Electroconvulsive Seizures Research Articles

Molecular and Cellular Actions of Chronic Electroconvulsive Seizures

Recent studies have begun to examine the influence of electroconvulsive shock (ECS) on the expression of growth factors in brain, as well as alterations in the function and structure of certain populations of neurons. These studies demonstrate that long-term ECS increases the expression of brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, in limbic brain regions. BDNF, a member of the nerve growth-factor family, has been shown to increase the synaptic strength, survival, and growth of adult neurons. Studies in vivo and in cultured cells indicate that the induction of BDNF and TrkB is mediated by the cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), a transcription factor that is activated by cAMP and Ca2+ intracellular pathways. Chronic ECS is also reported to induce sprouting of hippocampal neurons, and studies in BDNF mutant mice indicated that this sprouting is partially dependent on upregulation of BDNF. Increased expression of BDNF and sprouting could also contribute to the altered electrophysiologic properties of hippocampal neurons. These effects of chronic ECS are discussed with respect to recent studies demonstrating that the pathophysiology of stress and depression involves atrophy or death of hippocampal neurons. This work has led to the hypothesis that ECS and antidepressant drugs, via regulation of neurotrophic factors, reverse the atrophy of stress-vulnerable neurons or protect these neurons from further damage.

Initial seizure threshold in bilateral electroconvulsive therapy

The extent to which electrical dose exceeds the seizure threshold is an important determinant of the efficacy of electroconvulsive therapy (ECT) but seizure thresholds have not before been evaluated using an ECT machine made in the UK. In this study seizure threshold was empirically titrated at the outset of bilateral ECT given to 100 consecutive depressed patients treated with an Ectron Series 5A ECT machine. No patient received anti-epileptic drugs. Men and women under 30 years of age (n=14) had low thresholds and men of 60 years or more (n=3) had high thresholds. Seizure thresholds varied at least threefold among other groups, suggesting that empirical titration may be desirable for most patients treated by bilateral ECT.

BDNF restores the expression of Jun and Fos inducible transcription factors in the rat brain following repetitive electroconvulsive seizures.

The expression of inducible transcription factors was studied following repetitive electroconvulsive seizures (ECS), c-Fos, c-Jun, JunB, and JunD immunoreactivities were investigated following a single (1 x ECS) or repetitive ECS evoked once per day for 4, 5, or 10 days (4 x ECS, 5 x ECS, or 10 x ECS). Animals were killed 3 or 12 h following the last ECS. Three hours after 1 x ECS, c-Fos was expressed throughout the cortex and hippocampus. After 5 x ECS and 10 x ECS, c-Fos was reexpressed in the CA4 area, but was completely absent in the other hippocampal areas and cortex. In these areas, c-Fos became only reinducible when the time lag between two ECS stimuli was 5 days. In contrast to c-Fos, intense JunB expression was inducible in the cortex and hippocampus, but not CA4 subfield, after 1 x ECS, 5 x ECS, and 10 x ECS. Repetitive ECS did not effect c-Jun and JunD expression. In a second model of systemic excitation of the brain, repetitive daily injection of kainic acid for 4 days completely failed to express c-Fos, c-Jun, and JunB after the last application whereas injection of kainic acid once per week did not alter the strong expressions compared to a single application of kainic acid. In order to study the maintenance of c-Fos expression during repetitive seizures, brain-derived neurotrophic factor (BDNF) was applied in parallel for 5 or 10 days via miniosmotic pumps and permanent cannula targeted at the hippocampus or the parietal cortex. Infusion of BDNF completely reinduced c-Fos expression during 5 x ECS or 10 x ECS in the cortex ipsilaterally to the cannula and, to a less extent, also increased the expression of c-Jun and JunB when compared to saline-treated controls. BDNF had no effect on the expression patterns in the hippocampus. ECS with or without BDNF infusion did not change the expression patterns of the constitutive transcription factors ATF-2, CREB, and SRF. These data demonstrate that various transcription factors substantially differ in their response to acute and chronic neural stimulation. Repetitive pathophysiological excitation decreases the transcriptional actions of neurons over days in the adult brain, and this decrement can be prevented by BDNF restoring the neuroplasticity at the level of gene transcription.

