Improved sensitivity and microvascular weighting of 3T laminar fMRI with GE-BOLD using NORDIC and phase regression.

INTRODUCTION: Functional MRI with spatial resolution in the submillimeter domain enables measurements of activation across cortical layers in humans. This is valuable as different types of cortical computations, e.g., feedforward versus feedback related activity, take place in different cortical layers. Laminar fMRI studies have almost exclusively employed 7T scanners to overcome the reduced signal stability associated with small voxels. However, such systems are relatively rare and only a subset of those are clinically approved. In the present study, we examined if the feasibility of laminar fMRI at 3T could be improved by use of NORDIC denoising and phase regression. METHODS: 5 healthy subjects were scanned on a Siemens MAGNETOM Prisma 3T scanner. To assess across-session reliability, each subject was scanned in 3-8 sessions on 3-4 consecutive days. A 3D gradient echo EPI (GE-EPI) sequence was used for BOLD acquisitions (voxel size 0.82 mm isotopic, TR = 2.2 s) using a block design finger tapping paradigm. NORDIC denoising was applied to the magnitude and phase time series to overcome limitations in temporal signal-to-noise ratio (tSNR) and the denoised phase time series were subsequently used to correct for large vein contamination through phase regression. RESULTS AND CONCLUSION: NORDIC denoising resulted in tSNR values comparable to or higher than commonly observed at 7T. Layer-dependent activation profiles could thus be extracted robustly, within and across sessions, from regions of interest located in the hand knob of the primary motor cortex (M1). Phase regression led to substantially reduced superficial bias in obtained layer profiles, although residual macrovascular contribution remained. We believe the present results support an improved feasibility of laminar fMRI at 3T.

Imaging Neurodegenerative Metabolism in Amyotrophic Lateral Sclerosis with Hyperpolarized [1-13C]pyruvate MRI.

The cause of amyotrophic lateral sclerosis (ALS) is still unknown, and consequently, early diagnosis of the disease can be difficult and effective treatment is lacking. The pathology of ALS seems to involve specific disturbances in carbohydrate metabolism, which may be diagnostic and therapeutic targets. Magnetic resonance imaging (MRI) with hyperpolarized [1-13C]pyruvate is emerging as a technology for the evaluation of pathway-specific changes in the brain's metabolism. By imaging pyruvate and the lactate and bicarbonate it is metabolized into, the technology is sensitive to the metabolic changes of inflammation and mitochondrial dysfunction. In this study, we performed hyperpolarized MRI of a patient with newly diagnosed ALS. We found a lateralized difference in [1-13C]pyruvate-to-[1-13C]lactate exchange with no changes in exchange from [1-13C]pyruvate to 13C-bicarbonate. The 40% increase in [1-13C]pyruvate-to-[1-13C]lactate exchange corresponded with the patient's symptoms and presentation with upper-motor neuron affection and cortical hyperexcitability. The data presented here demonstrate the feasibility of performing hyperpolarized MRI in ALS. They indicate potential in pathway-specific imaging of dysfunctional carbohydrate metabolism in ALS, an enigmatic neurodegenerative disease.

Lactate saturation limits bicarbonate detection in hyperpolarized 13 C-pyruvate MRI of the brain.

