and odor memory). The possible role of these changes as biological markers of the disorder will be discussed, as will potentially productive directions for future research.

Orbitofrontal alteration in schizophrenia has not been well characterized, likely due to marked anatomical variability. To investigate the presence of such alterations, we evaluated the sulcogyral pattern of this 'H-shaped' sulcus. Fifty patients with schizophrenia (100 hemispheres) and 50 age- and gender-matched control subjects (100 hemispheres) were evaluated using 3D high-spatial resolution MRI. Based on a previous study by Chiavaras and Petrides (2000), the sulcogyral pattern of the 'H-shaped' sulcus, which forms the boundaries of major orbitofrontal gyri, was classified into three types (Type I, II and III, in order of frequency) within each hemisphere. Chi-square analysis was performed to compare the sulcogyral pattern, and categorical regression was applied to investigate clinical/cognitive associations. The control data replicated the orbitofrontal sulcogyral pattern reported by Chiavaras and Petrides (P = 0.90-0.95), where the distribution was significantly different between the left and right hemisphere (Type I: right > left, Type II, III: left > right, chi2 = 6.41, P = 0.041). For schizophrenics, the distribution differed significantly from controls (chi2 = 11.90, P = 0.003), especially in the right hemisphere (chi2 = 13.67, P = 0.001). Moreover, the asymmetry observed in controls was not present in schizophrenia (chi2 = 0.13, P = 0.94). Specifically, the most frequent Type I expression was decreased and the rarest Type III expression was increased in schizophrenia, relative to controls. Furthermore, patients with Type III expression in any hemisphere evinced poorer socioeconomic status, poorer cognitive function, more severe symptoms and impulsivity, compared to patients without Type III expression. In contrast, patients with Type I in any hemisphere showed better cognitive function and milder symptoms compared to patients without Type I. Structurally, patients with Type III had significantly smaller intra-cranial contents (ICC) volumes than did patients without Type III (t(40) = 2.29, P = 0.027). The present study provides evidence of altered distribution of orbitofrontal sulcogyral pattern in schizophrenia, possibly reflecting a neurodevelopmental aberration in schizophrenia. Such altered sulcogyral pattern is unlikely to be due to secondary effects of the illness such as medication. Moreover, the structural association between Type III and small ICC volume, observed in the patient group, may suggest that Type III expression could be part of a systematic neurodevelopmental alteration, given that the small ICC volume could reflect early reduction of cranial growth driven by brain growth. The observed contrasting association of Type III expression with poorer outcome, and that of Type I expression with better outcome, further suggests clinical heterogeneity, and possible differences in treatment responsiveness in schizophrenia.

Attentional control is a key function of working memory that is hypothesized to play an important role in psychometric intelligence. To test the neuropsychological underpinnings of this hypothesis, we examined full-scale IQ, as measured by the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III), and attentional control, as measured by Trails B response time and Wisconsin Card Sorting (WCS) test perseverative errors in 78 healthy participants, 25 of whom also had available magnetic resonance imaging (MRI) gray matter volume studies of the orbital frontal cortex (OFC) parcellated into three regions: gyrus rectus, middle orbital gyrus, and lateral orbital gyrus. Hierarchical regression indicated that Trails B response time specifically explained 15.13% to 19.18% of the variation in IQ and WCS perseverative errors accounted for an additional 8.12% to 11.29% of the variance. Full-scale IQ correlated very strongly with right middle orbital gyrus gray matter volume (r=0.610,p=0.002), as did Trails B response time with left middle orbital gyrus gray matter volume (r=-0.608,p=0.003). Trails B response time and right middle orbital gyrus gray matter volume jointly accounted for approximately 32.95% to 54.82% of the variance in IQ scores. These results provided evidence of the unique contributions of attentional control and OFC gray matter to intelligence.

Several functional neuroimaging studies have implicated the cerebellar vermis in post-traumatic stress disorder (PTSD), but there have been no structural neuroimaging studies of this brain structure in PTSD. We utilized magnetic resonance imaging (MRI) with manual tracing to quantify the volumes of three divisions of the mid-sagittal vermis, and their total, within an identical, co-twin control design that employed Vietnam veterans discordant for combat exposure in Vietnam. Each structure's volume was significantly correlated between twins, indicating a partial familial determination: for anterior superior vermis, r=0.73; for posterior superior vermis, r=0.47; for inferior posterior vermis, r=0.51; and for total vermis, r=0.57. There were no significant differences between the PTSD and non-PTSD veterans for any vermis volume, and no significant main effects or interactions when their non-combat-exposed co-twins were added to the analyses. Thus, the results do not support the structural abnormality of cerebellar vermis in combat-related PTSD.

