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Biomedical subjects

K M Welch

Publications and source records attributed to K M Welch.

At least 19 recordsLinked to original sources
PubMed2000

Headache and major depression: is the association specific to migraine?

OBJECTIVE: To examine the relationship between migraine and major depression, by estimating the risk for first-onset major depression associated with prior migraine and the risk for first migraine associated with prior major depression. We also examined the extent to which comorbidity with major depression is specific to migraine or is observed in other severe headaches. METHODS: Representative samples of persons 25 to 55 years of age with migraine or other severe headaches (i.e., disabling headaches without migraine features) and controls with no history of severe headaches were identified by a telephone survey and later interviewed in person to ascertain history of common psychiatric disorders. RESULTS: Lifetime prevalence of major depression was approximately three times higher in persons with migraine and in persons with severe headaches compared with controls. Significant bidirectional relationships were observed between major depression and migraine, with migraine predicting first-onset depression and depression predicting first-onset migraine. In contrast, persons with severe headaches had a higher incidence of first-onset major depression (hazard ratio = 3.6), but major depression did not predict a significantly increased incidence of other severe headaches (hazard ratio = 1.6). CONCLUSIONS: The contrasting results regarding the relationship of major depression with migraine versus other severe headaches suggest that different causes may underlie the co-occurrence of major depression in persons with migraine compared with persons with other severe headaches.

Adult↗
PubMed2000

Effects of the anti-migraine drug sumatriptan on muscle energy metabolism: relationship to side-effects.

Sumatriptan succinate (Imitrex) is a 5-HT (5-hydroxytryptamine) agonist used for relief of migraine symptoms. Some individuals experience short-lived side-effects, including heaviness of the limbs, chest heaviness and muscle aches and pains. The effects of this drug on skeletal muscle energy metabolism were studied during short submaximal isometric exercises. We studied ATP flux from anaerobic glycolysis (An Gly), the creatine kinase reaction (CK) and oxidative phosphorylation (Ox Phos) using 31P nuclear magnetic resonance spectroscopy (31P MRS) kinetic data collected during exercise. It was found that side-effects induced acutely by injection of 6 mg sumatriptan succinate s.c. were associated with reduced oxygen storage in peripheral skeletal muscle 5-20 min after injection as demonstrated by a transient reduction in mitochondrial function at end-exercise. These results suggest that mild vasoconstriction in peripheral skeletal muscle is associated with the action of sumatriptan and is likely to be the source of the side-effects experienced by some users. Migraine with aura patients were more susceptible to this effect than migraine without aura patients.

Adenosine Triphosphate↗
PubMed2000

Language hemispheric dominance in patients with congenital lesions of eloquent brain.

OBJECTIVE: In 90% of normal subjects, the left hemisphere is dominant for language function. We investigated whether congenital lesions of the left perisylvian regions altered cortical language representation in right-handed individuals. METHODS: Using functional magnetic resonance imaging, we studied language hemispheric dominance in five right-handed adult patients with congenitally acquired arteriovenous malformations (AVMs) originating from left hemispheric cortical language regions. The AVMs had not caused neurological symptoms during early development, but patients presented as adults with migraine, seizure, or minor hemorrhage. Results obtained from the AVM patients were contrasted to those from right-handed brain-injured stroke patients recovering from aphasia and to those from right-handed normal subjects. RESULTS: During silent picture naming and verb generation tasks, cortical language networks lateralized primarily to the right hemisphere in the AVM group, compared with the left hemisphere in the normal group. This right hemisphere-shifted language network in the AVM group exceeded the shifts toward right hemispheric dominance found in the stroke group. CONCLUSION: Patients with AVMs affecting the left perisylvian regions recruited the right hemisphere into language processing networks during early development, presumably in response to congenitally aberrant circulation. This early right hemisphere recruitment in the AVM patients exceeded the similar process in the brains of stroke patients whose left cortical language networks were damaged in adulthood. Our data provide evidence of effective plasticity in the developing human brain compared with the mature brain response to injury. Knowledge of cortical language representation should assist presurgical planning in patients with developmental anomalies affecting apparently language-dominant brain regions.

Adult↗
PubMed2000

Migraine: imaging the aura.

