Genetic contributions to regional variability in human brain structure: methods and preliminary results.

Twin studies provide one approach for investigating and partitioning genetic and environmental contributions to phenotypic variability in human brain structure. Previous twin studies have found that cerebral volume, hemispheric volume, ventricular volume, and cortical gyral pattern variability were heritable. We investigated the contributions of genetic and environmental factors to both global (brain volume and lateral ventricular volume) and regional (parcellated gray matter) variability in brain structure. We examined MR images from 10 pairs of healthy monozygotic and 10 pairs of same-sex dizygotic twins. Regional gray matter volume was estimated by automated image segmentation, transformation to standard space, and parcellation using a digital atlas. Heritability was estimated by path analysis. Estimated heritability for brain volume variability was high (0.66; 95% confidence interval 0.17, 1.0) but the major effects on lateral ventricular volume variability were common and unique environmental factors. We constructed a map of regional brain heritability and found large genetic effects shared in common between several bilateral brain regions, particularly paralimbic structures and temporal-parietal neocortex. We tested three specific hypotheses with regard to the genetic control of brain variability: (i) that the strength of the genetic effect is related to gyral ontogenesis, (ii) that there is greater genetic control of left than of right hemisphere variability, and (iii) that random or fluctuating asymmetry in bilateral structures is not heritable. We found no evidence in support of the first two hypotheses, but our results were consistent with the third hypothesis. Finally, we used principal component (PC) analysis of the genetic correlation matrix, to identify systems of anatomically distributed gray matter regions which shared major genetic effects in common. Frontal and parietal neocortical areas loaded positively on the first PC; some paralimbic and limbic areas loaded negatively. Bilateral insula, some frontal regions, and temporal neocortical regions functionally specialized for audition and language loaded strongly on the second PC. We conclude that large samples are required for powerful investigation of genetic effects in imaging data from twins. However, these preliminary re. sults suggest that genetic effects on structure of the human brain are regionally variable and predominantly symmetric in paralimbic structures and lateral temporal cortex.

An in vitro assessment of tissue compression damage during circular stapler approximation tests, measuring expulsion of intracellular fluid and force.

Circular staplers are among the many instruments used during minimally invasive or open surgery that should approximate soft tissue within safe compression limits. Previous in vivo suture-line blood flow measurement has suggested a safe thickness reduction limit of 25 per cent during circular stapling procedures. The present work investigates in vitro assessment of the maximum safe compression of large and small porcine intestines, measuring the required compressive force and the expelled intracellular fluid (measured as a potassium solution). A test-rig mounted on a materials testing machine allowed staplers of three sizes to compress tissue samples to thicknesses ranging from 90 to 45 per cent of original thickness. The expelled fluid was collected in 40 ml of 0.9 per cent NaCl and analysed in a flame photometer. The force measurements indicated that the small intestinal tissue samples underwent a sharp increase in stiffness over a strain range of 0.19-0.34. The large bowel tissue underwent a similar increase in stiffness over a planar compressive strain range of 0.19-0.40. The regularity of the potassium output results was limited, making it difficult to draw firm conclusions, although there was some indication that the potassium output from small intestinal tissue may change from erratic to approximately linear at a strain of approximately 0.19, while that of the large bowel tissue appeared to be approximately linear over the entire strain range tested. From the force measurements, it is concluded that strain-induced structural change may help provide a useful definition of safe tissue approximation. The possible implications for reduced dehiscence (wound disintegration) and stricture incidence in stapled anastomoses are discussed.

The influence of orthotic devices and vastus medialis strength and timing on patellofemoral loads during running.