Background The hippocampus has been shown to be abnormal in schizophrenia. The fornix is one of the main fiber tracts connecting the hippocampus with other brain regions. Few studies have evaluated the fornix in schizophrenia, however. A focus on fornix abnormalities and their association with hippocampal abnormalities might figure importantly in our understanding of the pathophysiology of schizophrenia. Methods Line-scan diffusion tensor imaging (DTI) was used to evaluate diffusion in the fornix in 24 male patients with chronic schizophrenia and 31 male control subjects. Maps of fractional anisotropy (FA) and mean diffusivity (D m ), which are indices sensitive to white-matter integrity, were generated to quantify diffusion within the fornix. We used high spatial resolution magnetic resonance imaging (MRI) to measure hippocampal volume. Results FA and cross-sectional area of the fornix were significantly reduced in patients compared with control subjects. D m was significantly increased, whereas hippocampal volume was bilaterally reduced in patients. Reduced hippocampal volume was correlated with increased mean D m and reduced cross-sectional area of the fornix for patients. Patients also showed a significant correlation between reduced scores on neuropsychologic measures of declarative-episodic memory and reduced hippocampal volumes. Conclusions These findings demonstrate a disruption in fornix integrity in patients with schizophrenia.

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 multi-directional 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.

The purpose of this study was to investigate abnormalities in the surface complexity of the prefrontal cortex and in the hemispheric asymmetry of cortical complexity in first-episode patients with schizophrenia.An estimate of the surface complexity of the prefrontal cortex was derived from the number of voxels along the boundary between gray matter and CSF. Magnetic resonance imaging scans were acquired from patients with a first episode of schizophrenia (N=17), patients with a first episode of affective psychosis (N=17), and normal comparison subjects (N=17), age-matched within a narrow age range (18-29 years). This study group was the focus of a previous study that showed lower prefrontal cortical volume in patients with schizophrenia.Prefrontal cortical complexity was not significantly different among the groups. However, the schizophrenia patients differed significantly from the normal comparison subjects in asymmetry, with the schizophrenia patients showing less left-greater-than-right asymmetry in cortical complexity than the comparison subjects.An abnormal pattern of asymmetry in the prefrontal cortex of first-episode patients with schizophrenia provides evidence for a neurodevelopmental mechanism in the etiology of schizophrenia.

We created a spatial probability atlas of schizophrenia to provide information about the neuroanatomic variability of brain regions of patients with the disorder. Probability maps of 16 regions of interest (ROIs) were constructed by taking manually parcellated ROIs from subjects’ magnetic resonance images (MRIs) and linearly transforming them into Talairach space using the Montreal Neurological Institute (MNI) template. ROIs included temporal, parietal, and prefrontal cortex subregions, with a principal focus on temporal lobe structures. Subject Ns ranged from 11 to 28 for the different ROIs. Our global measure of the spatial distribution of the transformed ROI was the sum of voxels with 50% overlap among subjects. The superior temporal gyrus (STG) and fusiform gyrus (FG) had lower values for schizophrenic subjects than for normal controls, suggestive of greater spatial variability for these ROIs in schizophrenic subjects. For the computation of statistical significance of group differences in portions of the ROI, we used voxel-wise comparisons and Fisher's exact test. First-episode schizophrenic patients compared with controls showed lower probability (P < 0.05) at dorso-posterior areas of planum temporale and Heschl's gyrus, lateral and anterior regions in the left hippocampus (HIPP), and dorsolateral regions of fusiform gyrus. Importantly, most ROIs of schizophrenic subjects showed a significantly lower spatial overlap than controls, even after nonlinear spatial normalization, suggesting a greater heterogeneity in the spatial distribution of ROIs. There is consequently a need for caution in neuroimaging studies where data from schizophrenic subjects are normalized to a particular stereotaxic coordinate system based on healthy controls. Apparent group differences in activation may simply reflect a greater heterogeneity of spatial distribution in schizophrenia.

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.

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.

Research suggests that the normal left-greater-than-right angular gyrus volume asymmetry is reversed in chronic schizophrenia. The authors examined whether angular gyrus volume and asymmetry were abnormal in patients with first-episode schizophrenia.Magnetic resonance imaging scans were obtained from 14 inpatients at their first hospitalization for psychosis and 14 normal comparison subjects. Manual editing was undertaken to delineate postcentral, supramarginal, and angular gyri gray matter volumes.Group comparisons revealed that the left angular gyrus gray matter volume in patients was 14.8% less than that of the normal subjects. None of the other regions measured showed significant group volume or asymmetry differences.Patients with new-onset schizophrenia showed smaller left angular gyrus volumes than normal subjects, consistent with other studies showing parietal lobe volume abnormalities in schizophrenia. Angular gyrus pathology in first-episode patients suggests that the angular gyrus may be a neuroanatomical substrate for the expression of schizophrenia.

