Demonstration of fast multi-slice quasi-steady-state chemical exchange saturation transfer (QUASS CEST) human brain imaging at 3T.

PURPOSE: To combine multi-slice chemical exchange saturation transfer (CEST) imaging with quasi-steady-state (QUASS) processing and demonstrate the feasibility of fast QUASS CEST MRI at 3T. METHODS: Fast multi-slice echo planar imaging (EPI) CEST imaging was developed with concatenated slice acquisition after single radiofrequency irradiation. The multi-slice CEST signal evolution was described by the spin-lock relaxation during saturation duration (Ts ) and longitudinal relaxation during the relaxation delay time (Td ) and post-label delay (PLD), from which the QUASS CEST was generalized to fast multi-slice acquisition. In addition, numerical simulations, phantom, and normal human subjects scans were performed to compare the conventional apparent and QUASS CEST measurements with different Ts , Td, and PLD. RESULTS: The numerical simulation showed that the apparent CEST effect strongly depends on Ts , Td , and PLD, while the QUASS CEST algorithm minimizes such dependences. In the L-carnosine gel phantom, the proposed QUASS CEST effects (2.68 ± 0.12% [mean ± SD]) were higher than the apparent CEST effects (1.85 ± 0.26%, p < 5e-4). In the human brain imaging, Bland-Altman analysis bias of the proposed QUASS CEST effects was much smaller than the PLD-corrected apparent CEST effects (0.03% vs. -0.54%), indicating the proposed fast multi-slice CEST imaging is robust and accurate. CONCLUSIONS: The QUASS processing enables fast multi-slice CEST imaging with minimal loss in the measurement of the CEST effect.

A method to mitigate spatio-temporally varying task-correlated motion artifacts from overt-speech fMRI paradigms in aphasia.

Quantifying accurate functional magnetic resonance imaging (fMRI) activation maps can be dampened by spatio-temporally varying task-correlated motion (TCM) artifacts in certain task paradigms (e.g., overt speech). Such real-world tasks are relevant to characterize longitudinal brain reorganization poststroke, and removal of TCM artifacts is vital for improved clinical interpretation and translation. In this study, we developed a novel independent component analysis (ICA)-based approach to denoise spatio-temporally varying TCM artifacts in 14 persons with aphasia who participated in an overt language fMRI paradigm. We compared the new methodology with other existing approaches such as "standard" volume registration, nonselective motion correction ICA packages (i.e., AROMA), and combining the novel approach with AROMA. Results show that the proposed methodology outperforms other approaches in removing TCM-related false positive activity (i.e., improved detectability power) with high spatial specificity. The proposed method was also effective in maintaining a balance between removal of TCM-related trial-by-trial variability and signal retention. Finally, we show that the TCM artifact is related to clinical metrics, such as speech fluency and aphasia severity, and the implication of TCM denoising on such relationship is also discussed. Overall, our work suggests that routine bulkhead motion based denoising packages cannot effectively account for spatio-temporally varying TCM. Further, the proposed TCM denoising approach requires a one-time front-end effort to hand label and train the classifiers that can be cost-effectively utilized to denoise large clinical data sets.

White matter hyperintensity volumes are related to processing speed in long-term survivors of childhood cerebellar tumors.

