Biomedical subjects

P M Matthews

Publications and source records attributed to P M Matthews.

At least 19 recordsLinked to original sources

PubMed2000

An fMRI study of the lateralization of motor cortex activation in acallosal patients.

Transcranial magnetic stimulation (TMS) studies have suggested that callosal afferents may mediate inhibition of the ipsilateral motor cortex (IMC) during unilateral hand movements. To test this concept, we used fMRI to determine whether acallosal patients have increased IMC activation with either complex or simple unilateral finger movements. Neither the localization of motor cortical regions activated, the volumes of activation, or the relative hemispheric lateralization of activations were different between the patients and normal controls. The potential callosal inhibitory pathway identified by TMS therefore does not appear to contribute to the interhemispheric suppression of physiologically relevant activations in the motor cortex as measured by fMRI.

Adult↗

PubMed2000

Learning about pain: the neural substrate of the prediction error for aversive events.

Associative learning is thought to depend on detecting mismatches between actual and expected experiences. With functional magnetic resonance imaging (FMRI), we studied brain activity during different types of mismatch in a paradigm where contrasting-colored lights signaled the delivery of painful heat, nonpainful warmth, or no stimulation. When painful heat stimulation was unexpected, there was increased FMRI signal intensity in areas of the hippocampus, superior frontal gyrus, cerebellum, and superior parietal gyrus that was not found with mismatch between expectation and delivery of nonpainful warmth stimulation. When painful heat stimulation was unexpectedly omitted, the FMRI signal intensity decreased in the left superior parietal gyrus and increased in the other regions. These contrasting activation patterns correspond to two different mismatch concepts in theories of associative learning (Rescorla-Wagner, temporal difference vs. Pearce-Hall, Mackintosh). Searching for interventions to specifically modulate activation of these brain regions therefore offers an approach to identifying new treatments for chronic pain, which often has a substantial associative learning component.

Association Learning↗

PubMed2000

Attention to touch modulates activity in both primary and secondary somatosensory areas.

We used fMRI to establish whether attention to touch enhances somatosensory cortical activity. Subjects received somatosensory and visual stimulation and were instructed to attend selectively to one modality during alternating stimulus detection periods interspersed with rest periods during which no stimulus was delivered. The maximum signal change for each task versus rest was measured in anatomically defined regions of interest for each subject. Attended touch produced greater signal change than unattended touch in primary (S1) and secondary (S2) somatosensory cortex. In contrast to the conclusions of some previous studies, we found that the enhancement of activation with attention was at least as great in S1 as in S2. The attentional effect was unilateral in S1 and bilateral in S2 and the somatosensory insula.

Adult↗

PubMed2000

Using fMRI to study recovery from acquired dysphasia.

We have used functional magnetic resonance imaging (fMRI) to characterize brain activations associated with two distinct language tasks performed by a 28-year-old woman after partial recovery from dysphasia due to a left frontal hemispheric ischemic stroke. MRI showed that her ischemic lesion extended posteriorly from the left inferior frontal to the perisylvian cortex. fMRI scans of both language tasks revealed substantial differences in activation pattern relative to controls. The nature of this difference was task-specific. During performance of a verbal semantic decision task, the patient, in contrast to controls, activated a network of brain areas that excluded the inferior frontal gyrus (in either hemisphere). A second task involving rhyme judgment was designed to place a heavier cognitive load on language production processes and activated the left inferior frontal gyrus (Broca's area) strongly in normal controls. During this task, the most prominent frontal activation in the patient occurred in the right homologue of Broca's area. Subsequent analysis of this data by methods able to deal with responses of changing amplitude revealed additional, less sustained recruitment by the patient of cortex adjacent to the infarct in the region inferior to Broca's area during rhyming. These results suggest that in addition to changes in cognitive strategy, recovery from dysphasia could be mediated by both the preservation of neuronal networks in and around the infarct and the use of homologous regions in the contralateral hemisphere.

Adult↗

PubMed2000

Relating axonal injury to functional recovery in MS.

A patient was followed after the new onset of hemiparesis from relapse of MS with serial MR spectroscopy and functional MRI. The association of clinical improvement with recovery of N-acetylaspartate, a marker of neuronal integrity, and progressive reduction of abnormally large functional MRI cortical activation with movement demonstrates that dynamic reorganization of the motor cortex accompanies remission of MS.

Adult↗

PubMed2000

Axonal injury or loss in the internal capsule and motor impairment in multiple sclerosis.

