D C Silveira

Boston Children's Hospital, Boston, Massachusetts, United States

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Publications (34)79.37 Total impact

  • Byung Ho Cha · Cigdem Akman · Diosely C Silveira · Xianzeng Liu · Gregory L Holmes
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    ABSTRACT: It is known that evoked seizures can increase neurogenesis in the dentate gyrus in adult rats. Whether spontaneous seizures occurring after status epilepticus (SE) also results in alterations in neurogenesis is not known. Here, we measured neurogenesis in rats with and without spontaneous seizures following SE. Lithium-pilocarpine was used to induce seizures in postnatal (P) day 20 rats. Spontaneous seizure frequency was assessed 2 months using video monitoring. Rats then received bromodeoxyuridine to label dividing DNA and were sacrificed 24 h later. Animals with spontaneous seizures (n = 9) had a modest increase in neurogenesis compared to animals with SE (n = 6) and no spontaneous seizures and control rats (n = 10). These findings demonstrate that the hippocampus is capable of generating new neurons weeks following SE and further that recurrent seizures enhance the production of new neurons. These alterations in neurogenesis may contribute to ongoing pathological changes week and months following SE.
    No preview · Article · Oct 2004 · Brain and Development
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    ABSTRACT: Networks of GABAergic interneurons are of utmost importance in generating and promoting synchronous activity and are involved in producing coherent oscillations. These neurons are characterized by their fast-spiking rate and by the expression of the Ca(2+)-binding protein parvalbumin (PV). Alteration of their inhibitory activity has been proposed as a major mechanism leading to epileptic seizures and thus the role of PV in maintaining the stability of neuronal networks was assessed in knockout (PV-/-) mice. Pentylenetetrazole induced generalized tonic-clonic seizures in all genotypes, but the severity of seizures was significantly greater in PV-/- than in PV+/+ animals. Extracellular single-unit activity recorded from over 1000 neurons in vivo in the temporal cortex revealed an increase of units firing regularly and a decrease of cells firing in bursts. In the hippocampus, PV deficiency facilitated the GABA(A)ergic current reversal induced by high-frequency stimulation, a mechanism implied in the generation of epileptic activity. We postulate that PV plays a key role in the regulation of local inhibitory effects exerted by GABAergic interneurons on pyramidal neurons. Through an increase in inhibition, the absence of PV facilitates synchronous activity in the cortex and facilitates hypersynchrony through the depolarizing action of GABA in the hippocampus.
    Full-text · Article · May 2004 · Molecular and Cellular Neuroscience
  • Diosely C Silveira · Byung Ho Cha · Gregory L Holmes
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    ABSTRACT: The cholinergic system modulates cerebral excitability. We recently reported that immunolesions of the basal forebrain (BF) cholinergic neurons in adult rats increase the susceptibility to generalized seizures. In this study we investigated the effects of lesions of the BF cholinergic neurons in neonatal rats on seizure susceptibility and cognitive function. Neonatal rats at postnatal day (P) 7 received intracerebroventricular (i.c.v.) injections of 192 IgG-saporin (SAP) or phosphate-buffered saline. Following 3 weeks after the injection the first group of rats was implanted with hippocampal electrodes for electroencephalogram (EEG) recordings while the second group of rats was tested for visual spatial memory using the hidden platform version of the water maze test. The first group of rats was then tested for seizure susceptibility using flurothyl 1 week after the electrode implantation. Rats that received immunolesions of the BF cholinergic neurons at P7 had significantly shorter latencies to onset of myoclonic jerks and tonic-clonic seizures than controls. However, no significant differences were found in the duration of seizures, or EEG ictal duration. No significant deficits in spatial learning were found between rats that received i.c.v. injections of SAP at P7 and controls. As in adult rats, lesions of the BF cholinergic system in rat pups result in subsequent increase in seizure susceptibility.