Differential Intracellular Sorting of Immediate Early Gene mRNAs Depends on Signals in the mRNA Sequence

This study characterizes the differential targeting of recently synthesized immediate early gene (IEG) mRNAs to neuronal cell bodies versus dendrites and tests the hypothesis that this targeting is based on signals in the encoded proteins. A single electroconvulsive seizure induces the expression of a number of IEG mRNAs in granule cells of the dentate gyrus. Most of these IEG mRNAs remain in the cell body, including two that are characterized in the present study (the mRNAs for NGFI-A and COX-2). In contrast, the mRNA for Arc moved rapidly into dendrites at an apparent rate of approximately 300 micron/hr. Inhibiting protein synthesis with cycloheximide did not disrupt the differential mRNA sorting, demonstrating that the differential targeting of mRNAs is not dependent on translation.

Signals that regulate astroglial gene expression: induction of GFAP mRNA following seizures or injury is blocked by protein synthesis inhibitors.

Previous studies have revealed that a single electroconvulsive seizure (ECS) strongly induces glial fibrillary acidic protein (GFAP) expression in astrocytes in the hippocampal dentate gyrus. The signals that trigger this induction are not known, but circumstantial evidence suggests the hypothesis that GFAP expression may be induced as a result of the induction of growth factor expression by dentate granule cells that also occurs as a result of the ECS and other types of seizures. The present study tests one prediction of this hypothesis by evaluating whether increases in GFAP mRNA levels after ECS are blocked by inhibiting protein synthesis at various times after the ECS. We report that the upregulation of GFAP expression following ECS is blocked by protein synthesis inhibitors given 5 min before or up to 12 h after a single ECS. This temporal gradient suggests an intermediate step involving the increased expression of a protein growth factor.

Seizures, memory and synaptic plasticity

Electrophysiological studies of the rodent hippocampus show that repeated seizure activity has a profound, deleterious effect on an important form of synaptic plasticity (long-term potentiation, LTP) which has been suggested to underlie memory formation. It appears that seizure activity incrementally causes an indiscriminate and widespread induction of long-term potentiation, consuming and thereby reducing overall hippocampal plasticity available for information processing. Consistent with this finding, severe deficits in a form of learning known to be mediated by hippocampal function are observed in rat subjected to repeated electroconvulsive seizures (ECS). The effect on synaptic function gradually resolves over a period of around 40 days, paralleling the time course of the transitory cognitive impairment seen following electrical seizure induction (ECT) in humans being treated for severe affective disorder. The effect is likely to be mediated by NMDA receptor activation during seizure activity, as the phenomenon can be prevented by the administration of a non-competitive NMDA receptor associated channel blocker (ketamine) immediately before seizure induction. The mechanisms described may account for the inter-ictal cognitive disturbance observed in patients suffering from poorly controlled epilepsy.

Rat nurr1 is prominently expressed in perirhinal cortex, and differentially induced in the hippocampal dentate gyrus by electroconvulsive vs. kindled seizures

We isolated a rat orphan nuclear hormone receptor from a brain cortex cDNA library. The sequence of the cDNA insert was 2154 bp with an open reading frame of 1794 bp encoding a putative protein of 598 amino acids and predicted molecular mass of 65 kDa. The deduced amino acid sequence showed a strong homology to the mouse nurr1 and human NOT1 orphan nuclear hormone receptors of the NGFI-B/nur77/NAK1 gene subfamily. We refer to this rat clone as r-nurr1. Northern blot analysis showed that r-nurr1 mRNA was highly expressed in the brain and moderately in the lung as a 4.0 kb transcript. A smaller transcript of 2.5 kb was also detected in the testes. The level of r-nurr1 transcript in the heart, skeletal muscle, liver, kidney and spleen was marginal. In situ hybridization showed that r-nurr1 mRNA was constitutively expressed in various regions of the CNS, particularly in the deeper layers (IV to VI) of the perirhinal cortex and area 2 of parietal cortex. We further evaluated the modulation of r-nurr1 expression in CNS by an electroconvulsive seizure (ECS) and by an amgydala-kindled seizure. A single ECS administered via earclip electrodes induced a rapid and transient increase of r-nurr1 mRNA in the granule cells of the dentate gyrus, being significant at 15 min after the seizure, maximal ≈1 h and back to baseline at 4 h. The amygdala kindled seizure revealed a less robust and restricted nurr-1 induction in the CNS, as only two of the four kindled animals showed a unilateral induction of nurr1 mRNA in the dentate gyrus. These results suggest that r-nurr1 is an immediate-early gene that is differentially induced by ECS vs. kindled seizures. In addition, as r-nurr1 is prominently expressed in the specific brain sites associated with memory acquisition and consolidation, it may play a role in memory processing.

