Optimization of sensitivity to disease-associated cortical metabolic abnormality by evidence-based quantification of in vivo proton magnetic resonance spectroscopy data from 3 Tesla and 7 Tesla

In vivo proton magnetic resonance spectroscopy (1H MRS) is the only method available to measure small-molecule metabolites in living human tissue, including the brain, without ionizing radiation or invasive medical procedures. Despite its attendant potential for supporting clinical diagnostics in a range of neurological and psychiatric conditions, the metabolite concentration estimates produced by 1H-MRS experiments, and therefore their sensitivity and specificity to any particular biological phenomenon under study, are readily distorted by a number of confounds. These include but are not limited to static and radiofrequency field characteristics, signal relaxation dynamics, macromolecule and lipid contributions to the spectral baseline, spectral fitting artifacts, and other uncontrolled idiosyncrasies of 1H-MRS data acquisition, processing, and quantification. Using 1H-MRS data obtained via 3-Tesla and 7-Tesla magnetic resonance (MR) scanners from healthy controls, individuals with progressive and relapsing-remitting multiple sclerosis (MS), and individuals with post-traumatic stress disorder (PTSD) and/or major depressive disorder (MDD), this work therefore aims to build and apply a framework for quantifying and thereby reducing such confounds introduced to 1H-MRS estimates of in vivo metabolite concentrations at the steps of data processing and quantification, with an ultimate aim to maximizing the potential of 1H MRS for supporting sensitive and specific clinical diagnosis of neurological or psychiatric disease. The steps examined include spectral quantification by linear combination modeling (Chapter 2), absolute quantification by internal concentration referencing (Chapter 3), and cross-sectional statistical analysis of results (Chapters 4 and 5). Chapter 2 designs and implements a graphical user interface (GUI)-supported validation pipeline for measuring how data quality, spectral baseline, and baseline model affect the precision and accuracy of 1H-MR spectral quantification by linear combination modeling. This validation pipeline is then used to show that spectral data quality indices signal to noise ratio (SNR) and full width at half maximum (FWHM) interact with spectral baseline to influence not only the precision but also the accuracy of resultant metabolite concentration estimates, with fit residuals poorly indicative of true fit error and spectral baselines modeled as regularized cubic splines not significantly outperformed by those employing simulated macromolecules. A novel method for extending the commonly used spectral quantification precision estimate Cramér-Rao Lower Bound (CRLB) to incorporate considerations of continuous and piecewise polynomial baseline shapes is therefore presented, tested, and similarly integrated into a GUI-supported toolkit to improve the correspondence between estimated CRLB and metabolite fit error variability when this now empirically justified approach to spectral baseline modeling is used. In Chapter 3, age- and disease-associated differences in transverse (T2) water signal relaxation measured at 7 Tesla in the prefrontal cortex of individuals with progressive (N=21) relative to relapsing-remitting (N=26) or no (N=25) multiple sclerosis are shown to influence absolute quantification of metabolite concentrations by internal referencing to water. In Chapter 4, these findings from Chapters 2 and 3 are used to justify an evidence-based 1H-MR spectral processing and quantification protocol that focuses optimization efforts on baseline modeling approach and references metabolite concentration estimates to internal creatine instead of water. When this protocol is applied to 7-Tesla prefrontal cortex 1H-MR spectra from the aforementioned multiple sclerosis and control cohorts, it supports metabolite concentration estimates that, in the absence of any additional supporting data, inform supervised-learning-enabled identification of progressive multiple sclerosis at nearly 80% held-out validation sensitivity and specificity. Finally, in Chapter 5, the same processing, quantification, and machine-learning pipeline employed in Aim 3 is independently applied to a new set of 7-Tesla prefrontal cortex 1H-MRS raw data from an entirely different cohort of individuals with (N=20) and without (N=18) PTSD and/or comorbid or primary MDD. Here the processing, quantification, and statistics procedures designed using lessons in Chapters 2 and 3 and optimized for classifying multiple sclerosis phenotype in Chapter 4 generalize directly to metabolite-only classification of PTSD and/or MDD with sensitivity and specificity similarly near to or greater than 80%. In both Chapters 4 and 5, supervised learning avoids dimensionally reducing metabolite feature sets in order to pinpoint the specific metabolites most informative for identifying each disease group. Taken together, these findings justify the potential and continued development of 1H MRS, at least as applied in the human brain and especially as supported by multivariate approaches including supervised learning, as an auxiliary or mainstay of clinical diagnostics for neurological or psychiatric disease

sj-docx-1-css-10.1177_24705470221128004 - Supplemental material for Proton Magnetic Resonance Spectroscopy in Post-Traumatic Stress Disorder—Updated Systematic Review and Meta-Analysis

