Regional brain volumes, diffusivity, and metabolite changes after electroconvulsive therapy for severe depression.

OBJECTIVE: To investigate the role of hippocampal plasticity in the antidepressant effect of electroconvulsive therapy (ECT). METHOD: We used magnetic resonance (MR) imaging including diffusion tensor imaging (DTI) and proton MR spectroscopy (1 H-MRS) to investigate hippocampal volume, diffusivity, and metabolite changes in 19 patients receiving ECT for severe depression. Other regions of interest included the amygdala, dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex, and hypothalamus. Patients received a 3T MR scan before ECT (TP1), 1 week (TP2), and 4 weeks (TP3) after ECT. RESULTS: Hippocampal and amygdala volume increased significantly at TP2 and continued to be increased at TP3. DLPFC exhibited a transient volume reduction at TP2. DTI revealed a reduced anisotropy and diffusivity of the hippocampus at TP2. We found no significant post-ECT changes in brain metabolite concentrations, and we were unable to identify a spectral signature at ≈1.30 ppm previously suggested to reflect neurogenesis induced by ECT. None of the brain imaging measures correlated to the clinical response. CONCLUSION: Our findings show that ECT causes a remodeling of brain structures involved in affective regulation, but due to their lack of correlation with the antidepressant effect, this remodeling does not appear to be directly underlying the antidepressant action of ECT.

Sex-specifics of ECT outcome.

OBJECTIVE: Electroconvulsive therapy (ECT) is the most effective treatment for patients with severe major depressive disorder (MDD). Given the known sex differences in MDD, improved knowledge may provide more sex-specific recommendations in clinical guidelines and improve outcome. In the present study we examine sex differences in ECT outcome and its predictors. METHODS: Clinical data from 20 independent sites participating in the Global ECT-MRI Research Collaboration (GEMRIC) were obtained for analysis, totaling 500 patients with MDD (58.6 % women) with a mean age of 54.8 years. Severity of depression before and after ECT was assessed with validated depression scales. Remission was defined as a HAM-D score of 7 points or below after ECT. Variables associated with remission were selected based on literature (i.e. depression severity at baseline, age, duration of index episode, and presence of psychotic symptoms). RESULTS: Remission rates of ECT were independent of sex, 48.0 % in women and 45.7 % in men (X2(1) = 0.2, p = 0.70). In the logistic regression analyses, a shorter index duration was identified as a sex-specific predictor for ECT outcome in women (X2(1) = 7.05, p = 0.01). The corresponding predictive margins did show overlapping confidence intervals for men and women. CONCLUSION: The evidence provided by our study suggests that ECT as a biological treatment for MDD is equally effective in women and men. A shorter duration of index episode was an additional sex- specific predictor for remission in women. Future research should establish whether the confidence intervals for the corresponding predictive margins are overlapping, as we find, or not.

Powerful inhibition of kainic acid seizures by neuropeptide Y via Y5-like receptors.

Neuropeptide Y (NPY) is widely distributed in interneurons of the central nervous system (CNS), including the hippocampus and cerebral cortex, in concentrations exceeding those of any other known neuropeptides. Sequence data comparing different species show that NPY is highly conserved. This suggests a critical role in regulation of regional neuronal excitability. Kainic acid, a glutamate agonist at kainic acid receptors, causes severe limbic motor seizures culminating in status epilepticus. We here report that NPY administered into the lateral ventricle is a powerful inhibitor of motor as well as electroencephalographic (EEG) seizures induced by kainic acid. This effect was mediated via receptors with a pharmacological profile similar to the recently cloned rat Y5 receptor. The present study is the first to demonstrate that NPY possesses anticonvulsant activity. This is consistent with the concept that NPY is an endogenous anticonvulsant and suggests that agonists acting at Y5-like receptors may constitute a novel group of drugs in antiepileptic therapy.

Synaptic proteins after electroconvulsive stimulation.

Quantitative immunoelectrophoresis of rat brain synaptic proteins following a series of electroconvulsive stimulations demonstrated changes suggestive of an increase in the number of synaptic vesicles, in a preparedness for glycolytic demands, and a delayed development of a certain area in the brain. The increased synaptic remodeling may be important for the action of electroconvulsive therapy.