102-3 - NPY increases in rat brain following electroconvulsive seizures: An animal model for the working action of ECT

102-3 - NPY increases in rat brain following electroconvulsive seizures: An animal model for the working action of ECT

Chronic Fos-Related Antigens: Stable Variants of ΔFosB Induced in Brain by Chronic Treatments

Fos family transcription factors are believed to play an important role in the transcriptional responses of the brain to a variety of stimuli. Previous studies have described 35 and 37 kDa Fos-like proteins, termed chronic Fos-related antigens (FRAs), that are induced in brain in a region-specific manner in response to several chronic perturbations, including chronic electroconvulsive seizures, psychotropic drug treatments, and lesions. We show in this study that the chronic FRAs are isoforms of deltaFosB, a truncated splice variant of FosB that accumulate in brain after chronic treatments because of their stability. doffaFosB cDNA encodes the expression of 33, 35, and 37 kDa proteins that arise from a single AUG translation start site. The 35 and 37 kDa proteins correspond to the chronic FRAs that are induced in brain by chronic treatments, whereas the 33 kDa protein corresponds to a Fos-like protein that is induced in brain by acute treatments, findings based on migration on one- and two-dimensional Western blots with anti-FRA and anti-FosB antibodies. Using cells in which deltaFosB or FosB expression is under the control of a tetracycline-regulated gene expression system, we show that the 37 kDa deltaFosB protein exhibits a remarkably long half-life, the 35 kDa DeltaFosB protein exhibits an intermediate half-life, and the 33 kDa deltaFosB protein and all FosB-derived proteins exhibit relatively short half-lives. Moreover, we show that the 33 kDa deltaFosB protein is the first to appear after activation of deltaFosB expression. Finally, deltaFosB proteins are shown to possess DNA-binding activity and to exert potent transactivating effects in reporter gene assays. Together, these findings support a scheme wherein deltaFosB, expressed as a 33 kDa protein, is modified to form highly stable isoforms of 35 and 37 kDa. As a result, these stable isoforms gradually accumulate in the brain with repeated treatments to mediate forms of long-lasting neural and behavioral plasticity.

Anterograde transport of endogenous brain-derived neurotrophic factor in hippocampal mossy fibers.

Neurotrophic factors such as brain-derived neurotrophic factor (BDNF) are assumed to provide trophic support via a target-derived, retrograde mechanism of action. However, recent studies suggest that neurotrophic factors can act in an autocrine fashion and perhaps even in an anterograde direction similar to neurotransmitters. To further explore this hypothesis, we compared the neuroanatomical pattern of BDNF mRNA and protein in response to electroconvulsive seizures (ECS) or kainic acid-induced seizure activity. Using in situ hybridization, we found that chronic ECS induced BDNF mRNA predominantly in the granule neurons of the dentate gyrus. However, immunohistochemistry with an anti-BDNF antibody revealed that ECS increased endogenous BDNF protein in the mossy fibers, which are composed of axons projecting from the granule neurons of the dentate gyrus to the CA3 pyramidal layer of the hippocampus. Kainic acid administration (10 mg/kg, i.p., once) was used to lesion CA3 neurons selectively, as these are a possible retrograde source of BDNF protein in mossy fibers. Three weeks later, a prolonged elevation of BDNF mRNA in granule neurons, but not elsewhere in hippocampus, was accompanied by an increase in BDNF protein in the mossy fibers. These results suggest that BDNF was transcribed and translated in granule neuron cell bodies but transported in an anterograde direction to provide trophic support of CA3 pyramidal neurons.

