Structural covariance of brain region volumes is associated with both structural connectivity and transcriptomic similarity.

An organizational pattern seen in the brain, termed structural covariance, is the statistical association of pairs of brain regions in their anatomical properties. These associations, measured across a population as covariances or correlations usually in cortical thickness or volume, are thought to reflect genetic and environmental underpinnings. Here, we examine the biological basis of structural volume covariance in the mouse brain. We first examined large scale associations between brain region volumes using an atlas-based approach that parcellated the entire mouse brain into 318 regions over which correlations in volume were assessed, for volumes obtained from 153 mouse brain images via high-resolution MRI. We then used a seed-based approach and determined, for 108 different seed regions across the brain and using mouse gene expression and connectivity data from the Allen Institute for Brain Science, the variation in structural covariance data that could be explained by distance to seed, transcriptomic similarity to seed, and connectivity to seed. We found that overall, correlations in structure volumes hierarchically clustered into distinct anatomical systems, similar to findings from other studies and similar to other types of networks in the brain, including structural connectivity and transcriptomic similarity networks. Across seeds, this structural covariance was significantly explained by distance (17% of the variation, up to a maximum of 49% for structural covariance to the visceral area of the cortex), transcriptomic similarity (13% of the variation, up to maximum of 28% for structural covariance to the primary visual area) and connectivity (15% of the variation, up to a maximum of 36% for structural covariance to the intermediate reticular nucleus in the medulla) of covarying structures. Together, distance, connectivity, and transcriptomic similarity explained 37% of structural covariance, up to a maximum of 63% for structural covariance to the visceral area. Additionally, this pattern of explained variation differed spatially across the brain, with transcriptomic similarity playing a larger role in the cortex than subcortex, while connectivity explains structural covariance best in parts of the cortex, midbrain, and hindbrain. These results suggest that both gene expression and connectivity underlie structural volume covariance, albeit to different extents depending on brain region, and this relationship is modulated by distance.

Variability of brain anatomy for three common mouse strains.

The way in which brain structures express different morphologies is not fully understood. Here we investigate variability in brain anatomy using ex vivo MRI of three common laboratory mouse strains: in two inbred strains (C57BL/6 and 129S6) and one outbred strain (CD-1). We use Generalised Procrustes Analysis (GPA) to estimate modes of anatomical variability. We find three distinct bilateral modes of anatomical surface variability associated with the motor cortex, the anterior somatosensory, the retrosplenial and the entorhinal cortex. The modes of variability that are associated with the motor cortex and anterior somatosensory cortex are predominantly due to genetic, i.e. strain differences. Next, we specifically test if a particular strain is more variable. We find that only the mode associated with motor cortex size has a slightly larger variance in the outbred CD-1 mice compared to the two inbred strains. This suggests that the hypothesis that outbred strains are more variable in general is not true for brain anatomy and the use of outbred CD-1 mice does probably not come at the price of increased variability. Further, we show that the first two principal components distinguish between the three strains with 91% accuracy. This indicates that neuroanatomical strain differences are captured by considerably fewer dimensions than necessary for atlas-based or voxel-wise testing. Statistical comparisons based on shape models could thus be a powerful complement to traditional atlas and voxel-based methods at detecting gene-related brain differences in mice. Finally, we find that the principal components of individual brain structures are correlated, suggesting a tightly coupled network of interdependent developmental trajectories. These results raise the question to what degree neuroanatomical variability is directly genetically determined or the result of experience and epigenetic mechanisms.

Reassessing cortical reorganization in the primary sensorimotor cortex following arm amputation.

The role of cortical activity in generating and abolishing chronic pain is increasingly emphasized in the clinical community. Perhaps the most striking example of this is the maladaptive plasticity theory, according to which phantom pain arises from remapping of cortically neighbouring representations (lower face) into the territory of the missing hand following amputation. This theory has been extended to a wide range of chronic pain conditions, such as complex regional pain syndrome. Yet, despite its growing popularity, the evidence to support the maladaptive plasticity theory is largely based on correlations between pain ratings and oftentimes crude measurements of cortical reorganization, with little consideration of potential contributions of other clinical factors, such as adaptive behaviour, in driving the identified brain plasticity. Here, we used a physiologically meaningful measurement of cortical reorganization to reassess its relationship to phantom pain in upper limb amputees. We identified small yet consistent shifts in lip representation contralateral to the missing hand towards, but not invading, the hand area. However, we were unable to identify any statistical relationship between cortical reorganization and phantom sensations or pain either with this measurement or with the traditional Euclidian distance measurement. Instead, we demonstrate that other factors may contribute to the observed remapping. Further research that reassesses more broadly the relationship between cortical reorganization and chronic pain is warranted.

