No Longer Phineas Gage: How to Improve Memory, Planning, Self-Control, Conscientiousness, Executive function, and Get Control of Your Life.

Everyone who’s ever taken a neuroscience course knows about Phineas Gage. For those of us who haven’t, all you need to know is that he was a nineteenth century railroad construction foreman who, in a freak accident, got a large iron rod driven through his head, destroying most of his brain’s left frontal lobe. Remarkably, he survived. Here is one researcher’s account of how Gage was changed after his injury:

“The equilibrium or balance, so to speak, between his intellectual faculties and animal propensities, seems to have been destroyed. He is fitful, irreverent, indulging at times in the grossest profanity (which was not previously his custom), manifesting but little deference for his fellows, impatient of restraint or advice when it conflicts with his desires, at times pertinaciously obstinate, yet capricious and vacillating, devising many plans of future operations, which are no sooner arranged than they are abandoned in turn for others appearing more feasible. A child in his intellectual capacity and manifestations, he has the animal passions of a strong man. Previous to his injury, although untrained in the schools, he possessed a well-balanced mind, and was looked upon by those who knew him as a shrewd, smart businessman, very energetic and persistent in executing all his plans of operation. In this regard his mind was radically changed, so decidedly that his friends and acquaintances said he was “no longer Gage”.”

Accounts of his post-injury neuropsychiatric symptoms have taken on mythic proportions over the years, and are probably often quite exaggerated. Nevertheless, based on what we know of the functions of the frontal lobes today, it would make sense that many of the changes described, though perhaps exaggerated, are probably pretty solidly based in fact.

The frontal lobes contain the prefrontal cortex, the area of the brain that is evolutionarily the newest and the one that makes us most human. From Wikipedia:

The prefrontal cortex (PFC) is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.

This brain region has been implicated in planning complex cognitive behavior, personality expression, decision making, and moderating social behavior.[1] The basic activity of this brain region is considered to be orchestration of thoughts and actions in accordance with internal goals.[2]

The most typical psychological term for functions carried out by the prefrontal cortex area is executive function. Executive function relates to abilities to differentiate among conflicting thoughts, determine good and bad, better and best, same and different, future consequences of current activities, working toward a defined goal, prediction of outcomes, expectation based on actions, and social “control” (the ability to suppress urges that, if not suppressed, could lead to socially unacceptable outcomes).

Many authors have indicated an integral link between a person’s personality and the functions of the prefrontal cortex.[3]

Probably the best way I’ve ever heard of summing up the role of the prefrontal cortex is to imagine that the whole brain is an orchestra, and all the various regions musicians in it, except for the prefrontal cortex, which is the conductor. The conductor makes sure that all the musicians are playing the same piece of music in harmony and synchronicity.

Have you ever wondered how meditation exerts positive effects on the brain and personality of practitioners? It does so because the act of meditating requires intense activation of the prefrontal cortex, which “conducts” the rest of the brain to work in a way that doesn’t come to it easily. Just like a muscle, the prefrontal cortex becomes stronger from this intense usage and the more you meditate, the stronger your prefrontal cortex becomes. This results in improvements in many areas of neuropsychiatric functioning, including reductions in the symptoms of ADHD, depression, pain, anxiety, and stress, as well as increases in self-control and good mood.1 2 3 4 5 6 7

Meditation is arguably the ultimate neuropsychiatric treatment. However, many people aren’t psychologically prepared to invest the necessary time into practicing it often enough to see significant results (which seems to be meditating for fifteen minutes a day for two weeks). For those of us with limited time and/or patience, there are other ways to improve the functioning of our prefrontal cortex. Several dopaminergic and noradrenergic antidepressant and ADHD medications stimulate the prefrontal cortex to some extent, but they do so weakly, and they non-selectively stimulate subcortical areas as well. There are a few exceptions to this rule though. The best I’ve found so far is a pharmaceutical drug called guanfacine.

Guanfacine is a noradrenergic agonist (meaning that it mimics norepineprhrine, a neurotransmitter that regulates alertness, attention, etc.) that stimulates the alpha-2A receptors in the prefrontal cortex with a high degree of selectivity.8 It is designed to ameliorate the prefrontal cortex dysfunction typically seen in people with ADHD or ADD. The title of the 1998 study that persuaded me to try guanfacine was: “Guanfacine, But Not Clonidine, Improves Planning and Working Memory Performance in Humans”. The authors concluded: “The 29 μg/kg dose of guanfacine improved spatial working memory and planning. It is possible that the greater selectivity of guanfacine for α2A-adrenoceptor subtype may underlie its differences from clonidine.” I’m a big proponent of anything that selectively stimulates the prefrontal cortex, so I thought I’d give it a try.

