Iron-based biomarkers for personalizing pharmacological ascorbate therapy in glioblastoma: insights from a phase 2 clinical trial.

BACKGROUND: Pharmacological ascorbate (intravenous delivery reaching plasma concentrations ≈ 20 mM; P-AscH-) has emerged as a promising therapeutic strategy for glioblastoma. Recently, a single-arm phase 2 clinical trial demonstrated a significant increase in overall survival when P-AscH- was combined with temozolomide and radiotherapy. As P-AscH- relies on iron-dependent mechanisms, this study aimed to assess the predictive potential of both molecular and imaging-based iron-related markers to enhance the personalization of P-AscH- therapy in glioblastoma participants. METHODS: Participants (n = 55) with newly diagnosed glioblastoma were enrolled in a phase 2 clinical trial conducted at the University of Iowa (NCT02344355). Tumor samples obtained during surgical resection were processed and stained for transferrin receptor and ferritin heavy chain expression. A blinded pathologist performed pathological assessment. Quantitative susceptibility mapping (QSM) measures were obtained from pre-radiotherapy MRI scans following maximal safe surgical resection. Circulating blood iron panels were evaluated prior to therapy through the University of Iowa Diagnostic Laboratory. RESULTS: Through univariate analysis, a significant inverse association was observed between tumor transferrin receptor expression and overall and progression-free survival. QSM measures exhibited a significant, positive association with progression-free survival. Subjects were actively followed until disease progression and then were followed through chart review or clinical visits for overall survival. CONCLUSIONS: This study analyzes iron-related biomarkers in the context of P-AscH- therapy for glioblastoma. Integrating molecular, systemic, and imaging-based markers offers a multifaceted approach to tailoring treatment strategies, thereby contributing to improved patient outcomes and advancing the field of glioblastoma therapy.

HIGHLIGHTS: Pharmacological ascorbate shows significant promise to enhance glioblastoma clinical outcomes. Transferrin receptor and ferritin heavy chain expression represent potential molecular markers to predict pharmacological ascorbate treatment response. Quantitative Susceptibility Mapping is an MRI technique that can serve as a non-invasive marker of iron metabolism to evaluate progression-free survival. Systemic iron metabolic markers are readily available diagnostic tests that can potentially be used to prognosticate overall survival.

Brain abnormalities in bipolar disorder detected by quantitative T1ρ mapping.

Abnormal metabolism has been reported in bipolar disorder, however, these studies have been limited to specific regions of the brain. To investigate whole-brain changes potentially associated with these processes, we applied a magnetic resonance imaging technique novel to psychiatric research, quantitative mapping of T1 relaxation in the rotating frame (T1ρ). This method is sensitive to proton chemical exchange, which is affected by pH, metabolite concentrations and cellular density with high spatial resolution relative to alternative techniques such as magnetic resonance spectroscopy and positron emission tomography. Study participants included 15 patients with bipolar I disorder in the euthymic state and 25 normal controls balanced for age and gender. T1ρ maps were generated and compared between the bipolar and control groups using voxel-wise and regional analyses. T1ρ values were found to be elevated in the cerebral white matter and cerebellum in the bipolar group. However, volumes of these areas were normal as measured by high-resolution T1- and T2-weighted magnetic resonance imaging. Interestingly, the cerebellar T1ρ abnormalities were normalized in participants receiving lithium treatment. These findings are consistent with metabolic or microstructural abnormalities in bipolar disorder and draw attention to roles of the cerebral white matter and cerebellum. This study highlights the potential utility of high-resolution T1ρ mapping in psychiatric research.

Magnetite nanoparticles as a kinetically favorable source of iron to enhance GBM response to chemoradiosensitization with pharmacological ascorbate.