Rotarod training in mice is associated with changes in brain structure observable with multimodal MRI.

The brain has been shown to remain structurally plastic even throughout adulthood. However, little is known how motor-skill training affects different MRI modalities in the adult mouse brain. The aim of this study is to investigate whether rotarod training, a simple motor training task taken from the standard test battery, is associated with structural plasticity observable with different MRI modalities in adult C57BL/6 mice. The rotarod is a standard test that taxes motor coordination and balance. We use T2-weighted MRI followed by deformation-based morphometry to assess local volume and fractional anisotropy (FA) derived from diffusion MRI to assess microstructure ex-vivo. Using deformation-based morphometry we found that the hippocampus, frontal cortex and amygdala are larger in rotarod-trained mice compared to untrained controls. Surprisingly, the cerebellum and white matter in the corpus callosum underlying the primary motor cortex are smaller after training. We also found that the volume of the motor cortex is positively correlated with better rotarod performance. Diffusion imaging indicates group differences and behavioral correlations with FA, a measure of microstructure. Trained mice have higher FA in the hippocampus. Better rotarod performance is associated with higher FA in the hippocampus and lower FA in the primary visual cortex. This is the first study to reveal the substantial structural reorganization of the adult mouse brain following only a relatively brief period of motor-skill training by using complementary measures of microstructure and volume.

Environmental enrichment is associated with rapid volumetric brain changes in adult mice.

Environmental enrichment is a model of increased structural brain plasticity. Previous histological observations have shown molecular and cellular changes in a few pre-determined areas of the rodent brain. However, little is known about the time course of enrichment-induced brain changes and how they distribute across the whole brain. Here we expose adult mice to three weeks of environmental enrichment using a novel re-configurable maze design. In-vivo MRI shows volumetric brain changes in brain areas related to spatial memory, navigation, and sensorimotor experience, such as the hippocampal formation and the sensorimotor cortex. Evidence from a second cohort of mice indicates that these plastic changes might occur as early as 24h after exposure. This suggests that novel experiences are powerful modulators of plasticity even in the adult brain. Understanding and harnessing the underlying molecular mechanisms could advance future treatments of neurological disease.

Changes in functional connectivity and GABA levels with long-term motor learning.

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.

Motor skill learning induces changes in white matter microstructure and myelination.

Learning a novel motor skill is associated with well characterized structural and functional plasticity in the rodent motor cortex. Furthermore, neuroimaging studies of visuomotor learning in humans have suggested that structural plasticity can occur in white matter (WM), but the biological basis for such changes is unclear. We assessed the influence of motor skill learning on WM structure within sensorimotor cortex using both diffusion MRI fractional anisotropy (FA) and quantitative immunohistochemistry. Seventy-two adult (male) rats were randomly assigned to one of three conditions (skilled reaching, unskilled reaching, and caged control). After 11 d of training, postmortem diffusion MRI revealed significantly higher FA in the skilled reaching group compared with the control groups, specifically in the WM subjacent to the sensorimotor cortex contralateral to the trained limb. In addition, within the skilled reaching group, FA across widespread regions of WM in the contralateral hemisphere correlated significantly with learning rate. Immunohistological analysis conducted on a subset of 24 animals (eight per group) revealed significantly increased myelin staining in the WM underlying motor cortex in the hemisphere contralateral (but not ipsilateral) to the trained limb for the skilled learning group versus the control groups. Within the trained hemisphere (but not the untrained hemisphere), myelin staining density correlated significantly with learning rate. Our results suggest that learning a novel motor skill induces structural change in task-relevant WM pathways and that these changes may in part reflect learning-related increases in myelination.

Gray matter volume is associated with rate of subsequent skill learning after a long term training intervention.

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 6weeks, 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 4weeks 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.

Mapping registration sensitivity in MR mouse brain images.

