Consistency is key: influence of skull density ratio distribution on the formation of clinically effective lesions and long-term tremor suppression following treatment with MR-guided focused ultrasound.

OBJECTIVE: Skull density ratio (SDR) influences the permeability of the skull to the ultrasound waves used in magnetic resonance-guided focused ultrasound (MRgFUS) for the treatment of tremor. SDR values vary across the skull and the mean value is known to be predictive of sonication thermal increase. The aim of this investigation was to explore the effects of the SDR distribution on clinical outcomes following treatment with MRgFUS. METHODS: Data from 61 patients with essential or dystonic tremor treated with MRgFUS targeting the ventral intermediate nucleus (Vim) were retrospectively analyzed. Tremor suppression was assessed using the Clinical Rating Scale for Tremor (CRST) and hand tremor score (HTS). Vim ablation volume was measured on the T1-weighted MR image acquired both at 1 day and 12 months after treatment. The numerical distribution of SDR values measured for each element in the ultrasound transducer was quantified by calculating the mean, standard deviation, skewness, entropy, and kurtosis of the SDR histogram. The effect of the SDR metrics on change in CRST and HTS was examined using a linear mixed-effects model. Additionally, the effect of the regional distribution of SDR values was explored in an element-wise analysis between patients with above- and below-average tremor suppression. RESULTS: A significant positive effect was found between SDR kurtosis and improvement in CRST (ß = 0.33, p = 0.004) and HTS (ß = 0.38, p < 0.001). The effect was found to be significant at 1 month posttreatment (CRST: ß = 0.415, p = 0.008; HTS: ß = 0.369, p = 0.016), and at the most recent clinical follow-up (CRST: ß = 0.395, p < 0.001; HTS: ß = 0.386, p < 0.001). One hundred seventy-one significant elements were identified in the element-wise analysis. The mean percentage difference from the mean SDR in these elements was associated with improvement in CRST (ß = 0.27, p < 0.008) and HTS (ß = 0.27, p < 0.015). Higher SDR kurtosis was associated with increased lesion volume at 12 months (p = 0.040) and less reduction in volume relative to the day-1 lesion volume (p = 0.007). CONCLUSIONS: Greater SDR kurtosis was associated with larger, more stable lesions at 12 months posttreatment and increased tremor suppression at long-term follow-up. SDR kurtosis may provide a more meaningful prognostic factor than the mean SDR.

Deep learning distinguishes connectomes from focal epilepsy patients and controls: feasibility and clinical implications.

The application of deep learning models to evaluate connectome data is gaining interest in epilepsy research. Deep learning may be a useful initial tool to partition connectome data into network subsets for further analysis. Few prior works have used deep learning to examine structural connectomes from patients with focal epilepsy. We evaluated whether a deep learning model applied to whole-brain connectomes could classify 28 participants with focal epilepsy from 20 controls and identify nodal importance for each group. Participants with epilepsy were further grouped based on whether they had focal seizures that evolved into bilateral tonic-clonic seizures (17 with, 11 without). The trained neural network classified patients from controls with an accuracy of 72.92%, while the seizure subtype groups achieved a classification accuracy of 67.86%. In the patient subgroups, the nodes and edges deemed important for accurate classification were also clinically relevant, indicating the model's interpretability. The current work expands the evidence for the potential of deep learning to extract relevant markers from clinical datasets. Our findings offer a rationale for further research interrogating structural connectomes to obtain features that can be biomarkers and aid the diagnosis of seizure subtypes.

High angular diffusion tensor imaging estimation from minimal evenly distributed diffusion gradient directions.