Ferumoxytol (FMX) is an FDA-approved magnetite (Fe3O4) nanoparticle used to treat iron deficiency anemia that can also be used as an MR imaging agent in patients that can't receive gadolinium. Pharmacological ascorbate (P-AscH-; IV delivery; plasma levels ≈ 20 mM) has shown promise as an adjuvant to standard of care chemo-radiotherapy in glioblastoma (GBM). Since ascorbate toxicity mediated by H2O2 is enhanced by Fe redox cycling, the current study determined if ascorbate catalyzed the release of ferrous iron (Fe2+) from FMX for enhancing GBM responses to chemo-radiotherapy. Ascorbate interacted with Fe3O4 in FMX to produce redox-active Fe2+ while simultaneously generating increased H2O2 fluxes, that selectively enhanced GBM cell killing (relative to normal human astrocytes) as opposed to a more catalytically active Fe complex (EDTA-Fe3+) in an H2O2 - dependent manner. In vivo, FMX was able to improve GBM xenograft tumor control when combined with pharmacological ascorbate and chemoradiation in U251 tumors that were unresponsive to pharmacological ascorbate therapy. These data support the hypothesis that FMX combined with P-AscH- represents a novel combined modality therapeutic approach to enhance cancer cell selective chemoradiosentization in the management of glioblastoma.

Global and regional cortical thinning in first-episode psychosis patients: relationships with clinical and cognitive features.

BACKGROUND: The thickness of the cortical mantle is a sensitive measure for identifying alterations in cortical structure. We aimed to explore whether first episode schizophrenia patients already show a significant cortical thinning and whether cortical thickness anomalies may significantly influence clinical and cognitive features. METHOD: We investigated regional changes in cortical thickness in a large and heterogeneous sample of schizophrenia spectrum patients (n=142) at their first break of the illness and healthy controls (n=83). Magnetic resonance imaging brain scans (1.5 T) were obtained and images were analyzed by using brains2. The contribution of sociodemographic, cognitive and clinical characterictics was investigated. RESULTS: Patients showed a significant total cortical thinning (F=17.55, d=-0.62, p<0.001) and there was a diffuse pattern of reduced thickness (encompassing frontal, temporal and parietal cortices) (all p's<0.001, d's>0.53). No significant group×gender interactions were observed (all p's>0.15). There were no significant associations between the clinical and pre-morbid variables and cortical thickness measurements (all r's<0.12). A weak significant negative correlation between attention and total (r=-0.24, p=0.021) and parietal cortical thickness (r=-0.27, p=0.009) was found in patients (thicker cortex was associated with lower attention). Our data revealed a similar pattern of cortical thickness changes related to age in patients and controls. CONCLUSIONS: Cortical thinning is independent of gender, age, age of onset and duration of the illness and does not seem to significantly influence clinical and functional symptomatology. These findings support a primary neurodevelopment disorder affecting the normal cerebral cortex development in schizophrenia.

Quantum chemical insight into the effects of the local electron environment on T2*-based MRI.

T2* relaxation is an intrinsic magnetic resonance imaging (MRI) parameter that is sensitive to local magnetic field inhomogeneities created by the deposition of endogenous paramagnetic material (e.g. iron). Recent studies suggest that T2* mapping is sensitive to iron oxidation state. In this study, we evaluate the spin state-dependence of T2* relaxation using T2* mapping. We experimentally tested this physical principle using a series of phantom experiments showing that T2* relaxation times are directly proportional to the spin magnetic moment of different transition metals along with their associated magnetic susceptibility. We previously showed that T2* relaxation time can detect the oxidation of Fe2+. In this paper, we demonstrate that T2* relaxation times are significantly longer for the diamagnetic, d10 metal Ga3+, compared to the paramagnetic, d5 metal Fe3+. We also show in a cell culture model that cells supplemented with Ga3+ (S = 0) have a significantly longer relaxation time compared to cells supplemented with Fe3+ (S = 5/2). These data support the hypothesis that dipole-dipole interactions between protons and electrons are driven by the strength of the electron spin magnetic moment in the surrounding environment giving rise to T2* relaxation.

Hippocampal volume in chronic posttraumatic stress disorder (PTSD): MRI study using two different evaluation methods.