Nonlinear registration algorithms provide a way to estimate structural (brain) differences based on magnetic resonance images. Their ability to align images of different individuals and across modalities has been well-researched, but the bounds of their sensitivity with respect to the recovery of salient morphological differences between groups are unclear. Here we develop a novel approach to simulate deformations on MR brain images to evaluate the ability of two registration algorithms to extract structural differences corresponding to biologically plausible atrophy and expansion. We show that at a neuroanatomical level registration accuracy is influenced by the size and compactness of structures, but do so differently depending on how much change is simulated. The size of structures has a small influence on the recovered accuracy. There is a trend for larger structures to be recovered more accurately, which becomes only significant as the amount of simulated change is large. More compact structures can be recovered more accurately regardless of the amount of simulated change. Both tested algorithms underestimate the full extent of the simulated atrophy and expansion. Finally we show that when multiple comparisons are corrected for at a voxelwise level, a very low rate of false positives is obtained. More interesting is that true positive rates average around 40%, indicating that the simulated changes are not fully recovered. Simulation experiments were run using two fundamentally different registration algorithms and we identified the same results, suggesting that our findings are generalizable across different classes of nonlinear registration algorithms.

Fornix microstructure correlates with recollection but not familiarity memory.

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.

Addressing a systematic vibration artifact in diffusion-weighted MRI.

We have identified and studied a pronounced artifact in diffusion-weighted MRI on a clinical system. The artifact results from vibrations of the patient table due to low-frequency mechanical resonances of the system which are stimulated by the low-frequency gradient switching associated with the diffusion-weighting. The artifact manifests as localized signal-loss in images acquired with partial Fourier coverage when there is a strong component of the diffusion-gradient vector in the left-right direction. This signal loss is caused by local phase ramps in the image domain which shift the apparent k-space center for a particular voxel outside the covered region. The local signal loss masquerades as signal attenuation due to diffusion, severely disrupting the quantitative measures associated with diffusion-tensor imaging (DTI). We suggest a way to improve the interpretation of affected DTI data by including a co-regressor which accounts for the empirical response of regions affected by the artifact. We also demonstrate that the artifact may be avoided by acquiring full k-space data, and that subsequent increases in TE can be avoided by employing parallel acceleration.

In situ infrared spectroscopic analysis of the water modes of [Zr4(OH)8(H2O)16]8+ during the thermal dehydration of ZrOCl2.8H2O.

An in situ infrared spectroscopic analysis of the thermal dehydration of zirconyl chloride octahydrate was carried out to identify bending mode vibrations of distinctive water molecules in this well-defined zirconium(IV) cluster cation. TG-MS analysis revealed the particular temperatures where one water molecule at a time was removed from the solid hydrate. In situ IR data unveiled remarkable spectral changes featuring isosbestic behavior. We were able to experimentally distinguish between delta(H(2)O) modes from coordinatively bound water molecules (Zr-(OH(2))(3), 1595 cm(-1)), tetrahedrally coordinated lattice water (H(2)O dimer, 1620 cm(-1)), as well as strongly H-bonded lattice waters accommodating hydrated protons (1705 and 1666 cm(-1)). Spectral changes in the range from 1050 and 900 cm(-1) during dehydration are discussed.

White matter integrity in the vicinity of Broca's area predicts grammar learning success.

Humans differ substantially in their ability to implicitly extract structural regularities from experience, as required for learning the grammar of a language. The mechanisms underlying this fundamental inter-individual difference, which may determine initial success in language learning, are incompletely understood. Here, we use diffusion tensor magnetic resonance imaging (DTI) to determine white matter integrity around Broca's area, which is crucially involved in both natural and artificial language processing. Twelve young, right-handed individuals completed an artificial grammar learning task, and DTI of their brains were acquired. Inter-individual variability in performance correlated with white matter integrity (increasing fractional anisotropy (FA)) in fibres arising from Broca's area (left BA 44/45), but not from its right-hemispheric homologue. Variability in performance based on superficial familiarity did not show this association. Moreover, when Broca's area was used as a seed mask for probabilistic tractography, we found that mean FA values within the generated tracts was higher in subjects with better grammar learning. Our findings provide the first evidence that integrity of white matter fibre tracts arising from Broca's area is intimately linked with the ability to extract grammatical rules. The relevance of these findings for acquisition of a natural language has to be established in future studies.

MRI characteristics of the substantia nigra in Parkinson's disease: a combined quantitative T1 and DTI study.