OBJECTIVE: To use a musculoskeletal model and simulation of running to examine: (1) the influence of two commonly prescribed treatments for patellofemoral pain (vastus medialis oblique strengthening and orthoses) and (2) the functional significance of timing differences between vastus medialis oblique and vastus lateralis on lateral patellofemoral joint loads. DESIGN: A three-dimensional musculoskeletal model of the lower extremity was used to simulate running at 4 m/s. BACKGROUND: Repetitive and excessive joint loading is often associated with overuse injuries that require clinical treatments to reduce pain and restore function. Affecting one in four runners, patellofemoral pain is one of the most common injuries in running. Although conservative treatments have been reported to successfully treat patellofemoral pain, the effectiveness is often based on subjective or empirical data, which have generated disagreement on the most effective treatment. METHODS: Nine subject specific running simulations were generated and experiments were performed by applying the treatments and timing differences to the nominal simulations. RESULTS: Both treatments significantly reduced the average patellofemoral joint load and the vastus medialis strengthening also significantly reduced the peak patellofemoral joint load. In addition, when the vastus medialis oblique timing was delayed and advanced relative to the vastus lateralis timing, a significant increase and decrease in the joint load was observed, respectively, during the loading response.Conclusions. Increasing vastus medialis oblique strength yielded more consistent results across subjects than the orthosis in reducing patellofemoral joint loads during running. The effect of orthoses was highly variable and sensitive to the individual subject's running mechanics. Vastus medialis oblique activation timing is an important determinant of lateral patellofemoral joint loading during the impact phase. RELEVANCE: These findings indicate that a reduction in patellofemoral pain may be achieved through techniques that selectively increase the vastus medialis oblique strength. Therefore, future studies should be directed towards identifying such techniques. Additionally, the functional significance of timing differences between the vastus medialis oblique and vastus lateralis is an important consideration in patellofemoral pain treatment and orthoses may be beneficial for some patients depending on their running mechanics.

Common and distinct neural substrates for pragmatic, semantic, and syntactic processing of spoken sentences: an fMRI study.

Extracting meaning from speech requires the use of pragmatic, semantic, and syntactic information. A central question is: Does the processing of these different types of linguistic information have common or distinct neuroanatomical substrates? We addressed this issue using functional magnetic resonance imaging (fMRI) to measure neural activity when subjects listened to spoken normal sentences contrasted with sentences that had either (A) pragmatical, (B) semantic (selection restriction), or (C) syntactic (subcategorical) violations sentences. All three contrasts revealed robust activation of the left-inferior-temporal/fusiform gyrus. Activity in this area was also observed in a combined analysis of all three experiments, suggesting that it was modulated by all three types of linguistic violation. Planned statistical comparisons between the three experiments revealed (1) a greater difference between conditions in activation of the left-superior-temporal gyrus for the pragmatic experiment than the semantic/syntactic experiments; (2) a greater difference between conditions in activation of the right-superior and middle-temporal gyrus in the semantic experiment than in the syntactic experiment; and (3) no regions activated to a greater degree in the syntactic experiment than in the semantic experiment. These data show that, while left- and right-superior-temporal regions may be differentially involved in processing pragmatic and lexico-semantic information within sentences, the left-inferior-temporal/fusiform gyrus is involved in processing all three types of linguistic information. We suggest that this region may play a key role in using pragmatic, semantic (selection restriction), and subcategorical information to construct a higher representation of meaning of sentences.

The influence of foot positioning on ankle sprains.

The goal of this study was to examine the influence of changes in foot positioning at touch-down on ankle sprain occurrence. Muscle model driven computer simulations of 10 subjects performing the landing phase of a side-shuffle movement were performed. The relative subtalar joint and talocural joint angles at touchdown were varied, and each subject-specific simulation was exposed to a set of perturbed floor conditions. The touchdown subtalar joint angle was not found to have a considerable influence on sprain occurrence, while increased touchdown plantar flexion caused increased ankle sprain occurrences. Increased touchdown plantar flexion may be the mechanism which causes ankles with a history of ankle sprains to have an increased susceptibility to subsequent sprains. This finding may also reveal a mechanism by which taping of a sprained ankle or the application of an ankle brace leads to decreased ankle sprain susceptibility.

