Revolving hexameric ATPases as asymmetric motors to translocate double-stranded DNA genome along one strand.

DsDNA translocation through nanoscale pores is generally accomplished by ATPase biomotors. The discovery of the revolving dsDNA translocation mechanism, as opposed to rotation, in bacteriophage phi29 elucidated how ATPase motors move dsDNA. Revolution-driven, hexameric dsDNA motors have been reported in herpesvirus, bacterial FtsK, Streptomyces TraB, and T7 phage. This review explores the common relationship between their structure and mechanisms. Commonalities include moving along the 5'→3' strand, inchworm sequential action leading to an asymmetrical structure, channel chirality, channel size, and 3-step channel gating for controlling motion direction. The revolving mechanism and contact with one of the dsDNA strands addresses the historic controversy of dsDNA packaging using nicked, gapped, hybrid, or chemically modified DNA. These controversies surrounding dsDNA packaging activity using modified materials can be answered by whether the modification was introduced into the 3'→5' or 5'→3' strand. Perspectives concerning solutions to the controversy of motor structure and stoichiometry are also discussed.

Electric Fields Regulate In Vitro Surface Phosphatidylserine Exposure of Cancer Cells via a Calcium-Dependent Pathway.

Cancer is the second leading cause of death worldwide after heart disease. The current treatment options to fight cancer are limited, and there is a critical need for better treatment strategies. During the last several decades, several electric field (EF)-based approaches for anti-cancer therapies have been introduced, such as electroporation and tumor-treating fields; still, they are far from optimal due to their invasive nature, limited efficacy and significant side effects. In this study, we developed a non-contact EF stimulation system to investigate the in vitro effects of a novel EF modality on cancer biomarkers in normal (human astrocytes, human pancreatic ductal epithelial -HDPE-cells) and cancer cell lines (glioblastoma U87-GBM, human pancreatic cancer cfPac-1, and MiaPaCa-2). Our results demonstrate that this EF modality can successfully modulate an important cancer cell biomarker-cell surface phosphatidylserine (PS). Our results further suggest that moderate, but not low, amplitude EF induces p38 mitogen-activated protein kinase (MAPK), actin polymerization, and cell cycle arrest in cancer cell lines. Based on our results, we propose a mechanism for EF-mediated PS exposure in cancer cells, where the magnitude of induced EF on the cell surface can differentially regulate intracellular calcium (Ca2+) levels, thereby modulating surface PS exposure.

Phosphatidylserine: The Unique Dual-Role Biomarker for Cancer Imaging and Therapy.

Cancer is among the leading causes of death worldwide. In recent years, many cancer-associated biomarkers have been identified that are used for cancer diagnosis, prognosis, screening, and early detection, as well as for predicting and monitoring carcinogenesis and therapeutic effectiveness. Phosphatidylserine (PS) is a negatively charged phospholipid which is predominantly located in the inner leaflet of the cell membrane. In many cancer cells, PS externalizes to the outer cell membrane, a process regulated by calcium-dependent flippases and scramblases. Saposin C coupled with dioleoylphosphatidylserine (SapC-DOPS) nanovesicle (BXQ-350) and bavituximab, (Tarvacin, human-mouse chimeric monoclonal antibodies) are cell surface PS-targeting drugs being tested in clinical trial for treating a variety of cancers. Additionally, a number of other PS-selective agents have been used to trigger cytotoxicity in tumor-associated endothelial cells or cancer cells in pre-clinical studies. Recent studies have demonstrated that upregulation of surface PS exposure by chemodrugs, radiation, and external electric fields can be used as a novel approach to sensitize cancer cells to PS-targeting anticancer drugs. The objectives of this review are to provide an overview of a unique dual-role of PS as a biomarker/target for cancer imaging and therapy, and to discuss PS-based anticancer strategies that are currently under active development.

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.

NMR shutter-speed elucidates apparent population inversion of 1 H2 O signals due to active transmembrane water cycling.