The substantia nigra contains dopaminergic cells that project to the striatum and are affected by the neurodegenerative process that appears in Parkinson's disease (PD). For accurate differential diagnosis and for disease monitoring the availability of a sensitive and non-invasive biomarker for Parkinson's disease would be essential. Although there has been notable progress in studying correlates of nigral degeneration by means of magnetic resonance imaging (MRI) in the past decade, MRI and analysis techniques that allow accurate high-resolution mapping of the SN within a clinically acceptable acquisition time are still elusive. The main purpose of the preliminary study was to evaluate the potential role of the driven equilibrium single pulse observation of T1 (DESPOT1) method for delineation of the SN and differentiation of PD patients from healthy control subjects (n=10 in each group). We also investigated whether additional measures that can be obtained with diffusion tensor imaging (DTI) can further improve the MRI-guided discrimination between PD patients and controls. Our results show that the DESPOT1 method allows for a clear visualisation of the SN as a whole. Volumetric comparisons between ten PD patients and ten healthy subjects revealed significantly smaller volumes in patients for both the left and the right sides when the whole SN was considered. Combining SN volumetry and its connectivity with the thalamus improved the classification sensitivity to 100% and specificity to 80% for PD (discriminant function analysis with leave-one-out cross validation). Combining DESPOT1 imaging and DTI could therefore serve as a diagnostic marker for idiopathic Parkinson's disease in the future.

The rate of visuomotor adaptation correlates with cerebellar white-matter microstructure.

Convergent experimental evidence points to the cerebellum as a key neural structure mediating adaptation to visual and proprioceptive perturbations. In a previous study, we have shown that activity in the anterior cerebellum varies with the rate of learning, with fast learners exhibiting more activity in this region than slow learners. Here, we investigated whether this variability in behavior may partly reflect inter-individual differences in the structural properties of cerebellar white-matter output tracts. For this purpose, we used diffusion-weighted magnetic resonance imaging to estimate fractional anisotropy (FA), and correlated the FA with the rate of adaptation to an optical rotation in 11 subjects. We found that FA in a region consistent with the superior cerebellar peduncle (SCP), containing fibers connecting the cerebellar cortex with motor and premotor cortex, was positively correlated with the rate of adaptation but not with the general level of performance or the initial deviation. The same pattern was observed in a region of the lateral posterior cerebellum. In contrast, FA in the angular gyrus of the posterior parietal cortex correlated positively both with the rate of adaptation and the overall level of performance. Our results show that the rate of learning a visuomotor task is associated with FA of cerebellar pathways.

Neuroanatomic Differences Associated With Stress Susceptibility and Resilience.

BACKGROUND: We examined the neurobiological mechanisms underlying stress susceptibility using structural magnetic resonance imaging and diffusion tensor imaging to determine neuroanatomic differences between stress-susceptible and resilient mice. We also examined synchronized anatomic differences between brain regions to gain insight into the plasticity of neural networks underlying stress susceptibility. METHODS: C57BL/6 mice underwent 10 days of social defeat stress and were subsequently tested for social avoidance. For magnetic resonance imaging, brains of stressed (susceptible, n = 11; resilient, n = 8) and control (n = 12) mice were imaged ex vivo at 56 µm resolution using a T2-weighted sequence. We tested for behavior-structure correlations by regressing social avoidance z-scores against local brain volume. For diffusion tensor imaging, brains were scanned with a diffusion-weighted fast spin echo sequence at 78 µm isotropic voxels. Structural covariance was assessed by correlating local volume between brain regions. RESULTS: Social avoidance correlated negatively with local volume of the cingulate cortex, nucleus accumbens, thalamus, raphe nuclei, and bed nucleus of the stria terminals. Social avoidance correlated positively with volume of the ventral tegmental area (VTA), habenula, periaqueductal gray, cerebellum, hypothalamus, and hippocampal CA3. Fractional anisotropy was increased in the hypothalamus and hippocampal CA3. We observed synchronized anatomic differences between the VTA and cingulate cortex, hippocampus and VTA, hippocampus and cingulate cortex, and hippocampus and hypothalamus. These correlations revealed different structural covariance between brain regions in susceptible and resilient mice. CONCLUSIONS: Stress-integrative brain regions shape the neural architecture underlying individual differences in susceptibility and resilience to chronic stress.