Diffusion-weighted Imaging (DWI) is a non-invasive imaging technique based on Magnetic Resonance Imaging (MRI) principles to measure water diffusivity and reveal details of the underlying brain micro-structure. By fitting a tensor model to quantify the directionality of water diffusion a Diffusion Tensor Image (DTI) can be derived and scalar measures, such as fractional anisotropy (FA), can then be estimated from the DTI to summarise quantitative microstructural information for clinical studies. In particular, FA has been shown to be a useful research metric to identify tissue abnormalities in neurological disease (e.g. decreased anisotropy as a proxy for tissue damage). However, time constraints in clinical practice lead to low angular resolution diffusion imaging (LARDI) acquisitions that can cause inaccurate FA value estimates when compared to those generated from high angular resolution diffusion imaging (HARDI) acquisitions. In this work, we propose High Angular DTI Estimation Network (HADTI-Net) to estimate an enhanced DTI model from LARDI with a set of minimal and evenly distributed diffusion gradient directions. Extensive experiments have been conducted to show the reliability and generalisation of HADTI-Net to generate high angular DTI estimation from any minimal evenly distributed diffusion gradient directions and to explore the feasibility of applying a data-driven method for this task. The code repository of this work and other related works can be found at https://mri-synthesis.github.io/.

Tremor suppression following treatment with MRgFUS: skull density ratio consistency and degree of posterior dentatorubrothalamic tract lesioning predicts long-term clinical outcomes in essential tremor.

Objectives: Magnetic resonance-guided focussed ultrasound (MRgFUS) is an incisionless ablative procedure, widely used for treatment of Parkinsonian and Essential Tremor (ET). Enhanced understanding of the patient- and treatment-specific factors that influence sustained long-term tremor suppression could help clinicians achieve superior outcomes via improved patient screening and treatment strategy. Methods: We retrospectively analysed data from 31 subjects with ET, treated with MRgFUS at a single centre. Tremor severity was assessed with parts A, B and C of the Clinical Rating Scale for Tremor (CRST) as well as the combined CRST. Tremor in the dominant and non-dominant hand was assessed with Hand Tremor Scores (HTS), derived from the CRST. Pre- and post-treatment imaging data were analysed to determine ablation volume overlap with automated thalamic segmentations, and the dentatorubrothalamic tract (DRTT) and compared with percentage change in CRST and HTS following treatment. Results: Tremor symptoms were significantly reduced following treatment. Combined pre-treatment CRST (mean: 60.7 ± 17.3) and HTS (mean: 19.2 ± 5.7) improved by an average of 45.5 and 62.6%, respectively. Percentage change in CRST was found to be significantly negatively associated with age (ß = -0.375, p = 0.015), and SDR standard deviation (SDRSD; ß = -0.324, p = 0.006), and positively associated with ablation overlap with the posterior DRTT (ß = 0.535, p < 0.001). Percentage HTS improvement in the dominant hand decreased significantly with older age (ß = -0.576, p < 0.01). Conclusion: Our results suggest that increased lesioning of the posterior region of the DRTT could result in greater improvements in combined CRST and non-dominant hand HTS, and that subjects with lower SDR standard deviation tended to experience greater improvement in combined CRST.

Hippocampal Neuronal Integrity and Functional Connectivity Within the Default Mode Network in Mild Cognitive Impairment: A Multimodal Investigation.

Background: In older people with mild cognitive impairment (MCI), the relationship between early changes in functional connectivity and in vivo changes in key neurometabolites is not known. Two established correlates of MCI diagnosis are decreased N-acetylaspartate (NAA) in the hippocampus, indicative of decreased neuronal integrity, and changes in the default mode network (DMN) functional network. If and how these measures interrelate is yet to be established, and such understanding may provide insight into the processes underpinning observed cognitive decline. Objectives: To determine the relationship between NAA levels in the left hippocampus and functional connectivity within the DMN in an aging cohort. Methods: In a sample of 51 participants with MCI and 30 controls, hippocampal NAA was determined using magnetic resonance spectroscopy, and DMN connectivity was quantified using resting-state functional MRI. The association between hippocampal NAA and the DMN functional connectivity was tested within the MCI group and separately within the control group. Results: In the DMN, we showed a significant inverse association between functional connectivity and hippocampal NAA in 20 specific brain connections for patients with MCI. This was despite no evidence of any associations in the healthy control group or group differences in either of these measures alone. Conclusions: This study suggests that decreased neuronal integrity in the hippocampus is associated with functional change within the DMN for those with MCI, in contrast to healthy older adults. These results highlight the potential of multimodal investigations to better understand the processes associated with cognitive decline. Impact statement This study measured activity within the default mode network (DMN) and quantified N-acetylaspartate (NAA), a measure of neuronal integrity, within the hippocampus in participants with mild cognitive impairment (MCI) and healthy controls. In participants with MCI, NAA levels were inversely associated with connectivity between specific regions of the DMN, a relationship not evident in healthy controls. This association was present even in the absence of group differences in DMN connectivity or NAA levels. This research illustrates the possibility of using multiple magnetic resonance modalities for more sensitive measures of early cognitive decline to identify and intervene earlier.

