1H MR Spectroscopy of Fine-Needle Aspiration Biopsy Specimens for the Discrimination of Breast Cancer.

Purpose: To determine whether MR spectroscopic assessment of fine-needle aspiration (FNA) biopsy specimens from suspicious breast lesions could be used to improve the diagnostic utility of FNA biopsies for the characterization of breast lesions. Materials and Methods: In this prospective study, a previously reported technique using high-spatial-resolution proton MR spectroscopy was modified and used to examine the utility of FNA biopsies in the evaluation of suspicious breast lesions. Tissue samples from 115 lesions (from 102 women; average age, 54 years) were excised by using FNA and core biopsies and were collected between September 7, 2012, and April 11, 2014. Histologic results from core biopsy specimens determined the lesions to be benign (n = 55), invasive ductal carcinoma (n = 51), invasive lobular carcinoma (n = 5), or ductal carcinoma in situ (n = 4). Measures of phosphocholine (PC), glycerophosphocholine, and choline relative to each other and to total creatine (tCr) were obtained from usable spectra. Planned comparisons among lesion groups were carried out using t test contrasts, and differences of each contrast level from zero were judged significant when the two-tailed P value was less than .05. Results: Of the 115 samples, 69 (60%) yielded no usable MR spectra. Analysis of the 46 with usable spectra found that only the difference in PC/tCr between benign and cancer lesions was statistically significant (P = .028). Conclusion: Given that 60% of FNA biopsy specimens yielded no usable spectra and that results were largely inconclusive when derived from usable spectra, the combined MR and FNA technique, as modified and implemented in this study, is of little value for detection and diagnosis of breast cancer.Keywords: Breast, MR-Spectroscopy, Neoplasms-Primary© RSNA, 2020.

Neurophysiological effects of multiple mood episodes in bipolar disorder.

OBJECTIVES: Bipolar disorder is marked by progressive symptomatic changes, which have been linked with episode-related structural findings-particularly in the prefrontal cortex. However, few studies have examined neurofunctional and neurochemical effects of disease burden. In this study, we compared first- and multi-episode bipolar individuals. We hypothesized that the latter would demonstrate evidence of neurophysiological differences consistent with a model of progressive functional degradation of these networks. METHODS: First- and multi-episode manic bipolar subjects participated in functional magnetic resonance imaging (fMRI) including a continuous performance task with emotional distractors, and in single-voxel (1 H) magnetic resonance spectroscopy (MRS). A priori fMRI regions-of-interest (ROI) included structures comprising prefrontal-striatal-amygdala networks; (1 H)MRS voxels were placed within bilateral ventrolateral prefrontal (VLPFC) and anterior cingulate cortex (ACC). Both ROI and voxel-based brain activation in response to emotional stimuli, and neurochemical concentrations derived from (1 H)MRS were compared across bipolar groups. RESULTS: Multi-episode bipolar subjects showed relatively lower regional activation across prefrontal-striatal-amygdala networks, including bilateral VLPFC, orbitofrontal cortex, ACC, putamen, caudate, and amygdala. Exploratory whole-brain, voxel-based analysis suggested additional areas of lower activation extending into Brodmann area 22, posterior parietal regions, and right thalamus. Glutamate and N-acetylaspartate (NAA) concentrations were also relatively lower in the ACC of multi-episode subjects. CONCLUSIONS: Disease burden, exemplified by multiple affective episodes is associated with evidence of widespread decrements in affective network activity. Lower ACC NAA concentration is similarly consistent with a model of progressive functional deficits. These findings support the functional significance of previously observed progressive structural changes throughout these regions.

Longitudinal proton spectroscopy study of the prefrontal cortex in youth at risk for bipolar disorder before and after their first mood episode.