We examined variability in performance on widely-used neuropsychological Wechsler tests of intelligence and memory in a large sample of persons with chronic schizophrenia, a subset of whom had also undergone prior studies of magnetic resonance imaging (MRI) of the orbital frontal cortex (OFC) gray matter and diffusion tensor imaging (DTI) of the cingulum bundle (CB) and the uncinate fasiculus (UF) white matter. In comparison to controls, persons with schizophrenia showed lower scores across neuropsychological tests, with most pronounced drops in processing speed and immediate memory, in relation to oral reading. For patients, greater declines in intelligence and memory each correlated with reduced CB white matter fractional anisotropy and reduced OFC gray matter, respectively. However, only memory decline correlated with severity of negative symptoms. Taken together, these data raise the intriguing question as to whether communication and motivational deficits expressed in negative symptoms may contribute to the relationship of auditory memory decline and OFC volume observed in this patient sample.

Previous studies have shown that frontostriatal networks, especially those involving dorsolateral prefrontal cortex (DLPFC) and ventrolateral prefrontal cortex (VLPFC) mediate cognitive functions some of which are abnormal in schizophrenia. This study examines white matter integrity of the tracts connecting DLPFC/VLPFC and striatum in patients with first-episode schizophrenia (FESZ), and their associations with cognitive and clinical correlates.Diffusion tensor and structural magnetic resonance images were acquired on a 3T GE Echospeed system from 16 FESZ and 18 demographically comparable healthy controls. FreeSurfer software was used to parcellate regions of interest. Two-tensor tractography was applied to extract fibers connecting striatum with rostral middle frontal gyrus (rMFG) and inferior frontal gyrus (IFG), representing DLPFC and VLPFC respectively. DTI indices, including fractional anisotropy (FA), trace, axial diffusivity (AD) and radial diffusivity (RD), were used for group comparisons. Additionally, correlations were evaluated between these diffusion indices and the Wisconsin Card Sorting Task (WCST) and the Brief Psychiatric Rating Scale (BPRS).FA was significantly reduced in the left IFG-striatum tract, whereas trace and RD were significantly increased in rMFG-striatum and IFG-striatum tracts, bilaterally. The number of WCST categories completed correlated positively with FA of the right rMFG-striatum tract, and negatively with trace and RD of right rMFG-striatum and right IFG-striatum tracts in FESZ. The BPRS scores did not correlate with these indices.These data suggest that white matter tract abnormalities between rMFG/IFG and striatum are present in FESZ and appear to be significantly associated with executive dysfunction but not with symptom severity.

Thalamo-cortical feedback loops play a key role in the processing and coordination of processing and integration of perceptual inputs and outputs, and disruption in this connection has long been hypothesized to contribute significantly to neuropsychological disturbances in schizophrenia. To test this hypothesis, we applied diffusion tensor tractography on eighteen patients suffering schizophrenia and 20 control subjects. Fractional anisotropy (FA) was evaluated in the bilateral anterior and posterior limbs of the internal capsule, and correlated with clinical and neurocognitive measures. Patients diagnosed with schizophrenia showed significantly reduced FA bilaterally in the anterior but not the posterior limb of the internal capsule, compared with healthy control subjects. Lower FA correlated with lower scores on tests of declarative episodic memory in the patient group only. These findings suggest that disruptions, bilaterally, in thalamo-cortical connections in schizophrenia may contribute to disease-related impairment in the coordination of mnemonic processes of encoding and retrieval that are vital for efficient learning of new information.

In this study we use high resolution Magnetic Resonance imaging (MRI) and apply rigorous manual tracing criteria in order to assess volumetrically the prefrontal cortex (PFC) in schizophrenia. Previous MRI studies suggested PFC is included in neural systems necessary for emotional processing and cognition, and regional PFC abnormalities might, thus, lead to specific negative symptoms, as well as a frequent association of poorer performance in category switching. The aim of this study was to use 3T imaging and reliable manual parcellation to determine if, as hypothesized, this higher precision would reveal additional MRI abnormalities in PFC in schizophrenia, and an association between PFC abnormalities and specific negative symptoms, as well as in category switching. Using 3-T MRI, 27 schizophrenia patients and 27 healthy controls were examined. PFC was manually parcellated into frontal pole, superior frontal gyrus (SFG), middle frontal gyrus (MFG), and inferior frontal gyrus (IFG). Left SFG (p=0.004), bilateral MFG (left: p=0.007; right: p=0.007), and bilateral IFG (left: p0.001; right: p=0.002) showed volume reduction. There were symptom associations between smaller left MFG volumes and more affective flattening (R=-0.465, p=0.015), and smaller left IFG volumes and poorer performance on the alternating semantic category test (R=0.440, p=0.025). In summary, 3-T imaging revealed widespread gyral volume deficits in PFC gyri, and specific associations with selective negative symptoms, such as affective flattening, and with deficits in cognitive switching.