UNLABELLED: The hippocampus is discussed as one of the key regions in the pathogenesis of Posttraumatic Stress Disorder (PTSD). MRI results concerning the volume of the hippocampus are, however, inconsistent. This may be due to the heterogeneity of patients' traumata or postprocessing of the imaging data. To overcome these problems, the present study investigates volume changes in well-characterized chronic PTSD patients in comparison to controls using two different evaluation methods. MATERIAL AND METHODS: 15 patients with chronic PTSD, traumatized at the same air show plane crash in 1988 (Ramstein, Germany), and 15 matched healthy controls participated in this study. All patients suffered from significant impairment by the PTSD; none had a history of drug or alcohol abuse. Hippocampus volume changes were processed by a semi-automated standard procedure performed with BRAINS2 as well as the voxel based morphometry (VBM) using SPM2. RESULTS: No differences in total brain grey or white matter were detected between patients and controls. No differences in total hippocampal volume or in right and left parts were seen, even when hippocampal volumes were corrected by total brain volume or correlated with clinical data. Finally, no significant differences were detected between patients and controls in hippocampal regions using VBM. DISCUSSION: This is the first study examining long-term changes in hippocampal volumes in chronic PTSD patients compared to matched controls using two different evaluation methods. Neither conventional volumetry nor VBM could detect any differences in the volume and structure. This supports the hypothesis that previously described hippocampal volume reduction is not necessarily due to PTSD or at least that, after 15 years, volume changes have been restored or have not yet developed.

Regional frontal abnormalities in schizophrenia: a quantitative gray matter volume and cortical surface size study.

BACKGROUND: Previous structural studies of the frontal lobe in schizophrenia have had somewhat inconsistent results, but most of them have measured the frontal lobe as a single brain structure. To investigate more specific abnormalities in frontal subregions, we measured gray matter volume and cortical surface size in 10 subregions in drug-naive patients during the early stages of the illness. METHODS: Magnetic resonance imaging was used to measure frontal subregions in 34 healthy male volunteers, and 26 male, drug-naive schizophrenia patients at early stages of the illness. Frontal subregions were manually traced using our locally developed parcellation method. RESULTS: Patients with schizophrenia had a significant deficit in cortical surface size in the right straight gyrus and left orbitofrontal cortex. No differences were found in gray matter volumes. CONCLUSIONS: Frontal structural abnormalities found in drug-naive schizophrenic patients appear to be subtle and circumscribed to ventral portions. Anomalies in the cortical surface size suggest neurodevelopmental abnormalities might occur during the early stages of the gyrogenesis. Further investigations are needed to explore the implications of paralimbic ventral frontal regions (i.e., straight gyrus and orbitofrontal cortex) in the pathophysiology of schizophrenia.

Tumor size evaluated by pelvic examination compared with 3-D quantitative analysis in the prediction of outcome for cervical cancer.

PURPOSE: Tumor size estimated by pelvic examination (PE) is an important prognostic factor in cervical cancer treated with radiation therapy (RT). Recent histologic correlation studies also showed that magnetic resonance (MR) imaging provides highly accurate measurements of the actual tumor volume. The purpose of this study was to: (a) compare the accuracy of PE and MR in predicting outcome, and (b) correlate tumor measurements by PE versus MR. METHODS AND MATERIALS: Tumor measurements were performed prospectively in 43 patients with advanced cervical cancer. MR and PE were performed at the same time intervals: (a) at the start of RT, (b) after 20-24 Gy/2-2.5 weeks, (c) after 40-50 Gy/4-5 weeks, and (d) at follow-up (1-2 months after RT completion). PE measured tumor diameters in anteroposterior, lateral, and craniocaudal direction, and PE-derived tumor size was computed as maximum diameter, average diameter, and ellipsoid volume. MR-derived tumor size was calculated by summation of the tumor areas in each section and multiplication by the section thickness. Tumor regression during RT was calculated for each method as percentage of initial volume. The measurements were correlated with local failure and disease-free survival. Median follow-up was 29 months (range: 9-56 months). RESULTS: Prediction of local control: Overall, tumor regression rate (rapid versus slow) was more precise than the initial tumor size in the prediction of outcome. MR provided a more accurate and earlier prediction of local control (at 2-2.5 weeks, and at 4-5 weeks of RT) than PE (only at follow-up). Based on the initial tumor size, MR was also better than PE in predicting disease-free survival and local control, particularly in large (> or = 100 cm3) tumors. Size correlation: Tumor size (maximum diameter, average diameter, volume) by PE and MR did not correlate well (r = 0.51, 0.61, and 0.58, respectively). When using MR measurements as a reference, PE tended to overestimate intermediate-size (40-99 cm3) tumors. CONCLUSION: This preliminary study suggests that increased precision of tumor volume measurement leads to more accurate and earlier prediction of outcome in cervical cancer. MR tumor volumetry may be useful as an adjunct to PE in selected cases, and holds the potential to impact therapeutic decision-making.

