N-acetylcysteine during critical neurodevelopmental periods prevents behavioral and neurochemical deficits in the Poly I:C rat model of schizophrenia.

Schizophrenia is a chronic neurodevelopmental disorder with an inflammatory/prooxidant component. N-acetylcysteine (NAC) has been evaluated in schizophrenia as an adjuvant to antipsychotics, but its role as a preventive strategy has not been sufficiently explored. We aimed to evaluate the potential of NAC administration in two-time windows before the onset of symptoms in a schizophrenia-like maternal immune stimulation (MIS) rat model. Pregnant Wistar rats were injected with Poly I:C or Saline on gestational day (GD) 15. Three different preventive approaches were evaluated: 1) NAC treatment during periadolescence in the offspring (from postnatal day [PND] 35 to 49); 2) NAC treatment during pregnancy after MIS challenge until delivery (GD15-21); and 3) NAC treatment throughout all pregnancy (GD1-21). At postnatal day (PND) 70, prepulse inhibition (PPI) and anxiety levels were evaluated. In vivo magnetic resonance (MR) imaging was acquired on PND100 to assess structural changes in gray and white matter, and brain metabolite concentrations. Additionally, inflammation and oxidative stress (IOS) markers were measured ex vivo in selected brain regions. MIS offspring showed behavioral, neuroanatomical, and biochemical alterations. Interestingly, NAC treatment during periadolescence prevented PPI deficits and partially counteracted some biochemical imbalances. Moreover, NAC treatments during pregnancy not only replicated the beneficial outcomes reported by the treatment in periadolescence, but also prevented some neuroanatomical deficits, including reductions in hippocampal and corpus callosum volumes. This study suggests that early reduction of inflammation and prooxidation could help prevent the onset of schizophrenia-like symptoms, supporting the importance of anti-IOS compounds in ameliorating this disorder.

Simple beam hardening correction method (2DCalBH) based on 2D linearization.

Objective. The polychromatic nature of the x-ray spectrum in computed tomography leads to two types of artifacts in the reconstructed image: cupping in homogeneous areas and dark bands between dense parts, such as bones. This fact, together with the energy dependence of the mass attenuation coefficients of the tissues, results in erroneous values in the reconstructed image. Many post-processing correction schemes previously proposed require either knowledge of the x-ray spectrum or the heuristic selection of some parameters that have been shown to be suboptimal for correcting different slices in heterogeneous studies. In this study, we propose and validate a method to correct the beam hardening artifacts that avoids such restrictions and restores the quantitative character of the image.Approach. Our approach extends the idea of the water-linearization method. It uses a simple calibration phantom to characterize the attenuation for different soft tissue and bone combinations of the x-ray source polychromatic beam. The correction is based on the bone thickness traversed, obtained from a preliminary reconstruction. We evaluate the proposed method with simulations and real data using a phantom composed of PMMA and aluminum 6082 as materials equivalent to water and bone.Main results. Evaluation with simulated data showed a correction of the artifacts and a recovery of monochromatic values similar to that of the post-processing techniques used for comparison, while it outperformed them on real data.Significance. The proposed method corrects beam hardening artifacts and restores monochromatic attenuation values with no need of spectrum knowledge or heuristic parameter tuning, based on the previous acquisition of a very simple calibration phantom.

Infrared-Emitting Multimodal Nanostructures for Controlled In Vivo Magnetic Hyperthermia.

