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D D Spencer

Publications and source records attributed to D D Spencer.

At least 19 recordsLinked to original sources
PubMed2006

Changes in glial glutamate transporters in human epileptogenic hippocampus: inadequate explanation for high extracellular glutamate during seizures.

Temporal lobe epilepsy (TLE) with hippocampal sclerosis is associated with high extracellular glutamate levels, which could trigger seizures. Down-regulation of glial glutamate transporters GLAST (EAAT1) and GLT-1 (EAAT2) in sclerotic hippocampi may account for such increases. Their distribution was compared immunohistochemically in non-sclerotic and sclerotic hippocampi and localized only in astrocytes, with weaker immunoreactivity for both transporters in areas associated with pronounced neuronal loss, especially in CA1, but no decrease or even an increase in areas with less neuronal loss, like CA2 and the subiculum in the sclerotic group. Such compensatory changes in immunoreactivity may account for the lack of differences between the groups in immunoblot studies as blots show the average concentrations in the samples. These data suggest that differences in glial glutamate transporter distribution between the two groups of hippocampi may be an insufficient explanation for the high levels of extracellular glutamate in sclerotic seizure foci observed through in vivo dialysis studies.

Adolescent↗
PubMed2006

Quantitative glutamate spectroscopic imaging of the human hippocampus.

We have evaluated a three-dimensional localized spectroscopic imaging sequence that uses two pairs of adiabatic full-passage pulses, which optimizes the detection of glutamate resonances at moderate echo times. This sequence provides excellent volume localization while simultaneously reducing J-modulation losses of glutamate. We have simulated the performance of this sequence for glutamate and used it to quantitatively measure glutamate in the human hippocampus using a linear components model. Using tissue segmentation and regression analysis, we measured a glutamate concentration of 8.8 +/- 2.1 mM in hippocampal and temporal gray matter and 3.7 +/- 1.1 mM in temporal white matter (95% CI). We have used this approach in a small group of patients (n = 5) with unilateral hippocampal epilepsy.

Adult↗
PubMed2005

Neural correlates of temporal-order judgments versus those of spatial-location: deactivation of hippocampus may facilitate spatial performance.

The retrieval of temporal-order versus spatial-location information was investigated using fMRI. The primary finding in the hippocampus proper, seen in region of interest analyses, was an increase in BOLD signal intensity for temporal retrieval, and a decrease in signal intensity for spatial retrieval, relative to baseline. The negative BOLD signal change with spatial memory processing, while unexpected, is consistent with the recent fMRI literature indicating decreased BOLD can be associated with neuronal activation, and it is argued that the deactivation observed here may facilitate spatial performance. Spatial-location judgments also yielded a stronger (positive) response in the right midfrontal gyrus, while temporal-order judgments (autobiographic condition only) showed greater activity in the left superior temporal gyrus, suggesting greater working memory demands and greater semantization for each judgment type, respectively. Finally, all conditions activated the left midfrontal gyrus, although autobiographic memories showed additional activity in the medial frontal gyrus.

Adult↗
PubMed2005

Regional energetic dysfunction in hippocampal epilepsy.

OBJECTIVES: There is increasing evidence for a dysfunctional metabolic network in human mesial temporal lobe epilepsy (MTLE). To further describe this, we evaluated the bioenergetic status in unilateral MTLE inter-regionally and in relation to neuropathology. MATERIALS AND METHODS: We used whole brain high field (4 T) 31P MR spectroscopic imaging to determine in vivo PCr and ATP, studying n=22 patients (all candidates for hippocampal resection) and n=14 control volunteers. The degree of bioenergetic impairment was assessed by calculating the ratio of PCr to ATP. RESULTS: Compared to controls, patients demonstrated significant decreases in PCr/ATP from the ipsilateral amygdala and pes (0.84 +/- 0.14, 0.87 +/- 0.10, respectively, patients vs 0.97 +/- 0.15, 0.98 +/- 0.16, controls). In patients, the ipsilateral thalamic energetics positively correlated with contralateral hippocampal energetics. In addition, the ipsilateral thalamic and striatal energetics negatively correlated with hippocampal total glial counts. CONCLUSIONS: These data are consistent with a view that in MTLE, the bilateral hippocampi, ipsilateral thalamus and striatum are linked in their energetic depression, possibly reflecting the propagation of seizures throughout the brain.

