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1.  The NMDA receptor partial agonist d-cycloserine does not enhance motor learning 
Rationale:
There has recently been increasing interest in pharmacological manipulations that could potentially enhance exposure-based cognitive behaviour therapy for anxiety disorders. One such medication is the partial NMDA agonist d-cycloserine. It has been suggested that d-cycloserine enhances cognitive behaviour therapy by making learning faster. While animal studies have supported this view of the drug accelerating learning, evidence in human studies has been mixed. We therefore designed an experiment to measure the effects of d-cycloserine on human motor learning.
Methods:
Fifty-four healthy human volunteers were randomly assigned to a single dose of 250mg d-cycloserine versus placebo in a double-blind design. They then performed a motor sequence learning task.
Results:
D-cycloserine did not increase the speed of motor learning or the overall amount learnt. However, we noted that participants on d-cycloserine tended to respond more carefully (shifting towards slower, but more correct responses).
Conclusion:
The results suggest that d-cycloserine does not exert beneficial effects on psychological treatments via mechanisms involved in motor learning. Further studies are needed to clarify the influence on other cognitive mechanisms.
doi:10.1177/0269881116658988
PMCID: PMC5066480  PMID: 27436230
NMDA; motor learning; d-cycloserine
2.  Revealing the neural fingerprints of a missing hand 
eLife  null;5:e15292.
The hand area of the primary somatosensory cortex contains detailed finger topography, thought to be shaped and maintained by daily life experience. Here we utilise phantom sensations and ultra high-field neuroimaging to uncover preserved, though latent, representation of amputees’ missing hand. We show that representation of the missing hand’s individual fingers persists in the primary somatosensory cortex even decades after arm amputation. By demonstrating stable topography despite amputation, our finding questions the extent to which continued sensory input is necessary to maintain organisation in sensory cortex, thereby reopening the question what happens to a cortical territory once its main input is lost. The discovery of persistent digit topography of amputees’ missing hand could be exploited for the development of intuitive and fine-grained control of neuroprosthetics, requiring neural signals of individual digits.
DOI: http://dx.doi.org/10.7554/eLife.15292.001
eLife digest
The brain has a remarkable ability to adapt to changes in circumstances. But what happens to the brain when it loses a key source of input, for example, following the amputation of a limb? A region of the brain known as primary somatosensory cortex processes sensory inputs from all over the body. The more sensitive an area of the body is, the more fine-grained its representation is in the cortex. For example, the hand is represented with a highly detailed map, with each finger represented seperately.
The brain is thought to require ongoing sensory signals from the body to maintain these detailed representations in the cortex. Indeed, textbooks typically state that the brain will ‘overwrite’ its representation of a body part if input from that area no longer arrives. According to this view, people who have lost a hand should show little or no activity in the area of primary somatosensory cortex that used to represent it.
However, many people who have had a limb amputated continue to experience vivid sensations of the missing limb long after its loss. When asked to move their so-called ‘phantom’ limb, these individuals report being able to feel the movement. Kikkert, Kolasinski et al. now show, using advanced imaging techniques, that the brains of individuals with phantom hands continue to represent the missing hand several decades after its loss. Indeed, asking the subjects to move individual fingers of their phantom hand activates fine-grained representations of those fingers, similar to those seen in two-handed controls.
By showing that the brain ‘remembers’ an amputated hand, Kikkert, Kolasinski et al. demonstrate that ongoing sensory input is not required to maintain representations of the body in somatosensory cortex. This, in turn, offers new hope for developing prosthetic limbs that are under direct brain control. If the brain continues to represent individual fingers many years after their loss, it should be possible to exploit those pathways to achieve intuitive fine-grained control of artificial fingers.
DOI: http://dx.doi.org/10.7554/eLife.15292.002
doi:10.7554/eLife.15292
PMCID: PMC5040556  PMID: 27552053
plasticity; somatotopy; motor control; sensory deprivation; functional MRI; Human
3.  Grey matter abnormalities in methcathinone abusers with a Parkinsonian syndrome 
Brain and Behavior  2016;6(11):e00539.
Abstract
Background
A permanent Parkinsonian syndrome occurs in intravenous abusers of the designer psychostimulant methcathinone (ephedrone). It is attributed to deposition of contaminant manganese, as reflected by characteristic globus pallidus hyperintensity on T1‐weighted MRI.
Methods
We have investigated brain structure and function in methcathinone abusers (n = 12) compared to matched control subjects (n = 12) using T1‐weighted structural and resting‐state functional MRI.
Results
Segmentation analysis revealed significant (p < .05) subcortical grey matter atrophy in methcathinone abusers within putamen and thalamus bilaterally, and the left caudate nucleus. The volume of the caudate nuclei correlated inversely with duration of methcathinone abuse. Voxel‐based morphometry showed patients to have significant grey matter loss (p < .05) bilaterally in the putamina and caudate nucleus. Surface‐based analysis demonstrated nine clusters of cerebral cortical thinning in methcathinone abusers, with relative sparing of prefrontal, parieto‐occipital, and temporal regions. Resting‐state functional MRI analysis showed increased functional connectivity within the motor network of patients (p < .05), particularly within the right primary motor cortex.
