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.

Aerobic activity is a powerful stimulus for improving mental health and for generating structural changes in the brain. We review the literature documenting these structural changes and explore exactly where in the brain these changes occur as well as the underlying substrates of the changes including neural, glial, and vasculature components. Aerobic activity has been shown to produce different types of changes in the brain. The presence of novel experiences or learning is an especially important component in how these changes are manifest. We also discuss the distinct time courses of structural brain changes with both aerobic activity and learning as well as how these effects might differ in diseased and elderly groups.

The brain regions functionally engaged in motor sequence performance are well-established, but the structural characteristics of these regions and the fiber pathways involved have been less well studied. In addition, relatively few studies have combined multiple magnetic resonance imaging (MRI) and behavioral performance measures in the same sample. Therefore, the current study used diffusion tensor imaging (DTI), probabilistic tractography, and voxel-based morphometry (VBM) to determine the structural correlates of skilled motor performance. Further, we compared these findings with fMRI results in the same sample. We correlated final performance and rate of improvement measures on a temporal motor sequence task (TMST) with skeletonized fractional anisotropy (FA) and whole brain gray matter (GM) volume. Final synchronization performance was negatively correlated with FA in white matter (WM) underlying bilateral sensorimotor cortex—an effect that was mediated by a positive correlation with radial diffusivity. Multi-fiber tractography indicated that this region contained crossing fibers from the corticospinal tract (CST) and superior longitudinal fasciculus (SLF). The identified SLF pathway linked parietal and auditory cortical regions that have been shown to be functionally engaged in this task. Thus, we hypothesize that enhanced synchronization performance on this task may be related to greater fiber integrity of the SLF. Rate of improvement on synchronization was positively correlated with GM volume in cerebellar lobules HVI and V—regions that showed training-related decreases in activity in the same sample. Taken together, our results link individual differences in brain structure and function to motor sequence performance on the same task. Further, our study illustrates the utility of using multiple MR measures and analysis techniques to specify the interpretation of structural findings.

Transcranial direct current stimulation, a form of non-invasive brain stimulation, is showing increasing promise as an adjunct therapy in rehabilitation following stroke. However, although significant behavioural improvements have been reported in proof-of-principle studies, the underlying mechanisms are poorly understood. The rationale for transcranial direct current stimulation as therapy for stroke is that therapeutic stimulation paradigms increase activity in ipsilesional motor cortical areas, but this has not previously been directly tested for conventional electrode placements. This study was performed to test directly whether increases in ipsilesional cortical activation with transcranial direct current stimulation are associated with behavioural improvements in chronic stroke patients. Patients at least 6 months post-first stroke participated in a behavioural experiment (n = 13) or a functional magnetic resonance imaging experiment (n = 11), each investigating the effects of three stimulation conditions in separate sessions: anodal stimulation to the ipsilesional hemisphere; cathodal stimulation to the contralesional hemisphere; and sham stimulation. Anodal (facilitatory) stimulation to the ipsilesional hemisphere led to significant improvements (5–10%) in response times with the affected hand in both experiments. This improvement was associated with an increase in movement-related cortical activity in the stimulated primary motor cortex and functionally interconnected regions. Cathodal (inhibitory) stimulation to the contralesional hemisphere led to a functional improvement only when compared with sham stimulation. We show for the first time that the significant behavioural improvements produced by anodal stimulation to the ipsilesional hemisphere are associated with a functionally relevant increase in activity within the ipsilesional primary motor cortex in patients with a wide range of disabilities following stroke.

The feeling of “body ownership” may be experimentally investigated by perceptual illusions. The “rubber hand illusion” (RHI) leads human subjects to experience an artificial hand as their own. According to functional imaging, the ventral premotor cortex (PMv) plays a key role in the integration of multisensory inputs allowing the “incorporation” of the rubber hand into body representation. However, causal structure–function relationships can only be obtained by lesion studies.

Here, we tested the RHI in 70 stroke patients and in 40 age-matched healthy controls. Additionally, asomatognosia, the unawareness of one’s own body parts, was assessed in a subgroup of 64 stroke patients. Ischemic lesions were delineated on diffusion-weighted magnetic resonance images and normalized. Right-hemispheric lesions were mirrored across the midline. Voxels that might be essential for RHI and/or somatognosia were defined by voxel-based lesion-symptom mapping. Probabilistic diffusion tractography was used to identify tracts passing through these voxels.