An intron 1 polymorphism in the cholecystokinin-A receptor gene associated with schizophrenia in males.

OBJECTIVE: To identify whether a genetic variation (rs1800857; IVS1-5T>C) in the neuropeptide cholecystokinin-A receptor (CCKAR) gene is a risk factor in the pathogenesis of schizophrenia. METHOD: The variation was analysed in a case-control design comprising 508 patients with schizophrenia and 1619 control subjects. A possible functional impact of this variant on CCKAR protein synthesis through alterations in splicing was analysed in an exon-trapping assay. RESULTS: In males only, the risk variant, IVS1-5C, was associated with a significantly increased risk of schizophrenia. Carrying one risk allele was associated with an increased risk of 1.74 (Odds Ratio, OR) and homozygosity (CC) was associated with an OR of 3.19. The variation had no impact on protein synthesis of CCKAR. CONCLUSION: This is the first report associating the CCKAR gene variant with schizophrenia specifically in men. Our study strengthens the conclusion that a CCKAR dysfunction could be involved in the aetiology of schizophrenia.

Long-term decrease in the hippocampal [3H]inositoltriphosphate binding following repeated electroshock in the rat.

A quantitative autoradiographic study was made on the binding of the phosphatidylinositol system ligand [3H]inositol(1,4,5)-triphosphate (IP3) to forebrain sections from electroconvulsive shock (ECS)-treated rats. One group of rats was sacrificed 1 day and 1 month, respectively, after 12 ECSs administered three times weekly for 4 weeks. SHAM-stimulated rats served as controls. A single ECS did not change the [3H]IP3 binding in any of the brain regions examined. One day after the last of 12 ECSs, a decrease in [3H]IP3 binding (21%) was found within the CA1 region of the hippocampus and the piriform cortex (39%). In rats sacrificed 1 month after the last of 12 ECSs, the [3H]IP3 binding in piriform cortex had returned to control level. In the CA1 region of the hippocampus, the binding was still decreased (24%). It is possible that changes in the phosphatidylinositol system may play a part in the neurobiological events responsible for the therapeutic effect of electroconvulsive therapy.

Electroconvulsive shock and lidocaine-induced seizures in the rat activate astrocytes as measured by glial fibrillary acidic protein.

The effects of repeated electroconvulsive shock (ECS) and/or lidocaine treatment in the rat were studied by means of biochemical markers: GFAP (glial fibrillary acidic protein), NCAM (neural cell adhesion molecule), NSE (neuron specific enolase) and D3-protein. In adult rats given daily either ECS alone or in combination with lidocaine (experiment 1) we found that ECS significantly increased the concentration of the glial marker GFAP in limbic areas: hippocampus, amygdala, and piriform cortex. The maximal increase in GFAP was found in the piriform cortex (77%). In both piriform cortex and amygdala ECS also induced a significant decrease in D3-protein (a marker of mature synapses), but no change in NCAM (especially enriched in newly formed synapses). In piriform cortex the ratio between NCAM and D3-protein was significantly increased (4%) by ECS. The lidocaine treatment, which induced seizures in some of the animals, was without significant effect on the biochemical markers. However, multiple lidocaine-induced seizures (experiment 2) were found to be associated with a significant increase in GFAP in amygdala and piriform cortex. The study shows that seizures, whether electrically or pharmacologically induced, activate astrocytes in certain brain regions. This activation is especially pronounced in the piriform cortex and may be caused by a particularly marked synaptic vulnerability and remodeling in this area, as demonstrated by the increased NCAM/D3-ratio. Synaptic remodeling and activation of astrocytes may well influence brain function and could play a role in the chain of neurobiological events underlying the clinical effects of electroconvulsive therapy (ECT).

No loss of hippocampal hilar somatostatinergic neurons after repeated electroconvulsive shock: a combined stereological and in situ hybridization study.