Deliberate and local increase of the temperature within solid tumors represents an effective therapeutic approach. Thermal therapies embrace this concept leveraging the capability of some species to convert the absorbed energy into heat. To that end, magnetic hyperthermia (MHT) uses magnetic nanoparticles (MNPs) that can effectively dissipate the energy absorbed under alternating magnetic fields. However, MNPs fail to provide real-time thermal feedback with the risk of unwanted overheating and impeding on-the-fly adjustment of the therapeutic parameters. Localization of MNPs within a tissue in an accurate, rapid, and cost-effective way represents another challenge for increasing the efficacy of MHT. In this work, MNPs are combined with state-of-the-art infrared luminescent nanothermometers (LNTh; Ag2 S nanoparticles) in a nanocapsule that simultaneously overcomes these limitations. The novel optomagnetic nanocapsule acts as multimodal contrast agents for different imaging techniques (magnetic resonance, photoacoustic and near-infrared fluorescence imaging, optical and X-ray computed tomography). Most crucially, these nanocapsules provide accurate (0.2 °C resolution) and real-time subcutaneous thermal feedback during in vivo MHT, also enabling the attainment of thermal maps of the area of interest. These findings are a milestone on the road toward controlled magnetothermal therapies with minimal side effects.

Omega-3 fatty acids during adolescence prevent schizophrenia-related behavioural deficits: Neurophysiological evidences from the prenatal viral infection with PolyI:C.

The likely involvement of inflammation and oxidative stress (IOS) in mental disease has led to advocate anti-oxidant and anti-inflammatory drugs as therapeutic strategies in the treatment of schizophrenia. Since omega-3 fatty acids (ω-3) show anti-inflammatory/neuroprotective properties, we aim to evaluate whether ω-3 treatment during adolescence in the maternal immune stimulation (MIS) animal model of schizophrenia could prevent the brain and behavioural deficits described in adulthood. At gestational day 15, PolyI:C (4 mg/kg) or saline (VH) were injected to pregnant Wistar rats. Male offspring received ω-3 (800 mg/kg) or saline (Sal) daily from postnatal day (PND) 35-49, defining 4 groups: MIS-ω-3; MIS-Sal; VH-ω-3 and VH-Sal. At PND70, rats were submitted to prepulse inhibition test (PPI). FDG-PET and T2-weighted MRI brain studies were performed in adulthood and analyzed by means of SPM12. IOS markers were measured in selected brain areas. MIS-offspring showed a PPI deficit compared with VH-offspring and ω-3 treatment prevented this deficit. Also, ω-3 reduced the brain metabolism in the deep mesencephalic area and prevented the volumetric abnormalities in the hippocampus but not in the ventricles in MIS-offspring. Besides, ω-3 reduced the expression of iNOS and Keap1 and increased the activity/concentration of HO1, NQO1 and GPX. Our study demonstrates that administration of ω-3 during adolescence prevents PPI behavioural deficits and hippocampal volumetric abnormalities, and partially counteracts IOS deficits via iNOS and Nrf2-ARE pathways in the MIS model. This study highlights the need for novel strategies based on anti-inflammatory/anti-oxidant compounds to alter the disease course in high-risk populations at early stages.

Simplified Statistical Image Reconstruction for X-ray CT With Beam-Hardening Artifact Compensation.

CT images are often affected by beam-hardening artifacts due to the polychromatic nature of the X-ray spectra. These artifacts appear in the image as cupping in homogeneous areas and as dark bands between dense regions such as bones. This paper proposes a simplified statistical reconstruction method for X-ray CT based on Poisson statistics that accounts for the non-linearities caused by beam hardening. The main advantages of the proposed method over previous algorithms are that it avoids the preliminary segmentation step, which can be tricky, especially for low-dose scans, and it does not require knowledge of the whole source spectrum, which is often unknown. Each voxel attenuation is modeled as a mixture of bone and soft tissue by defining density-dependent tissue fractions and maintaining one unknown per voxel. We approximate the energy-dependent attenuation corresponding to different combinations of bone and soft tissues, the so-called beam-hardening function, with the 1D function corresponding to water plus two parameters that can be tuned empirically. Results on both simulated data with Poisson sinogram noise and two rodent studies acquired with the ARGUS/CT system showed a beam hardening reduction (both cupping and dark bands) similar to analytical reconstruction followed by post-processing techniques but with reduced noise and streaks in cases with a low number of projections, as expected for statistical image reconstruction.

