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.

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.

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.

Lithium compartmentation in brain by 7Li MRS: effect of total lithium concentration.

In previous work at 4.7 T, the individual components of biexponential (7) Li transverse (T2 ) spin relaxation in rat brain in vivo were tentatively identified with intra- and extracellular Li. The goal in this work was to estimate Li's compartmental distribution as a function of total Li concentration in brain from the biexponential decays. Here a localized, biexponential (7) Li T2 MR spin-relaxation study with isotopically enriched (7) LiCl is reported in rat brain in vivo at 7 T. Additionally, a simple linear interpolation using the biexponential T2 values to estimate intracellular Li from individual monoexponential T2 decays was assessed. Intracellular T2 was 14.8 ± 4.3 ms and extracellular T2 was 295 ± 61 ms. The fraction of intracellular brain Li ranged from 37.3 to 64.8% (mean 54.5 ± 6.7%) and did not correlate with total Li concentration. The estimated intracellular Li concentration ranged from 47 to 80% (mean 68.3 ± 8.5%) of the total brain Li concentration and was highly correlated with it. The monoexponential estimates of the intracellular-Li fractions and derived concentrations averaged about 15% higher than the corresponding biexponential estimates. This work supports the previous conclusion that a large fraction of Li in the brain is within the intracellular compartment.

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.

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.

31P NMR of phospholipid metabolites in prostate cancer and benign prostatic hyperplasia.

(1)H MRSI in vivo is increasingly being used to diagnose prostate cancer noninvasively by measurement of the resonance from choline-containing phospholipid metabolites. Although (31) P NMR in vivo or in vitro is potentially an excellent method for probing the phospholipid metabolites prominent in prostate cancer, it has been little used recently. Here, we report an in vitro (31)P NMR comparison of prostate cancer and benign prostatic hyperplasia, focusing on the levels of the major phospholipid metabolites. Unlike phosphocholine and glycerophosphocholine, phosphoethanolamine and glycerophosphoethanolamine (and their ratio) were significantly different between cancer and benign prostatic hyperplasia. The high level of phosphoethanolamine+glycerophosphoethanolamine relative to phosphocholine+glycerophosphocholine suggests that the former may be significant contributors to the "total choline" resonance observed by (1)H MRSI in vivo.

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.

Phospholipid composition of postmortem schizophrenic brain by 31P NMR spectroscopy.

Cell membrane abnormalities due to changes in phospholipid (PL) composition and metabolism have been implicated in schizophrenia pathogenesis. That work has generally assessed membrane phospholipids from nonneural tissues such as erythrocytes and platelets. High-resolution (31)P NMR spectroscopy was used to characterize PLs of gray matter in postmortem brain for 20 schizophrenics, 20 controls, and 7 patients with other mental illnesses (psychiatric controls). Tissues from frontal, temporal, and occipital cortices were extracted with hexane-isopropanol, and (31)P NMR spectra were obtained in an organic-solvent system to resolve the major PL classes (based on headgroups) and subclasses (based on linkage at the sn - 1 position). Surprisingly, repeated-measures multivariate analysis of variance revealed no overall differences among the groups. There were no significant differences (P < .05) among the three groups for any individual PL subclass, including lysophospholipids. The sum of all phosphatidylethanolamine headgroups was significantly lower for schizophrenics than for controls or psychiatric controls in the frontal cortex. The present results are minimally correlated with previous results for aqueous PL metabolites on these same samples. The metabolite changes measured by in vivo (31)P MRS in schizophrenia do not appear to reflect PL concentration changes. The present results offer very little support for the phospholipid hypothesis of schizophrenia.

Evidence of resilience: neuroimaging in former prisoners of war.

In this study, single voxel proton magnetic resonance spectroscopic imaging ((1)H-MRS) and volumetric analysis of hippocampal magnetic resonance imaging (MRI) images were used to determine if any differences in hippocampal biochemistry or volume were present between former prisoners of war (POWs) with and without posttraumatic stress disorder (PTSD) and control subjects matched for age and education. This study did not find lower hippocampal concentrations of N-acetylaspartate (NAA), smaller hippocampal volumes, or more impaired memory function in older veterans with PTSD compared with a group matched for traumatic experience or a nontraumatized control group.

Relationship of in vivo medial temporal lobe magnetic resonance spectroscopy to documented combat exposure in veterans with chronic posttraumatic stress disorder.

Veterans diagnosed with combat-related posttraumatic stress disorder (PTSD) and comparison subjects underwent single voxel proton magnetic resonance spectroscopy (1H-MRS) of the medial temporal lobe (MTL). PTSD subjects were divided into combat and non-combat groups based on military records. Combat PTSD subjects did not have lower MTL levels of N-acetylaspartate compared with non-combat PTSD subjects.

Brain metabolite concentration ratios in vivo: multisite reproducibility by single-voxel 1H MR spectroscopy.