Regulation of c-Fos and NGF1-A by antidepressant treatments.

The influence of antidepressant treatments on the expression of c-Fos and NGF-1A, two immediate early gene (IEG) transcription factors, was examined. Administration of electroconvulsive seizures (ECS), tranylcypromine, or imipramine, three different classes of antidepressants, increased the expression of c-Fos mRNA and immunoreactivity in rat frontal cortex, but the magnitude of the increase for each treatment differed and the effect of imipramine was preceded by inhibition of c-Fos expression. Expression of NGF-1A was increased by acute or chronic administration of ECS or tranylcypromine, and by chronic (21 d), but not acute, administration of imipramine. To study the mechanisms underlying these differences, we examined the neurotransmitter receptors that regulate the expression of c-Fos. ECS- and tranylcypromine induction of c-Fos immunoreactivity in frontal cortex was partially inhibited by pretreatment with specific antagonists for alpha 1-adrenergic, beta-adrenergic, and 5-HT2A/2C, but not D2-dopamine receptors. ECS induction of c-Fos was also inhibited by D1-dopamine and NMDA glutamate receptor antagonists, suggesting that the greater induction of c-Fos by ECS results from activation of these, and possibly other, neurotransmitter receptors. In the hippocampus, antagonism of tranylcypromine was similar to that in frontal cortex, except the D1-dopamine receptor antagonist also blocked the c-Fos response. In contrast, antagonism of the ECS response in hippocampus was only blocked by the NMDA receptor antagonist. The results demonstrate that ECS- and tranylcypromine induction of c-Fos is mediated by activation of several different neurotransmitter receptors, but that the exact pharmacological profile is different for each treatment and brain region.

Regulation of c‐Fos and NGF1‐A by antidepressant treatments

The influence of antidepressant treatments on the expression of c-Fos and NGF-1A, two immediate early gene (IEG) transcription factors, was examined. Administration of electroconvulsive seizures (ECS), tranylcypromine, or imipramine, three different classes of antidepressants, increased the expression of c-Fos mRNA and immunoreactivity in rat frontal cortex, but the magnitude of the increase for each treatment differed and the effect of imipramine was preceded by inhibition of c-Fos expression. Expression of NGF-1A was increased by acute or chronic administration of ECS or tranylcypromine, and by chronic (21 d), but not acute, administration of imipramine. To study the mechanisms underlying these differences, we examined the neurotransmitter receptors that regulate the expression of c-Fos. ECS- and tranylcypromine induction of c-Fos immunoreactivity in frontal cortex was partially inhibited by pretreatment with specific antagonists for α1-adrenergic, β-adrenergic, and 5-HT2A/2C, but not D2-dopamine receptors. ECS induction of c-Fos was also inhibited by D1-dopamine and NMDA glutamate receptor antagonists, suggesting that the greater induction of c-Fos by ECS results from activation of these, and possibly other, neurotransmitter receptors. In the hippocampus, antagonism of tranylcypromine was similar to that in frontal cortex, except the D1-dopamine receptor antagonist also blocked the c-Fos response. In contrast, antagonism of the ECS response in hippocampus was only blocked by the NMDA receptor antagonist. The results demonstrate that ECS- and tranylcypromine induction of c-Fos is mediated by activation of several different neurotransmitter receptors, but that the exact pharmacological profile is different for each treatment and brain region. Synapse 25:313–320, 1997. © 1997 Wiley-Liss, Inc.

