Detecting objective and subjective cognitive effects of electroconvulsive therapy: intensity, duration and test utility in a large clinical sample.

BACKGROUND: Electroconvulsive therapy (ECT) is an effective treatment for depression but the extent and persistence of cognitive side-effects remain uncertain. It has been reported that there is little evidence that impairments last longer than up to 15 days post-ECT. However, relatively few studies have followed patients for even as long as 1 month post-ECT. Here we report results from a brief cognitive battery given prior to ECT and repeated five times up to 6 months post-ECT. METHOD: In a retrospective case-note study of routinely collected clinical data 126 patients treated with ECT completed two neuropsychological tests [Cambridge Neuropsychological Test Automated Battery (CANTAB) spatial recognition memory (SRM) and Mini Mental State Examination (MMSE)] and two subjective reports of memory function, prior to ECT. Patients were reassessed following ECT and at 1, 3 and 6 months post-ECT although not all patients completed all assessments. RESULTS: Performance relative to pre-ECT baseline was significantly poorer at each post-ECT assessment up to 3 months post-ECT using the CANTAB SRM, but was improved at 6 months. Conversely, MMSE score showed improvements relative to baseline from 1 month post-ECT. Mood and subjective memory scores improved following ECT and were correlated with one another, but not with either neuropsychological measure. CONCLUSIONS: The CANTAB SRM task revealed reversible cognitive deficiencies relative to a pre-ECT baseline for at least 3 months following ECT, while MMSE score and patients' subjective reports showed only improvement. Visuospatial memory scores eventually exceeded baseline 6 months post-ECT.

Using the Cambridge Neuropsychological Test Automated Battery (CANTAB) to assess the cognitive impact of electroconvulsive therapy on visual and visuospatial memory.

BACKGROUND: The cognitive impact of electroconvulsive therapy (ECT) is rarely measured systematically in everyday clinical practice even though patient and clinician acceptance is limited by its adverse affect on memory. If patients are tested it is often with simple paper and pencil tests of visual or verbal memory. There are no reported studies of computerized neuropsychological testing to assess the cognitive impact of ECT on visuospatial memory. METHOD: Twenty-four patients with severe depression were treated with a course of bilateral ECT and assessed with a battery of visual memory tests within the Cambridge Neuropsychological Test Automated Battery (CANTAB). These included spatial and pattern recognition memory, pattern-location associative learning and a delayed matching to sample test. Testing was carried out before ECT, during ECT, within the week after ECT and 1 month after ECT. RESULTS: Patients showed significant impairments in visual and visuospatial memory both during and within the week after ECT. Most impairments resolved 1 month following ECT; however, significant impairment in spatial recognition memory remained. This is one of only a few studies that have detected anterograde memory deficits more than 2 weeks after treatment. CONCLUSIONS: Patients receiving ECT displayed a range of visual and visuospatial deficits over the course of their treatment. These deficits were most prominent for tasks dependent on the use of the right medial temporal lobe; frontal lobe function may also be implicated. The CANTAB appears to be a useful instrument for measuring the adverse cognitive effects of ECT on aspects of visual and visuospatial memory.

Polymorphisms in the SLC6A4 and HTR2A genes influence treatment outcome following antidepressant therapy.

The majority of antidepressant drugs act by increasing synaptic serotonin levels in the brain. Genetic variation in serotonin-related genes may therefore influence antidepressant efficacy. In this study, nine polymorphisms in four serotonin receptor genes (HTR1B, HTR2A, HTR5A and HTR6) and the serotonin transporter gene (SLC6A4) were analysed to investigate their influence on antidepressant response in a well-characterized unipolar depressive population (n=166) following a protocolized treatment regimen. 5-HTTLPR short-allele homozygotes were significantly associated with both remission (odds ratios (OR)=4.00, P=0.04) and response (OR=5.06, P=0.02) following second switch treatment, with a similar trend observed following initial treatment and paroxetine therapy. Following initial treatment, unipolar patients homozygous for the SLC6A4 intron 2 repeat polymorphism were significantly associated with lack of remission (OR=0.38, P=0.02) and lack of response (OR=0.42, P=0.01). Additionally, the HTR2A C(1354)T polymorphism showed an association with remission (OR=7.50, P=0.002) and response (OR=5.25, P=0.01) following paroxetine therapy. These results suggest that genetically determined variation in serotonin receptor genes makes a significant contribution to the efficacy of commonly prescribed antidepressant drugs.

Influence of 5,7-dihydroxytryptamine lesions of the rat fornix-fimbria and cingulum bundles on spontaneous activity in an aversive maze.

