Posted comment on ´The importance of forgetting` written by L. Gravitz and published in Nature 2019 vol 571 25th July 2019 S12-S14 doi 10.1038/d41586-019-02211-5
Gravitz introduces her article by describing the development of the idea that forgetting is not a passive process of memory decay and recall failure, but an active functional process. Therefore, it was said that the standard state of the brain is not to remember, but to forget. The forgetting process is one largely overlooked by researchers and it is possible that a better understanding of it may lead to breakthroughs in the treatments of conditions such as anxiety, post-traumatic stress disorder and Alzheimer`s disease where dysfunctional forgetting play a role.
The article begins with a general summary of the memory processes and its requirement for neuronal plasticity which strengthens the connectivity and firing of the active neurons representing the event characteristics. This event representation (referred to in the article as an engram) may consist of synaptic connections across several areas of brain and each neuron and synapse of the network can be involved in multiple engrams. Recall strengthens the neural network of firing cells and Gravitz describes the consistent recall as encoding the memory in both hippocampus and cortex areas until eventually the long-term storage reflects only cortex activity. The article continues by looking at the various aspects of the memory mechanisms from the viewpoint of forgetting and not memory formation.
The discussion begins by looking at the association of neurotransmitters with forgetting. Gravitz describes the first reports of active forgetting as work reported in 2012 from Davis. Davis used fruit flies in his studies and looked at the action of dopamine released from other neurons on the mushroom bodies, which are dense networks of neurons in insect brains that store olfactory and other sensory information. Conditioning experiments were performed with flies avoiding odours associated with electric shocks. It was found that dopamine blocked the conditioned avoidance response, but inhibition of the same neurons preserved the memory. Therefore, Davis concluded that dopamine regulated how memories could be expressed. Hence, dopamine was said to provide the ´forget` signal. It was also found that dopamine neurons were active for long periods and this observation was interpreted as the brain always trying to forget the information it has learnt. An association between forgetting and neurotransmitters was also described for rats. In this case, the active process of forgetting was shown by Hardt to involve glutamatergic AMPA receptors. AMPA receptors are known to be part of the memory storage process by being trafficked to the post-synapse membrane and forgetting was described as the destruction of the connections at the synapse. Again, the premise that forgetting is not a failure of memory, but a function of it was stated.
Gravitz`s article then went on to describe the association between forgetting and neurogenesis, which is a process normally associated with memory formation. In this case, the research by Frankland and neurogenesis of hippocampal cells in mice was cited. Using the knowledge that memory formation requires newly formed neurons, Frankland looked at whether increasing neurogenesis would aid memory recall in adult mice. The team found instead that under these conditions increased neurogenesis which would normally provide a greater neuronal capacity actually led to increased memory loss. This was explained by the new neurons in the hippocampus integrating into already established neuronal network actually causing ´disruption` of the network and making information harder to access. Although not always beneficial, it is used to advantage because of the constantly changing environment that the individual lives in and the need for continual learning of new information and adaptation of learnt material by over-writing.
The article then continues by looking at studies on human memory. Gravitz cites Richards who states that the ability to generalise new experiences is due to the brain`s ability to carry out controlled forgetting. This Richards says prevents ´overfitting` which relates to artificial intelligence where the mathematical model is so good at matching programmed information that the AI is unable to predict what comes next. Richards explains that memory of gist rather than detail allows generalisation of experiences and use of that information in novel situations. This view is supported by Levine with reference to real-life situations where people can have highly superior autobiographical memory (HSAM) or severely deficient autobiographical memory (SDAM). In HSAM, an extraordinary level of detail is remembered, but there is limited informational processing capability and an increased tendency to obsessiveness. These characteristics are attributed to a person´s lack of ability to extract themselves from the pure data. In SDAM the individual is unable to vividly recall specific events and has a problem with projection into future events, but they are good at problem solving and abstract thinking.