OBJECTIVE: To test the hypothesis that axonal damage extending into primarily normal-appearing white matter is clinically important by comparing the concentrations of N-acetylaspartate (NAA) bilaterally within the internal capsule with lateralization of motor impairment in patients with multiple sclerosis (MS) and persistent asymmetrical motor deficit. DESIGN: We performed magnetic resonance spectroscopy and T2-weighted imaging of the internal capsule, calculated central motor conduction times, and related these results to measures of motor function asymmetry in 12 patients with MS. RESULTS: Levels of NAA from normal-appearing white matter of the internal capsule in patients with MS were significantly lower than those in control subjects (P = .05). Side-to-side differences in NAA levels were also significantly greater in patients with MS than in controls (P = .01). There was a correlation between asymmetry in motor function for the left and right limbs and asymmetry of internal capsule NAA concentrations (r = 0.60; P = .04). This correlation seemed slightly stronger when tests specifically of arm and hand motor asymmetry were considered alone. Central motor conduction times were abnormal in most patients with MS and showed a side-to-side difference that also correlated with asymmetry in motor function. CONCLUSION: Our demonstration of a graded association between NAA concentrations within primarily normal-appearing white matter of a specific tract and functional impairments referable to that tract suggests that axonal pathology distant from macroscopic lesions might be an important determinant of disability in MS.

Adult↗

PubMed2000

Susceptibility-induced loss of signal: comparing PET and fMRI on a semantic task.

Functional magnetic resonance imaging (fMRI) has become a popular tool for investigations into the neural correlates of cognitive activity. One limitation of fMRI, however, is that it has difficulty imaging regions near tissue interfaces due to distortions from macroscopic susceptibility effects which become more severe at higher magnetic field strengths. This difficulty can be particularly problematic for language tasks that engage regions of the temporal lobes near the air-filled sinuses. This paper investigates susceptibility-induced signal loss in the temporal lobes and proposes that by defining a priori regions of interest and using the small-volume statistical correction of K. J. Worsley, S. Marrett, P. Neelin, A. C. Vandal, K. J. Friston, and A. C. Evans (1996, Hum. Brain Mapp. 4: 58-83), activations in these areas can sometimes be detected by increasing the statistical power of the analysis. We conducted two experiments, one with PET and the other with fMRI, using almost identical semantic categorization paradigms and comparable methods of analysis. There were areas of overlap as well as differences between the PET and fMRI results. One anticipated difference was a lack of activation in two regions in the temporal lobe on initial analyses in the fMRI data set. With a specific region of interest, however, activation in one of the regions was detected. These experiments demonstrate three points: first, even for almost identical cognitive tasks such as those in this study, PET and fMRI may not produce identical results; second, differences between the two methods due to macroscopic susceptibility artifacts in fMRI can be overcome with appropriate statistical corrections, but only partially; and third, new data acquisition paradigms are necessary to fully deal with susceptibility-induced signal loss if the sensitivity of the fMRI experiment to temporal lobe activations is to be enhanced.

Adult↗

PubMed2000

Correlating magnetic resonance imaging markers of axonal injury and demyelination in motor impairment secondary to stroke and multiple sclerosis.

The primary pathological mechanisms in stroke and multiple sclerosis (MS) are very different but in both diseases, impairment may arise from a final common pathway of axonal damage. We aimed to examine the relationship between motor impairment, magnetisation transfer ratio (MTR) (an index of demyelination), and N-acetyl aspartate (NAA) loss (an index of axonal injury) localised to the descending motor pathways in stroke and MS. Twelve patients between 1 and 10 months after first ischaemic stroke causing a motor deficit and 12 patients with stable MS with asymmetric motor deficit were examined. T(2)-weighted imaging of the brain together with MTR and proton (voxel 1.5x2x2 cm(3)) MRS localised to the posterior limb of the internal capsule were performed and correlated to a composite motor deficit score. MTR and NAA in the internal capsule were reduced in both stroke and MS patients compared to controls. NAA loss correlated with motor deficit score in both stroke and MS (p<0.001 and p = 0.04, respectively). Correlations were seen between MTR and motor deficit (p<0.001) MTR and NAA loss (p <0.001) in stroke patients but not in MS patients. Axonal injury in the descending motor tracts would appear to be an important determinant of motor impairment in both stroke and MS. In stroke, MTR measures of demyelination are closely related to axonal damage and thus also correlate with motor deficit. However in MS, MTR measures of demyelination do not correlate with NAA loss or motor deficit suggesting that demyelination and gliosis may occur independently of axonal damage and are less closely linked with functional impairment.