The effects of ankle compliance and flexibility on ankle sprains.

PURPOSE: The goal of this study was to examine the influence of changes in subtalar joint flexibility and compliance on ankle sprain occurrence. METHODS: Muscle model driven simulations of 10 subjects performing the landing phase of a side-shuffle movement were performed. The passive flexibility or compliance of the subtalar joint was varied, and each subject-specific simulation was exposed to a set of perturbed floor conditions. RESULTS: Increases in flexibility and compliance both led to an increase in the occurrence of excessive supination, while changes in flexibility had a greater influence. Changes in flexibility or compliance caused only small changes in the occurrence of excessive supination torques. CONCLUSION: These results suggest that increased mechanical laxity does not directly cause an increase in sprain occurrence during side-shuffle movements.

Meta-analysis of regional brain volumes in schizophrenia.

OBJECTIVE: The authors' goal was to determine whether patients with schizophrenia differ from comparison subjects in regional brain volumes and whether these differences are similar in male and female subjects. METHOD: They conducted a systematic search for structural magnetic resonance imaging (MRI) studies of patients with schizophrenia that reported volume measurements of selected cortical, subcortical, and ventricular regions in relation to comparison groups. They carried out a meta-analysis of the volumes of these regions in the patients with schizophrenia and the comparison subjects using a random effects model; they also used random effects regression analysis to examine the influence of gender on effect sizes. RESULTS: Fifty-eight studies were identified as suitable for analysis; these studies included 1,588 independent patients with schizophrenia. Assuming a volume of 100% in the comparison group, they found that the mean cerebral volume of the subjects with schizophrenia was smaller (98%), but the mean total ventricular volume of the subjects with schizophrenia was greater (126%). Relative to the cerebral volume differences, the regional volumes of the subjects with schizophrenia were 94% in the left and right amygdala, 94% in the left and 95% in the right hippocampus/amygdala, and 93% in the left and 95% in the right parahippocampus. Relative to the global ventricular system differences, the largest differences in ventricular subdivisions were in the right and left body of the lateral ventricle, where the volumes of schizophrenic subjects were 116% and 116%, respectively. For most regions, effect size was not significantly related to gender. CONCLUSIONS: Regional structural differences in patients with schizophrenia include bilaterally reduced volume of medial temporal lobe structures. There is a need for greater integration of results from structural MRI studies to avoid redundant research activity.

A Method for Numerical Simulation of Single Limb Ground Contact Events: Application to Heel-Toe Running.

The objective of this work was to develop a method to simulate single-limb ground contact events, which may be applied to study musculoskeletal injuries associated with such movements. To achieve this objective, a three-dimensional musculoskeletal model was developed consisting of the equations of motion for the musculoskeletal system, and models for the muscle force generation and ground contact elements. An optimization framework and a weighted least-squares objective function were presented that generated muscle stimulation patterns that optimally reproduced subject-specific movement data. Experimental data were collected from a single subject to provide initial conditions for the simulation and tracking data for the optimization. As an example application, a simulation of the stance phase of running was generated. The results showed that the average difference between the simulation and subject's ground reaction force and joint angle data was less than two inter-trial standard deviations. Further, there was good agreement between the model's muscle excitation patterns and experimentally collected electromyography data. These results give confidence in the model to examine musculoskeletal loading during a variety of landing movements and to study the effects of various factors associated with injury. Limitations were examined and areas of improvement for the model were presented.

Supra-regional brain systems and the neuropathology of schizophrenia.