Supplemental material, sj-docx-1-css-10.1177_24705470221128004 for Proton Magnetic Resonance Spectroscopy in Post-Traumatic Stress Disorder—Updated Systematic Review and Meta-Analysis by Kelley M. Swanberg, Leonardo Campos, Chadi G. Abdallah and Christoph Juchem in Chronic Stress</p

The effects of emotional content on reality-monitoring performance in young and older adults.

Reality monitoring refers to a person’s ability to distinguish between perceived and imagined events. Prior research has demonstrated that young adults show a reality-monitoring advantage for negative arousing information as compared with neutral information. The present research examined whether this reality-monitoring benefit extends to positive information in young adults and whether older adults show a reality-monitoring advantage for emotional information of either valence. Two studies revealed no evidence for a reality-monitoring advantage for positive information; in both age groups, the reality-monitoring advantage existed only for negative information. Older adults were, however, more likely to remember that a positive item had been included on a study list than they were to remember that a nonemotional item had been studied. Young adults did not show this mnemonic enhancement for positive information. These results indicate that although older adults may show some mnemonic benefits for positive information (i.e., an enhanced ability to remember that a positive item was studied), they do not always show enhanced memory for source-specifying details of a positive item’s presentation

Preclinical Evidence of Rapid-Onset Antidepressant-Like Effect in Radix Polygalae Extract

<div><p>Radix Polygalae (the root of <i>Polygala tenuifolia</i>) is a herb widely used in traditional Asian medicine that is thought to exert a variety of neuropsychiatric effects. Radix Polygalae extract can protect against N-methyl D-aspartate (NMDA) neurotoxicity and induce brain-derived neurotrophic factor (BDNF) expression, suggesting modulatory roles at glutamatergic synapses and possible antidepressant action. In accordance with this hypothesis, Radix Polygalae extract demonstrated antidepressant-like effects in 8-week-old male C57Bl/6 mice by decreasing behavioral despair in the forced swim and tail suspension tasks and increasing hedonic-like behavior in the female urine sniffing test 30 minutes after a single oral administration of 0.1 mg/kg. Reduced latency to acquire a food pellet in the novely suppressed feeding paradigm, without change in anxiety-like behaviors suggested a rapid-onset nature of the antidepressant-like effect. In addition, it decreased the number of failed escapes in the learned helplessness paradigm after two oral administrations 24 hours and 30 minutes before the first test. Finally, it reversed anhedonia as measured by saccharin preference in mice exposed to the chronic stress model after two administrations of 0.1 mg/kg, in contrast to the repeated administration generally needed for similar effect by monoamergic antidepressants. Immobility reduction in tail suspension task was blocked by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist NBQX, a pattern previously demonstrated by ketamine and other ketamine-like rapid-onset antidepressants. Also similarly to ketamine, Radix Polygalae appeared to acutely decrease phosphorylation of GluR1 serine-845 in the hippocampus while leaving the phosphorylation of hippocampal mTOR serine 2448 unchanged. These findings serve as preclinical evidence that Radix Polygalae extract exerts rapid-onset antidepressant effects by modulating glutamatergic synapses in critical brain circuits of depression and may be worthy of further evaluation as a safe substitute to other rapid-onset antidepressants known to have unacceptable side effects.</p></div

Acute-onset antidepressant-like effect of Radix Polygalae in mice.

<p>(A) Novelty suppressed feeding test. Latency to take a food pellet was reduced by RP (0.1 mg/kg, p.o.) administered 30 minutes before test, suggesting either rapid-onset anxiolytic or antidepressant-like effect. * p<0.05, student t-test. (B) Elevated plus maze. There was no statistical difference between mice administered RP (0.1 mg/kg, p.o.) or controls administered distilled water in the total time spent in open arms which meant RP does not change anxiety-like behaviors at the given dose. (C) Learned helplessness paradigm. Number of escape failures reduced within 24 hours after RP treatment (0.1 mg/kg, p.o.) but not by fluoxetine (20 mg/kg i.p.), suggesting a rapid-onset antidepressant-like effect. ** p<0.01 *** p<0.001 vs vehicle on the same day. Two-way ANOVA, Tukey's post hoc test. (D) Tail suspension test. The antidepressant-like effect of RP (0.1 mg/kg, p.o.) was blocked by NBQX injection (10 mg/kg). ANOVA, Tukey's post hoc test. Vehicle: distilled water, RP: Radix Polygalae. All data represent mean ± SEM.</p

Procedure of chronic mild stress.