Contralesional rubber hand illusion failure (RHIF) was observed in 18 (26%) of 70 stroke patients, an additional ipsilesional RHIF in seven of these patients. RHIF-associated lesion voxels were located subcortically adjacent to the insula, basal ganglia, and within the periventricular white matter. Tractography revealed fiber tract connections of these voxels with premotor, parietal, and prefrontal cortex. Contralesional asomatognosia was found in 18 (28%) of 64 stroke patients. In contrast to RHIF, asomatognosia-associated lesion voxels showed no connection with PMv.

The results point to a role of PMv and its connections in mediating changes in the sense of limb ownership driven by multisensory stimulation.

Despite the prominence of parietal activity in human neuromaging investigations of sensorimotor and cognitive processes there remains uncertainty about basic aspects of parietal cortical anatomical organization. Descriptions of human parietal cortex draw heavily on anatomical schemes developed in other primate species but the validity of such comparisons has been questioned by claims that there are fundamental differences between the parietal cortex in humans and other primates. A scheme is presented for parcellation of human lateral parietal cortex into component regions on the basis of anatomical connectivity and the functional interactions of the resulting clusters with other brain regions. Anatomical connectivity was estimated using diffusion-weighted magnetic resonance image (MRI) based tractography and functional interactions were assessed by correlations in activity measured with functional MRI (fMRI) at rest. Resting state functional connectivity was also assessed directly in the rhesus macaque lateral parietal cortex in an additional experiment and the patterns found reflected known neuroanatomical connections. Cross-correlation in the tractography-based connectivity patterns of parietal voxels reliably parcellated human lateral parietal cortex into ten component clusters. The resting state functional connectivity of human superior parietal and intraparietal clusters with frontal and extrastriate cortex suggested correspondences with areas in macaque superior and intraparietal sulcus. Functional connectivity patterns with parahippocampal cortex and premotor cortex again suggested fundamental correspondences between inferior parietal cortex in humans and macaques. In contrast, the human parietal cortex differs in the strength of its interactions between the central inferior parietal lobule region and the anterior prefrontal cortex.

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.

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.

Purpose of review

Diffusion tractography uses non-invasive brain imaging data to trace fibre bundles in the human brain in vivo. This raises immediate possibilities for clinical application but responsible use of this approach requires careful consideration of the scope and limitations of the technique.

Recent findings

To illustrate the potential for tractography to provide new information in clinical neuroscience we review recent studies in three broad areas: First, use of tractography for quantitative comparisons of specific white matter pathways in disease; second, evidence from tractography for the presence of qualitatively different pathways in congenital disorders or following recovery; third, use of tractography to gain insights into normal brain anatomy that can aid our understanding of the consequences of localised pathology, or guide interventions.

Summary

Diffusion tractography opens exciting new possibilities for exploring features of brain anatomy that previously were not visible to us in vivo.

Variation in brain structure may reflect variation in functional properties of specific brain systems. Structural variation may therefore reflect variation in behavioural performance. Here, we use diffusion-weighted magnetic resonance imaging to show that variation in white matter integrity in a specific region in the body of the corpus callosum is associated with variation in performance of a bimanual co-ordination task. When the callosal region showing this association is used as a seed for probabilistic tractography, inter-hemispheric pathways are generated to the supplementary motor area and caudal cingulate motor area. This provides further evidence for the role of medial wall motor areas in bimanual co-ordination and supports the idea that variation in brain structure reflects inter-individual differences in skilled performance.

The cerebellum processes information from functionally diverse regions of the cerebral cortex. Cerebellar input and output nuclei have connections with prefrontal, parietal, and sensory cortex as well as motor and premotor cortex. However, the topography of the connections between the cerebellar and cerebral cortices remains largely unmapped, as it is relatively unamenable to anatomical methods. We used resting-state functional magnetic resonance imaging to define subregions within the cerebellar cortex based on their functional connectivity with the cerebral cortex. We mapped resting-state functional connectivity voxel-wise across the cerebellar cortex, for cerebral–cortical masks covering prefrontal, motor, somatosensory, posterior parietal, visual, and auditory cortices. We found that the cerebellum can be divided into at least 2 zones: 1) a primary sensorimotor zone (Lobules V, VI, and VIII), which contains overlapping functional connectivity maps for domain-specific motor, somatosensory, visual, and auditory cortices; and 2) a supramodal zone (Lobules VIIa, Crus I, and II), which contains overlapping functional connectivity maps for prefrontal and posterior-parietal cortex. The cortical connectivity of the supramodal zone was driven by regions of frontal and parietal cortex which are not directly involved in sensory or motor processing, including dorsolateral prefrontal cortex and the frontal pole, and the inferior parietal lobule.

Summary

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.

