Identification of brain functional connectivity during acute transcutaneous tibial nerve stimulation: A 3T fMRI study.

OBJECTIVES: A feasibility proof-of-concept study was conducted to assess the effects of acute tibial nerve stimulation (TNS) on the central nervous system in healthy volunteers using functional magnetic resonance imaging (fMRI). MATERIALS AND METHODS: Fourteen healthy volunteers were included in a prospective, single-site study conducted on a clinical 3T MRI scanner. Four scans of functional MRI, each lasting 6 min, were acquired: two resting-state fMRI scans (prior and following the TNS intervention) and in-between two fMRI scans, both consisting of alternating rest periods and noninvasive acute transcutaneous TNS (TTNS). Whole brain seed-based functional connectivity (FC) correlation analysis was performed comparing TTNS stimulation with rest periods. Cluster-level familywise error (FWE) corrected p and a minimal cluster size of 200 voxels were used to explore FC patterns. RESULTS: Increased FC is reported between inferior frontal gyrus, posterior cingulate gyrus, and middle temporal gyrus with the precuneus as central receiving node. In addition, decreased FC in the cerebellum, hippocampus, and parahippocampal areas was observed. CONCLUSIONS: Altered FC is reported in areas which have been described to be also involved in lower urinary tract control. Although conducted with healthy controls, the assumption that the underlying therapeutic effect of TNS involves the central nervous system is supported and has to be further examined in patients with incomplete spinal cord injury.

Metabolic profile of complete spinal cord injury in pons and cerebellum: A 3T 1H MRS study.

The aim of this exploratory study was the assessment of the metabolic profiles of persons with complete spinal cord injury (SCI) in three region-of-interests (pons, cerebellar vermis, and cerebellar hemisphere), with magnetic resonance spectroscopy, and their correlations to clinical scores. Group differences and association between metabolic and clinical scores were examined. Fifteen people with chronic SCI (cSCI), five people with subacute SCI (sSCI) and fourteen healthy controls were included. Group comparison between cSCI and HC showed lower total N-acetyl-aspartate (tNAA) in the pons (p = 0.04) and higher glutathione (GSH) in the cerebellar vermis (p = 0.02). Choline levels in the cerebellar hemisphere were different between cSCI and HC (p = 0.02) and sSCI and HC (p = 0.02). A correlation was reported for choline containing compounds (tCho) to clinical scores in the pons (rho = - 0.55, p = 0.01). tNAA to total creatine (tNAA/tCr ratio) correlated to clinical scores in the cerebellar vermis (rho = 0.61, p = 0.004) and GSH correlated to the independence score in the cerebellar hemisphere (rho = 0.56, p = 0.01). The correlation of tNAA, tCr, tCho and GSH to clinical scores might be indicators on how well the CNS copes with the post-traumatic remodeling and might be further examined as outcome markers.

The longitudinal influence of tDCS on occipital GABA and glutamate/glutamine levels in episodic migraineurs.

This study investigated differences in the concentration of gamma-aminobutyric acid (GABA) and the combination of glutamine and glutamate (as GLX) in the early visual cortex of patients with episodic migraine and the influence of transcranial direct current stimulation (tDCS) on GABA and GLX. In this single-blind, sham-controlled trial, we randomly assigned patients with episodic migraine to receive daily anodal tDCS or sham stimulation. In addition, we included healthy controls. We acquired proton MR spectroscopy data of the visual cortex with 3 Tesla MRI at baseline and from migraine patients directly after the stimulation period and 4 months later. In 22 migraineurs and 25 controls, the GABA and the GLX concentrations did not differ at baseline between the groups. tDCS resulted in reduced concentrations of GABA but not GLX or the migraine frequency directly after the stimulation period, but not 4 months later. The changes in the levels of GABA in the early visual cortex of patients with episodic migraine in the interictal period suggest an effect of tDCS that allowed for subsequent changes in the migraine frequency. However, we might have missed relevant variations in the concentrations of these neurotransmitters during the follow-up period, as changes in migraine frequency appeared after the first MRI and disappeared before the second.

Mean kurtosis-Curve (MK-Curve) correction improves the test-retest reproducibility of diffusion kurtosis imaging at 3 T.