Adult↗

PubMed2000

Muscle responses to exercise in health and disease.

Exercise intolerance is a common presenting symptom. The physiology of exercise intolerance in illustrative neurologic diseases is reviewed. Roles for exercise testing are identified, particularly in the evaluation of metabolic myopathies. The potential benefits of low intensity aerobic exercise training are described.

Energy Metabolism↗

PubMed2000

Regional axonal loss in the corpus callosum correlates with cerebral white matter lesion volume and distribution in multiple sclerosis.

Previous imaging studies have suggested that there is substantial axonal loss in the normal-appearing white matter (NAWM) of brains from multiple sclerosis patients and that this axonal loss may be an important determinant of disability. Recently, substantial axonal loss in the NAWM has been confirmed directly in post-mortem tissue. Whether the NAWM changes occur as a consequence of damage to axons traversing lesions or to a more diffuse injury process is uncertain. Using formalin-fixed brains of eight multiple sclerosis patients and eight age-matched controls, we examined the relationship between demyelinating lesion load in three volumes of the cerebral white matter and the loss of axons in NAWM of the corresponding three projection regions (anterior, middle, posterior) in the corpus callosum (CC). There was a significant loss of calculated total number of axons crossing the CC in each of the three regions relative to the non-multiple sclerosis controls. Strong correlations were found between the regional lesion load and both the axonal density (r = -0.673, P: = 0.001) and the total estimated number of axons crossing the corresponding projection area in the CC (r = -0. 656, P: = 0.001) for the patients. This suggests that Wallerian degeneration of axons transected in the demyelinating lesions makes a major contribution to the substantial, diffuse loss of axons in the NAWM in multiple sclerosis. These findings emphasize the need to consider the consequences of multiple sclerosis lesions in terms of both local and distant effects in functionally connected regions of the brain.

Adult↗

PubMed2000

Relating MRI changes to motor deficit after ischemic stroke by segmentation of functional motor pathways.

BACKGROUND AND PURPOSE: Infarct size on T2-weighted MRI correlates only modestly with outcome, particularly for small strokes. This may be largely because of differences in the locations of infarcts and consequently in the functional pathways that are damaged. To test this hypothesis quantitatively, we developed a "mask" of the corticospinal pathway to determine whether the extent of stroke intersection with the pathway would be more closely related to clinical motor deficit and axonal injury in the descending motor pathways than total stroke lesion volume. METHODS: Eighteen patients were studied > or =1 month after first ischemic stroke that caused a motor deficit by use of brain T2-weighted imaging, MR spectroscopic (MRS) measurements of the neuronal marker compound N-acetyl aspartate in the posterior limb of the internal capsule, and motor impairment and disability measures. A corticospinal mask based on neuroanatomic landmarks was generated from a subset of the MRI data. The maximum proportion of the cross-sectional area of this mask occupied by stroke was determined for each patient after all brain images were transformed into a common stereotaxic brain space. RESULTS: There was a significant linear relationship between the maximum proportional cross-sectional area of the corticospinal mask occupied by stroke and motor deficit (r(2)=0.82, P<0.001), whereas the relationship between the total stroke volume and motor deficit was better described by a cubic curve (r(2)=0.76, P<0.001). Inspection of the data plots showed that the total stroke volume discriminated poorly between smaller strokes with regard to the extent of associated motor deficit, whereas the maximum proportion of the mask cross-sectional area occupied by stroke appeared to be a more discriminatory marker of motor deficit and also N-acetyl aspartate reduction. CONCLUSIONS: Segmentation of functional motor pathways on MRI allows estimation of the extent of damage specifically to that pathway by the stroke lesion. The extent of stroke intersection with the motor pathways was more linearly related to the magnitude of motor deficit than total lesion volume and appeared to be a better discriminator between small strokes with regard to motor deficit. This emphasizes the importance of the anatomic relationship of the infarct to local structures in determining functional impairment. Prospective studies are necessary to assess whether this approach would allow improved early estimation of prognosis after stroke.

Adult↗

PubMed2000

Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis.