Usefulness of tumor volumetry by magnetic resonance imaging in assessing response to radiation therapy in carcinoma of the uterine cervix.

PURPOSE: Clinical evaluation of tumor size in cervical cancer is often difficult, and clinical signs of radiation therapy failure may not be present until well after completion of treatment. The purpose of this study is to investigate early indicators of treatment response using magnetic resonance (MR) imaging for quantitative assessment of tumor volume and tumor regression rate before, during, and after radiation therapy. METHODS AND MATERIALS: Thirty-four patients with cervical cancer Stages IB [5], IIB [8], IIIA [1], IIIB [14], IVA [3], IVB [1], and recurrent [2] were studied prospectively with four serial MR examinations obtained at the start of radiation therapy, at 2-2.5 weeks (20-24 Gy), at 4-5 weeks (40-50 Gy), and 1-2 months after treatment completion. Tumor volume was assessed by three-dimensional volumetric measurements using T2-weighted images of each MR examination. The volume regression rate was generated based on the four sequential MR studies. These findings were correlated with local control, metastasis rate, and disease-free survival. Median follow-up was 18 months (range: 9-43 months). RESULTS: The tumor regression rate after a dose of 40-50 Gy correlated significantly with treatment outcome. The actuarial 2-year disease-free survival was 88.4% in patients with tumors regressing to < 20% of the initial volume compared with 45.4% in those with > or = 20% residual (p = 0.007). The incidence of local recurrence was 9.5% (2 out of 21) and 76.9% (10 out of 13), respectively (p < 0.001). Analysis by initial tumor volume showed that this observation was valid in patients with initial volumes between 40 and 100 cm3. Analysis by FIGO stage confirmed this observation in all patients except those with Stage IB. CONCLUSION: Sequential tumor volumetry using MR imaging appears to be a sensitive measure of the responsiveness of cervical cancer to irradiation. Treatment response can be assessed as early as during the course of radiation therapy by measurement of initial tumor volume and regression rate at 40-50 Gy. In patients with large (> 40 cm3) and advanced (Stage > or = IIIA) tumors, this technique may be helpful in supplementing the clinical examination for response assessment. The identification of patients at high risk for treatment failure may ultimately lead to improved clinical outcome.

Tumor perfusion studies using fast magnetic resonance imaging technique in advanced cervical cancer: a new noninvasive predictive assay.

PURPOSE: This study investigated sequential changes in tumor blood supply using magnetic resonance (MR) perfusion imaging and assessed their significance in the prediction of outcome of patients with advanced cervical cancer. The purpose of this project was to devise a simple, noninvasive method to predict early signs of treatment failure in advanced cervical cancer treated with conventional radiation therapy. METHODS AND MATERIALS: Sixty-eight MR perfusion studies were performed prospectively in 17 patients with squamous carcinomas (14) and adenocarcinomas (3) of the cervix, Stages bulky IB (1), IIB (5), IIIA (1), IIIB (8), and IVA (1), and recurrent (1). Four sequential studies were obtained in each patient: immediately before radiation therapy (pretherapy), after a dose of 20-22 Gy/ approximately 2 weeks (early therapy), after a dose of 40-45 Gy/ approximately 4-5 weeks (midtherapy), and 4-6 weeks after completion of therapy (follow-up). Perfusion imaging of the tumor was obtained at 3-s intervals in the sagittal plane. A bolus of 0.1 mmol/kg of MR contrast material (gadoteridol) was injected intravenously 30 s after beginning image acquisition at a rate of 9 ml/s using a power injector. Time/signal-intensity curves to reflect the onset, slope, and relative signal intensity (rSI) of contrast enhancement in the tumor region were generated. Median follow-up was 8 months (range 3-18 months). RESULTS: Tumors with a higher tissue perfusion (rSI > or = 2.8) in the pretherapy and early therapy (20-22 Gy) studies had a lower incidence of local recurrence than those with a rSI of < 2.8, but this was not statistically significant (13% vs. 67%; p = 0.05). An increase in tumor perfusion early during therapy (20-22 Gy), particularly to an rSI of > or = 2.8, was the strongest predictor of local recurrence (0% vs. 78%; p = 0.002). However, pelvic examination during early therapy (20-22 Gy) commonly showed no appreciable tumor regression. The slope of the time/signal-intensity curve obtained before and during radiation therapy also correlated with local recurrence. Follow-up perfusion studies did not provide information to predict recurrence. CONCLUSION: These preliminary results suggest that two simple MR perfusion studies before and early in therapy can offer important information on treatment outcome within the first 2 weeks of radiation therapy before response is evident by clinical examination. High tumor perfusion before therapy and increasing or persistent high perfusion early during the course of therapy appear to be favorable signs. High perfusion suggests a high blood and oxygen supply to the tumor. The increase in tumor perfusion seen in some patients early during radiation therapy suggests improved oxygenation of previously hypoxic cells following early cell kill. Radiation therapy is more effective in eradicating these tumors, resulting in improved local control. Our technique may be helpful in identifying early-while more aggressive therapy can still be implemented-those patients who respond poorly to conventional radiation therapy.

