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Biomedical subjects

Michael M Haglund

Publications and source records attributed to Michael M Haglund.

7 recordsLinked to original sources
PubMed2005

Furosemide and mannitol suppression of epileptic activity in the human brain.

Most research on basic mechanisms of epilepsy and the design of new antiepileptic drugs has focused on synaptic transmission or action potential generation. However, a number of laboratory studies have suggested that nonsynaptic mechanisms, such as modulation of electric field interactions via the extracellular space (ECS), might also contribute to neuronal hypersynchrony and epileptogenicity. To date, a role for nonsynaptic modulation of epileptic activity in the human brain has not been investigated. Here we studied the effects of molecules that modulate the volume and water content of the ECS on epileptic activity in patients suffering from neocortical and mesial temporal lobe epilepsy. Electrophysiological and optical imaging data were acquired from the exposed cortices of anesthetized patients undergoing surgical treatment for intractable epilepsy. Patients were given a single intravenous injection containing either 20 mg furosemide (a cation-chloride cotransporter antagonist) or 50 g mannitol (an osmolyte). Furosemide and mannitol both significantly suppressed spontaneous epileptic spikes and electrical stimulation-evoked epileptiform discharges in all subjects, completely blocking all epileptic activity in some patients without suppressing normal electroencephalographic activity. Optical imaging suggested that the spread of electrical stimulation-evoked activity over the cortex was significantly reduced by these treatments, but the magnitude of neuronal activation near the stimulating electrode was not diminished. These results suggest that nonsynaptic mechanisms play a critical role in modulating the epileptogenicity of the human brain. Furosemide and other drugs that modulate the ECS might possess clinically useful antiepileptic properties, while avoiding the side effects associated with the suppression of neuronal excitability.

Adolescent↗
PubMed2004

Optical imaging of epileptiform activity in human neocortex.

The surgical outcomes of patients suffering from neocortical epilepsy are not as successful as the surgical outcomes from resections of epilepsy patients with mesial temporal sclerosis. The main difficulty in the treatment of neocortical epilepsy is that current technology has limited accuracy in mapping neocortical epileptogenic tissue. It is known that the optical spectroscopic properties of brain tissue are correlated with changes in neuronal activity. The method of mapping these activity-evoked optical changes is known as imaging of intrinsic optical signals (IIOS). Activity-evoked optical changes measured in neocortex are generated by changes in cerebral hemodynamics (i.e., changes in blood oxygenation and blood volume). Our experimental approach was to acquire high-resolution IIOS maps of epileptiform activity in patients undergoing surgery for medically intractable neocortical epilepsy. Both spontaneous and stimulation-evoked epileptiform activity was monitored. Imaging of intrinsic optical signals was able to localize neocortical epileptic foci precisely by using changes in blood volume in contrast to changes in blood oxygenation. IIOS has the potential to translate from a purely research tool to a new intraoperative approach for the surgical treatment of neocortical epilepsy.

Blood Volume↗
PubMed2003

Possible role for vascular cell proliferation in cerebral vasospasm after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: During vasospasm after subarachnoid hemorrhage (SAH), cerebral blood vessels show structural changes consistent with the actions of vascular mitogens. We measured platelet-derived vascular growth factors (PDGFs) in the cerebrospinal fluid (CSF) of patients after SAH and tested the effect of these factors on cerebral arteries in vivo and in vitro. METHODS: CSF was sampled from 14 patients after SAH, 6 patients not suffering SAH, and 8 normal controls. ELISA was performed for PDGF-AB, transforming growth factor-beta1, and vascular endothelial growth factor. A mouse model was used to compare cerebral vascular cell proliferation and PDGF staining in SAH compared with sham-operated controls. Normal human pial arteries were incubated for 7 days in vitro, 2 groups with human blood clot and 1 with and 1 without PDGF antibodies. RESULTS: PDGF-AB concentrations in CSF from SAH patients were significantly higher than those from non-SAH patients and normal controls, both during the first week after SAH and for all time points measured. Smooth muscle and fibroblast proliferation was observed after SAH in the mouse model, and this cellular replication was observed in conjunction with PDGF protein at the sites of thrombus. In human pial arteries, localized thrombus stimulated vessel wall proliferation, and proliferation was blocked by neutralizing antibodies directed against PDGFs. CONCLUSIONS: Vascular mitogens are increased in the CSF of patients after SAH. Proliferation of cells in the vascular wall is associated with perivascular thrombus. Cellular proliferation and subsequent vessel wall thickening may contribute to the syndrome of delayed cerebral vasospasm.