Conclusion
Taken together, these results suggest that the manganese exposure associated with prolonged methcathinone abuse results in widespread structural and functional changes affecting both subcortical and cortical grey matter and their connections. Underlying the distinctive movement disorder caused by methcathinone abuse, there is a more widespread pattern of brain involvement than is evident from the hyperintensity restricted to the basal ganglia as shown by T1‐weighted structural MRI.
doi:10.1002/brb3.539
PMCID: PMC5102639  PMID: 27843694
ephedrone; manganese toxicity; methcathinone; MRI; Parkinsonism
4.  Multi-modal characterization of rapid anterior hippocampal volume increase associated with aerobic exercise 
NeuroImage  2015;131:162-170.
The hippocampus has been shown to demonstrate a remarkable degree of plasticity in response to a variety of tasks and experiences. For example, the size of the human hippocampus has been shown to increase in response to aerobic exercise. However, it is currently unknown what underlies these changes. Here we scanned sedentary, young to middle-aged human adults before and after a six-week exercise intervention using nine different neuroimaging measures of brain structure, vasculature, and diffusion. We then tested two different hypotheses regarding the nature of the underlying changes in the tissue. Surprisingly, we found no evidence of a vascular change as has been previously reported. Rather, the pattern of changes is better explained by an increase in myelination. Finally, we show hippocampal volume increase is temporary, returning to baseline after an additional six weeks without aerobic exercise. This is the first demonstration of a change in hippocampal volume in early to middle adulthood suggesting that hippocampal volume is modulated by aerobic exercise throughout the lifespan rather than only in the presence of age related atrophy. It is also the first demonstration of hippocampal volume change over a period of only six weeks, suggesting gross morphometric hippocampal plasticity occurs faster than previously thought.
doi:10.1016/j.neuroimage.2015.10.090
PMCID: PMC4848119  PMID: 26654786
neurogenesis; angiogenesis; dentate gyrus; hippocampus; fitness; exercise; aging; environmental enrichment; myelin; plasticity
5.  A systematic review of MRI studies examining the relationship between physical fitness and activity and the white matter of the ageing brain 
Neuroimage  2016;131:81-90.
Higher levels of physical fitness or activity (PFA) have been shown to have beneficial effects on cognitive function and grey matter volumes in older adults. However, the relationship between PFA and the brain's white matter (WM) is not yet well established. Here, we aim to provide a comprehensive and systematic review of magnetic resonance imaging studies examining the effects of PFA on the WM of the ageing brain. Twenty-nine studies were included in the review: eleven examined WM volume, fourteen WM lesions, and nine WM microstructure. While many studies found that higher levels of PFA were associated with greater WM volumes, reduced volume or severity of WM lesions, or improved measures of WM microstructure, a number of negative findings have also been published. Meta-analyses of global measures of WM volume and WM lesion volume yielded significant, but small, effect sizes. Overall, we found evidence for cautious support of links between PFA and WM structure, and highlighted key areas for future research including the extent to which the relationship between PFA and WM structure is anatomically specific, the influence of possible confounding factors, and the relationship between PFA, WM and cognition.
Highlights
•We review MRI studies of PFA and the WM of the ageing brain.•Higher levels of PFA were often associated with improved WM outcomes.•Meta-analyses yielded significant, but small, effect sizes.
doi:10.1016/j.neuroimage.2015.09.071
PMCID: PMC4851455  PMID: 26477656
Ageing; Fitness; Magnetic resonance imaging; Physical activity; Review; White matter
6.  Investigating the Stability of Fine-Grain Digit Somatotopy in Individual Human Participants 
The Journal of Neuroscience  2016;36(4):1113-1127.
Studies of human primary somatosensory cortex (S1) have placed a strong emphasis on the cortical representation of the hand and the propensity for plasticity therein. Despite many reports of group differences and experience-dependent changes in cortical digit somatotopy, relatively little work has considered the variability of these maps across individuals and to what extent this detailed functional architecture is dynamic over time. With the advent of 7 T fMRI, it is increasingly feasible to map such detailed organization noninvasively in individual human participants. Here, we extend the ability of ultra-high-field imaging beyond a technological proof of principle to investigate the intersubject variability of digit somatotopy across participants and the stability of this organization across a range of intervals. Using a well validated phase-encoding paradigm and an active task, we demonstrate the presence of highly reproducible maps of individual digits in S1, sharply contrasted by a striking degree of intersubject variability in the shape, extent, and relative position of individual digit representations. Our results demonstrate the presence of very stable fine-grain somatotopy of the digits in human S1 and raise the issue of population variability in such detailed functional architecture of the human brain. These findings have implications for the study of detailed sensorimotor plasticity in the context of both learning and pathological dysfunction. The simple task and 10 min scan required to derive these maps also raises the potential for this paradigm as a tool in the clinical setting.
