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1.  Local GABA concentration is related to network-level resting functional connectivity 
eLife  2014;3:e01465.
Anatomically plausible networks of functionally inter-connected regions have been reliably demonstrated at rest, although the neurochemical basis of these ‘resting state networks’ is not well understood. In this study, we combined magnetic resonance spectroscopy (MRS) and resting state fMRI and demonstrated an inverse relationship between levels of the inhibitory neurotransmitter GABA within the primary motor cortex (M1) and the strength of functional connectivity across the resting motor network. This relationship was both neurochemically and anatomically specific. We then went on to show that anodal transcranial direct current stimulation (tDCS), an intervention previously shown to decrease GABA levels within M1, increased resting motor network connectivity. We therefore suggest that network-level functional connectivity within the motor system is related to the degree of inhibition in M1, a major node within the motor network, a finding in line with converging evidence from both simulation and empirical studies.
eLife digest
Even when your body is at rest, your brain remains active. Subjects lying in brain scanners without any specific task to perform show coordinated and reproducible patterns of brain activity. Areas of the brain with similar functions, such as those involved in vision or in movement, tend to increase or decrease their activity in sync, and these coordinated patterns are referred to as resting state networks.
The functions of these networks are unclear—they may support introspection, memory recall or planning for the future, or they may help to strengthen newly acquired skills by enabling the brain to replay previous learning episodes. There is evidence that resting state networks are altered in disorders such as Alzheimer’s disease, autism and schizophrenia, but little is known about how these changes arise or what they might mean.
Now, Stagg et al. have used a type of brain scan called magnetic resonance spectroscopy to gain insights into the mechanisms by which one particular network—the resting motor network—is generated. This network consists of areas involved in planning, monitoring and executing movements, and includes the primary motor cortex, which initiates movements by sending instructions to the spinal cord.
The levels of a chemical called GABA—a neurotransmitter molecule that tends to inhibit the activity of nerve cells—were measured in the primary motor cortex of young healthy volunteers as they lay idle in a scanner. GABA levels were negatively correlated with the amount of coordinated activity within the resting motor network. By contrast, no relation was seen between coordinated activity and the levels of the neurotransmitter glutamate, which tends to increase the activity of nerve cells. Furthermore, when a weak electric current was applied through the subjects’ scalp to their primary motor cortex—a technique previously shown to lower levels of GABA in the region—the resting motor network became stronger.
In addition to providing new information on how the rhythmic patterns of activity seen in the resting brain arise, the work of Stagg et al. contributes to the more general effort to understand the complex patterns of connections within the human brain.
PMCID: PMC3964822  PMID: 24668166
magnetic resonance spectroscopy; GABA; resting state fMRI; human
2.  Studying the Effects of Transcranial Direct-Current Stimulation in Stroke Recovery Using Magnetic Resonance Imaging 
Transcranial direct-current stimulation (tDCS) is showing increasing promise as an adjunct therapy in stroke rehabilitation. However questions still remain concerning its mechanisms of action, which currently limit its potential. Magnetic resonance (MR) techniques are increasingly being applied to understand the neural effects of tDCS. Here, we review the MR evidence supporting the use of tDCS to aid recovery after stroke and discuss the important open questions that remain.
PMCID: PMC3859898  PMID: 24376413
transcranial direct-current stimulation; stroke recovery; MRI; humans; MRS spectroscopy
3.  GABA Predicts Time Perception 
The Journal of Neuroscience  2014;34(12):4364-4370.
Our perception of time constrains our experience of the world and exerts a pivotal influence over a myriad array of cognitive and motor functions. There is emerging evidence that the perceived duration of subsecond intervals is driven by sensory-specific neural activity in human and nonhuman animals, but the mechanisms underlying individual differences in time perception remain elusive. We tested the hypothesis that elevated visual cortex GABA impairs the coding of particular visual stimuli, resulting in a dampening of visual processing and concomitant positive time-order error (relative underestimation) in the perceived duration of subsecond visual intervals. Participants completed psychophysical tasks measuring visual interval discrimination and temporal reproduction and we measured in vivo resting state GABA in visual cortex using magnetic resonance spectroscopy. Time-order error selectively correlated with GABA concentrations in visual cortex, with elevated GABA associated with a rightward horizontal shift in psychometric functions, reflecting a positive time-order error (relative underestimation). These results demonstrate anatomical, neurochemical, and task specificity and suggest that visual cortex GABA contributes to individual differences in time perception.