Septum pellucidum (SP) and cavum SP (CSP) were delineated in two samples. The Longitudinal Study examined structural MR-images in first-episode schizophrenia (FESZ) and controls at two time-points. The Cross-Sectional Study examined structural and diffusion-tensor MR measures, including hippocampus and fornix, in chronic schizophrenia (SZ) at one time-point. CSP and SP measurements remained stable over time in FESZ and controls. Compared to controls, CSP were smaller in FESZ, but not in chronic SZ. SP were larger in chronic SZ, but not in FESZ. In chronic SZ only, SP-Length was correlated negatively with fornix-FA and hippocampal volume, and positively with chlorpromazine-equivalent dosage.

The current report used structural magnetic resonance imaging (MRI) to objectively measure olfactory bulb volume and olfactory sulcal depth in patients diagnosed with chronic schizophrenia and healthy controls. Additional measures were obtained to assess olfactory function. The olfactory bulb and sulcus were manually traced on structural 3T MRIs for 25 right-handed male patients diagnosed with chronic schizophrenia and 25 matched male healthy controls. A sub-set of subjects received the University of Pennsylvania Smell Identification Test (UPSIT). Olfactory bulb volume was significantly decreased in patients with schizophrenia compared to healthy controls, as was their performance on the UPSIT. Additionally, a positive correlation was seen in patients between right bulb volume and UPSIT scores. Overall, our findings support earlier research studies showing morphometric and functional changes in the olfactory system in patients with schizophrenia.

Introduction Higher cognitive functioning is mediated by frontal-subcortical cognitive and limbic feedback sub-loops. The thalamo-cortical projection through the anterior limb of the internal capsule (ALIC) serves as the final step in these feedback sub-loops. We evaluated abnormalities in the ALIC fiber tract in schizophrenia using both structural MRI and diffusion tensor imaging (DTI). Methods 20 chronic schizophrenia patients and 22 male, normal controls group matched for handedness, age, and parental SES, underwent structural and DTI brain imaging on a 1.5 Tesla GE system. We manually measured ALIC volume normalized for intracranial contents (ICC) using structural brain images and then registered these high resolution structural brain scan derived ALIC label maps to DTI space allowing for the measurement in the ALIC of diffusion indices including, fractional anisotropy (FA) mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD). Results We found in the ALIC of chronic schizophrenia subjects, compared with normal controls, bilaterally lower FA and bilaterally higher RD, but no differences in AD, MD, or relative volume. Cognitive correlations in schizophreni a patients showed, in particular, that higher left ALIC FA correlated positively with better verbal and nonverbal declarative/episodic memory performance. Discussion Using a novel approach to assess both diffusion and volume measures in the ALIC in schizophrenia, we found abnormalities in measures of diffusion, but not volume, supporting their importance as sensitive indices of abnormalities in white matter fiber bundles in schizophrenia. Our findings also support the role of ALIC white matter tract FA abnormalities in declarative/episodic memory in schizophrenia.

Cigarette smoking rates remain remarkably high in schizophrenia relative to smoking in other psychiatric groups. Impairments in the reward system may be related to elevated rates of nicotine dependence and lower cessation rates in this psychiatric group. Smokers with schizophrenia and schizoaffective disorder (SWS; n = 15; M age = 54.87, SD = 6.51, 100% male) and a non-psychiatric control group of smokers (NCL; n = 16; M age = 50.38, SD = 11.52; 93.8% male) were administered a computerized signal detection task to measure reward-based learning. Performance on the signal detection task was assessed by response bias, discriminability, reaction time, and hit rate. Clinician-assessed and self-reported measures of smoking and psychiatric symptoms were completed. SWS exhibited similar patterns of reward-based learning compared to control smokers. However, decreased reward-based learning was associated with increased levels of nicotine dependence in SWS, but not among control smokers. Nicotine withdrawal and urge to smoke were correlated with anhedonia within the SWS group. Among SWS, reduced reward responsiveness and increased anhedonia were associated with and may contribute to greater co-occurring nicotine dependence. These findings emphasize the importance of targeting reward system functioning in smoking cessation treatment for individuals with schizophrenia.