High frequency transcranial magnetic stimulation mimics the effects of ECS in upregulating astroglial gene expression in the murine CNS

The present study evaluates the consequences of high frequency (25 hz) trans-cranial magnetic stimulation on the expression of glial fibrillary acidic protein (GFAP) in the murine CNS. Trains of transcranial magnetic stimulation (1–30 trains at 25 Hz, 10 s duration) were delivered to mice via 5-cm diameter round coils. The stimulation produced stimulus-locked motor responses but did not elicit behavioral seizures. GFAP mRNA levels were evaluated 12, 24, 36, 48 h, 4 days, and 8 days following stimulation by in situ hybridization. Following multiple 25 Hz trains, there were dramatic increases in the levels of GFAP mRNA in the hippocampal dentate gyrus; more modest increases were observed in the cerebral cortex. The selective increases in GFAP mRNA in the dentate gyrus were similar to those observed following single electroconvulsive seizures (ECS). These results indicate that trans-cranial magnetic stimulation can be used to modulate astroglial gene expression, inducing the first stage of a reactive response that is similar to what occurs following nervous system injury.

Electroconvulsive seizures increase levels of PS4, the TRH-enhancing peptide [prepro-TRH(160-169)], in rat brain.

We report the development of a radioimmunoassay for prepro-TRH(160-169) (PS4), a thyrotropin-releasing hormone (TRH) enhancing peptide, and its use in characterizing the effect of electroconvulsive seizures on the levels of this peptide in various brain regions of male Wistar rats. We found that electroconvulsive seizures significantly elevated the PS4 levels in hippocampus, amygdala, pyriform (olfactory) cortex, and anterior cortex but not in striatum, motor cortex, locus ceruleus, or ventral lateral medulla. The levels of PS4 were highly correlated with the corresponding TRH (p-Glu-His-Pro-NH2) and TRH-Gly (p-Glu-His-Pro-Gly) levels in hippocampus, amygdala, and pyriform cortex, consistent with the prepro-TRH source of all of these peptides. The PS4 levels in hippocampus and amygdala were significantly correlated with the immobility time in the Porsolt forced swim test, an established animal model for antidepressant effects. The PS4 levels in peripheral blood, hypothalamus, anterior cortex, amygdala, and eyes increased severalfold at 20 min following intracisternal injection of 228 microg of this peptide, suggesting that it readily crosses the blood-brain barrier. The pituitary levels of PS4 and TRH-Gly, on the other hand, were decreased within 20 min by intracisternal PS4, suggesting PS4 stimulated the release of prepro-TRH peptides from the pituitary. Fresh rat and human serum rapidly degraded PS4, indicating that it may act primarily as a paracrine modulator of TRH effects in pituitary, brain, and reproductive system.

Representation Activity of The Right and Left Hemispheres of the Brain

Drawings by psychiatric patients were studied in various states (i) in depression; (ii) after neuroleptic injection; and (iii) during left hemisphere suppression induced by unilateral electroconvulsive seizure (UES). In these states, right hemisphere activation predominates. The results of the study demonstrate that, under the predominance of right hemisphere activation over the left hemisphere, there is a tendency to reproduce the image of the object and to represent it in near space. Drawings by psychiatric patients were also investigated in (i) the manic state; (ii) after injection of psychotropic drugs which improved the mood; and (iii) during right hemisphere suppression following right-sided UES. Under these conditions, left hemisphere activation predominates and the drawings loose the illusion of three-dimensional space. A tendency to reproduce the knowledge and the ideas of the object and to represent it in distant space was observed. Thus, both hemispheres may represent space and elaborate perceptive and conceptional models of the world in different ways. It is probable that different types of representation are based on global (right-hemispheric) in comparison with focal (left-hemispheric) attention to space.

Representation activity of the right and left hemispheres of the brain.

Drawings by psychiatric patients were studied in various states (i) in depression; (ii) after neuroleptic injection; and (iii) during left hemisphere suppression induced by unilateral electroconvulsive seizure (UES). In these states, right hemisphere activation predominates. The results of the study demonstrate that, under the predominance of right hemisphere activation over the left hemisphere, there is a tendency to reproduce the image of the object and to represent it in near space. Drawings by psychiatric patients were also investigated in (i) the manic state; (ii) after injection of psychotropic drugs which improved the mood; and (iii) during right hemisphere suppression following right-sided UES. Under these conditions, left hemisphere activation predominates and the drawings loose the illusion of three-dimensional space. A tendency to reproduce the knowledge and the ideas of the object and to represent it in distant space was observed. Thus, both hemispheres may represent space and elaborate perceptive and conceptional models of the world in different ways. It is probable that different types of representation are based on global (right-hemispheric) in comparison with focal (left-hemispheric) attention to space.