We currently conceive of a migraine attack as originating in the brain. Triggers of an attack initiate a depolarizing neuroelectric and metabolic event likened to the spreading depression of Leao. This event activates the headache and associated features of the attack by mechanisms that remain to be determined, but appear to involve either peripheral trigeminovascular or brainstem pathways, or both. The excitability of cell membranes, perhaps partly genetically determined, is the brain's susceptibility to attacks. Factors that increase or decrease neuronal excitability constitute the threshold for triggering attacks. Using a model of visual stress-induced migraine or by studying spontaneous attacks and applying advanced imaging and neurophysiological methods, results have been obtained that support spreading neuronal inhibition as the basis of aura. This neuroelectric event is accompanied by hyperoxia of the brain, possibly associated with vasodilation. Evidence has also been obtained that the spreading cortical event can activate the subcortical centers possibly involved in nociception and associated symptoms of the migraine attack. Susceptibility to migraine attacks appears to be related to brain hyperexcitability. These newer techniques of functional neuroimaging have confirmed the primary neural basis of the migraine attack with secondary vascular changes, reconciling previous theories into a neurovascular mechanism.

Brain↗
PubMed1999

Analysis of MEG signals of spreading cortical depression with propagation constrained to a rectangular cortical strip. I. Lissencephalic rabbit model.

Magnetic fields arising from the rabbit cortex during spreading cortical depression (SCD) were measured in order to study the currents in the neocortex during SCD. SCD was constrained to propagate in a rectangular cortical strip perpendicular to the midline. This simplified in vivo cortical preparation enabled us to correlate magnetoencephalographic (MEG) signals to their underlying currents within the cortical strip. The propagation of SCD was monitored with an array of electrodes placed along the strip. The propagation speed for SCD in the lissencephalic rabbit brain was 3. 5+/-0.3 mm/min (mean+/-S.E.M., n=14). Slow, quasi-dc, MEG signals were observed as the SCD entered into the longitudinal fissure. The currents giving rise to the MEG signals were perpendicular to the cortical surface and directed from the surface to deeper layers of the cortex. A distributed dipolar source model was used to relate the data to the underlying cortical current. The moment of the single equivalent current dipole source was 38+/-9 nA-m (n=17). This study clarified the nature of the cortical currents during SCD in a lissencephalic in vivo preparation.

Animals↗
PubMed1999

Analysis of MEG signals of spreading cortical depression with propagation constrained to a rectangular cortical strip. II. Gyrencephalic swine model.

Currents produced during spreading cortical depression (SCD) in a gyrencephalic species (swine) were studied with magnetoencephalography (MEG) and electrocorticography (ECoG). SCD, initiated using electrical stimulation of the cortex, was constrained to propagate within a rectangular cortical strip in order to simplify the interpretation of the underlying currents. The ECoG signals monitored along the strip revealed that SCD propagated from an initiation site on the gyrus at a rate of 7.9+/-3.2 mm/min (n=23), entered the deep coronal sulcus and in most cases emerged from the other side of the sulcus, continuing to propagate across the next gyrus at a rate of 5.9+/-2.7 mm/min (n=22). The apparent propagation velocity within the sulcus was reduced to 1.7+/-0.8 mm/min (n=21). Strong MEG signals were observed as SCD entered the sulcus. The direction of magnetic field was opposite for SCD's on opposite banks of the sulcus. The currents were directed from a superficial layer to deeper layers of the cortex. The characteristics of SCD and associated MEG patterns from a gyrencephalic species may be similar to those in human patients during migraine aura.

Animals↗
PubMed1999

Butenolide endothelin antagonists with improved aqueous solubility.

Continued development around our ETA-selective endothelin (ET) antagonist 1 (CI-1020) has led to the synthesis of analogues with improved aqueous solubility profiles. Poor solubility characteristics displayed by 1 required a complex buffered formulation in order to conduct iv studies. To overcome the use of specific iv formulations for preclinical studies on additional drug candidates, analogues with improved aqueous solubility were desired. Several analogues were synthesized with substitution patterns that allowed for the formation of either acid or base addition salts. These derivatives had dramatically improved aqueous solubility. In addition, these analogues retained equivalent or improved ETA receptor selectivity and antagonist potency, versus 1, both in vitro and in vivo. Compound 29, which contains as a substituent the sodium salt of a sulfonic acid, has an ETA IC50 = 0.38 nM, ETA selectivity of 4200-fold, and ETA functional activity of KB = 7.8, all of which are similar or superior to those of 1. Compound 29 also has vastly superior aqueous solubility and solubility duration, compared to 1. Furthermore, 29 after iv infusion displays improved activity to 1 in preventing acute hypoxia-induced pulmonary hypertension in rats with an ED50 = 0.3 microg/kg/h.

Animals↗
PubMed1999

Functional MRI-BOLD of visually triggered headache in patients with migraine.