Frontal-subcortical cognitive and limbic feedback loops modulate higher cognitive functioning. The final step in these feedback loops is the thalamo-cortical projection through the anterior limb of the internal capsule (AL-IC). Using diffusion tensor imaging (DTI), we evaluated abnormalities in the AL-IC fiber tract in schizophrenia. Participants comprised 16 chronic schizophrenia patients and 19 male, normal controls, who were group matched for handedness, age, and parental socioeconomic status, and underwent DTI on a 1.5 Tesla GE system. We measured the diffusion indices, fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD), and manually segmented, based on FA maps, AL-IC volume, normalized for intracranial contents (ICC). The results showed a significant reduction in the ICC-corrected volume of the AL-IC in schizophrenia, but did not show diffusion measure group differences in the AL-IC in FA, MD, RD or AD. In addition, in the schizophrenia patients, AL-IC FA correlated positively with performance on measures of spatial and verbal declarative/episodic memory, and right AL-IC ICC-corrected volume correlated positively with more perseverative responses on the Wisconsin Card Sort Test (WCST). We found a reduction in AL-IC ICC-corrected volume in schizophrenia, without FA, MD, RD or AD group differences, implicating the presence of a structural abnormality in schizophrenia in this subcortical white matter region which contains important cognitive, and limbic feedback pathways that modulate prefrontal cortical function. Despite not demonstrating a group difference in FA, we found that AL-IC FA was a good predictor of spatial and verbal declarative/episodic memory performance in schizophrenia.

Diffusion tensor imaging (DTI) and fiber tractography are useful tools for reconstructing white matter tracts (WMT) in the brain. Previous tractography studies have sought to segment reconstructed WMT into anatomical structures using several approaches, but quantification has been limited to extracting mean values of diffusion indices. Delineating WMT in schizophrenia is of particular interest because schizophrenia has been hypothesized to be a disorder of disrupted connectivity, especially between frontal and temporal regions of the brain. In this study, we aim to differentiate diffusion properties of thalamo-frontal pathways in schizophrenia from normal controls. We present a quantitative group comparison method, which combines the strengths of both tractography-based and voxel-based studies. Our algorithm extracts white matter pathways using whole brain tractography. Functionally relevant bundles are selected and parsed from the resulting set of tracts, using an internal capsule (IC) region of interest (ROI) as "source", and different Brodmann area (BA) ROIs as "targets". The resulting bundles are then longitudinally parameterized so that diffusion properties can be measured and compared along the WMT. Using this processing pipeline, we were able to find altered diffusion properties in male patients with chronic schizophrenia in terms of fractional anisotropy (FA) decreases and mean diffusivity (MD) increases in precise and functionally relevant locations. These findings suggest that our method can enhance the regional and functional specificity of DTI group studies, thus improving our understanding of brain function.

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.

Context: Previous magnetic resonance imaging (MRI) findings have demonstrated psychopathological symptom–related smaller gray matter volumes in various cingulate gyrus subregions in schizophrenia and bipolar disorder. However, it is unclear whether these gray matter abnormalities show a subregional specificity to either disorder and whether they show postonset progression. Objective: To determine whether there are initial and progressive gray matter volume deficits in cingulate gyrus subregions in patients with first-episode schizophrenia (FESZ) and patients with first-episode affective psychosis (FEAFF, mainly manic) and their specificity to FESZ or FEAFF. Design: A naturalistic cross-sectional study at first hospitalization for psychosis and a longitudinal follow-up approximately 1 1 U2 years later. Setting and Participants: Patients were from a private psychiatric hospital. Thirty-nine patients with FESZ and 41 with FEAFF at first hospitalization for psychosis and 40 healthy control subjects (HCs) recruited from the community underwent high-spatial-resolution MRI, with follow-up scans in 17 FESZ patients, 18 FEAFF patients, and 18 HCs. Individual subjects were matched for age, sex, parental socioeconomic status, and handedness. Main Outcome Measures: Cingulate gyrus gray matter volumes in 3 anterior subregions (subgenual, affective, and cognitive) and 1 posterior subregion, and whether there was a paracingulate sulcus. Results: At first hospitalization, patients with FESZ showed significantly smaller left subgenual (P=.03), left (P=.03) and right (P=.005) affective, right cognitive (P=.04), and right posterior (P=.003) cingulate gyrus gray matter subregions compared with HCs. Moreover, at the 11U2-year follow-up, patients with FESZ showed progressive gray matter volume decreases in the subgenual (P=.002), affective (P.001), cognitive (P.001), and posterior (P=.02) cingulate subregions compared with HCs. In contrast, patients with FEAFF showed only initial (left,P.001; right, P=.002) and progressive subgenual subregion abnormalities (P.001). Finally, patients with FESZ showed a less asymmetric paracingulate pattern than HCs (P=.02). Conclusions: Patients with FEAFF and FESZ showed differences in initial gray matter volumes and in their progression. Initial and progressive changes in patients with FEAFF were confined to the subgenual cingulate, a region strongly associated with affective disorder, whereas patients with FESZ evinced widespread initial and progressively smaller volumes.