I started taking about 2.9mg of guanfacine day three days ago, and the change in my behavior has been fairly dramatic. I’ve been planning a lot more since I started taking it, to the point that my girlfriend complained today that I’m planning too much, a criticism which I assure you has never been leveled at me in my entire life. I’ve also found myself being more helpful around the house, having more self-control, and being more productive. I attribute the fact that I started this blog yesterday to the effects of guanfacine.

So, if you have a disorder like ADD, ADHD, or depression in which the prefrontal cortex isn’t being stimulated enough, or if you just feel like you could use some help with planning, short term memory, and other higher cognitive functions, I highly recommend trying guanfacine and seeing if it works for you.

References:

1: ADHD, Brain Functioning, and Transcendental Meditation Practice (2011).

2: Mindfulness meditation counteracts self-control depletion (2012).

3: The effectiveness of a stress coping program based on mindfulness meditation on the stress, anxiety, and depression experienced by nursing students in Korea (2009).

4: How Does Mindfulness Reduce Anxiety, Depression, and Stress? An Exploratory Examination of Change Processes in Wait-List Controlled Mindfulness Meditation Training (2013).

5: Mindfulness-Based Stress Reduction, Mindfulness-Based Cognitive Therapy, and Zen Meditation for Depression, Anxiety, Pain, and Psychological Distress (2012).

6: The Effect of Mindfulness-Based Therapy on Anxiety and Depression: A Meta-Analytic Review (2010).

7: Loving-kindness and compassion meditation: Potential for psychological interventions (2011).

8: Pharmacological and therapeutic directions in ADHD: Specificity in the PFC (2007).

How to Cure Alzheimer’s, Dementia, Depression, Parkinson’s, Cardiovascular Disease, Diabetes, and Cancer, all while Boosting your Intelligence, Memory, and Ability to Learn with Epigenetics: HDAC is the one.

If something sounds too good to be true, it usually is. But sometimes it isn’t. The most exciting exception to this rule of thumb I’ve ever seen is the potential of novel selective HDAC2 and HDAC3 inhibitors to cure neurodegenerative diseases including Alzheimer’s, depression, Parkinson’s, as well as boost the intelligence, memory, and ability to learn of “healthy” neurotypical humans. Other HDAC inhibitors can also cure or at least reduce the symptoms of cancer, diabetes, heart disease, and virtually every other chronic disease.

Don’t Get Your DNA in a Bunch

First, some background. Within every cell in our body, the strands of our DNA are wound up into a ball called chromatin by proteins called histones. Which genes on the DNA are expressed and translated into proteins is determined by how tightly the histones coil the DNA. The more tightly the DNA is coiled by the histones, the fewer genes will be physically exposed to DNA polymerase; those genes that are coiled up and hidden from DNA polymerase will not be expressed and translated into protein.

The Epigenetic Miracle Cure

The family of enzymes that controls how tightly the histones coil DNA is called the histone deacetylases, or HDACs. The more HDACs you have in your cells, the more tightly the DNA will be coiled around the histones and the fewer genes will be expressed. Why might this become a problem? Well, the most obvious example is if an HDAC silences a gene that induces apoptosis (healthy cell death), cell differentiation, or some other important gene controlling the cell cycle, which gives you cancer. And indeed, HDAC inhibitors that shrink tumors have been on the market for years now, most prominently for hematological cancers like refractory T-cell lymphoma.1 2 3

More recently, scientists have been discovering that inhibiting the various HDACs can do a lot more than just shrink cancer tumors. According to one study, “HDACs are implicated as a regulator in various pathological heart diseases such as fibrosis, arrhythmia, ischemic heart diseases, and heart failure.”4 According to another,“Surprisingly, HDAC inhibitors have also been shown to be efficacious in preclinical models of heart failure.”5  

HDAC inhibitors also show a lot of promise forimproving insulin sensitivity in patients with diabetes mellitus or obesity.6 7

HDAC inhibitors also have the potential to treat autoimmune and transplantation related disorders, as well as any kind of inflammatory disease (which most chronic diseases are).8 9

Just in case you weren’t already convinced that HDAC inhibitors are the most awesome thing since the invention of antibiotics, it gets even better. HDAC inhibitors have also proven effective at treating neurodegenerative diseases like Alzheimer’s, dementia, Parkinson’s, Huntington’s, and depression.10

So what’s the catch? Why isn’t there already an HDAC inhibitor panacea drug for all that ails you on the market? Well, the problem is that there are at least eighteen different kinds of HDACs, which are grouped into four different classes. Some HDACs do good things, and only a small minority of them seems to be responsible for disease.11