Adolescent↗
PubMed2002

Use of vagal nerve stimulation as a treatment for refractory epilepsy in dogs.

OBJECTIVE: To evaluate safety and efficacy of vagal nerve stimulation in dogs with refractory epilepsy. DESIGN: Placebo-controlled, double-masked, crossover study. ANIMALS: 10 dogs with poorly controlled seizures. PROCEDURE: A programmable pacemaker-like device designed to deliver intermittent stimulation to the left cervical trunk of the vagus was surgically implanted in each dog. Dogs were assigned randomly to two 13-week test periods, 1 with nerve stimulation and 1 without nerve stimulation. Owners recorded data on seizure frequency, duration, and intensity, as well as adverse effects. RESULTS: No significant difference in seizure frequency, duration, or severity was detected between overall 13-week treatment and control periods. During the final 4 weeks of the treatment period, a significant decrease in mean seizure frequency (34.4%) was detected, compared with the control period. Complications included transient bradycardia, asystole, and apnea during intraoperative device testing, and seroma formation, subcutaneous migration of the generator, and transient Horner's syndrome during the 14-day period between surgery and suture removal. No adverse effects of stimulation were detected, and most owners were satisfied with the treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Vagal nerve stimulation is a potentially safe approach to seizure control that appears to be efficacious in certain dogs and should be considered a possible treatment option when antiepileptic medications are ineffective.

Animals↗
PubMed2002

Phase II trial of carmustine plus O(6)-benzylguanine for patients with nitrosourea-resistant recurrent or progressive malignant glioma.

PURPOSE: We conducted a phase II trial of carmustine (BCNU) plus the O(6)-alkylguanine-DNA alkyltransferase inhibitor O(6)-benzylguanine (O(6)-BG) to define the activity and toxicity of this regimen in the treatment of adults with progressive or recurrent malignant glioma resistant to nitrosoureas. PATIENTS AND METHODS: Patients were treated with O(6)-BG at an intravenous dose of 120 mg/m(2) followed 1 hour later by 40 mg/m(2) of BCNU, with cycles repeated at 6-week intervals. RESULTS: Eighteen patients were treated (15 with glioblastoma multiforme, two with anaplastic astrocytoma, and one with malignant glioma). None of the 18 patients demonstrated a partial or complete response. Two patients exhibited stable disease for 12 weeks before their tumors progressed. Three patients demonstrated stable disease for 6, 12, and 18 weeks before discontinuing therapy because of hematopoietic toxicity. Twelve patients experienced reversible > or = grade 3 hematopoietic toxicity. There was no difference in half-lives (0.56 +/- 0.21 hour v 0.54 +/- 0.20 hour) or area under the curve values (4.8 +/- 1.7 microg/mL/h v 5.0 +/- 1.3 microg/mL/h) of O(6)-BG for patients receiving phenytoin and those not treated with this drug. CONCLUSION: These results indicate that O(6)-BG plus BCNU at the dose schedule used in this trial is unsuccessful in producing tumor regression in patients with nitrosourea-resistant malignant glioma, although stable disease was seen in five patients for 6, 12, 12, 12, and 18 weeks. Future use of this approach will require strategies to minimize dose-limiting toxicity of BCNU such as regional delivery or hematopoietic stem-cell protection.

Adult↗
PubMed2002

Electrophysiological correlates to the intrinsic optical signal in the rat neocortical slice.

The study sought to further our understanding of the correlation between electrophysiological activity and the intrinsic optical signal (IOS) in neocortical slice by combining imaging of IOS with whole-cell and extracellular electrical recording. Columnar-shaped areas of IOS were evoked with electrical stimulation of the layer VI/white matter border. The distribution of IOS intensities linearly correlated with the distribution of evoked excitatory post-synaptic potential amplitudes (R=0.89). The distribution of field potentials was narrower than the distribution of IOS intensities with significantly smaller amplitude of the normalized field potentials in the edge of the column. The data suggest that in the neocortical slice the IOS at the edge of the evoked column reflects primarily the sub-threshold excitatory synaptic activity.

Action Potentials↗