Previously, we reported abnormal volume and global shape in the caudate nucleus in schizotypal personality disorder (SPD). Here, we use a new shape measure which importantly permits local in addition to global shape analysis, as well as local correlations with behavioral measures.Thirty-two female and 15 male SPDs, and 29 female and 14 male normal controls (NCLs), underwent brain magnetic resonance imaging (MRI). We assessed caudate shape measures using spherical harmonic-point distribution model (SPHARM-PDM) methodology.We found more pronounced global shape differences in the right caudate in male and female SPD, compared with NCLs. Local shape differences, principally in the caudate head, survived statistical correction on the right. Also, we performed correlations between local surface deformations with clinical measures and found significant correlations between local shape deflated deformations in the anterior medial surface of the caudate with verbal learning capacity in female SPD.Using SPHARM-PDM methodology, we found both global and local caudate shape abnormalities in male and female SPD, particularly right-sided, and largely restricted to limbic and cognitive anterior caudate. The most important and novel findings were bilateral statistically significant correlations between local surface deflations in the anterior medial surface of the head of the caudate and verbal learning capacity in female SPD. By extension, these local caudate correlation findings implicate the ventromedial prefrontal cortex (vmPFC), which innervates that area of the caudate, and demonstrate the utility of local shape analysis to investigate the relationship between specific subcortical and cortical brain structures in neuropsychiatric conditions.

Orbitofrontal Cortex (OFC) structural abnormality in schizophrenia has not been well characterized, probably due to marked anatomical variability and lack of consistent definitions. We previously reported OFC sulcogyral pattern alteration and its associations with social disturbance in schizophrenia, but OFC volume associations with psychopathology and cognition have not been investigated. We compared chronically treated schizophrenia patients with healthy control (HC) subjects, using a novel, reliable parcellation of OFC subregions and their association with cognition, especially the Iowa Gambling Task (IGT), and with schizophrenic psychopathology including thought disorder. Twenty-four patients with schizophrenia and 25 age-matched HC subjects underwent MRI. OFC Regions of Interest (ROI) were manually delineated according to anatomical boundaries: Gyrus Rectus (GR); Middle Orbital Gyrus (MiOG); and Lateral Orbital Gyrus (LOG). The OFC sulcogyral pattern was also classified. Additionally, MiOG probability maps were created and compared between groups in a voxel-wise manner. Both groups underwent cognitive evaluations using the IGT, Wisconsin Card Sorting Test, and Trail Making Test (TMT). An 11% bilaterally smaller MiOG volume was observed in schizophrenia, compared with HC (F(1,47) = 17.4, P = 0.0001). GR and LOG did not differ, although GR showed a rightward asymmetry in both groups (F(1,47) = 19.2, P < 0.0001). The smaller MiOG volume was independent of the OFC sulcogyral pattern, which differed in schizophrenia and HC (chi2 = 12.49, P = 0.002). A comparison of MiOG probability maps suggested that the anterior heteromodal region was more affected in the schizophrenia group than the posterior paralimbic region. In the schizophrenia group, a smaller left MiOG was strongly associated with worse 'positive formal thought disorder' (r = -0.638, P = 0.001), and a smaller right MiOG with a longer duration of the illness (r = -0.618, P = 0.002). While schizophrenics showed poorer performance than HC in the IGT, performance was not correlated with OFC volume. However, within the HC group, the larger the right hemisphere MiOG volume, the better the performance in the IGT (r = 0.541, P = 0.005), and the larger the left hemisphere volume, the faster the switching attention performance for the TMT, Trails B (r = -0.608, P = 0.003). The present study, applying a new anatomical parcellation method, demonstrated a subregion-specific OFC grey matter volume deficit in patients with schizophrenia, which was independent of OFC sulcogyral pattern. This volume deficit was associated with a longer duration of illness and greater formal thought disorder. In HC the finding of a quantitative association between OFC volume and IGT performance constitutes, to our knowledge, the first report of this association.

Structural brain abnormalities, including larger cerebrospinal fluid (CSF) volumes, have been observed in men diagnosed as having schizotypal personality disorder (SPD).To determine whether women with SPD have abnormalities similar to those of men with SPD and to elucidate specific SPD regional volume deficits and symptom correlations.Naturalistic study.Thirty neuroleptic-naive women with SPD and 29 female control subjects, both recruited from the community. Participants were group matched for age, parental socioeconomic status, handedness, and IQ.A new segmentation method was applied to magnetic resonance images to automatically parcel the images into CSF, gray matter, and white matter. The neocortex was manually separated from subcortical and other nonneocortical structures. Voxel-based morphometry was applied to determine global and regional volume deficits.Left and right neocortical gray matter, white matter, and CSF relative volumes as well as clinical symptoms from the Structured Interview for Schizotypy and the Schizotypal Personality Questionnaire-Brief Version.Smaller left (3.84%) and right (3.83%) neocortical gray matter relative volumes associated with larger left (9.66%) and right (9.61%) sulcal CSF relative volumes were found in women with SPD compared with controls. Voxel-based morphometry showed that the neocortical deficits in SPD were especially prominent in the left superior and middle temporal gyri, left inferior parietal region with postcentral gyrus, and right superior frontal and inferior parietal gyri. In the SPD group, larger lateral ventricle volumes correlated with more severe symptoms on the Structured Interview for Schizotypy and the Schizotypal Personality Questionnaire-Brief Version.The smaller neocortical gray matter volume and larger sulcal CSF volume provide evidence of the brain basis of this personality disorder and emphasize the communality of brain abnormalities in the schizophrenia spectrum.