Building a tissue-unbiased brain template of fiber orientation distribution and tractography with multimodal registration.

PURPOSE: Brain templates provide an essential standard space for statistical analysis of brain structure and function. Despite recent advances, diffusion MRI still lacks a template of fiber orientation distribution (FOD) and tractography that is unbiased for both white and gray matter. Therefore, we aim to build up a set of such templates for better white-matter analysis and joint structural and functional analysis. METHODS: We have developed a multimodal registration method to leverage the complementary information captured by T1 -weighted, T2 -weighted, and diffusion MRI, so that a coherent transformation is generated to register FODs into a common space and average them into a template. Consequently, the anatomically constrained fiber-tracking method was applied to the FOD template to generate a tractography template. Fiber-centered functional connectivity analysis was then performed as an example of the benefits of such an unbiased template. RESULTS: Our FOD template preserves fine structural details in white matter and also, importantly, clear folding patterns in the cortex and good contrast in the subcortex. Quantitatively, our templates show better individual-template agreement at the whole-brain scale and segmentation scale. The tractography template aligns well with the gray matter, which led to fiber-centered functional connectivity showing high cross-group consistency. CONCLUSION: We have proposed a novel methodology for building a tissue-unbiased FOD and anatomically constrained tractography template based on multimodal registration. Our templates provide a standard space and statistical platform for not only white-matter analysis but also joint structural and functional analysis, therefore filling an important gap in multimodal neuroimage analysis.

New insights into anatomical connectivity along the anterior-posterior axis of the human hippocampus using in vivo quantitative fibre tracking.

The hippocampus supports multiple cognitive functions including episodic memory. Recent work has highlighted functional differences along the anterior-posterior axis of the human hippocampus, but the neuroanatomical underpinnings of these differences remain unclear. We leveraged track-density imaging to systematically examine anatomical connectivity between the cortical mantle and the anterior-posterior axis of the in vivo human hippocampus. We first identified the most highly connected cortical areas and detailed the degree to which they preferentially connect along the anterior-posterior axis of the hippocampus. Then, using a tractography pipeline specifically tailored to measure the location and density of streamline endpoints within the hippocampus, we characterised where these cortical areas preferentially connect within the hippocampus. Our results provide new and detailed insights into how specific regions along the anterior-posterior axis of the hippocampus are associated with different cortical inputs/outputs and provide evidence that both gradients and circumscribed areas of dense extrinsic anatomical connectivity exist within the human hippocampus. These findings inform conceptual debates in the field and emphasise the importance of considering the hippocampus as a heterogeneous structure. Overall, our results represent a major advance in our ability to map the anatomical connectivity of the human hippocampus in vivo and inform our understanding of the neural architecture of hippocampal-dependent memory systems in the human brain.