Exposure to aversive environmental stimuli stimulates the serotonergic neurones that project to the forebrain and inhibit spontaneous activity when studied in a simple maze. This study explored the putative role of the principal 5-hydroxytryptamine (5-HT) neurones that project to the hippocampus from the median raphe nucleus in this response to an aversive environment by lesioning the 5-HT fibres that project through the fornix/fimbria and cingulum bundles. The effects of the lesions were investigated in independent groups of animals tested in an enclosed four-arm maze and a more aversive elevated maze of the same dimensions composed entirely of four open arms. The rats were significantly less active in the open maze, the principal effect of maze design being observed during the first 5 min sub-trial of a 15 min trial. This response to the more aversive environment was totally abolished by the lesion. It is concluded that exposure to an explicitly aversive environment elicits a brief stimulation of the 5-HT neurones that project to the hippocampus from the median raphe nucleus and that this stimulation inhibits the initial burst of exploratory activity that is observed in animals placed in a less aversive novel environment.

The enigma of olfactory learning.

It has been suggested, on the basis of neuroanatomical and behavioural data, that olfactory discrimination in the rat provides privileged access to higher cognitive processes, involves the acquisition of a learning-set and, importantly, can be used to model human hippocampal function and dysfunction. In this article, Ian C. Reid and Richard G. M. Morris question the assumptions upon which these claims have been based and criticize the application of odour discrimination learning in the rat to the study of human memory.

Behavioural and neurochemical responses evoked by repeated exposure to an elevated open platform.

Increased psychophysiological resistance to chronic stress has been related to increased 5-HT release in the dorsal hippocampus. This study investigated the changes in 5-HT release and turnover in the hippocampus evoked by acute and repeated exposure to an inescapable stressor, an elevated open platform, and compared them to the changes evoked in the frontal cortex. Repeated exposure to this stressor results in habituation of the plasma corticosterone response to the test, with full habituation being observed after 20 trials. Repeated exposure to the stressor for 5 or 10 occasions increased 5-HT turnover in the hippocampus. By contrast, 5-HT turnover in frontal cortex was increased by acute exposure to the stressor. Microdialysis studies showed that acute stress increased 5-HT overflow in prefrontal cortex but not dorsal hippocampus whereas repeated daily (10 days) exposure to the stressor increased basal extracellular 5-HT in the dorsal hippocampus, but not the prefrontal cortex. Prior exposure to the stressor on up to 10 occasions enhanced the plasma corticosterone response to a challenge in an elevated plus-maze performed 24h later whereas repeated, but not acute, exposure to the stressor, elicited anxiolytic-like behavioural responses in this test. It is concluded that acute exposure to this form of inescapable stress selectively stimulates the 5-HT projections to the frontal cortex; repeated stress elicits a sustained increase in 5-HT release and turnover in the hippocampus. The data are consistent with the hypothesis that increased 5-HT release in the hippocampus may be implicated in the mechanisms underlying habituation to inescapable stress.

The N-methyl-D-aspartate receptor, synaptic plasticity, and depressive disorder. A critical review.

The roles of the N-methyl-D-aspartate (NMDA) receptor and NMDA receptor-mediated synaptic plasticity are reviewed in the context of depressive disorder and its treatment. The mode of action of antidepressant treatment is poorly understood. Animal studies have suggested that many antidepressant drugs show activity at the NMDA receptor and that NMDA antagonists have antidepressant profiles in preclinical models of depression. A post-mortem study in humans has suggested that certain binding characteristics of the NMDA receptor may be down-regulated in the brains of suicide victims. "Depressogenic" stressors in animals and chronic administration of antidepressant agents perturb NMDA-dependent synaptic plasticity in the hippocampus.

Modifiable neuronal connections: an overview for psychiatrists.

Synaptic plasticity is currently the target of much neurobiological research, because it is thought to play an important role in brain function (particularly memory formation). However, it has attracted little attention from psychiatrists to date despite accumulating evidence that links it to various clinical syndromes, including amnesia and possibly psychosis. The purpose of this article is to present an overview of the two major arms of synaptic plasticity research-theoretical (the field of neural network modeling) and neurobiological (long-term potentiation). Artificial neural networks are a class of theoretical model that has been developed with the aim of understanding how information could, in principle, be represented by large numbers of interconnected and relatively simple units. Over the past few decades, several theoretical accounts of information-processing mechanisms have been developed, and these are briefly reviewed. The principle common to representation formation in nearly all neural networks is that of "associability"-the idea that streams of information are combined by forming, strengthening, or pruning connections between them to form new representations that can later be retrieved. Associability also lies at the heart of psychological theories of information storage in the brain. Research into associability has directed the attention of many experimenters toward the possible biological correlates of such mechanisms. Of particular interest is the recent discovery that some neurons appear to possess connections of modifiable strength. The implications of this finding for psychiatry are discussed in relation to representational disorders such as delusions and amnesia.