OBJECTIVES: To investigate neurochemical abnormalities in the left and right ventrolateral prefrontal cortex (VLPFC) and anterior cingulate cortex (ACC) of youth at risk for bipolar disorder using proton magnetic resonance spectroscopy before and after their first mood episode. METHODS: Children and adolescents offspring of parents with bipolar I disorder (at-risk group, n = 117) and matched healthy controls (HC group, n = 61) were recruited at the University of Cincinnati. At-risk subjects had no lifetime major mood and psychotic disorders at baseline, and were followed up every 4 months to monitor for development of a major depressive, manic, hypomanic, or mixed mood episode. Levels of N-acetyl-aspartate (NAA), phosphocreatine plus creatine (PCr + Cr), choline-containing compounds, myo-inositol, and glutamate were determined using LCModel and corrected for partial volume effects. RESULTS: There were no baseline differences in metabolite levels for any of the brain regions between at-risk and HC youth. Nineteen at-risk subjects developed a first mood episode during follow-up. Survival analyses showed that baseline PCr + Cr levels in the left VLPFC significantly predicted a mood episode during follow-up in the at-risk group (HR: 0.47, 95% CI: 0.27-0.82, P = 0.008). There were no longitudinal changes in metabolites levels in the VLPFC and ACC before and after a mood episode in at-risk subjects. CONCLUSIONS: We found no evidence for abnormal proton spectroscopy metabolite levels in the VLPFC and ACC of at-risk youth, prior and after the development of their first mood episode. Preliminary findings of association between baseline PCr + Cr levels in the left VLPFC and risk to develop a mood episode warrant further investigation.

Prediction of lithium response in first-episode mania using the LITHium Intelligent Agent (LITHIA): Pilot data and proof-of-concept.

OBJECTIVES: Individualized treatment for bipolar disorder based on neuroimaging treatment targets remains elusive. To address this shortcoming, we developed a linguistic machine learning system based on a cascading genetic fuzzy tree (GFT) design called the LITHium Intelligent Agent (LITHIA). Using multiple objectively defined functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy (1 H-MRS) inputs, we tested whether LITHIA could accurately predict the lithium response in participants with first-episode bipolar mania. METHODS: We identified 20 subjects with first-episode bipolar mania who received an adequate trial of lithium over 8 weeks and both fMRI and 1 H-MRS scans at baseline pre-treatment. We trained LITHIA using 18 1 H-MRS and 90 fMRI inputs over four training runs to classify treatment response and predict symptom reductions. Each training run contained a randomly selected 80% of the total sample and was followed by a 20% validation run. Over a different randomly selected distribution of the sample, we then compared LITHIA to eight common classification methods. RESULTS: LITHIA demonstrated nearly perfect classification accuracy and was able to predict post-treatment symptom reductions at 8 weeks with at least 88% accuracy in training and 80% accuracy in validation. Moreover, LITHIA exceeded the predictive capacity of the eight comparator methods and showed little tendency towards overfitting. CONCLUSIONS: The results provided proof-of-concept that a novel GFT is capable of providing control to a multidimensional bioinformatics problem-namely, prediction of the lithium response-in a pilot data set. Future work on this, and similar machine learning systems, could help assign psychiatric treatments more efficiently, thereby optimizing outcomes and limiting unnecessary treatment.

fMRI brain activation changes following treatment of a first bipolar manic episode.

OBJECTIVES: We tested the hypothesis that, with treatment, functional magnetic resonance imaging (fMRI) regional brain activation in first-episode mania would normalize - i.e., that differences from healthy subjects would diminish over time, and would be associated with clinical remission status, potentially identifying neuroanatomic treatment response markers. METHODS: Forty-two participants with bipolar I disorder were recruited during their first manic episode, pseudo-randomized to open-label lithium or quetiapine, and followed for 8 weeks. fMRI scans were obtained at baseline and then after 1 and 8 weeks of treatment, while participants performed a continuous performance task with emotional distracters. Healthy participants received fMRI scans at these same intervals. Specific region-of-interest (ROI) activations within prefrontal emotional networks were assessed as potential measures of treatment response. RESULTS: ROI data were reduced using exploratory factor analysis, which identified five factors that were organizationally consistent with functional anatomic models of human emotion modulation. Half of the participants with bipolar disorder achieved remission by Week 8 and were contrasted with the other half that did not. Analyses demonstrated that, in the bipolar disorder group in general, treatment led to decreases in activation across brain regions toward healthy subject values. However, differences in activation changes were observed between subjects with bipolar disorder who did or did not achieve remission in subcortical and amygdala factors. CONCLUSIONS: These findings provide evidence for potential neuroanatomic treatment response markers in first-episode bipolar disorder.

Effects of fish oil supplementation on prefrontal metabolite concentrations in adolescents with major depressive disorder: a preliminary 1H MRS study.

