We’ve written before that the dietary supplement citicoline improved depression in both unipolar and bipolar patients with methamphetamine dependence, reduced cocaine use in bipolar depressed patients with cocaine dependence, and improved cognition in healthy middle-aged women. Findings from a 2013 Italian study by Gareri et al. published in Clinical Interventions in Aging suggests that citicoline improves mild vascular cognitive impairment in older adults, though the study was not randomized, so its results may not be reliable. Citicoline is a natural substance found in the brain and the liver that can also be taken as a nutritional supplement.
The study examined 349 patients over age 64 (mean age 79.9) who had memory impairment and evidence of vascular lesions in the brain (but not Alzheimer’s disease). Participants who received citicoline (500mg twice daily for 9 months) scored better on a memory examination at 3 months and at the completion of the study, while participants who did not receive citicoline performed worse on the exam. Those who received citicoline also saw some statistically non-significant improvement in mood.
The researchers believe that citicoline’s effects may also extend to Alzheimer’s dementia because citicoline contributes to the synthesis of acetylcholine. (Most Alzheimer’s drugs inhibit the breakdown of acetylcholine).
Side effects were minimal, and included occasional excitability or restlessness, digestive intolerance, and headaches.
German researchers have found that MDMA (ecstasy) users who took more than 10 pills in a one-year period showed deficits in visual memory. Wagner et al. published the study in the journal Addiction in 2012.
In tests where participants were trained to associate certain words with certain images and then recall one in response to the other, those who had taken ecstasy at least ten times the previous year showed deterioration in both their immediate and delayed recall skills.
Given the role of the hippocampus in relational memory, the researchers suspect that there is a relationship between ecstasy use and hippocampal dysfunction.
Editor’s Note: This is the most definitive study on this subject so far because it observed new users before and after they had used ecstasy for at least 10 times in one year (unlike many retrospective studies that observed participants only after they had been using the drug for some time, so it was impossible to know if they had pre-existing memory problems).
Other data in animals and humans suggest that ecstasy burns out the terminals of serotonergic neurons and thus causes brain damage. It now appears this damage to the brain and memory can occur even during short-term or casual ecstasy use.
New research shows that cocaine, defeat stress, the rapid-acting antidepressant ketamine, and learning and memory can change the size, shape, or number of spines on the dendrites of neurons. Dendrites conduct electrical impulses into the cell body from neighboring neurons.
Several researchers, including Peter Kalivas at the Medical University of South Carolina, have reported that cocaine increases the size of the spines on the dendrites of a certain kind of neurons (GABAergic medium spiny neurons) in the nucleus accumbens (the reward center in the brain). This occurs through a dopamine D1 selective mechanism. N-acetylcysteine, a drug that can be found in health food stores, decreases cocaine intake in animals and humans, and also normalizes the size of dendritic spines.
Depression in animals and humans is associated with decreases in Rac1, a protein in the dendritic spines on GABA neurons in the nucleus accumbens. Rac1 regulates actin and other molecules that alter the shape of the spines.
In an animal model of depression called defeat stress, rodents are stressed by repeatedly being placed in a larger animal’s territory. Their subsequent behavior mimics clinical depression. This kind of social defeat stress decreases Rac1 and causes spines to become thin and lose some function. Replacing Rac1 returns the spines to a more mature mushroom shape and reverses the depressive behavior of these socially defeated animals. Researcher Scott Russo has also found Rac1 deficits in the nucleus accumbens of depressed patients who committed suicide. Russo suggests that decreases in Rac1 are responsible for the manifestation of social avoidance and other depressive behaviors in the defeat stress animal model, and that finding ways to increase Rac1 in humans would be an important new target for antidepressant drug development.
Another animal model of depression called chronic intermittent stress (in which the animals are exposed to a series of unexpected stressors like sounds or mild shocks) also induces depression-like behavior and makes the dendritic spines thin and stubby. The drug ketamine, which can bring about antidepressant effects in humans in as short a time as 2 hours, rapidly reverses the depressive behavior in animals and converts the spines back to the larger, more mature mushroom-shape they typically have.
Learning and Extinction of Fear
Researcher Wenbiao Gan has reported that fear conditioning can change the number of dendritic spines. When animals hear a tone paired with an electrical shock, they begin to exhibit a fear response to the tone. In layer 5 of the prefrontal cortex, spines are eliminated when conditioned fear develops, and are reformed (near where the eliminated spines were) during extinction training, when animals hear the tones without receiving the shock and learn not to fear the tone. However, in the primary auditory cortex the changes are opposite: new spines are formed with learning, and spines are eliminated with extinction.