SIGNIFICANCE STATEMENT We applied ultra-high-resolution fMRI at 7 T to map sensory digit representations in the human primary somatosensory cortex (S1) at the level of individual participants across multiple time points. The resulting fine-grain maps of individual digits in S1 reveal the stability in this fine-grain functional organization over time, contrasted with the variability in these maps across individuals.
doi:10.1523/JNEUROSCI.1742-15.2016
PMCID: PMC4728720  PMID: 26818501
7 T; digit; mapping; reproducibility; somatotopy
7.  Changes in white matter microstructure in the developing brain—A longitudinal diffusion tensor imaging study of children from 4 to 11 years of age 
Neuroimage  2016;124(Pt A):473-486.
The purpose of the present study was to detail the childhood developmental course of different white matter (WM) characteristics. In a longitudinal diffusion tensor imaging (DTI) study of 159 healthy children between 4 and 11 years scanned twice, we used tract-based spatial statistics as well as delineation of 15 major WM tracts to characterize the regional pattern of change in fractional anisotropy (FA), mean (MD), radial (RD) and axial diffusivity (AD). We tested whether there were decelerations of change with increasing age globally and tract-wise, and also illustrated change along medial-to-lateral, posterior-to-anterior and inferior-to-superior gradients. We found a significant linear increase in global FA, and decrease in MD and RD over time. For mean AD, a weak decrease was observed. The developmental changes in specific WM tracts showed regional differences. Eight WM tracts showed non-linear development patterns for one or several DTI metrics, with a deceleration in change with age. Sex did not affect change in any DTI metric. Overall, greater rate of change was found in the left hemisphere. Spatially, there was a posterior-to-anterior gradient of change with greater change in frontal regions for all metrics. The current study provides a comprehensive characterization of the regional patters of change in WM microstructure across pre-adolescence childhood.
Highlights
•We explore longitudinal change in white matter (WM) microstructure in children.•Using TBSS to delineate 15 WM tracts and several gradients in the brain•Global WM change show linear developmental patterns from age 4 to 11 years.•Greater WM change in the anterior compared to the posterior brain region.•The developmental patterns for WM tracts show regional differences.
doi:10.1016/j.neuroimage.2015.09.017
PMCID: PMC4655940  PMID: 26375208
WM, White matter; DTI, Diffusion tensor imaging; FA, fractional anisotropy; MD, Mean diffusivity; RD, Radial diffusivity; AD, Axial diffusivity; LCBC, Research Group for Lifespan Changes in Brain and Cognition; MoBa, Norwegian Mother and Child Cohort Study; tp1, Time point one; tp2, Time point two; MRI, Magnetic resonance imaging; CNS, Central nervous system; TR, Repetition time; TE, Echo time; GRAPPA, GeneRalized Autocalibrating Partially Parallel Acquisition; FMRIB, Oxford Centre for Functional Magnetic Resonance Imaging of the Brain; TBSS, Tract-Based Spatial Statistics; GLM, General linear model; SDR, Studentized Deleted Residuals; GAMM, General additive mixed model; JHU, Johns Hopkins University; ATR, Anterior thalamic radiation; CCG, Cingulum-cingulate gyrus; CHG, Cingulum-hippocampus gyrus; CC, corpus callosum; IFOF, Inferior fronto-occipital fasciculus; ILF, Inferior longitudinal fasciculus; SLF, Superior fronto-occipital fasciculus; SFOF, Superior fronto-occipital fasciculus; UF, Uncinate fasciculus; Development; White matter maturation; MRI; DTI; Longitudinal; Children
8.  An Ultra-High Field Magnetic Resonance Spectroscopy Study of Post Exercise Lactate, Glutamate and Glutamine Change in the Human Brain 
During strenuous exercise there is a progressive increase in lactate uptake and metabolism into the brain as workload and plasma lactate levels increase. Although it is now widely accepted that the brain can metabolize lactate, few studies have directly measured brain lactate following vigorous exercise. Here, we used ultra-high field magnetic resonance spectroscopy of the brain to obtain static measures of brain lactate, as well as brain glutamate and glutamine after vigorous exercise. The aims of our experiment were to (a) track the changes in brain lactate following recovery from exercise, and (b) to simultaneously measure the signals from brain glutamate and glutamine. The results of our experiment showed that vigorous exercise resulted in a significant increase in brain lactate. Furthermore, both glutamate and glutamine were successfully resolved, and as expected, although contrary to some previous reports, we did not observe any significant change in either amino acid after exercise. We did however observe a negative correlation between glutamate and a measure of fitness. These results support the hypothesis that peripherally derived lactate is taken up by the brain when available. Our data additionally highlight the potential of ultra-high field MRS as a non-invasive way of measuring multiple brain metabolite changes with exercise.
doi:10.3389/fphys.2015.00351
PMCID: PMC4681779  PMID: 26732236
brain; lactate; glutamate; magnetic resonance spectroscopy; exercise
9.  Transfer of tactile perceptual learning to untrained neighboring fingers reflects natural use relationships 
Journal of Neurophysiology  2015;115(3):1088-1097.
