Biomedical subjects

Thomas M Freiman

Publications and source records attributed to Thomas M Freiman.

9 recordsLinked to original sources

PubMed2006

Granule cell dispersion is not accompanied by enhanced neurogenesis in temporal lobe epilepsy patients.

Granule cell dispersion (GCD) in the dentate gyrus is a frequent feature of Ammon's horn sclerosis (AHS) which is often associated with temporal lobe epilepsy (TLE). It has been hypothesized that GCD may be caused by an abnormal migration of newly born granule cells. To test this hypothesis, we used markers of proliferation and neurogenesis and immunocytochemical methods as well as quantitative Western blot and real-time RT-PCR analyses in surgically resected hippocampi from TLE patients and controls. Below the age of 1 year, Ki-67-immunopositive nuclei were detected in the subgranular zone of the dentate gyrus, but not in the dentate of TLE patients independent of age. The expression of the proliferation marker minichromosome maintenance protein 2 (mcm2) and of doublecortin (DCX) decreased significantly with age in controls and in TLE patients, but the expression of both proteins was independent of the degree of AHS and GCD. Quantitative real-time RT-PCR confirmed these findings at the level of gene expression. In contrast, immunocytochemistry for glial fibrillary acidic protein (GFAP) and vimentin as well as Golgi staining revealed a radially aligned glial network in the region of GCD. GFAP-positive fiber length significantly increased with the severity of GCD. These results indicate that epileptic activity does not stimulate neurogenesis in the human dentate gyrus and that GCD probably does not result from a malpositioning of newly generated granule cells, but rather from an abnormal migration of mature granule cells along a radial glial scaffold.

Adolescent↗

PubMed2006

K(+)-evoked [(3)H]-norepinephrine release in human brain slices from epileptic and non-epileptic patients is differentially modulated by gabapentin and pinacidil.

The modulation of K(+)-evoked [(3)H]-norepinephrine ([(3)H]-NE) release by gabapentin (GBP) and pinacidil (PIN), a known K(ATP) agonist, was examined in human brain slices. We compared the pharmacological effects on NE-release in human epileptic neocortex and epileptic hippocampus to non-epileptic neocortex. GBP (100 microM) decreased [(3)H]-NE release by 22% in non-epileptic neocortical slices, whereas this inhibition was absent in slices from epileptic hippocampus and epileptic neocortex. PIN (10 microM) also reduced [(3)H]-NE release by 30% in non-epileptic neocortical slices and only by 5% in epileptic hippocampal slices. The blockade of voltage-gated calcium channels by omega-conotoxins MVIIA and MVIIC (0.1 microM) reduced [(3)H]-NE release in epileptic and non-epileptic neocortical slices to the same extend. The data show a marked reduction in K(+)-evoked [(3)H]-NE release by GBP and PIN in epileptic hippocampus and neocortex, suggesting an alteration of K(ATP) channel function, whereas the effects of the calcium channel modulators omega-conotoxins MVIIA and MVIIC are similar in both epileptic and non-epileptic neocortex.

Adrenergic alpha-Agonists↗

PubMed2006

Lesion-induced axonal sprouting in the central nervous system.

Injury or neuronal death often come about as a result of brain disorders. Inasmuch as the damaged nerve cells are interconnected via projections to other regions of the brain, such lesions lead to axonal loss in distal target areas. The central nervous system responds to deafferentation by means of plastic remodeling processes, in particular by inducing outgrowth of new axon collaterals from surviving neurons (collateral sprouting). These sprouting processes result in a partial reinnervation, new circuitry, and functional changes within the deafferented brain regions. Lesioning of the entorhinal cortex is an established model system for studying the phenomenon of axonal sprouting. Using this model system, it could be shown that the sprouting process respects the pre-existing lamination pattern of the deafferented fascia dentata, i. e., it is layer-specific. A variety of different molecules are involved in regulating this reorganization process (extracellular matrix molecules, cell adhesion molecules, transcription factors, neurotrophic factors, growth-associated proteins). It is proposed here that molecules of the extracellular matrix define the boundaries of the laminae following entorhinal lesioning and in so doing limit the sprouting process to the deafferented zone. To illustrate the role of axonal sprouting in disease processes, special attention is given to its significance for neurodegenerative disorders, particularly Alzheimer's disease (AD), and temporal lobe epilepsy. Finally, we discuss both the beneficial as well as disadvantageous functional implications of axonal sprouting for the injured organism in question.