PURPOSE: Across several clinical populations, higher white matter hyperintensity (WMH) burden is consistently associated with decreases in cognitive performance, especially processing speed. Research of childhood cancer survivors has not utilized WMH quantification methodology to better understand the impact of WMH burden and its relationship with core cognitive skills. The present study aimed to quantify WMH volumes in a sample of long-term survivors of childhood cerebellar tumor and investigate the relationships with performance on a measure of oral processing speed. To further explore brain-behavior relationships, multivariate sparse canonical correlations was employed to identify WMH areas that predict processing speed performance. METHODS: Thirty-five survivors and 56 healthy controls underwent neuroimaging and completed a measure of oral processing speed. The survivor group was further divided based on treatment (i.e., chemoradiation therapy (n = 20) vs. surgery only (n = 15)) to better understand the impact of treatment. RESULTS: Survivors, and especially those treated with chemoradiation therapy, showed higher total WMH volumes and slower processing speed. Higher total WMH volumes were significantly associated with poorer processing speed (r = - 0.492, p = 0.003). Multivariate brain-behavior relationships revealed that periventricular WMHs were significantly associated with slower processing speed performance (p < 0.05). CONCLUSION: Results exemplify that long-term survivors treated with and without chemoradiation therapy are at increased risk of developing higher WMH volumes compared to healthy peers. In addition, processing speed was robustly shown to be related to periventricular WMHs using an automated neuroimaging pipeline. This methodology to monitor WMH burden has the potential to be implemented efficiently with routine clinical neuroimaging of cancer survivors.

Neuroplasticity and aphasia treatments: new approaches for an old problem.

Given the profound impact of language impairment after stroke (aphasia), neuroplasticity research is garnering considerable attention as means for eventually improving aphasia treatments and how they are delivered. Functional and structural neuroimaging studies indicate that aphasia treatments can recruit both residual and new neural mechanisms to improve language function and that neuroimaging modalities may hold promise in predicting treatment outcome. In relatively small clinical trials, both non-invasive brain stimulation and behavioural manipulations targeting activation or suppression of specific cortices can improve aphasia treatment outcomes. Recent language interventions that employ principles consistent with inducing neuroplasticity also are showing improved performance for both trained and novel items and contexts. While knowledge is rapidly accumulating, larger trials emphasising how to select optimal paradigms for individualised aphasia treatment are needed. Finally, a model of how to incorporate the growing knowledge into clinical practice could help to focus future research.

Task-residual functional connectivity of language and attention networks.

Functional connectivity using task-residual data capitalizes on remaining variance after mean task-related signal is removed from a time series. The degree of network specificity in language and attention domains featured by task-residual and resting-state data types were compared. Functional connectivity based on task-residual data evidenced stronger laterality of the language and attention connections and thus greater network specificity compared to resting-state functional connectivity of the same connections. Covariance between network nodes of task-residuals may thus reflect the degree to which two regions are coordinated in their specific activity, rather than a general shared co-activation. Task-residual functional connectivity provides complementary data to that of resting-state, emphasizing network relationships during task engagement.

Correction and optimization of a T2-based approach to map blood oxygenation in small cerebral veins.

PURPOSE: Cerebral venous blood oxygenation (Yv ) is an important biomarker in brain physiology and function. The present study proposes a procedure to provide a quantitative map of the brain's intravascular Yv. THEORY AND METHODS: The method is based on a pulse sequence, T2 -Relaxation-Under-Phase-Contrast (TRU-PC) MRI, with postprocessing approaches to correct eddy-current effects. A complete scan protocol consists of four TRU-PC scans sensitized to large and small vessels with anterior-posterior and foot-head flow-encoding directions, and the data are analyzed conjunctively. Eddy-current correction was performed by fitting the tissue phase to a hyperplane, and then subtracting the eddy-current phase from the measured vessel phase. The reproducibility of the Yv-maps was examined in five participants. Sensitivity of the Yv map to a caffeine challenge was studied in another five participants. RESULTS: Removal of eddy-current induced artifact allowed for the correction of T2 measurements, as demonstrated in vivo and with simulation. A Yv-map depicting all vessels in the slice can be obtained with the proposed protocol. Test-retest variability of the Yv -map was 3.7 ± 1.2%. Yv reduction can be reliably detected (P < 0.001) following the caffeine ingestion. CONCLUSION: With the proposed TRU-PC protocol and eddy-current correction procedure, an accurate, vessel-specific Yv map of the human brain can be obtained.

T1 and T2 values of human neonatal blood at 3 Tesla: Dependence on hematocrit, oxygenation, and temperature.