    No preview · Article · Jan 2003 · Developmental Brain Research
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    S Faverjon · D C Silveira · D D Fu · B H Cha · C Akman · Y Hu · G L Holmes
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    ABSTRACT: There is increasing evidence that enriching the environment can improve cognitive and motor deficits following a variety of brain injuries. Whether environmental enrichment can improve cognitive impairment following status epilepticus (SE) is not known. To determine whether the environment in which animals are raised influences cognitive function in normal rats and rats subjected to SE. Rats (n = 100) underwent lithium-pilocarpine-induced SE at postnatal (P) day 20 and were then placed in either an enriched environment consisting of a large play area with toys, climbing objects, and music, or in standard vivarium cages for 30 days. Control rats (n = 32) were handled similarly to the SE rats but received saline injections instead of lithium-pilocarpine. Rats were then tested in the water maze, a measure of visual-spatial memory. A subset of the rats were killed during exposure to the enriched or nonenriched environment and the brains examined for dentate granule cell neurogenesis using bromodeoxyuridine (BrdU) and phosphorylated cyclic AMP response element binding protein (pCREB) immunostaining, a brain transcription factor important in long-term memory. Both control and SE rats exposed to the enriched environment performed significantly better than the nonenriched group in the water maze. There was a significant increase in neurogenesis and pCREB immunostaining in the dentate gyrus in both control and SE animals exposed to the enriched environment compared to the nonenriched groups. Environmental enrichment resulted in no change in SE-induced histologic damage. Exposure to an enriched environment in weanling rats significantly improves visual-spatial learning. Even following SE, an enriched environment enhances cognitive function. An increase in neurogenesis and activation of transcription factors may contribute to this enhanced visual-spatial memory.
    Full-text · Article · Dec 2002 · Neurology
  • Byung Ho Cha · Diosely C Silveira · Xianzeng Liu · Yingchun Hu · Gregory L Holmes
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    ABSTRACT: Topiramate, an antiepileptic drug with a number of mechanisms of action including inhibition of glutamate activity at the AMPA and KA receptors, was assessed as a neuroprotective agent following seizures. We administered topiramate, 80 mg/kg, or saline for 4 weeks following a series of 25 neonatal seizures or status epilepticus (SE) induced by lithium-pilocarpine in postnatal day 20 rats. Age-matched control rats without a history of seizures were administered topiramate or saline. Following completion of the topiramate injections, animals were tested in the water maze for spatial learning and the brains examined for cell loss and sprouting of mossy fibers. While there was a trend for improved visual-spatial performance in the water maze following topiramate therapy in rats with neonatal seizures, no differences were found in the histological examination of the hippocampus. Neonatal rats exposed to 4 weeks of topiramate did not differ from non-treated controls in water maze performance or histological examination. In weanling rats subjected to SE, topiramate provided a moderate degree of neuroprotection, with topiramate-treated rats performing better in the water maze than rats receiving saline. However, no differences in cell loss or mossy fiber sprouting were found in the histological examination of the brains. These findings demonstrate that chronic treatment with topiramate following SE improves cognitive function. In addition, long-term administration of high-dose topiramate in the normal developing rat brain does not appear to impair cognitive performance.
    No preview · Article · Nov 2002 · Epilepsy Research
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    ABSTRACT: Status epilepticus (SE) has a high mortality and morbidity rate in children. Disturbances in learning and memory are frequently associated with SE although it is not clear when the cognitive deficits occur. If cognitive dysfunction occurs immediately following the seizure, the window of opportunity for therapeutic intervention is limited. The first goal of this study was to determine the timing of cognitive dysfunction following SE in weanling rats. As there is evidence that enriching the environment can improve cognitive and motor deficits following brain injury, our second goal was to determine whether environmental enrichment improves cognitive function following SE. Rats underwent lithium-pilocarpine-induced SE at postnatal (P) day 20 and were then tested for visual-spatial memory in the water maze at P22, P25, P30, or P50. Rats with SE performed significantly worse in the water maze than control rats at all time points. Once the time-courses of visual-spatial memory deficits were determined, a second group of P20 rats were subjected to SE and were then placed in an enriched environment (enriched group) or remained in standard cages in the vivarium (nonenriched group) for 28 days. Following environmental manipulation, the animals were tested in the water maze. Rats housed in an enriched environment following the SE performed substantially better in the water maze than rats housed in standard cages. However, no differences were found between the enriched and nonenriched groups in EEG or histological evaluation. Although SE results in cognitive impairment within days of the seizure, housing in an enriched environment after SE has a beneficial effect on cognitive performance in rats.