BACKGROUND: Spreading depression of Leao has been hypothesized as the basis for the visual aura of the migraine attack, supported by cerebral blood flow measurements of spreading hypoperfusion. The early depolarizing or activation phase of experimental spreading depression, however, is associated with a transient but pronounced cerebral blood flow increase that precedes spreading hypoperfusion. OBJECTIVE: To study this early phase of the migraine attack, we investigated visually triggered attacks of headache and visual symptoms using a red-green checkerboard stimulus in patients with migraine. INTERVENTIONS: We studied occipital cortex activation during visual stimulation by measuring occipital cortex perfusion with functional magnetic resonance imaging-blood oxygenation level-dependent contrast in 10 patients with migraine with aura and 2 patients with migraine without aura and 6 healthy subjects. RESULTS: In 6 patients with migraine with aura and 2 patients with migraine without aura, their typical headache with (n = 2) or without visual change was visually triggered at 7.3 minutes (mean time) after visual stimulation began. In 5 of these patients, the onset of headache or visual change, or both, was preceded by suppression of initial activation (mean onset time, 4.3 minutes; P<.001) The suppression slowly propagated into contiguous occipital cortex at a rate ranging from 3 to 6 mm/ min. This neuronal suppression was accompanied by baseline contrast intensity increases that indicated vasodilatation and tissue hyperoxygenation. CONCLUSIONS: We conclude that visually triggered headache and visual change in patients with migraine is accompanied by spreading suppression of initial neuronal activation and increased occipital cortex oxygenation. We postulate that this spreading suppression may be associated with initial activation of a migraine attack, independent of whether there are associated aura symptoms. We further postulate that there may be an association between vasodilation accompanying the initial stage of suppression and the induction of headache.

Adult↗
PubMed1999

Magnesium and pH imaging of the human brain at 3.0 Tesla.

Multislice, two-dimensional phosphorus 31 spectroscopic imaging (SI) of human brain was performed in 15 normal volunteers on a 3-Tesla magnetic resonance system. Images of free magnesium concentrations and pH as well as phosphoesters, inorganic phosphate, phosphocreatine, and adenosine triphosphate (ATP), were calculated from the SI data. By using the equations of Golding and Golding (Magn. Reson. Med. 1995;33: 467-474), average [Mg2+] for all brain regions studied was 0.42+/-0.05 mM, whereas average brain pH was found to be 7.07+/-0.03, with no significant regional variations. Phosphorus metabolite concentrations (relative to ATP, assumed to be 3.0 mM/kg wet weight)were 5.39+/-1.88, 1.30+/-0.39, 5.97+/-3.17, and 4.33+/-1.45 mM/kg wet weight for phosphomonoesters, inorganic phosphate, phosphodiesters, and phosphocreatine (PCr), respectively. These values are in good general agreement with those reported previously. Typical signal-to-noise ratios of 15:1 were obtained for PCr in spectra from nominal 31.5 cc voxel sizes with a 34-min scan time. Limits on spatial resolution and the likely error of the magnesium and pH values are discussed.

Adenosine Triphosphate↗
PubMed1999

31P MRS studies of exercising human muscle at high temporal resolution.

Methods for measuring mitochondrial activity from 31P magnetic resonance spectroscopy data collected during and after exercise were compared in controls, weight lifters, and peripheral vascular occlusive disease (PVOD) patients. There were trends toward increasing mitochondrial activity during exercise in order from PVOD patients, moderately active controls, highly active controls, to weight lifters. Results from PVOD patients show divergence of some measures due to 1) the non-exponential nature of phosphocreatine recovery, and 2) potential breakdown of [ADP] control of the mitochondria due to lack of oxygen (for Qmax calculation). These results demonstrate the utility of obtaining and directly analyzing high time resolution data rather than assuming monoexponential behavior of metabolite recovery.

Adenosine Diphosphate↗
PubMed1999

The cortical silent period is shortened in migraine with aura.

OBJECTIVES: Central neuronal hyperexcitability may be the physiological disturbance that predisposes subjects to migraine attacks. To test this hypothesis, we studied the cortical stimulation silent period (CSSP) elicited by transcranial magnetic stimulation (TMS), which is in part a measure of central inhibition of motor pathways in migraine with aura (MwA) patients and normal controls. METHODS: In nine MwA patients (mean age 35.9 +/- 7) and 9 controls (mean age 37.6 +/- 7), we carried out transcranial stimulation using a 95 mm circular coil and Caldwell MES 10 stimulator to determine resting motor threshold (MT) for bilateral FDI muscles. All subjects performed isometric voluntary contraction of bilateral FDI maintained at 20% of maximal effort, during which we measured bilateral CSSP at (i) the stimulus intensity (SI) determined for the MT and (ii) an SI of 1.5 x MT. RESULTS: Although the mean MT was higher in MwA compared with controls (63.1 +/- 14.4 vs 58.1 +/- 8.9), the difference was not significant. At an SI of 1.5 x MT the mean CSSP did not differ between the groups (MwA 141.7 +/- 31.9 vs controls 162.4 +/- 36.6). At the SI of the MT, however, the CSSP was shorter in MwA patients than in controls (62.9 +/- 27.3 vs 106.3 +/- 19.6, p = 0.001). There was an inverse correlation between the duration of CSSP and an increased frequency of headache (p = 0.02). CONCLUSIONS: The shortened CSSP that we measured in MWA patients compared to normal with low intensity magnetic stimulation suggests reduced central inhibition resulting in increased excitability of cortical neurons in migraine subjects. The association of CSSP reduction with increased frequency of migraine is further suggestive that brain excitability is the basis of susceptibility to migraine attacks.