PURPOSE: The desire to quantitatively discriminate the extra- and intracellular tissue 1 H2 O MR signals has gone hand-in-hand with the continual, historic increase in MRI instrument magnetic field strength [B0 ]. However, recent studies have indicated extremely valuable, novel metabolic information can be readily accessible at ultra-low B0 . The two signals can be distinguished, and the homeostatic activity of the cell membrane sodium/potassium pump (Na+ ,K+ ,ATPase) detected. The mechanism allowing 1 H2 O MRI to do this is the newly discovered active transmembrane water cycling (AWC) phenomenon, which we found using paramagnetic extracellular contrast agents at clinical B0 values. AWC is important because Na+ ,K+ ,ATPase can be considered biology's most vital enzyme, and its in vivo steady-state activity has not before been measurable, let alone amenable to mapping with high spatial resolution. Recent reports indicate AWC correlates with neuronal firing rate, with malignant tumor metastatic potential, and inversely with cellular reducing equivalent fraction. We wish to systematize the ways AWC can be precisely measured. METHODS: We present a theoretical longitudinal relaxation analysis of considerable scope: it spans the low- and high-field situations. RESULTS: We show the NMR shutter-speed organizing principle is pivotal in understanding how trans-membrane steady-state water exchange kinetics are manifest throughout the range. Our findings illuminate an aspect, apparent population inversion, which is crucial in understanding ultra-low field results. CONCLUSIONS: Without an appreciation of apparent population inversion, significant misinterpretations of future data are likely. These could have unfortunate diagnostic consequences.

Magnetic resonance imaging study of eye congenital birth defects in mouse model.

PURPOSE: Embryonic eyelid closure is a well-documented morphogenetic episode in mammalian eye development. Detection of eyelid closure defect in humans is a major challenge because eyelid closure and reopen occur entirely in utero. As a consequence, congenital eye defects that are associated with failure of embryonic eyelid closure remain unknown. To fill the gap, we developed a mouse model of defective eyelid closure. This preliminary work demonstrates that the magnetic resonance imaging (MRI) approach can be used for the detection of extraocular muscle abnormalities in the mouse model. METHODS: Mice with either normal (Map3k1+/- ) or defective (Map3k1-/- ) embryonic eyelid closure were used in this study. Images of the extraocular muscles were obtained with a 9.4 T high resolution microimaging MRI system. The extraocular muscles were identified, segmented, and measured in each imaging slice using an in-house program. RESULTS: In agreement with histological findings, the imaging data show that mice with defective embryonic eyelid closure develop less extraocular muscle than normal mice. In addition, the size of the eyeballs was noticeably reduced in mice with defective embryonic eyelid closure. CONCLUSIONS: We demonstrated that MRI can potentially be used for the study of extraocular muscle in the mouse model of the eye open-at-birth defect, despite the lack of specificity of muscle group provided by the current imaging resolution.

Sequential delivery of erlotinib and doxorubicin for enhanced triple negative Breast cancer treatment using polymeric nanoparticle.

Recent studies of signaling networks point out that an order of drugs to be administrated to the cancerous cells can be critical for optimal therapeutic outcomes of recalcitrant metastatic and drug-resistant cell types. In this study, a development of a polymeric nanoparticle system for sequential delivery is reported. The nanoparticle system can co-encapsulate and co-deliver a combination of therapeutic agents with different physicochemical properties [i.e. epidermal growth factor receptor (EGFR) inhibitor, erlotinib (Ei), and doxorubicin (Dox)]. Dox is hydrophilic and was complexed with anionic lipid, 1,2-dioleoyl-sn-glycero-3-phosphate (DOPA), via ion pairing to form a hydrophobic entity. Then it was co-encapsulated with hydrophobic Ei in a poly(L-lactide)-b-polyethylene glycol (PLA-b-PEG) nanoparticle by nanoprecipitation. The complexation of Dox with DOPA greatly helps the encapsulation of Dox, and substantially reduces the release rate of Dox. This nanoparticle system was found to burst the release of Ei with a slow and sustained profile of Dox, which is an optimal course of administration for these two drugs as previously reported. The efficacy of this sequential delivery nanoparticle system was validated in vitro and its in vivo potential applicability was substantiated by fluorescent imaging of high tumor accumulation.