Deep brain stimulation improves behavior and modulates neural circuits in a rodent model of schizophrenia.

Schizophrenia is a debilitating psychiatric disorder with a significant number of patients not adequately responding to treatment. Deep brain stimulation (DBS) is a surgical technique currently investigated for medically-refractory psychiatric disorders. Here, we use the poly I:C rat model of schizophrenia to study the effects of medial prefrontal cortex (mPFC) and nucleus accumbens (Nacc) DBS on two behavioral schizophrenia-like deficits, i.e. sensorimotor gating, as reflected by disrupted prepulse inhibition (PPI), and attentional selectivity, as reflected by disrupted latent inhibition (LI). In addition, the neurocircuitry influenced by DBS was studied using FDG PET. We found that mPFC- and Nacc-DBS alleviated PPI and LI abnormalities in poly I:C offspring, whereas Nacc- but not mPFC-DBS disrupted PPI and LI in saline offspring. In saline offspring, mPFC-DBS increased metabolism in the parietal cortex, striatum, ventral hippocampus and Nacc, while reducing it in the brainstem, cerebellum, hypothalamus and periaqueductal gray. Nacc-DBS, on the other hand, increased activity in the ventral hippocampus and olfactory bulb and reduced it in the septal area, brainstem, periaqueductal gray and hypothalamus. In poly I:C offspring changes in metabolism following mPFC-DBS were similar to those recorded in saline offspring, except for a reduced activity in the brainstem and hypothalamus. In contrast, Nacc-DBS did not induce any statistical changes in brain metabolism in poly I:C offspring. Our study shows that mPFC- or Nacc-DBS delivered to the adult progeny of poly I:C treated dams improves deficits in PPI and LI. Despite common behavioral responses, stimulation in the two targets induced different metabolic effects.

Waking-like brain function in embryos.

BACKGROUND: Experience-dependent plastic changes in the brain underlying complex forms of learning are generally initiated when organisms are awake, and this may limit the earliest developmental time at which learning about external events can take place. It is not known whether waking-like brain function is present prenatally in higher vertebrate (bird or mammal) embryos, or whether embryos have brain circuitry that can selectively turn on a waking-like state in response to salient external sensory stimulation. RESULTS: Combining submillimeter-resolution brain positron emission tomography (PET), structural X-ray computed tomography (CT) of the skeleton for fine-scale embryo aging, and noninvasive behavioral recording of chicken embryos in the egg revealed unexpectedly wide variation in prenatal brain activity, inversely related to behavioral activity, which developed into different sleep-like fetal brain states. Brief prenatal exposure to a salient chicken vocalization (eliciting strong postnatal behavioral responses) increased higher-brain activity significantly more than a spectrally and temporally matching "nonvocal" noise analog. Patterns of correlated activity between the brainstem and higher-brain areas resembling awake, posthatching animals were seen exclusively in chicken-stimulated embryos. CONCLUSIONS: Waking-like brain function is present in a latent but inducible state during the final 20% of embryonic life, selectively modulated by context-dependent monitoring circuitry. These data also reveal the developmental emergence of sleep-like behavior and its linkage to metabolic brain states and highlight problems with assigning embryo brain states based on behavioral observations.

Regional specificity of thalamic volume deficits in male adolescents with early-onset psychosis.