PMCID: PMC3960474  PMID: 24647956
4.  What are we measuring with GABA magnetic resonance spectroscopy? 
A number of recent papers1–3 have demonstrated a relationship between in vivo concentration of GABA, as assessed using Magnetic Resonance Spectroscopy (MRS), and an individual's task performance, giving a unique insight into the relationship between physiology and behavior. However, interpretation of the functional significance of the MRS GABA measure is not straightforward. Here we discuss some of the outstanding questions as to how total concentration of GABA within a cortical region relates to phasic and tonic GABA activity within the cortical volume studied.
PMCID: PMC3204132  PMID: 22046466
gamma-amino butyric acid (GABA); motor cortex; magnetic resonance spectroscopy; human; inter-individual differences
5.  Widespread Modulation of Cerebral Perfusion Induced during and after Transcranial Direct Current Stimulation Applied to the Left Dorsolateral Prefrontal Cortex 
The Journal of Neuroscience  2013;33(28):11425-11431.
Noninvasive neuromodulatory techniques such as transcranial direct current stimulation (tDCS) are attracting increasing interest as potential therapies for a wide range of neurological and psychiatric conditions. When targeted to the dorsolateral prefrontal cortex (DLPFC), anodal, facilitatory tDCS has been shown to improve symptoms in a range of domains including working memory, mood, and pain perception (Boggio et al., 2008a; Dockery et al., 2009; Kalu et al., 2012). However, the mechanisms underlying these promising behavioral effects are not well understood. Here, we investigated brain perfusion changes, as assessed using whole-brain arterial spin labeling (ASL), during tDCS applied to the left DLPFC in healthy humans. We demonstrated increased perfusion in regions closely anatomically connected to the DLPFC during anodal tDCS in conjunction with a decreased functional coupling between the left DLPFC and the thalami bilaterally. Despite highly similar effects on cortical excitability during and after stimulation (Nitsche and Paulus, 2000, 2001), cortical perfusion changes were markedly different during these two time periods, with widespread decreases in cortical perfusion being demonstrated after both anodal and cathodal tDCS compared to the period during stimulation. These findings may at least partially explain the different effects on behavior in these time periods described previously in the motor system (Stagg et al., 2011). In addition, the data presented here provide mechanistic explanations for the behavioral effects of anodal tDCS applied to the left DLPFC in terms of modulating functional connectivity between the DLPFC and thalami, as has been hypothesized previously (Lorenz et al., 2003).
PMCID: PMC3724554  PMID: 23843514
6.  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 (CMRO2), 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 CMRO2. 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.
PMCID: PMC3493993  PMID: 22828998
arterial spin labeling; BOLD; cerebral blood flow; cerebral blood volume; cerebrovascular disease; neurovascular coupling
7.  Whole-brain magnetic resonance spectroscopic imaging measures are related to disability in ALS 
Neurology  2013;80(7):610-615.
To demonstrate the sensitivity of a recently developed whole-brain magnetic resonance spectroscopic imaging (MRSI) sequence to cerebral pathology and disability in amyotrophic lateral sclerosis (ALS), and compare with measures derived from diffusion tensor imaging.
Whole-brain MRSI and diffusion tensor imaging were undertaken in 13 patients and 14 age-similar healthy controls. Mean N-acetylaspartate (NAA), fractional anisotropy, and mean diffusivity were extracted from the corticospinal tract, compared between groups, and then in relation to disability in the patient group.
Significant reductions in NAA were found along the course of the corticospinal tracts on whole-brain MRSI. There were also significant changes in fractional anisotropy (decreased) and mean diffusivity (increased) in the patient group, but only NAA showed a significant relationship with disability (r = 0.65, p = 0.01).