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.

Tissue-dependent cerebral energy metabolism in adolescents with bipolar disorder.

OBJECTIVES: To investigate tissue-dependent cerebral energy metabolism by measuring high energy phosphate levels in unmedicated adolescents diagnosed with bipolar I disorder. METHODS: Phosphorus-31 magnetic resonance spectroscopic imaging data were acquired over the entire brain of 24 adolescents with bipolar I disorder and 19 demographically matched healthy comparison adolescents. Estimates of phosphocreatine (PCr) and adenosine triphosphate (ATP, determined from the γ-resonance) in homogeneous gray and white matter in the right and left hemispheres of the cerebrum of each subject were obtained by extrapolation of linear regression analyses of metabolite concentrations vs. voxel gray matter fractions. RESULTS: Multivariate analyses of variance showed a significant effect of group on high energy phosphate concentrations in the right cerebrum (p=0.0002) but not in the left (p=0.17). Post-hoc testing in the right cerebrum revealed significantly reduced concentrations of PCr in gray matter and ATP in white matter in both manic (p=0.002 and 0.0001, respectively) and euthymic (p=0.004 and 0.002, respectively) bipolar I disorder subjects relative to healthy comparisons. LIMITATIONS: The small sample sizes yield relatively low statistical power between manic and euthymic groups; cross-sectional observations limit the ability to determine if these findings are truly independent of mood state. CONCLUSIONS: Our results suggest bioenergetic impairment - consistent with downregulation of creatine kinase - is an early pathophysiological feature of bipolar I disorder.

Impact of functional magnetic resonance imaging (fMRI) scanner noise on affective state and attentional performance.

INTRODUCTION: Previous research has shown that performance on cognitive tasks administered in the scanner can be altered by the scanner environment. There are no previous studies that have investigated the impact of scanner noise using a well-validated measure of affective change. The goal of this study was to determine whether performance on an affective attentional task or emotional response to the task would change in the presence of distracting acoustic noise, such as that encountered in a magnetic resonance imaging (MRI) environment. METHOD: Thirty-four young adults with no self-reported history of neurologic disorder or mental illness completed three blocks of the affective Posner task outside of the scanner. The task was meant to induce frustration through monetary contingencies and rigged feedback. Participants completed a Self-Assessment Manikin at the end of each block to rate their mood, arousal level, and sense of dominance. During the task, half of the participants heard noise (recorded from a 4T MRI system), and half heard no noise. RESULTS: The affective Posner task led to significant reductions in mood and increases in arousal in healthy participants. The presence of scanner noise did not impact task performance; however, individuals in the noise group did report significantly poorer mood throughout the task. CONCLUSIONS: The results of the present study suggest that the acoustic qualities of MRI enhance frustration effects on an affective attentional task and that scanner noise may influence mood during similar functional magnetic resonance imaging (fMRI) tasks.

Adaptive speech enhancement using directional microphone in a 4-T MRI scanner.

OBJECTIVE: To evaluate the effectiveness of the proposed adaptive speech enhancement (ASE) system for the magnetic resonance imaging (MRI) environment to reduce the loud scanning noise without disrupting the communication between patients and MRI operators. MATERIALS AND METHODS: The developed system employed the idea of differential directional microphones for measuring and distinguishing the speech signals and MRI acoustic noises simultaneously. Two-stage adaptive filters with normalized least mean square algorithms were adopted. Two common MRI scanning sequences, echo planar imaging (EPI) and gradient echo multi-slice (GEMS), were tested using a 4T MRI scanner. RESULTS: A total of 1.4 and 3.3 dB speech enhancements quantified by the cepstral distance assessment were achieved for the speech signal contaminated with the EPI and GEMS noises, respectively. The speech signal was noticeably recovered, and a clear speech waveform was observed after treated with the ASE system. Furthermore, a non-adaptive post-processing approach [i.e. simply using spectral subtraction (SS) technique] was also adopted to process the abovementioned results. Additional reductions were achieved for the non-coherent MRI acoustic noises. CONCLUSION: The results showed that combining the proposed ASE system along with the SS approach has a great potential for treating MRI acoustic noise to guarantee an effective communication from patient to MRI operators.