Tactile learning transfers from trained to untrained fingers in a pattern that reflects overlap between the representations of fingers in the somatosensory system (e.g., neurons with multifinger receptive fields). While physical proximity on the body is known to determine the topography of somatosensory representations, tactile coactivation is also an established organizing principle of somatosensory topography. In this study we investigated whether tactile coactivation, induced by habitual inter-finger cooperative use (use pattern), shapes inter-finger overlap. To this end, we used psychophysics to compare the transfer of tactile learning from the middle finger to its adjacent fingers. This allowed us to compare transfer to two fingers that are both physically and cortically adjacent to the middle finger but have differing use patterns. Specifically, the middle finger is used more frequently with the ring than with the index finger. We predicted this should lead to greater representational overlap between the former than the latter pair. Furthermore, this difference in overlap should be reflected in differential learning transfer from the middle to index vs. ring fingers. Subsequently, we predicted temporary learning-related changes in the middle finger's representation (e.g., cortical magnification) would cause transient interference in perceptual thresholds of the ring, but not the index, finger. Supporting this, longitudinal analysis revealed a divergence where learning transfer was fast to the index finger but relatively delayed to the ring finger. Our results support the theory that tactile coactivation patterns between digits affect their topographic relationships. Our findings emphasize how action shapes perception and somatosensory organization.
doi:10.1152/jn.00181.2015
PMCID: PMC4808091  PMID: 26631145
perceptual learning; primary somatosensory cortex; co-activation; generalization; topography
10.  Modulation of GABA and resting state functional connectivity by transcranial direct current stimulation 
eLife  null;4:e08789.
We previously demonstrated that network level functional connectivity in the human brain could be related to levels of inhibition in a major network node at baseline (Stagg et al., 2014). In this study, we build upon this finding to directly investigate the effects of perturbing M1 GABA and resting state functional connectivity using transcranial direct current stimulation (tDCS), a neuromodulatory approach that has previously been demonstrated to modulate both metrics. FMRI data and GABA levels, as assessed by Magnetic Resonance Spectroscopy, were measured before and after 20 min of 1 mA anodal or sham tDCS. In line with previous studies, baseline GABA levels were negatively correlated with the strength of functional connectivity within the resting motor network. However, although we confirm the previously reported findings that anodal tDCS reduces GABA concentration and increases functional connectivity in the stimulated motor cortex; these changes are not correlated, suggesting they may be driven by distinct underlying mechanisms.
DOI: http://dx.doi.org/10.7554/eLife.08789.001
doi:10.7554/eLife.08789
PMCID: PMC4654253  PMID: 26381352
brain stimulation; GABA; tDCS; resting state networks; functional connectivity; plasticity; human
11.  Imaging Surrogates of Disease Activity in Neuromyelitis Optica Allow Distinction from Multiple Sclerosis 
PLoS ONE  2015;10(9):e0137715.
Inflammatory demyelinating lesions of the central nervous system are a common feature of both neuromyelitis optica and multiple sclerosis. Despite this similarity, it is evident clinically that the accumulation of disability in patients with neuromyelitis optica is relapse related and that a progressive phase is very uncommon. This poses the question whether there is any pathological evidence of disease activity or neurodegeneration in neuromyelitis optica between relapses. To investigate this we conducted a longitudinal advanced MRI study of the brain and spinal cord in neuromyelitis optica patients, comparing to patients with multiple sclerosis and controls. We found both cross-sectional and longitudinal evidence of diffusely distributed neurodegenerative surrogates in the multiple sclerosis group (including thalamic atrophy, cervical cord atrophy and progressive widespread diffusion and myelin water imaging abnormalities in the normal appearing white matter) but not in those with neuromyelitis optica, where localised abnormalities in the optic radiations of those with severe visual impairment were noted. In addition, between relapses, there were no new silent brain lesions in the neuromyelitis optica group. These findings indicate that global central nervous system neurodegeneration is not a feature of neuromyelitis optica. The work also questions the theory that neurodegeneration in multiple sclerosis is a chronic sequela to prior inflammatory and demyelinating pathology, as this has not been found to be the case in neuromyelitis optica where the lesions are often more destructive.
doi:10.1371/journal.pone.0137715
PMCID: PMC4575169  PMID: 26381510
12.  The Homeostatic Interaction Between Anodal Transcranial Direct Current Stimulation and Motor Learning in Humans is Related to GABAA Activity 
Brain Stimulation  2015;8(5):898-905.
Background
The relative timing of plasticity-induction protocols is known to be crucial. For example, anodal transcranial direct current stimulation (tDCS), which increases cortical excitability and typically enhances plasticity, can impair performance if it is applied before a motor learning task. Such timing-dependent effects have been ascribed to homeostatic plasticity, but the specific synaptic site of this interaction remains unknown.
Objective
We wished to investigate the synaptic substrate, and in particular the role of inhibitory signaling, underpinning the behavioral effects of anodal tDCS in homeostatic interactions between anodal tDCS and motor learning.
