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

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

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

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

Impact of the lung allocation score on survival beyond 1 year.

Implementation of the lung allocation score (LAS) in 2005 led to transplantation of older and sicker patients without altering 1-year survival. However, long-term survival has not been assessed and emphasizing the 1-year survival metric may actually sustain 1-year survival while not reflecting worsening longer-term survival. Therefore, we assessed overall and conditional 1-year survival; and the effect of crossing the 1-year threshold on hazard of death in three temporal cohorts: historical (1995-2000), pre-LAS (2001-2005) and post-LAS (2005-2010). One-year survival post-LAS remained similar to pre-LAS (83.1% vs. 82.1%) and better than historical controls (75%). Overall survival in the pre- and post-LAS cohorts was also similar. However, long-term survival among patients surviving beyond 1 year was worse than pre-LAS and similar to historical controls. Also, the hazard of death increased significantly in months 13 (1.44, 95% CI 1.10-1.87) and 14 (1.43, 95% CI 1.09-1.87) post-LAS but not in the other cohorts. While implementation of the LAS has not reduced overall survival, decreased survival among patients surviving beyond 1 year in the post-LAS cohort and the increased mortality occurring immediately after 1 year suggest a potential negative long-term effect of the LAS and an unintended consequence of increased emphasis on the 1-year survival metric.

Metabolomics and cancer preventive behaviors in the BC Generations Project.

Metabolomics can detect metabolic shifts resulting from lifestyle behaviors and may provide insight on the relevance of changes to carcinogenesis. We used non-targeted nuclear magnetic resonance to examine associations between metabolic measures and cancer preventive behaviors in 1319 participants (50% male, mean age 54 years) from the BC Generations Project. Behaviors were dichotomized: BMI < 25 kg/m2, ≥ 5 servings of fruits or vegetables/day, ≤ 2 alcoholic drinks/day for men or 1 drink/day for women and ≥ 30 min of moderate or vigorous physical activity/day. Linear regression was used to estimate coefficients and 95% confidence intervals with a false discovery rate (FDR) of 0.10. Of the 218 metabolic measures, 173, 103, 71 and 6 were associated with BMI, fruits and vegetables, alcohol consumption and physical activity. Notable findings included negative associations between glycoprotein acetyls, an inflammation-related metabolite with lower BMI and greater fruit and vegetable consumption, a positive association between polyunsaturated fatty acids and fruit and vegetable consumption and positive associations between high-density lipoprotein subclasses with lower BMI. These findings provide insight into metabolic alterations in the context of cancer prevention and the diverse biological pathways they are involved in. In particular, behaviors related to BMI, fruit and vegetable and alcohol consumption had a large metabolic impact.

Irradiation-mediated rescue of T cell-specific V(D)J recombination and thymocyte differentiation in severe combined immunodeficient mice by bone marrow cells.

In SCID (severe combined immunodeficient) mice, proper assembly of immunoglobulin and T cell receptor (TCR) genes is blocked by defective V(D)J recombination so that B and T lymphocyte differentiation is arrested at an early precursor stage. Treating the mice with gamma irradiation rescues V(D)J rearrangement at multiple TCR loci, promotes limited thymocyte differentiation, and induces thymic lymphomas. These effects are not observed in the B cell lineage. Current models postulate that irradiation affects intrathymic T cell precursors. Surprisingly, we found that transfer of irradiated SCID bone marrow cells to unirradiated host animals rescues both TCR rearrangements and thymocyte differentiation. These data indicate that irradiation affects precursor cells at an earlier stage of differentiation than was previously thought and suggest new models for the mechanism of irradiation rescue.

A complex of Shc and Ran-GTPase localises to the cell nucleus.

The three isoforms of the adaptor protein Shc play diverse roles in cell signalling. For example, the observation of p46 Shc in the nuclei of hepatocellular carcinoma cells suggests a function quite distinct from the better characterised cytoplasmic role. Ligands responsible for the transport of various Shc isoforms into organelles such as the nucleus have yet to be reported. To identify such ligands a far western approach was used to determine the p52 Shc interactome. The Ran-GTPase nuclear transport protein was identified and found to bind to p52 Shc in vitro with low micromolar affinity. Co-immunoprecipitation, pull down and fluorescence lifetime imaging microscopy experiments in stable cells confirmed cellular interaction and nuclear localisation. The nuclear transport factor protein NTF2, which functions in cohort with Ran, was shown to form a complex with both RAN and Shc, suggesting a mechanism for Shc entry into the nucleus as part of a tertiary complex.

Treated wastewater effluent reduces sperm motility along an osmolality gradient.