Adult↗
PubMed1999

Cortical language activation in stroke patients recovering from aphasia with functional MRI.

BACKGROUND AND PURPOSE: Two mechanisms for recovery from aphasia, repair of damaged language networks and activation of compensatory areas, have been proposed. In this study, we investigated whether both mechanisms or one instead of the other take place in the brain of recovered aphasic patients. METHODS: Using blood oxygenation level-dependent functional MRI (fMRI), we studied cortical language networks during lexical-semantic processing tasks in 7 right-handed aphasic patients at least 5 months after the onset of left-hemisphere stroke and had regained substantial language functions since then. RESULTS: We found that in the recovered aphasic patient group, functional language activity significantly increased in the right hemisphere and nonsignificantly decreased in the left hemisphere compared with that in the normal group. Bilateral language networks resulted from partial restitution of damaged functions in the left hemisphere and activation of compensated (or recruited) areas in the right hemisphere. Failure to restore any language function in the left hemisphere led to predominantly right hemispheric networks in some individuals. However, better language recovery, at least for lexical-semantic processing, was observed in individuals who had bilateral rather than right hemisphere-predominant networks. CONCLUSIONS: The results indicate that the restoration of left-hemisphere language networks is associated with better recovery and inversely related to activity in the compensated or recruited areas of the right hemisphere.

Adult↗
PubMed1999

Scientific basis of migraine: speculation on the relationship to cyclic vomiting.

The pathogenesis of migraine is reviewed. Migraine is a brain disorder that is activated by various triggers working on a susceptibility to attacks, in part genetically determined. The frequency of attacks is determined by triggers working on a threshold that determines excitability of brain. The mechanisms of the attack may involve both cortical and brain-stem structures and their dysfunction. It remains to be determined if cortical or brain-stem centers "generate the attack." Because migraine involves severe nausea and vomiting, this review contains speculations on similarities in the mechanisms of migraine and cyclic vomiting.

Adolescent↗
PubMed1998

Preliminary clinical-radiological assessment of a MR tissue signature model in human stroke.

We evaluated the ability of an MR signature model (SM) of cerebral ischemic injury to stage the evolution of cellular damage in human stroke. In 19 patients with ischemic stroke of presumed embolic or non-embolic cause we carried out diffusion-weighted and T2-weighted MR imaging within 48 h of onset, and obtained apparent diffusion coefficient of water (ADCw), and T2 weighted images. We used the signatures obtained from these ADCw/T2 maps to formulate two patterns of damage signifying accelerated or non-accelerated progression of cellular death after stroke onset. Those patients with the accelerated pattern corresponded to those with the neuroradiological (NRC) and clinical diagnosis (TOAST.1 and TOAST.2) of presumed embolic stroke, with clinical diagnosis performed blinded both to NRC and to SM. Agreement between the SM and NRC was substantial (kappa=0.62), moderate (0.60<kappa<0.40) between the SM or NRC and TOAST.2, and fair (0.40<kappa<0.20) among the SM or NRC and TOAST.1. We believe these results constitute a preliminary validation of the MR tissue signature modeling in clinical stroke assessment.

Adult↗
PubMed1998

Assessment of endothelin receptor subtype-mediated increases of [Ca2+]i in distinct rat cell types using fluorimetric imaging.

Activation of endothelin (ET) receptor subtypes by various agonists causes an increase in [Ca2+]i in different cell types. This effect can be readily monitored in a 96-well plate format by detecting 1-s fluorescence changes of cell-permeant, Ca(2+)-sensitive dyes (e.g., Calcium Green-1 AM) using a fluorimetric imaging plate reader. This device was used to assess the ET receptor subtypes in primary cultures of rat mixed neocortical neuronal/glial cells and aortic smooth-muscle cells. Pharmacologic experiments with several ET receptor agonists and antagonists indicated that the ETA receptor subtype was functionally responsive in the smooth-muscle cells and that the ETB receptor subtype had a similar role in the mixed neuronal/glial cells.

Animals↗