OBJECTIVE: To use proton magnetic resonance spectroscopy ((1)H MRS) to investigate the effects of fish oil (FO) supplementation on cortical metabolite concentrations in adolescents with major depressive disorder (MDD). METHODS: Metabolite concentrations were determined by (1)H MRS in the anterior cingulate cortex and bilateral dorsolateral prefrontal cortex (DLPFC) of adolescents with MDD before and following 10-week open-label supplementation with low (2.4 g/day, n = 7) or high (16.2 g/day, n = 7) dose FO. Depressive symptom severity scores and erythrocyte fatty acid levels were also determined. RESULTS: Baseline erythrocyte eicosapentaenoic acid (EPA) composition was positively correlated, and arachidonic acid (AA) and the AA/EPA ratio were inversely correlated, with choline (Cho) concentrations in the right DLPFC. Docosahexaenoic acid (DHA) composition was inversely correlated with myo-inositol (mI) concentrations in the left DLPFC. Erythrocyte EPA and DHA composition increased, and AA decreased, significantly following low-dose and high-dose FO supplementation. In the intent-to-treat sample, depressive symptom severity scores decreased significantly in the high-dose group (-40%, P < 0.0001) and there was a trend in the low-dose group (-20%, P = 0.06). There were no significant baseline-endpoint changes in metabolite levels in each voxel. In the low-dose group there were changes with large effect sizes, including a decrease in mI in the left DLPFC (-12%, P = 0.18, d = 0.8) and increases in glutamate + glutamine (Glx) (+12%, P = 0.19, d = 0.8) and Cho (+15%, P = 0.08, d = 1.2) in the right DLPFC. In the high-dose group, there was a trend for increases in Cho in the right DLPFC (+10%, P = 0.09, d = 1.2). DISCUSSION: These preliminary data suggest that increasing the LCn-3 fatty acid status of adolescent MDD patients is associated with subtle changes in Glx, mI, and Cho concentrations in the DLPFC that warrant further evaluation in a larger controlled trial.

N-acetyl aspartate levels in adolescents with bipolar and/or cannabis use disorders.

OBJECTIVE: Bipolar and cannabis use disorders commonly co-occur during adolescence, and neurochemical studies may help clarify the pathophysiology underlying this co-occurrence. This study compared metabolite concentrations in the left ventral lateral prefrontal cortex among adolescents with bipolar disorder (bipolar group; n = 14), adolescents with a cannabis use disorder (cannabis use group; n = 13), adolescents with cannabis use and bipolar disorders (bipolar and cannabis group; n = 25), and healthy adolescents (healthy controls; n = 15). We hypothesized that adolescents with bipolar disorder (with or without cannabis use disorder) would have decreased N-acetyl aspartate levels in the ventral lateral prefrontal cortex compared to the other groups and that the bipolar and cannabis group would have the lowest N-acetyl aspartate levels of all groups. METHODS: N-acetyl aspartate concentrations in the left ventral lateral prefrontal cortex were obtained using proton magnetic resonance spectroscopy. RESULTS: Adolescents with bipolar disorder showed significantly lower left ventral lateral prefrontal cortex N-acetyl aspartate levels, but post hoc analyses indicated that this was primarily due to increased N-acetyl aspartate levels in the cannabis group. The cannabis use disorder group had significantly higher N-acetyl aspartate levels compared to the bipolar disorder and the bipolar and cannabis groups (p = .0002 and p = .0002, respectively). Pearson correlations revealed a significant positive correlation between amount of cannabis used and N-acetyl aspartate concentrations. CONCLUSIONS: Adolescents with cannabis use disorder showed higher levels of N-acetyl aspartate concentrations that were significantly positively associated with the amount of cannabis used; however, this finding was not present in adolescents with comorbid bipolar disorder.

Magnetic resonance spectroscopy imaging of lactate in patients with bipolar disorder.

Although brain lactate levels are typically low and difficult to measure, a few previous investigators have reported that brain lactate levels are elevated in patients with bipolar disorder. The present study investigated the distribution of lactate in bipolar and healthy brains using 2D proton magnetic resonance spectroscopic imaging on a 4-Tesla magnetic resonance imaging system. Ratios of the concentration of lactate to N-acetylaspartate, and of lactate to total creatine, were significantly higher in bipolar than in healthy subjects. Lactate signals were primarily localized to the bipolar subjects' caudate and anterior cingulate cortices, components of the frontal-subcortical circuit, suggesting that affective dysregulation may be related to metabolic abnormalities in this network.

Neurochemical effects of quetiapine in patients with bipolar mania: a proton magnetic resonance spectroscopy study.