BACKGROUND: Thalamic volume deficits are associated with psychosis but it is unclear whether the volume reduction is uniformly distributed or whether it is more severe in particular thalamic regions. AIMS: To quantify whole and regional thalamic volume in males with early-onset psychosis and healthy male controls. METHOD: Brain scans were obtained for 80 adolescents: 46 individuals with early-onset psychosis with a duration of positive symptoms less than 6 months and 34 healthy controls. All participants were younger than 19 years. Total thalamic volumes were assessed using FreeSurfer and FSL-FIRST, group comparisons of regional thalamic volumes were studied with a surface-based approach. RESULTS: Total thalamic volume was smaller in participants with early-onset psychosis relative to controls. Regional thalamic volume reduction was most significant in the right anterior mediodorsal area and pulvinar. CONCLUSIONS: In males with minimally treated early-onset psychosis, thalamic volume deficits may be most pronounced in the anterior mediodorsal and posterior pulvinar regions, adding strength to findings from post-mortem studies in adults with psychosis.

Brain morphology and neurological soft signs in adolescents with first-episode psychosis.

BACKGROUND: Adolescents with first-episode psychosis have increased severity of neurological soft signs when compared with controls, but it is unclear whether increased severity of neurological soft signs is an expression of specific structural brain deficits. AIMS: To examine whether increased severity of neurological soft signs was associated with decreased brain volumes in adolescents with first-episode psychosis. METHOD: Brain scans were obtained for 70 adolescents (less than 18 years of age) with first-episode psychosis (duration of positive symptoms less than 6 months). Volumes were assessed using voxel-based morphometry and through segmentation of anatomical structures. RESULTS: Increased severity of sensory integration neurological soft signs correlated with smaller right and left thalamus volume, whereas increased severity of sequencing of complex motor acts neurological soft signs correlated with smaller right caudate volume. CONCLUSIONS: Neurological soft signs may be an easy-to-assess marker of region-specific structural brain deficits in adolescents with first-episode psychosis.

The novel DNA methylation inhibitor zebularine is effective against the development of murine T-cell lymphoma.

Gene silencing by CpG island promoter hypermethylation has awakened the interest for DNA demethylating agents as chemotherapy drugs. Zebularine (1-[beta-D-ribofuranosil]-1,2-dihydropyrimidin-2-1) has been recently described as a new DNA methylation inhibitor. Here we have studied its effects in a mouse model of radiation-induced lymphomagenesis using nuclear magnetic resonance (NMR) and positron emission tomography (PET). All control animals presented large thymic T lymphomas and died between 4 and 5.5 months. In contrast, 40% (12 of 30) of zebularine-treated animals were still alive after 1 year (Kaplan-Meier P < .001). NMR and PET imaging showed that surviving animals presented a thymus structure/volume similar to normal mice of the same age. Most important, zebularine demonstrated a complete lack of toxicity in nonirradiated control mice. DNA hypomethylation induced by zebularine occurred in association with depletion in extractable DNA methyltransferase 1 protein. Thus, our data support the role of zebularine as a DNA demethylating agent with antitumor activity and little toxicity.

The expression of GLP-1 receptor mRNA and protein allows the effect of GLP-1 on glucose metabolism in the human hypothalamus and brainstem.

In the present work, several experimental approaches were used to determine the presence of the glucagon-like peptide-1 receptor (GLP-1R) and the biological actions of its ligand in the human brain. In situ hybridization histochemistry revealed specific labelling for GLP-1 receptor mRNA in several brain areas. In addition, GLP-1R, glucose transporter isoform (GLUT-2) and glucokinase (GK) mRNAs were identified in the same cells, especially in areas of the hypothalamus involved in feeding behaviour. GLP-1R gene expression in the human brain gave rise to a protein of 56 kDa as determined by affinity cross-linking assays. Specific binding of 125I-GLP-1(7-36) amide to the GLP-1R was detected in several brain areas and was inhibited by unlabelled GLP-1(7-36) amide, exendin-4 and exendin (9-39). A further aim of this work was to evaluate cerebral-glucose metabolism in control subjects by positron emission tomography (PET), using 2-[F-18] deoxy-D-glucose (FDG). Statistical analysis of the PET studies revealed that the administration of GLP-1(7-36) amide significantly reduced (p < 0.001) cerebral glucose metabolism in hypothalamus and brainstem. Because FDG-6-phosphate is not a substrate for subsequent metabolic reactions, the lower activity observed in these areas after peptide administration may be due to reduction of the glucose transport and/or glucose phosphorylation, which should modulate the glucose sensing process in the GLUT-2- and GK-containing cells.