The good news is that we now know which ones are the bad guys and which are the good. HDAC3 appears to cause over seventeen inherited neurodegenerative diseases, including Huntington’s.12 HDAC6 is implicated in the pathogenesis of Alzheimer’s, Parkinson’s, ALS, FTLD, and CMT.13 HDAC2 is the principal villain behind diabetes, inflammation, depression, Alzheimer’s, and dementia.14 15 16 17 18 Perhaps most excitingly, not only does inhibiting HDAC2 and HDAC3 reverse these diseases, it also has the potential in healthy humans to enhance neuroplasticity and improve the ability to remember, form new memories, and learn, making it the ultimate nootropic or “smart-drug”.19

Unfortunately, the only HDAC inhibitors on the market today are woefully non-specific, meaning that they inhibit several kinds of HDACs, the good and the bad. That doesn’t mean specific inhibitors of HDAC2 and HDAC3 don’t exist though. It just means they’re stuck in the research phase.20 However, a patent entitled “INHIBITION OF HDAC2 TO PROMOTE MEMORY” detailing exactly how to make your very own HDAC2 inhibitor is freely available online here. I’ve got a 93 year old uncle with dementia who’s quality of life and happiness would be greatly increased by taking an HDAC2 inhibitor to whom I’d like to offer the option, so if you are or know a chemist capable of synthesizing this compound, please let me know.

Over the Counter HDAC Inhibitors

Worth mentioning is that curcumin, the active compound found in the spice turmeric, has been found to reduce inflammation, prevent stress induced damage to various organs, inhibit tumor growth in cancer, reduce depression and seizures, and improve memory and learning. 21 22 23 24 25 26 27 28 29 It is a non-specific HDAC inhibitor that is easily and reasonably cheaply available over the counter. It’s probably not as effective as future specific HDAC2 and 3 inhibitors, but it won’t hurt you either—in fact it will probably help significantly with a variety of diseases—and it’s the easiest to get next best thing for now.

References:

1: HDAC inhibitors in cancer care (2010).

2: HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications.

3: Curbing autophagy and histone deacetylases to kill cancer cells

4: Roles and Targets of Class I and IIa Histone Deacetylases in Cardiac Hypertrophy (2010).

5: Therapeutic Potential for HDAC Inhibitors in the Heart (2012).

6: Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-β1-induced renal injury (2009).

7: Improving Insulin Sensitivity With HDAC Inhibitor (2012).

8: Rationale for HDAC inhibitor therapy in autoimmunity and transplantation (2011).

9: Immunomodulatory effects of deacetylase inhibitors: therapeutic targeting of FOXP3+ regulatory T cells.

10: Multiple roles of HDAC inhibition in neurodegenerative conditions (2009).

11: HDAC inhibitors and neurodegeneration: at the edge between protection and damage.

12: Histone Deacetylase Complexes Promote Trinucleotide Repeat Expansions

13: HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs?

14: HDAC2 negatively regulates memory formation and synaptic plasticity (2009).

15: Antidepressant actions of histone deacetylase inhibitors (2009).

16: Affective disorders: Antidepressant action through gene regulation (2009).

17: Epigenetics of the Depressed Brain: Role of Histone Acetylation and Methylation (2013).

18: Reversing Alzheimer’s gene ‘blockade’ can restore memory, other cognitive functions: Neuroscientists show that HDAC2 enzyme could be a good target for new drugs (2012).

19: Learning and memory: HDAC2 is the one (2009).

20: Novel histone deacetylase (HDAC) inhibitors with improved selectivity for HDAC2 and 3 protect against neural cell death (2011).

21: Curcumin improves learning and memory ability and its neuroprotective mechanism in mice.

22: Mechanisms of cancer chemoprevention by curcumin (2001).

23: Inhibitory effects of curcumin on tumorigenesis in mice (1997).

24: Inhibition of angiogenic differentiation of human umbilical vein endothelial cells by curcumin (1998).

25: Protective effect of curcumin against intracerebral streptozotocin induced impairment in memory and cerebral blood flow (2009).

26: Adaptogenic potential of curcumin in experimental chronic stress and chronic unpredictable stress-induced memory deficits and alterations in functional homeostatis (2001).

27: Curcumin ameliorates memory deficits via neuronal nitric oxide synthase in aged mice (2013).

28: A pyrazole derivative of curcumin enhances memory (2010).

29: Ameliorative effect of Curcumin on seizure severity, depression like behavior, learning and memory deficit in post-pentylenetetrazole-kindled mice (2013).