PURPOSE: Knowledge of blood T1 and T2 is of major importance in many applications of MRI in neonates. However, to date, there has not been a systematic study to examine neonatal blood T1/T2 relaxometry. This present study aims to investigate this topic. METHODS: Using freshly collected blood samples from human umbilical cord, we performed in vitro experiments under controlled physiological conditions to measure blood T1 and T2 at 3 Tesla (T) and their dependence on several factors, including hematocrit (Hct), oxygenation (Y) and temperature. RESULTS: The arterial T1 in neonates was 1825 ± 184 ms (Hct = 0.42 ± 0.08), longer than that of adult blood. Neonatal blood T1 was strongly dependent on Hct (P < 0.001) and Y (P = 0.005), and the dependence of T1 on Y was more prominent at higher Hct. The arterial T2 of neonatal blood was 191 ms at an Hct of 0.42, which was also longer than adult blood. Neonatal blood T2 was positively associated with blood oxygenation and negatively associated with hematocrit level, and can be characterized by an exchange model. Neonatal blood T1 was also positively associated with temperature (P < 0.001). CONCLUSION: The values provided in this report may provide important reference and calibration information for sequence optimization and quantification of in vivo neonatal MRI studies.

Vessel-specific quantification of blood oxygenation with T2-relaxation-under-phase-contrast MRI.

PURPOSE: Measurement of venous oxygenation (Yv) is a critical step toward quantitative assessment of brain oxygen metabolism, a key index in many brain disorders. The present study aims to develop a noninvasive, rapid, and reproducible method to measure Yv in a vessel-specific manner. THEORY: The method, T2-Relaxation-Under-Phase-Contrast MRI, utilizes complex subtraction of phase-contrast to isolate pure blood signal, applies nonslice-selective T2-preparation to measure T2, and converts T2 to oxygenation using a calibration plot. METHODS: Following feasibility demonstration, several technical aspects were examined, including validation with an established global Yv technique, test-retest reproducibility, sensitivity to detect oxygenation changes due to hypoxia and caffeine challenges, applicability of echo-planar-imaging (EPI) acquisition to shorten scan duration, and ability to study veins with a caliber of 1-2 mm. RESULTS: T2-Relaxation-Under-Phase-Contrast was able to simultaneously measure Yv in all major veins in the brain, including sagittal sinus, straight sinus, great vein, and internal cerebral vein. T2-Relaxation-Under-Phase-Contrast results showed an excellent agreement with the reference technique, high sensitivity to oxygenation changes, and test-retest variability of 3.5 ± 1.0%. The use of segmented-EPI was able to reduce the scan duration to 1.5 minutes. It was also feasible to study pial veins and deep veins. CONCLUSION: T2-Relaxation-Under-Phase-Contrast MRI is a promising technique for vessel-specific oxygenation measurement.

Dependence of blood T(2) on oxygenation at 7 T: in vitro calibration and in vivo application.

PURPOSE: The calibratable relationship between blood oxygenation (Y) and T(2) allows quantification of cerebral venous oxygenation. We aim to establish a calibration plot between blood T(2) , Y, and hematocrit at 7 T, and using T(2) -relaxation-under-spin-tagging MRI, determine human venous blood oxygenation in vivo. METHODS: In vitro experiments were performed at 7 T on bovine blood samples using a Carr-Purcell-Meiboom-Gill-T2 sequence, from which we characterized the relationship among T(2) , Y, and hematocrit. T(2) -relaxation-under-spin-tagging MRI was implemented at 7 T to measure venous blood T2 in vivo, from which oxygenation was estimated using the in vitro calibration plot. Hyperoxia was performed to test the sensitivity of the method to oxygenation changes, and the 7 T results were compared with those at 3 T. RESULTS: In vitro data showed that arterial and venous T(2) at 7 T are 68 and 20 ms, respectively, at a typical hematocrit of 0.42. In vivo measurement showed a cerebral venous oxygenation of 64.7 ± 5.0% and a test-retest coefficient-of-variation of 3.6 ± 2.4%. Hyperoxia increased Yv by 9.0 ± 1.4% (P = 0.001) and the 3 and 7 T results showed a strong correlation (R = 0.95) across individuals. CONCLUSION: We provided an in vitro calibration plot for conversion of blood T(2) to oxygenation at 7 T and demonstrated its utility in vivo.