Detection of the arcuate fasciculus in congenital amusia depends on the tractography algorithm.

The advent of diffusion magnetic resonance imaging (MRI) allows researchers to virtually dissect white matter fiber pathways in the brain in vivo. This, for example, allows us to characterize and quantify how fiber tracts differ across populations in health and disease, and change as a function of training. Based on diffusion MRI, prior literature reports the absence of the arcuate fasciculus (AF) in some control individuals and as well in those with congenital amusia. The complete absence of such a major anatomical tract is surprising given the subtle impairments that characterize amusia. Thus, we hypothesize that failure to detect the AF in this population may relate to the tracking algorithm used, and is not necessarily reflective of their phenotype. Diffusion data in control and amusic individuals were analyzed using three different tracking algorithms: deterministic and probabilistic, the latter either modeling two or one fiber populations. Across the three algorithms, we replicate prior findings of a left greater than right AF volume, but do not find group differences or an interaction. We detect the AF in all individuals using the probabilistic 2-fiber model, however, tracking failed in some control and amusic individuals when deterministic tractography was applied. These findings show that the ability to detect the AF in our sample is dependent on the type of tractography algorithm. This raises the question of whether failure to detect the AF in prior studies may be unrelated to the underlying anatomy or phenotype.

Phantom pain is associated with preserved structure and function in the former hand area.

Phantom pain after arm amputation is widely believed to arise from maladaptive cortical reorganization, triggered by loss of sensory input. We instead propose that chronic phantom pain experience drives plasticity by maintaining local cortical representations and disrupting inter-regional connectivity. Here we show that, while loss of sensory input is generally characterized by structural and functional degeneration in the deprived sensorimotor cortex, the experience of persistent pain is associated with preserved structure and functional organization in the former hand area. Furthermore, consistent with the isolated nature of phantom experience, phantom pain is associated with reduced inter-regional functional connectivity in the primary sensorimotor cortex. We therefore propose that contrary to the maladaptive model, cortical plasticity associated with phantom pain is driven by powerful and long-lasting subjective sensory experience, such as triggered by nociceptive or top-down inputs. Our results prompt a revisiting of the link between phantom pain and brain organization.

Deprivation-related and use-dependent plasticity go hand in hand.

Arm-amputation involves two powerful drivers for brain plasticity-sensory deprivation and altered use. However, research has largely focused on sensory deprivation and maladaptive change. Here we show that adaptive patterns of limb usage after amputation drive cortical plasticity. We report that individuals with congenital or acquired limb-absence vary in whether they preferentially use their intact hand or residual arm in daily activities. Using fMRI, we show that the deprived sensorimotor cortex is employed by whichever limb individuals are over-using. Individuals from either group that rely more on their intact hands (and report less frequent residual arm usage) showed increased intact hand representation in the deprived cortex, and increased white matter fractional anisotropy underlying the deprived cortex, irrespective of the age at which deprivation occurred. Our results demonstrate how experience-driven plasticity in the human brain can transcend boundaries that have been thought to limit reorganisation after sensory deprivation in adults. DOI: http://dx.doi.org/10.7554/eLife.01273.001.

White matter integrity of the descending pain modulatory system is associated with interindividual differences in placebo analgesia.

The ability for endogenous pain control varies considerably among individuals. The mechanisms underlying this interindividual difference are incompletely understood. We used placebo analgesia as a classic model of endogenous pain modulation in combination with diffusion tensor magnetic resonance imaging to test the hypothesis of a structural predisposition for the individual capacity of endogenous pain control. Specifically we determined white matter integrity within and between regions of the descending pain modulatory system. Twenty-four healthy participants completed a placebo paradigm and underwent diffusion tensor magnetic resonance imaging. The individual placebo analgesic effect was correlated with white matter integrity indexed by fractional anisotropy. The individual placebo analgesic effect was positively correlated with FA in the right dorsolateral prefrontal cortex, left rostral anterior cingulate cortex, and the periaqueductal grey. Probabilistic tractography seeded in these regions showed that stronger placebo analgesic responses were associated with increased mean fractional anisotropy values within white matter tracts connecting the periaqueductal grey with pain control regions such as the rostral anterior cingulate cortex and the dorsolateral prefrontal cortex. Our findings provide the first evidence that the white matter integrity within and between regions of the descending pain modulatory network is critically linked with the individual ability for endogenous pain control.