Editor’s Note: It appears that we have arrived at a new milestone in psychiatry. In the field of neurology, changes seen in the brains of patients with strokes or Alzheimer’s dementia have been considered “real” because cells were obviously lost or dead. Psychiatry, in comparison, has been considered a soft science because neuronal changes have been more difficult to see and illnesses were and still are called “mental.” Now that new technologies have made a deeper level of precision, observation, and analysis possible, we know that the brain’s 12 billion neurons and 4 times as many glial cells are exquisitely plastic–capable of biochemical and structural changes that can be reversed using appropriate therapeutic maneuvers.
The changes associated with abnormal behaviors, addictions, and even normal processes of learning and memory now have clearly been shown to correspond with the size, shape, and biochemistry of dendritic spines. These subtle, reproducible changes in the brain and body are amenable to therapeutic intervention, and are now even more demanding of sophisticated medical attention.
Synthetic marijuana, otherwise known as spice, skank, or K2, is not only vastly more potent than the tetrahydrocannabinol (THC) in marijuana plants, but it also lacks cannabidiol (CBD), the calming, antipsychotic substance also present in the plants. This makes spice much more likely to induce major psychiatric effects.
New evidence links use of spice during pregnancy to a tragic birth defect, anencephaly, or absence of the cerebral cortex. It can also lead to the later development of attention-deficit hyperactivity disorder, learning disabilities, memory impairment, depression, and aggression.
Effects of THC on gestation may occur as early as two weeks after conception, meaning by the time a woman realizes she is pregnant, the fetus may have been harmed by exposure to the drug.
Other new finding associate use of spice with acute coronary syndrome and the kind of acute kidney injury that can lead to the organ shutting down.
Editor’s Note: It has now been found that synthetic marijuana, or spice, can lead to psychosis, delirium, acute coronary syndrome (heart attack) in young people, and now kidney dysfunction, in addition to causing birth defects if used by pregnant women. Not only is spice made up of more potent THC without the calming effects of CBD, but it is often laced with unknown contaminants, which are likely the cause of the heart and kidney damage.
Smoking regular marijuana is bad enough—it doubles the risk of psychosis and may precipitate the onset of schizophrenia. It may also cause long-lasting effects on cognitive function. Since many states are legalizing marijuana, it is important to know the risks. In any case the risks are much more serious with the synthetic product, and synthetic marijuana should be avoided at all costs.
As young mice transition into adolescence, they experience a “sensitive” period in which their context-based fear memories are temporarily suppressed. In a recent study, young animals learned to avoid an environment associated with a mild shock. Later, when they entered adolescence, this learning was temporarily forgotten or suppressed. However, when the same mice aged into adulthood, they reacquired this learned fear memory and began to again avoid the environment associated with the earlier shock. This temporary loss of fear memory differs in mice depending on their genes.
At the 2012 meeting of the Society of Biological Psychiatry, researcher Francis S. Lee reported that mice with a certain genetic variation display an impairment of this fear memory process. There are several common variants of the gene responsible for the production of brain-derived neurotrophic factor (BDNF), which protects neurons and is necessary for long-term memory. Mice with the poorer functioning variant known as Val66Met (as opposed to the better functioning Val66Val) fail to recall the earlier fear-related events not only in adolescence, but also in adulthood when the fear memory is usually retrievable again.
Editor’s Note: In mice and humans, Val66Val is the most frequently occurring allele in the population, but Val66Met is also a fairly common variation of the BDNF gene. It is this Val66Met allele that is associated with not retaining earlier learned experience about a “dangerous” environment that should be avoided.
These data suggest an intriguing explanation for some of the “wild” behavior and poor judgment to which even the smartest adolescents are prone. This kind of behavior may be based in part on the temporary forgetting in adolescence of earlier learning about which situations or environments are safe versus which ones are dangerous. Read more
In last week’s article we discussed how fearful memories can be changed during the window in which they are reconsolidated (5 minutes to 1 hour after active recall of the long-term memory). Now the memory reconsolidation window has been used in animals and people to extinguish an addiction to cocaine or heroin. The results in humans were reported by Xue et al. in the journal Science in April 2012.
In a typical recovery scenario, a cocaine addict is repeatedly presented cocaine cues (such as paraphernalia) without the delivery of cocaine, and craving for cocaine becomes extinguished. While the patient stops craving the drug, some biological signs of the addiction remain, such as autonomic hyper-reactivity (e.g. changes in skin conductance, pulse, or blood pressure) in response to the cocaine cues. When the sober cocaine addict leaves the recovery program, he may believe he is no longer subject to cocaine craving even upon the sight of cocaine-related cues, but this craving can return spontaneously or be reactivated by cocaine-related environments or friends who were also users, and he typically relapses.