PURPOSE: To investigate the potential effects of [1-13 C]lactate RF saturation pulses on [13 C]bicarbonate detection in hyperpolarized [1-13 C]pyruvate MRI of the brain. METHODS: Thirteen healthy rats underwent MRI with hyperpolarized [1-13 C]pyruvate of either the brain (n = 8) or the kidneys, heart, and liver (n = 5). Dynamic, metabolite-selective imaging was used in a cross-over experiment in which [1-13 C]lactate was excited with either 0° or 90° flip angles. The [13 C]bicarbonate SNR and apparent [1-13 C]pyruvate-to-[13 C]bicarbonate conversion (kPB ) were determined. Furthermore, simulations were performed to identify the SNR optimal flip-angle scheme for detection of [1-13 C]lactate and [13 C]bicarbonate. RESULTS: In the brain, the [13 C]bicarbonate SNR was 64% higher when [1-13 C]lactate was not excited (5.8 ± 1.5 vs 3.6 ± 1.3; 1.2 to 3.3-point increase; p = 0.0027). The apparent kPB decreased 25% with [1-13 C]lactate saturation (0.0047 ± 0.0008 s-1 vs 0.0034 ± 0.0006 s-1 ; 95% confidence interval, 0.0006-0.0019 s-1 increase; p = 0.0049). These effects were not present in the kidneys, heart, or liver. Simulations suggest that the optimal [13 C]bicarbonate SNR with a TR of 1 s in the brain is obtained with [13 C]bicarbonate, [1-13 C]lactate, and [1-13 C]pyruvate flip angles of 60°, 15°, and 10°, respectively. CONCLUSIONS: Radiofrequency saturation pulses on [1-13 C]lactate limit [13 C]bicarbonate detection in the brain specifically, which could be due to shuttling of lactate from astrocytes to neurons. Our results have important implications for experimental design in studies in which [13 C]bicarbonate detection is warranted.

Initial Experience on Hyperpolarized [1-13C]Pyruvate MRI Multicenter Reproducibility-Are Multicenter Trials Feasible?

BACKGROUND: Magnetic resonance imaging (MRI) with hyperpolarized [1-13C]pyruvate allows real-time and pathway specific clinical detection of otherwise unimageable in vivo metabolism. However, the comparability between sites and protocols is unknown. Here, we provide initial experiences on the agreement of hyperpolarized MRI between sites and protocols by repeated imaging of same healthy volunteers in Europe and the US. METHODS: Three healthy volunteers traveled for repeated multicenter brain MRI exams with hyperpolarized [1-13C]pyruvate within one year. First, multisite agreement was assessed with the same echo-planar imaging protocol at both sites. Then, this was compared to a variable resolution echo-planar imaging protocol. In total, 12 examinations were performed. Common metrics of 13C-pyruvate to 13C-lactate conversion were calculated, including the kPL, a model-based kinetic rate constant, and its model-free equivalents. Repeatability was evaluated with intraclass correlation coefficients (ICC) for absolute agreement computed using two-way random effects models. RESULTS: The mean kPL across all examinations in the multisite comparison was 0.024 ± 0.0016 s-1. The ICC of the kPL was 0.83 (p = 0.14) between sites and 0.7 (p = 0.09) between examinations of the same volunteer at any of the two sites. For the model-free metrics, the lactate Z-score had similar site-to-site ICC, while it was considerably lower for the lactate-to-pyruvate ratio. CONCLUSIONS: Estimation of metabolic conversion from hyperpolarized [1-13C]pyruvate to lactate using model-based metrics such as kPL suggests close agreement between sites and examinations in volunteers. Our initial results support harmonization of protocols, support multicenter studies, and inform their design.

Facilitatory Effect of Intermittent Repetitive Transcranial Magnetic Stimulation on Perceptual Distortion of the Face.

Orofacial pain patients often report that the painful facial area is "swollen" without clinical signs - known as perceptual distortion (PD). The neuromodulatory effect of facilitatory repetitive transcranial magnetic stimulation (rTMS) on PD in healthy individuals was investigated, to provide further support that the primary somatosensory cortex (SI) is involved in facial PD. Participants were allocated to active (n = 26) or sham (n = 26) rTMS group in this case-control study. PD was induced experimentally by injecting local anesthesia (LA) in the right infraorbital region. PD was measured at baseline, 6 min after LA, immediately, 20 and 40 min after rTMS. Intermittent theta-burst stimulation (iTBS) as active rTMS and sham rTMS was applied to the face representation area of SI at 10 min after LA. The magnitude of PD was compared between the groups. The magnitude of PD significantly increased immediately after iTBS compared with sham rTMS (P = .009). The PD was significantly higher immediately after iTBS compared to 6 min after LA (P = .004) in the active rTMS group, but not in the sham rTMS group (P = .054). iTBS applied to a somatotopic-relevant cortical region appears to facilitate facial PD further supporting the involvement of SI in the processing of one´s own face and PD. PERSPECTIVE: This study provides information on neural substrate responsible for processing of perceptual distortion of the face which is speculated to contribute to the chronification of orofacial pain. The findings of this study may aid in mechanism-based management of the condition in orofacial pain disorders and possibly other chronic pain states.