Alzheimer Disease↗

PubMed2004

Input resistance is voltage dependent due to activation of Ih channels in rat CA1 pyramidal cells.

The contribution of the hyperpolarization-activated cation current (I(h)) to input resistance (R(N)) and resting potential (RP) was investigated during whole-cell patch-clamp recordings in CA1 pyramidal cells of rat hippocampal slices. In current-clamp mode, R(N) was determined at different membrane potentials. R(N) decreased with increasing hyperpolarization, from about 260 Momega to 140 Momega at potentials of about -60 mV and -110 mV, respectively. Both the potential of half-maximal reduction of R(N) and the potential of half-maximal I(h) activation (determined in voltage-clamp mode) were approximately -90 mV. The analysis of the voltage sag indicative of I(h) activation revealed a preferential activity of I(h) channels in a voltage range between -70 and -95 mV. ZD7288 (50 microM), a specific I(h) blocker, led to a hyperpolarization by about 4.8 mV, increased R(N) by approximately 45% within a potential range between -65 and -80 mV, and abolished the voltage dependence of R(N). Gabapentin (GBP, 100 microM), an I(h) channel agonist, led to a depolarization by about 2.4 mV and reduced R(N) by about 20% within a potential range between -65 and -80 mV. In conclusion, our data show that R(N) is voltage dependent due to I(h) channel activation and that I(h) channels are preferentially active at voltages between -70 and -95 mV. Furthermore, we demonstrated that R(N) can be modulated by antiepileptic drugs such as GBP, which may partly explain its antiepileptic effect as due to decreasing the sensitivity to excitatory input.

4-Aminopyridine↗

PubMed2004

Neuronavigation-assisted cranial reconstruction.

OBJECTIVE: Cranial defects resulting from congenital deformities, ablative resection of osseous tumors, traumatic injury, and destructive infectious lesions are often severe enough to warrant surgical reconstruction. In particular cases, satisfactory cosmetic results may be difficult to achieve because of the extent and location of the lesion. METHODS: We evaluated the role of neuronavigation for reconstruction of large cranial defects with prefabricated titanium and intraoperatively constructed neuronavigation-assisted polymethylmethacrylate implants. RESULTS: Neuronavigation-assisted cranial reconstruction was performed in 14 patients. Surgical procedure, illustrative cases, postoperative results, and apparent benefits of the technique are presented and discussed. In all patients, excellent cosmetic results were achieved. CONCLUSION: In cranial reconstruction, neuronavigation is of value not only for intraoperative determination of resection margins but also for preoperative assessment and planning. The combination of navigation techniques with prefabricated or intraoperatively constructed implants enables achievement of excellent cosmetic results.

Adult↗

PubMed2004

Complex visual hallucinations (Charles Bonnet syndrome) in visual field defects following cerebral surgery. Report of four cases.

The development of visual hallucinations after loss of vision is known as the Charles Bonnet syndrome. This phenomenon was first described in 1760 by Charles Bonnet and others during their observations of elderly patients with degeneration of the retina or cornea. To date a clear association between visual hallucinations and neurosurgical procedures has not been reported. Because of their clear demarcation, however, surgical lesions in the cerebrum offer a unique opportunity to determine the pathoanatomical aspects of visual hallucinations. During a 3-year period, 41 consecutive patients who acquired visual field defects after neurosurgery were examined for the occurrence of visual hallucination. Postoperatively, four of these patients experienced visual hallucinations. In two of them an upper quadrantanopia developed after the patients had undergone selective amygdalohippocampectomy. In the other two patients a complete hemianopia developed, in one case after resection of a parietal astrocytoma and in the other after resection of an occipital glioblastoma multiforme. The visual hallucinations were transient and gradually disappeared between 4 days and 6 months postoperatively. The patients were aware of the fact that their hallucinations were fictitious and displayed no psychosis. Electroencephalographic recordings were obtained in only two patients and epileptic discharges were found. Deafferentiation of cortical association areas may lead to the spontaneous generation of complex visual phenomena. In the present series this phenomenon occurred in approximately 10% of patients with postoperative visual field defects. In all four cases the central optic radiation was damaged between the lateral geniculate nucleus and the primary visual cortex. The complex nature of the visual hallucination indicates that they were generated in visual association areas.

