Michael D. Noseworthy

Dissociation of response inhibition and performance monitoring in the stop signal task using event‐related fMRI

We examined the neural substrate of motor response inhibition and performance monitoring in the stop signal task (SST) using event‐related functional magnetic resonance imaging (fMRI). The SST involves a go task and the occasional requirement to stop the go response. We posit that both the go and the stop phases of the SST involve components of inhibition and performance monitoring. The goal of this study was to determine whether inhibition and performance monitoring during go and stop phases of the task activated different networks. We isolated go‐phase activities underlying response withholding, monitoring, and sensorimotor processing and contrasted these with successful inhibition to identify the substrate of response inhibition. Error detection activity was isolated using trials in which a stop signal appeared but the response was executed. These trials were modeled as a hand‐specific go trial followed by error processing. Cognitive go‐phase processes included response withholding and monitoring and activated right prefrontal and midline networks. Response withdrawal additionally activated right inferior frontal gyrus and basal ganglia (caudate). Error detection invoked by failed inhibition activated dorsal anterior cingulate cortex (dACC) and right middle frontal Brodmanns area 9. Our results confirm that there are distinct aspects of inhibition and performance monitoring functions which come into play at various phases within a given trial of the SST, and that these are separable using fMRI. Hum Brain Mapp, 2007.

Diffusion tensor imaging in evaluation of human skeletal muscle injury

To explore the capability and reliability of diffusion tensor magnetic resonance imaging (DTI) in the evaluation of human skeletal muscle injury.

Diffusion tensor imaging of white matter after cranial radiation in children for medulloblastoma: Correlation with IQ

Treatment of children with cranial-spinal radiation (CSR) for brain tumors is associated with adverse intellectual outcome and white matter damage. However, the correlation between IQ and measures of white matter integrity has received little attention. We examined apparent diffusion coefficient (ADC), fractional anisotropy (FA), and intelligence in pediatric patients treated with CSR for medulloblastoma relative to control subjects. ADC and FA measures were obtained for eight patients and eight control children and evaluated in multiple regions of interest in the cerebral hemispheres. Mean ADC and mean FA for each region were calculated, group differences were evaluated, and the relationship between these measures and intelligence were examined. In our study group, decreased IQ was associated with increased ADC and decreased FA (P < 0.01). Mean IQ for the CSR group was lower than that for the control group, but the difference was not significant when controlling for overall mean FA or ADC (P > 0.10). Overall mean FA was lower and ADC was higher in the CSR group relative to controls (P < 0.01). Specifically, FA was lower in the genu of the corpus callosum, the anterior and posterior limbs of the internal capsule, inferior frontal white matter, and high frontal white matter, and ADC was higher in all regions in patients relative to controls (P < 0.01). Compromised white matter integrity was observed for multiple regions within the cerebral hemispheres following CSR. A novel finding was that microscopic damage in normal-appearing white matter, as indexed by higher ADC and lower FA, was related to poor intellectual outcome relative to age-matched controls.

White matter growth as a mechanism of cognitive development in children

We examined the functional role of white matter growth in cognitive development. Specifically, we used hierarchical regression analyses to test the unique contributions of age versus white matter integrity in accounting for the development of information processing speed. Diffusion tensor imaging was acquired for 17 children and adolescents (age range 6-17 years), with apparent diffusion coefficient (ADC) and fractional anisotropy (FA) calculated for 10 anatomically defined fiber pathways and 12 regions of hemispheric white matter. Measures of speeded visual-spatial searching, rapid picture naming, reaction time in a sustained attention task, and intelligence were administered. Age-related increases were evident across tasks, as well as for white matter integrity in hemispheric white matter. ADC was related to few measures. FA within multiple hemispheric compartments predicted rapid picture naming and standard error of reaction time in sustained attention, though it did not contribute significantly to the models after controlling for age. Independent of intelligence, visual-spatial searching was related to FA in a number of hemispheric regions. A novel finding was that only right frontal-parietal regions contributed uniquely beyond the effect of age in accounting for performance: age did not contribute to visual-spatial searching when FA within these regions was first included in the models. Considering we found that both FA in right frontal-parietal regions and speed of visual-spatial searching increased with age, our findings are consistent with the growth of regional white matter organization as playing an important role in increased speed of visual searching with age.

Cortical thickness of the frontopolar area in typically developing children and adolescents

The development of the frontopolar cortex (FPC) through late childhood and adolescence was investigated using measures of cortical thickness. T(1)-weighted structural MRIs from 35 typically developing participants aged 8-20 years were used to construct 3D models of the brain, from which cortical thickness was measured. There was a significant inverse association between age and cortical thickness, such that cortical thickness decreased as age increased between 8 and 20 years. There was no effect of laterality or gender on cortical thickness.

The relations between white matter and declarative memory in older children and adolescents.

