Whether you learned about it in school or from the movies, schizophrenia is known about in pop culture for its wild symptoms. As a schizophrenic, being able to conjure up a person so vividly that they think they are seeing a real person that they can have a conversation with was bound to end up in a movie executives lap at some point. Having hallucinations such as these are part of the “positive” symptoms, or things that have been added on to normal everyday, schizophrenic life. There are also negative symptoms, which are a lack of doing something, such as depression or a lack of facial emotivity. Both of these kinds of symptoms have been hallmarks of the disorder for well over a century, and so treatment has also been experimented on for about as long. 

Lithium (yes, the element, in pill form) has been used as a treatment for schizophrenia since at least the late 19th century. It didn’t become a scientifically-based treatment until 1949, and then took another 20 years to get approval from the FDA. The fact that it wasn’t scientifically recognized didn’t stop it from being an effective treatment well before 1949 though, and amazingly, it is still used to this day as one of the most effective treatments for schizophrenia.

This speaks to one of two things. We as a society have either lagged behind in research and development and haven’t been able to adequately come up with, discover, or create a better treatment than lithium, or we luckily discovered one of the best treatments possible for schizophrenia patients early on (way before a lot of medicinal updates) and so to this day it still works as an adequate treatment option that works well. The truth is closer to the second one, of course we’ve come up with more treatment options; we’ve been able to create synthetic antipsychotics that certainly do their job, all thanks to modern medicine. Lithium however, has stood the test of time, continuing to be one of the most effective, responsive treatments for schizophrenia. 

Wnt signalling, a pathway for gene transcription among other things, is influenced by lithium. Lithium works to inhibit GSK3β, which is one of the principal problems discovered within schizophrenia. Overactive GSK3β means a lessened TCF/LEF-transcription factor output, of which lithium can mediate to increase transcription and alleviate the severity of schizophrenic symptoms. This is the mechanism by which lithium acts, but what are some of the other treatments for lithium, and what makes it so effective?

Drugs that treat schizophrenia are often overlapped with bipolar disorder, because the drugs work for both disorders. Comparing the 4 drugs that are commonly used for both, which include lithium, Valproate, Olanzapine, and Quetiapine, lithium can be found to display several benefits. Effective treatment of schizophrenia can be characterized by the ability to take the drug for as long as possible without the downsides of the side effects outweighing the benefits of the drug itself. When a drug is stopped due to this effect, it’s known as treatment failure. Lithium, when compared to the other 3 drugs here, had the longest treatment failure times. It also appeared to be the most effective treatment to prevent relapse or recurrence of bipolar disorder and may prolong the time before complimentary prescribing is necessary.

On that note, a meta-analysis was done on 20 different studies that looked at the effectiveness of lithium and found that as a sole agent, lithium wasn’t as effective as when prescribed with another drug for treating schizophrenia. This is referred to as lithium augmentation, and although some sources disagree, most confirm that this method is the best way to treat either of these disorders. 

There are almost no other drugs that can be said to have been the most effective drug for a disorder for over 150 years, but lithium is in that category. 

Role of Hippocampus:

The hippocampus is a region in the brain located between the inner folds of the temporal lobe. This region plays an especially important role in the formation of two specific types of memories. These include spatial relationship and declarative memories. Spatial relationship memories help us derive directions whereas declarative memories are related to the facts and events. These two types of memories help transform short term memories into long term memories and then they will be stored elsewhere. More information on the role of the hippocampus and memory can be found at https://www.positivemed.com/2018/06/02/role-of-the-hippocampus/.

How the Hippocampus Relates to Anxiety:

The hippocampus is an important area to look at when studying anxiety. When an individual undergoes chronic anxiety, they have an increase in glucocorticoids which are hormones that contribute to the flight or fight response. This increase in glucocorticoids causes a raise in cortisol levels which ultimately impairs the fragile hippocampus.

One major impairment to the hippocampus from chronic anxiety is the decrease in this regions size. Many studies have proven that individuals undergo a shrinkage of their hippocampus if they are under sever anxiety. Decreasing of size in any area of the brain is not ideal and, in this case, memory formation becomes extremely hard. When one loses volume in their hippocampus, that means they also lose storage space for all the memories that are within the spatial relationship and declarative memory categories. These memories are often used to pull certain events together and create a memory. Less volume equals less memories formed.

Alzheimer’s Disease and Anxiety:

Following the chain of events within anxiety we can trace our way to Alzheimer’s disease. Individuals with Alzheimer’s disease struggle with memory formation and retrieval. To no surprise the hippocampus is playing a large role in this disease. Those with Alzheimer’s also show a decrease in volume to their hippocampus. It is no coincidence then that individuals with anxiety are more likely to develop Alzheimer’s.

Can You Grow What Has Been Lost?

After reading about the negative impacts anxiety has on the hippocampus region of your brain, one questions the possibility of healing. When chronic anxiety levels have become so high that physical volume in your brain starts to decrease, what can one do to help? Although treatments are subjective to the individual, researchers passionately believe that you can slowly grow volume size back. Through Exercise one can start to create new hippocampus neurons which ultimately leads to increase of size. Exercising with the balance of a good diet will help increase the hippocampus. Studies also show that challenging yourself with brain training will also help memory function and increase volume in the brain region. More information of the explanation of these “treatments” can be found at https://www.growthengineering.co.uk/train-your-hippocampus/.

