Fetal and adult human CNS stem cells have similar molecular characteristics and developmental potential.

The mammalian central nervous system (CNS) contains multipotent stem cells that develop into neurons, astrocytes and oligodendrocytes. Our current data show that fetal and adult human CNS stem cell isolates display similar proliferation kinetics, differentiate into three major cell types of the nervous system and express similar sets of regulatory genes. However, each individual CNS stem cell isolate could be distinguished by its specific gene expression and developmental potential.

Presurgical contribution of quantitative stereotactic positron emission tomography in temporo limbic epilepsy.

BACKGROUND: We quantified the interictal metabolic changes associated with temporal lobe epilepsy by using an accurate stereotactic method. METHODS: We selected 16 patients who had proven unilateral focal or regional temporal onset defined by SEEG criteria. Each patient underwent stereotactic MRI and stereotactic [18 fluoro] fluorodeoxyglucose positron emission tomography (PET). RESULTS: Asymmetries (mean, +/- SD) were found in mesio-temporal structures: amygdala (-0.033+/-0.027, p = 0.0002), hippocampus (-0.035+/-0.032, p = 0.0006), and superior temporal gyrus (-0.036+/-0.032, p = 0.0004). Four of the sixteen patients had previously had unlocalized qualitative nonstereotactic PET analysis. CONCLUSIONS: The quantitative stereotactical PET method allows a higher resolution study of mesio-temporal structures.

Subthalamic stimulation in Parkinson's disease. Preliminary results.

OBJECTIVES: We wanted to evaluate chronic subthalamic nucleus (STN) stimulation as an alternative to pallidotomy for severe Parkinson's disease symptomatology. METHODS: Nine patients met clinical criteria for unilateral standard pallidotomy. All had severe medically refractory drug-induced dyskinesia and had reached maximal daily levodopa therapy. Pre- and postoperative videos, neuropsychometric testings and clinical stagings were administered. Three patients were selected to undergo stereotactic implantation of a deep brain stimulator (DBS) after Institutional Review Board approval and informed consent. These were performed using digitized microrecordings. The other group received unilateral pallidotomy. RESULTS: At a mean follow-up of 6 months, our results support recent findings of significant major improvement in motor scores, activity of daily living and decrease in amount of daily levodopa intake by close to 50% after 3 months of stimulation. CONCLUSIONS: Chronic stimulation of the STN appears to provide significant motor improvement in patients with severe Parkinson's disease and is more beneficial than pallidotomy.

MKM-guided resection of diffuse brainstem neoplasms.

OBJECTIVES: Some primary brainstem tumors, when extensive, are considered inoperable. We wanted to assess the value of robotic image-guided microscopic surgery in the resection of these tumors and to improve survival and quality of life for these patients. METHODS: Two patients with extensive brainstem tumors were evaluated at our center. They previously underwent several biopsies, attempted partial resections, radiotherapy and shunting. They presented with progressive neurological deterioration, 'coma vigil' for several months, and required life-supporting measures prior to surgery. Both patients underwent frameless stereotactic craniotomy using a MKM robotic microscope, intraoperative neurophysiological monitoring, and extensive resection of their recurrent brainstem tumors. RESULTS: In the immediate weeks after surgery, both patients became interactive and regained major motor and cranial nerve deficits present prior to surgery. Nine months after surgery, 1 patient succumbed to pneumonia. At 2 years after the operation, 1 patient has maintained his neurological status and showed no recurrence on imaging studies. CONCLUSIONS: Image-guided surgery with an MKM microscope allows surgical outlines to be injected in the microscope viewer and facilitates resection of extensive brainstem tumors previously considered inoperable.

Stereotactic Transcerebellar Approach to Pontine Lesions through the Middle Cerebellar Peduncle.

SUMMARY: A stereotactic approach to the pons through the middle cerebellar peduncle based on MR studies was used to biopsy 18 patients. The stereotactic coordinates and angles were defined with reference to three orthogonal planes (midsagittal, IVth ventricular floor and pontomedullary junction). The pathological diagnoses were in keeping with clinical outcome and comprised five highgrade astrocytomas, three low-grade astrocytomas, two glioblastomas multiforme, two oligodendrogliomas, two primitive neuroectodermic tumours, two lymphomas, one medulloblastoma, and one tuberculosis. This approach provides a high yield of positive histological diagnoses with little morbidity (transient neurological deficits in two cases) and thereby avoids inappropriate therapy.

