Cobbers on the Brain

Stress has been associated with Depression for a long time. The occurrence of major negative events over life, especially early life, has been shown to be strongly associated with developing Major Depressive Disorder. However, a mechanism explaining this connection has and continues to elude the scientific community. A recent review article titled From Stress to Inflammation and Major Depressive Disorder: A Social Signal Transduction Theory of Depression proposed A Social Signal Transduction Theory of Depression. Overall, this hypothesis connects stress to inflammation, and then inflammation to MDD. Detailing a mechanism provides a basis for future treatment and understanding of MDD and its development.
The overall goal of this paper was to show that stress can induce inflammation, which can then induce depression-like symptoms. First of all, what is inflammation? Inflammation is the body’s natural immune response in response to a pathogen, injury, or another external stimulus. Our body sends signals from the brain to our immune cells in order to modify protein production, transcription and translation, and create an inflammatory response. The response is the gathering of immune cells to an area and its eventual repair/disinfection.  For our purposes, the stress response to major life events that are known to correlate with depression are important, like social exclusion, loss of job, loss or relationship, etc….What is supposed to happen is seen below, the brain perceives a threat, releases cortisol which prepares the body to deal with the threat by inducing that flight or fight response while at the same time depressing inflammation response. After the threat has been taken care of, the cortisol levels drop and cytokine levels rise (increased inflammation) to deal with the likely injury of said stressful event. What happens in the proposed hypothesis is that glucocorticoid resistance develops in the immune cells of the body. Like insulin resistance in Diabetes, glucocorticoid resistance leads to immune cells not responding to their signal. Effectively, this removes the suppression of inflammation from cortisol released during stressful events. This leads to elevated basal levels of inflammation markers in the body (simply meaning more overall inflammation) due to lack of suppression and can actually lead to increased levels of cortisol. This increase in cortisol has to happen so the body can still maintain the functionality of cortisol through the developing resistance. As you can see, this can turn into a snowball effect. Increased stress and cortisol lead to resistance, resistance leads to the need for higher amounts of cortisol, more resistance and it continues. 

The pairing of inflammation and depression isn’t as straightforward. Because a simple, obvious mechanism of interaction isn’t easy to see, the connection must be shown through large studies and experimentation. The first body of evidence to jump out is that there are several inflammation-related disorders that co-occur with depression, including asthma, arthritis, metabolic syndrome and more. Secondly, elevated levels of inflammatory activity are seen in patients with depression. Certain cytokines present in an inflammatory response can reduce serotonin and other neurotransmitters by decreasing the availability of the precursor. The administration of certain inflammation agents into mice show the development of depression symptoms. Possibly the biggest piece of evidence for this connection is the effectiveness of anti-inflammatory agents in alleviating depression, like aspirin.

The article’s social signal transduction theory is depicted above. First, a social-environmental experience indicating a threat or adversity experience and processed in the brain. Then a brain signal goes out through the hypothalamic-pituitary-adrenal axis (2), sympathetic nervous system (3) and efferent vagus nerve (5).This leads to the production of glucocorticoids (cortisol), epinephrine, and acetylcholine respectively. Glucocorticoids and acetylcholine are anti-inflammatory, and epinephrine is pro. These effects are produced by transcription modification of immune response agents (6). Cytokines then pass through the blood-brain barrier at leaky spots (6). And then finally, cytokine stimulation of primary afferent nerve fibers to the vagus nerve relays info about mood, motor activity, motivation, and much more. This novel mechanism presents a better way of understanding depression, including its development, treatment, mechanism, and interaction with other diseases. Inflammation in the brain is a new topic that is involved in many other disorders beyond depression and further research detailing it and its effect on the brain may open the door for treatment of a variety of illnesses.