Although the neurophysiology underlying pharmacotherapy for bipolar disorder remains poorly understood, recent studies suggest that therapeutic mechanisms may be reflected in changes in concentrations of N-acetylaspartate (NAA), a putative measure of neuronal integrity and metabolism. In this study, we used magnetic resonance spectroscopy (MRS) to examine prefrontal NAA in patients receiving quetiapine for bipolar mania. On the basis of previous findings, we hypothesized that remission would be associated with increased NAA concentrations in the prefrontal cortex. Thirty-one manic bipolar patients and 13 healthy subjects were recruited to participate in this prospective study. All subjects participated in MRS at baseline and after 8 weeks of treatment. Bipolar subjects received open-label quetiapine monotherapy (mean dose [SD], 584 [191] mg). Fourteen patients remitted (Young Mania Rating Scale ≤ 12) ("remitters"), 11 patients did not ("nonremitters"), and 6 patients were lost to follow-up. Bipolar and healthy subjects did not significantly differ in baseline NAA or degree of change during the 8 weeks. Remitters showed greater mean baseline NAA concentrations in the right ventrolateral prefrontal cortex compared with nonremitters (P < 0.05). In the anterior cingulate, remitters showed near significantly decreased baseline NAA concentrations at baseline (P < 0.06), and significant differences in NAA change during the 8 weeks of treatment (P < 0.03). Manic patients who remitted with quetiapine treatment in the course of this study exhibited distinct patterns of baseline prefrontal NAA concentration, coupled with decreased NAA in the anterior cingulate with treatment; the latter possibly reflecting disparate effects of quetiapine on neuronal metabolism. These data support suggestions that therapeutic effects of quetiapine involve metabolic effects on specific prefrontal regions.

A pilot study of anterior cingulate cortex neurochemistry in adolescents with generalized anxiety disorder.

BACKGROUND/AIMS: This study used proton magnetic resonance spectroscopy (¹H MRS) to evaluate the neurochemistry of the anterior cingulate cortex (ACC) in adolescents with generalized anxiety disorder (GAD). METHODS: Adolescents with GAD (n = 10) and healthy subjects (n = 10) underwent a ¹H MRS scan at 4 T. Glutamate (Glu), N-acetyl aspartate, creatine (Cr) and myo-inositol concentrations were measured in the ACC and were compared between untreated adolescents with GAD and age- and sex-matched healthy subjects. RESULTS: Glu/Cr ratios in the ACC correlated with the severity of both generalized anxiety symptoms on the Pediatric Anxiety Rating Scale and with total anxiety symptom severity as measured by the Hamilton Anxiety Rating Scale, but did not differ between adolescents with GAD and healthy subjects. In addition, no differences in N-acetyl aspartate, Cr, or myo-inositol were detected between groups. CONCLUSION: These findings suggest that Glu/Cr in untreated adolescents with GAD may relate to the severity of anxiety symptoms and raise the possibility that dysregulation of Glu within the ACC may be linked to the pathophysiology of pediatric GAD.

Low docosahexaenoic acid status is associated with reduced indices in cortical integrity in the anterior cingulate of healthy male children: a 1H MRS Study.

Docosahexaenoic acid (DHA, 22:6n-3) is the principal omega-3 fatty acid in mammalian brain gray matter, and emerging preclinical evidence suggests that DHA has neurotrophic and neuroprotective properties. This study investigated relationships among DHA status, neurocognitive performance, and cortical metabolism measured with proton magnetic resonance spectroscopy (1H MRS) in healthy developing male children (aged 8-10 years, n = 38). Subjects were segregated into low-DHA (n = 19) and high-DHA (n = 19) status groups by a median split of erythrocyte DHA levels. Group differences in 1H MRS indices of cortical metabolism, including choline (Cho), creatine (Cr), glutamine + glutamate + γ-aminobutyric acid (Glx), myo-inositol (mI), and n-acetyl aspartate (NAA), were determined in the right and left dorsolateral prefrontal cortex (R/L-DLPFC, BA9) and bilateral anterior cingulate cortex (ACC, BA32/33). Group differences in neurocognitive performance were evaluated with the Kaufman Brief Intelligence Test and identical-pairs version of the continuous performance task (CPT-IP). Subjects in the low-DHA group consumed fish less frequently (P = 0.02), had slower reaction times on the CPT-IP (P = 0.007), and exhibited lower mI (P = 0.007), NAA (P = 0.007), Cho (P = 0.009), and Cr (P = 0.01) concentrations in the ACC compared with the high-DHA group. There were no group differences in ACC Glx or any metabolite in the L-DLPFC and R-DLPFC. These data indicate that low-DHA status is associated with reduced indices of metabolic function in the ACC and slower reaction time during sustained attention in developing male children.