Methods
We used transcranial magnetic stimulation (TMS) to investigate cortical excitability and inhibitory signaling following tDCS and motor learning. Each subject participated in four experimental sessions and data were analyzed using repeated measures ANOVAs and post-hoc t-tests as appropriate.
Results
As predicted, we found that anodal tDCS prior to the motor task decreased learning rates. This worsening of learning after tDCS was accompanied by a correlated increase in GABAA activity, as measured by TMS-assessed short interval intra-cortical inhibition (SICI).
Conclusion
This provides the first direct demonstration in humans that inhibitory synapses are the likely site for the interaction between anodal tDCS and motor learning, and further, that homeostatic plasticity at GABAA synapses has behavioral relevance in humans.
Highlights
•We investigated the homeostatic relationship between motor learning and anodal tDCS.•Anodal tDCS applied to M1 slowed learning of a subsequent motor task.•The worsening of learning after tDCS was accompanied by an GABAA activity increase.•The learning worsening and GABAA activity increase after tDCS were closely related.
doi:10.1016/j.brs.2015.04.010
PMCID: PMC4742653  PMID: 26279408
Non-invasive brain stimulation (NIBS); Motor learning; GABA; Homeostatic plasticity
13.  Network-level reorganisation of functional connectivity following arm amputation 
Neuroimage  2015;114:217-225.
One of the most striking demonstrations of plasticity in the adult human brain follows peripheral injury, such as amputation. In the primary sensorimotor cortex, arm amputation results in massive local remapping of the missing hands' cortical territory. However, little is known about the consequences of sensorimotor deprivation on global brain organisation. Here, we used resting-state fMRI to identify large-scale reorganisation beyond the primary sensorimotor cortex in arm amputees, compared with two-handed controls. Specifically, we characterised changes in functional connectivity between the cortical territory of the missing hand in the primary sensorimotor cortex (‘missing hand cortex’) and two networks of interest: the sensorimotor network, which is typically strongly associated with the hand cortex, and the default mode network (DMN), which is normally dissociated from it. Functional connectivity values between the missing hand cortex and the sensorimotor network were reduced in amputees, and connectivity was weaker in individuals amputated for longer periods. Lower levels of functional coupling between the missing hand cortex and the sensorimotor network were also associated with emerged coupling of this cortex with the DMN. Our results demonstrate that plasticity following arm amputation is not restricted to local remapping occurring within the sensorimotor homunculus of the missing hand but rather produces a cascade of cortical reorganisation at a network-level scale. These findings may provide a new framework for understanding how local deprivation following amputation could elicit complex perceptual experiences of phantom sensations, such as phantom pain.
doi:10.1016/j.neuroimage.2015.02.067
PMCID: PMC4461307  PMID: 25776216
Neuroimaging; Deprivation; Plasticity; Resting state networks; Somatosensory; Motor
14.  Ventral Striatum/Nucleus Accumbens Activation to Smoking-Related Pictorial Cues in Smokers and Nonsmokers: A Functional Magnetic Resonance Imaging Study 
Biological psychiatry  2005;58(6):488-494.
Background
Converging evidence from several theories of the development of incentive-sensitization to smoking-related environmental stimuli suggests that the ventral striatum plays an important role in the processing of smoking-related cue reactivity.
Methods
Twenty-six healthy right-handed volunteers (14 smokers and 12 nonsmoking controls) underwent functional magnetic resonance imaging (fMRI) during which neutral and smoking-related images were presented. Region of interest analyses were performed within the ventral striatum/nucleus accumbens (VS/NAc) for the contrast between smoking-related (SR) and nonsmoking related neutral (N) cues.
Results
Group activation for SR versus N cues was observed in smokers but not in nonsmokers in medial orbitofrontal cortex, superior frontal gyrus, anterior cingulate cortex, and posterior fusiform gyrus using whole-brain corrected Z thresholds and in the ventral VS/NAc using uncorrected Z-statistics (smokers Z = 3.2). Region of interest analysis of signal change within ventral VS/NAc demonstrated significantly greater activation to SR versus N cues in smokers than controls.
Conclusions
This is the first demonstration of greater VS/NAc activation in addicted smokers than nonsmokers presented with smoking-related cues using fMRI. Smokers, but not controls, demonstrated activation to SR versus N cues in a distributed reward signaling network consistent with cue reactivity studies of other drugs of abuse.
doi:10.1016/j.biopsych.2005.04.028
PMCID: PMC4439461  PMID: 16023086
Nucleus accumbens; smoking; nicotine; tobacco; cue reactivity; fMRI
15.  Accelerated Changes in White Matter Microstructure during Aging: A Longitudinal Diffusion Tensor Imaging Study 
The Journal of Neuroscience  2014;34(46):15425-15436.