Many toxic effects of treated wastewater effluent on organismal and reproductive health have been documented. However, the physicochemical environment of treated wastewater effluent frequently differs considerably from that of its receiving waters and may affect organismal function independently of toxic effects. Teleost sperm, for example, may be affected by the higher osmolality of treated wastewater, as this sperm is activated for a brief period of time following ejaculation due to the sudden decrease in osmolality of its surrounding environment. In this study, we examined the effects of treated wastewater effluent on sperm motility to test the hypothesis that the higher osmolality of effluent compared to river water will adversely affect sperm activation in a concentration-dependent relationship. Treated wastewater effluent was collected on 5 days from the outflow of the Metropolitan Wastewater Treatment Plant, St. Paul, Minnesota, and from an upstream site on the Mississippi River. Milt aliquots collected from goldfish were diluted in an isotonic extender solution and subsequently activated in either deionized water, 100%, 50%, or 10% effluent, a synthetic ion mixture, or river water. Sperm motility and velocity were assessed at 15-s intervals for 1 min using a computer assisted sperm analyzer. Significant differences in performance parameters were found only at 15 s, with sperm motility and velocity declining rapidly at later sampling times. Predictably, deionized water resulted in the greatest activation of sperm motility, while motility exhibited a concentration-dependent decline in 10%, 50%, and 100% treated wastewater effluent. Interestingly, Mississippi River water and a synthetic ion mixture with an osmolality comparable to 50% effluent both resulted in the least amount of sperm activation. However, sperm activation in river water varied between collection days during the study. River water and 100% effluent both had low sperm activation characteristics despite a 10-fold difference in osmolality between these two treatments (1 and 10 mOsmol kg(-1), respectively). Results of this study indicate a concentration-dependent decrease in sperm motility in treated wastewater effluent as well as significant fluctuations of sperm activation in Mississippi River water. This study illustrates the complexity of assessing the effects of treated wastewater effluents and the difficulty of determining appropriate reference sites for such studies.

Dendritic cell vaccination plus low-dose doxorubicin for the treatment of spontaneous canine hemangiosarcoma.

Angiosarcoma is a deadly neoplasm of the vascular endothelium. Metastatic disease is often present at diagnosis, and 5-year survival is only 10-35%. Although there exist no immunocompetent mouse models of angiosarcoma with which to study immune-based approaches to therapy, angiosarcoma is a major killer of companion dogs, responsible for up to 2% of all canine deaths in some susceptible breeds or an estimated 120,000 per year in the US. The canine disease (HSA) often presents in the spleen as acute hemoabdomen secondary to splenic rupture. Even if life-saving splenectomy is performed, median overall survival (OS) is only 48 days, and 1-year survival is negligible. Here we report the analysis of a pilot phase I open-label trial of chemo-immunotherapy performed on consecutively presenting splenectomized canines with histologically verified HSA. Subjects received an abbreviated course of low-dose doxorubicin plus alpha interferon and an autologous dendritic cell-therapy reported to enhance durable CD8+ memory. Disease was monitored monthly by abdominal ultrasound, chest X-ray, and echocardiogram. Median OS in the per protocol population was 109 days including one of five animals that died cancer-free at 16 months after documented resolution of relapsed disease. These results indicate that therapeutic administration of chemo-immunotherapy is both feasible and safe, substantiating the rationale for additional veterinary and human clinical studies.

Segregated hemispheric pathways through the optic chiasm distinguish primates from rodents.

At the optic chiasm retinal fibers either cross the midline, or remain uncrossed. Here we trace hemispheric pathways through the marmoset chiasm and show that fibers from the lateral optic nerve pass directly toward the ipsilateral optic tract without any significant change in fiber order and without approaching the midline, while those from medial regions of the nerve decussate directly. Anterograde labeling from one eye shows that the two hemispheric pathways remain segregated through the proximal nerve and chiasm with the uncrossed confined laterally. Retrograde labeling from the optic tract confirms this. This clearly demonstrates that hemispheric pathways are segregated through the primate chiasm. Previous chiasmatic studies have been undertaken mainly on rodents and ferrets. In these species there is a major change in fiber order pre-chiasmatically, where crossed and uncrossed fibers mix, reflecting their embryological history when all fibers approach the midline prior to their commitment to innervate either hemisphere. This pattern was thought to be common to placental mammals. In marsupials there is no change in fiber order and uncrossed fibers remain confined laterally through nerve and chiasm, again, reflecting their developmental history when all uncrossed fibers avoid the midline. Recently it has been shown that this distinction is not a true dichotomy between placental mammals and marsupials, as fiber order in tree shrews and humans mirrors the marsupial pattern. Architectural differences in the mature chiasm probably reflect different developmental mechanisms regulating pathway choice. Our results therefore suggest that both the organization and development of the primate optic chiasm differ markedly from that revealed in rodents and carnivores.

A stereotaxic atlas of the brain of the naked mole-rat (Heterocephalus glaber).

The naked mole-rat (Rodentia, Bathyergidae: Heterocephalus glaber) is a strictly subterranean eusocial mammal. These rodents show a suite of morphological and physiological adaptations, including brain specializations, to this underground milieu that they have inhabited since the early Miocene. Recently, naked mole-rats have received considerable attention as the longest living rodent known, and some of these brain specializations may be potentially important to their exceptional longevity. To serve as a basis for future brain studies, we have constructed a stereotaxic atlas of the brain of this species, labeling all major brain structures.