The brain allows us to perceive and interact with our environment and to create and recall memories about our day-to-day lives. A sea-horse shaped structure in the brain, called the hippocampus, is critical for translating our perceptions into memories, and it does so in coordination with other brain regions. For example, different regions of the cerebral cortex (the outer layer of the brain) support different aspects of cognition, and pathways of information flow between the cerebral cortex and hippocampus underpin the healthy functioning of memory. Decades of research conducted into the brains of non-human primates show that specific regions of the cerebral cortex anatomically connect with different parts of the hippocampus to support this information flow. These insights form the foundation for existing theoretical models of how networks of neurons in the hippocampus and the cerebral cortex are connected. However, the human cerebral cortex has greatly expanded during our evolution, meaning that patterns of connectivity in the human brain may diverge from those in the brains of non-human primates. Deciphering human brain circuits in greater detail is crucial if we are to gain a better understanding of the structure and operation of the healthy human brain. However, obtaining comprehensive maps of anatomical connections between the hippocampus and cerebral cortex has been hampered by technical limitations. For example, magnetic resonance imaging (MRI), an approach that can be used to study the living human brain, suffers from insufficient image resolution. To overcome these issues, Dalton et al. used an imaging technique called diffusion weighted imaging which is used to study white matter pathways in the brain. They developed a tailored approach to create high-resolution maps showing how the hippocampus anatomically connects with the cerebral cortex in the healthy human brain. Dalton et al. produced detailed maps illustrating which areas of the cerebral cortex have high anatomical connectivity with the hippocampus and how different parts of the hippocampus preferentially connect to different neural circuits in the cortex. For example, the experiments demonstrate that highly connected areas in a cortical region called the temporal cortex connect to very specific, circumscribed regions within the hippocampus. These findings suggest that the hippocampus may consist of different neural circuits, each preferentially linked to defined areas of the cortex which are, in turn, associated with specific aspects of cognition. These observations further our knowledge of hippocampal-dependant memory circuits in the human brain and provide a foundation for the study of memory decline in aging and neurodegenerative diseases.

White matter alterations in focal to bilateral tonic-clonic seizures.

We examined the white matter of patients with and without focal to bilateral tonic-clonic seizures (FBTCS), and control participants. A neural network based tract segmentation model (Tractseg) was used to isolate tract-specific, track-weighted tensor-based measurements from the tracts of interest. We compared the group differences in the track-weighted tensor-based measurements derived from whole and hemispheric tracts. We identified several regions that displayed significantly altered white matter in patients with focal epilepsy compared to controls. Furthermore, patients without FBTCS showed significantly increased white matter disruption in the inferior fronto-occipital fascicle and the striato-occipital tract. In contrast, the track-weighted tensor-based measurements from the FBTCS cohort exhibited a stronger resemblance to the healthy controls (compared to the non-FBTCS group). Our findings revealed marked alterations in a range of subcortical tracts considered critical in the genesis of seizures in focal epilepsy. Our novel application of tract-specific, track-weighted tensor-based measurements to a new clinical dataset aided the elucidation of specific tracts that may act as a predictive biomarker to distinguish patients likely to develop FBTCS.

A robust framework for characterising diffusion metrics of the median and ulnar nerves: Exploiting state-of-the-art tracking methods.

Diffusion-weighted imaging has been used to quantify peripheral nerve properties; however, traditional post-processing techniques have several limitations. Advanced neuroimaging techniques, which overcome many of these limitations, have not been applied to peripheral nerves. Here, we use state-of-the-art diffusion analysis tools to reconstruct the median and ulnar nerves and quantify their diffusion properties. Diffusion-weighted MRI scans were obtained from eight healthy adult subjects. Constrained spherical deconvolution was combined with probabilistic fibre tracking to compute track-weighted fibre orientation distribution (TW-FOD). The tensor was computed and used along with the tracks to estimate TW apparent diffusion coefficient (TW-ADC), TW fractional anisotropy (TW-FA), TW axial diffusivity (TW-AD), and TW radial diffusivity (TW-RD). Variability of TW measurements was used to estimate power size information. The population intersession mean (± SD) measurements for the median nerve were TW-FOD 1.30 (±0.17), TW-ADC 1.16 (±0.13) × 10-3  mm2 /s, TW-FA 0.60 (±0.05), TW-AD 2.05 (±0.16) × 10-3  mm2 /s, and TW-RD 0.72 (±0.12) × 10-3  mm2 /s. The corresponding measurements for the ulnar nerve were TW-FOD 1.25 (±0.14), TW-ADC 1.13 (±0.10) × 10-3  mm2 /s, TW-FA 0.56 (±0.06), TW-AD 1.93 (±0.01) × 10-3  mm2 /s, and TW-RD 0.74 (±0.12) × 10-3  mm2 /s. Based on these measurements, a sample size of 37 would be sufficient to detect a 10% difference in any of the measured TW metrics. A sample size of 20 would be large enough to detect within-subject differences as small as 2.9% (TW-AD, ulnar nerve) and between-subject differences as small as 3.8% (TW-AD, ulnar nerve).