Insular cortex abnormalities in schizophrenia: a structural magnetic resonance imaging study of first-episode patients.

The insular cortex is a limbic integration region that is engaged in emotional and cognitive functions. To investigate possible insular cortex abnormalities in schizophrenia, we measured insular gray matter volume and cortical surface size in drug-naive first-episode patients. Magnetic resonance images were used to explore the morphology of the insular cortex of 25 healthy male volunteers, and 25 male schizophrenic patients. Groups were matched for age, sex, height, and parental socio-economic status. Clinical dimension scores were correlated with insular gray matter volume and cortical surface area. Patients had a significant reduction in cortical surface area [patients=2020 (206); controls=2142 (204); F=5.83, df=1, 47; P=0.01] and gray matter volume [patients=8.12 (0.77); controls=8.57 (0.94); F=3.93, df=1,47; P=0.05] in the left insular cortex. Insular gray matter volume and cortical surface size correlated negatively and significantly with the psychotic symptom dimension. Schizophrenic patients show morphological abnormalities in the insular cortex at early stages of the illness. These abnormalities are related to the severity of psychotic symptoms. Further investigations are needed to evaluate the role of the insula in the pathophysiology of schizophrenia.

Severe occlusive carotid artery disease: hemodynamic assessment by MR perfusion imaging in symptomatic patients.

BACKGROUND AND PURPOSE: Cerebral hemodynamic status has been reported to influence the occurrence and outcome of acute stroke. The purpose of this study was to assess hemodynamic compromise in symptomatic patients with severe occlusive disease of the carotid artery by the use of echo-planar perfusion imaging. METHODS: Spin-echo echo-planar perfusion imaging was performed in 11 patients (two had bilateral disease) with severe stenosis or occlusion of the carotid artery who had experienced either a recent transient ischemic attack or minor stroke. Relative cerebral blood volume (rCBV) maps and relative mean transit time (rMTT) maps were generated from the time-concentration curve. Findings on T2-weighted images, angiograms, rCBV maps, and rMTT maps were compared and assessed qualitatively and quantitatively. RESULTS: Although the abnormalities on T2-weighted images were absent, minimal, and/or unrelated to the degree of stenosis or collateral circulation, rMTT maps showed much larger and more distinct perfusion abnormalities along the vascular distribution of the affected vessels in all 13 vascular territories of the 11 patients. Despite obvious abnormalities on rMTT maps, none of the patients had evidence of decreased rCBV in the affected brain tissue (increased in three, normal in eight). A statistically significant difference in rMTT values was found between the affected and unaffected brain tissue, whereas no significant difference was seen in rCBV values. CONCLUSION: Echo-planar perfusion imaging is a noninvasive and rapid method for evaluating the hemodynamics in severe occlusive carotid artery disease and the compensatory vascular changes, and it may be useful in patient management.

Outcome of acute ischemic lesions evaluated by diffusion and perfusion MR imaging.