Smells are no surer: rapid improvement in olfactory discrimination is not due to the acquisition of a learning set.

The claim that rats can demonstrate the 'primate-like' learning capacity of learning set formation when trained with olfactory cues, rather than visual or auditory cues, has generated considerable interest in recent years. In this study, the claim is evaluated in detail by using a series of experimental and control procedures to determine whether rats do indeed develop the abstract 'win-stay, lose-shift' strategy which underlies learning set formation in monkeys. We report here that although exposure to a series of novel olfactory discrimination problems gives rise to progressive improvement in the rate of learning, it is not a necessary condition for the development of that rapid learning. Furthermore, even rats which fail to display progressive improvement in olfactory reversal learning show rapid learning on novel olfactory discrimination problems. Each of these findings suggests that although olfactory learning may be rapid, learning set formation does not occur over a short series of problems.

Repeated ECS induces GluR1 mRNA but not NMDAR1A-G mRNA in the rat hippocampus.

The neural basis underlying the cognitive side effects of ECT is unknown. Recent studies suggest that the memory dysfunction may be caused by alterations in hippocampal synaptic efficacy [20]. In situ hybridisation was used to examine the possible receptor mechanisms responsible for this effect. Repeated ECS markedly increased mRNA expression for the GluR1 subunit of the AMPA receptor, but not the NMDAR1A-G subtypes of the NMDA receptor, relative to control treatments. This effect was present 24 h after the last seizure and may be responsible for the expression of the ECS-induced increase in synaptic efficacy.

Repeated ECS and fluoxetine administration have equivalent effects on hippocampal synaptic plasticity.

RATIONALE: Recent studies have implicated intracellular transduction pathways and neurotrophic factors in the action of antidepressants. Adaptation in these pathways may ultimately affect electrophysiological and morphological properties of neurones. We have previously shown that repeated electroconvulsive stimulation, a safe and effective antidepressant treatment, has profound effects on hippocampal synaptic connectivity and plasticity in the rat. Here, we investigated whether these electrophysiological properties were shared by the chemical antidepressant, fluoxetine. OBJECTIVES: To compare the electrophysiological and cognitive effects of two very different antidepressant treatments: repeated electroconvulsive stimulation (rECS); and chronic administration of the serotonin specific re-uptake inhibitor (SSRI), fluoxetine. METHODS: Rats were exposed to either rECS or daily fluoxetine administration for 15 days. The animals were then anaesthetised and dentate field excitatory post-synaptic potential (fEPSP) characteristics were measured before and after the induction of long-term potentiation (LTP) by high frequency perforant path stimulation. In a separate experiment, the effects of rECS and chronic fluoxetine administration on acquisition and retention of a spatial learning task in the Morris watermaze were determined. RESULTS: Chronic fluoxetine administration and rECS produced equivalent increases in dentate fEPSP compared to respective control groups. LTP induction was attenuated in both groups. Spatial learning was, in contrast, unaffected by fluoxetine treatment but significantly impaired following rECS. CONCLUSIONS: Given that fluoxetine and rECS share antidepressant properties, but differ in their effects on learning and memory, we propose that the common effects on dentate connectivity and synaptic plasticity described here are more likely to relate to affective rather than cognitive function. This result is consistent with other experiments showing that a reduction in dentate connectivity correlates with stress susceptibility in animals.

Effects of intraventricular infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist AP5 on spatial memory of rats in a radial arm maze.

Rats were trained to asymptotic performance in an 8-arm radial maze. They then received chronic intraventricular infusion of either artificial CSF or the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5- phosphonopentanoic acid (AP5), at a concentration (30 mM) that has been shown previously to prevent the induction of long-term potentiation in the dentate gyrus of the hippocampus in vivo. Subsequently the rats received another 9 trials in the maze in a quasi-random order, 3 uninterrupted trials, and another 6 trials each with mid-trial delays of 5, 20 or 60 min during which the animals were placed in their home cage. The mean number of errors for the AP5 rats did not differ significantly from that of the controls in the uninterrupted trials throughout the experiment, nor did it differ from that of the controls in any of the 3 delayed trials when these were first introduced. However, the control animals performed better at the longer delays when these were introduced for the second time, whilst there was no such improvement (but rather a deterioration) for the AP5 animals. The impairment of performance in the AP5 rats during the second block of delayed trials was significant, and independent of the length of the delay. These results show that NMDA receptor blockade does not impair working memory in the radial maze per se, but that it does prevent an improvement of working memory persistence with further training.