Human hippocampal AMPA and NMDA mRNA levels in temporal lobe epilepsy patients.

This study was designed to determine whether hippocampal neuronal AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) and NMDA (N-methyl-D-aspartate) mRNA levels were differentially increased in temporal lobe epilepsy patients compared with those measured in control tissue from non-seizure autopsies. Hippocampi from hippocampal sclerosis patients (n = 28) and temporal mass lesion cases (n = 12) were compared with those from the autopsies (n = 4), and studied for AMPA GluR1-3 and NMDAR1-2 mRNAs using semi-quantitative in situ hybridization, along with fascia dentata and Ammon's horn neuron densities. Compared with the autopsies, and without correction for neuron counts, the mass lesion cases with neuron densities similar to autopsies showed: (i) significantly increased NMDAR2 hybridization densities for fascia dentata granule cells; (ii) increased AMPA GluR3 mRNA densities for Ammon's horn pyramids; and (iii) similar or numerically increased mRNAs for all other subunits and hippocampal subfields. Compared with the autopsies, hippocampal sclerosis cases with decreased neuron densities showed: (i) significantly decreased AMPA GluR1-2 and NMDAR1-2 hybridization densities for Ammon's horn pyramids and (ii) similar or numerically decreased mRNAs for all other subunits and subfields. However, correcting for changes in neuron densities showed that hippocampal sclerosis patients had increased AMPA and NMDA mRNA levels per neuron compared with autopsies, and in the CA2 resistant sector GluR2 mRNA levels were numerically greater than autopsies and mass lesion cases. Furthermore, relative to autopsies both sclerosis and mass lesion hippocampi showed that, in the stratum granulosum, the greatest mRNA increases were in AMPA GluR1 and NMDAR2 compared with the other mRNAs. In chronic temporal lobe seizure patients these results indicate that mass lesion and sclerosis cases show differential increases in hippocampal AMPA and NMDA mRNA levels per neuron compared with autopsies, especially for AMPA GluR1 and NMDAR2 in fascia dentata granule cells. These findings support the hypothesis that temporal lobe seizures are associated with increased ionotropic glutamate receptor mRNA levels and alterations in receptor subunit composition that probably contribute to neuronal hyperexcitability, synchronization and seizure generation.

The pathophysiologic relationships between lesion pathology, intracranial ictal EEG onsets, and hippocampal neuron losses in temporal lobe epilepsy.

In temporal lobe epilepsy (TLE) lesion patients the pathology, location of intracranial ictal EEG onsets, and hippocampal neuron losses were compared. Patients (n = 63) were classified into: (1) Tumors (n = 26, e.g. astrocytomas, gangliogliomas); (2) vascular (n = 9, e.g. cavernous and venous angiomas); (3) developmental (n = 17, e.g. cortical dysplasia, heterotopias); or (4) atrophic (n = 11, e.g. cortical or white matter encephalomalacia). Other variables were; (1) the location of the temporal lesion in the mesial to lateral, and anterior to posterior plane, (2) a clinical history of an initial precipitating injury (IPI) prior to the onset of TLE (e.g. prolonged first seizure, head trauma), (3) hippocampal neuron densities, (4) focal or regional location by intracranial depth EEG of ictal onsets, and (5) seizure outcomes. Results showed that severe hippocampal neuron losses were associated with two statistically significant findings. First, patients with mesial lesions in or adjacent to the body of the hippocampus had greater neuron losses compared to mesial lesions anterior or posterior to the hippocampus (P = 0.04). Second, lesion patients with an IPI history had greater Ammon's horn (AH) neuron losses compared to those without IPI histories (P = 0.0005), and the profile of loss was similar to hippocampal sclerosis (HS). Granule cell losses correlated in a complex manner in that; 1) by regression analysis densities decreased with longer intervals of TLE (P = 0.006), (2) tumor patients with IPIs had less granule cell loss compared to those without IPIs intervals of TLE (P = 0.006), (2) tumor patients with IPIs had less granule cell loss compared to those without IPIs (P = 0.05), and (3) developmental patients with IPIs had greater granule cell loss than patients without IPIs (P = 0.009). Mesial-temporal depth EEG electrodes were the first areas of ictal activity in 15 of 16 patients (94%), and greater hippocampal neuron losses were not associated with focal mesial-temporal EEG onsets. Seizure outcomes were worse in tumor patients compared to HS patients (P = 0.01), and patients with post-resection seizures had incomplete resections of their lesions and/or hippocampi. These results indicate that in TLE lesion patients the amount and pattern of hippocampal neuron loss depends on the location of the lesion, the pathologic classification, and a history of an IPI. Further, despite variable neuron losses, in temporal lesion patients the hippocampus was nearly always involved in the genesis or propagation of the chronic seizures.