At what levels of brain organization might pathological change in schizophrenia be anatomically expressed: global, regional or supraregional? We hypothesised that brain structure reflects a set of supra-regional anatomical systems with common developmental influences. We conducted an exploratory analysis to identify supraregional brain systems and to investigate whether abnormal brain architecture in schizophrenia is manifested within one or more of these systems. Magnetic resonance (MR) images were acquired from 27 patients with schizophrenia and 37 control subjects. After segmentation and registration of each individual MRI dataset in the standard space of Talairach and Tournoux, grey matter and ventricular-cerebrospinal fluid (CSF) maps were automatically parcellated into 104 regions. We used principal components analysis of the multiple regional grey matter and ventricular-CSF measurements, on all 64 subjects, to extract the five main normative supra-regional systems. The first two of these components represented global variation in grey matter and ventricular-CSF regional measures. We interpreted the other three components as representing supra-regional systems comprising: a frontal-parietal system, a frontal-temporal system and a frontal-basal ganglia system. Schizophrenic group mean scores on the first component (global grey matter-ventricular contrast) and fourth component (frontal-temporal system) were significantly reduced compared to controls. These results suggest that pathological change in schizophrenia may be expressed at two mutually independent levels of anatomical organization: global change in a grey matter/ventricular system and supra-regional change in a frontal-temporal system.

Muscle coordination and function during cutting movements.

PURPOSE: The objectives of this study were to: 1) establish a database of kinematic and EMG data during cutting movements, 2) describe normal muscle function and coordination of 12 lower extremity muscles during cutting movements susceptible to ankle sprains, and 3) identify potential muscle coordination deficiencies that may lead to ankle sprain injuries. METHODS: Kinematic, EMG, and GRF data were collected from 10 recreationally active male subjects during both a side-shuffle and v-cut movement. RESULTS: The data showed that muscles functioned similarly during both movements. The primary function of the hip and knee extensors was to decelerate the center-of-mass during landing and to provide propulsion during toe-off. The hip add/abductors functioned primarily to stabilize the hip rather than provide mechanical power. The ankle plantar flexors functioned to provide propulsion during toe-off, and the gastrocnemius had an additional burst of activity to plantarflex the foot before touchdown during the side-shuffle to help absorb the impact. The tibialis anterior functioned differently during each movement: to dorsiflex and supinate the foot after toe-off in preparation for the next step cycle during the side-shuffle and to dorsiflex the foot before impact to provide the heel-down landing and ankle stability in the stance phase during the v-cut. CONCLUSIONS: The muscles crossing the ankle joint, especially the tibialis anterior and peroneus longus, may play an important role to prevent ankle sprain injuries. Both muscles provided stability about the subtalar joint by preventing excessive joint rotations. Future theoretical studies with forward dynamic simulations incorporating individual muscle actuators are needed to quantify the segment accelerations induced by active muscles which may prevent or lead to ankle sprain injuries.

Mapping of grey matter changes in schizophrenia.

Studies of brain changes in schizophrenia have suggested that the disorder is associated with reductions in both global and regional grey matter. In this study, we used structural neuroimaging to differentiate between these two types of change and to examine regional grey matter throughout the whole brain. Grey matter from magnetic resonance images was segmented and transformed into stereotactic space, and patients with schizophrenia and controls were compared with respect to regional grey matter (after compensating for global grey matter differences). In two preliminary analyses to test our methodology, we demonstrated that: (1) in the transformed grey matter maps, voxel values at the location of the caudate nuclei were correlated with region-of-interest measurements of caudate area in native image space, and (2) the technique detected regional grey matter changes resulting from artificial lesions created in the native images. We then used a factorial design to examine data from two studies, comprising a total of 42 schizophrenics and 52 controls. Analysis of the main effect of schizophrenia on regional grey matter revealed significant reductions in (a) the right temporal pole, insula and amygdala, (b) the left temporal pole, insula and dorsolateral prefrontal cortex.

Investigation of facial recognition memory and happy and sad facial expression perception: an fMRI study.