Electrically induced seizures with anesthesia and muscle relaxation (ECT) is commonly used in the therapy of psychotic depression in humans. Unmodified electroshock (ECS) is used as a model for epilepsy in the rat. In several seizure models of epilepsy, in particular the dentate hilar somatostatin-containing (SSergic) neurons have been found to undergo degeneration. To assess the potential loss of SSergic hilar neurons after repeated ECS, 10 rats were given 110 ECS, one per day, 5 days a week. One day after the last ECS the rats were anesthesized, perfused, the brains cut on a vibratome and prepared for nonradioactive in situ hybridization for somatostatin along with five control rats. Like rats given 10-36 ECS in earlier studies, the ECS-treated rats displayed a markedly increased neuronal hybridization labeling when compared with control rats. The total number of dentate hilar SSergic neurons of each rat was estimated using the optical disector technique. The mean number of hilar SSergic neurons in the ECS-treated rats was 12,785, compared to 12,392 in the control rats. The total number of hilar SSergic neurons in ECS-treated versus control rats was not significantly different (Student's t test; t value = .35; p = .74). We conclude that repeated ECS treatment does not cause loss of hilar SSergic neurons.

Increased neurogenesis in a model of electroconvulsive therapy.

BACKGROUND: Electroconvulsive therapy (ECT) is a widely used and efficient treatment modality in psychiatry, although the basis for its therapeutic effect is still unknown. Past research has shown seizure activity to be a regulator of neurogenesis in the adult brain. This study examines the effect of a single and multiple electroconvulsive seizures on neurogenesis in the rat dentate gyrus. METHODS: Rats were given either a single or a series of 10 electroconvulsive seizures. At different times after the seizures, a marker of proliferating cells, Bromodeoxyuridine (BrdU), was administered to the animals. Subsequently, newborn cells positive for BrdU were counted in the dentate gyrus. Double staining with a neuron-specific marker indicated that the newborn cells displayed a neuronal phenotype. RESULTS: A single electroconvulsive seizure significantly increased the number of new born cells in the dentate gyrus. These cells survived for at least 3 months. A series of seizures further increased neurogenesis, indicating a dose-dependent mechanism. CONCLUSIONS: We propose that generation of new neurons in the hippocampus may be an important neurobiologic element underlying the clinical effects of electroconvulsive seizures.

Cerebral blood flow in rats with renal and spontaneous hypertension: resetting of the lower limit of autoregulation.

The effect of chronic hypertension on cerebral blood flow (CBF) was studied in anaesthetised rats. CBF was measured with the intracarotid 133Xe injection method. Rats with spontaneous and renal hypertension were compared with normotensive controls. The lower limit of autoregulation was determined during controlled haemorrhage. In the normotensive rats, CBF remained constant until mean arterial pressure (MAP) had decreased to the range of 50-69 mm Hg. Thereafter, CBF decreased with each further decrease in MAP. In both types of hypertensive rats, CBF remained constant until MAP had decreased to the range of 70-89 mm Hg. Thus, a 20-mm Hg shift of the lower limit of CBF autoregulation was found in both spontaneous and renal hypertensive rats. A neuropathological study revealed ischaemic brains lesions in half of the hypertensive rats following hypotension, whereas only a single lesion was found in one of six normotensive rats. No ischaemic brain lesions were found in a control study in which CBF was shown to be stable over a 21/2-h period. In conclusion, hypertensive rats showed a shift of the lower limit of CBF autoregulation as well as an increased susceptibility to ischaemic brain damage during hypotension. These findings presumably reflect hypertensive structural changes in the cerebral circulation.

Does ECT alter brain structure?

OBJECTIVE: The purpose of this study was to evaluate whether ECT causes structural brain damage. METHOD: The literature review covered the following areas: cognitive side effects, structural brain imaging, autopsies of patients who had received ECT, post-mortem studies of epileptic subjects, animal studies of electroconvulsive shock (ECS) and epilepsy, and the neuropathological effects of the passage of electricity, heat generation, and blood-brain barrier disruption. RESULTS: ECT-induced cognitive deficits are transient, although spotty memory loss may persist for events immediately surrounding the ECT course. Prospective computerized tomography and magnetic resonance imaging studies show no evidence of ECT-induced structural changes. Some early human autopsy case reports from the unmodified ECT era reported cerebrovascular lesions that were due to agonal changes or undiagnosed disease. In animal ECS studies that used a stimulus intensity and frequency comparable to human ECT, no neuronal loss was seen when appropriate control animals, blind ratings, and perfusion fixation techniques were employed. Controlled studies using quantitative cell counts have failed to show neuronal loss even after prolonged courses of ECS. Several well-controlled studies have demonstrated that neuronal loss occurs only after 1.5 to 2 hours of continuous seizure activity in primates, and adequate muscle paralysis and oxygenation further delay these changes. These conditions are not approached during ECT. Other findings indicate that the passage of electricity, thermal effects, and the transient disruption of the blood-brain barrier during ECS do not result in structural brain damage. CONCLUSIONS: There is no credible evidence that ECT causes structural brain damage.