Age-dependent decreases of high energy phosphates in cerebral gray matter of patients with bipolar I disorder: a preliminary phosphorus-31 magnetic resonance spectroscopic imaging study.

OBJECTIVES: To identify abnormalities in high energy phosphate cerebral metabolism in euthymic bipolar disorder. METHODS: Phosphorus-31 magnetic resonance spectroscopic imaging ((31)P MRSI) data were acquired from the entire brain of 9 euthymic adults with bipolar disorder and 13 healthy adults. Estimates of phosphocreatine (PCr) and adenosine triphosphate (ATP) in homogeneous gray and white matter were obtained by tissue regression analysis. RESULTS: Analyses of covariance revealed the effect of age to be significantly different between bipolar and healthy groups for concentrations of PCr (p=0.0018) and ATP (p=0.013) in gray matter. These metabolites were negatively correlated with age in gray matter in bipolar subjects while PCr was positively correlated with age in gray matter of healthy subjects. Additionally, age-corrected concentrations of PCr in gray matter were significantly elevated in bipolar subjects (p=0.0048). LIMITATIONS: Given that this cross-sectional study possessed a small sample and potentially confounding effects of medication status, we recommend a larger, longitudinal study to more robustly study relationships between bioenergetic impairment and duration of disease. CONCLUSIONS: Our results suggest bioenergetic impairment related to mitochondrial function may be progressive in multi-episode bipolar subjects as they age.

Imaging of brain tumors with paramagnetic vesicles targeted to phosphatidylserine.

PURPOSE: To investigate paramagnetic saposin C and dioleylphosphatidylserine (SapC-DOPS) vesicles as a targeted contrast agent for imaging phosphatidylserine (PS) expressed by glioblastoma multiforme (GBM) tumors. MATERIALS AND METHODS: Gd-DTPA-BSA/SapC-DOPS vesicles were formulated, and the vesicle diameter and relaxivity were measured. Targeting of Gd-DTPA-BSA/SapC-DOPS vesicles to tumor cells in vitro and in vivo was compared with nontargeted paramagnetic vesicles (lacking SapC). Mice with GBM brain tumors were imaged at 3, 10, 20, and 24 h postinjection to measure the relaxation rate (R1) in the tumor and the normal brain. RESULTS: The mean diameter of vesicles was 175 nm, and the relaxivity at 7 Tesla was 3.32 (s*mM)(-1) relative to the gadolinium concentration. Gd-DTPA-BSA/SapC-DOPS vesicles targeted cultured cancer cells, leading to an increased R1 and gadolinium level in the cells. In vivo, Gd-DTPA-BSA/SapC-DOPS vesicles produced a 9% increase in the R1 of GBM brain tumors in mice 10 h postinjection, but only minimal changes (1.2% increase) in the normal brain. Nontargeted paramagnetic vesicles yielded minimal change in the tumor R1 at 10 h postinjection (1.3%). CONCLUSION: These experiments demonstrate that Gd-DTPA-BSA/SapC-DOPS vesicles can selectively target implanted brain tumors in vivo, providing noninvasive mapping of the cancer biomarker PS.

Myelin water mapping by spatially regularized longitudinal relaxographic imaging at high magnetic fields.