Whole-brain MRSI has potential as a quantifiable neuroimaging marker of disability in ALS. It offers renewed hope for a neuroimaging outcome measure with the potential for harmonization across multiple sites in the context of a therapeutic trial.
PMCID: PMC3590062  PMID: 23325907
8.  Relationships between functional and structural corticospinal tract integrity and walking post stroke 
Clinical Neurophysiology  2012;123(12):2422-2428.
► We investigated the relationship between walking impairment after stroke and integrity of the corticospinal tract (CST). ► We used transcranial magnetic stimulation and diffusion tensor imaging to assess CST integrity. ► We demonstrate that patients with more ipsilateral connectivity between the unlesioned M1 and the affected leg had more structural damage to their CST.
Studies on upper limb recovery following stroke have highlighted the importance of the structural and functional integrity of the corticospinal tract (CST) in determining clinical outcomes. However, such relationships have not been fully explored for the lower limb. We aimed to test whether variation in walking impairment was associated with variation in the structural or functional integrity of the CST.
Transcranial magnetic stimulation was used to stimulate each motor cortex while EMG recordings were taken from the vastus lateralis (VL) bilaterally; these EMG measures were used to calculate both ipsilateral and contralateral recruitment curves for each lower limb. The slope of these recruitment curves was used to examine the strength of functional connectivity from the motor cortex in each hemisphere to the lower limbs in chronic stroke patients and to calculate a ratio between ipsilateral and contralateral outputs referred to as the functional connectivity ratio (FCR). The structural integrity of the CST was assessed using diffusion tensor MRI to measure the asymmetry in fractional anisotropy (FA) of the internal capsule. Lower limb impairment and walking speed were also measured.
The FCR for the paretic leg correlated with walking impairment, such that greater relative ipsilateral connectivity was associated with slower walking speeds. Asymmetrical FA values, reflecting reduced structural integrity of the lesioned CST, were associated with greater walking impairment. FCR and FA asymmetry were strongly positively correlated with each other.
Patients with relatively greater ipsilateral connectivity between the contralesional motor cortex and the paretic lower limb were more behaviorally impaired and had more structural damage to their ipsilesional hemisphere CST.
Measures of structural and functional damage may be useful in the selection of therapeutic strategies, allowing for more tailored and potentially more beneficial treatments.
PMCID: PMC3778984  PMID: 22717679
CST, corticospinal tract; DTI, diffusion tensor imaging; FA, fractional anisotropy; FCR, functional connectivity ratio; M1, primary motor cortex; TMS, transcranial magnetic stimulation; VL, vastus lateralis; Stroke; Locomotion; Motor recovery; TMS; DTI
9.  A combined post-mortem magnetic resonance imaging and quantitative histological study of multiple sclerosis pathology 
Brain  2012;135(10):2938-2951.
Multiple sclerosis is a chronic inflammatory neurological condition characterized by focal and diffuse neurodegeneration and demyelination throughout the central nervous system. Factors influencing the progression of pathology are poorly understood. One hypothesis is that anatomical connectivity influences the spread of neurodegeneration. This predicts that measures of neurodegeneration will correlate most strongly between interconnected structures. However, such patterns have been difficult to quantify through post-mortem neuropathology or in vivo scanning alone. In this study, we used the complementary approaches of whole brain post-mortem magnetic resonance imaging and quantitative histology to assess patterns of multiple sclerosis pathology. Two thalamo-cortical projection systems were considered based on their distinct neuroanatomy and their documented involvement in multiple sclerosis: lateral geniculate nucleus to primary visual cortex and mediodorsal nucleus of the thalamus to prefrontal cortex. Within the anatomically distinct thalamo-cortical projection systems, magnetic resonance imaging derived cortical thickness was correlated significantly with both a measure of myelination in the connected tract and a measure of connected thalamic nucleus cell density. Such correlations did not exist between these markers of neurodegeneration across different thalamo-cortical systems. Magnetic resonance imaging lesion analysis depicted clearly demarcated subcortical lesions impinging on the white matter tracts of interest; however, quantitation of the extent of lesion-tract overlap failed to demonstrate any appreciable association with the severity of markers of diffuse pathology within each thalamo-cortical projection system. Diffusion-weighted magnetic resonance imaging metrics in both white matter tracts were correlated significantly with a histologically derived measure of tract myelination. These data demonstrate for the first time the relevance of functional anatomical connectivity to the spread of multiple sclerosis pathology in a ‘tract-specific’ pattern. Furthermore, the persisting relationship between metrics from post-mortem diffusion-weighted magnetic resonance imaging and histological measures from fixed tissue further validates the potential of imaging for future neuropathological studies.