Diffusion kurtosis imaging (DKI) is applied to gain insights into the microstructural organization of brain tissues. However, the reproducibility of DKI outside brain white matter, particularly in combination with advanced estimation to remedy its noise sensitivity, remains poorly characterized. Therefore, in this study, we investigated the variability and reliability of DKI metrics while correcting implausible values with a fit method called mean kurtosis (MK)-Curve. A total of 10 volunteers (four women; age: 41.4 ± 9.6 years) were included and underwent two MRI examinations of the brain. The images were acquired on a clinical 3-T scanner and included a T1-weighted image and a diffusion sequence with multiple diffusion weightings suitable for DKI. Region of interest analysis of common kurtosis and tensor metrics derived with the MK-Curve DKI fit was performed, including intraclass correlation (ICC) and Bland-Altman (BA) plot statistics. A p value of less than 0.05 was considered statistically significant. The analyses showed good to excellent agreement of both kurtosis tensor- and diffusion tensor-derived MK-Curve-corrected metrics (ICC values: 0.77-0.98 and 0.87-0.98, respectively), with the exception of two DKI-derived metrics (axial kurtosis in the cortex: ICC = 0.68, and radial kurtosis in deep gray matter: ICC = 0.544). Non-MK-Curve-corrected kurtosis tensor-derived metrics ranged from 0.01 to 0.52 and diffusion tensor-derived metrics from 0.06 to 0.66, indicating poor to moderate reliability. No structural bias was observed in the BA plots for any of the diffusion metrics. In conclusion, MK-Curve-corrected DKI metrics of the human brain can be reliably acquired in white and gray matter at 3 T and DKI metrics have good to excellent agreement in a test-retest setting.

Glutathione in the Pons Is Associated With Clinical Status Improvements in Subacute Spinal Cord Injury.

OBJECTIVES: In spinal cord injury (SCI), the primary mechanical injury is followed by secondary sequelae that develop over the subsequent months and manifests in biochemical, functional, and microstructural alterations, at the site of direct injury but also in the spinal cord tissue above and below the actual lesion site. Noninvasive magnetic resonance spectroscopy (MRS) can be used to assess biochemical modulation occurring in the secondary injury phase, in addition to and supporting conventional MRI, and might help predict and improve patient outcome. In this article, we aimed to examine the metabolic levels in the pons of subacute SCI by means of in vivo proton MRS at 3 T and explore the association to clinical scores. MATERIALS AND METHODS: In this prospective study, between November 2015 and February 2018, single-voxel short-echo MRS data were acquired in healthy controls and in SCI subjects in the pons once during rehabilitation. Besides the single-point MRS examination, in addition, in participants with SCI, the clinical status (ie, motor, light touch, and pinprick scores) was assessed twice: (1) around the MRS session (approximately 10 weeks postinjury) and (2) before discharge (at approximately 9 months postinjury). The group differences were assessed with Kruskal-Wallis test, the post hoc comparison was assessed with Wilcoxon rank sum test, and the clinical correlations were conducted with Spearman rank correlation test. Bayes factor calculations completed the statistical part providing relevant evidence values. RESULTS: Twenty healthy controls (median age, 50 years; interquartile range, 41-55 years; 18 men) and 18 subjects with traumatic SCI (median age, 50 years; interquartile range, 32-58 years; 16 men) are included. Group comparison showed an increase of total N -acetylaspartate and combined glutamate and glutamine levels in complete SCI and a reduction of total creatine in incomplete paraplegic SCI. The proton MRS-based glutathione levels at baseline correlate to the motor score improvement during rehabilitation in incomplete subacute SCI. CONCLUSIONS: This exploratory study showed an association of the metabolite concentration of glutathione in the pons assessed at approximately 10 weeks after injury with the improvements of the motor score during the rehabilitation. Pontine glutathione levels in subjects with traumatic subacute incomplete SCI acquired remote from the injury site correlate to clinical score and might therefore be beneficial in the rehabilitation assessments.

Functional connectivity and amplitude of low-frequency fluctuations changes in people with complete subacute and chronic spinal cord injury.

After spinal cord injury (SCI), reorganization processes and changes in brain connectivity occur. Besides the sensorimotor cortex, the subcortical areas are strongly involved in motion and executive control. This exploratory study focusses on the cerebellum and vermis. Resting-state functional magnetic resonance imaging (fMRI) was performed. Between-group differences were computed using analysis of covariance and post-hoc tests for the seed-based connectivity measure with vermis and cerebellum as regions of interest. Twenty participants with complete SCI (five subacute SCI, 15 with chronic SCI) and 14 healthy controls (HC) were included. Functional connectivity (FC) was lower in all subjects with SCI compared with HC in vermis IX, right superior frontal gyrus (pFDR = 0.008) and right lateral occipital cortex (pFDR = 0.036). In addition, functional connectivity was lower in participants with chronic SCI compared with subacute SCI in bilateral cerebellar crus I, left precentral- and middle frontal gyrus (pFDR = 0.001). Furthermore, higher amplitude of low-frequency fluctuations (ALFF) was found in the left thalamus in individuals with subacute SCI (pFDR = 0.002). Reduced FC in SCI indicates adaptation with associated deficit in sensory and motor function. The increased ALFF in subacute SCI might reflect reorganization processes in the subacute phase.