Neuroanatomic abnormalities in adolescents with generalized anxiety disorder: a voxel-based morphometry study.

BACKGROUND: Despite recent data implicating functional abnormalities in the neurocircuitry underlying emotional processing in pediatric anxiety disorders, little is known regarding neurostructural abnormalities within these systems. METHODS: Using voxel-based morphometry, gray and white matter volumes were compared in 15 medication-free adolescents with generalized anxiety disorder (GAD; and no comorbid major depressive disorder) and 28 age- and sex-matched healthy comparison subjects. RESULTS: Compared to healthy adolescents, youth with GAD had larger gray matter volumes in the right precuneus and right precentral gyrus and decreased gray matter volumes in the left orbital gyrus and posterior cingulate. White matter volumes were decreased in the left medial and superior frontal gyrus and were increased in the left inferior temporal gyrus in youth with GAD relative to healthy subjects. CONCLUSIONS: Adolescents with GAD, who are early in the course of their illness, exhibit abnormalities in neural structures that subserve threat appraisal, modulation of fear responses, attachment, and mentalization.

1H NMR analysis of choline metabolites in fine-needle-aspirate biopsies of breast cancer.

OBJECT: The relative amounts of choline (Cho), phosphocholine (PC), and glycerophosphocholine (GPC) may be sensitive indicators of breast cancer and the degree of malignancy. Here we implement some simple modifications to a previously developed (1)H NMR analysis of fine-needle-aspirate (FNA) biopsies designed to yield sufficient spectral resolution of Cho, PC, and GPC for usable relative quantitation of these metabolites. MATERIALS AND METHODS: FNA biopsies of eighteen breast lesions were examined using our modified procedure for direct (1)H NMR at 400 MHz. Resonances of choline metabolites and potential interferences were fit using the computer program NUTS. RESULTS: Quantitation of PC, GPC, and Cho relative to each other and to (phospho)creatine was obtained for eleven confirmed cases of infiltrating ductal carcinoma. Reliable results could not be obtained for the remaining cases primarily due to interference from lidocaine anesthetic. CONCLUSION: Some simple modifications of a previously developed (1)H NMR analysis of FNAs yielded sufficient spectral resolution of Cho, PC, and GPC to permit usable relative quantitation at 400 MHz. In 9 of the 11 quantified cases the sum of GPC and Cho exceeded 42 % of the total choline-metabolite peak area.

Neurometabolite effects of response to quetiapine and placebo in adolescents with bipolar depression.

OBJECTIVE: Mood stabilizers have been reported to affect brain concentrations of myo-inositol (mI) and N-acetylaspartate (NAA). We examined the effects of quetiapine (QUET), an atypical antipsychotic, on these neurochemicals, and potential predictors of response to QUET in adolescents with bipolar depression. METHODS: Twenty-six adolescents with bipolar depression participated in an 8-week placebo-controlled trial of QUET monotherapy. Subjects were scanned at baseline and after 8 weeks with proton magnetic resonance spectroscopy (1H-MRS) at 3T and 4T at two sites, with 8 cm(3) voxels placed in the right and left dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). LCModel was used to calculate absolute concentrations of NAA and mI. RESULTS: Twenty-six subjects had pre- and posttreatment scans (mean age=15.6 years, 9 boys). Of these subjects, 5 out of 16 subjects receiving QUET and 5 out of 10 receiving placebo (PBO) were responders (50% decrease in Children's Depression Rating Scale [CDRS] score). Although baseline ACC mI did not predict responder status, responders had significantly lower posttreatment ACC mI values than did nonresponders (3.27±.71 vs. 4.23±.70; p=0.004). There were no significant differences in the changes in ACC and DLPFC NAA levels in the QUET group compared with the PBO group (ACC: -0.55±1.3 vs.+0.25±1.5, p=0.23; right-DLPFC: -0.55±1.3 vs. 0.33±0.89, p=0.13; left-DLPFC: -0.04±0.91 vs.+0.29±0.61, p=0.41). CONCLUSION: We found that posttreatment, not baseline, ACC mI levels were associated with response to QUET in adolescents with bipolar depression. There were no differences in NAA concentration changes between the QUET and PBO groups. Larger studies including different brain regions would help to clarify the effects of QUET on neurochemistry in patients with bipolar disorder.