Work by Anderson and team on how active forgetting occurs is cited in the article. They found that in situations where thoughts are actively suppressed then high GABA levels are linked with greater suppression of the prefrontal cortex on the hippocampus. Gravitz says in her article that work on GABA and this type of suppression may explain the action of anti-anxiety benzodiazepines (eg. diazepam) which are known to enhance GABA receptors. The action of benzodiazepines is explained by the prefrontal cortex commanding the hippocampus to inhibit the thought. However, if the hippocampus does not have enough GABA then it cannot carry out the command and therefore, the increase in GABA receptors by anti-anxiety drugs will increase the hippocampus response. Gravitz goes on to say that GABA´s role in suppressing unwanted thoughts hence may be part of the mechanisms linked to phobias, schizophrenia and depression. These conditions present with various symptoms (eg. flashbacks, obsessive and/or depressive thoughts and difficulty in controlling thoughts) which may be linked to an overactive hippocampus. Anderson`s observations and the switch off mechanism orchestrated by GABA may play a role in removing these cognitive problems. Anderson also suggests that this might have implications for treatment of post-traumatic distress syndrome which may be failure to forget. It has been found that people who report more traumatic experiences are particularly good at repressing specific memories. The hypothesis may also apply to Alzheimer´s disease where memories are lost. Hardt thinks that the malfunction of forgetting lies with an overactive forgetting mechanism erasing more than it should may be at play rather than with a dysfunctional recall mechanism.
Gravitz concluded her article with a description of the shift of focus of research from the brain´s ability to form memories to the brain`s ability to forget, hence indicating this aspect`s rise in importance. The importance is said to be understandable since in a changing environment adaptive memory with the capability of updating knowledge enables individuals to move forwards and for adaptive memory to exist, forgetting is required.
What makes this article so interesting is that it discusses ´forgetting` which is one of the many mechanisms involved in memory. Unlike learning, forgetting cannot be thought of as a single type of process because it applies to at least two different situations. The first is where forgetting is ´failure to remember`, a situation such as that occurring with Alzheimer disease and is essentially regarded as negative. This situation refers to when information is no longer available for recall even under prompting due to destruction of the neuronal network required for its representation. And the second situation is where ´forgetting` means that stored information cannot be remembered because it has been ´overwritten`. In this case, the original information has been updated because perhaps it is no longer relevant or needed. This type of situation occurs in for example, extinction in conditioning experiments or more simply knowing how to operate your first mobile of over 20 years ago. In this case, ´forgetting` may mean that the new information supercedes the old information and that it is truly gone or the new information has higher priority in the recall process. Here, the old information is still there, but only comes to mind when prompted to a high degree or when deliberately and specifically searched for. So, here is the first point about using the word ´forgetting`. Forgetting refers to how we, the individual, refers to the recall of the information and not how the brain as a physiological structure views the recall of the information. This indicates how we should look at forgetting in terms of neurochemical mechanisms.
If we look at the first situation, where forgetting is ´failure to remember` this occurs because the information is no longer there or accessible to us due to physiological destruction. This is a different situation to not being able to remember something because it was never there (ie. long-term memories were never formed from the real-time neural representations independent of the reason). Therefore, for this forgotten information we can assume that the physiological mechanisms required to form long-term memories were at some point carried out. This also means that the long-term memories are located in the relevant cortical areas or cerebellum and are in the form of a network of cells (neuronal assembly) that represent the event. The cells of the network fire together in response to a particular stimulus leading to the recall of the characteristics they represent. Firing of the network is ameliorated (´fire together, wire together`) by the physiological changes that occur to its constituent cells on event storage, eg. increased AMPA receptors (long-term potentiation), increased connectivity through dendrite formation as well as gene modulation that aids neurotransmitter production, vesicle recycling, energy supply and glial cell functioning for example. Two things are assumed here: the first is that the neuronal assembly stays relatively stable for a period of time from its conception to its first use; and secondly, that the hippocampus is purely a relay station in charge of the recall stimulus and timing of event recall, real-time input and real-time informational processing. (Its role in binding of event characteristics and synchronising firing of different areas in the formation of the neuronal assembly is no longer applicable when the information is recalled.) Therefore, in the case of forgetting where forgetting is ´failure to remember` the overlying physiological cause is the decay of the ´silent` neuronal assembly so that a stimulus no longer initiates the firing of the neurons that made it up and that represented the event experienced in the past. The event can be forgotten in its entirety or only part as in the forgetting of certain characteristics.
If we assume that memory retrieval involves the reinstatement of the neuronal firing patterns, then memory decay involves the physiological destruction or dysfunction of the relevant neurons and the connectivity between them. There are a number of different causes for such failure. The obvious one is the large scale physical destruction of the neuronal cells and this is seen in situations such as injuries, lesions and Alzheimer`s disease. It is clear therefore, that if the cells are no longer present then the network cannot be reactivated and the event cannot be remembered.