Adenosine Triphosphate↗
PubMed2004

Ictal neocortical slowing in temporal lobe epilepsy.

BACKGROUND: Temporal lobe epilepsy (TLE) may affect brain regions outside the temporal lobe, causing impaired neocortical function during seizures. METHODS: The authors selected 11 consecutive patients with mesial TLE and hippocampal sclerosis who underwent intracranial EEG monitoring and had no seizures during a follow-up period of at least 1 year after temporal lobe resection. Secondarily generalized seizures were excluded, and up to three seizures were analyzed per patient (31 seizures total). Electrode contacts were assigned to one of nine cortical regions based on MRI surface reconstructions. EEG during seizures was analyzed for specific patterns including low-voltage fast (LVF), rhythmic polyspike, spike-wave, irregular slowing, and postictal suppression. RESULTS: Mesial and lateral temporal contacts on the side of seizure onset showed significant increases in ictal patterns such as LVF and polyspike activity, followed by postictal suppression. Bilateral frontal and ipsilateral parietal cortex exhibited large amplitude irregular slow waves during seizures. This frontoparietal slowing persisted into the postictal period. Perirolandic and occipital cortex were relatively spared. These EEG patterns were accompanied by bland staring, minor automatisms, and unresponsiveness or amnesia in the majority of patients studied. CONCLUSIONS: Prominent irregular slowing occurs in bilateral frontal and ipsilateral parietal association cortex during and after temporal lobe seizures. EEG slowing in the frontoparietal association cortex may signify physiologic impairment that contributes to widespread altered cerebral function during partial seizures.

Adolescent↗
PubMed2004

Loss of glutamine synthetase in the human epileptogenic hippocampus: possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy.

BACKGROUND: High extracellular glutamate concentrations have been identified as a likely trigger of epileptic seizures in mesial temporal lobe epilepsy (MTLE), but the underlying mechanism remains unclear. We investigated whether a deficiency in glutamine synthetase, a key enzyme in catabolism of extracellular glutamate in the brain, could explain the perturbed glutamate homoeostasis in MTLE. METHODS: The anteromedial temporal lobe is the focus of the seizures in MTLE, and surgical resection of this structure, including the hippocampus, leads to resolution of seizures in many cases. By means of immunohistochemistry, western blotting, and functional enzyme assays, we assessed the distribution, quantity, and activity of glutamine synthetase in the MTLE hippocampus. FINDINGS: In western blots, the expression of glutamine synthetase in the hippocampus was 40% lower in MTLE than in non-MTLE samples (median 44 [IQR 30-58] vs 69 [56-87]% of maximum concentration in standard curve; p=0.043; n=8 and n=6, respectively). The enzyme activity was lower by 38% in MTLE vs non-MTLE (mean 0.0060 [SD 0.0031] vs 0.0097 [0.0042] U/mg protein; p=0.045; n=6 and n=9, respectively). Loss of glutamine synthetase was particularly pronounced in areas of the MTLE hippocampus with astroglial proliferation, even though astrocytes normally have high content of the enzyme. Quantitative immunoblotting showed no significant change in the amount of EAAT2, the predominant glial glutamate transporter in the hippocampus. INTERPRETATION: A deficiency in glutamine synthetase in astrocytes is a possible molecular basis for extracellular glutamate accumulation and seizure generation in MTLE. Further studies are needed to define the cause, but the loss of glutamine synthetase may provide a new focus for therapeutic interventions in MTLE.

Adolescent↗
PubMed2003

Long-term seizure outcome in patients initially seizure-free after resective epilepsy surgery.