Background The caudate nucleus might contribute to the psychopathological and cognitive deficits observed in schizotypal personality disorder (SPD), a schizophrenia spectrum disorder. Here we focused on female patients, because this group is underrepresented in studies of SPD and schizophrenia, and we might learn more about the caudate and clinical and cognitive impairments that are unique to female patients diagnosed with SPD. Methods Magnetic resonance imaging scans, obtained on a 1.5-T magnet with 1.5-mm contiguous slices, were used to measure the caudate in 32 neuroleptic-naive women with SPD and in 29 female normal comparison subjects. Subjects were group-matched for age, parental socioeconomic status, and intelligence quotient. Results We found significantly reduced left and right caudate relative volume (8.3%, 7.7%) in female SPD subjects compared with normal comparison subjects. In female SPD subjects, we found significant correlations between smaller total caudate relative volume and worse performance on the Wisconsin Card Sorting test (nonperseverative errors) and on the California Verbal Learning Test (verbal memory and learning), and significant correlations between smaller total caudate relative volume and both positive and negative symptoms on the Structured Interview for Schizotypy. Conclusions These findings demonstrate that, for female SPD subjects, smaller caudate volume is associated with poorer cognitive performance and more schizotypal symptomatology.

Background: Findings from postmortem studies suggest reduced prefrontal cortical thickness in schizophrenia; however, cortical thickness in first-episode schizophrenia has not been evaluated using magnetic resonance imaging (MRI). Methods: Prefrontal cortical thickness was measured using MRI in first-episode schizophrenia patients (n 17), first-episode affective psychosis patients (n 17), and normal control subjects (n 17); subjects were age-matched within 2 years and within a narrow age range (18 –29 years). A previous study using the same subjects reported reduced prefrontal gray matter volume in first-episode schizophrenia. Manual editing was performed on those prefrontal segmentations before cortical thickness was measured. Results: Prefrontal cortical thickness was not significantly different among groups. Prefrontal gray matter volume and thickness were, however, positively correlated in both schizophrenia and control subjects. The product of boundary complexity and thickness, an alternative measure of volume, was positively correlated with volume for all three groups. Finally, age and age at first medication were negatively correlated with prefrontal cortical thickness only in first-episode schizophrenia. Conclusions: This study demonstrates the potential usefulness of MRI for the study of cortical thickness abnormalities in schizophrenia. Correlations between cortical thickness and age and between cortical thickness and age at first medication suggest that the longer the schizophrenic process has been operative, the thinner the prefrontal cortex, although this needs confirmation in a longitudinal study.

We measured the shape of the head of the caudate nucleus with a new approach based on magnetic resonance imaging (MRI) in schizotypal personality disorder (SPD) subjects in whom we previously reported decreased caudate nucleus volume. We believe MRI shape analysis complements traditional MRI volume measurements.Magnetic resonance imaging scans were used to measure the shape of the caudate nucleus in 15 right-handed male subjects with SPD, who had no prior neuroleptic exposure, and in 14 matched normal comparison subjects. With MRI processing tools, we measured the head of the caudate nucleus using a shape index, which measured how much a given shape deviates from a sphere.In relation to comparison subjects, neuroleptic never-medicated SPD subjects had significantly higher (more "edgy") head of the caudate shape index scores, lateralized to the right side. Additionally, for SPD subjects, higher right and left head of the caudate SI scores correlated significantly with poorer neuropsychological performance on tasks of visuospatial memory and auditory/verbal working memory, respectively.These data confirm the value of measuring shape, as well as volume, of brain regions of interest and support the association of intrinsic pathology in the caudate nucleus, unrelated to neuroleptic medication, with cognitive abnormalities in the schizophrenia spectrum.