Exercise is a familiar phenomenon when it comes to living a healthy lifestyle. The general population understands the idea of exercising for 30 minutes per day along with eating healthy is recommended in order to live a healthy life. Much research and publicity have been put into the benefits of exercise. Some of the well-known benefits include, but are not limited to, mood improvement, an increase in energy, prevention of health problems, as well as memory improvement. With anxiety, exercise has been shown to reduce the perception of stress, be a coping mechanism, and improve mental health in general. Exercise is divided into three categories; aerobic, anaerobic, and flexibility. Each category is further divided into mild, moderate, and intense levels.
Some of the ways stress affect the brain is understood. Stress induces a high concentration of corticosterone hormone in order to decrease inflammation within immune cells in the brain. Within anxiety, however, resistance to corticosterone hormone can be seen within the immune cells in the brain resulting in a need for an even higher concentration in order for a decrease in inflammation. However, there are categories of exercise which have been shown to have different effects within human and animal studies on anxiety.
Mild/Moderate exercise counteracts stress behaviors by changing neural activity, however, the mechanism is not understood yet. This would include exercise like walking, jogging, swimming, lifting, etc. for a shorter period of time than intense exercise. Post-Traumatic Stress Disorder (PTSD) has been linked to reduced hippocampal volume whereas regular exercise has the opposing effect by increasing cognition, working memory, hippocampal neurogenesis, and an increase in BDNF. Military veterans suffering from PTSD show that the majority also have anxiety and/or depression.  A barrier PTSD veterans face for treatment is the stigma, access, and cost for treatment, but an alternative treatment a study completed with veterans suggest exercise as a management option. Within nonveteran patients with PTSD, exercise was also shown to alleviate the symptoms of the disorders, including anxiety and depression.

Intense and/or forced exercise has been shown to have the adverse effect by increasing the stress level within animal studies. Chronic stress is reported to suppress neurogenesis and negatively impact hippocampal function. Stress may lead to stem cells being differentiated into astrocytes rather than neurons within the dentate gyrus of the hippocampus. Therefore, the rate of new neurons decreases.  Intense exercise is defined as above lactate threshold. Lactate has shown a critical role in long-term memory by being involved in growth-factor signalings, such as BDNF, and expression of genes. Studies done with mice show exercise above the LT and exercise forced by shocks resulted in higher stress shown by an increase in corticosterone and adrenocorticotropic hormone concentration and produced lower results for hippocampal neurogenesis in mice. Stress from exercise indicates that exercise benefits have a lessened effect on the management of anxiety. Therefore, intense and/or forced exercise can be shown to lower hippocampal neurogenesis and not help in the management of anxiety through the stress that is caused by an intense and forced type of exercise.

Compared to other mental health disorders, schizophrenia is not very common; however, its symptoms can be incredibly disabling. Schizophrenia is a chronic mental disorder that severely impact a person’s behaviors, thoughts, and feelings. Individuals with schizophrenia are transported into “psychosis,” or a loss of contact with reality.
According to the National Institute of Mental Health, Schizophrenia is characterized by three types of symptoms: cognitive symptoms, positive symptoms, and negative symptoms.
Cognitive Symptoms:

• Poor “executive functioning” (the ability to understand information and use it to make decisions)
• Trouble focusing or paying attention
• Problems with “working memory” (the ability to use information immediately after learning it)

Positive Symptoms:

• Hallucinations
• Delusions
• Thought disorders
• Movement disorders

Negative Symptoms

• “Flat affect” (reduced expression of emotions via facial expression or voice tone)
• Reduced feelings of pleasure in everyday life
• Difficulty beginning and sustaining activities
• Reduced speaking

Comparatively, the negative symptoms of schizophrenia receive less attention than the other types of symptoms, possibly because they are more subtle. However, negative symptoms are the major contributor to low functioning and debilitation in most patients with schizophrenia. Negative symptoms can be categorized into 5 different categories.

Clearly, these symptoms, although not as obvious as positive symptoms like hallucinations or delusions, can have detrimental consequences to a person’s ability to find success in life. For example, one cannot successfully function at school or work if they have poor motivation. In addition, inattention to social cues or unresponsive affect may deteriorate friendships and relationships with family members.
Fundamentally, the three types of symptoms in schizophrenia are caused by two distinct dopaminergic pathways in the brain. Positive symptoms appear when there is too much dopamine in the mesolimbic pathway, spanning from the midbrain to the limbic system. On the other hand, negative symptoms and cognitive symptoms develop from not enough dopamine in the mesocortical pathway, spanning from the midbrain to the cerebral cortex.