In order to make the extinction learning more powerful, it must be experienced during the reconsolidation window. In the animal experiments by Xue et al., rodents were trained to press a lever to receive an injection of cocaine or heroin. In the extinction process, the animals were returned for 15 minutes to the same environment where they had learned to press the lever and receive the drug. This was meant to activate memories associated with the drug. Then, after a 10-minute waiting period, a 180-minute extinction training was given. The process was repeated daily for 14 days and resulted in almost complete absence of relapse to drug use with passage of time (spontaneous recovery), exposure to the drug (reinstatement), or exposure to the drug-associated environment (renewal). Moreover, the expected changes in heart rate and blood pressure upon re-exposure to the drug cues were also fully extinguished. Extinction training that began one hour after activation of the memory was also successful.
When the same extinction training was given 6 hours after placing the animal in the drug administration environment, the animal remained prone to drug re-instatement and relapse in the same or different environments or spontaneously. It can be presumed that this occurred because the extinction training took place after the reconsolidation window had closed.
These well-controlled data with both cocaine and heroin self-administration in animals were then taken to the clinic to test their validity in humans.
The same procedure worked in humans addicted to heroin. Two consecutive days of sixty-minute extinction learning within the reconsolidation window, i.e. starting 10 minutes after a 5-minute retrieval of drug-associated memories by watching a video resulted in amelioration of drug craving for at least 184 days, and amazingly, as in the animals, also resulted in the loss of the unconscious biological reactivity in heart rate and to a lesser extent, blood pressure. Patients did not relapse during 6 months of followup. The same extinction process was unsuccessful when it occurred outside of the reconsolidation window, i.e. 6 hours after retrieving the drug-related memories.
Editor’s Note: These results could be of considerable potential therapeutic value in a variety of psychiatric illnesses. This process is conceptual breakthrough that has great promise for clinical use. Psychiatrists, psychologists, and patients should become familiar with these data and the principles of exploiting the reconsolidation window for potentially transformational results.
How quickly these principles can be incorporated into mainstream psychotherapeutic encounters remains to be seen. However, clinicians should begin to familiarize themselves with these data and concepts so that they can soon be put to use for more effective clinical treatment of psychiatric conditions involving pathological learning, conditioning, and habits.
Opening The Reconsolidation Window to Extinguish Fear Memories: A New Conceptual Approach to Psychotherapeutics
Memory processes occur in several phases. Short-term memory is converted to long-term memory by a process of consolidation that requires the synthesis of new proteins. Transcription factors in the nuclei of hundreds of millions of nerve cells are activated so that specific synapses can be modified for the long term. If protein synthesis is inhibited during a period within a few hours after new learning has occurred, what was learned never gets consolidated and is essentially forgotten. It is thought that this phase of consolidation happens when a memory trace moves from short-term storage in the hippocampus to long-term storage in the cerebral cortex.
Recently a later phase of memory storage called reconsolidation has been identified. When an old memory is recalled, the reconsolidation window opens, and the memory trace becomes temporarily amenable to change. The reconsolidation window (the period during which the trace can be revised) is thought to begin five minutes after a memory is recalled and last for an hour or possibly two. New learning that takes place during the reconsolidation window can be more profound than learning that occurs without recall of the related memory or after the reconsolidation window has closed.
Consider the example of a fearful memory created when a person is attacked in a dark alley. If the person repeatedly visits the same alley without being attacked, they can eventually become less afraid of dark places. Repeated viewing of pictures of dark places can also extinguish the fear. These are typical ways in which a fear memory is extinguished. However, the original fear is subject to spontaneous recovery (the fear of dark places returns without provocation) or to reactivation (if another dangerous situation is encountered, the person may regain their fear of dark alleys).
The new findings suggest that if the extinction process (the repeated exposures to the pictures of the dark alley) takes place during the reconsolidation window after the fear memory of being attacked is recalled, the old fear can be permanently reversed (wiped clean, or re-edited such that it appears forgotten) so that it is no longer subject to spontaneous recovery or reactivation.
Editor’s Note: To accomplish extinction training within the reconsolidation window, first a person must actively recall the old memory, opening the reconsolidation window. Then, after a 5-minute delay, extinction training (e.g. new learning that the old feared place is now safe) should take place within the next hour. This process has been demonstrated in animal studies and is thought to be clinically relevant for humans in the case of phobic anxiety and post-traumatic stress disorder (PTSD). The psychotherapeutic implications of using the reconsolidation window to better ameliorate PTSD fears, avoidance, and flashbacks are enormous.
Observing the Amygdala’s Role in the Extinction of Fear Memory Traces
The amygdala is a crucial part of the learned or conditioned fear pathway. It is activated during fear conditioning and during the recall of cues associated with the fear experience. If the amygdala is removed, conditioning fear does not occur.