    No preview · Article · Sep 2002 · European Journal of Neuroscience
  • Diosely C Silveira · Yoshimi Sogawa · Gregory L Holmes
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    ABSTRACT: The expression of limbic seizures following kainic acid (KA) administration starts at approximately postnatal day (P) 19 in rats. In this study we investigated whether the expression of Fos-like immunoreactivity (Fos-IR) in limbic regions occurs concomitantly with the behavioural expression of limbic seizures. Immunohistochemistry for c-Fos protein was examined 1, 2, 4, 12 and 24 h following seizure onset (KA-treated rats) or saline injections (controls) in immature and adult rats at P7, P13, P20 and P60. The expression of Fos-IR in limbic structures following KA-induced seizures is age-dependent. There is a strong and selective induction of Fos-IR in the CA3 region of the hippocampus following KA-induced seizures in rats at P7. However, the expression of Fos-IR in KA-treated rats at P13, P20 and P60 involved other hippocampal structures in addition to CA3. Abundant induction of Fos-IR was found in the CA1, CA3 and dentate gyrus (DG) in KA-treated rats at P13, P20 and P60. While immature rats at P7 and P13 showed very few or no Fos-IR neurons in most amygdala nuclei, rat pups at P20 showed strong induction of Fos-IR in the amygdala. Our results demonstrated that the induction of Fos-IR in most amygdala nuclei and the full expression of behavioural limbic seizures occur at the same developmental age, which is consistent with the idea that the amygdala may play a role in the modulation of limbic seizures.
    No preview · Article · Feb 2002 · European Journal of Neuroscience
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    ABSTRACT: Neonatal seizures are frequently associated with cognitive impairment and reduced seizure threshold. Previous studies in our laboratory have demonstrated that rats with recurrent neonatal seizures have impaired learning, lower seizure thresholds, and sprouting of mossy fibers in CA3 and the supragranular region of the dentate gyrus in the hippocampus when studied as adults. The goal of this study was to determine the age of onset of cognitive dysfunction and alterations in seizure susceptibility in rats subjected to recurrent neonatal seizures and the relation of this cognitive impairment to mossy fiber sprouting and expression of glutamate receptors. Starting at postnatal day (P) 0, rats were exposed to 45 flurothyl-induced seizures over a 9-day period of time. Visual-spatial learning in the water maze and seizure susceptibility were assessed in subsets of the rats at P20 or P35. Brains were evaluated for cell loss, mossy fiber distribution, and AMPA (GluR1) and NMDA (NMDAR1) subreceptor expression at these same time points. Rats with neonatal seizures showed significant impairment in the performance of the water maze and increased seizure susceptibility at both P20 and P35. Sprouting of mossy fibers into the CA3 and supragranular region of the dentate gyrus was seen at both P20 and P35. GluR1 expression was increased in CA3 at P20 and NMDAR1 was increased in expression in CA3 and the supragranular region of the dentate gyrus at P35. Our findings indicate that altered seizure susceptibility and cognitive impairment occurs prior to weaning following a series of neonatal seizures. Furthermore, these alterations in cognition and seizure susceptibility are paralleled by sprouting of mossy fibers and increased expression of glutamate receptors. To be effective, our results suggest that strategies to alter the adverse outcome following neonatal seizures will have to be initiated during, or shortly following, the seizures.