Test-Retest Reliability of Short-Interval Intracortical Inhibition Assessed by Threshold-Tracking and Automated Conventional Techniques.

Two novel short-interval intracortical inhibition (SICI) protocols, assessing SICI across a range of interstimulus intervals (ISIs) using either parallel threshold-tracking transcranial magnetic stimulation (TT-TMS) or automated conventional TMS (cTMS), were recently introduced. However, the test-retest reliability of these protocols has not been investigated, which is important if they are to be introduced in the clinic. SICI was recorded in 18 healthy subjects using TT-TMS (T-SICI) and cTMS (A-SICI). All subjects were examined at four identical sessions, i.e., morning and afternoon sessions on 2 d, 5-7 d apart. Both SICI protocols were performed twice at each session by the same observer. In one of the sessions, another observer performed additional examinations. Neither intraobserver nor interobserver measures of SICI differed significantly between examinations, except for T-SICI at ISI 3 ms (p = 0.00035) and A-SICI at ISI 2.5 ms (p = 0.0103). Intraday reliability was poor-to-good for A-SICI and moderate-to-good for T-SICI. Interday and interobserver reliabilities of T-SICI and A-SICI were moderate-to-good. Although between-subject variation constituted most of the total variation, SICI repeatability in an individual subject was poor. The two SICI protocols showed no considerable systematic bias across sessions and had a comparable test-retest reliability profile. Findings from the present study suggest that both SICI protocols may be reliably and reproducibly employed in research studies, but should be used with caution for individual decision-making in clinical settings. Studies exploring reliability in patient cohorts are warranted to investigate the clinical utility of these two SICI protocols.

Early diagnosis of amyotrophic lateral sclerosis by threshold tracking and conventional transcranial magnetic stimulation.

BACKGROUND AND PURPOSE: Short-interval intracortical inhibition by threshold tracking (T-SICI) has been proposed as a diagnostic tool for amyotrophic lateral sclerosis (ALS) but has not been compared directly with conventional amplitude measurements (A-SICI). This study compared A-SICI and T-SICI for sensitivity and clinical usefulness as biomarkers for ALS. METHODS: In all, 104 consecutive patients referred with suspicion of ALS were prospectively included and were subsequently divided into 62 patients with motor neuron disease (MND) and 42 patient controls (ALS mimics) by clinical follow-up. T-SICI and A-SICI recorded in the first dorsal interosseus muscle (index test) were compared with recordings from 53 age-matched healthy controls. The reference standard was the Awaji criteria. Clinical scorings, conventional nerve conduction studies and electromyography were also performed on the patients. RESULTS: Motor neuron disease patients had significantly reduced T-SICI and A-SICI compared with the healthy and patient control groups, which were similar. Sensitivity and specificity for discriminating MND patients from patient controls were high (areas under the receiver operating characteristic curves 0.762 and 0.810 for T-SICI and A-SICI respectively at 1-3.5 ms). Paradoxically, T-SICI was most reduced in MND patients with the fewest upper motor neuron (UMN) signs (Spearman ρ = 0.565, p = 4.3 × 10-6 ). CONCLUSIONS: Amplitude-based measure of cortical inhibition and T-SICI are both sensitive measures for the detection of cortical involvement in MND patients and may help early diagnosis of ALS, with T-SICI most abnormal before UMN signs have developed. The gradation in T-SICI from pathological facilitation in patients with minimal UMN signs to inhibition in those with the most UMN signs may be due to progressive degeneration of the subset of UMNs experiencing facilitation.

Metabolic MRI with hyperpolarized [1-13C]pyruvate separates benign oligemia from infarcting penumbra in porcine stroke.