Ten normal subjects were scanned identically at three separate sites (Little Rock, Houston, and New Orleans) to evaluate the reproducibility of brain metabolite ratios in single-voxel (1)H point-resolved spectroscopy sequence (PRESS) magnetic resonance (MR) spectroscopy in vivo. All scans were processed by a single individual at a single site. Coefficients of variation of the measured metabolite ratios generally were in the range found for previous single-voxel, single-site reproducibility studies. No differences were found among the sites for ratios of N-acetylaspartate to creatine (NAA/Cr) or choline to Cr (Cho/Cr) in left thalamus by multivariate ANOVA. Metabolite ratios of Cr or Cho relative to local brain H(2)O did not vary among the sites. However, by multivariate ANOVA, NAA/H(2)O differed between Little Rock and New Orleans, but not between those sites and Houston. Intraclass correlation coefficients suggested reasonable reproducibility between Little Rock and New Orleans, but not between those sites and Houston.

Estimating intracellular lithium in brain in vivo by localized 7Li magnetic resonance spectroscopy.

The therapeutic mechanism of action of lithium (Li) in bipolar disorder is unknown. While Li is presumed to work intracellularly in the brain, the fraction of intracellular Li in the brain in vivo is not known. It has not yet been possible to determine, directly and noninvasively, the intra- to extracellular distribution of Li in human brain in vivo. Lithium-7 ((7)Li) MR is the only technique available for measuring noninvasively the concentration of Li in the brain in vivo. Here the individual components of biexponential (7)Li transverse (T(2)) relaxation in rat brain in vivo are identified with intra- and extracellular Li, and used to estimate its compartmental distribution. Intracellular T(2) was 14.6 +/- 6.9 ms, while extracellular T(2) was 160 +/- 52 ms in nine rats. The fraction of intracellular brain Li ranged from 37% to 75% (mean: 63 +/- 11%). Further, the biexponential T(2) results provided the basis for estimating Li compartmental distribution from monoexponential T(2) decays using a simple linear approximation. The fraction of intracellular Li estimated from monoexponential T(2) decays agreed with the corresponding biexponential estimates in most cases.

31P NMR spectroscopy of phospholipid metabolites in postmortem schizophrenic brain.

Evidence has been accumulating that schizophrenia involves abnormalities in the composition and metabolism of cell membrane phospholipids (PLs) in the brain. In vivo 31P MRS has been used to measure the metabolic precursors and degradation products of PL metabolism in schizophrenia. Because in vivo line widths are substantially broader than in solution, only the broad phosphomonoester (PME) and phosphodiester bands, or partly resolved resonances of individual metabolites, are typically measured in vivo in the 31P spectrum. In addition to poor resolution, the relatively low signal-to-noise ratio (SNR) makes precise quantitation difficult. An alternative with substantially better resolution and precision for quantitation is high-resolution NMR spectroscopy of extracts of samples from postmortem brain. Here we determine absolute concentrations of the individual PL metabolites phosphocholine (pc), phosphoethanolamine (pe), glycerophosphocholine (gpc), and glycerophosphoethanolamine in aqueous extracts of tissue from frontal, temporal, and occipital cortex of postmortem brain for schizophrenics, controls, and patients with other mental illnesses (psychiatric controls [PC]) using high-resolution 31P NMR spectroscopy. For the complete groups, which included both males and females, there were no statistically significant differences for schizophrenics vs. controls for any of the four PL metabolites in any of the three brain regions. Trends (0.05 < P < 0.10) were noted for increased gpc in schizophrenia in all three regions. PC differed from both controls and schizophrenics in several measures. When only males were considered, gpc was significantly (P < 0.05) elevated in all three brain regions in schizophrenia.

Biomedical applications of 7Li NMR.

The biomedical applications of 7Li MRS and MRI have been progressing slowly. The interest derives primarily from the clinical use of Li to treat bipolar disorder. One area of concern is the nature of ionic transport and binding, so as to elucidate the mechanism(s) of therapeutic action and toxicity. Another is the development of a non-invasive, in vivo analytical tool to measure brain Li concentration and environment in humans, both as an adjunct to treatment and as a mechanistic probe. Here we review the most recent progress toward these goals.

Localized 7Li MR spectroscopy and spin relaxation in rat brain in vivo.

Localized 7Li MR point-resolved spectroscopy (PRESS) was developed as a technique to measure lithium (Li) concentration in rat brain in vivo. Localized 7Li spectra could be obtained at 4.7 T in a 0.7-ml voxel in rat brain over the entire therapeutic range of serum Li for humans. Localized 7Li spin-lattice (T1) and spin-spin (T2) relaxation times were measured. Measured intensities were corrected for spin relaxation effects and 7Li MR visibility in vivo. The average T1 was 3.3 +/- 0.9 sec, and the average T2 was 82 +/- 20 ms. Neither T1 nor T2 correlated with brain concentration. No statistically significant change was found in either T1 or T2 from approximately 7-17 days of Li dosing.

Localized 7Li MR spectroscopy: in vivo brain and serum concentrations in the rat.

The brain concentration of lithium (Li) in treated rats was measured using a recently developed method based on in vivo 7Li PRESS localized MRS. Comparison was made to the corresponding serum concentration at two treatment durations. The brain and serum Li concentrations were highly correlated with each other, more so than found previously for humans. The brain and serum Li concentrations also correlated with dose. Both the brain Li concentration and the serum concentration at 16.1 days of treatment correlated with the corresponding measure at 6.6 days. After correction of the brain Li concentrations for reduced 7Li MRS visibility, the mean brain/serum Li ratio for rats was close to unity, unlike most previous values found for humans. However, in some individual cases the ratio deviated substantially from the mean, suggesting that serum Li is not always a reliable indicator of brain Li.