A new study published in Science this year by Agren et al. indicates that in humans, the amygdala-based response to conditioned fear can be completely abolished using extinction training within the memory reconsolidation window. Training that took place 10 minutes after the fear memory was activated was successful, while training that took place 6 hours later was not. Read more
Anti-Alzheimer’s Drug Memantine (Namenda) Has Positive Effects On Cognitive Dysfunction In Patients With Bipolar Disorder
Many patients with bipolar disorder experience cognitive dysfunction, but few treatments are available for this aspect of the illness. In an abstract presented at the 67th Annual Meeting of the Society of Biological Psychiatry in 2012, Dan V. Iosifescu reported that in a randomized 12-week study in which the anti-Alzheimer’s drug memantine was given to 72 euthymic bipolar subjects experiencing cognitive deficits, the drug was associated with improvement in spatial and working memory, verbal and episodic memory, and other indices that included measurements of attention and language skills. In conjunction with this treatment, a subgroup of subjects had increases in left hippocampal NAA (a measure of neuronal viability) and increases in choline in the right hippocampus. The initial improvements in these neuropsychological test results remained over 12 weeks of open follow-up.
Editor’s Note: These data are of considerable importance. Many studies indicate that the severity of the cognitive dysfunction patients experience while euthymic varies directly as a function of the number of prior episodes of mania or depression they have experienced. The degree of cognitive dysfunction in patients with bipolar disorder is also correlated with disability in social and economic functioning. Thus, the data that memantine can lead to improvement in several types of memory tests suggest that the drug could be useful in treating these deficits in some patients with bipolar disorder.
Memantine acts in part by blocking glutamate NMDA receptors and provides a different mechanism of action compared to the other drugs used to treat Alzheimer’s, which increase acetylcholine by blocking acetylcholinesterase.
Memantine has also shown promising effects in enhancing the antidepressant effects of lamotrigine, a drug that inhibits glutamate release. Thus, the similar target of action by which lamotrigine (blocking glutatmate release) and memantine (blocking glutamate receptors) operate suggest that the two drugs used in conjunction might produce additive effects in decreasing glutamate function. The current data suggest that memantine compared to placebo as an add-on to other agents in euthymic bipolar patients improves several measures of cognition as well.
New data published by Koukopoulos in the Journal of Affective Disorders in 2012 suggest that memantine (10-30mg/day) is an effective add-on treatment in severely ill patients with treatment-resistant bipolar disorder. Among those in Koukopoulos’ study, 72.5% were much or very much improved, thus there is a strong rationale for considering this drug.
Memories are created in a series of phases in which different neurobiological mechanisms are required. In order for short-term memories to be placed in long-term storage, new protein synthesis is required. If protein synthesis is inhibited during a window about 2-4 hours after the short-term memory was encoded, consolidation into long-term memory does not occur.
In addition to the initial phase of memory consolidation, a second phase of memory reconsolidation is now recognized. During this phase, memory is again alterable.
The alterability of memories has implications for some types of post-traumatic stress disorder (PTSD), in which emotional memories repeatedly intrude into consciousness. Pharmacological intervention during the period of memory reconsolidation may be able to reduce the impact of traumatic memories.
One example of an attempt to alter memory consolidation or reconsolidation after trauma has been reported by researcher Ariel Shalev and colleagues. These researchers found that administration of a high dose of intravenous cortisone (100 to 240mg) immediately following an extreme trauma was able to decrease the incidence of PTSD. One month after a traumatic event, the incidence of PTSD was 60% in those who received placebo, compared to only 16% in those who received the intravenous cortisone.
A recent study found that in rodents, new negative memories can be deleted. Rats in the study were taught conditioned avoidance. For example, a light or a sound would signal that a mild shock would be delivered through the floor of the chamber in which the rat was housed. The rat could avoid the shock by running to the other side of the cage. Once the rat learned that the light or sound signal preceded a shock, the rat began switching sides when the light or sound cue appeared, even if no shock was given. This response to the conditioned signal is evidence that learning has taken place and is stored in memory.
The researchers found that when a rat formed a new conditioned avoidance memory, there were increases in cyclic AMP response element binding (CREB) protein in specific neurons in the rat’s lateral amygdala (about 20% of the total number of neurons in the amygdala). Then, using extraordinarily sophisticated molecular biology, the investigators attached a diphtheria toxin onto the CREB protein, which caused the specific neurons involved in the conditioned avoidance learning to be killed while the other neurons in the amygdala (those not associated with the new memory) survived. As a result, the animals couldn’t remember anything about the specific avoidance learning, but other memories could be formed and remained accessible.
Obviously, this type of approach is not yet pertinent to clinical therapeutics in humans, but this research does teach us that in rodents, a conditioned avoidance memory activates a subset of the neurons in the lateral amygdala, and the elimination of these neurons eliminates specific learned memories, but not other types of learning.
Ultimately this kind of preclinical data may lead to novel clinical approaches to specific traumatic memories that are associated with post-traumatic stress disorder (PTSD).