It is well established that human brain white matter structure changes with aging, but the timescale and spatial distribution of this change remain uncertain. Cross-sectional diffusion tensor imaging (DTI) studies indicate that, after a period of relative stability during adulthood, there is an accelerated decline in anisotropy and increase in diffusivity values during senescence; and, spatially, results have been discussed within the context of several anatomical frameworks. However, inferring trajectories of change from cross-sectional data can be challenging; and, as yet, there have been no longitudinal reports of the timescale and spatial distribution of age-related white matter change in healthy adults across the adult lifespan. In a longitudinal DTI study of 203 adults between 20 and 84 years of age, we used tract-based spatial statistics to characterize the pattern of annual change in fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity and examined whether there was an acceleration of change with age. We found extensive and overlapping significant annual decreases in fractional anisotropy, and increases in axial diffusivity, radial diffusivity, and mean diffusivity. Spatially, results were consistent with inferior-to-superior gradients of lesser-to-greater vulnerability. Annual change increased with age, particularly within superior regions, with age-related decline estimated to begin in the fifth decade. Charting white matter microstructural changes in healthy aging provides essential context to clinical studies, and future studies should compare age trajectories between healthy participants and at-risk populations and also explore the relationship between DTI rates of change and cognitive decline.
doi:10.1523/JNEUROSCI.0203-14.2014
PMCID: PMC4228140  PMID: 25392509
aging; DTI; lifespan; longitudinal; white matter
16.  A Tractography Analysis of Two Deep Brain Stimulation White Matter Targets for Depression 
Biological psychiatry  2008;65(4):276-282.
Background
Deep brain stimulation (DBS) of the subcallosal cingulate white matter (SCCwm) or anterior limb of the internal capsule (ALIC) may be effective in treating depression. Connectivity patterns of these regions may inform on mechanisms of action for DBS of these targets.
Methods
Diffusion tensor imaging (DTI) and probabilistic tractography were performed in 13 nondepressed subjects to determine connectivity patterns of SCCwm and ALIC. Tract maps were generated for each target in each subject, and tract voxels were coded as being unique to either target or shared. Group level tract maps were generated by including only those voxels common to at least 10 of 13 (>75%) subjects.
Results
The two targets have distinct patterns of connectivity with regions of overlap. The SCCwm showed consistent ipsilateral connections to the medial frontal cortex, the full extent of the anterior and posterior cingulate, medial temporal lobe, dorsal medial thalamus, hypothalamus, nucleus accumbens, and the dorsal brainstem. The ALIC seed, in contrast, demonstrated widespread projections to frontal pole, medial temporal lobe, cerebellum, nucleus accumbens, thalamus, hypothalamus, and brainstem. Common to both targets, albeit through distinct white matter bundles, were connections to frontal pole, medial temporal lobe, nucleus accumbens, dorsal thalamus, and hypothalamus.
Conclusions
Connectivity patterns of these two DBS white matter targets suggest distinct neural networks with areas of overlap in regions implicated in depression and antidepressant response.
doi:10.1016/j.biopsych.2008.09.021
PMCID: PMC4423548  PMID: 19013554
DBS; deep brain stimulation; depression; diffusion tensor imaging; DTI; internal capsule; subgenual cingulate; tractography
17.  Poor sleep quality is associated with increased cortical atrophy in community-dwelling adults 
Neurology  2014;83(11):967-973.
Objective:
To examine the relationship between sleep quality and cortical and hippocampal volume and atrophy within a community-based sample, explore the influence of age on results, and assess the possible confounding effects of physical activity levels, body mass index (BMI), and blood pressure.
Methods:
In 147 community-dwelling adults (92 female; age 53.9 ± 15.5 years), sleep quality was measured using the Pittsburgh Sleep Quality Index and correlated with cross-sectional measures of volume and longitudinal measures of atrophy derived from MRI scans separated by an average of 3.5 years. Exploratory post hoc analysis compared correlations between different age groups and included physical activity, BMI, and blood pressure as additional covariates.
Results:
Poor sleep quality was associated with reduced volume within the right superior frontal cortex in cross-sectional analyses, and an increased rate of atrophy within widespread frontal, temporal, and parietal regions in longitudinal analyses. Results were largely driven by correlations within adults over the age of 60, and could not be explained by variation in physical activity, BMI, or blood pressure. Sleep quality was not associated with hippocampal volume or atrophy.
Conclusions:
We found that longitudinal measures of cortical atrophy were widely correlated with sleep quality. Poor sleep quality may be a cause or a consequence of brain atrophy, and future studies examining the effect of interventions that improve sleep quality on rates of atrophy may hold key insights into the direction of this relationship.
doi:10.1212/WNL.0000000000000774
PMCID: PMC4162301  PMID: 25186857
18.  Sleep-dependent motor memory consolidation in older adults depends on task demands 
Neurobiology of Aging  2015;36(3):1409-1416.
It is often suggested that sleep-dependent consolidation of motor learning is impaired in older adults. The current study challenges this view and suggests that the degree of motor consolidation seen with sleep in older age groups depends on the kinematic demands of the task. We show that, when tested with a classic sequence learning task, requiring individuated finger movements, older adults did not show sleep-dependent consolidation. By contrast, when tested with an adapted sequence learning task, in which movements were performed with the whole hand, sleep-dependent motor improvement was observed in older adults. We suggest that age-related decline in fine motor dexterity may in part be responsible for the previously described deficit in sleep-dependent motor consolidation with aging.
doi:10.1016/j.neurobiolaging.2014.12.014
PMCID: PMC4353561  PMID: 25618616
Sleep; Motor memory; Consolidation; Aging; Fine motor skill; Sequence learning
19.  Changes in functional connectivity and GABA levels with long-term motor learning 
Neuroimage  2015;106:15-20.