    No preview · Article · Dec 2001 · Developmental Brain Research
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    ABSTRACT: Seizures in preterm infants are associated with a high risk of neurological sequelae. In the neonatal rat recurrent seizures have been associated with long-term changes in cerebral excitability and cognition as well as sprouting of mossy fiber terminals in the granule cell layer of the dentate gyrus and hippocampal CA3 subfield. To evaluate the relationship between seizure-induced morphological changes and cognitive function we subjected newborn rats to 55 seizures with flurothyl during the first 12 days of life. During adolescence rats with prior recurrent seizures were compared with controls in electroencephalographic power and performance in the Morris water maze and open field test. Rats subjected to recurrent seizures had marked impairment in water maze performance and never reached the level of learning seen in controls despite a total of 54 trials. Recurrent seizures were also associated with an overall reduction in spectral power which was most pronounced in the theta range. On histological examination rats with recurrent neonatal seizures had sprouting of mossy fiber terminals in CA3 and the granule cell layer of the dentate gyrus without any accompanying cell loss. Sprouting in CA3, but not the granule cell layer of the dentate gyrus, correlated with water maze performance. This study demonstrates that recurrent neonatal seizures can result in profound impairment of water maze performance and reduction of electroencephalographic power despite the lack of discernible cell loss and that this cognitive impairment correlates with mossy fiber sprouting in CA3.
    No preview · Article · Aug 2001 · Developmental Brain Research
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    Preview · Article · Jun 2001 · Developmental Brain Research
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    ABSTRACT: Following kainic acid (KA)-induced status epilepticus (SE), the ketogenic diet (KD) retards the development of epileptogenesis, with fewer spontaneous recurrent seizures (SRS) and less mossy fiber sprouting than rats on a normal diet. In this study, we investigated whether there is a critical period for initiation of the KD, in terms of the diet's effectiveness in reducing SRS. In addition, we investigated whether early treatment with the KD prevents the deficits in spatial learning and memory that ordinarily follow KA-induced SE. Young rats (P30) underwent KA-induced SE, followed by assignment to one of three treatment groups: control diet ('KA'), KD begun 2 days after SE ('KD2'), and KD begun fourteen days after SE ('KD14'). For 12 weeks following SE, rats were monitored by closed circuit video recording (12 h/wk) to detect SRS. KD2 rats had significantly fewer SRS than rats in the control or KD14 groups. On water maze testing to assess spatial learning and memory, KD2 rats had significantly poorer acquisition of place learning than control (KA alone) or KD14 rats. KD2 rats also failed to gain weight well. There was no difference between groups on routine histologic examination of the hippocampus. In summary, P30 rats placed on the KD 2 days after SE were relatively protected from recurrent seizures, but showed behavioral and physical impairment. Rats placed on the KD 14 days after KA-induced SE did not differ from controls with regard to spontaneous seizure rate.
    No preview · Article · Jun 2001 · Developmental Brain Research
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    ABSTRACT: The purpose of this study was to compare the serum levels of androgens between hyposexual and non-hyposexual patients with epilepsy. Adult male patients with epilepsy were investigated. Serum levels of testosterone (T) and free-T, estradiol, and sex hormone binding globulin (SHBG) were measured and the free androgen index (FAI) was calculated. While there were no differences between hyposexual and non-hyposexual patients in the serum levels of T, free-T, and estradiol, or to the FAI, the serum levels of SHBG were significantly higher in hyposexual patients than in non-hyposexual patients. Thus, the effects of increased SHBG upon serum levels of testosterone biologically active in patients with epilepsy and hyposexuality were not detected by the methods used in this study. Four (44%) of nine hyposexual patients who were re-evaluated after two years follow-up improved sexual performance. Thus, clinical treatment that results in good seizure control may improve sexual performance in some patients with epilepsy.