OBJECTIVE: To evaluate the likelihood of and risk factors for seizure recurrence in patients initially seizure-free after resective surgery for intractable epilepsy. METHODS: One hundred seventy-five patients who underwent lobectomy between 1972 and 1992 and were seizure-free during the first postoperative year were retrospectively studied. Outcome was measured by relapse risk, presence of auras in otherwise seizure-free patients, and seizure frequency among relapsers. Factors significant in bivariate or Kaplan-Meier analysis or considered potentially predictive a priori were included in multivariate models. RESULTS: Of the 175 patients (mean follow-up 8.4 years), 63% never relapsed. The likelihood of being seizure-free was 83 +/- 6% 3 years after surgery, 72 +/- 7% after 5 years, and 56 +/- 9% after 10 years. After adjusting for age at surgery, duration of preoperative epilepsy, and resection site, normal pathology was associated with increased risk of relapse compared to mesial temporal sclerosis or other pathology (p = 0.036; hazard ratio [HR] 2.38; 95% CI 1.06 to 5.34). Among patients otherwise seizure-free, preoperative illness of > or =20 years was associated with increased risk of postoperative auras (p = 0.040; HR 3.55; 95% CI 1.06 to 11.90). Among relapsers, 51% experienced one or fewer seizures per year. Normal pathology and earlier relapse were associated with higher postoperative seizure frequency. CONCLUSIONS: In patients seizure-free during the first year after resective epilepsy surgery, the likelihood of remaining seizure-free declined to 56% over 10 years, but half of patients who relapsed had at most one seizure per year. Longer preoperative illness and normal pathology predicted poorer outcome.

Adolescent↗
PubMed2003

Chemokine modulation of high-conductance Ca(2+)-sensitive K(+) currents in microglia from human hippocampi.

During acute pathological processes, microglia transform into an activated state characterized by a defined morphology and current profile, and are recruited to injury sites by chemokines. No information is available on the ion channels and the mode of action of chemokines in microglia in brain slices from humans with a chronic pathology. Thus, patch-clamp recordings of microglia were performed in hippocampal slices from seven patients who underwent surgery for pharmaco-resistant epilepsy. Cells were identified as microglia by positive labelling with fluorescein-conjugated tomato lectin before recording. All the recorded cells had an ameboid morphology characteristic of activated microglia. However, they had a high input resistance (3.6 G omega), a zero-current resting potential of -16 mV, and lacked Na+ currents, inwardly rectifying and delayed rectifying K+ currents such as non-activated microglia. Importantly, recorded cells expressed Ca2+-sensitive outward currents that activated at 0 mV with non-buffered intracellular Ca2+ and were sensitive to 1 mm tetraethylammonium (TEA). The estimated single-channel conductances were 187 pS in cell-attached and 149 pS in outside-out patches, similar to those of high-conductance Ca2+-dependent K+ channels. The chemokine MIP1-alpha increased whole-cell outward current amplitudes measured at +60 mV by a factor of 3.3. Thus, microglia in hippocampi from epileptic patients express high-conductance Ca2+-dependent K+ channels that are modulated by the chemokine MIP1-alpha. This modulation may contribute to the migratory effect of MIP1-alpha on microglia.

Calcium↗
PubMed2001

Quantitative (31)P spectroscopic imaging of human brain at 4 Tesla: assessment of gray and white matter differences of phosphocreatine and ATP.

This report describes the implementation and application of a multicompartment analysis of (31)P spectroscopic imaging data to determine the tissue-specific heterogeneities in metabolite content in the human brain and surrounding tissue. Using this information and a multicompartment regression analysis the phosphocreatine and ATP content of "pure" cerebral gray and white matter, the cerebellum, and skeletal muscle was determined in a group of 10 healthy volunteers. The data were converted to mM units using previously reported values for the T(1)s of phosphocreatine and ATP at 4 T, the water content of human brain, and an external reference for absolute quantification. The phosphocreatine concentration in cerebral gray and white matter, the cerebellum, and skeletal muscle was 3.53 +/- 0.33, 3.33 +/- 0.37, 3.75 +/- 0.66, and 25.8 +/- 2.3 mM, respectively. The ATP concentration in cerebral gray and white matter, the cerebellum, and skeletal muscle was 2.19 +/- 0.33, 3.41 +/- 0.33, 1.75 +/- 0.58, and 8.5 +/- 1.9 mM, respectively. Magn Reson Med 45:46-52, 2001.

Adenosine Triphosphate↗
PubMed2001

Repetition time in echo planar functional MRI.