Neural communication between the temporal and frontal cortex underlies mature declarative memory skills. The integrity of white matter pathways connecting these regions is likely critical in supporting this communication. Little is known about the relationship between white matter and declarative memory in older children and adolescents, an age period when advanced function in this domain is established. We acquired diffusion tensor imaging (DTI) data for 22 participants (9-15 years). Multiple DTI indices were calculated for the uncinate fasciculus - the major white matter tract connecting temporal and prefrontal regions. Indices were also calculated for compartments of lobar and posterior fossa white matter. Measures of visual-perceptual and auditory-verbal memory were administered. Correlation analyses were used to examine the relations between age, DTI indices, and memory. Voxel-wise analyses were also conducted. Age-related increases in FA were evident for frontal, parietal, and temporal hemispheric white matter. Proficiency in auditory-verbal memory was related to white matter integrity in the left uncinate fasciculus as well as parietal and cerebellar white matter. Proficiency in recall of a complex design was related to integrity within parietal and temporal regions. Our findings support the role of white matter in facilitating connectivity between cerebral regions important for declarative memory.

Skeletal muscle metabolic dysfunction in obesity and metabolic syndrome.

Obesity and the related metabolic syndrome have become a worldwide epidemic. Inactivity appears to be a primary causative factor in the pathogenesis of this obesity and metabolic syndrome. There are two possible, perhaps not mutually exclusive, events that may lead to intramyocellular lipid accumulation and mitochondrial dysfunction in patients with obesity. First, obesity, with high intake-associated lipid accumulation in muscle may interfere with cellular mitochondrial function through generation of reactive oxygen species leading to lipid membrane peroxidative injury and disruption of mitochondrial membrane-dependent enzymes. This in turn leads to impaired oxidative metabolism. Secondly, a primary defect in mitochondrial oxidative metabolism may be responsible for a reduction in fatty acid oxidation leading to intramyocellular lipid accumulation as a secondary event. Non-invasive techniques such as proton (1H) and phosphorus (31P) magnetic resonance spectroscopy, coupled with specific magnetic resonance imaging techniques, may facilitate the investigation of the effects of various ergometric interventions on the pathophysiology of obesity and the metabolic syndrome. Exercise has positive effects on glucose metabolism, aerobic metabolism, mitochondrial density, and respiratory chain proteins in patients with metabolic syndrome, and we propose that this may be due to the exercise effects on AMP kinase, and a prospective physiological mechanism for this benefit is presented. A physiological model of the effect of intramyocellular lipid accumulation on oxidative metabolism and insulin mediated glucose uptake is proposed.

Advanced MR Imaging Techniques for Skeletal Muscle Evaluation

Diagnostic imaging procedures for muscle evaluation have typically provided basic information concerning gross anatomical change resulting from pathology. Up until recently the musculoskeletal radiologist has been fairly limited to using simple proton-density weighted fat-saturated and short tau inversion recovery magnetic resonance imaging scans for assessment of skeletal muscle. Recent advances, however, have resulted in development of newer scans and postprocessing methods that provide much more than gross muscle structure. Scans providing fine structure, muscle function, and metabolism can easily be done using clinical scanners. Here we describe how diffusion tensor imaging (DTI) and blood oxygenation level-dependent (BOLD) imaging together can provide detailed information on muscle structural and functional changes. DTI is useful for visualizing muscle tears, and BOLD can be used for vascular insufficiency (e.g., compartment syndrome). In clinical sites that are gaining experience using these techniques, imaging of muscle pathology is becoming increasingly thorough. In the future, these methods will reduce the need for invasive approaches to study muscle pathology.

Skeletal Muscle Metabolism in Cystic Fibrosis and Primary Ciliary Dyskinesia

Previous studies have reported differences in muscle function and metabolism between patients with cystic fibrosis (CF) and healthy controls (HC), but it is currently unknown whether these abnormalities are specific to CF or also seen in other airway diseases. In this study, we used magnetic resonance spectroscopy (MRS) during exercise to assess muscle metabolism in CF patients. Twenty patients with CF and 20 age, gender, and habitual activity-matched HCs and a respiratory disease comparison group with primary ciliary dyskinesia (PCD; n = 10) were studied. 31Phosphorus MRS (31P-MRS) was used to characterize muscle bioenergetic metabolism at rest and after high-, moderate-, and low-intensity exercise. CF patients exhibited lower resting ATP/phosphocreatine (PCr) ratio and significantly higher end-exercise pH values compared with both HC and PCD patients. Both CF and PCD patients demonstrated significantly slower PCr recovery time constants after high-intensity exercise. Our results suggest that not only there are specific abnormalities of muscle metabolism in CF patients but also there is a nonspecific impact of respiratory disease on muscle function.

Early Cerebral Small Vessel Disease and Brain Volume, Cognition, and Gait

Decline in cognitive function begins by the 40s, and may be related to future dementia risk. We used data from a community‐representative study to determine whether there are age‐related differences in simple cognitive and gait tests by the 40s, and whether these differences were associated with covert cerebrovascular disease on magnetic resonance imaging (MRI).