Comparisons of MEG, EEG, and ECoG source localization in neocortical partial epilepsy in humans.

In order to delineate the characteristics of epileptic spikes, 1946 different spikes were studied in 6 patients with complex partial epilepsy. Non-invasive MEG and EEG source analysis of interictal spikes were contrasted to ECoG localization, surgical outcome and presence of lesions on MRI. Results indicated that: (1) using the most frequent occurring spike topography patterns from a large sample of spikes improved goodness-of-fit values for both MEG and EEG localization, (2) when spike patterns could be appropriately matched on several successive MEG measurements to provide an adequate matrix (3 of 6 subjects), there was excellent agreement between MEG dipole sources and ECoG sources as well as surgical outcome and presence of MRI lesions, (3) EEG source analyses also gave good results but not as consistently as MEG.

Surgical treatment of partial epilepsy arising from the insular cortex. Report of two cases.

Despite its documented connections with many limbic structures, the role of the insula in the etiology of partial seizures is poorly understood. Two patients are described in whom lesions of the insula were associated with intractable partial seizures. In the first patient, the seizures involved visceral sensory hallucinations followed by motor automatism. Seizures in the second patient began with somatic sensory hallucinations and then produced visceral motor effects. Both patients were found to have low-grade astrocytomas of the insula. In both instances, resection of the lesion and adjacent insular cortex resulted in a cure of the seizures. These cases are placed within the context of the existing literature on the subject.

Somatotopy of human hand somatosensory cortex as studied in scalp EEG.

We recorded somatosensory evoked potentials (SEPs) in scalp EEGs during stimulation of the median nerve, the ulnar nerve and the individual digits in 3 normal subjects and in 1 epilepsy patient. In this patient we also measured SEPs from chronically indwelling subdural grid electrodes during electrocorticography (ECoG). We applied dipole modelling technique to study the 3-dimensional intracerebral locations and time activities of the neuronal sources underlying stimulation of different peripheral receptive fields. The sources underlying median nerve SEPs were located an average of 10.8 mm lateral inferior to those underlying ulnar nerve SEPs. Digit SEP sources showed a somatotopic arrangement from lateral inferior to medial superior in the order thumb, index finger, middle finger, ring finger and little finger, with some overlap or reversal for adjacent digits. The average distance between thumb and little finger was 12.5 mm. Thumb, index finger and middle finger were clustered around median nerve cortical representation, whereas ring finger and little finger were arranged around ulnar nerve cortex. In the epilepsy patient, the source localizations obtained in scalp EEGs showed good agreement with those on ECoGs. We conclude that SEPs recorded in scalp EEGs can be used to study functional topography of human somatosensory cortex non-invasively.

Single mossy fiber axonal systems of human dentate granule cells studied in hippocampal slices from patients with temporal lobe epilepsy.