A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in patients with 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.

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.

The heterogeneity of schizoaffective disorder: implications for treatment.

Until the 1970s, schizophrenia tended to be broadly defined in the United States, and the diagnosis subsumed patients who had affective as well as schizophrenic symptoms. With the introduction of lithium, however, manic-depressive illness became susceptible to treatment and gained attractiveness as a diagnosis. The ambiguous position of patients with schizoaffective disorder became clear. Cross-sectionally they were seen to resemble schizophrenic patients, but longitudinally they were more akin to patients with affective disorder. Numerous studies have attempted to establish that they are diagnostically distinct, but without clear results. The authors suggest that schizoaffective disorder is heterogeneous and that its treatment should be determined by specific indices as to its subtype.

Correlations of premorbid adjustment in schizophrenia with auditory event-related potential and neuropsychological abnormalities.

OBJECTIVE: The authors examined the relationship between premorbid adjustment in schizophrenia and event-related potential data and neuropsychological data obtained after onset of the illness. METHOD: They interviewed 13 male veterans with chronic schizophrenia, 12 normal comparison subjects, and their first-degree relatives and also obtained objective data from the patients' school records and charts. They used interview and objective data to score the Cannon-Spoor Premorbid Adjustment Scale. Patients and comparison subjects were also given event-related potential tests, the Wisconsin Card Sorting Test, and the Wechsler Memory Scale-Revised. RESULTS: Worse premorbid adjustment in the schizophrenic patients was significantly associated with a marked reduction of the N2 component amplitude of the auditory event-related potential measured over the left temporal and central regions, but it was not associated with the P3 component amplitude. Worse Premorbid Adjustment Scale scores were significantly associated with more perseverative errors on the Wisconsin Card Sorting Test and worse performance on the visual memory span task of the Wechsler Memory Scale. CONCLUSIONS: Premorbid adjustment may predict the severity of specific neurophysiological and neuropsychological abnormalities in schizophrenia.

Abnormal angular gyrus asymmetry in schizophrenia.

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

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

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

Brain abnormalities in early-onset schizophrenia spectrum disorder observed with statistical parametric mapping of structural magnetic resonance images.

OBJECTIVE: The purpose of this study was to assess neuroanatomic abnormalities in children and adolescents with childhood-onset schizophrenia by using whole-brain voxel-based morphometric analyses. Previous volumetric studies of brain abnormalities in childhood-onset schizophrenia have revealed anomalies similar to those in subjects with adult-onset schizophrenia. Specifically, low cerebral volume, high ventricular volume, and thalamic, basal ganglia, callosal, and temporal lobe abnormalities have been observed in childhood-onset schizophrenia. Relatively few anatomical structures have been delineated and measured in this rare population, partly because of the labor involved in the slice-by-slice region definition required of conventional volumetric image analyses. METHOD: The subjects were 10 normal children and adolescents and nine children and adolescents with early-onset schizophrenia (mean age at diagnosis, 11.0 years; range, 7-16 years). The authors conducted voxel-by-voxel and volumetric statistical analyses of high-resolution structural magnetic resonance images. RESULTS: Statistical parametric maps of gray matter, white matter, and CSF differences between the groups revealed that the subjects with early-onset schizophrenia had larger ventricles, predominantly in the posterior horns of the lateral ventricles, and midcallosal, posterior cingulate, caudate, and thalamic abnormalities. Volumetric analyses of the lateral ventricles in native image data space confirmed significantly higher volume in posterior, but not anterior, regions. Randomization tests confirmed the overall statistical significance of the group differences and validity of the parametric maps. CONCLUSIONS: These findings are generally consistent with the findings of other research groups, but localization of enlarged ventricles specific to the posterior region may be a new finding in the literature on childhood-onset schizophrenia.

Auditory mismatch negativity in schizophrenia: topographic evaluation with a high-density recording montage.

OBJECTIVE: The mismatch negativity, a negative component in the auditory event-related potential, is thought to index automatic processes involved in sensory or echoic memory. The authors' goal in this study was to examine the topography of auditory mismatch negativity in schizophrenia with a high-density, 64-channel recording montage. METHOD: Mismatch negativity topography was evaluated in 23 right-handed male patients with schizophrenia who were receiving medication and in 23 nonschizophrenic comparison subjects who were matched in age, handedness, and parental socioeconomic status. The Positive and Negative Syndrome Scale was used to measure psychiatric symptoms. RESULTS: Mismatch negativity amplitude was reduced in the patients with schizophrenia. They showed a greater left-less-than-right asymmetry than comparison subjects at homotopic electrode pairs near the parietotemporal junction. There were correlations between mismatch negativity amplitude and hallucinations at left frontal electrodes and between mismatch negativity amplitude and passive-apathetic social withdrawal at left and right frontal electrodes. CONCLUSIONS: Mismatch negativity was reduced in schizophrenia, especially in the left hemisphere. This finding is consistent with abnormalities of primary or adjacent auditory cortex involved in auditory sensory or echoic memory.