Acute ischemic stroke patients benefit from reperfusion in a short time-window after debut. Later treatment may be indicated if viable brain tissue is demonstrated and this outweighs the inherent risks of late reperfusion. Magnetic resonance imaging (MRI) with hyperpolarized [1-13C]pyruvate is an emerging technology that directly images metabolism. Here, we investigated its potential to detect viable tissue in ischemic stroke. Stroke was induced in pigs by intracerebral injection of endothelin 1. During ischemia, the rate constant of pyruvate-to-lactate conversion, kPL, was 52% larger in penumbra and 85% larger in the infarct compared to the contralateral hemisphere (P = 0.0001). Within the penumbra, the kPL was 50% higher in the regions that later infarcted compared to non-progressing regions (P = 0.026). After reperfusion, measures of pyruvate-to-lactate conversion were slightly decreased in the infarct compared to contralateral. In addition to metabolic imaging, we used hyperpolarized pyruvate for perfusion-weighted imaging. This was consistent with conventional imaging for assessment of infarct size and blood flow. Lastly, we confirmed the translatability of simultaneous assessment of metabolism and perfusion with hyperpolarized MRI in healthy volunteers. In conclusion, hyperpolarized [1-13C]pyruvate may aid penumbral characterization and increase access to reperfusion therapy for late presenting patients.

Online control of an assistive active glove by slow cortical signals in patients with amyotrophic lateral sclerosis.

Objective.A brain-computer interface (BCI) allows users to control external devices using brain signals that can be recorded non-invasively via electroencephalography (EEG). Movement related cortical potentials (MRCPs) are an attractive option for BCI control since they arise naturally during movement execution and imagination, and therefore, do not require an extensive training. This study tested the feasibility of online detection of reaching and grasping using MRCPs for the application in patients suffering from amyotrophic lateral sclerosis (ALS).Approach.A BCI system was developed to trigger closing of a soft assistive glove by detecting a reaching movement. The custom-made software application included data collection, a novel method for collecting the input data for classifier training from the offline recordings based on a sliding window approach, and online control of the glove. Eight healthy subjects and two ALS patients were recruited to test the developed BCI system. They performed assessment blocks without the glove active (NG), in which the movement detection was indicated by a sound feedback, and blocks (G) in which the glove was controlled by the BCI system. The true positive rate (TPR) and the positive predictive value (PPV) were adopted as the outcome measures. Correlation analysis between forehead EEG detecting ocular artifacts and sensorimotor area EEG was conducted to confirm the validity of the results.Main results.The overall median TPR and PPV were >0.75 for online BCI control, in both healthy individuals and patients, with no significant difference across the blocks (NG versus G).Significance.The results demonstrate that cortical activity during reaching can be detected and used to control an external system with a limited amount of training data (30 trials). The developed BCI system can be used to provide grasping assistance to ALS patients.

Cortical GABA in migraine with aura -an ultrashort echo magnetic resonance spectroscopy study.

OBJECTIVE: The aim of this cross-sectional study was to investigate the cortical metabolite concentrations in patients suffering from migraine with aura (MWA). We hypothesized that occipital γ-aminobutyric acid (GABA) levels are lower in MWA patients. BACKGROUND: Recent studies have indicated that a disturbance in the inhibitory GABA is involved in triggering the migraine aura. We aimed to explore this using a novel magnetic resonance spectroscopy sequence. METHODS: Using spin echo full intensity acquired localized spectroscopy on a Siemens 3 Tesla magnetic resonance scanner, we obtained occipital and parietal metabolite concentrations in 14 patients suffering from migraine with aura and a group of 16 matched healthy subjects. All scans were performed at Aarhus University Hospital, at the Center for Functionally Integrative Neuroscience (CFIN). RESULTS: No difference was found in GABA/(Total creatine) levels in either the occipital cortex (p = 0.744) or in the somatosensory cortex (p = 0.305). CONCLUSION: These findings indicate that cortical GABA levels are normal in patients suffering from relatively few migraine attacks. Previous studies have reported that cortical GABA in patients with more frequent migraines is reduced; further investigation of the inhibitory system in migraine patients is warranted to determine the underlying mechanisms.

Attenuation of dopamine-induced GABA release in problem gamblers.