To date, surprisingly little attention has been directed toward determining the optimum TR in a functional imaging experiment. A survey of the literature reveals a wide range of TRs, but little justification for a specific TR. Long-TR functional imaging experiments provide maximum signal-to-noise ratio (SNR) in the raw images; allow for the collection of a large number of slice locations; and decrease the size of the data set acquired, simplifying storage and handling. This work, however, demonstrates that long-TR imaging sacrifices statistical power when the paradigm timing is held fixed. That is, for a fixed-run duration consisting of multiple activation/control blocks, shorter TR acquisitions (on the order of 1000 ms) provide better discrimination between the activated and nonactivated brain tissue regions than do long-TR acquisitions (on the order of 4000 ms). Results are shown for modeling the functional imaging experiment and for three different paradigms performed on normal subjects.

Adult↗
PubMed2001

Interictal 99mTc-HMPAO SPECT in temporal lobe epilepsy: relation to clinical variables.

PURPOSE: Factors affecting blood flow observed by interictal single-photon emission computed tomography (SPECT) images in temporal lobe epilepsy (TLE) have not been systematically studied or consistently demonstrated. We evaluated interictal SPECT results with respect to many clinical variables in a large population of TLE patients, all of whom underwent temporal lobectomy. METHODS: Interictal 99mTc-HMPAO SPECT scans from 61 TLE patients were obtained before an anterior temporal lobectomy. SPECT was analyzed using a region of interest analysis (ROI) in the cerebellum, anterior temporal lobe, lateral temporal lobe, mesial temporal lobe, whole temporal lobe, and inferior frontal lobe. Asymmetry indices (AIs) were calculated. Correlative analysis of AIs and clinical variables was performed. RESULTS: The AIs from TLE patients differed significantly from those of controls in the anterior temporal (p < 0.01), lateral temporal (p < 0.001), and whole temporal (p < 0.01) regions. No consistent overall correlation between the AIs and clinical variables existed. In right TLE (RTLE) only, AIs in the lateral and whole temporal lobe were positively correlated with age of onset (r = 0.470, p < 0.05; r = 0.548, p < 0.01, respectively). Similarly, in RTLE only, duration of epilepsy was negatively correlated with the anterior (r = -0.395, p < 0.05) and mesial (r = -0.45, p < 0.05) temporal lobe AI. No correlations were found between clinical variables and AIs in left TLE (LTLE) patients. CONCLUSIONS: Significant correlation of age at onset and duration of epilepsy with AIs in RTLE but not LTLE suggests physiologic processes may be determined in part by laterality of TLE. Clinical applications are problematic.

Adult↗
PubMed2001

Functional MRI of language processing: dependence on input modality and temporal lobe epilepsy.

PURPOSE: Functional magnetic resonance imaging (MRI) using two language-comprehension tasks was evaluated to determine its ability to lateralize language processing and identify regions that must be spared in surgery. METHODS: Two parallel cognitive language tasks, one using auditory input and the other visual input, were tested in a group of control subjects and in temporal lobe epilepsy patients who were candidates for surgical intervention. The patient studies provide an opportunity to compare functional MRI language localization with that obtained using Wada testing and electrocorticography. All of the patients in this study underwent all three procedures and a battery of neuropsychological testing. Such studies provide an opportunity not only to validate the fMRI findings but also, by comparing the patient results with those obtained in control subjects, to provide insight into the impact of a pathology such as epilepsy on cortical organization or functional patterns of activation. RESULTS: The results reveal both modality-dependent and modality-independent language-processing patterns for visual versus auditory task presentation. The visual language task activated distinct sites in Broca's area, BA (Brodmann area) 44 that were not activated in the auditory language task. The auditory language task strongly activated contralateral right BA22-21 area (homologous to Wernicke's area on the left). Language lateralization scores were significantly stronger for visual than for auditory task presentation. The conjunction of activation from the two different input modalities (modality-independent areas) likely highlights regions that perform more abstract computations (e.g., syntactic or pragmatic processing) in language processing. Modality-specific areas (e.g., right Wernicke, left fusiform gyrus, Broca BA44, supramarginal gyrus), appear to cope with the computations relevant to making contact with these more abstract dimensions. Patients showed recruitment of contralateral homologous language areas (p < 0.005) that was significantly above that found in a normal control group. Extra- and intraoperative cortical stimulations were concordant with the fMRI data in eight of 10 cases. The fMRI lateralization scores were also consistent with the Wada testing in 8/10 patients. CONCLUSIONS: The fMRI results demonstrate that the epileptic brain may be a progressive model for cortical plasticity.