Examination of acute spin exercise on GABA levels in aging and stroke: The EASE study protocol.

BACKGROUND: Changes in regional levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) may indicate the potential for favorable responses to the treatment of stroke affecting the upper extremity. By selectively altering GABA levels during training, we may induce long-term potentiation and adjust excitatory/inhibitory balance (E/I balance). However, the impact of this alteration may be limited by neural damage or aging. Aerobic exercise has been shown to increase GABA levels in the sensorimotor cortex and improve motor learning by widening the dynamic range of E/I balance. The cross-sectional project, Effects of Acute Exercise on Functional Magnetic Resonance Spectroscopy Measures of GABA in Aging and Chronic Stroke (EASE), is designed to assess the functional relevance of changes in GABA concentration within the sensorimotor cortex before and after an acute aerobic exercise session. METHODS/DESIGN: EASE will enroll 30 participants comprised of healthy younger adults (18-35 years; n = 10), older adults (60+ years; n = 10), and persons with chronic stroke (n = 10) affecting distal upper extremity function. We will use resting magnetic resonance spectroscopy to measure all participants' GABA levels at rest before and after aerobic exercise. In addition, we will employ functional magnetic resonance spectroscopy using motor skill acquisition and recall tasks in healthy adults. We hypothesize that acute aerobic exercise will increase resting sensorimotor GABA concentration and that higher GABA resting levels will predict better motor learning performance on measures taken both inside and outside the magnet. We also hypothesize that a higher dynamic range of GABA during task-based spectroscopy in healthy adults will predict better motor skill acquisition and recall. DISCUSSION: The EASE project will evaluate the effect of acute exercise on GABA levels as a biomarker of upper extremity motor skill learning with two populations (aging adults and those with chronic stroke). We predict that acute exercise, higher sensorimotor GABA levels, and broader dynamic range will be related to better motor skill acquisition.

Rostral anterior cingulate connectivity in older adults with subthreshold depressive symptoms: A preliminary study.

Subthreshold depressive symptoms are highly prevalent among older adults and are associated with numerous health risks including cognitive decline and decreased physical health. One brain region central to neuroanatomical models of depressive disorders is the anterior cingulate cortex (ACC). The rostral portion of the ACC-comprised of the pregenual ACC and subgenual ACC-is implicated in emotion control and reward processing. The goal of the current study was to examine how functional connectivity in subregions of the rostral ACC relate to depressive symptoms, measured by the Beck Depression Inventory-Second Edition, in an ethnically diverse sample of 28 community-dwelling older adults. Based on meta-analyses of previous studies in primarily young adults with clinical depression, we hypothesized that greater depressive symptoms would be associated with primarily increased resting-state functional connectivity from both the subgenual ACC and pregenual ACC to default mode network regions and the dorsolateral PFC. We instead found that higher depressive symptoms were associated with lower functional connectivity of the ACC to the dorsolateral PFC and regions within the default mode network, including from the subgenual ACC to the dorsolateral PFC and anterior cingulate and from the pregenual ACC to the middle cingulate gyrus. This preliminary study highlights brain alterations at subthreshold levels of depressive symptoms in older adults, which could serve as targets for interventions.

Preliminary evidence of prolonged timing effects of theta-burst stimulation in the reading system.