Influence of D-cycloserine on the anticonvulsant activity of phenytoin and carbamazepine against electroconvulsions in mice.

D-Cycloserine (DCS) is a high-efficacy partial agonist at the strychnine-insensitive glycine modulatory site within the N-methyl-D-aspartate (NMDA)-receptor/ionophore complex. Previous studies demonstrated that DCS exhibits anticonvulsant activity in a variety of experimental epilepsy models. In this study, we determined the influence of DCS in subprotective doses on the anticonvulsant action of phenytoin (PHT) and carbamazepine (CBZ) in mice. Two electroconvulsive tests were used, i.e., determination of seizure threshold and maximal electroshock seizures. Antiepileptic drug-induced motor and long-term memory deficits were quantified by using the chimney test and the passive-avoidance test, respectively. In addition, plasma levels of PHT and CBZ were measured by fluorescence polarization immunoassay to exclude any pharmacokinetic interactions. DCS, when used alone in doses of 80 and 160 mg/kg, significantly increased the threshold for electroconvulsive seizures. DCS in a wide range of doses (1.25-40 mg/kg) was combined with either PHT or CBZ and tested in electroconvulsive tests. DCS, at doses of 2.5 and 10 mg/kg, was the most effective in potentiating the threshold-increasing action of PHT; higher doses of DCS (20 and 40 mg/kg) were required to achieve a similar effect of CBZ. In maximal electroshock-induced seizures, DCS (10 mg/kg) augmented the protective action of PHT, but was ineffective at a dose of 40 mg/kg with CBZ. DCS did not potentiate the neurotoxicity produced by PHT and CBZ in the chimney test. Both PHT and CBZ induced impairments of long-term memory; PHT-induced memory adverse effects were counteracted by DCS (10 mg/kg). There was no such effect on CBZ-induced memory impairment, and a worsening influence was observed. Any pharmacokinetic interactions were excluded by measuring total and free plasma levels of both antiepileptic drugs. Our results suggest that combining DCS with PHT and CBZ may be beneficial in treating epileptic seizures.

S-5-1 - NPY increases in rat brain following electro-convulsive seizures: An animal model for the Working action of ECT

S-5-1 - NPY increases in rat brain following electro-convulsive seizures: An animal model for the Working action of ECT

Prolonged induction of c-fos in neuropeptide Y-and somatostatin-immunoreactive neurons of the rat dentate gyrus after electroconvulsive stimulation

Induction of c-fos mRNA and Fos was studied in the hilus and granular layer of the dentate gyrus at various times up to 24 h after single electroconvulsive stimulation (ECS) using in situ hybridization and immunocytochemistry. In both areas of the dentate gyrus, a prominent induction of c-fos mRNA and Fos was observed. Compared to the granular layer, however, c-fos mRNA and Fos in hilar cells reached maximum later and remained elevated considerably longer. Several neurochemically distinct populations of hilar neurons have been described, some of which contain neuropeptide Y (NPY) and/or somatostatin (SS). Using double-labelling immunocytochemistry, we examined to what extent Fos was induced in these hilar neurons after ECS. Although a minor population of non-NPY non-SS cells displayed Fos induction early after ECS, prolonged induction of Fos almost exclusively occurred in NPY or SS neurons. The Fos-immunoreactive NPY or SS neurons only amounted to about 50% of the total hilar population of NPY or SS neurons. The present observations suggest that a subpopulation of hilar NPY and SS neurons may be central to the actions of electroconvulsive seizures in the dentate gyrus.

513. - Distinct memory deficits from bilateral vs. unilateral electroconvulsive seizures

513. - Distinct memory deficits from bilateral vs. unilateral electroconvulsive seizures