Adult↗
PubMed2001

GABA uptake and heterotransport are impaired in the dentate gyrus of epileptic rats and humans with temporal lobe sclerosis.

In vivo dialysis and in vitro electrophysiological studies suggest that GABA uptake is altered in the dentate gyrus of human temporal lobe epileptics characterized with mesial temporal sclerosis (MTLE). Concordantly, anatomical studies have shown that the pattern of GABA-transporter immunoreactivity is also altered in this region. This decrease in GABA uptake, presumably due to a change in the GABA transporter system, may help preserve inhibitory tone interictally. However, transporter reversal can also occur under several conditions, including elevations in [K(+)]o, which occurs during seizures. Thus GABA transporters could contribute to seizure termination and propagation through heterotransport. To test whether GABA transport is compromised in both the forward (uptake) and reverse (heterotransport) direction in the sclerotic epileptic dentate gyrus, the physiological effects of microapplied GABA and nipecotic acid (NPA; a compound that induces heterotransport) were examined in granule cells in hippocampal slices from kainate (KA)-induced epileptic rats and patients with temporal lobe epilepsy (TLE). GABA- and NPA-induced responses were prolonged in granule cells from epileptic rats versus controls (51.3 and 31.3% increase, respectively) while the conductance change evoked with NPA microapplication was reduced by 40%. Furthermore the ratio of GABA/NPA conductance, but not duration, was significantly >1 in epileptic rats but not controls, suggesting a compromise in transporter function in both directions. Similar changes were observed in tissue resected from epileptic patients with medial temporal sclerosis but not in those without the anatomical changes associated with MTLE. These data suggest that the GABA transporter system is functionally compromised in both the forward and reverse directions in the dentate gyrus of chronically epileptic tissue characterized by mesial temporal sclerosis. This alteration may enhance inhibitory tone interically yet be permissive for seizure propagation due to a decreased probability for GABA heterotransport during seizures.

Animals↗
PubMed2001

Patterns of functional magnetic resonance imaging activation in association with structural lesions in the rolandic region: a classification system.

OBJECT: Functional magnetic resonance (fMR) imaging of the motor cortex is a potentially powerful tool in the preoperative planning of surgical procedures in and around the rolandic region. Little is known about the patterns of fMR imaging activation associated with various pathological lesions in that region or their relation to motor skills before surgical intervention. METHODS: Twenty-two control volunteers and 44 patients whose pathologies included arteriovenous malformations (AVMs; 16 patients), congenital cortical abnormalities (11 patients), and tumors (17 patients) were studied using fMR imaging and a hand motor task paradigm. Activation maps were constructed for each participant, and changes in position or amplitude of the motor activation on the lesion side were compared with the activation pattern obtained in the contralateral hemisphere. A classification scheme of plasticity (Grades 1-6) based on interhemispheric pixel asymmetry and displacement of activation was used to compare maps between patients, and relative to hand motor dexterity and/or weakness. There was 89.4% interobserver agreement on classification of patterns of fMR imaging activation. Displacement of activation by mass effect was more likely with tumors. Cortical malformations offer a much higher functional reorganization than AVMs or tumors. High-grade plasticity is recruited to compensate for severe motor impairment. CONCLUSIONS: Pattern modification of fMR imaging activation can be systematized in a classification of motor cortex plasticity. This classification has shown good correlation among grading, brain lesions, and motor skills. This proposal of a classification scheme, in addition to facilitating data collection and processing from different institutions, is well suited for comparing risks associated with surgical intervention and patterns of functional recovery in relation to preoperative fMR imaging categorization. Such studies are underway at the authors' institution.

Adolescent↗
PubMed2001

Strategies for reoperation after comprehensive epilepsy surgery.