Another important cause of memory failure is the destruction of neuronal connectivity which leads to synchronisation and timing issues. The cells representing the event act together and to a large extent retrieval of information relies on the reactivation of the same end cells that fired during encoding. The connectivity of the network relies on the activity of a number of brain areas, eg. greater similarity between patterns of firing of the dorsal lateral prefrontal cortex during encoding and retrieval relate to better memory recall performance (Javadi) and the increased connectivity between the perirhinal cortex and other areas relate to object recognition performance (Staresinaln). The specificity of this brain area connectivity is sometimes associated with particular information content of the memory, eg. autobiographical memory preferentially activates the areas of the default mode network (Chen) whereas visual memories activate parietal and frontoparietal areas (Chen and Ye) with both memory types having functional connectivity to the hippocampus (Westphal). Therefore, destruction of the connectivity or dysfunctional connectivity can lead to decay of neuronal networks specific for the event representation with the result that recall of the specific information fails. Dysfunctional connectivity also links to the failure of the instigation of appropriate brain waves consistent with memory reenactment, eg. beta waves between visual regions and parahippocampal cortex being required for the reinstatement of neural patterns matching the retrieval of visual information (Staudigl).
Failure to remember can also be due to micro-scale dysfunction at the neuron level since firing of each relevant cell is a necessary process for event characteristic retrieval. Since there are many components and processes required for satisfactory neuronal function in both encoding and recall of event characteristics there are many points at which dysfunction or deficit can prohibit the firing process necessary for re-enactment. For example, loss of memory reported in traumatic brain injury is related to loss of dendritic spines (Sen) which would diminish the capacity to receive the transmitted signal whereas forgetting of spatial memories is said to be caused by the removal of the AMPA receptors at the neuronal cell membrane (Migues). These are normally required for long-term plasticity of the neurons required for the event representation.
It is clear therefore, that forgetting can be due to failure to re-instigate the event representation due to dysfunction and deficits of the neurons and networks that contribute to it. However, forgetting can also be due to failure to adapt existing memory when new information is presented. In this situation, the old information is remembered, but the failure to update with the new information means that this will be ´forgotten` at the next demand for retrieval. Updating event representations is an important part of the memory process and requires a number of correctly operating processes in the appropriate order. For example, it requires retrieval of past information (event representation re-enactment), simultaneous input of the ´new` information, ´comparison to or addition to` type decision mechanisms, and physiological processes for long-term storage as part of the re-consolidation of the ´old` information and binding and storage of the ´new` information.
The correct functioning of two brain areas in particular, the hippocampus and the prefrontal cortex, appears to be required if ´overwriting` is successful. In the case of the hippocampus, this area plays a vital role in the relay of information and its binding during the event`s encoding. With regards to ´overwriting`, it is likely that it plays equivalent roles not only in the relay of the new information to the upper cortical areas, but also maintains that firing in order for the ´comparison` mechanisms to be carried out. This view is supported by research that shows the hippocampus`s requirement in matching of ´old` information to ´new` information as seen in face-diagnosis memory with connectivity with the left middle temporal gyrus (Brod) and contextual fear conditioning where learning is required if the recalled information does not match the new input (Bernier). Theta gamma rhythms involving the hippocampus at the time of retrieval appear to be important as to whether ´new` information overwrites the ´old` in fear memory consolidation (Radiske). Therefore, failure to overwrite manifesting as ´forgetting` may be caused by a dysfunctional hippocampus activity during the encoding and recall processes.
The other important brain area relating to failure to overwrite the old information with new information is the functioning of the prefrontal cortex. This is a key area in decision-making processes which relates to the question whether the ´new` information is assessed as being ´valuable` and hence, an overwrite is necessary or irrelevant and classed as ´interference` and ignored. Research shows that the prefrontal cortex performs this role in the case of reward prediction errors with connectivity to the ventral tegmental area with the decision whether to maintain or deviate from previously learned cue-reward interactions (Ellwood). It is likely that both the dorsolateral prefrontal cortex (known for its role in strategic control and working memory – value assessment of incoming stimuli) and the ventromedial prefrontal cortex (known for its role in value assessment and comparison, decision-making awareness of choice and switching of attention) are involved. Therefore, failure to overwrite can be caused by the failure of the prefrontal cortex to bring about the decision to update.
