New Neurons in Your Narco Brain

 

When I first was diagnosed with narcolepsy, I was devastated. I had put together the story that was being told about my brain: probably autoimmune, neurodegenerative, and sorry but you will be this way for the rest of your life.  The assumption that there is a neurodegenerative loss of hypocretin/orexin-secreting cells of the hypothalamus in narcoleptic brains is probably not totally inaccurate.  Throughout the course of my research, however, I became convinced that an underlying food intolerance could mediate the autoimmune process;  if I cut out the food I was intolerant to, I could turn off that process and cool my brain down. And it worked. A month after going gluten free, my symptoms of narcolepsy disappeared.

Even though I was excited to not be tired anymore, I was concerned about this supposed neurodegeneration that was happening in my brain. Even as a scientist, I was taught all throughout school that once you lost a neuron, that was it. Game over. No new neurons for you. However, at the time, there were a few studies coming out demonstrating how aerobic exercise could promote neurogenesis.  So — I started running. As I run, I like to image the little dendrites of the hypocretin-secreting neurons I do have left reaching out and making new connections, restoring my narco brain to something not handicapped by some mysterious autoimmune process.

The plan was (and still is) simple: 1) stop all future neurodegeneration by turning off the autoimmune and inflammatory processes (this was made possible by going gluten free), and 2) promote new neuronal growth by exercising every day.

All of that was fine and dandy, but as a rational person, I needed some proof. What if the current view was right? There was always a crippling fear in the back of my mind that I was wrong. That somehow, someway, the narcolepsy was going to win.

I lived with this fear, until I read this paper: Adult Neurogenesis in the Hypothalamus. And there it was. I could stop the inflammation with a gluten free diet, and make new neurons in areas that I thought may have been completely ablated. The realization that we all in fact have the potential to make these new neurons is nothing but relief.

It means, without a doubt, that once you turn off the inflammation, you can turn your brain back on. 

Narcolepsy gene in a celiac patient.

As many of you know, autoimmune diseases are generally complex diseases, where people on a certain genetic background (i.e. those whore are “predisposed”) come into contact with environmental triggers and eventually develop autoimmune disease.

Particularly important for autoimmune diseases, the genetic predisposition seems to lie within a region of our genes called Human Leukocyte Antigen or HLA for short. Narcolepsy has one of the highest genetic (HLA) associations, with more than 90% of individuals with narcolepsy possessing the MHC clas II gene HLA DQB1*0602.  

Celiac disease is also shown to be associated with certain HLA genes, in particular with MHC class II HLA-DQ2.  In this recent study, a patient with confirmed celiac disease was demonstrated to have the narcolepsy gene DQB1*0602.

Schizophrenia, autoantibodies and responses to gluten

 

Schizophrenia is a complex disease that many of us are peripherally familiar with, at least in part. For many of us, the term “schizophrenia” conjures up images of people talking to themselves, ranting and running naked in the park.

So why are we talking about it on Autoimmune Patient?  

Schizophrenia is not definitively recognized as an autoimmune disease, but it warrants attention here because there is increasing evidence that it may share some autoimmune etiology. Like all autoimmune diseases, there seems to be a genetic component to schizophrenia, although one responsible gene has not been found, indicating that environmental factors play a role in the development of the disease.  Celiac disease has long been suspected a being connected with schizophrenia, but a common link has yet to be found.

In the first place, at least for men, schizophrenia tends to appear in late adolescence/early adulthood, a feature that is also shared by many autoimmune diseases including multiple sclerosis, lupus, autoimmune thyroid disease, and narcolepsy, just to name a few.

Secondly, autoantibodies to various receptors (muscarinic, nicotinic, dopaminergic, and NMDA) are found in schizophrenia, and there is a strong association with schizophrenia and the risk of developing other autoimmune disease.   In a recent study, individuals with schizophrenia were reported to have an increased risk of Graves disease, psoriasis, autoimmune anemia, Sjogren’s syndrome, myasthenia gravis, and celiac disease.

More recently, it was discovered that individuals with schizophrenia elicit distinct immunological reactions to gluten that are clinically distinct form those reactions seen in celiac disease, and not controlled by the canonical “celiac disease genes” HLA DQ2/DQ8.

 

Eating Disorder and Metabolism in Narcoleptic Patients

In the recent article, Eating Disorder and Metabolism in Narcoleptic Patients, it was shown that the energy balance of narcoleptic individuals was impaired compared to healthy individuals.

It had been long reported by doctors that their narcoleptic patients tended to be overweight compared to other patients, and that patients tended to have a higher BMI (body mass index) “regardless of whether they were treated with drugs increasing appetite, and regardless of whether they had cataplexy.” More importantly, not only are narcoleptics more overweight than the “healthy” control population, but they are also more overweight than their family members, suggesting that the etiology of obesity and narcolepsy extends beyond a familial predisposition to be a little bit thicker.

In the hypothalamus, hypocretin neurons are found in the region of the brain called the feeding center, and when it was found that narcoleptics have a reduction in hypocretin-producing neurons in the brain, it was then suggested that metabolic functioning may also be impaired.  In the paper reviewed here, the authors set out to determine energy expenditure in more than 500 narcoleptic patients. Some patients had cataplexy, while some did not, but all were not taking any treatments at the time of the study for their narcolepsy.