BACKGROUND AND PURPOSE: Diffusion and perfusion MR imaging have been reported to be valuable in the diagnosis of acute ischemia. Our purpose was to ascertain the value of these techniques in the prediction of ischemic injury and estimation of infarction size, as determined on follow-up examinations. METHODS: We studied 18 patients with acute ischemic stroke who underwent echo-planar perfusion and diffusion imaging within 72 hours of symptom onset. Quantitative volume measurements of ischemic lesions were derived from relative mean transit time (rMTT) maps, relative cerebral blood volume (rCBV) maps, and/or apparent diffusion coefficient (ADC) maps. Follow-up examinations were performed to verify clinical suspicion of infarction and to calculate the true infarction size. RESULTS: Twenty-five ischemic lesions were detected during the acute phase, and 14 of these were confirmed as infarcts on follow-up images. Both ADC and rMTT maps had a higher sensitivity (86%) than the rCBV map (79%), and the rCBV map had the highest specificity (91%) for detection of infarction as judged on follow-up images. The rMTT and ADC maps tended to overestimate infarction size (by 282% and 182%, respectively), whereas the rCBV map appeared to be more precise (117%). Significant differences were found between ADC and rMTT maps, and between rCBV and rMTT maps. CONCLUSION: Our data indicate that all three techniques are sensitive in detecting early ischemic injury within 72 hours of symptom onset but tend to overestimate the true infarction size. The best methods for detecting ischemic injury and for estimating infarction size appear to be the ADC map and the rCBV map, respectively, and the diffusion abnormality may indicate early changes of both reversible and irreversible ischemia.

Cerebral cortex: a topographic segmentation method using magnetic resonance imaging.

Remarkable developments in magnetic resonance imaging (MRI) technology provide a broad range of potential applications to explore in vivo morphological characteristics of the human cerebral cortex. MR-based parcellation methods of the cerebral cortex may clarify the structural anomalies in specific brain subregions that reflect underlying neuropathological processes in brain illnesses. The present study describes detailed guidelines for the parcellation of the cerebral cortex into 41 subregions. Our method conserves the topographic uniqueness of individual brains and is based on our ability to visualize the three orthogonal planes, the triangulated gray matter isosurface and the three-dimensional (3D) rendered brain simultaneously. Based upon topographic landmarks of individual sulci, every subregion was manually segmented on a set of serial coronal or transaxial slices consecutively. The reliability study indicated that the cerebral cortex could be parcelled reliably; intraclass correlation coefficients for each subregion ranged from 0.60 to 0.99. The validity of the method is supported by the fact that gyral subdivisions are similar to regions delineated in functional imaging studies conducted in our center. Ultimately, this method will permit us to detect subtle morphometric impairments or to find abnormal patterns of functional activation in circumscribed cortical subregions. The description of a thorough map of regional structural and functional cortical abnormalities will provide further insight into the role that different subregions play in the pathophysiology of brain illnesses.

Generating random series with known values of Kendall's tau.

Kendall's tau(a) offers statistical advantages to the more common Pearson's correlation and both are common in biomedical research. While generating random X-Y pairs from a known population value of Pearson's correlation is straightforward, the process for generating random sequences for a known value of Kendall's tau(a) is more complicated. Algorithms are presented that yield random numbers from a population with a known expected tau(a). They begin with a small set of values that have a known tau. These values are 'grown' to produce an arbitrarily large population that has the same expectation as the smaller set. Two examples are given. One example simulated samples from a population where tau(a) equaled 0.33 and confidence intervals are produced. A second example illustrates how the algorithm can be used to provide statistical power estimates for research studies using Kendall's tau(a).

White matter integrity, as measured by diffusion tensor imaging, distinguishes between impaired and unimpaired older adult decision-makers: A preliminary investigation.

In the context of normal ageing, some individuals experience cognitive changes that affect their decision-making abilities. We investigated whether such cognitive changes could be related to the integrity of cortical white matter, as measured by diffusion tensor imaging (DTI). Participants were administered a well-validated laboratory decision-making task, and were subsequently grouped as either poor decision-makers (older-impaired, n = 9) or strong decision-makers (older-unimpaired, n = 7). Participants also underwent magnetic resonance imaging (MRI) that collected high-resolution structural images, including DTI of the brain. The key variable of interest to be contrasted between the groups was fractional anisotropy (FA), as calculated from the tensor images. We hypothesised that FA values would be lower (indicating poorer integrity of tracts) in the older-impaired participants. The results supported our hypothesis, indicating significant differences in FA values between the participant groups for the entire brain as well as several subregions. The results suggest that poorer decision-making abilities are associated with the integrity of cortical white matter across multiple regions of the brain, and support the call for additional research in this area.