    Preview · Article · Apr 2001 · Arquivos de Neuro-Psiquiatria
  • B K McCabe · D C Silveira · M R Cilio · B H Cha · XZ Liu · Y Sogawa · G L Holmes
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    ABSTRACT: Although neonatal seizures are quite common, there is controversy regarding their consequences. Despite considerable evidence that seizures may cause less cell loss in young animals compared with mature animals, there are nonetheless clear indications that seizures may have other potentially deleterious effects. Because it is known that seizures in the mature brain can increase neurogenesis in the hippocampus, we studied the extent of neurogenesis in the granule cell layer of the dentate gyrus over multiple time points after a series of 25 flurothyl-induced seizures administered between postnatal day 0 (P0) and P4. Rats with neonatal seizures had a significant reduction in the number of the thymidine analog 5-bromo-2'-deoxyuridine-5'-monophosphate- (BrdU) labeled cells in the dentate gyrus and hilus compared with the control groups when the animals were killed either 36 hr or 2 weeks after the BrdU injections. The reduction in BrdU-labeled cells continued for 6 d after the last seizure. BrdU-labeled cells primarily colocalized with the neuronal marker neuron-specific nuclear protein and rarely colocalized with the glial cell marker glial fibrillary acidic protein, providing evidence that a very large percentage of the newly formed cells were neurons. Immature rats subjected to a single seizure did not differ from controls in number of BrdU-labeled cells. In comparison, adult rats undergoing a series of 25 flurothyl-induced seizures had a significant increase in neurogenesis compared with controls. This study indicates that, after recurrent seizures in the neonatal rat, there is a reduction in newly born granule cells.
    No preview · Article · Apr 2001 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: We investigated whether basal forebrain cholinergic neurons influence the expression of generalized seizures. Animals received intracerebroventricular injections of saporin (lesioned) or saline (controls) and were tested for susceptibility to flurothyl- or pentylenetetrazole-induced seizures. Lesioned rats had significantly shorter latencies to onset of generalized tonic-clonic seizures than controls. Our findings suggest that basal forebrain cholinergic neurons may participate in the modulation of generalized seizures.
    No preview · Article · Oct 2000 · Brain Research
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    ABSTRACT: In order to evaluate the psychological variables that affect sexual dysfunction (SD) in epilepsy, where compared 60 epileptics (Group 1) with 60 healthy individuals (Group 2), through the State-Trait Anxiety Inventory (Spielberger et al., 1970), Beck Depression Inventory (Beck, 1974) and Sexual Behavior Interview (Souza, 1995). Sexual dysfunction (SD), anxiety and depression were found more frequently in Group 1 than in Group 2 and were not related to sex. Variables such as the onset duration and frequency of seizures as well as the use to medication were not associated with SD. Temporal lobe epilepsy was related to SD (p = 0.035) but not to anxiety or depression. Anxiety and depression were related to SD in both groups. Perception in controlling the seizures was closely related to anxiety (p = 0) and depression (p = 0.009). We conclude that psychological factors play an important role in the alteration of sexual behavior in epileptics and that suitable attention must be given to the control of these variables.
    Preview · Article · Jul 2000 · Arquivos de Neuro-Psiquiatria
  • D C Silveira · S C Schachter · D L Schomer · G L Holmes
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    ABSTRACT: Autonomic changes accompany seizures in both animals and humans. While ictal autonomic dysfunction can be life-threatening, the participating neural networks involved are poorly understood. In this study we examined the activation of Fos following generalized seizures in brainstem structures known to mediate autonomic function. Adult female rats were sacrificed 2 h after flurothyl-induced seizures. Double-immunostaining for c-Fos and dopamine-beta-hydroxylase (DBH), and c-Fos and phenylethanol-N-methyl-transferase (PNMT) were performed in brainstem slices. Numbers of DBH-labeled neurons expressing Fos-like immunoreactivity (FLI) (DBH/Fos) and PNMT labeled neurons expressing FLI (PNMT/Fos) were counted in the noradrenergic (A1, A2, A5, A7) and adrenergic (C1, C2) cell groups localized in pons and medulla oblongata. Among the experimental animals, the highest degree of co-localization of DBH/Fos neurons was observed in the locus coeruleus (A6; 87.7%), and in the A1(72.8%) cell group located in the caudal ventrolateral medulla (VLM). No co-localization of DBH/Fos neurons was observed in control animals. The highest degree of co-localization of PNMT/Fos neurons was observed in the C1 adrenergic cell group (84.2%) located in the rostral VLM. Control animals showed very few (5.5%) PNMT/Fos co-localized neurons in the C1 adrenergic cell group. Our results indicate that flurothyl-induced generalized seizures in rats activate catecholaminergic neurons in the pons and medulla oblongata. Further studies are necessary to determine whether activation of brainstem catecholaminergic neurons contribute to the autonomic manifestations that frequently accompany epileptic seizures.