Theta-burst stimulation (TBS) is a repetitive transcranial magnetic stimulation technique that can be used to upregulate or downregulate different brain regions. However, the timing of its effects and the differing effects of continuous TBS (cTBS) versus intermittent TBS (iTBS) in the reading system have not been explored. This study assessed how stimulation type and post-stimulation timing affected change in performance during a phonological discrimination and sight word recognition task after stimulation of supramarginal gyrus (SMG). Fourteen right-handed young adults (age 18-27 years; 44% male) were block-randomized to receive either iTBS or cTBS to the supramarginal gyrus. Participants then performed a pseudoword discrimination task and an orthographic awareness task (behavioral control) at four different time points and change in reaction time compared to baseline was measured from each time point. There was no effect of stimulation type on change in reaction time [t(16) = -0.2, p = 0.9], suggesting that both types of TBS caused similar effects. Percent change in reaction time decreased over time in the pseudoword task [t(50) = -5.9, p < 0.001], indicating faster pseudoword processing speed with better performance 60-70 min after stimulation. In contrast, no change was demonstrated over time for the behavioral control task [t(43) = -0.6, p = 0.6], suggesting that the change over time seen in the test condition was not a learning effect. These findings provide insight into the effects of TBS on the reading system and can guide future study designs.

ASL MRI informs blood flow to chronic stroke lesions in patients with aphasia.

Introduction: Response to post-stroke aphasia language rehabilitation is difficult to anticipate, mainly because few predictors can help identify optimal, individualized treatment options. Imaging techniques, such as Voxel-based Lesion Symptom Mapping have been useful in linking specific brain areas to language behavior; however, further development is required to optimize the use of structural and physiological information in guiding individualized treatment for persons with aphasia (PWA). In this study, we will determine if cerebral blood flow (CBF) mapped in patients with chronic strokes can be further used to understand stroke-related factors and behavior. Methods: We collected perfusion MRI data using pseudo-Continuous Arterial Spin Labeling (pCASL) using a single post-labeling delay of 2,200 ms in 14 chronic PWA, along with high-resolution structural MRI to compute maps of tissue damage using Tissue Integrity Gradation via T2w T1w Ratio (TIGR). To quantify the CBF in chronic stroke lesions, we tested at what point spatial smoothing should be applied in the ASL analysis pipeline. We then related CBF to tissue damage, time since stroke, age, sex, and their respective cross-terms to further understand the variability in lesion CBF. Finally, we assessed the feasibility of computing multivariate brain-behavior maps using CBF and compared them to brain-behavior maps extracted with TIGR MRI. Results: We found that the CBF in chronic stroke lesions is significantly reduced compared to its homologue grey and white matter regions. However, a reliable CBF signal (although smaller than expected) was detected to reveal a negative relationship between CBF and increasing tissue damage. Further, the relationship between the lesion CBF and age, sex, time since stroke, and tissue damage and cross-terms suggested an aging-by-disease interaction. This relationship was strongest when smoothing was applied in the template space. Finally, we show that whole-brain CBF relates to domain-general visuospatial functioning in PWA. The CBF-based brain-behavior maps provide unique and complementary information to structural (lesion-based) brain-behavior maps. Discussion: Therefore, CBF can be detected in chronic stroke lesions using a standard pCASL MRI acquisition and is informative at the whole-brain level in identifying stroke rehabilitation targets in PWAs due to its relationship with demographic factors, stroke-related factors, and behavior.

Methodologies for task-fMRI based prognostic biomarkers in response to aphasia treatment.