Antipsychotic dose and diminished neural modulation: a multi-site fMRI study.

BACKGROUND: The effect of antipsychotics on the blood oxygen level dependent signal in schizophrenia is poorly understood. The purpose of the present investigation is to examine the effect of antipsychotic medication on independent neural networks during a motor task in a large, multi-site functional magnetic resonance imaging investigation. METHODS: Seventy-nine medicated patients with schizophrenia and 114 comparison subjects from the Mind Clinical Imaging Consortium database completed a paced, auditory motor task during functional magnetic resonance imaging (fMRI). Independent component analysis identified temporally cohesive but spatially distributed neural networks. The independent component analysis time course was regressed with a model time course of the experimental design. The resulting beta weights were evaluated for group comparisons and correlations with chlorpromazine equivalents. RESULTS: Group differences between patients and comparison subjects were evident in the cortical and subcortical motor networks, default mode networks, and attentional networks. The chlorpromazine equivalents correlated with the unimotor/bitemporal (rho=-0.32, P=0.0039), motor/caudate (rho=-0.22, P=0.046), posterior default mode (rho=0.26, P=0.020), and anterior default mode networks (rho=0.24, P=0.03). Patients on typical antipsychotics also had less positive modulation of the motor/caudate network relative to patients on atypical antipsychotics (t(77)=2.01, P=0.048). CONCLUSION: The results suggest that antipsychotic dose diminishes neural activation in motor (cortical and subcortical) and default mode networks in patients with schizophrenia. The higher potency, typical antipsychotics also diminish positive modulation in subcortical motor networks. Antipsychotics may be a potential confound limiting interpretation of fMRI studies on the disease process in medicated patients with schizophrenia.

Iterative active deformational methodology for tumor delineation: Evaluation across radiation treatment stage and volume.

PURPOSE: To introduce, implement, and assess an iterative modification to the active deformational image segmentation method as applied to cervical cancer tumors. MATERIALS AND METHODS: A comparison by Jaccard similarity (JS) between this active deformational method and manual segmentation was performed on tumors of various sizes across preradiation, 3 weeks postradiation, and 6 weeks postradiation using a General Linear Mixed Model across 121 studies from 52 patients with Stage IIB-IV cervical cancers. RESULTS: The deformable segmentation method produced promising levels of agreement including JS factors of 0.71+/-0.11 in the preradiation studies. The analysis illustrated a rate of improvement in JS with increasing tumor volume that differed between the preradiation and 6 weeks postradiation stage (P=0.0474). In the large preradiated tumors each additional cm3 of volume was associated with an increase or improvement in JS of 0.0008 (95% confidence interval [CI]: 0.0003, 0.0014). In the smaller postradiation tumors, each additional cm3 of volume was associated with a more robust improvement in JS of 0.0046 (95% CI: 0.0009, 0.0082). CONCLUSION: Agreement was strongly affected by tumor volume, and its performance was most impacted across volume in the later stages of radiation therapy. The deformation-based segmentation method appears to demonstrate utility for delineating cervical cancer tumors, particularly in the earliest stages of radiation treatment, where agreement is greatest.

Visualization of subthalamic nuclei with cortex attenuated inversion recovery MR imaging.

There is a significant amount of interest in studying the thalamus because of its central location in the brain and its role as a gatekeeper to higher centers of cognition. Imaging and measuring of the individual subnuclei of the thalamus has proven extremely difficult in MR because of the contrast-to-noise (CNR) of the MR sequences used. This report describes a novel MR pulse sequence known as cortex attenuated inversion recovery (CAIR), which increases the CNR in images and allows the individual subnuclei of the thalamus to be visualized by selectively nulling the gray matter in the brain using an inversion recovery sequence with an inversion time of 700 ms at 1.5 T.