Previous histological and immunocytochemical studies suggest that reorganization of the dentate granule cell axons, the mossy fibers, can occur in epileptic human hippocampus (Sutula et al., 1989; Houser et al., 1990; Babb et al., 1991) and in animal models of epilepsy (Tauck and Nadler, 1985; Sutula et al., 1988; Cronin et al., 1992). However, neuroanatomical analyses of the trajectory and morphology of reorganized axons are not yet available. The present study was conducted to investigate single dentate granule cell axonal systems in human epileptic hippocampus. Individual mossy fibers were directly visualized by injecting a tracer (biocytin or Lucifer yellow) intracellularly in hippocampal slices prepared from temporal lobes that were surgically removed from patients for treatment of intractable epilepsy. Two major arborization patterns were identified: (1) the parent axons extended to and coursed through the hilus toward CA3, leaving collaterals along their paths in the hilus (N = 19 neurons); (2) in addition to the aforementioned axonal system, collateral(s) branched from the parent axon near the soma and projected to the granule cell layer and molecular layer, forming an aberrant axonal pathway (N = 9 neurons). These aberrant collaterals bore large boutons similar to those of the hilar axons and formed extensive plexuses in the granule cell layer and/or in the molecular layer. The summed length of collaterals in the granular/molecular layers was 1110.8 microns on average, which was one-fourth of the total summed length of the mossy fibers (3698.5 microns on average). The size of the somata in neurons that had aberrant collaterals was significantly larger than that of neurons without such collaterals (p < 0.025). In four cases, filopodium-like fine processes were present near the axon hillock and proximal parts of the parent axon, suggesting that the aberrant collateral formation might be an ongoing process in these tissues. The lack of control slices from normal living human hippocampus makes it difficult to assess to what extent the present findings are epilepsy associated. However, the presence of aberrant mossy fiber collaterals in the hippocampi used in the present study has been confirmed by Timm's staining and/or dynorphin immunohistochemistry in comparison with nonepileptic autopsy material, indicating its relation to epilepsy (Babb et al., 1991, 1992). At present, there seems to be a consensus that the projection of mossy fiber collaterals to the supragranular layer is a rare occurrence in normal rats (Lorento de Nó, 1934; Claiborne et al., 1986; Seress et al., 1991; present study), normal monkeys (Seress et al., 1991), and normal humans (Houser et al., 1990).(ABSTRACT TRUNCATED AT 400 WORDS)

Temperature changes in nickel-chromium intracranial depth electrodes during MR scanning.

The authors sought to determine whether there are any heating effects of 1.5-T MR scanning upon nickel-chromium electrodes and to confirm the safety of scanning these electrodes after intracranial surgical implantation in epilepsy patients. Since there was no significant temperature increase of the electrodes tested in their experiments, the authors conclude that nickel-chromium electrodes implanted in the brain are thermally safe for MR scanning.

Correlation of unit recordings with regional cell counts in epileptogenic human temporal lobe.

The previously reported diminished incidence of neuronal activity recorded from areas ipsilateral to a seizure focus may result from either cell loss or pathophysiologic changes in hippocampus and related structures. We examined records of single-cell discharge from 471 electrode bundles in 62 patients who later had cell counts taken from samples of resected tissue. Analysis of variance showed that amygdala and parahippocampal gyrus had more activity than hippocampus and the subicular complex and that the resected side had less activity overall. Only the posterior subicular complex showed more high-amplitude (> 50 microV) activity on the epileptogenic side; all other areas showed more activity contralaterally. Activity between 25 and 50 microV did not differ across sides or structures. Percentage of maximal cell count was correlated with the number of electrodes with high-amplitude activity only in the subicular complex. Low-amplitude activity in nonresected hippocampus, however, was strongly negatively correlated with cell counts on the resected side, perhaps owing to compensatory mechanisms. Cell counts in hippocampus correlated negatively with high-amplitude unit activity in resected amygdala, suggesting reciprocity between these areas. These results suggest that the amount of cell activity recorded from mesiotemporal structures involves bilateral factors more complex than simple cell loss.

Seizure outcome following standard temporal lobectomy: correlation with hippocampal neuron loss and extrahippocampal pathology.

