Pharmacological disruption of maladaptive memory (from: Cognitive Enhancement – 2015)

Pharmacological disruption of maladaptive memory.  (from: Cognitive Enhancement)

Many psychiatric disorders are characterized by intrusive, distracting, and disturbing memories that either perpetuate the illness or hinder successful treatment. For example, posttraumatic stress disorder (PTSD) involves such strong reemergence of memories associated with a traumatic event that the individual feels like the event is happening again. Furthermore, drug addiction is characterized by compulsive use and repeated relapse that is often driven by internal memories of drug use and/or by exposure to external stimuli that were associated with drug use. Therefore, identifying pharmacological methods to weaken the strength of maladaptive memories is a major goal of research efforts aimed at finding new treatments for these disorders. The primary mechanism by which memories could be pharmacologically disrupted or altered is through manipulation of memory reconsolidation. Reconsolidation occurs when an established memory is remembered or reactivated, reentering a labile state before again being consolidated into long-term memory storage. Memories are subject to disruption during this labile state. In this chapter we will discuss the preclinical and clinical studies identifying potential pharmacological methods for disrupting the integrity of maladaptive memory to treat mental illness.

The book is comprehensive and covers many areas,  including:

  • Part I    Basic Approaches and Perspectives

    Methods for Delivering and Evaluating the Efficacy of Cognitive Enhancement

    Animal Paradigms to Assess Cognition with Translation to Humans
    Signaling Pathways Relevant to Cognition-Enhancing Drug Targets

    Role of Adult Hippocampal Neurogenesis in Cognition in Physiology and Disease: Pharmacological Targets and Biomarkers

  • Part II    Cognitive Domains for Pharmacological Intervention: Implications for Neuropsychiatric and Neurological Illnesses

    Executive Function

    Declarative Memory

    Verbal Memory

    Emotional Memory

    Social Cognition

  • Part III    Developmental Disorders, Alternative Approaches,and Emerging Technologies

    Neural Targets in the Study and Treatment of Social Cognition in Autism Spectrum Disorder
    Assessing Cognitive Improvement in People with Down Syndrome:

    Pharmacological Disruption of Maladaptive Memory

    Non-pharmacological Approaches to Cognitive Enhancement

    Optogenetics and Deep Brain Stimulation Neurotechnologies

    Closing Thoughts for Cognitive Enhancement

Novel interventions for maladaptive memories include:

NMDA receptor manipulations
Adrenergic/noradrenergic manipulations, including propranolol
Manipulating glucocorticoid receptors
GABA manipulations, including midazolam and ethanol
Targeting intracellular signaling molecules, including the use of rapamycin, a mTOR inhibitor

“Schizophrenia is characterized by positive, negative, and cognitive symptoms. The cognitive symptoms are unquestionably characterized by disruptions in learning and memory (e.g., working memory) that could benefit from cognitive-enhancing agents. However, the positive symptoms, specifically the formation and persistence of elaborate delusions, may also arise from the formation of maladaptive memories that we have argued involve aberrant reconsolidation mechanisms (Corlett et al. 2009, 2010). For example, several studies have found that the psychotomimetic drug ketamine can disrupt processing of learning-based prediction errors in frontocortical regions and that the degree of activation to prediction errors under placebo conditions predicted the severity of delusional thoughts experienced under ketamine (e.g., Corlett et al. 2006; Corlett and Fletcher 2012). Specifically, the persistence of delusions may be due to overactive memory reconsolidation systems that persistently strengthen and reinforce the bizarre beliefs despite little evidence for the accuracy of these beliefs. Indeed, evidence for this hypothesis was supported by the finding that when fear memories are reactivated under the influence of ketamine, they are stronger when recalled the following day, suggesting that memories may be more likely to undergo reconsolidation in the psychotic state (Corlett et al.2013). Therefore, there is a possibility that unpleasant delusions may in fact represent maladaptive memories that could be subject to pharmacological disruption, which might improve the social function and quality of life of those with schizophrenia.

Schizophrenia is a disorder that involves impaired cognition and disordered thoughts that can lead to the formation of bizarre associations and beliefs that impair an individual’s ability to function. One could envision a scenario where memory  for  these  bizarre  beliefs  is  disrupted  through  interfering  with reconsolidation of the memory and that this could improve overall functioning.On the other hand, dysfunctional memory consolidation and reconsolidation processes could lead to the creation of these bizarre beliefs, so it may also be possible to improve function by normalizing learning and memory circuitry. While these hypotheses have not been tested directly, one study has examined whether induction of a psychotic-like state can alter memory reconsolidation. Corlett andcolleagues gave healthy subjects a subanesthetic, mildly psychotogenic dose of ketamine prior to retrieval of a previously learned fear memory. Ketamine produced dissociative and slight psychosis-like effects that mimicked some of the features of psychosis in schizophrenia. The subjects whose memory was reactivated under ketamine had stronger fear memories the following day in the absence of ketamine than subjects whose reactivated the memory after placebo administration (Corlett et al.2013). The conclusion from this study is that conditions that produce a psychotic-like state favor enhancement of reconsolidation, which could lead to the abnormal strengthening of delusional thoughts, turning these thoughts into strong beliefs. The learning theory of delusions is intriguing, and future studies will have to validate these results, preferably in subjects with schizophrenia. The mechanism of the effect is also unclear because ketamine is an NMDA antagonist, which, as described above, almost always disrupts memory reconsolidation rather than facilitating it. However, in the clinical study, ketamine was given before the reactivation session, creating a psychotogenic state before the memory was reactivated that may have enhanced destabilization of the memory. It may be that a post-reactivation infusion would disrupt reconsolidation by altering memory restabilization, and indeed, we have unpublished data that suggests this is the case (Honsberger, Corlett, and Taylor, in submission). Ketamine also acts on other neurotransmitter systems, raising the possibility that the effect was not solely mediated by NMDA receptor blockade.”

The use of ECT is interesting:

“In one study, depressed subjects were asked to recall an emotional episodic memory prior to ECT. Control subjects were given ECT but did not reactivate the memory beforehand. The results showed that ECT disrupted reconsolidation of the memory only in the reactivation condition (Kroes et al.2014). Therefore, emotional memories can be disrupted in depressed subjects using reconsolidation blockade. It will be interesting in future studies to determine if blocking the reconsolidation of memories associated with the negative thoughts and ruminations that characterize depression can improve treatment.”

See also:

Are some Auditory Verbal Hallucinations trauma/fear memories that are amendable via therapy & pharmacologically enhanced reconsolidation/extinction?

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