Overall, they found that:

1) Narcoleptics tended to have a higher median BMI.  That is to say, we narcos are usually fatter.

2) Narcoleptics have lower rest energy expenditure.  This means that, when not moving, we burn calories at a lower basal rate than non-narcoleptics.

3) Typical, but not atypical narcoleptic patients tended to eat less.  In the study, they separated narcoleptics with cataplexy (“typical”) and those without (“atypical”) and found that typical patients ate less than “healthy controls.”  While there was no food intake difference between typical and atypical narcoleptics, overweight narcoleptic patients ate 1/2 as much as narcoleptic patients with a healthy weight.

4) Narcoleptic patients demonstrate a higher rate of eating disorders, particularly bulemia. Narcoleptic patients tended to demonstrate impaired eating behaviors, including the use of binge eating to control daytime sleepiness. There was no difference between typical and atypical narcoleptic patients, and they found that 1/2 of narcoleptic patients suffered from a mild form of eating disorder.

Narcos are fat.

No offense, but we narcoleptics are fat [1].  In fact, of all of the narcoleptics I have met, I have only met two people (both young men, mind you) that were even remotely in shape.  For me, the fact of obesity and narcolepsy is one of the most unfair aspects of the disease. In the first place, people who don’t know anything about narcolepsy, assume that we are lazy. “Just make your bed and sleep less!” seems to be their cure-all answer.

Indeed, the official stance of The Standford Center for Sleep Sciences and Medicine (home to the famous Dr. Mignot) appears to be: “Many patients with narcolepsy also gain weight as the result of inactivity and sleepiness.”

For years, narcoleptics have fought a huge social stigma that we are somehow lazy sloths that just want to sleep and eat all day, despite the facts that we actually sleep less efficiently than other people, and still gain weight on diets that work for other people!   

Fortunately for us, there is a body of research linking metabolic dysfunction and narcolepsy.  The excitement about these advances (for me, at least) is overwhelming, and there are several reviews on the site summarizing them.

Recently, it was shown that we narcos don’t produce a lot (if any) hypocretin.

hypocretin A

Structure of hypocretin

Our brains are simply deficient in the production hypocretin (also called orexin), and it is hypothesized, though not proven, that we may have a complete loss in the neurons of the hypothalamus responsible for producing hypocretin.  For everyone, hypocretin controls arousal, wakefulness and appetite. A deficiency in hypocretin impairs sleep as well as metabolism, and in addition to being sleepy, narcoleptics have a lower basal metabolism than other people. Because of this, narcoleptics tend to gain weight in spite of eating fewer overall calories than most people. 

Orexin is not only active in the central nervous system, but it has wide ranging action throughout the periphery.  Indeed, mice that lack orexin gain weight as a result of brown fat hypoactivity and reduced energy expenditure. Remember, brown fat is good fat. White fat is the “bad fat” that makes you appear fat.

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So what does this mean? Surely, it doesn’t mean that we are now allowed to sleep and eat as much as we want. But it does mean that WE ARE NOT JUST LAZY!  For me, the problem of metabolism and narcolepsy (in addition to the metabolic problems that stem from my hypothyroidism), is an ongoing battle. On the one hand, I am able to harness the power of diet and nutrition to help control my symptoms, but on the other, I am always fighting. Even when I exercise, I can’t eat more than 1,000 – 1,200 calories a day without gaining weight (very quickly, I might add)!

It is clear that narcolepsy is more than just a disease of sleepiness. It is a disease with many faces, encompassing tiredness as well as impaired metabolic homeostasis. In fact, it was recently reported that obese individuals had lower circulating levels of orexin A. The results from the study indicate orexin doesn’t only work in your brain, but that the receptors for orexin (specifically in the gut and pancreas) contribute to systemic effects of orexin itself, and that a deficiency in orexin not only can have neurological effects, but systemic ones as well.

Diet Therapy For Narcolepsy

In 2004, Dr. A. M. Husain published an article in Neurology called “Diet Therapy for Narcolepsy.”  Dr. Husain conducted a study on the effects of a low-carbohydrate ketogenic diet (LCKD) on people with narcolepsy.  Basically, he put a few patients on the Atkins Diet, and asked: “Were they less sleepy?” Over the course of just 2 months, the patients that were able to adhere to the diet noted a significant reduction in their total sleepiness (assessed by a Narcolepsy Symptom Status Questionaire).  Overall, patients reported an 18% reduction in daytime sleepiness.   

So why is this paper interesting?

1. It demonstrates that diet can affect how tired you are.

Food affects how you feel.  Particularly, specific foods may make you more tired, especially if there is an underlying intolerance to a specific food group. By eliminating self-identified foods that seem to make you more tired, it is possible to manage the symptoms of narcolepsy, at least in part, through diet modification.

2. It also points to a group of foods that may be causing the sleepiness in the first place! 

Low-carbohydrate ketogenic diets (LCKD), such as the Atkins and more recently popular Paleo diets, restrict carbohydrates which usually come from grains.  Of these, wheat is the most common source of carbohydrate in the American/Western diet.  By going on a low-carb diet, you are in part severely limiting grain and wheat flour consumption.