We assessed axonal loss in the normal appearing white matter of the corpus callosum in postmortem brains of patients with multiple sclerosis, using quantitative measures of both axonal density and white matter atrophy. The calculated total number of axons was reduced significantly (mean +/- SD, 5.4 x 10(7) +/- 3.1 x 10(7)) compared with normal controls (11.6 x 10(7) +/- 2.2 x 10(7), p = 0.001) with a reduction both in axonal density (median, 34%; range, 16-56%; p = 0.004) and area (mean +/- SD: multiple sclerosis, 584 +/- 170 mm2; controls, 871 +/- 163 mm2; p = 0.004). These results confirm substantial axonal loss in the normal appearing white matter and demonstrate that measures of both axonal density and white matter volume are necessary to appreciate the full extent of axonal loss.

Adult↗

PubMed2000

The motor cortex shows adaptive functional changes to brain injury from multiple sclerosis.

Although multiple sclerosis (MS) is an inflammatory demyelinating disease, there can be substantial axonal injury and loss. We therefore hypothesized that adaptive cortical changes may contribute to limiting functional impairment, particularly in the early stages of the disease. To test our hypothesis, we used functional magnetic resonance imaging (MRI) to characterize the localization and volumes of activation in the motor cortex during simple flexion-extension finger movements. There were differences in the patterns of cortical activation with movement between the 12 MS patients and the 12 normal controls. All patients showed greater relative supplementary motor area activation than did the normal controls. The relative hemispheric lateralization of sensorimotor cortex (SMC) activation decreased in direct proportion to the total cerebral T2-weighted MRI hyperintense lesion load. This appeared to be due primarily to increases in ipsilateral SMC activation with increasing lesion load in white matter of the hemisphere contralateral to the limb moved. The center of activation in the contralateral SMC was shifted a mean of 8.8 mm posterior in patients relative to controls, providing additional evidence for cortical adaptive responses to injury. The magnitude of this posterior shift in the SMC activation increased with greater T2 lesion loads. These observations demonstrate that cortical recruitment for simple finger movements can change both quantitatively and qualitatively in the SMCs of MS patients, suggesting that cortical reorganization or "unmasking" of latent pathways can contribute to functional recovery. These adaptive changes are another factor potentially limiting the strength of the relationship between MRI measures of pathology and clinical measures of disability.

Adaptation, Physiological↗

PubMed2000

Proton MR spectroscopy to assess axonal damage in multiple sclerosis and other white matter disorders.

Proton MR spectroscopy allows in vivo measurement of N-acetylaspartate in white matter, providing a biochemical index of axonal integrity. Several recent studies of patients with multiple sclerosis and other white matter disorders have shown both transient and sustained decreases in N-acetylaspartate in white matter lesions and in brain regions appearing normal on conventional MRI. These data have emphasised that a substantial amount of axonal damage or loss (presumably secondary to myelin pathology) is consistently present in most of these disorders. Recent post-mortem studies support these results. In contrast to changes seen with conventional MR imaging, decreases in N-acetylaspartate have shown a close correlation with changes in neurological status. This suggests that axonal damage may be more relevant than demyelination for determining chronic functional impairments in primary white matter diseases. Thus, serial measurement of brain N-acetylaspartate with proton MR spectroscopy can provide a reliable and clinically-relevant monitor of disease evolution. As pathological changes responsible for long-term morbidity are logically important targets for therapeutic agents, early treatment directed at axonal protection should be useful in these disorders.

Axons↗

PubMed1999

Dichloroacetate stabilizes the mutant E1alpha subunit in pyruvate dehydrogenase deficiency.

OBJECTIVE: To determine whether dichloroacetate (DCA) treatment can increase pyruvate dehydrogenase (PDH) activity in PDH-deficient cell lines harboring pathogenic mutations in the PDH E1alpha gene. BACKGROUND: PDH deficiency is a nuclear-encoded mitochondrial disorder and a major recognized cause of neonatal encephalomyopathies associated with primary lactic acidosis. Over the last decade, DCA has been used therapeutically, but it has not been clear which patients might benefit. Recent studies suggest that chronic DCA treatment may act by increasing the stability of mutant E1alpha polypeptide. The relative effects of DCA treatment on PDH-deficient cell lines with E1alpha mutations primarily affecting polypeptide stability or catalytic activity were determined and the mechanism of enhancement of residual PDH activity explored. METHODS: The effect of chronic 5-day DCA treatment on PDH activity was assessed in PDH-deficient cell lines containing the R378H, R141Q, K387(FS), and R302C E1alpha mutations. PDH subunit turnover and steady-state E1alpha levels before and after DCA treatment were measured in the R378H mutant line. RESULTS: Chronic DCA treatment resulted in 25% (p = 0.0434), 31% (p = 0.0014) increases in PDH activity in the K387(FS) and R378H cell lines, both of which are associated with decreased mutant polypeptide stability. In the R378H mutant cell line, chronic DCA treatment increased steady-state E1alpha levels and slowed the rate of E1alpha turnover twofold. In contrast, PDH activity did not change in the chronically DCA-treated R302C mutant line, in which the mutant polypeptide has normal stability and reduced catalytic activity. CONCLUSIONS: Chronic DCA treatment can increase PDH activity in PDH-deficient cell lines harboring mutations that affect E1alpha stability, suggesting a biochemical criterion by which DCA-responsive patients might be selected.