Apart from dysfunctioning at one or both of these areas, another reason for failure is that the neuronal firing attributed to the new information is not strong enough to overcome the recalled information if it is contrasting, or not strong enough to form part of the event representation if the characteristic is to be added. Similarity to the ´old` information may be an advantage with greater similarity to the stored information being shown to be more easily encoded so leading to an improvement in memory performance with time (seen with face-diagnosis pairs – Brod). This may be due to the sharing of cells already exhibiting strong firing from the similar characteristic. However, the lack of strength of the firing for the new event characteristics may be due to input deficiencies, eg. poor visual input due to changing gaze, interference of visual details by flashing lights. Two factors may play roles here and these are emotional status and age which are both attributed as causing changes in memory performance. For example, negative emotional status such as from fear or stress is known not only to negatively impact informational input by changing attentional performance in general, but can also affect specific content. In the case of stress, there is interference with long-term memory for associated material (Trammel) and impaired memory selective for content, eg. memory for items is deficient, but not for background information (Steinmetz). The highest state of anxiety is shown to cause the inhibition of retrieval for both threatening and non-threatening informational categories (Nunez) and therefore, this will have an impact on whether event representations are updated or not. This appears to be the case also with avoidance strategy where an ability to suppress unwanted, upsetting memories. This is shown to have effects on the recall not only of the distressing event, but also of other details (Quang) and low arousal emotion can facilitate the recall for peripheral information if directly relating to it (Davidson). Therefore, if information is not being recalled, the capability to ´overwrite` it is disrupted. Positive emotions can also affect memory retrieval as shown in the case of episodic memory where performance is lower following a highly positive event even though the executive control performance is unaffected (Lagner). Therefore, as described, memory enhancement or impairment by emotion depends on the nature of the information to be retrieved and the circumstance (McKenzie).
Another factor that can affect the performance of updating memories appears to be the age of the individual. Ageing has been shown to have an effect on memory performance attributed to physiological changes of the neuronal network, eg. aged rats exhibit defective recognition memory and alterations in hippocampal synaptic plasticity through defective LTP and enhanced LTD (Arias-Cavieres) and episodic memory declines with age, an observation that correlates to regional connectivity of the default mode network plus the medial prefrontal cortex (Huo). However, the situation is not clear cut, since age is not the reason for changes in specificity of detail retrieved for autobiographical memories since both young and older age groups show deficits (Aizpurua) and the frequency of involuntary autobiographical remembering appears not to decline with age (Berntsen). Reduced capability levels may be attributed to an inability to inhibit the incoming and storage of irrelevant material which is shown to increase with age rather than the more severe long-term physiological deficiencies. This view is supported by the reported positive effects of cognitive training which may increase older individuals` abilities to inhibit irrelevant material whereas for younger individuals it leads to an improvement in their cue-integration capability (Cappelleti). Therefore, forgetting may be due to selective failure to store new information to overwrite the old.
Therefore, this comment shows that the topic of forgetting cannot be regarded as a simple failure to remember. It may involve different mechanisms depending on the circumstances in which it occurs or is demanded. Gravitz in her article supports the view of Davis that the brain is always trying to forget, but this is not strictly correct. The brain tries to remember but only remembers what it can when given the right conditions to do so, or what it is demanded to remember through conscious control. However, the transient physiological nature of neuronal cells means that the memory system is always in flux and cells are destroyed and formed to try to maintain what is important to the individual and recalled information normally means ´important`. This demand is not always fulfilled and success at memory retrieval is not always possible with information being lost or not being updated so effectively ´lost`. Therefore, as Hardt says, this latter type of forgetting is a function of memory and not a failure of it. It is possible that a through a greater understanding of the mechanisms that contribute to desired forgetting, solutions to the unwanted forgetting as seen in dementia for example may come to light.
Since we`re talking about the topic………………………
….a single electroconvulsive therapy (ECT) application is known to disrupt reactivated, but not non-reactivated memory recall for an emotional event in patients suffering from depression (Kroes). Would controlled staged recall of a highly emotional event interrupted with ECT applications lead to forgetting of the event in its entirety over time or would the repetition of the recall at each state consolidate the memory even more?
….–recent memories are generally recalled from a first person perspective and older memories from a third person perspective (Butler). The repeated retrieval of visual details in the first person is shown to lead to better retention of material and slowing of the shift from first person to third (Butler). Can we assume that by directing retrieval with imagery or cues (Harris) and instructing recounting in the first person that recall performance may show an improvement?
….the capability to update information into beliefs relies to some extent on whether the information is desirable or undesirable, with the former greater than the latter (Garrett). This biasness does not exist when there is perceived threat to the environment (Garrett). Therefore, would ensuring that the way information is ´phrased` is positive lead to an improvement of event characteristic recall?