Intramuscular fat in children with unilateral cerebral palsy.

BACKGROUND: Many children with cerebral palsy develop muscle contractures. The mechanisms of contracture are not well understood. We investigated the possibility that, because fat is stiffer than passive muscle, elevated intramuscular fat contributes to contracture. In this cross-sectional study, we compared the quantity and distribution of intramuscular fat in muscles from typically developing children and children with cerebral palsy who have contractures. METHODS: mDixon magnetic resonance images were obtained from the legs of 20 ambulant children with unilateral spastic cerebral palsy who had ankle contractures (mean age 11 SD 3 years, 13 male, mean moderate level contracture) and 20 typically developing children (mean age 11 SD 4 years, 13 male). The images were analyzed to quantify the intramuscular fat fraction of the medial gastrocnemius muscles. The amount and distribution of intramuscular fat were compared between muscles of children with cerebral palsy and typically developing children. FINDINGS: In typically developing children, the medial gastrocnemius muscles had a mean intramuscular fat fraction of 4.7% (SD 1.6%). In children with cerebral palsy, the mean intramuscular fat fractions in the more- and less-affected medial gastrocnemius muscle were 11.4% (8.1%) and 6.9% (3.4%) respectively. There were small but statistically significant regional differences in the distribution of intramuscular fat. There was no evidence of a relationship between intramuscular fat fraction and severity of contracture. INTERPRETATION: Children with cerebral palsy have higher proportions of intramuscular fat than typically developing children. There is no clear relationship between intramuscular fat fraction and dorsiflexion range of motion in children with cerebral palsy.

Intramuscular Fat in the Medial Gastrocnemius Muscle of People Who Have Had a Stroke.

Objective: To compare intramuscular fat fraction in people who have ankle contractures following stroke with the intramuscular fat fraction in control participants. Design: mDixon MRI images were used to quantify intramuscular fat fractions in the medial gastrocnemius muscles of people who had experienced a hemiparetic stroke (n = 14, mean age 60 ± 13 years) and control participants (n = 18, mean age 66 ± 12 years). Results: Intramuscular fat fractions were similar in the paretic and non-paretic sides of stroke patients (mean on paretic side 14.5%, non-paretic side 12.8%, difference 1.6%, 95% confidence interval -0.7 to 4.1%). The intramuscular fat fraction on the paretic side was higher than in the control group (mean intramuscular fat fraction in control muscles 7.6%; difference 7.8%, 95% confidence interval 4.6-10.9%). The difference between intramuscular fat fractions in non-paretic and control legs increased with age. Body mass index was similar in stroke patients and controls. There was no association between medial gastrocnemius intramuscular fat fraction and dorsiflexion range. Conclusion: Muscles of stroke patients had elevated intramuscular fat fractions compared to muscles from control participants which were not explained by differences in body mass index. There is no clear relationship between intramuscular fat in the medial gastrocnemius muscle and dorsiflexion range of motion.

Architecture of the medial gastrocnemius muscle in people who have had a stroke: A diffusion tensor imaging investigation.