Ketamine prevents ECS-induced synaptic enhancement in rat hippocampus.

Electrical induction of seizure activity profoundly impairs hippocampal long-term potentiation (LTP) in rats. A similar effect may account for the memory dysfunction observed after electroconvulsive stimulation in humans and other species. The co-administration of ketamine with the induction of electroconvulsive seizures (ECS) was evaluated as a possible method for reducing the impact of ECS on hippocampal synaptic plasticity in rats. Electrophysiological studies in vivo showed that both the enhancement of the EPSP slope and the subsequent reduction of experimentally induced LTP in the dentate gyrus by repeated, spaced ECS were significantly attenuated by ketamine anaesthesia. The findings suggest that ketamine may protect against ECS-induced memory impairment and thus prove useful in reducing the transient cognitive impairment following electroconvulsive therapy (ECT).

The effect of clomipramine treatment on plasma lipoproteins and high density lipoprotein subfractions in healthy subjects.

The effect of clomipramine on plasma lipoproteins, including high density lipoprotein (HDL) subfractions in five healthy males was investigated. The concentrations of total plasma cholesterol and low density lipoprotein cholesterol decreased slightly while that of total HDL-cholesterol showed a small increase, giving a decrease (p less than 0.05) in the ratio of total plasma cholesterol to HDL-cholesterol. The level of HDL2-cholesterol increased (p less than 0.01) with clomipramine treatment while there was no significant change in the concentration of HDL3-cholesterol. Gradient gel electrophoresis showed that administration of the drug was associated with an increase in the relative concentration of HDL2a as well as of HDL2b and a decrease in that of HDL3b/3c. The plasma concentration of apolipoprotein (Apo) A-I showed a small but insignificant increase. These changes in lipoprotein profile are characteristic of those associated with a decrease in coronary risk.

Relationship between observed NMR changes and brain water content following electroconvulsive stimulation in the rat.

The administration of electroconvulsive stimuli to anaesthetised rats results in changes in the relaxation times and water content of grey and white matter, but not in mid brain, hind brain or cerebellum. White matter changes occur in both T1 and T2, are biphasic in character and related to water content. Grey matter changes are confined to T1 and water content only. It is suggested that these changes are related to altered compartmentalisation of water, manifesting in a different manner in the two tissues probably due to their different cellular and biochemical composition.

Sucrose consumption as an hedonic measure following chronic unpredictable mild stress.

The consumption of, and preference for, a rewarding 0.9% sucrose solution was examined in rats subjected chronically (8 wk) to a regimen of unpredictable mild stressors. Intake of sucrose was reduced in stressed animals compared to controls after 3 wk. However, correction for body weight changes revealed no significant difference in sucrose consumption between the groups. A comparison of the mean sucrose intakes of matched low-weight rats, with low weight a function of either immaturity or stress, failed to differentiate between the groups. Total sucrose consumption and total fluid intake correlated significantly with body weight of stressed animals and controls. Percentage preference for sucrose solution did not differ between controls and stressed animals. It is concluded that the validity and reliability of sucrose consumption as an hedonic measure within the context of exposure to chronic unpredictable mild stress must be questioned.

Chronic mild stress and sucrose consumption: validity as a model of depression.

Sucrose consumption and preference were examined in rats subjected to a 6-week regimen of unpredictable mild stressors, after Willner et al. (11). These subjects were compared with groups exposed to: 1. only the food deprivation element of the stress protocol; or 2. the stress protocol without the food deprivation element. A control group was not exposed to stressors. Body weight and sucrose consumption were significantly reduced in stressed and food-deprived animals compared to the other 2 groups. These variables therefore appeared dependent on food deprivation and independent of other elements of the stress protocol. Neither sucrose consumption per gram body weight nor sucrose preference differed significantly among the 4 groups. These results indicate that food deprivation is not only necessary, but sufficient, to produce sucrose consumption deficits in rats. It is, therefore, likely that reduced sucrose consumption in stressed rats results solely from diminished body weight rather than exposure to the series of stressors. We conclude that sucrose consumption is not a valid index of reward responsiveness. Other measures (such as place-preference conditioning or intracranial self-stimulation threshold) should be evaluated also with respect to body weight change when considering the validity of stressor-based models of depressive disorder.

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.