Cell Line↗

PubMed1999

Delayed labelling of brain glutamate after an intra-arterial [13C]glucose bolus: evidence for aerobic metabolism of guinea pig brain glycogen store.

Glycogen in glial cells is the largest store of glucose equivalents in the brain. Here we describe evidence that brain glycogen contributes to aerobic energy metabolism of the guinea pig brain in vivo. Five min after an intra-arterial bolus injection of d-[U-14C]glucose, 28+/-11% of the radioactivity in brain tissue was associated with the glycogen fraction, indicating that a significant proportion of labelled glucose taken up by the brain is converted to glycogen shortly after bolus infusion. Incorporation of 13C-label into lactate generated by brains made ischaemic after d-[1-13C]glucose injection confirms that these glucose equivalents can be mobilised for anaerobic glucose metabolism. Aerobic metabolism was monitored by following the time course of 13C-incorporation into glutamate in guinea pig cortex and cerebellum in vivo. After an intra-arterial bolus injection of d-[1-13C]glucose, glutamate labelling reached a maximum 40-60 min after injection, suggesting that a slowly metabolised pool of labelled glucose equivalents was present. As the concentration of 13C-labelled glucose in blood was shown to decrease below detectable levels within 5 min of bolus injection, this late phase of glutamate labelling must occur with mobilisation of a brain storage pool of labelled glucose equivalents. We interpret this as evidence that glucose equivalents in glycogen may contribute to energy metabolism in the aerobic guinea pig brain.

Aerobiosis↗

PubMed1999

Dissociating pain from its anticipation in the human brain.

The experience of pain is subjectively different from the fear and anxiety caused by threats of pain. Functional magnetic resonance imaging in healthy humans was applied to dissociate neural activation patterns associated with acute pain and its anticipation. Expectation of pain activated sites within the medial frontal lobe, insular cortex, and cerebellum distinct from, but close to, locations mediating pain experience itself. Anticipation of pain can in its own right cause mood changes and behavioral adaptations that exacerbate the suffering experienced by chronic pain patients. Selective manipulations of activity at these sites may offer therapeutic possibilities for treating chronic pain.

Adult↗

PubMed1999

Mitochondrial enzyme expression in the hippocampus in relation to Alzheimer-type pathology.

Recent reports have suggested that mitochondrial dysfunction may contribute to the progression of the pathology of Alzheimer's disease (AD). However, both increases and decreases in the activity of cytochrome oxidase have been described in the hippocampi of AD patients. In this study we used immunohistochemistry and quantitative autoradiographic methods to study the expression pattern of two cytochrome oxidase subunit proteins (nuclear-encoded COX IV and mitochondrial-encoded COX I) in the hippocampus in relation to the development of AD-type pathology. We found heterogeneous expression of both COX subunits in AD with an increased expression of both subunit proteins in healthy, non-tangle-bearing, neurones but absence of both subunit proteins in tangle-bearing neurones. Levels of COX IV but not of COX I were related to the amount of hyperphosphorylated tau accumulated in the same hippocampal region but not to the amount of amyloid deposited in sporadic AD. In Down's syndrome COX I and COX IV were similarly increased in the presence of AD pathology in non-tangle-bearing neurones. However, in these cases levels of enzyme expression were correlated to the amount of amyloid accumulation but not the amount of hyperphosphorylated tau in the hippocampus. We believe that heterogeneity of expression of mitochondrial enzyme proteins between neurones may contribute to the conflicting conclusions in previous reports regarding relative levels of cytochrome oxidase activity in the hippocampus in AD. We hypothesise that the increased mitochondrial enzyme expression in healthy-appearing neurones of AD brains may represent a physiological response to increased functional demand on surviving neurones as a consequence of AD-related neuronal pathology.

Adolescent↗