Predicting Antidepressant Effects of Ketamine: the Role of the Pregenual Anterior Cingulate Cortex as a Multimodal Neuroimaging Biomarker.

BACKGROUND: Growing evidence underscores the utility of ketamine as an effective and rapid-acting treatment option for major depressive disorder (MDD). However, clinical outcomes vary between patients. Predicting successful response may enable personalized treatment decisions and increase clinical efficacy. METHODS: We here explored the potential of pregenual anterior cingulate cortex (pgACC) activity to predict antidepressant effects of ketamine in relation to ketamine-induced changes in glutamatergic metabolism. Prior to a single i.v. infusion of ketamine, 24 patients with MDD underwent functional magnetic resonance imaging during an emotional picture-viewing task and magnetic resonance spectroscopy. Changes in depressive symptoms were evaluated using the Beck Depression Inventory measured 24 hours pre- and post-intervention. A subsample of 17 patients underwent a follow-up magnetic resonance spectroscopy scan. RESULTS: Antidepressant efficacy of ketamine was predicted by pgACC activity during emotional stimulation. In addition, pgACC activity was associated with glutamate increase 24 hours after the ketamine infusion, which was in turn related to better clinical outcome. CONCLUSIONS: Our results add to the growing literature implicating a key role of the pgACC in mediating antidepressant effects and highlighting its potential as a multimodal neuroimaging biomarker of early treatment response to ketamine.

Acute effects of ketamine on the pregenual anterior cingulate: linking spontaneous activation, functional connectivity, and glutamate metabolism.

Ketamine exerts its rapid antidepressant effects via modulation of the glutamatergic system. While numerous imaging studies have investigated the effects of ketamine on a functional macroscopic brain level, it remains unclear how altered glutamate metabolism and changes in brain function are linked. To shed light on this topic we here conducted a multimodal imaging study in healthy volunteers (N = 23) using resting state fMRI and proton (1H) magnetic resonance spectroscopy (MRS) to investigate linkage between metabolic and functional brain changes induced by ketamine. Subjects were investigated before and during an intravenous ketamine infusion. The MRS voxel was placed in the pregenual anterior cingulate cortex (pgACC), as this region has been repeatedly shown to be involved in ketamine's effects. Our results showed functional connectivity changes from the pgACC to the right frontal pole and anterior mid cingulate cortex (aMCC). Absolute glutamate and glutamine concentrations in the pgACC did not differ significantly from baseline. However, we found that stronger pgACC activation during ketamine was linked to lower glutamine concentration in this region. Furthermore, reduced functional connectivity between pgACC and aMCC was related to increased pgACC activation and reduced glutamine. Our results thereby demonstrate how multimodal investigations in a single brain region could help to advance our understanding of the association between metabolic and functional changes.

Vitamin D supplementation in chronic spinal cord injury (VitD-SCI): study protocol for a randomised controlled trial.

INTRODUCTION: Vitamin D insufficiency, a vitamin D status or serum 25(OH)D concentration of ≤75 nmol/L, is highly prevalent in individuals with a spinal cord injury (SCI). Vitamin D is important for the functioning of the musculoskeletal, immune and respiratory systems, which are relevant determinants of secondary health conditions in SCI. An insufficiency should be treated with vitamin D supplementation. However, there is a lack of evidence regarding the optimal dosage and duration of vitamin D supplementation for individualised and long-term management of the vitamin D status in the context of SCI. This paper presents the protocol for the vitamin D supplementation in chronic spinal cord injury (VitD-SCI) trial that aims to investigate the effect of a 12-month intake of vitamin D supplementation on vitamin D status as well as on several secondary parameters among individuals with a chronic SCI. METHODS AND ANALYSES: The VitD-SCI trial is a randomised, placebo-controlled, double-blinded, parallel-group, superiority trial, conducted at the Swiss Paraplegic Centre. A total of 45 participants living with an SCI for at least 3 years (chronic SCI) and a vitamin D insufficiency at the first study visit, will be randomly assigned to one of three intervention groups. Participants receive either a monthly dosage of 24 000 IU or 48 000 IU vitamin D or a placebo for 12 months. Measurements taking place every 3 months include the assessment of vitamin D status (primary outcome) as well as bone mineral density, handgrip strength, fatigue, mood, pain and pressure injuries (secondary outcomes). Safety and tolerance of vitamin D supplementation will also be evaluated. ETHICS AND DISSEMINATION: The Swiss Ethics Committee for Northwest/Central Switzerland (EKNZ, 2020-01493) and the Swiss Agency for Therapeutic Products (Swissmedic, 2020DR3150) approved this study. Findings will be disseminated through peer-reviewed publications. TRIAL REGISTRATION NUMBERS: NCT04652544 and SNCTP000004032.