INTRODUCTION: We have previously shown that an interaction between medial prefrontal and parietal cortices is instrumental in promoting self-awareness via synchronizing oscillations in the gamma range. The synchronization of these oscillations is modulated by dopamine release. Given that such oscillations result from intermittent GABA stimulation of pyramidal cells, it is of interest to determine whether the dopaminergic system regulates GABA release directly in cortical paralimbic regions. Here, we test the hypothesis that the regulation of the GABA-ergic system by the dopaminergic system becomes attenuated in problem gamblers resulting in addictive behaviors and impaired self-awareness. METHODS: [11 C]Ro15-4513 PET, a marker of benzodiazepine α1/α5 receptor availability in the GABA receptor complex, was used to detect changes in synaptic GABA levels after oral doses of 100mg L-dopa in a double-blind controlled study of male problem gamblers (N = 10) and age-matched healthy male controls (N = 10). RESULTS: The mean reduction of cortical gray matter GABA/BDZ receptor availability induced by L-dopa was significantly attenuated in the problem gambling group compared to the healthy control group (p = 0.0377). CONCLUSIONS: Our findings demonstrate that: (a) Exogenous dopamine can induce synaptic GABA release in healthy controls. (b) This release is attenuated in frontal cortical areas of males suffering from problem gambling, possibly contributing to their loss of inhibitory control. This suggests that dysfunctional dopamine regulation of GABA release may contribute to problem gambling and gambling disorder.

Evaluation of the noradrenergic system in Parkinson's disease: an 11C-MeNER PET and neuromelanin MRI study.

Pathological involvement of the noradrenergic locus coeruleus occurs early in Parkinson's disease, and widespread noradrenaline reductions are found at post-mortem. Rapid eye movement sleep behaviour disorder (RBD) accompanies Parkinson's disease and its presence predicts an unfavourable disease course with a higher propensity to cognitive impairment and orthostatic hypotension. MRI can detect neuromelanin in the locus coeruleus while 11C-MeNER PET is a marker of noradrenaline transporter availability. Here, we use both imaging modalities to study the association of RBD, cognition and autonomic dysfunction in Parkinson's disease with loss of noradrenergic function. Thirty non-demented Parkinson's disease patients [16 patients with RBD and 14 without RBD, comparable across age (66.6 ± 6.7 years), sex (22 males), and disease stage (Hoehn and Yahr, 2.3 ± 0.5)], had imaging of the locus coeruleus with neuromelanin sensitive MRI and brain noradrenaline transporter availability with 11C-MeNER PET. RBD was confirmed with polysomnography; cognitive function was assessed with a neuropsychological test battery, and blood pressure changes on tilting were documented; results were compared to 12 matched control subjects. We found that Parkinson's disease patients with RBD showed decreased locus coeruleus neuromelanin signal on MRI (P < 0.001) and widespread reduced binding of 11C-MeNER (P < 0.001), which correlated with amount of REM sleep without atonia. Parkinson's disease with RBD was also associated with a higher incidence of cognitive impairment, slowed EEG activity, and orthostatic hypotension. Reduced 11C-MeNER binding correlated with EEG slowing, cognitive performance, and orthostatic hypotension. In conclusion, reduced noradrenergic function in Parkinson's disease was linked to the presence of RBD and associated with cognitive deterioration and orthostatic hypotension. Noradrenergic impairment may contribute to the high prevalence of these non-motor symptoms in Parkinson's disease, and may be of relevance when treating these conditions in Parkinson's disease.

Exogenous dopamine reduces GABA receptor availability in the human brain.

BACKGROUND: While it has recently been shown that dopamine release stimulates conscious self-monitoring through the generation of gamma oscillations in medial prefrontal/anterior cingulate cortex, and that the GABAergic system is effective in producing such oscillations, interaction of the two transmitter systems has not been demonstrated in humans. We here hypothesize that dopamine challenge stimulates the GABA system directly in the medial prefrontal/anterior cingulate region in the human brain. METHODS: Positron emission tomography (PET) with the GABA receptor α1/α5 subtype ligand [(11)C] Ro15-4513 was used to detect changes in GABA receptor availability after clinical oral doses of levodopa in a double blind controlled study. RESULTS: We here provide the first direct evidence for such coupling in the cerebral cortex, in particular in the medial prefrontal anterior cingulate region, by showing that exogenous dopamine decreases [(11)C] Ro15-4513 binding widely in the human brain compatible with a fall in α1 subtype availability in GABA complexes due to increased GABA activity.