Learning novel motor skills alters local inhibitory circuits within primary motor cortex (M1) (Floyer-Lea et al., 2006) and changes long-range functional connectivity (Albert et al., 2009). Whether such effects occur with long-term training is less well established. In addition, the relationship between learning-related changes in functional connectivity and local inhibition, and their modulation by practice, has not previously been tested.
Here, we used resting-state functional magnetic resonance imaging (rs-fMRI) to assess functional connectivity and MR spectroscopy to quantify GABA in primary motor cortex (M1) before and after a 6 week regime of juggling practice. Participants practiced for either 30 min (high intensity group) or 15 min (low intensity group) per day. We hypothesized that different training regimes would be reflected in distinct changes in brain connectivity and local inhibition, and that correlations would be found between learning-induced changes in GABA and functional connectivity.
Performance improved significantly with practice in both groups and we found no evidence for differences in performance outcomes between the low intensity and high intensity groups. Despite the absence of behavioral differences, we found distinct patterns of brain change in the two groups: the low intensity group showed increases in functional connectivity in the motor network and decreases in GABA, whereas the high intensity group showed decreases in functional connectivity and no significant change in GABA. Changes in functional connectivity correlated with performance outcome. Learning-related changes in functional connectivity correlated with changes in GABA.
The results suggest that different training regimes are associated with distinct patterns of brain change, even when performance outcomes are comparable between practice schedules. Our results further indicate that learning-related changes in resting-state network strength in part reflect GABAergic plastic processes.
Highlights
•Long-term learning modulated functional connectivity.•Changes in functional connectivity correlated with performance outcome.•Long-term learning decreased GABA levels.•Learning-related changes in functional connectivity correlated with changes in GABA.
doi:10.1016/j.neuroimage.2014.11.032
PMCID: PMC4405007  PMID: 25463472
Plasticity; Functional connectivity; GABA; Motor learning
20.  Normalisation of brain connectivity through compensatory behaviour, despite congenital hand absence 
eLife  null;4:e04605.
Previously we showed, using task-evoked fMRI, that compensatory intact hand usage after amputation facilitates remapping of limb representations in the cortical territory of the missing hand (Makin et al., 2013a). Here we show that compensatory arm usage in individuals born without a hand (one-handers) reflects functional connectivity of spontaneous brain activity in the cortical hand region. Compared with two-handed controls, one-handers showed reduced symmetry of hand region inter-hemispheric resting-state functional connectivity and corticospinal white matter microstructure. Nevertheless, those one-handers who more frequently use their residual (handless) arm for typically bimanual daily tasks also showed more symmetrical functional connectivity of the hand region, demonstrating that adaptive behaviour drives long-range brain organisation. We therefore suggest that compensatory arm usage maintains symmetrical sensorimotor functional connectivity in one-handers. Since variability in spontaneous functional connectivity in our study reflects ecological behaviour, we propose that inter-hemispheric symmetry, typically observed in resting sensorimotor networks, depends on coordinated motor behaviour in daily life.
DOI: http://dx.doi.org/10.7554/eLife.04605.001
doi:10.7554/eLife.04605
PMCID: PMC4281879  PMID: 25562885
neuroimaging; rehabilitation; plasticity; human
21.  FAST INdiCATE Trial protocol. Clinical efficacy of functional strength training for upper limb motor recovery early after stroke: Neural correlates and prognostic indicators 
International Journal of Stroke  2013;9(2):240-245.
Rationale
Functional strength training in addition to conventional physical therapy could enhance upper limb recovery early after stroke more than movement performance therapy plus conventional physical therapy.
Aims
To determine (a) the relative clinical efficacy of conventional physical therapy combined with functional strength training and conventional physical therapy combined with movement performance therapy for upper limb recovery; (b) the neural correlates of response to conventional physical therapy combined with functional strength training and conventional physical therapy combined with movement performance therapy; (c) whether any one or combination of baseline measures predict motor improvement in response to conventional physical therapy combined with functional strength training or conventional physical therapy combined with movement performance therapy.
Design
Randomized, controlled, observer-blind trial.
Study
The sample will consist of 288 participants with upper limb paresis resulting from a stroke that occurred within the previous 60 days. All will be allocated to conventional physical therapy combined with functional strength training or conventional physical therapy combined with movement performance therapy. Functional strength training and movement performance therapy will be undertaken for up to 1·5 h/day, five-days/week for six-weeks.