With the diversity in aphasia coupled with diminished gains at the chronic phase, it is imperative to deliver effective rehabilitation plans. Treatment outcomes have therefore been predicted using lesion-to-symptom mapping, but this method lacks holistic functional information about the language-network. This study, therefore, aims to develop whole-brain task-fMRI multivariate analysis to neurobiologically inspect lesion impacts on the language-network and predict behavioral outcomes in persons with aphasia (PWA) undergoing language therapy. In 14 chronic PWA, semantic fluency task-fMRI and behavioral measures were collected to develop prediction methodologies for post-treatment outcomes. Then, a recently developed imaging-based multivariate method to predict behavior (i.e., LESYMAP) was optimized to intake whole-brain task-fMRI data, and systematically tested for reliability with mass univariate methods. We also accounted for lesion size in both methods. Results showed that both mass univariate and multivariate methods identified unique biomarkers for semantic fluency improvements from baseline to 2-weeks post-treatment. Additionally, both methods demonstrated reliable spatial overlap in task-specific areas including the right middle frontal gyrus when identifying biomarkers of language discourse. Thus whole-brain task-fMRI multivariate analysis has the potential to identify functionally meaningful prognostic biomarkers even for relatively small sample sizes. In sum, our task-fMRI based multivariate approach holistically estimates post-treatment response for both word and sentence production and may serve as a complementary tool to mass univariate analysis in developing brain-behavior relationships for improved personalization of aphasia rehabilitation regimens.

White matter hyperintensities relate to executive dysfunction, apathy, but not disinhibition in long-term adult survivors of pediatric cerebellar tumor.

White matter hyperintensities (WMHs) have been related to executive dysfunction, apathy and disinhibition in a wide range of neurological populations. However, this relationship has not been examined in survivors of pediatric brain tumor. The goal of this study was to investigate how executive dysfunction, apathy, and disinhibition relate to WMHs in 31 long-term survivors of pediatric cerebellar brain tumor and 58 controls, using informant-report data from the Frontal Systems Behavior Scale. Total WMH volume was quantified using the Lesion Growth Algorithm. Further, periventricular, and subcortical volumes were identified based on proximity to custom ventricle masks generated in FSL. A ratio of WMH volume to whole brain volume was used to obtain normalized WMH volumes. Additionally, a multivariate regression analysis was performed. On average, informant-report scores were within normal limits and only executive dysfunction was significantly higher in survivors compared to controls (t(47.9) = -2.4, p=.023). Informants reported clinically significant levels of apathy in 32.3% of survivors. Informants also reported clinically significant executive dysfunction in 19.4 % of survivors and clinically significant disinhibition in, again, 19.4 % of survivors. Increased volume of WMHs was positively correlated with executive dysfunction (r = 0.33, p = 0.02) and apathy (r = 0.23, p = .04). Similarly, multivariate regression demonstrated correlations with executive dysfunction (p=.05, FDR corrected) and apathy (p=.05, FDR corrected). Exploratory analysis demonstrated an interaction wherein the relationship between total WMHs and executive dysfunction and apathy depends on whether the participant was a survivor. The current findings indicate that increased WMH volumes are associated with higher ratings of apathy and executive dysfunction, and that these results are likely unique to cerebellar brain tumor survivors. WMH burden may serve as a useful marker to identify survivors at risk of executive dysfunction or increased apathy.

The association between language-based task-functional magnetic resonance imaging hemodynamics and baseline GABA+ and glutamate-glutamine measured in pre-supplementary motor area: A pilot study in an aging model.

Aging is a natural phenomenon that elicits slow and progressive cerebrovascular and neurophysiological changes that eventually lead to cognitive decline. The objective of this pilot study is to examine the association of GABA+ and glutamate-glutamine (Glx) complex with language-based blood oxygen level dependent (BOLD) hemodynamics in an aging model. More specifically, using standard BOLD we will first attempt to validate whether previously reported findings for BOLD amplitude and resting neurochemical relationships hold in an aging model. Secondly, we will investigate how our recently established neurosensitized task-BOLD energetics relate to resting GABA+ and Glx, especially accounting for titration of task difficulty. To support the above endeavors, we optimize the baseline fitting for edited magnetic resonance spectroscopy (MRS) difference spectra to sensitize GABA+ and Glx concentrations to aging-related differences. We identify a spline-knot spacing of 0.6ppm to yield the optimal aging-related differences in GABA+ and Glx. The optimized MRS values were then graduated to relate to task-BOLD hemodynamics. Our results did not replicate previous findings that relate task-BOLD amplitude and resting GABA+ and Glx. However, we did identify neurochemistry relationships with the vascularly-driven dispersion component of the hemodynamic response function, specifically in older participants. In terms of neuro-sensitized BOLD energetics and the underlying role of GABA+ and Glx, our data suggests that the task demands are supported by both neurometabolites depending on the difficulty of the task stimuli. Another novelty is that we developed task-based functional parcellation of pre-SMA using both groups. In sum, we are the first to demonstrate that multimodal task-fMRI and MRS studies are beneficial to improve our understanding of the aging brain physiology, and to set the platform to better inform approaches for clinical care in aging-related neurovascular diseases. We also urge future studies to replicate our findings in a larger population incorporating a lifespan framework.