<p>CF: confinement, FWD: food and water deprivation, LO: light on, NO: novelty object, SI: stroboscope illumination, SPT: saccharin preference test, TC : tilting cage, WB : wet bedding, WN : white noise (80dB).</p

Antidepressant-like effect of Radix Polygalae in mouse models of behavioral despair and hedonism.

<p>(A) Immobility in tail suspension test measured 30 minutes after RP (0.1, 1 and 10 mg/kg p.o.). There was a significant dose effect [F(3,31) = 5.62, p = 0.0038]. Immobility reduction was most prominent in the 0.1 mg/kg group (p<0.001). (B) Immobility in tail suspension test measured 30, 60, and 120 minutes after 0.1 mg/kg RP administration. There was a significant difference among groups [F(3,31) = 11.4, p<0.001]. RP administered 30 minutes before the test induced the most significant reduction in immobility (p = 0.005). (C) Immobility in forced swim test measured 30 minutes after RP (0.1, 1, and 10 mg/kg p.o.). A significant difference among doses emerged [F(3,31) = 2.99, p = 0.048]. RP 1 mg/kg reduced immobility relative to distilled water controls (p = 0.006). (D) Sniffing time in female urine sniffing test. No differences between mice administered RP (0.1 mg/kg p.o.) and distilled water controls emerged in the sniffing time of distilled water, but sniffing time to estrus female urine significantly increased in the RP group relative to control (p = 0.02). Vehicle: distilled water, RP: Radix Polygalae extract. All data represent mean ± SEM. * p<0.05, ** p<0.01 *** p<0.001 vs controls. ANOVA, Tukey's post hoc test for (A), (B) and (C). Student t-test for (D).</p

Antidepressant-like effect of Radix Polygalae is associated with phosphorylation of hippocampal AMPA receptor GluR1 but not mTOR.

<p>(A) RP treatment (0.1 mg/kg p.o.) reduced hippocampal GluR1 phosphorylation (S845) but not when RP was co-administered with NBQX (10 mg/kg, i.p.) [F(2,15) = 4.38, p = 0.032]. There was no significant change in total GluR1 levels. (B) There was no significant effect on hippocampal phospho-mTOR (S2448) and total mTOR expression by RP or of RP + NBQX. Vehicle: distilled water, RP: Radix Polygalae. All data represent mean ± SEM. ANOVA, Tukey's post hoc test.</p

Antidepressant-like effect of Radix Polygalae in mouse models of chronic stress.

<p>CMS was delivered to mice for 6 weeks as described in methods. (A) Body weight. CMS mice gained less body weight compared with unstressed controls [repeated measures ANOVA; F = 136.0, p<0.001]. (B) Saccharin preference. CMS mice showed a gradual decrease of preference [repeated measures ANOVA; F = 12.3, p = 0.001]. (C) Saccharin preference after treatment of either vehicle (normal saline), RP (0.1 mg/kg p.o.), or ketamine (10 mg/kg i.p.) administered 24 hours and 30 minutes before measurement to mice exposed to CMS for 6 weeks. A significant difference existed between treatment groups [F(5,29) = 18.1, p<0.001]. Among CMS exposed mice, RP (p = 0.002) and ketamine (p = 0.005)-treated mice showed a significantly higher preference than vehicle treated mice. (D) Immobility in forced swim test from mice exposed to CMS for 6 weeks. Mice were given either vehicle (normal saline), RP (0.1 mg/kg p.o.), or ketamine (10 mg/kg i.p.) administered 48 hours, 24 hours, and 30 minutes before test. A significant group difference emerged [F(5,29) = 12.9, p<0.001)]. In CMS exposed mice, RP (p = 0.004), and ketamine (p = 0.02) reduced immobility. CMS: chronic mild stress. RP: Radix Polygalae. All data represent mean ± SEM. * p<0.05, ** p<0.01 *** p<0.001 vs control or vehicle-treated non-CMS. ^# p<0.05, ^## p<0.01, vs vehicle-treated CMS. 2-way ANOVA for (A) and (B), ANOVA for (C) and (D). Tukey's post hoc test.</p