People who have had a stroke often develop ankle contractures which may be caused by changes in architecture of calf muscles. Anatomically constrained diffusion tensor imaging has recently been used to make three-dimensional, whole-muscle measurements of muscle architecture. Here, we compared the architecture of the medial gastrocnemius muscle in the paretic and non-paretic sides of people who have had a hemiparetic stroke and control participants using novel imaging techniques. METHODS: MRI techniques (diffusion tensor imaging and mDixon imaging) were used to obtain muscle volume, fascicle length, pennation angle, physiological cross-sectional area and curvature in 14 stroke patients (mean age 60 SD 13 years) and 18 control participants (mean age 66 SD 12 years). FINDINGS: On average, the ankle on the paretic side had 11° (95% confidence interval 8 to 13°) less dorsiflexion range than on the non-paretic side, and 6° (1 to 13°) less dorsiflexion range than ankles of control participants. The medial gastrocnemius muscles on the paretic side were, on average, 15% (35.2 cm3, 95% confidence interval 5.2 to 65.2 cm3) smaller in volume than the muscles on the non-paretic side, and 16% (36.9 cm3, 95% confidence interval 3.1 to 70.6 cm3) smaller than in control participants. No statistically significant differences between paretic, non-paretic and control muscles were detected for fascicle length, pennation angle, physiological cross-sectional area or curvature. CONCLUSIONS: People with hemiparetic stroke and reduced range of motion have, on average, a smaller medial gastrocnemius muscle on the paretic side than on the non-paretic side. Other muscle architectural parameters appear unchanged.

Muscle architecture in children with cerebral palsy and ankle contractures: an investigation using diffusion tensor imaging.

BACKGROUND: Children with cerebral palsy frequently have ankle contractures which may be caused by changes in architecture of calf muscles. Here, we compared the architecture of medial gastrocnemius muscles in children with unilateral cerebral palsy and typically developing children using novel imaging techniques. METHODS AND PROCEDURES: Muscle volumes, fascicle lengths, pennation angles and physiological cross-sectional areas were measured from diffusion tensor images and mDixon scans obtained from 20 ambulant children with unilateral spastic cerebral palsy who had ankle contractures (age 11 ±â€¯3 years; mean ±â€¯standard deviation) and 20 typically developing children (11 ±â€¯4 years). FINDINGS: In children with cerebral palsy, the more-affected side had, on average, 13° less dorsiflexion range and the medial gastrocnemius muscle had 4.9 mm shorter fascicles, 50 cm3 smaller volume and 9.5 cm2 smaller physiological cross-sectional area than the less-affected side. Compared to typically developing children, the more-affected side had 10° less dorsiflexion range and the medial gastrocnemius muscle had 4.2 mm shorter fascicles, 51 cm3 smaller volume and 10 cm2 smaller physiological cross-sectional area. We did not detect differences between the less-affected and typically developing legs. INTERPRETATION: Three-dimensional measurement of whole medial gastrocnemius muscles confirmed that the architecture of muscles on the more-affected side of children with cerebral palsy differs from the less-affected side and from muscles of typically developing children. Reductions in fascicle length, muscle volume and physiological cross-sectional area may contribute to muscle contracture.

Validity and reliability of measurements of aponeurosis dimensions from magnetic resonance images.

Muscle performance is closely related to the structure and function of tendons and aponeuroses, the sheet-like, intramuscular parts of tendons. The architecture of aponeuroses has been difficult to study with magnetic resonance imaging (MRI) because these thin, collagen-rich connective tissues have very short transverse relaxation (T2) times and therefore provide a weak signal with conventional MRI sequences. Here, we validated measurements of aponeurosis dimensions from two MRI sequences commonly used in muscle-tendon research (mDixon and T1-weighted images), and an ultrashort echo time (UTE) sequence designed for imaging tissues with short T2 times. MRI-based measurements of aponeurosis width, length, and area of 20 sheep leg muscles were compared to direct measurements made with three-dimensional (3D) quantitative microdissection. The errors in measurement of aponeurosis width relative to the mean width were 1.8% for UTE, 3.7% for T1, and 18.8% for mDixon. For aponeurosis length, the errors were 7.6% for UTE, 1.9% for T1, and 21.0% for mDixon. Measurements from T1 and UTE scans were unbiased, but mDixon scans systematically underestimated widths, lengths, and areas of the aponeuroses. Using the same methods, we then found high inter-rater reliability (intraclass correlation coefficients >0.92 for all measures) of measurements of the dimensions of the central aponeurosis of the human tibialis anterior muscle from T1-weighted scans. We conclude that valid and reliable measurements of aponeurosis dimensions can be obtained from UTE and from T1-weighted scans. When the goal is to study the macroscopic architecture of aponeuroses, UTE does not hold an advantage over T1-weighted imaging.