    No preview · Article · Apr 2000 · Epilepsy Research
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    D C Silveira · P Klein · B J Ransil · Z Liu · A Hori · G L Holmes · S de LaCalle · J Elmquist · AG Herzog
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    ABSTRACT: Reproductive disorders are unusually frequent among women with temporal lobe seizures. The particular type of disorder may be related to the laterality and focality of epileptiform discharges. Here we examined whether unilateral amygdaloid seizures activate hypothalamic neurons involved in reproductive function and reproductive endocrine secretion in female rats and whether such activation shows lateral asymmetry. Numbers of Fos-immunoreactive (Fos-ir) neurons in various hypothalamic regions were compared for three groups of animals: (a) unilateral amygdala-kindled, (b) implanted but unstimulated, and (c) unimplanted. Fos-ir neurons showed strong ipsilateral occurrence in the medial preoptic, ventrolateral part of the ventromedial, and ventral premammillary nuclei, sexually dimorphic regions involved in reproductive endocrine regulation. No significant lateral asymmetry was observed for other investigated hypothalamic regions. Unilateral amygdaloid seizures activate hypothalamic neurons that regulate reproductive endocrine secretion in a laterally asymmetric fashion. This may explain the clinical association of different reproductive endocrine disorders with left and right temporal epileptiform discharges.
    Full-text · Article · Feb 2000 · Epilepsia
  • B Schwaller · A Villa · P Tandon · I V Tetko · D C Silveira · M R Celio

    No preview · Article · Jan 2000
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    ABSTRACT: Previous studies have demonstrated that recurrent seizures during the neonatal period lead to permanent changes in seizure threshold and learning and memory. The pathophysiological mechanisms for these changes are not clear. To determine if neonatal seizures cause changes in hippocampal excitability or inhibition, we subjected rats to 50 flurothyl-induced seizures during the first 10 days of life (five seizures per day). When the rats were adults, we examined seizure threshold using flurothyl inhalation, and learning and memory in the water maze. In separate groups of animals, we evaluated in vivo paired-pulse facilitation and inhibition in either CA1 with stimulation of the Schaffer collaterals or dentate gyrus with stimulation of the perforant path. Following these studies, the animals were sacrificed and the brains evaluated for mossy fiber sprouting with the Timm stain. Compared to control animals, rats with 50 flurothyl seizures had a reduced seizure threshold, impaired learning and memory in the water maze, and sprouting of mossy fibers in the CA3 pyramidal cell layer and molecular layer of the dentate gyrus. No significant differences in impaired paired-pulse inhibition was noted between the flurothyl-treated and control rats. This study demonstrates that recurrent neonatal seizures result in changes of neuronal connectivity and alterations in seizure susceptibility, learning and memory. However, the degree of impairment following 50 seizures was modest, demonstrating that the immature brain is remarkably resilient to seizure-induced damage.
    No preview · Article · Dec 1999 · Developmental Brain Research
  • D. C Silveira · S. C Schachter · D. L Schomer
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    ABSTRACT: The inferior colliculus (IC) plays a key role in modulating audiogenic seizures (AS) in rats. We investigated whether acoustic brainstem nuclei express Fos-like immunoreactivity (FLI) after flurothyl-induced generalized seizures in rats. Compared to controls, experimental animals showed significantly (P
    No preview · Article · Mar 1999 · Epilepsy Research

Publication Stats

1k Citations
79.37 Total Impact Points


  • 2002-2004
    • Boston Children's Hospital
      • Department of Neurology
      Boston, Massachusetts, United States
  • 1999-2004
    • Harvard Medical School
      • Department of Neurology
      Boston, Massachusetts, United States
  • 1999-2000
    • Beth Israel Deaconess Medical Center
      Boston, Massachusetts, United States
  • 1998
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1991-1996
    • University of Campinas
      • • Departamento de Neurologia
      • • Faculty of Medical Sciences
      Conceição de Campinas, São Paulo, Brazil