18F-FDG positron emission tomography staging and restaging in rectal cancer treated with preoperative chemoradiation.

PURPOSE: To assess the information supplied by FDG-PET in patients with locally advanced rectal cancer both in the initial staging and in the evaluation of tumor changes induced by preoperative chemoradiation (restaging). METHODS AND MATERIALS: Twenty-five consecutive patients with rectal cancer were included, with tumor stages (c)T(2-4)N(x)M(0), during the period 1997-1999. We prospectively performed two FDG-PET scans in all patients to assess disease stage (1) at initial diagnosis and (2) presurgically, 4 to 5 weeks after protracted chemoradiation. Protracted chemoradiation was carried out during 5-6 weeks with 45-50 Gy, plus concurrent oral tegafur 1200 mg/day or 5-fluorouracil 500-1000 mg/m(2) administered as a 24-h continuous i.v. infusion on Days 1-4 and 21-25 of the radiotherapy treatment. Tumors were staged with CT in 95% of patients, whereas endorectal ultrasound was used in 90% of patients. Maximum standardized uptake value (SUVmax) was used as the quantitative parameter to estimate the tumor:tissue metabolic ratio. RESULTS: Preoperative chemoradiation significantly decreased the SUVMAX: 5.9 (mean SUVmax at initial staging) vs. 2.4 (mean SUVmax after chemoradiation) with p < 0.001. Unknown liver metastases were detected by FDG-PET in 2 patients, in 1 of them with the initial staging FDG-PET scan, and with the restaging FDG-PET scan in the other. After an average follow-up of 39 months, the value of SUVmax > or =6 allowed us to discriminate for survival at 3 years: 92% vs. 60% (p = 0.04). T downstaging (total 62%) was significantly correlated with SUVmax changes: 1.9 vs. 3.3 (p = 0.03). The degree of rectal cancer response to chemoradiation, established as mic vs. mac categories, was not associated with SUVmax differences (mean values of 2.0 vs. 2.7). CONCLUSION: Preliminary results observed suggest the potential utility of FDG-PET as a complementary diagnostic procedure in the initial clinical evaluation (8% of unsuspected liver metastases) as well as in the assessment of chemoradiation response (any T downstaged event) of locally advanced rectal cancer. Initial SUVmax might be of prognostic value related to long-term patient outcome.

Anatomical and functional brain variables associated with clozapine response in treatment-resistant schizophrenia.

Clozapine alleviates the symptoms of a significant proportion of treatment-resistant schizophrenic patients. Previous studies suggest that the response to clozapine may be associated with prefrontal and temporal anatomy as well as with prefrontal, basal ganglia and thalamic metabolism. A sample of 25 treatment-resistant (TR) schizophrenic patients underwent magnetic resonance imaging (MRI) and 18F-deoxyglucose positron emission tomography (PET) before and after treatment with clozapine. We investigated the association between changes in positive, disorganized, and negative schizophrenic syndromes with clozapine treatment and a set of cerebral variables that included total intracranial volume (ICV); hippocampal, dorsolateral prefrontal (DLPF) and temporal gray-matter volume and metabolism; and metabolic activity of the thalamus, pallidum/putamen, and caudate head. Improvement in positive symptoms with clozapine was directly related to temporal gray-matter volume, whereas improvement of disorganization symptoms was inversely related to ICV and hippocampal volume. Patients with high baseline DLPF cortical volume and metabolic activity were more likely to experience improvement in their negative symptoms. We conclude that clinical improvement with clozapine may be related with the anatomy and metabolic activity of specific brain areas, with the structural integrity of the DLPF and temporal regions showing the maximum predictive capacity.