The Relationship Between Resting Cerebral Blood Flow, Neurometabolites, Cardio-Respiratory Fitness and Aging-Related Cognitive Decline.

Older adults typically experience a decline in cognitive function, but improvements in physical health and lifestyle can be neuroprotective across the human lifespan. The primary objective of this study is to advance our basic understanding of how cardiorespiratory fitness and neurophysiological attributes relate to cognitive decline. While cerebral blood flow (CBF) is critical for the supply of nutrients to the tissue, the brain's major neurotransmitters (i.e., gamma-aminobutyric acid, GABA, and glutamate-glutamine complex, Glx) are closely linked to oxidative metabolism. Within the context of flow-metabolism coupling, the critical question is how these neurophysiological parameters interplay, resulting in cognitive decline. Further, how cardiorespiratory fitness may impact aging neurophysiology and cognition is not well understood. To address these questions, we recruited 10 younger and 12 older cognitively intact participants to collect GABA and Glx using magnetic resonance spectroscopy (MRS), CBF using pseudo-continuous arterial spin labeling Magnetic Resonance Imaging (MRI), VO2max as a measure of cardiorespiratory fitness using the YMCA submax test, and cognitive and motor-cognitive measures using a battery of behavioral assessments. We observed expected differences in GABA+, Glx, and CBF between younger and older participants in pre-SMA, a frontal domain-general region. When GABA+ and Glx were related to CBF via multiple linear regression, Glx was identified as the main contributor to the model. For higher-order executive function (i.e., inhibition versus color naming), GABA*Glx*CBF interaction was critical in younger, while only Glx was involved in older participants. For unimanual motor dexterity, GABA*Glx interaction was the common denominator across both groups, but younger participants' brain also engages CBF. In terms of selective motor inhibition, CBF from younger participants was the only major neurophysiological factor. In terms of fitness, cardiorespiratory fitness was significantly related to GABA, Glx, and motor performance when combining cohorts, but no group-specific relationships were observed. Taken together, our results indicate that Glx and CBF coupling decreases with aging, perhaps due to altered glial oxidative metabolism. Our data suggest that GABA, Glx, and CBF are engaged and weighted differently for different cognitive measures sensitized to aging, and higher fitness allows for a more efficient metabolic shift that facilitates improved performance on cognitive-motor tasks.

Frontal Metabolites and Alzheimer's Disease Biomarkers in Healthy Older Women and Women Diagnosed with Mild Cognitive Impairment.

BACKGROUND: Women account for two thirds of the prevalence and incidence of Alzheimer's disease (AD) and mild cognitive impairment (MCI). Evidence suggest that sex may differently influence the expression of proteins amyloid-beta (Aß1-42) and tau, for which early detection is crucial in prevention of the disease. OBJECTIVE: We investigated the effect of aging and cerebrospinal fluid (CSF) levels of Aß1-42 and tau on frontal metabolites measured with proton magnetic resonance spectroscopy (MRS) in a cohort of cognitively normal older women and women with MCI. METHODS: 3T single-voxel MRS was performed on the medial frontal cortex, using Point Resolved Spectroscopy (PRESS) and Mescher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) in 120 women (age range 50-85). CSF samples of Aß1-42 and tau and scores of general cognition were also obtained. RESULTS: Levels of frontal gamma aminobutyric acid (GABA+) were predicted by age, independently of disease and CSF biomarkers. Importantly, levels of GABA+ were reduced in MCI patients. Additionally, we found that levels of N-acetylaspartate relative to myo-inositol (tNAA/mI) predicted cognition in MCI patients only and were not related to CSF biomarkers. CONCLUSION: This study is the first to demonstrate a strong association between frontal GABA+ levels and neurological aging in a sample consisting exclusively of healthy older women with various levels of CSF tau and Aß1-42 and women with MCI. Importantly, our results show no correlation between CSF biomarkers and MRS metabolites in this sample.