PMCID: PMC3470716  PMID: 23065787
multiple sclerosis; post-mortem imaging; diffusion imaging; white matter tracts; neurodegeneration
10.  Diffusion imaging of whole, post-mortem human brains on a clinical MRI scanner 
Neuroimage  2011;57(1-4):167-181.
Diffusion imaging of post mortem brains has great potential both as a reference for brain specimens that undergo sectioning, and as a link between in vivo diffusion studies and “gold standard” histology/dissection. While there is a relatively mature literature on post mortem diffusion imaging of animals, human brains have proven more challenging due to their incompatibility with high-performance scanners. This study presents a method for post mortem diffusion imaging of whole, human brains using a clinical 3-Tesla scanner with a 3D segmented EPI spin-echo sequence. Results in eleven brains at 0.94 × 0.94 × 0.94 mm resolution are presented, and in a single brain at 0.73 × 0.73 × 0.73 mm resolution. Region-of-interest analysis of diffusion tensor parameters indicate that these properties are altered compared to in vivo (reduced diffusivity and anisotropy), with significant dependence on post mortem interval (time from death to fixation). Despite these alterations, diffusion tractography of several major tracts is successfully demonstrated at both resolutions. We also report novel findings of cortical anisotropy and partial volume effects.
Research highlights
► Acquisition and processing protocols for diffusion MRI of post-mortem human brains. ► Effect of post-mortem and scan intervals on diffusion indices. ► Tractography in post-mortem human brains. ► Radial diffusion anisotropy in cortical gray matter.
PMCID: PMC3115068  PMID: 21473920
Diffusion tensor imaging; Tractography; Post mortem; Human; Brain
11.  The Role of GABA in Human Motor Learning 
Current Biology  2011;21(6):480-484.
GABA modification plays an important role in motor cortical plasticity [1–4]. We therefore hypothesized that interindividual variation in the responsiveness of the GABA system to modification influences learning capacity in healthy adults. We assessed GABA responsiveness by transcranial direct current stimulation (tDCS), an intervention known to decrease GABA [5, 6]. The magnitude of M1 GABA decrease induced by anodal tDCS correlated positively with both the degree of motor learning and the degree of fMRI signal change within the left M1 during learning. This study therefore suggests that the responsiveness of the GABAergic system to modification may be relevant to short-term motor learning behavior and learning-related brain activity.
► Change in GABA due to transcranial stimulation correlates with motor learning behavior ► GABA change also correlates with localized fMRI responses during short-term learning ► No correlations are found for these measures with GABA levels in visual cortex
PMCID: PMC3063350  PMID: 21376596
12.  Relevance of Structural Brain Connectivity to Learning and Recovery from Stroke 
The physical structure of white matter fiber bundles constrains their function. Any behavior that relies on transmission of signals along a particular pathway will therefore be influenced by the structural condition of that pathway. Diffusion-weighted magnetic resonance imaging provides localized measures that are sensitive to white matter microstructure. In this review, we discuss imaging evidence on the relevance of white matter microstructure to behavior. We focus in particular on motor behavior and learning in healthy individuals and in individuals who have suffered a stroke. We provide examples of ways in which imaging measures of structural brain connectivity can inform our study of motor behavior and effects of motor training in three different domains: (1) to assess network degeneration or damage with healthy aging and following stroke, (2) to identify a structural basis for individual differences in behavioral responses, and (3) to test for dynamic changes in structural connectivity with learning or recovery.
PMCID: PMC2990506  PMID: 21119774
MRI; diffusion imaging; white matter; stroke; recovery; motor learning; human

Results 1-12 (12)