Highlights

► 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

Normal ageing is associated with gradual brain atrophy. Determining spatial and temporal patterns of change can help shed light on underlying mechanisms. Neuroimaging provides various measures of brain structure that can be used to assess such age-related change but studies to date have typically considered single imaging measures. Although there is consensus on the notion that brain structure deteriorates with age, evidence on the precise time course and spatial distribution of changes is mixed. We assessed grey matter (GM) and white matter (WM) structure in a group of 66 adults aged between 23 and 81. Multimodal imaging measures included voxel-based morphometry (VBM)-style analysis of GM and WM volume and diffusion tensor imaging (DTI) metrics of WM microstructure. We found widespread reductions in GM volume from middle age onwards but earlier reductions in GM were detected in frontal cortex. Widespread age-related deterioration in WM microstructure was detected from young adulthood onwards. WM decline was detected earlier and more sensitively using DTI-based measures of microstructure than using markers of WM volume derived from conventional T1-weighted imaging.

Studies in monkeys show clear anatomical and functional distinctions among networks connecting with subregions within the prefrontal cortex. Three such networks are centered on lateral orbitofrontal cortex, medial frontal and cingulate cortex, and lateral prefrontal cortex and all have been identified with distinct cognitive roles. Although these areas differ in a number of their cortical connections, some of the first anatomical evidence for these networks came from tracer studies demonstrating their distinct patterns of connectivity with the mediodorsal (MD) nucleus of the thalamus. Here, we present evidence for a similar topography of MD thalamus prefrontal connections, using non-invasive imaging and diffusion tractography (DWI–DT) in human and macaque. DWI–DT suggested that there was a high probability of interconnection between medial MD and lateral orbitofrontal cortex, between caudodorsal MD and medial frontal/cingulate cortex, and between lateral MD and lateral prefrontal cortex, in both species. Within the lateral prefrontal cortex a dorsolateral region (the principal sulcus in the macaque and middle frontal gyrus in the human) was found to have a high probability of interconnection with the MD region between the regions with a high probability of interconnection with other parts of the lateral prefrontal cortex and with the lateral orbitofrontal cortex. In addition to suggesting that the thalamic connectivity in the macaque is a good guide to human prefrontal cortex, and therefore that there are likely to be similarities in the cognitive roles played by the prefrontal areas in both species, the present results are also the first to provide insight into the topography of projections of an individual thalamic nucleus in the human brain.

The fornix is the main tract between the medial temporal lobe (MTL) and medial diencephalon, both of which are critical for episodic memory. The precise involvement of the fornix in memory, however, has been difficult to ascertain since damage to this tract in human amnesics is invariably accompanied by atrophy to surrounding structures. We used diffusion-weighted imaging to investigate whether individual differences in fornix white matter microstructure in neurologically healthy participants were related to differences in memory as assessed by two recognition tasks. Higher microstructural integrity in the fornix tail was found to be associated with significantly better recollection memory. In contrast, there was no significant correlation between fornix microstructure and familiarity memory or performance on two non-mnemonic tasks. Our findings support the idea that there are distinct MTL-diencephalon pathways that subserve differing memory processes.

Although experience-dependent structural changes have been demonstrated in adult gray matter, there is little evidence for such changes in white matter. Using diffusion imaging, we detected a localised increase in fractional anisotropy, a measure of microstructure, in white matter underlying the intraparietal sulcus, following training of a complex visuo-motor skill. This provides the first evidence for training related changes in white matter structure in the healthy human adult brain.

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.

To achieve greater understanding of the brain mechanisms underlying nicotine craving in female smokers, we examined the influence of nicotine non-abstinence vs. acute nicotine abstinence on cue-elicited activation of the ventral striatum. Eight female smokers underwent an event-related functional magnetic resonance imaging (fMRI) paradigm presenting randomized sequences of smoking-related and non-smoking related pictures. Participants were asked to indicate by a key press the gender of individuals in smoking-related and non-smoking related pictures (gender discrimination task), to maintain and evaluate attention to the pictures. There was a significant effect of smoking condition on reaction times (RT) for a gender discrimination task intended to assess and maintain attention to the photographs—suggesting a deprivation effect of acute nicotine abstinence and a statistical trend indicating greater RTs for smoking cues than neutral cues. BOLD contrast (smoking vs. non-smoking cues) was greater in the non-abstinent vs. acutely abstinent conditions in the ventral striatum including the nucleus accumbens (VS/NAc). Moreover, a significant positive correlation was observed between baseline cigarette craving prior to scanning and VS/NAc activation (r=0.84, p=0.009), but only in the non-abstinent condition. These results may either be explained by ceiling effects of nicotine withdrawal in the abstinent condition or, may indicate reduced relative activation (smoking vs. neutral contrast) in the VS/NAc in the abstinent vs. non-abstinent conditions in this group of female smokers.