PURPOSE: Magnetic resonance T1 -weighted images are routinely used for human brain segmentation, brain parcellation, and clinical diagnosis of demyelinating diseases. Myelin is thought to influence the longitudinal relaxation commonly described by a mono-exponential recovery, although reports of bi-exponential longitudinal relaxation have been published. The purpose of this work was to investigate if a myelin water T1 contribution could be separated in geometrically sampled Look-Locker trains of low flip angle gradient echoes. METHODS: T1 relaxograms from normal human brain were computed by a spatially regularized inverse Laplace transform after estimating the apparent inversion efficiency. RESULTS: With sufficiently long inversion-time sampling (ca. 5 × T1 of cerebrospinal fluid), the T1 relaxogram revealed a short-T1 peak (106-225 ms). The apparent fraction of this water component increased in human brain white matter from 8.3% at 3 T, to 11.3% at 4 T and 15.0% at 7 T. The T2 * of the short-T1 peak at 3 T was shorter, 27.9 ± 13.0 ms, than that of the long-T1 peak, 51.3 ± 5.6 ms. CONCLUSION: The short-T1 fraction is interpreted as the water resident in myelin. Its detection is facilitated by longer T1 of axoplasmic water at higher magnetic field.

Detecting brain structural changes as biomarker from magnetic resonance images using a local feature based SVM approach.

Detecting brain structural changes from magnetic resonance (MR) images can facilitate early diagnosis and treatment of neurological and psychiatric diseases. Many existing methods require an accurate deformation registration, which is difficult to achieve and therefore prevents them from obtaining high accuracy. We develop a novel local feature based support vector machine (SVM) approach to detect brain structural changes as potential biomarkers. This approach does not require deformation registration and thus is less influenced by artifacts such as image distortion. We represent the anatomical structures based on scale invariant feature transform (SIFT). Likelihood scores calculated using feature-based morphometry is used as the criterion to categorize image features into three classes (healthy, patient and noise). Regional SVMs are trained to classify the three types of image features in different brain regions. Only healthy and patient features are used to predict the disease status of new brain images. An ensemble classifier is built from the regional SVMs to obtain better prediction accuracy. We apply this approach to 3D MR images of Alzheimer's disease, Parkinson's disease and bipolar disorder. The classification accuracy ranges between 70% and 87%. The highly predictive disease-related regions, which represent significant anatomical differences between the healthy and diseased, are shown in heat maps. The common and disease-specific brain regions are identified by comparing the highly predictive regions in each disease. All of the top-ranked regions are supported by literature. Thus, this approach will be a promising tool for assisting automatic diagnosis and advancing mechanism studies of neurological and psychiatric diseases.

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 alterations in high energy phosphoryl compounds and intracellular pH in unmedicated adolescents with bipolar disorder.

BACKGROUND: Several lines of evidence suggest that mitochondrial dysfunction underlies the pathophysiology of bipolar disorder, including prior studies indicating abnormalities in phosphometabolites. We examined abnormalities in biomarkers of cellular metabolism including adenosine triphosphate and adenosine diphosphate as well as the pH levels in the anterior cingulate (ACC) and left ventrolateral prefrontal cortices (VLPFC) of adolescents with bipolar disorder. METHOD: Nineteen unmedicated manic and 14 unmedicated euthymic bipolar adolescents as well as 20 healthy adolescents underwent (1)H and (31)P magnetic resonance spectroscopy scans. Intracellular pH levels and concentrations of phosphometabolites were compared among groups. RESULTS: A significant reduction in pHi was found in the ACC of manic adolescents compared to healthy subjects (p=0.03) but not in the left VLPFC. There was no difference in concentration of adenosine triphosphate in the ACC or the left VLPFC among groups. However, compared to healthy subjects, adenosine diphosphate was significantly lower in manic subjects in the ACC (p=0.01) and in euthymic subjects in the left VLPFC (p=0.02). LIMITATIONS: This was a cross-sectional study with a modest sample size. A longitudinal study of a larger number of bipolar adolescents who are treatment naïve would clarify the impact of mood state on metabolic function. CONCLUSION: These results are suggestive of abnormal cellular metabolism and mitochondrial dysfunction in the pathophysiology of bipolar disorder.