Adult↗

PubMed2003

Gabapentin increases the hyperpolarization-activated cation current Ih in rat CA1 pyramidal cells.

PURPOSE: Gabapentin (GBP) is a commonly used drug in the treatment of partial seizures, but its mode of action is still unclear. The genesis of seizures in temporal lobe epilepsy is thought to be crucially influenced by intrinsic membrane properties. Because the Ih substantially contributes to the intrinsic membrane properties of neurons, the effects of GBP on the Ih were investigated in CA1 pyramidal cells of rat hippocampus. METHODS: CA1 pyramidal cells in hippocampal slices were examined by using the whole-cell patch-clamp technique. RESULTS: GBP increased the Ih amplitude in a concentration-dependent manner mainly by increasing the conductance, without significant changes in the activation properties or in the time course of Ih. The effects ranged from approximately 20% at 50 microM, approximately 25% at 75 microM, to approximately 35% at 100 microM GBP (at -110 mV). In the presence of intracellular cyclic adenosine monophosphate (cAMP), the effects of GBP on Ih were similar to those obtained in the absence of cAMP. CONCLUSIONS: These results suggest that GBP increases the Ih through a cAMP-independent mechanism. Because the applied GBP concentrations were in a clinically relevant range, the observed effect may contribute to the anticonvulsant action of GBP in partial seizures and may represent a new concept of how this anticonvulsant drug works.

Acetates↗

PubMed2002

K(+)-induced changes in the properties of the hyperpolarization-activated cation current I(h) in rat CA1 pyramidal cells.

The effects of rises in external K(+) (K(ext)) on I(h) were investigated in CA1 pyramidal cells of rat hippocampal slices using the whole-cell patch clamp technique. At the basal K(ext) level (2.5 mM), hyperpolarization-activated cation current (I(h)) had a maximal amplitude of -350+/-60 pA which was enhanced by approximately 60 and approximately 95% at 5 and 7.5 mM K(ext), respectively. The midpoint activation voltage was significantly shifted from -80 mV in the negative direction to about -87 mV at both 5 and 7.5 mM K(ext), without appreciable alterations of the current kinetics. The maximal conductance was approximately 2.4 nS under control conditions and significantly increased to approximately 3.3 and approximately 5.6 nS at 5 and 7.5 mM K(ext), respectively. The reversal potential was shifted in the positive direction, from a control value of approximately -30 mV by approximately 6 and approximately 14 mV at 5 and 7.5 mM K(ext), respectively. Our data demonstrate that even moderate changes in K(ext) have a substantial effect on the properties of I(h).

Animals↗

PubMed2002

Anterograde tracing of human hippocampus in vitro-a neuroanatomical tract tracing technique for the analysis of local fiber tracts in human brain.

Hippocampal slices were obtained from hippocampi of patients with temporal lobe epilepsy or from patients with mass lesions located in the temporal lobe. Hippocampal slices were kept alive in a slice chamber and the anterograde tracer neurobiotin was iontophoretically injected into the granule cell layer of the dentate gyrus. Single injections resulted in the labeling of small groups of granule cells. The axonal arbor of these cells could be partially reconstructed and single mossy fibers could be followed from the soma to the inner molecular layer of the sclerotic dentate gyrus. Electron microscopy revealed asymmetric mossy fiber synapses on spiny neurons in the inner molecular layer, presumably granule cells. These data demonstrate that in vitro anterograde tracing can be employed to study the local connectivity of the human brain at the light and electron microscopic level.

Biotin↗