Electroconvulsive therapy is generally used for individuals suffering from medication resistant depression. Though subject of much criticism, ECT is successful in approximately 80% of those individuals void of relief through pharmacological means (prochenka and norcross). Commonly, amnesia occurs as a side effect. Two methods of ECT are available. Unilateral ECT is the most common method of ECT. Unilateral ECT utilizes electrodes placed on the same plane of the skull. Generally, unilateral ECT is applied to the right side of the skull in order to minimize memory deficits. Bilateral ECT involves placement of electrodes on both sides of the skull resulting in total transient shock to the brain. After application of electrodes, a shock stimulus is applied at a magnitude higher than the seizure threshold of the individual. There is much debate regarding the therapeutic mechanisms of ECT and a number of neurophysiological, neurotransmitter, and neuromodulator theories have been proposed. Side effects of ECT include memory loss, cardiac dysfunctions, confusion, and in severe cases death. ECT can elicit both anterograde and retrograde amnesia, but the later is seen as more problematic.
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Frequent electroconvulsive shocks can induce up-regulation and saturation of glutamate and NMDA receptors which are essential to LTP1,2. This saturation is suggested to be long lasting, and as a result no new LTP can result, leading to the inability to form new memories2,3. Essentially, as treatment is repeated, an increase in the slope of excitatory post synaptic potential is observed until a peak is reached. This peak represents saturation of LTP, and at this point research suggests hippocampal plasticity is at its maximum1, 3. Once this maximum is reached, no substantial measures of LTP can be triggered, and therefore formation and consolidation of new memories becomes difficult1. The related amnesic side effects appear to begin after the fifth round of ECT which correlates with the peak of LTP response and lasts until EPSP slope decreases; which takes anywhere from one to twelve weeks post-treatment1.
1.3. Immuno-inflammatory Responses
Recent research has suggested that the immuno-inflammatory action of COX-2 may also have indirect effects on the up regulation of glutamate and therefore play a role in NMDA saturation3. Essentially, upon repetitive utilization of ECT the retrograde messenger PAF is released from and acts upon the post-synaptic membrane of CA1 neurons to increase glutamate signalling3. Furthermore, PAF release stimulates COX-2 expression which leads to disinhibition of glutamate signalling3. These increases in glutamate signalling enhance the stimulation of NMDA in the hippocampal neurons. Combined, these two effects may lead to saturation of LTP at the post-synaptic membrane and therefore prevent further development of new memories. Research in this area also suggests that these effects may explain retrograde amnesia caused by continuous ECT. Basically, NMDA receptor reactivation is required in order for systems consolidation of new memories to occur3. If these receptors are saturated in the membrane, reactivation cannot occur and systems consolidation may be compromised3. If the mechanisms essential for systems consolidation are defective, then retrograde amnesia could result.
1.4. Preventative Measures
2.1. Clinical Uses
Benzodiazepines are a commonly prescribed psychoanalytic and are used as sedatives, anxiolytics, hypnotics, muscle relaxants and anti-consultants. They are used in institutionalized clinical settings as well as in outpatient settings. Although effective in performing their primary role, benzodiazepines have a number of side effects which include anterograde and/or retrograde amnesia. The value and positivity of these amnesic side effects have been debated. Some clinicians suggest that the amnesic effects of benzodiazepines are beneficial in preventing patients from experiencing the negative stimuli associated with surgery4.
2.2. Benzodiazepine Administration and LTP/LTP Based Cognitive Deficits
The regulatory effects of benzodiazepines on GABAÂA receptors are suspected as the cause of benzodiazepine induced amnesia5,6. Benzodiazepines bind GABAÂA receptors at the BZ binding site and lead to enhanced action of GABA. Benzodiazepine binding to the BZ sites (specifically BZ2) has been shown to be in high correlation with the cognitive side effects of benzodiazepines6.
Research has focused more specifically on the effects of benzodiazepine induced GABA on LTP as well as long-term depression (LTD) in synaptic regions specific to the CA1 layer of the hippocampus6,7,8. Research in the area suggests that benzodiazepines play a role in creating inhibitory post synaptic potentials (IPSP) that inhibit LTP, which recent research has shown is important to learning and memory6,8(maubach). In order to inhibit LTP benzodiazepines have a negative effect on the NMDA receptors found in the CA1 layer of the hippocampus. After binding to a GABAA receptor can affect NMDA and the initiation of more frequent inhibitory post synaptic potentials through two possible mechanisms7,8. First, this binding can inhibit the interaction of GABAA receptors with the GABAB receptor isoform. Blockage of cross-talk between these receptors can weaken the refractory period associated with IPSPs in the CA1 region and lead to higher frequency IPSPs that exhibit less decay7, Prabhakar. Secondly, binding can result in amplification of IPSPs that fire during the refractory period, and lead to firing of more intense IPSPs7. In both cases, IPSPs lead to a decline in currents produced by the NMDA receptor and therefore interferes with the production and maintenance of LTP7. Without effective propagation of LTP, patients have difficulty forming new memories.
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Furthermore, benzodiazepines have been shown to regulate the effects of GABA agonists and the induction of LTD. Essentially, the addition of high concentrations of benzodiazepines at BZ2 receptors allows for agonist activation of GABAA receptors at agonist concentrations below base line6. In turn, GABAA activation at these less concentrated levels of agonist produces LTD6. When this effect is produced in the CA1 layer of the hippocampus, cognitive deficits such as memory loss can occur. The LTD induced deficits last approximately 120 minutes, or until washout of benzodiazepine6, 7. This time-frame juxtaposes well with memory deficits during clinical procedures as well as the short period following these procedures.