Outcomes and Analysis
Measurements will be undertaken before randomization, six-weeks thereafter, and six-months after stroke. Primary efficacy outcome will be the Action Research Arm Test. Explanatory measurements will include voxel-wise estimates of brain activity during hand movement, brain white matter integrity (fractional anisotropy), and brain–muscle connectivity (e.g. latency of motor evoked potentials). The primary clinical efficacy analysis will compare treatment groups using a multilevel normal linear model adjusting for stratification variables and for which therapist administered the treatment. Effect of conventional physical therapy combined with functional strength training versus conventional physical therapy combined with movement performance therapy will be summarized using the adjusted mean difference and 95% confidence interval. To identify the neural correlates of improvement in both groups, we will investigate associations between change from baseline in clinical outcomes and each explanatory measure. To identify baseline measurements that independently predict motor improvement, we will develop a multiple regression model.
doi:10.1111/ijs.12179
PMCID: PMC4228758  PMID: 24025033
functional strength training; movement performance therapy; neuroimaging; physical therapy; rehabilitation; stroke; upper limb
22.  Function in the Human Connectome: Task-fMRI and Individual Differences in Behavior 
NeuroImage  2013;80:169-189.
The primary goal of the Human Connectome Project (HCP) is to delineate the typical patterns of structural and functional connectivity in the healthy adult human brain. However, we know that there are important individual differences in such patterns of connectivity, with evidence that this variability is associated with alterations in important cognitive and behavioral variables that affect real world function. The HCP data will be a critical stepping-off point for future studies that will examine how variation in human structural and functional connectivity play a role in adult and pediatric neurological and psychiatric disorders that account for a huge amount of public health resources. Thus, the HCP is collecting behavioral measures of a range of motor, sensory, cognitive and emotional processes that will delineate a core set of functions relevant to understanding the relationship between brain connectivity and human behavior. In addition, the HCP is using task-fMRI (tfMRI) to help delineate the relationships between individual differences in the neurobiological substrates of mental processing and both functional and structural connectivity, as well as to help characterize and validate the connectivity analyses to be conducted on the structural and functional connectivity data. This paper describes the logic and rationale behind the development of the behavioral, individual difference, and tfMRI batteries and provides preliminary data on the patterns of activation associated with each of the fMRI tasks, at both a group and individual level.
doi:10.1016/j.neuroimage.2013.05.033
PMCID: PMC4011498  PMID: 23684877
Cognitive; Emotion; Sensory and Motor Function; Individual Differences; Task-fMRI; Personality; Connectivity
23.  Glial Biology in Learning and Cognition 
Neurons are exquisitely specialized for rapid electrical transmission of signals, but some properties of glial cells, which do not communicate with electrical impulses, are well suited for participating in complex cognitive functions requiring broad spatial integration and long-term temporal regulation. Astrocytes, microglia, and oligodendrocytes all have biological properties that could influence learning and cognition. Myelination by oligodendrocytes increases conduction velocity, affecting spike timing and oscillations in neuronal activity. Astrocytes can modulate synaptic transmission and may couple multiple neurons and synapses into functional assemblies. Microglia can remove synapses in an activity-dependent manner altering neural networks. Incorporating glia into a bicellular mechanism of nervous system function may help answer long-standing questions concerning the cellular mechanisms of learning and cognition.
doi:10.1177/1073858413504465
PMCID: PMC4161624  PMID: 24122821
memory; astrocyte; microglia; oligodendrocyte; myelin; synaptic plasticity; neuron–glia interactions
24.  Gray matter volume is associated with rate of subsequent skill learning after a long term training intervention 
Neuroimage  2014;96(100):158-166.
The ability to predict learning performance from brain imaging data has implications for selecting individuals for training or rehabilitation interventions. Here, we used structural MRI to test whether baseline variations in gray matter (GM) volume correlated with subsequent performance after a long-term training of a complex whole-body task. 44 naïve participants were scanned before undertaking daily juggling practice for 6 weeks, following either a high intensity or a low intensity training regime. To assess performance across the training period participants' practice sessions were filmed. Greater GM volume in medial occipito-parietal areas at baseline correlated with steeper learning slopes. We also tested whether practice time or performance outcomes modulated the degree of structural brain change detected between the baseline scan and additional scans performed immediately after training and following a further 4 weeks without training. Participants with better performance had higher increases in GM volume during the period following training (i.e., between scans 2 and 3) in dorsal parietal cortex and M1. When contrasting brain changes between the practice intensity groups, we did not find any straightforward effects of practice time though practice modulated the relationship between performance and GM volume change in dorsolateral prefrontal cortex. These results suggest that practice time and performance modulate the degree of structural brain change evoked by long-term training regimes.
Highlights
•Inter-individual differences in brain structure correlate with subsequent performance outcome.•Performance outcome plays an important role in positive structural brain change.•Performance outcome and amount of practice modulate structural brain change.
doi:10.1016/j.neuroimage.2014.03.056
PMCID: PMC4075341  PMID: 24680712
Structural plasticity; Skill learning; MRI
25.  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.
DOI: http://dx.doi.org/10.7554/eLife.01465.001
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.
DOI: http://dx.doi.org/10.7554/eLife.01465.002
doi:10.7554/eLife.01465
PMCID: PMC3964822  PMID: 24668166
magnetic resonance spectroscopy; GABA; resting state fMRI; human

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