Reliability and robustness of muscle architecture measurements obtained using diffusion tensor imaging with anatomically constrained tractography.

For detailed analyses of muscle adaptation mechanisms during growth, ageing or disease, reliable measurements of muscle architecture are required. Diffusion tensor imaging (DTI) and DTI tractography have been used to reconstruct the architecture of human muscles in vivo. However, muscle architecture measurements reconstructed with conventional DTI techniques are often anatomically implausible because the reconstructed fascicles do not terminate on aponeuroses, as real muscle fascicles are known to do. In this study, we tested the reliability of an anatomically constrained DTI-based method for measuring three-dimensional muscle architecture. Anatomical magnetic resonance images and diffusion tensor images were obtained from the left legs of eight healthy participants on two occasions one week apart. Muscle volumes, fascicle lengths, pennation angles and fascicle curvatures were measured in the medial and lateral gastrocnemius, soleus and the tibialis anterior muscles. Averaged across muscles, the intraclass correlation coefficient was 0.99 for muscle volume, 0.81 for fascicle length, 0.73 for pennation angle and 0.76 for fascicle curvature. Measurements of muscle architecture obtained using conventional DTI tractography were highly sensitive to variations in the stopping criteria for DTI tractography. The application of anatomical constraints reduced this sensitivity significantly. This study demonstrates that anatomically constrained DTI tractography can provide reliable and robust three-dimensional measurements of whole-muscle architecture. The algorithms used to constrain tractography have been made publicly available.

History-dependence of muscle slack length following contraction and stretch in the human vastus lateralis.

KEY POINTS: In reduced muscle preparations, the slack length and passive stiffness of muscle fibres have been shown to be influenced by previous muscle contraction or stretch. In human muscles, such behaviours have been inferred from measures of muscle force, joint stiffness and reflex magnitudes and latencies. Using ultrasound imaging, we directly observed that isometric contraction of the vastus lateralis muscle at short lengths reduces the slack lengths of the muscle-tendon unit and muscle fascicles. The effect is apparent 60 s after the contraction. These observations imply that muscle contraction at short lengths causes the formation of bonds which reduce the effective length of structures that generate passive tension in muscles. ABSTRACT: In reduced muscle preparations, stretch and muscle contraction change the properties of relaxed muscle fibres. In humans, effects of stretch and contraction on properties of relaxed muscles have been inferred from measurements of time taken to develop force, joint stiffness and reflex latencies. The current study used ultrasound imaging to directly observe the effects of stretch and contraction on muscle-tendon slack length and fascicle slack length of the human vastus lateralis muscle in vivo. The muscle was conditioned by (a) strong isometric contractions at long muscle-tendon lengths, (b) strong isometric contractions at short muscle-tendon lengths, (c) weak isometric contractions at long muscle-tendon lengths and (d) slow stretches. One minute after conditioning, ultrasound images were acquired from the relaxed muscle as it was slowly lengthened through its physiological range. The ultrasound image sequences were used to identify muscle-tendon slack angles and fascicle slack lengths. Contraction at short muscle-tendon lengths caused a mean 13.5 degree (95% CI 11.8-15.0 degree) shift in the muscle-tendon slack angle towards shorter muscle-tendon lengths, and a mean 5 mm (95% CI 2-8 mm) reduction in fascicle slack length, compared to the other conditions. A supplementary experiment showed the effect could be demonstrated if the muscle was conditioned by contraction at short lengths but not if the relaxed muscle was held at short lengths, confirming the role of muscle contraction. These observations imply that muscle contraction at short lengths causes the formation of bonds which reduce the effective length of structures that generate passive tension in muscles.