Dopamine is one of the major excitatory neurotransmitters in the brain. So it makes sense that too much activity between synapses in the mesolimbic pathway of schizophrenic patients results in seeing or hearing things that aren’t there. Similarly, it is reasonable that too little dopamine in the mesocortical pathway of schizophrenic patients causes depressive and lethargic behaviors.
The dichotomy of the etiology of these symptoms make it difficult to treat the disorder. The first drugs to treat schizophrenia are called “first generation” antipsychotics (ie. chlorpromazine and haloperidol). These antipsychotics are effective at treating the positive symptoms of schizophrenia, but they have negative side effects and do not effectively treat negative or cognitive symptoms.
A second generation of antipsychotics, called “atypical” antipsychotics, were an improvement in severity of side effects and treatment of negative symptoms (ie. Clozapine). treatment does not impact the negative symptoms present in schizophrenia.
Atypical antipsychotics, however, improve negative symptoms by about 25%, compared with 10 to 15% improvement with first generation agents, according to a 2002 study in Current Psychiatry. Even still, the debilitating effects of negative symptoms persist in patients with schizophrenia with the current treatment available.
All in all, one may never know the grim effects of schizophrenia until they experience the disorder first- or second-hand. Some of the most debilitating symptoms of schizophrenia remain untreated in many patients, and further research needs to be conducted to better understand the mechanisms of schizophrenia’s development.

It is safe to say that Schizophrenia is one of the most mysterious, misunderstood, and feared mental disorders today- both scientifically and socially. As our medical world is rapidly advancing, the search for the driving mechanism of action and effective treatments for this disease are being researched studiously. Even with current medicinal treatments though, the complexity of this disease still challenges researchers today. Similarly, as a mental disorder that often leads to social isolation, decreased ability to live independently, and odd behaviors, stigmatizing attitudes about Schizophrenia are incredibly common among society today.
However, far beyond all the intricate scientific details, lost in the darkness of stigmatizing beliefs, is a normal human being, deserved to be treated like any other.
Background
Schizophrenia is a severely debilitating mental disorder that affects how a person thinks, feels, and behaves. According to the National Institute of Mental Health (NIMH), approximately 1 in 100 people have Schizophrenia, which equates to about 26 million people worldwide. There are three types of symptoms that individuals with Schizophrenia can experience: positive, negative, and cognitive. Some of the most common include hallucinations and delusions, flat affect and withdrawal from social activity, and trouble with organization of thoughts and memories.
Though we know a lot of Schizophrenia, there are still many common misconceptions today that place a negative view on those suffering from the disorder. Three of the most popular and stigmatizing myths are discussed below.
Myth 1: People with schizophrenia are dangerous.
Most people with Schizophrenia are not violent, and most violent crimes are not committed by those with Schizophrenia. Of the little violence committed by those with Schizophrenia, it is often due to the individual having another comorbid disorder such as Substance Abuse Disorder and those with a past of Childhood Conduct Disorder. The real concern is the number of individuals with Schizophrenia that are a harm to themselves. It is estimated that 1 in 10 individuals suffering from Schizophrenia will take their own lives, with even more
Myth 2: People with schizophrenia are not smart.
Though some studies have supported the idea that individuals with Schizophrenia have more trouble on mental tasks such as attention, learning, and memory, there are also a number of studies that are looking at links between psychosis and creativity. Similarly, there have been many successful and intelligent individuals who become diagnosed with Schizophrenia, and in years later maintain their same IQ from before diagnosis.
Myth 3: People with schizophrenia alienate themselves.
Schizophrenia has been described as the most alienating disease. Social isolation is a common symptom of Schizophrenia and can either be connected to their psychosis, or due to the experience of anhedonia. However, just because it is a common symptom, does not always mean it is by choice that they isolate themselves. With the right encouragement, social interactions can be incredibly helpful, specifically in keeping individuals with Schizophrenia connected to reality.
 
So, I dare you. Next time, before you are quick to judge, just think.
 
What would it be like to experience the constant noise of inner voices that will not leave you alone? What would it be like to believe that you are constantly being tricked or fooled by the people surrounding you? And what would it be like to know that some people think you are crazy?
 
As Dr. Seuss once said, “A person’s a person, no matter how small.”