OBJECT: Prior reports of seizure control following reoperation for failed epilepsy surgery have shown good results. These studies included patients who presented during the era preceding magnetic resonance (MR) imaging, and the patients were often not monitored intracranially or underwent subtotal hippocampal resections. In this study, the authors hypothesized that reoperation for recurrent seizures following a more comprehensive initial workup and surgery would not yield such good results. METHODS: The authors examined a consecutive series of patients who underwent two operations at Yale-New Haven Hospital for medically intractable epilepsy and in whom there was a minimum of 1-year follow up after the second surgery. All patients were evaluated and treated according to a standard protocol, including preoperative MR imaging, a low threshold for invasive monitoring, and a radical amygdalohippocampectomy when indicated. Twenty-seven patients were identified (five with mesial temporal sclerosis, 20 with neocortical disease, and two with multifocal sites of seizure onset) of whom six (22%) underwent intentionally palliative second surgery (corpus callostomy or placement of a vagus nerve stimulator [VNS]). Of the remaining 21 patients, only four (19%) became seizure free after a second resective operation. The most common causes of treatment failure were dual pathology, recurrent tumor, limited resection to preserve function, widespread developmental abnormalities, and electrographic sampling error. Successful outcomes resulted from removal of recurrent tumors, completion of a functional hemispherectomy, or repeated invasive monitoring to correct a sampling error. Five (83%) of the six intentionally palliative second operations resulted in more than a 50% decrease in seizure frequency. CONCLUSIONS: If an aggressive preoperative evaluation and surgical resection are performed, reoperation for recurrent seizures has a much lower likelihood of cure than previously reported. Intentionally palliative surgery such as placement of a VNS unit may be considered for patients in whom the initial operation fails to decrease seizure frequency.

Adolescent↗
PubMed2001

Multiple subpial transections: the Yale experience.

PURPOSE: Although resection of an epileptogenic region is the mainstay of epilepsy surgery, epileptogenic areas in functionally critical cortex cannot be approached in that manner. Multiple subpial transection (MST) was developed to treat those refractory seizures without causing unacceptable neurologic deficit. We review our experience with this technique. METHODS: Twelve patients who underwent MST with or without resection between 1990 and 1998 were retrospectively reviewed with regard to seizure and neurologic outcome, and predictive factors. RESULTS: Five (42%) of 12 patients obtained a significant improvement in seizure frequency, and two other patients had a marked decrease in the severity of their seizures. Resection with MST reduced seizure frequency more, but this was not a significant difference. No predictive factors for outcome were identified. Only one patient sustained any persistent neurologic deficit. CONCLUSIONS: In selected patients, MST may be a viable alternative when the epileptogenic focus lies in unresectable cortex. A multicenter study with appreciable patient numbers will be necessary to define predictive factors for success.

Adolescent↗
PubMed2000

Mouse cytomegalovirus in developing brain tissue: analysis of 11 species with GFP-expressing recombinant virus.

Cytomegaloviruses (CMVs) are species-specific large double-stranded DNA viruses. Mouse and human CMVs have a similar morphology, similar gene sequence, and exert similar cellular effects, but the replication of the virus outside its primary host species is limited. This may confer upon CMV certain advantages for expression of foreign genes or cellular labels in brain cells of nonhost species. We examined the ability of recombinant mouse (m)CMV expressing green fluorescent protein (GFP) to serve as a vector for transgene expression in developing neurons and glia outside the normal host species. For comparative purposes, 11 species were examined. Mouse CMV reporter gene expression was particularly strong in the developing brain of its normal host species, mouse, where it replicated in cultures and brain slices, leading to cell death. All mammalian species tested (human, rat, gerbil, hamster, mouse) showed reporter gene expression after mCMV infection. High levels of mCMV infection were also found in chicken central nervous system cells in vitro, and a low level of mCMV expression was found after an initial delay in turtle neurons and glia. No mCMV reporter gene expression was found in frog cells or aplysia neurons or glia or in drosophila or fungal cells. Infection of nonmouse neurons by low concentrations of mCMV led to strong expression of GFP in dendrites and axons with normal morphology. Despite the lack of replication, high doses of mCMV induced morphologic changes in neurons and glia from hamster and rat brain slices, leading to cells rounding up, and to the formation of giant cells consisting of an aggregate of many cells fused together into a syncytium. In contrast, in human hippocampal slices, GFP-expressing cells infected with mCMV had a relatively normal appearance 12 days after inoculation. To determine whether a CMV from another species could serve as a vector for gene transfer, a recombinant human CMV-expressing GFP was used for transgene expression in rat brain cells in vitro. Cytomegaloviruses thus have potential as useful vectors for gene transfer and labeling central nervous system cells, with the actions of CMV being dependent on a number of factors.

Animals↗