Cerebral blood flow during delirium tremens and related clinical states studied with xenon-133 inhalation tomography.

The regional cerebral blood flow of 12 patients with severe alcohol withdrawal reactions (delirium tremens or impending delirium tremens) was measured during the acute state before treatment and after recovery. Greater cerebral blood flow was significantly correlated with visual hallucinations and agitation during the acute withdrawal reaction. The results suggest that delirium tremens and related clinical states represent a type of acute brain syndrome mainly characterized by CNS hyperexcitability.

Early maternal deprivation alters hippocampal levels of neuropeptide Y and calcitonin-gene related peptide in adult rats.

Stressful events early in life are reported to be more prevalent among patients with an adult life psychiatric disorder. Early maternal deprivation is considered an animal model of early life stress. Maternally deprived adult rats display long-term alterations in the neuroendocrine system, brain and behavior that are in many ways analogous to depressive and schizophrenic symptomatology. Neuropeptide Y (NPY) and calcitonin-gene related peptide (CGRP) have been implicated in both disorders and also been suggested to play a role in the neuroadaptational response to stress. Consequently, male Wistar rat-pups were subjected to early maternal deprivation or control handling, on postnatal day (pnd) 9. On pnd 21, pups were weaned and split into two groups that were reared either on a saw-dust floor or on a grid-floor, considered to be a mild stressor. On pnd 67, all animals were subjected to the prepulse inhibition test. One week later, the animals were sacrificed, the brains removed and dissected on ice. Levels of NPY-like immunoreactivity (LI) and CGRP-LI were quantified by radioimmunoassay in brain regional extracts. Maternal deprivation led to a significant reduction in basal startle amplitude and disruption of prepulse inhibition. These findings were paralleled by significantly reduced levels of NPY and CGRP in the hippocampus and occipital cortex. It is hypothesised that these changes may be of relevance to aspects of schizophrenic and affective symptomatology. The present study further shows that brain NPY and, in particular, CGRP are sensitive to long-term mild stress and further implicate the involvement of these peptides in the neuroendocrine stress response.

Electroconvulsive stimuli enhance both neuropeptide Y receptor Y1 and Y2 messenger RNA expression and levels of binding in the rat hippocampus.

Repeated electroconvulsive stimulations and other seizure modalities produce an increase in neuropeptide Y synthesis and local release in the rat hippocampus, and perhaps as a consequence, a change in the concentration of neuropeptide Y binding sites in the same region. The aim of the present study was to determine possible changes in the expression of neuropeptide Y receptor subtypes affected by repeated stimulations in the hippocampus. Rats were exposed to 14 daily stimulations, and the brains were removed 24h after the last stimulation. For in vitro receptor autoradiography and in situ hybridisation histochemistry, the brains were frozen, sectioned, and levels of neuropeptide Y binding sites and messenger RNA expressions were determined quantitatively on sections from the same animals. In order to determine the contribution of different neuropeptide Y receptor subtypes, serial sections were incubated with either 125I-labelled peptide YY alone or the same radio-labelled peptide mixed with an excess of a number of displacing compounds with affinity for either neuropeptide Y receptor subtype Y1, Y2, or both. Binding studies revealed that the majority of peptide YY binding sites was represented by Y2, and that electroconvulsive stimulations reduced the binding capacity or the concentration of this receptor. A prominent reduction of Y1-preferring binding sites was determined in the dentate gyrus, and to a lesser extent in the CA1 and CA3 regions. Similarly, the treatment produced a significant reduction of Y2-preferring binding sites in the CA1 and CA3 region, but not in the granular cell layer of the dentate gyrus. Using semi-quantitative in situ hybridization, Y1 receptor messenger RNA level in the granular cell layer of the dentate increased by the stimulations. In the same region, Y2 receptor messenger RNA was expressed in low to undetectable amounts, but after the repeated stimulations, this transcript was found in moderate to high levels. These data suggest that the neuropeptide Yergic system in the dentate gyrus and the pyramidal cell layer are affected by the treatment, and that this includes both Y1 and Y2 receptor subtypes. Because levels of messenger RNA and binding are distinctly regulated, the turnover of both Y1 and Y2 molecules is strongly increased under electroconvulsive stimulations, suggesting that the intrahippocampal neuropeptide Yergic neurotransmission is also increased under the stimulations.

Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat.

The generation of new neurons in the adult mammalian brain has been documented in numerous recent reports. Studies undertaken so far indicate that adult hippocampal neurogenesis is related in a number of ways to hippocampal function.Here, we report that subjecting adult rats to fractionated brain irradiation blocked the formation of new neurons in the dentate gyrus of the hippocampus. At different time points after the termination of the irradiation procedure, the animals were tested in two tests of short-term memory that differ with respect to their dependence on hippocampal function. Eight and 21 days after irradiation, the animals with blocked neurogenesis performed poorer than controls in a hippocampus-dependent place-recognition task, indicating that the presence of newly generated neurons may be necessary for the normal function of this brain area. The animals were never impaired in a hippocampus-independent object-recognition task. These results are in line with other reports documenting the functional significance of newly generated neurons in this region. As our irradiation procedure models prophylactic cranial irradiation used in the treatment of different cancers, we suggest that blocked neurogenesis contributes to the reported deleterious side effects of this treatment, consisting of memory impairment, dysphoria and lethargy.

Electroconvulsive shocks increase the expression of neuropeptide Y (NPY) mRNA in the piriform cortex and the dentate gyrus.

Repeated electroconvulsive stimulations represent one treatment modality for depressive disorders, but the mechanism leading to its effect is largely unknown. Studies of humans and rats have indicated that neuropeptide Y (NPY) is involved in major depression and anxiety. The purpose of the present investigation was to detect changes in the expression of preproNPY mRNA in the limbic cortex of rats exposed to electroconvulsive shocks (ECS) daily for 14 days. Twenty-four hours after the last ECS, the animals were sacrificed, brain sections were hybridized with a synthetic oligonucleotide probe complimentary to rat preproNPY mRNA. Semi-quantitative in situ hybridization histochemistry revealed an about ten-fold increase of preproNPY mRNA levels over the dentate gyrus and the piriform cortex in animals exposed to ECS compared to sham-treated controls. In the dentate gyrus dipped sections showed that the increase of gene expression took place in individual neurons in the polymorph layer. In the piriform cortex a moderate increase in the number of grains was observed over many individual cells in the pyramidal layer. These data show that the expression of preproNPY mRNA is markedly increased in specific brains regions after ECS, but whether this increase is a result of the ECS-induced seizures per se, or rather should be regarded as a protective adaptation to changes in neuronal activity pattern remains to be established.

Seizure threshold to lidocaine is decreased following repeated ECS (electroconvulsive shock).

Seizure susceptibility to lidocaine was investigated in rats which had received repeated ECS (electroconvulsive shock). In the first experiment three groups of rats received an ECS daily for 18 days, an ECS weekly for 18 weeks, and 18 sham treatments, respectively. Twelve weeks after the last ECS all rats received a lidocaine challenge (LC) in the form of an intraperitoneal (IP) injection of lidocaine (65 mg/kg). After the injection the animals were observed for occurrence of motor seizures. A total of 67% (10/15), 47% (7/15), and 0% (0/18) of the daily, weekly, and sham groups, respectively, had motor seizures in response to the LC. In the second experiment five groups of rats received an ECS daily for 0, 1, 6, 18, and 36 days, respectively. Eighteen weeks after the last ECS all rats received an LC and 0% (0/15), 13% (2/15), 20% (3/15), 53% (8/15), and 58% (7/12), respectively, developed seizures in response to the LC. In the third experiment two groups of rats received daily ECS and sham-ECS, respectively. Twenty-four hours after the last ECS all rats received an LC. A total of 60% (9/15) of the ECS group and 0% (0/10) of the sham-ECS group had seizures in response to the LC.(ABSTRACT TRUNCATED AT 250 WORDS)