2.3. Preventative Measures
The use of negative modulators of GABAA and GABAA antagonists have shown success in preventing the effects of benzodiazepine induced cognitive deficit and amnesia6. Brain derived neurotrophic factor (BDNF) has primarily been studied as a growth factor, but recent research has revealed that it may also be involved in synaptic transmission and modulation of neurotransmitter releaseakohn. Release of BDNF appears to be down-regulated by GABA release and therefore may play a mediating role in the amnesic effects caused by GABAA receptor activation by low concentration agonistsakohn. Introduction of BDNF into neurons prior to benzodiazepine administration has been shown to prevent the amnesic effects produced by benzodiazepinesakohn. Bacopa. Monniera, a herb used primarily for memory enhancement has also been used to counter memory deficits produced by benzodiazepinesprabhakar. B.monniera is thought to shift GABA receptor function to be excitatory rather than inhibitory and in turn prevent the memory loss associated with benzodiazepinesprbhakar.
3. Selective Erasure of a Fear Memory
3.1. Potential Benefits
In some cases, memory erasure is a beneficial and desired primary consequence of medication or therapy. Given that traumatic memory replays are a recurrent symptom of post-traumatic stress disorder and aid in the longevity of the disorder, erasure of these memories while preserving others would be a beneficial mechanism in treatment11, 12.
3.2. Chemical/Molecular Manipulation
Recent research has begun to manipulate the molecular properties of specific neurological pathways in relation to learning memory in attempts to selectively erase a targeted memory. Of particular interest have been the effects of erasure of the CREB protein and how this may affect learning and memory of a fear response. Research has linked increased levels of CREB in the lateral amygdala to learning and memory following fear training. This increase in CREB has therefore been suggested as a key component to learning of a fear response. Consequently, neurons expressing higher levels of CREB following a fear learning task are more probable to be recruited in learning of the specific fear response and in turn the creation of a memory trace 9. In order to ablate only those neurons expressing high levels of CREB in the lateral amygdala, transgenic mice were created which expressed diphtheria toxin receptors (DTR) activated by cre-recombinase. To specifically activate the DTRs present in CREB neurons, a CREB-cre vector was introduced to the specimen prior to addition of diphtheria toxin. Finally, the injection of diphtheria toxin leads to apoptosis of only activated CREB neurons 9. After injection of CREB-cre and therefore over expression of CREB, learning and memory of a fear response was enhanced. However, following diphtheria toxin injection and apoptosis of activated CREB neurons, this enhancement was reversed and the fear memory abolished 9. The positive results of this study suggest that deletion of neurons expressing CREB in correlation to fear learning and memory may be essential to ablation of specific fear memories.
An increase in Alpha-CaMKII expression at times of recall has also been linked to the ability to selectively erase a fear memory as well memory for novel objects. By creating transgenic mice that express higher than natural levels of alpha-CaMKII, experimenters were able to selectively allow over expression of alpha-CaMKII by utilizing NM-PPI, an alpha-CaMKII inhibitor. Over expression of alpha-CaMKII during recall of both old and new memories inhibits recall of these memories10. For example, participating in a contextual fear conditioning exercise, mice who on recall of the fear learned in this paradigm had high levels of alpha-CaMKII expression were unable to recall the learned response. Furthermore, when tested via the same paradigm at a later period in concert with NM-PPI, and therefore normal levels of alpha-CaMKII, the specimen still exhibited memory erasure. No motor or natural fear response behaviours were inhibited other than those learned suggesting that the memory erasure is specific for learned memories attempted to be recalled10. Speculation has been laid as to the possible mechanisms behind this effect. Researchers have suggested that inducing LTD like stimulation via NM-PPI after over expression of alpha-CaMKII may play a role in the apparent memory degradation or that over expression may lead to activation of ubiqutin pathways10. However, no clear mechanisms have been discovered.
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Current methods of erasure are more effective and are more easily attributed to pathways in the amygdala. Deletion of novel object memories is not as strong and the mechanisms behind the effect are not clear. CREB is a more specific and visualizable target for deletion when compared to CaMKII over expression. CaMKII over expression offers a wider range of erasure, including novel object recognition and not simply fear memory deletion. However, these methods are not ready for human trials and implementing an effective method based on the two mechanisms is difficult because humans are not transgenetically modifiable. It is possible that the current methods could be manipulated in order to affect upstream pathways rather than directly affecting the mentioned neurons and pathways directly to elicit similar results 10. Much research is the area is still required before specific memory erasure in human beings is feasible.
3.3. Ethical Concerns
There is variability in opinion pertaining to the use of mechanisms that ablate or dampen memory. In 2003, The Presidentâ€™s Commission of Bioethics released a report suggesting the positivity of memory erasure techniques while also commenting on the related ethical concerns. The commission suggest that although some memories may be traumatic, the brain is biologically designed to recall emotionally charged memories more efficiently and may play an important biological role. By dampening or deleting these memories one may be altering the evolved purpose of this type of recall. Furthermore, deletion of these types of memories may pose legal concerns and difficulties with regards to trial proceedings and witness statements13,14kobler. In addition, by deleting traumatic memories and relieving individuals from the reality of the pain related to them, essentially sensitizing individuals to distressing situations13. On a moral standpoint, the committee suggests that as a society we are obligated to maintain certain memories despite their painful nature in order to maintain a history and promote social growth13.