Capillary transit time heterogeneity and flow-metabolism coupling after traumatic brain injury.

Most patients who die after traumatic brain injury (TBI) show evidence of ischemic brain damage. Nevertheless, it has proven difficult to demonstrate cerebral ischemia in TBI patients. After TBI, both global and localized changes in cerebral blood flow (CBF) are observed, depending on the extent of diffuse brain swelling and the size and location of contusions and hematoma. These changes vary considerably over time, with most TBI patients showing reduced CBF during the first 12 hours after injury, then hyperperfusion, and in some patients vasospasms before CBF eventually normalizes. This apparent neurovascular uncoupling has been ascribed to mitochondrial dysfunction, hindered oxygen diffusion into tissue, or microthrombosis. Capillary compression by astrocytic endfeet swelling is observed in biopsies acquired from TBI patients. In animal models, elevated intracranial pressure compresses capillaries, causing redistribution of capillary flows into patterns argued to cause functional shunting of oxygenated blood through the capillary bed. We used a biophysical model of oxygen transport in tissue to examine how capillary flow disturbances may contribute to the profound changes in CBF after TBI. The analysis suggests that elevated capillary transit time heterogeneity can cause critical reductions in oxygen availability in the absence of 'classic' ischemia. We discuss diagnostic and therapeutic consequences of these predictions.

The capillary dysfunction hypothesis of Alzheimer's disease.

It is widely accepted that hypoperfusion and changes in capillary morphology are involved in the etiopathogenesis of Alzheimer's disease (AD). This is difficult to reconcile with the hyperperfusion observed in young high-risk subjects. Differences in the way cerebral blood flow (CBF) is coupled with the local metabolic needs during different phases of the disease can explain this apparent paradox. This review describes this coupling in terms of a model of cerebral oxygen availability that takes into consideration the heterogeneity of capillary blood flow patterns. The model predicts that moderate increases in heterogeneity requires elevated CBF in order to maintain adequate oxygenation. However, with progressive increases in heterogeneity, the resulting low tissue oxygen tension will require a suppression of CBF in order to maintain tissue metabolism. The observed biphasic nature of CBF responses in preclinical AD and AD is therefore consistent with progressive disturbances of capillary flow patterns. Salient features of the model are discussed in the context of AD pathology along with potential sources of increased capillary flow heterogeneity.

Visualization of altered neurovascular coupling in chronic stroke patients using multimodal functional MRI.

Evaluation of cortical reorganization in chronic stroke patients requires methods to accurately localize regions of neuronal activity. Blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is frequently employed; however, BOLD contrast depends on specific coupling relationships between the cerebral metabolic rate of oxygen (CMRO(2)), cerebral blood flow (CBF), and volume (CBV), which may not exist following stroke. The aim of this study was to understand whether CBF-weighted (CBFw) and CBV-weighted (CBVw) fMRI could be used in sequence with BOLD to characterize neurovascular coupling mechanisms poststroke. Chronic stroke patients (n=11) with motor impairment and age-matched controls (n=11) performed four sets of unilateral motor tasks (60 seconds/30 seconds off/on) during CBFw, CBVw, and BOLD fMRI acquisition. While control participants elicited mean BOLD, CBFw, and CBVw responses in motor cortex (P<0.01), patients showed only mean changes in CBF (P<0.01) and CBV (P<0.01), but absent mean BOLD responses (P=0.20). BOLD intersubject variability was consistent with differing coupling indices between CBF, CBV, and CMRO(2). Thus, CBFw and/or CBVw fMRI may provide crucial information not apparent from BOLD in these patients. A table is provided outlining distinct vascular and metabolic uncoupling possibilities that elicit different BOLD responses, and the strengths and limitations of the multimodal protocol are summarized.

Baseline GABA concentration and fMRI response.