Metabolites of neuroinflammation relate to neuropathic pain after spinal cord injury.

OBJECTIVE: To determine whether cervical cord levels of metabolites are associated with pain sensation after spinal cord injury (SCI) by performing magnetic resonance spectroscopy in patients with SCI with and without neuropathic pain (NP). METHODS: Cervical cord single-voxel spectroscopic data of 24 patients with SCI (14 with NP, 10 pain-free) and 21 healthy controls were acquired at C2/3 to investigate metabolite ratios associated with neuroinflammation (choline-containing compounds to myoinositol [tCho/mI]) and neurodegeneration (total N-acetylaspartate to myo-inositol [tNAA/mI]). NP levels were measured, and Spearman correlation tests assessed associations between metabolite levels, cord atrophy, and pinprick score. RESULTS: In patients with NP, tCho/mI levels were increased (p = 0.024) compared to pain-free patients and negatively related to cord atrophy (p = 0.006, r = 0.714). Better pinprick score was associated with higher tCho/mI levels (p = 0.032, r = 0.574). In pain-free patients, tCho/mI levels were not related to cord atrophy (p = 0.881, r = 0.055) or pinprick score (p = 0.676, r = 0.152). tNAA/mI levels were similar in both patient groups (p = 0.396) and were not associated with pinprick score in patients with NP (p = 0.405, r = 0.242) and pain-free patients (p = 0.117, r = 0.527). CONCLUSIONS: Neuroinflammatory metabolite levels (i.e., tCho/mI) were elevated in patients with NP, its magnitude being associated with less cord atrophy and greater pain sensation (e.g., pinprick score). This suggests that patients with NP have more residual spinal tissue and greater metabolite turnover than pain-free patients. Neurodegenerative metabolite levels (i.e., tNAA/mI) were associated with greater cord atrophy but unrelated to NP. Identifying the metabolic NP signature provides new NP treatment targets and could improve patient stratification in interventional trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that levels of magnetic resonance spectroscopy-identified metabolites of neuroinflammation were elevated in patients with SCI with NP compared to those without NP.

Test-Retest Reliability of the Brain Metabolites GABA and Glx With JPRESS, PRESS, and MEGA-PRESS MRS Sequences in vivo at 3T.

BACKGROUND: The optimization of magnetic resonance spectroscopy (MRS) sequences allows improved diagnosis and prognosis of neurological and psychological disorders. Thus, to assess the test-retest and intersequence reliability of such MRS sequences in quantifying metabolite concentrations is of clinical relevance. PURPOSE: To evaluate the test-retest and intersequence reliability of three MRS sequences to estimate GABA and Glx = Glutamine+Glutamate concentrations in the human brain. STUDY TYPE: Prospective. SUBJECTS: Eighteen healthy participants were scanned twice (range: 1 day to 1 week between the two sessions) with identical protocols. FIELD STRENGTH/SEQUENCE: 3T using a 32-channel SENSE head coil in the PCC region; PRESS, JPRESS, and MEGA-PRESS sequences. ASSESSMENT: Metabolite concentrations were estimated using LCModel (for PRESS and MEGA-PRESS) and ProFit2 (for JPRESS). STATISTICAL TESTS: The test-retest reliability was evaluated by Wilcoxon signed-rank tests, Pearson's r correlation coefficients, intraclass-correlation coefficients (ICC), coefficients of variation (CV), and by Bland-Altman (BA) plots. The intersequence reliability was assessed with Wilcoxon signed-rank tests, Pearson's r correlation coefficients, and BA plots. RESULTS: For GABA, only the MEGA-PRESS sequence showed a moderate test-retest correlation (r = 0.54, ICC = 0.5, CV = 8.8%) and the BA plots indicated good agreement (P > 0.05) for all sequences. JPRESS provided less precise results and PRESS was insensitive to GABA. For Glx, the r and ICC values for PRESS (r = 0.87, ICC = 0.9, CV = 2.9%) and MEGA-PRESS (r = 0.70, ICC = 0.7, CV = 5.3%) reflect higher correlations, compared with JPRESS (r = 0.39, ICC = 0.4, CV = 20.1%). DATA CONCLUSION: MEGA-PRESS and JPRESS are suitable for the reliable detection of GABA, the first being more precise. The three sequences included in the study can measure Glx concentrations. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2020;51:1181-1191.