Three-dimensional architecture of the whole human soleus muscle in vivo.

BACKGROUND: Most data on the architecture of the human soleus muscle have been obtained from cadaveric dissection or two-dimensional ultrasound imaging. We present the first comprehensive, quantitative study on the three-dimensional anatomy of the human soleus muscle in vivo using diffusion tensor imaging (DTI) techniques. METHODS: We report three-dimensional fascicle lengths, pennation angles, fascicle curvatures, physiological cross-sectional areas and volumes in four compartments of the soleus at ankle joint angles of 69 ± 12° (plantarflexion, short muscle length; average ± SD across subjects) and 108 ± 7° (dorsiflexion, long muscle length) of six healthy young adults. Microdissection and three-dimensional digitisation on two cadaveric muscles corroborated the compartmentalised structure of the soleus, and confirmed the validity of DTI-based muscle fascicle reconstructions. RESULTS: The posterior compartments of the soleus comprised 80 ± 5% of the total muscle volume (356 ± 58 cm3). At the short muscle length, the average fascicle length, pennation angle and curvature was 37 ± 8 mm, 31 ± 3° and 17 ± 4 /m, respectively. We did not find differences in fascicle lengths between compartments. However, pennation angles were on average 12° larger (p < 0.01) in the posterior compartments than in the anterior compartments. For every centimetre that the muscle-tendon unit lengthened, fascicle lengths increased by 3.7 ± 0.8 mm, pennation angles decreased by -3.2 ± 0.9° and curvatures decreased by -2.7 ± 0.8 /m. Fascicles in the posterior compartments rotated almost twice as much as in the anterior compartments during passive lengthening. DISCUSSION: The homogeneity in fascicle lengths and inhomogeneity in pennation angles of the soleus may indicate a functionally different role for the anterior and posterior compartments. The data and techniques presented here demonstrate how DTI can be used to obtain detailed, quantitative measurements of the anatomy of complex skeletal muscles in living humans.

How does passive lengthening change the architecture of the human medial gastrocnemius muscle?

There are few comprehensive investigations of the changes in muscle architecture that accompany muscle contraction or change in muscle length in vivo. For this study, we measured changes in the three-dimensional architecture of the human medial gastrocnemius at the whole muscle level, the fascicle level and the fiber level using anatomical MRI and diffusion tensor imaging (DTI). Data were obtained from eight subjects under relaxed conditions at three muscle lengths. At the whole muscle level, a 5.1% increase in muscle belly length resulted in a reduction in both muscle width (mean change -2.5%) and depth (-4.8%). At the fascicle level, muscle architecture measurements obtained at 3,000 locations per muscle showed that for every millimeter increase in muscle-tendon length above the slack length, average fascicle length increased by 0.46 mm, pennation angle decreased by 0.27° (0.17° in the superficial part and 0.37° in the deep part), and fascicle curvature decreased by 0.18 m-1 There was no evidence of systematic variation in architecture along the muscle's long axis at any muscle length. At the fiber level, analysis of the diffusion signal showed that passive lengthening of the muscle increased diffusion along fibers and decreased diffusion across fibers. Using these measurements across scales, we show that the complex shape changes that muscle fibers, whole muscles, and aponeuroses of the medial gastrocnemius undergo in vivo cannot be captured by simple geometrical models. This justifies the need for more complex models that link microstructural changes in muscle fibers to macroscopic changes in architecture.NEW & NOTEWORTHY Novel MRI and DTI techniques revealed changes in three-dimensional architecture of the human medial gastrocnemius during passive lengthening. Whole muscle belly width and depth decreased when the muscle lengthened. Fascicle length, pennation, and curvature changed uniformly or near uniformly along the muscle during passive lengthening. Diffusion of water molecules in muscle changes in the same direction as fascicle strains.