We investigated facial recognition memory (for previously unfamiliar faces) and facial expression perception with functional magnetic resonance imaging (fMRI). Eight healthy, right-handed volunteers participated. For the facial recognition task, subjects made a decision as to the familiarity of each of 50 faces (25 previously viewed; 25 novel). We detected signal increase in the right middle temporal gyrus and left prefrontal cortex during presentation of familiar faces, and in several brain regions, including bilateral posterior cingulate gyri, bilateral insulae and right middle occipital cortex during presentation of unfamiliar faces. Standard facial expressions of emotion were used as stimuli in two further tasks of facial expression perception. In the first task, subjects were presented with alternating happy and neutral faces; in the second task, subjects were presented with alternating sad and neutral faces. During presentation of happy facial expressions, we detected a signal increase predominantly in the left anterior cingulate gyrus, bilateral posterior cingulate gyri, medial frontal cortex and right supramarginal gyrus, brain regions previously implicated in visuospatial and emotion processing tasks. No brain regions showed increased signal intensity during presentation of sad facial expressions. These results provide evidence for a distinction between the neural correlates of facial recognition memory and perception of facial expression but, whilst highlighting the role of limbic structures in perception of happy facial expressions, do not allow the mapping of a distinct neural substrate for perception of sad facial expressions.

Attenuated frontal activation during a verbal fluency task in patients with schizophrenia.

OBJECTIVE: Functional magnetic resonance imaging was used to study changes in cerebral blood oxygenation in schizophrenic patients during a verbal fluency task. METHOD: Five right-handed male schizophrenic patients and five volunteers matched on demographic variables and verbal fluency performance participated in the study. Echoplanar images were acquired over 5 minutes at 1.5 T while the subjects performed two tasks. The first involved paced silent generation of words beginning with an aurally presented cue letter. This task alternated with paced silent repetition of the aurally presented word "rest." Generic brain activation maps were constructed from individual images by sinusoidal regression and non-parametric hypothesis testing. Between-group differences in the mean power of experimental response were identified on a voxelwise basis by an analysis of covariance that controlled for between-group differences in stimulus-correlated motion. RESULTS: The comparison group showed significant responses in the left prefrontal cortex, the insula bilaterally, the midline supplementary motor area, and the medial parietal cortex. Compared to those subjects, the schizophrenic subjects showed significantly reduced power of response in the left dorsal prefrontal cortex, the inferior frontal gyrus, and the insula but significantly increased power of response in the medial parietal cortex. In both groups frontal and parietal responses were negatively correlated. CONCLUSIONS: Schizophrenic patients displayed attenuated power of response in several frontal regions during word generation but greater power of response in the medial parietal cortex during word repetition.

Does dysplasia cause anatomical dysconnectivity in schizophrenia?

Evidence is reviewed that dysplastic brain development in the second half of pregnancy predisposes to schizophrenia. We suggest that an important corollary of aberrant development at this stage of ontogenesis is abnormal afferentation of the cortical plate, and that this may be macroscopically measurable in terms of abnormal correlational structure in adult brain imaging data. This prediction is tested by analysis of multiple cortical volume measures on magnetic resonance imaging data acquired from 35 male right-handed schizophrenics and 35 matched controls. There are no significant differences between groups in global, intra-hemispheric or inter-hemispheric correlational structure; but schizophrenics are shown to have significantly reduced dependencies between frontal and temporal lobe volumes, and frontal and hippocampal volumes, in the left hemisphere. We conclude that anatomical dysconnectivity (between frontal and temporal cortex) in schizophrenia may be caused by dysplasia.

Passive regulation of impact forces in heel-toe running.