MR Spectroscopy of the Cervical Spinal Cord in Chronic Spinal Cord Injury.

Purpose To investigate metabolic changes in chronic spinal cord injury (SCI) by applying MR spectroscopy in the cervical spinal cord. Materials and Methods Single-voxel short-echo spectroscopic data in study participants with chronic SCI and healthy control subjects were prospectively acquired in the cervical spinal cord at C2 above the level of injury between March 2016 and January 2017 and were compared between groups. Concentrations of total N-acetylaspartate (tNAA), myo-inositol (mI), total choline-containing compounds (tCho), creatine, and glutamine and glutamate complex were estimated from the acquired spectra. Participants were assessed with a comprehensive clinical evaluation investigating sensory and motor deficits. Correlation analysis was applied to investigate relationships between observed metabolic differences, lesion severity, and clinical outcome. Results There were 18 male study participants with chronic SCI (median age, 51 years; range, 30-68 years) and 11 male healthy control subjects (median age, 45 years; range, 30-67 years). At cervical level C2, tNAA/mI and tCho/mI ratios were lower in participants with SCI (tNAA/mI: -26%, P = .003; tCho/mI: -18%; P = .04) than in healthy control subjects. The magnitude of difference was greater with the severity of cord atrophy (tNAA/mI: R2 = 0.44, P = .003; tCho/mI: R2 = 0.166, P = .09). Smaller tissue bridges at the lesion site correlated with lower ratios of tNAA/mI (R2 = 0.69, P = .006) and tCho/mI (R2 = 0.51, P = .03) at the C2 level. Lower tNAA/mI and tCho/mI ratios were associated with worse sensory and motor outcomes (P < .05). Conclusion Supralesional metabolic alterations are observed in chronic spinal cord injury, likely reflecting neurodegeneration, demyelination, and astrocytic gliosis in the injured cervical cord. Lesion severity and greater clinical impairment are both linked to the biochemical changes in the atrophied cervical cord after spinal cord injury. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Lin in this issue.

In vivo estimation of transverse relaxation time constant (T2 ) of 17 human brain metabolites at 3T.

PURPOSE: The transverse relaxation times T2 of 17 metabolites in vivo at 3T is reported and region specific differences are addressed. METHODS: An echo-time series protocol was applied to one, two, or three volumes of interest with different fraction of white and gray matter including a total number of 106 healthy volunteers and acquiring a total number of 128 spectra. The data were fitted with the 2D fitting tool ProFit2, which included individual line shape modeling for all metabolites and allowed the T2 calculation of 28 moieties of 17 metabolites. RESULTS: The T2 of 10 metabolites and their moieties have been reported for the first time. Region specific T2 differences in white and gray matter enriched tissue occur in 16 of 17 metabolites examined including single resonance lines and coupled spin systems. CONCLUSION: The relaxation time T2 is regions specific and has to be considered when applying tissue composition correction for internal water referencing. Magn Reson Med 80:452-461, 2018. © 2018 International Society for Magnetic Resonance in Medicine.

The Application of Human Spinal Cord Magnetic Resonance Spectroscopy to Clinical Studies: A Review.

This article reviews the current state of magnetic resonance spectroscopy applied in the human spinal cord with respect to its clinical applications and challenges in comparison to investigations in the human brain. Results from several disease processes affecting the spinal cord are presented, and potential advantages of applying clinical MRS in their investigation are emphasized.

Neurochemical profile of the human cervical spinal cord determined by MRS.

MRS enables insight into the chemical composition of central nervous system tissue. However, technical challenges degrade the data quality when applied to the human spinal cord. Therefore, to date detection of only the most prominent metabolite resonances has been reported in the healthy human spinal cord. The aim of this investigation is to provide an extended metabolic profile including neurotransmitters and antioxidants in addition to metabolites involved in the energy and membrane metabolism of the human cervical spinal cord in vivo. To achieve this, data quality was improved by using a custom-made, cervical detector array together with constructive averaging of a high number of echo signals, which is enabled by the metabolite cycling technique at 3T. In addition, the improved spinal cord spectra were extensively cross-validated, in vivo, post-mortem in situ and ex vivo. Reliable identification of up to nine metabolites was achieved in group analyses for the first time. Distinct features of the spinal cord neurochemical profile, in comparison with the brain neurotransmission system, include decreased concentrations of the sum of glutamate and glutamate and increased concentrations of aspartate, γ-amino-butyric acid, scyllo-inositol and the sum of myo-inositol and glycine.