4-T 7Li 3D MR spectroscopy imaging in the brains of bipolar disorder subjects.

This work demonstrates the first whole brain "high spatial resolution" (7)Li MR spectroscopy imaging in bipolar disorder subjects. The in vivo quantification is validated by a phantom containing 5 mM lithium salt using the identical radiofrequency sequence and imaging protocol. This study is the first demonstration of the (7)Li distribution in the brain of bipolar disorder patients on lithium therapy using a 3D MR spectroscopy imaging approach. The results show that brain lithium level is strongly correlated with serum lithium concentration. The brain-to-serum lithium ratios for the average brain and the local maximum were 0.39 ± 0.08 (r = 0.93) and 0.92 ± 0.16 (r = 0.90), respectively. The lithium distribution is found to be nonuniform throughout the brain for all patients, which is somewhat unexpected and highly intriguing. This uneven distribution is more evident in subjects at a higher therapeutic serum lithium level. This finding may suggest that lithium targets specific brain tissues and/or certain enzymatic and macromolecular sites that are associated with therapeutic effect. Further investigations of bipolar disorder patients on lithium therapy using 3D (7)Li MR spectroscopy imaging are warranted.

Glutamatergic effects of divalproex in adolescents with mania: a proton magnetic resonance spectroscopy study.

OBJECTIVES: This study used proton magnetic resonance spectroscopy ((1)H MRS) to evaluate the in vivo effects of extended-release divalproex sodium on the glutamatergic system in adolescents with bipolar disorder, and to identify baseline neurochemical predictors of clinical remission. METHOD: Adolescents with bipolar disorder who were experiencing a manic or mixed episode (N = 25) were treated with open-label, extended-release divalproex (serum levels 85-125 µg/mL) and underwent (1)H MRS scanning at baseline (before treatment) and on days 7 and 28. Healthy comparison subjects (n = 15) also underwent (1)H MRS scanning at the same time points. Glutamate (Glu) and glutamate+glutamine (Glx) concentrations were measured in three voxels: anterior cingulate cortex (ACC), left ventrolateral prefrontal cortex (LVLPFC), and right ventrolateral prefrontal cortex (RVLPFC), and were compared between bipolar and healthy subjects. Within the bipolar subjects, Glu and Glx concentrations at baseline and each time point were also compared between remitters and nonremitters after divalproex treatment. RESULTS: At baseline, no differences in Glu or Glx concentrations between bipolar and healthy subjects were observed. Group (HC vs. BP) by time effects revealed an interaction for Glu in the ACC, and change over time effects for Glx were noted in the ACC in patients with bipolar disorder (increase from day 0 to day 7 and then a decrease from day 7 to day 28) but not in HC. Remitters had significantly lower baseline Glx concentrations in LVLPFC, and in remitters the change in LVLPFC Glu correlated with the change in YMRS score. CONCLUSIONS: Successful treatment of mania with divalproex may be predicted by lower baseline concentrations of Glx in the LVLPFC. In addition, in remitters, the degree of symptomatic improvement is related to the change in Glu concentrations in this region, suggesting that divalproex may work via modulation of the prefrontal glutamatergic system in youth with bipolar disorder.

Neurocircuitry of generalized anxiety disorder in adolescents: a pilot functional neuroimaging and functional connectivity study.

BACKGROUND: Dysfunction of neural systems responsible for the processing of emotional stimuli is hypothesized to be involved in the pathophysiology of generalized anxiety disorder (GAD) in adolescents. We used standard fMRI and functional connectivity analyses to examine the functional neurocircuitry of GAD in adolescents. METHODS: Ten adolescents with GAD and 10 healthy comparison subjects underwent fMRI while performing a continuous performance task with emotional and neutral distractors. Standard event-related voxel-wise fMRI and steady-state functional connectivity analyses were performed. RESULTS: Increased activation was observed in the left medial prefrontal cortex and right ventrolateral prefrontal cortex (VLPFC) in response to emotional images compared to neutral imagines in youth with GAD. Connectivity analyses using the right VLPFC seed region suggested decreased connectivity between this region and the bilateral medial prefrontal cortex. Connectivity analyses using the right amygdala seed region revealed decreased correlation with the posterior cingulate cortex in adolescents with GAD. The left amygdala seed region demonstrated increased connectivity with the ipsilateral precuneus in youth with GAD compared to healthy subjects. CONCLUSIONS: In addition to increased activation of the medial prefrontal cortex and right VLPFC, we observed altered connectivity between the amygdala or VLPFC and regions, which subserve mentalization (e.g. posterior cingulate cortex, precuneus, and medial prefrontal cortex). This suggests that structures that regulate emotion and affect interact abnormally with key structures that are involved in mentalization, a process known to be disrupted in GAD.