Relationships between frontal metabolites and Alzheimer's disease biomarkers in cognitively normal older adults.

Elevated expression of ß-amyloid (Aß1-42) and tau are considered risk-factors for Alzheimer's disease in healthy older adults. We investigated the effect of aging and cerebrospinal fluid levels of Aß1-42 and tau on 1) frontal metabolites measured with proton magnetic resonance spectroscopy (MRS) and 2) cognition in cognitively normal older adults (n = 144; age range 50-85). Levels of frontal gamma aminobutyric acid (GABA+) and myo-inositol relative to creatine (mI/tCr) were predicted by age. Levels of GABA+ predicted cognitive performance better than mI/tCr. Additionally, we found that frontal levels of n-acetylaspartate relative to creatine (tNAA/tCr) were predicted by levels of t-tau. In cognitively normal older adults, levels of frontal GABA+ and mI/tCr are predicted by aging, with levels of GABA+ decreasing with age and the opposite for mI/tCr. These results suggest that age- and biomarker-related changes in brain metabolites are not only located in the posterior cortex as suggested by previous studies and further demonstrate that MRS is a viable tool in the study of aging and biomarkers associated with pathological aging and Alzheimer's disease.

Percutaneous electric nerve field stimulation alters cortical thickness in a pilot study of veterans with fibromyalgia.

Objective: To evaluate changes in cortical thickness and right posterior insula (r-pIns) gamma-aminobutyric acid (GABA) concentrations in veterans with fibromyalgia treated with auricular percutaneous electric nerve field stimulation (PENFS). Materials & methods: This was a randomized, controlled, open label investigation conducted in a government hospital. Twenty-one veterans with fibromyalgia were randomized to receive either standard therapy (ST; i.e., 4 weekly visits with a pain practitioner) or ST with auricular PENFS (ST + PENFS). Neuroimaging data was collected at baseline (i.e. before the first treatment session) and again within 2 weeks post-treatment.​ Clinical pain and physical function were also assessed at these timepoints. Single-voxel magnetic resonance spectroscopy was carried out in r-pIns to assess changes in r-pIns GABA concentrations and high-resolution T1-weighted images were collected to assess changes in regional gray matter volume using cortical thickness. Results: Both the ST + PENFS and ST groups reported a decrease in pain with treatment. Volumetric: Cortical thickness significantly decreased in the left middle posterior cingulate (p = 0.018) and increased in the left cuneus (p = 0.014) following ST + PENFS treatment. These findings were significant following FDR correction for multiple comparisons. ST group right hemisphere insula cortical thickness increased post-treatment and was significantly (p = 0.02) inversely correlated with pain scores. ST + PENFS group right hemisphere posterior dorsal cingulate size significantly (p = 0.044) positively correlated with pain scores. GABA: There were no significant correlations with GABA, though a trend was noted towards increased GABA following treatment in both groups (p = 0.083) using a linear mixed effects model. Conclusions: Results suggest a novel effect of PENFS reflected by differential volumetric changes compared to ST. The changes in GABA that occur in both groups are more likely related to ST. Insular GABA and cortical thickness in key regions of interest may be developed as potential biomarkers for evaluating chronic pain pathology and treatment outcomes.