Coordination between glutamatergic excitatory neurons and gamma-aminobutyric acid (GABA)-ergic inhibitory interneurons is fundamental to the regulation of neuronal firing rates and is believed to have relevance to functional magnetic resonance imaging (fMRI) contrast. While much is known regarding the molecular behavior of excitatory and inhibitory processes, comparatively less is known regarding the role of such processes in explaining variations in fMRI and related hemodynamic imaging metrics. The relationship between baseline GABA levels, as measured by MR spectroscopy, and hemodynamic contrasts from four sequences in human visual cortex are investigated (n=12; field strength=3.0 T): blood oxygenation level-dependent (BOLD), cerebral blood flow (CBF)-weighted arterial spin labelling (ASL), cerebral blood volume (CBV)-weighted vascular-space-occupancy (VASO), and arterial CBV (aCBV)-weighted inflow VASO (iVASO). Results indicate that baseline GABA levels (GABA+ macromolecules normalized to creatine) inversely correlate with BOLD reactivity (R=-0.70; P=0.01) and magnitude CBV-weighted VASO reactivity (R=-0.71; P=0.01). A trend for significance was found between baseline aCBV-weighted iVASO (R=-0.50; P=0.10) and baseline GABA. A positive correlation was found between baseline CBF-weighted ASL signal and GABA (R=0.65; P=0.02) and ASL time-to-peak and baseline GABA (R=0.58; P=0.05). These findings demonstrate that both the dominant BOLD fMRI contrast, as well as other emerging MR hemodynamic contrasts, have signal variations that are linked to baseline GABA levels.

Cerebral blood flow, blood volume, and oxygen metabolism dynamics in human visual and motor cortex as measured by whole-brain multi-modal magnetic resonance imaging.

The development of neuroimaging methods to characterize flow-metabolism coupling is crucial for understanding mechanisms that subserve oxygen delivery. Functional magnetic resonance imaging (fMRI) using blood-oxygenation-level-dependent (BOLD) contrast reflects composite changes in cerebral blood volume (CBV), cerebral blood flow (CBF), and the cerebral metabolic rate of oxygen consumption (CMRO(2)). However, it is difficult to separate these parameters from the composite BOLD signal, thereby hampering MR-based flow-metabolism coupling studies. Here, a novel, noninvasive CBV-weighted MRI approach (VASO-FLAIR with 3D GRASE (GRadient-And-Spin-Echo)) is used in conjunction with CBF-weighted and BOLD fMRI in healthy volunteers (n=7) performing simultaneous visual (8 Hz flashing-checkerboard) and motor (1 Hz unilateral joystick) tasks. This approach allows for CBV, CBF, and CMRO(2) to be estimated, yielding (mean+/-s.d.): DeltaCBF=63%+/-12%, DeltaCBV=17%+/-7%, and DeltaCMRO(2)=13%+/-11% in the visual cortex, and DeltaCBF=46%+/-11%, DeltaCBV=8%+/-3%, and DeltaCMRO(2)=12%+/-13% in the motor cortex. Following the visual and motor tasks, the BOLD signal became more negative (P=0.003) and persisted longer (P=0.006) in the visual cortex compared with the motor cortex, whereas CBV and CBF returned to baseline earlier and equivalently. The proposed whole-brain technique should be useful for assessing regional discrepancies in hemodynamic reactivity without the use of intravascular contrast agents.

Cortical and spinal excitability changes after robotic gait training in healthy participants.

BACKGROUND: Recent studies have proposed a role for robotic gait training in participants with acquired brain injury, but the effects on the excitability of cortical and spinal neurons even in healthy participants are uncertain. OBJECTIVE: To investigate changes in corticospinal excitability in healthy participants after active and passive robotic gait training in a driven gait orthosis (DGO), the Lokomat. METHODS: Thirteen healthy participants took part in 2 experiments. Each participant performed 20 minutes of active and passive gait training in a DGO. Motor evoked potentials (MEP), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), F-wave frequency, and Mmax were measured in the right tibialis anterior muscle before and after training. RESULTS: Active training led to a decline in MEP amplitude and F-wave frequency. The MEP decline was associated with subjective muscle fatigue. Passive training induced a decrease in SICI lasting for 20 minutes after training. CONCLUSIONS: The decline in MEP after active training is most likely because of central fatigue, whereas the decreased F-wave frequency might represent short-term plastic changes in the spinal cord. The decrease in SICI after passive training probably reflects a decrease in intracortical GABA activity, which could benefit the acquisition of new motor skills.