The authors reviewed 149 patients who underwent standard anterior temporal lobectomies for intractable complex partial epilepsy with a mean follow-up period of 5 years. Quantitative analyses of hippocampal neuron loss showed that all patients had some cell loss compared to control hippocampi obtained at autopsy. The average hippocampal cell loss was categorized as severe (greater than 30% of autopsy control levels) or mild. Analysis of hippocampal and extrahippocampal pathologies showed that in 109 cases (73%, the hippocampal lesion group) hippocampal cell loss was mild in 17 cases (16%) and severe in 92 cases (84%); in the remaining 40 cases (27%, the extrahippocampal structural lesion group) hippocampal cell loss was mild in 24 cases (60%) and severe in 16 (40%). The first index of surgical outcome was worthwhile seizure reduction, which occurred in 94 cases (86%) with mild or severe hippocampal lesions and in 33 cases (82%) with extrahippocampal pathology. In the hippocampal lesion group, worthwhile seizure reduction occurred in 90% of cases with severe and in only 65% of cases with mild hippocampal cell loss (p = 0.015). In the extrahippocampal pathology group, worthwhile seizure was not statistically different, whether hippocampal cell loss was severe (94% of cases) or mild (75% of cases). The second index of surgical outcome was the occurrence of residual seizures in the patients with worthwhile seizure reduction, which would indicate remaining epileptogenic tissue. In the hippocampal lesion group, the incidence of residual seizures was not statistically different whether hippocampal cell loss was severe (24% of cases) or mild (45% of cases). However, in the extrahippocampal pathology group, residual seizures occurred in 53% of cases with severe cell loss (dual pathology) but in only 11% of cases with mild cell loss (p = 0.025). Worthwhile seizure reduction can be predicted by the presence of either severe hippocampal cell loss or an extrahippocampal structural lesion. However, residual seizures more frequently follow in cases with a combination of both (extrahippocampal pathology associated with severe hippocampal cell loss, or dual pathology), suggesting that epileptogenic tissue more likely extends outside the boundaries of a standard temporal lobectomy.

Cortical sensory representation of the human hand: size of finger regions and nonoverlapping digit somatotopy.

Findings differ on cortical representation of fingers between human and animal studies, and on digit somatotopy among human studies. To resolve these differences, we mapped cortical sensory representation of each of the five digits and of median and ulnar nerves in three patients, using focal peripheral electrical shock stimuli. We compared locations and sizes of cortical regions among digits and nerves, using the model of a current dipole in a sphere applied to electrocorticography from subdural grids. Cortical representation was larger for the index finger than for the little finger and for the middle finger than for the ring finger, which are similar to findings in the monkey but different from Penfield's classic sensory homunculus. The thumb was larger than the middle finger, as in the homunculus. There was nonoverlapping somatotopy of all digits in each patient. These findings demonstrate a previously unrecognized similarity of cortical sensory organization of the fingers between humans and other primates.

Human hand and lip sensorimotor cortex as studied on electrocorticography.

We investigated functional topography of human hand and lip sensorimotor cortex using somatosensory evoked potentials (SEPs) from chronically indwelling subdural grid electrodes (ECoG) in 3 epilepsy patients during stimulation of median nerve, ulnar nerve, and lower lip. We used dipole modeling to determine the cortical location of each peripheral sensory field. The cortical locations were in the postcentral gyrus and showed a clear somatotopic organization from medial superior to lateral inferior in the order: ulnar nerve, median nerve, and lip. The source localizations agreed with the results of cortical stimulations and anatomical features on intraoperative photographs. The cortical regions of median and ulnar nerve each could be modeled by sequential tangential and radial dipoles. The cortical region of lip was different and could be explained mostly by tangential dipoles. These findings suggest a difference in the cortical organization of human lip and hand sensory cortex and are consistent with a larger representation of lip in the posterior bank of central fissure in area 3b than on the gyral surface in area 1, similar to findings in macaque. Further studies in a larger population of patients with ECoG or normal subjects with scalp-EEG and MEG are warranted to test this hypothesis.

Topographic mapping of somatosensory evoked potentials helps identify motor cortex more quickly in the operating room.

Median nerve somatosensory evoked potentials were recorded from exposed cerebral cortex during craniotomies. This technique is valuable when knowledge of the motor cortex location can influence surgical decisions about resection limits or biopsy sites. Two different recording techniques were compared: strips of electrodes and arrays of electrodes. The arrays recorded electrical potentials suitable for topographic mapping. We found that motor cortex could be identified more quickly when using the topographic mapping of SEPs from arrays. We conclude that topographic mapping of SEP from sensorimotor regions during craniotomies works well in general and can be done more quickly than the traditional electrode strip technique.