OBJECTIVE: the purpose of this study was to determine whether passive mechanisms can account for impact force regulation with changing shoe hardness. DESIGN: A three-dimensional musculoskeletal model of the lower extremity was developed to simulate impact in running with two different shoe hardnesses. BACKGROUND: Considerable research has focused on developing shoe cushioning to reduce impact forces. However, only minimal changes in peak external impact force have been observed with changes in shoe hardness. It is hypothesized that passive mechanisms can regulate impact forces with changing shoe hardness, without changing muscle activities. METHODS: Initial kinematic inputs for the simulations were measured from nine male subjects performing heel-toe running. Simulations were performed with initial conditions and muscle stimulation patterns held constant while shoe hardness was varied between a hard and a soft condition. RESULTS: There was no significant difference between the soft and hard shoe peak impact forces. Peak rates of loading were greater for the hard shoe than the soft shoe. Muscle forces changed with shoe conditions. For some muscles (including the tibialis anterior) the forces were greater for the hard shoe, whereas for other muscles (including the peroneus) forces were greater for the soft shoe condition. CONCLUSIONS: Peak impact forces with changing shoe conditions can be regulated by passive mechanical changes without changing muscle activities or kinematics before touchdown. RELEVANCE: Potential injury causing loads on internal structures (e.g. muscles, tendons, etc.) during the impact phase of running can depend upon shoe hardness, but are not reflected in changes in external ground reaction force.

Structural brain abnormalities in male schizophrenics reflect fronto-temporal dissociation.

BACKGROUND: Many studies have separately reported abnormalities of frontal and temporal lobe structures in schizophrenia, but little is known of structural fronto-temporal associations in this condition. We investigated whether male patients with chronic schizophrenia would show abnormal patterns of correlation between regional brain volumes. METHODS: Structural magnetic resonance images of the brain in 42 patients were compared with 43 matched unaffected controls. We explored the pattern of association between regional brain volumes by correlational analyses, and non-parametrically tested for significance of between-group differences by randomization. RESULTS: The schizophrenics demonstrated significant volume deficits in several brain regions (left temporal lobe and hippocampus, right dorsolateral prefrontal cortex), and significant volume increases in the ventricular system (third ventricle and left temporal horn of the lateral ventricle). Controls demonstrated large positive correlations (r > 0.4) between prefrontal and temporal lobe regions. By contrast, inter-regional correlations significantly reduced in schizophrenics included those between prefrontal, anterior cingulate and temporal regions, and between posterior cingulate and hippocampus (P < 0.05). The most salient abnormality in patients was a dissociation between prefrontal and superior temporal gyrus volumes (P < 0.01). CONCLUSIONS: These results support the existence of a relative 'fronto-temporal dissociation' in schizophrenia which we suggest may be due to lack of mutually trophic influences during frontal and temporal lobe development.

Auditory hallucinations and the temporal cortical response to speech in schizophrenia: a functional magnetic resonance imaging study.

OBJECTIVE: The authors explored whether abnormal functional lateralization of temporal cortical language areas in schizophrenia was associated with a predisposition to auditory hallucinations and whether the auditory hallucinatory state would reduce the temporal cortical response to external speech. METHOD: Functional magnetic resonance imaging was used to measure the blood-oxygenation-level-dependent signal induced by auditory perception of speech in three groups of male subjects: eight schizophrenic patients with a history of auditory hallucinations (trait-positive), none of whom was currently hallucinating; seven schizophrenic patients without such a history (trait-negative); and eight healthy volunteers. Seven schizophrenic patients were also examined while they were actually experiencing severe auditory verbal hallucinations and again after their hallucinations had diminished. RESULTS: Voxel-by-voxel comparison of the median power of subjects' responses to periodic external speech revealed that this measure was reduced in the left superior temporal gyrus but increased in the right middle temporal gyrus in the combined schizophrenic groups relative to the healthy comparison group. Comparison of the trait-positive and trait-negative patients revealed no clear difference in the power of temporal cortical activation. Comparison of patients when experiencing severe hallucinations and when hallucinations were mild revealed reduced responsivity of the temporal cortex, especially the right middle temporal gyrus, to external speech during the former state. CONCLUSIONS: These results suggest that schizophrenia is associated with a reduced left and increased right temporal cortical response to auditory perception of speech, with little distinction between patients who differ in their vulnerability to hallucinations. The auditory hallucinatory state is associated with reduced activity in temporal cortical regions that overlap with those that normally process external speech, possibly because of competition for common neurophysiological resources.