Conclusion:

Overall, it is evident the severe complications anxiety can cause. With the increase of glucocorticoid and cortisol levels, the hippocampus Is proven to shrink. Shrinkage in this region of the brain leads to memory formation issues which later on can cause further complications such as Alzheimer’s disease. Trying to avoid the difficulties of anxiety can be very tough but one can help themselves which some daily changes.

Your heart rate spikes and yet you experience a shortness of breath. Your mind is overwhelmed with fear-filled stimulus. Your chest resists expansion and your lungs burn as your muscles ache for oxygen. An unbearable sense of dread floods your entire being. You may be experiencing an anxiety attack, one of many anxiety disorders. These include panic attacks, obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD). Let’s take a step over the edge into the depths of anxiety.

Ground Level

Anxiety is a result of Intense psychological stress which may induce physical/behavioral alterations as a result of changes in hippocampal brain function brought about by complex molecular signaling pathways.

There are interconnections between stress, behavior, and memory where stress plays an important role in long-term memory formation. Because memory and its formation are critical for our interactions with our environment and crucial to our survival (such as remembering a terrifying experience with peanut allergies from your past), stressful events induce the formation of long-lasting memories. These memories then influence our behaviors within our environment such as avoiding the peanut-butter and jelly sandwich a stranger handed you.

The Depths

Through the usage of rodent models and well-established stress-inducing experiments, the molecular mechanisms governing the observed changes related to stress and memory have been explored.

To briefly summarize the detailed pathways and mechanisms leading to anxiety and the formation of associated long-term memories, these events are closely related to glucocorticoids, MAPK, NMDA, and GABA, neural signaling pathways, which are all related to stress, behavioral changes, and long-term memory.

Recap

Subjection of individuals to traumatic or hyper stressful situations specifically early on in their development makes them more likely to develop anxiety disorders especially PTSD and is a result of an inability to properly cope with intense stresses. The link between stress, behavioral response, and memory is revealed, as aforementioned, through the interactions of glucocorticoids, NMDA, MAPK, and Gabaergic driven neural pathways in the regulation of gene transcription within the limbic system. Any disruptions to these pathways can result in stress-related disorders including PTSD. To summarize, a cascade of molecular interactions between several proteins and their effectors results in an increased Histone mark (H3S10pK14ac) which then encourages the stress induced transcription of two genes fos and erg1 which produces proteins important in the process of memory formation.

Relief

Further exploration and a deeper understanding of these mechanisms could lead to therapeutic treatments for stress-related disorders and shed light on the complex mechanisms that govern the link between stress, behavior, and memory.  the link between psychological stress, the changes in behavior, and the effects on memory is an important subject of investigation as it could yield potential therapeutics with intentions of relieving individuals of their symptoms or the disorder completely.

Memory is one of the most useful tools we have at our disposal. I’m sure you can come up with (from memory) countless examples right now of how memory has helped you live a better life than if you didn’t have it. Where did I last put my keys? How do I get to Target from here? What was that person’s name? All of these instances are incredibly useful for navigating everyday life, but there are also some times when memory is hindered, and for good reason. 

When in immediate danger, things can be a blur, and after the fact it can be hard to remember a  lot of the actual occurrences of the moment. It might seem counterintuitive at first to not be able to remember what transpired during a time of panic, but it does make a lot of sense evolutionarily. Flight or fight activates to allow you to survive immediate danger, and that means escaping or fighting. That doesn’t mean remembering the layout of the prowling tiger’s stripes, or what shade of grey the boulder was that was falling towards you from the cliffside. Memory in itself is important to survive, but if it happens to be the source of hindrance in which other things become more important in that moment in order to survive, it makes sense that it will be temporarily disabled. 

A phenomenon called LTP (Long-term potentiation) is what neurologically allows us to engage in a number of memory-related behaviors. LTP is thought to be one of the main components of storing long-term memories and is present in the brain’s ability to learn. The hippocampus, and specifically the dentate gyrus (DG) within the hippocampal formation, is crucial for memory formation through the use of LTP.

When stress is present, the ability to encode information (memory-wise) seems to be diminished, but several factors have to be addressed in order to further understand the relationship here. There are different types of stress, and which kind it is matters in trying to ascertain its impact on memory. Acute stress and chronic stress are the two main types that are mentioned in research, both names being self-explanitory. When either of the two types are present, LTP is virtually eliminated. There are some differences however: In chronic stress, LTP signalling in the hippocampal area of CA1 is imparied, while it has no effect on dentate gyrus function, though there have been other studies that showed the DG being imparied, specifically with unpredictable stress. In acute stress, signalling is a little more complicated, with some regions being facilitated with LTP, like the ventral hippocampus, while the dorsal hippocampus is inhibited. This speaks to the complexity of the task at hand of trying to discern the effect that stress has on brain systems. 

Animal models for different neurological disorders, such as Alzhiemers disease and post traumatic stress disorder, have been trying to figure out the relation between the two, with interesting results. In AD animal models, there is naturally imparied LTP functioning, simply as a result of the degeneration. What was found with these animal models is that acute stress actually facilitates LTP, which is notable as this the opposite of normal, healthy brains. In PTSD animal models, researchers found that a single prolonged stress (SPS) induced LTP-like deficits in the hippocampus and amygdala, but there was an increase in contextual fear response memory. 

There is certainly more to learn in this domain of research, but enough is known in the present moment to make informed decisions about the links between stress and memory.