Neurochemical alteration in the caudate: implications for the pathophysiology of bipolar disorder.

Several lines of evidence suggest that the neuropathophysiology of bipolar disorder is marked by structural and functional abnormalities in the caudate. We used magnetic resonance spectroscopy imaging (MRSI) to examine potential neurochemical changes in the caudate of adult bipolar patients (BP). 2D-MRSI scans including the caudate were obtained from 25 BP and 9 healthy subjects (HS). BP patients were further divided into medicated (n=14) and unmedicated (n=11) groups; the majority of medicated patients received atypical antipsychotics (AAP). Ratios of Cr/Cho, Cho/NAA and Cr/NAA in the caudate were compared between groups, controlling for age, gender and gray/white ratio. BP and HS did not significantly differ on any ratios. The Cr/Cho ratio, however, was significantly greater in medicated BP compared to HS. Conversely, the Cho/NAA ratio was non-significantly lower in medicated BP vs. HS. Medicated BP also showed significantly greater Cr/Cho and significantly smaller Cho/NAA ratios than unmedicated BP. Although we did not observe significant overall differences between BP and HS, our findings suggest the presence of reduced choline levels in the caudate of medicated BP receiving AAP. While speculative, these results suggest that AAP do not cause oxidative injury to neuronal membranes.

Polymer beacons for luminescence and magnetic resonance imaging of DNA delivery.

The delivery of nucleic acids with polycations offers tremendous potential for developing highly specific treatments for various therapeutic targets. Although materials have been developed and studied for polynucleotide transfer, the biological mechanisms and fate of the synthetic vehicle has remained elusive due to the limitations with current labeling technologies. Here, we have developed polymer beacons that allow the delivery of nucleic acids to be visualized at different biological scales. The polycations have been designed to contain repeated oligoethyleneamines, for binding and compacting nucleic acids into nanoparticles, and lanthanide (Ln) chelates [either luminescent europium (Eu(3+)) or paramagnetic gadolinium (Gd(3+))]. The chelated Lns allow the visualization of the delivery vehicle both on the nm/microm scale via microscopy and on the sub-mm scale via MRI. We demonstrate that these delivery beacons effectively bind and compact plasmid (p)DNA into nanoparticles and protect nucleic acids from nuclease damage. These delivery beacons efficiently deliver pDNA into cultured cells and do not exhibit toxicity. Micrographs of cultured cells exposed to the nanoparticle complexes formed with fluorescein-labeled pDNA and the europium-chelated polymers reveal effective intracellular imaging of the delivery process. MRI of bulk cells exposed to the complexes formulated with pDNA and the gadolinium-chelated structures show bright image contrast, allowing visualization of effective intracellular delivery on the tissue-scale. Because of their versatility, these delivery beacons posses remarkable potential for tracking and understanding nucleic acid transfer in vitro, and have promise as in vivo theranostic agents.

Brain-mapping techniques for evaluating poststroke recovery and rehabilitation: a review.

Brain-mapping techniques have proven to be vital in understanding the molecular, cellular, and functional mechanisms of recovery after stroke. This article briefly summarizes the current molecular and functional concepts of stroke recovery and addresses how various neuroimaging techniques can be used to observe these changes. The authors provide an overview of various techniques including diffusion-tensor imaging (DTI), magnetic resonance spectroscopy (MRS), ligand-based positron emission tomography (PET), single-photon emission computed tomography (SPECT), regional cerebral blood flow (rCBF) and regional metabolic rate of glucose (rCMRglc) PET and SPECT, functional magnetic resonance imaging (fMRI), near infrared spectroscopy (NIRS), electroencephalography (EEG), magnetoencephalography (MEG), and transcranial magnetic stimulation (TMS). Discussion in the context of poststroke recovery research informs about the applications and limitations of the techniques in the area of rehabilitation research. The authors also provide suggestions on using these techniques in tandem to more thoroughly address the outstanding questions in the field.