"Cognitive" circuits anatomically link the frontal lobe to subcortical structures; therefore, pathology in any of the core components of these circuits, such as in the caudate nucleus, may result in neurobehavioral syndromes similar to those of the frontal lobe. Neuroleptic medication, however, affects the size of the caudate nucleus. For this reason, individuals diagnosed with schizotypal personality disorder offer an ideal group for the measurement of the caudate nucleus because they may be genetically related to individuals with schizophrenia but do not require neuroleptic treatment because of their less severe symptoms.Magnetic resonance imagining (MRI) scans obtained on a 1.5-T magnet with 1.5-mm contiguous slices were used to measure the caudate nucleus and lateral ventricles in 15 right-handed male subjects with schizotypal personality disorder who had no previous neuroleptic exposure and in 14 normal comparison subjects. Subjects were group matched for parental socioeconomic status, handedness, and gender.First, the authors found significantly lower left and right absolute (13.1%, 13.2%) and relative (9.1%, 9.2%) caudate nucleus volumes in never-medicated subjects with schizotypal personality disorder than in normal subjects. Second, they found significant, inverse correlations between caudate nucleus volume and the severity of perseveration in two distinct working memory tasks in these neuroleptic-naive subjects with schizotypal personality disorder.These data are consistent with the findings of reduced caudate nucleus volume reported in studies of neuroleptic-naive patients experiencing their first episode of schizophrenia and support the association of intrinsic pathology in the caudate nucleus with abnormalities in working memory in the schizophrenia spectrum.

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.

Premorbid adjustment in schizophrenia is thought important (1) as a predictor of current pathology and course, and (2) as a psychosocial expression of brain pathology preceding psychosis. Its valid and reliable measurement, however, pose a major challenge. To address this issue we interviewed 12 chronic male schizophrenic veterans and their first degree relatives, plus 12 age and social class of origin matched normal controls and their relatives, using the Cannon-Spoor et al. Premorbid Adjustment Scale (PAS), for which we developed our own semi-structured interview. Objective data from school records were also obtained. Schizophrenic's PAS scores were significantly poorer, irrespective of whether PAS scores were based on information from subjects, first degree relatives or from 'combined sources'. PAS scores were worse at all developmental epochs, with a marked divergence beginning in late adolescence. Worse premorbid adjustment in schizophrenia was also highly correlated with current clinical state, more current negative symptoms, less independent living and longer duration of hospitalization. Additionally, worse premorbid adjustment in schizophrenia was associated with larger Magnetic Resonance (MR) Ventricular Brain Ratio (VBR) in an exploratory analysis using a subset of these patients. Premorbid adjustment, rigorously measured, is poorer in schizophrenics than in normal controls and correlates with psychosocial and ventricular pathology in schizophrenia.

Background In a preliminary dose-finding study, D-cycloserine, a partial agonist at the glycine modulatory site of the glutamatergic N -methyl-D-aspartate (NMDA) receptor, improved negative symptoms and cognitive function when added to conventional neuroleptics at a dose of 50 mg/d. Methods Forty-seven patients with schizophrenia meeting criteria for deficit syndrome were randomized to D-cycloserine, 50 mg/d (n=23) or placebo (n=24) added to their conventional neuroleptic for an 8-week, double-blind trial. Clinical assessments were performed at baseline and at weeks 1, 2, 4, 6, and 8. Serum concentrations of D-cycloserine, relevant amino acids, and homovanillic acid were assayed at baseline and at weeks 4 and 8. A cognitive battery was performed at baseline and at week 8. Results Thirty-nine patients completed the 8-week trial. Seven dropouts occurred in the D-cycloserine group and 1 in the placebo group. The mean reduction in negative symptoms with D-cycloserine (23%) was significantly greater than with placebo (7%) as calculated by slopes representing Scale for the Assessment of Negative Symptoms (SANS) total scores. Improvement of negative symptoms was predicted by low neuroleptic dose and low baseline SANS total score. No differences were found in performance on any cognitive test between groups or in changes in any other clinical measure. Clinical response did not correlate significantly with serum amino acid concentrations at baseline or with concentrations of D-cycloserine at weeks 4 and 8. Conclusion These results support the hypothesis that agents acting at the glycine modulatory site of the NMDA receptor improve primary negative symptoms.

Psychiatric illnesses involve complex interpersonal and biological processes that combine to produce certain clinical signs and symptoms of psychopathology on which psychiatric diagnostics are based. Nevertheless, the clinical presentation of some psychiatric disorders may vary from patient to patient or at different points in time on the same patient. The following case history serves to underscore the importance of the multi-axial approach in combination with longitudinal follow-up when an attempt is made to understand fully complex individuals. In particular, this case involves, at the minimum, the complex interweaving of a psychosis not easily subsumed under either pure schizophrenia or pure affective disorder together with substance abuse. It is the analysis of the serial unfolding of psychopathology that the authors feel will lead to a more comprehensive and better diagnostic formulation of an individual patient.