Is Lithium a Potential Aid in Traumatic Brain Injury?

Lithium carbonate serves as a primary treatment option in the treatment of mania and bipolar affective disorder.  An elemental metal, lithium has atomic number 3 in the periodic table of elements.

The mechanism of action for lithium carbonate in bipolar disorder is unclear.  Some of the proposed mechanisms for lithium in the central nervous system include:

• alteration of the neurotransmitter glutamate (affected by other drugs linked to therapeutic effect in bipolar disorder, i.e. sodium valproate and lamotrigine)
• alteration in gene expression
• inactivation of the GSK-3B (glycogen synthase kinase) enzyme known to be involved in circadian clock regulation
• interaction with the NO (nitrous oxide) signalling pathway

Inhibition of the GSK-3B enzyme has been shown to have potential beneficial effects in stimulating neuroplasticity as it is associated with enhanced expression of brain-derived neurotrophic factor (BDNF).  Fengshan Yu and colleagues at NIH and the University of Health Sciences have recently explored the effect of lithium on traumatic brain injury using a mouse model.

In their experiment, mice received doses of lithium chloride ranging form 1.0 to 5.0 mEq/kg dose of lithium or placebo following a controlled episode of brain trauma under anesthesia.  Doses were repeated daily for three days.

Brain injury response to lithium treatment was monitoring using neuropathological techniques as well as behavior and motor coordination tests.  The key results of the study include:

• Lithium chloride at 1.5 to 3.0 mEq/kg reduced brain lesion volume compared to control
• Lithium chloride reduced post-trauma related anxiety behavior during the outcome monitoring
• Lithium chloride reduced breakdown of the blood-brain barrior
• Short-term and long-term motor coordination was better in the lithium group

The authors note that their study suggests the neuroprotective effect of lithium administration following traumatic brain injury in the mouse model appears related to a GSK-3B mechanism.  The study timed lithium administration to 3 hours after the trauma providing a realistic model for a trial in human clinical scenarios.  They conclude "Our results that demonstrate its (lithium chloride) benefits in the mouse model pave the way for early clinical trials as potential treatment for TBI (traumatic brain injury) patients.

CT of traumatic brain injury showing cerebral contusion, cerebral hemmorhage, subdural hematoma and skull fracture from Wikipedia Creative Commons. Source: Rehman T, Ali R, Tawil I, Yonas H (2008). "Rapid progression of traumatic bifrontal contusions to transtentorial herniation: A case report". Cases journal 1 (1): 203. doi:10.1186/1757-1626-1-203. PMID 18831756. http://www.casesjournal.com/content/1/1/203


Yu F, Wang Z, Tchantchou F, Chiu CT, Zhang Y, & Chuang DM (2011). Lithium ameliorates neurodegeneration, suppresses neuroinflammation, and improves behavioral performance in a mouse model of traumatic brain injury. Journal of neurotrauma PMID: 21895523

Are Athletes Better Performers Outside Sport?

Marlins Mike Stanton Rounds Third Base After Homer

Performing at the highest level in many sports requires the development of a complex group of cognitive, fine motor, gross motor, eye-hand coordination and fitness skills.

These multiple skill domains are often performed in a emotionally-charged environment where multi-tasking.  Think a baseball batter monitoring signals from coaches, remembering a pitcher's preference for pitches in certain situation and performing on the road where a sell out crowd roars with each pitch.

This batter then need to use visual skills, timing and motor skills making a swing that where he hopes to land at least a base hit.

A sports exercise research team recently as a good research question related to this type of sport specific skill: "Do athletes perform better in non-sport \tasks that also require quick action and multitasking?

Laura Chaddock and a research team from the University of Illinois recently published online the results of their study in the journal Medicine & Science in Sports & Exercise.  The authors wanted to know if athletes with specific sport training would be able to perform a non-sport physical activity better than non-athletes.

To do this they developed a real-life virtual reality task of quickly and safely crossing a two-way street.  This paradigm requires a special facility and involves manual treadmills, computer simulation of traffic and wireless liquid crystal goggles that provide a sense of depth perception and movement.

The athlete group in the study include 18 University of Illinois participating in NCAA intercollegiate athletics (two baseball, one cross-country runner, one gymnast, two soccer players, five swimmer's, three tennis players, one track-and-field athlete and three wrestlers.  Athletes spent average of 20 hours per week practicing their college sport. Nonathlete controls were not involved in an athletic activites organized by the University of Illinois.

Athletes and controls completed three separate trials--one with no distraction, one while talking on a cell phone and one trial while listening to music through an iPod.

Both groups also completed a simple reaction time task using a desk top computer.

Here were the key results of the study:

• Athletes successfully crossed the street within a 30 second time limit 75% of the time with no distraction compared to only 56% in the non-athlete controls (statistically significant with p<.05)
• Athletes also were more successful under both distraction trials
• Athletes were less likely to be involved in a pedestrian collision during a simulation (23% vs 39% for non-athlete controls
• Athletes reaction time was significantly less than non-athlete controls and this variable negatively correlated with street crossing success rates (individuals with slow reaction times had lower success rates)

The authors note that their cross-sectional study cannot address causality.  One explanation for the results is that sport training provides improvements in reaction time and other psychomotor performance variables that translate to other non-sport multitasking setting.  An second possible explanation is that those with an innate psychomotor skill advantage perform better in athletics and other performance situations like the one found in this street-crossing simulation.  

It is also possible that both of the proposed explanations contribute something to this effects.  

This study also made me think about the effect of age-related reduction in reaction time and the performance in real-world street crossings and other potentially dangerous situations.  This type of simulation could be used in research related to this topic.

Photo of Mike Stanton homering against Chicago Cubs from the author's collection.


Chaddock, L., Neider, M., Voss, M., Gaspar, J., & Kramer, A. (2011). Do Athletes Excel At Everyday Tasks? Medicine & Science in Sports & Exercise DOI: 10.1249/MSS.0b013e318218ca74

Mango Sherbet

I've been kind of sick of eating commercial ice cream and packaged cookies with my lunch lately.  Eating tons of that crap just doesn't feel right.  Intuitively I think to myself that, sure I might be able to get away with it - especially taking buttloads of minerals and putting blackstrap molasses in all my food, but ideal? 

One of the main objectives of RBTI is to maximize the amount of vitamins and minerals that you absorb.  One way of looking at it is that you can get away with eating fewer nutrients because your body is absorbing them so much more effectively.  That's cool and all.  But knowing that I'm absorbing my food better just inspires me to want to eat better food!  So I've been doing some typical health nerd stuff like juicing, and switching from commercial desserts full of refined sugar (Reams believed that most people couldn't handle more than 2 pounds of refined sugar per year - but he did have hypoglycemics eating pie and ice cream like there was no tomorrow) to mostly fruit-sweetened desserts like light ice creams and sherbets.

Anyway, I've really been enjoying my eating now that I've got my Vitamix and juicer back in my possession after almost an entire year of being separated.  So here's a little show and tell.  I have made two sherbets (by the way a sherbet is basically just a fruit-based frozen dessert with dairy fat added - like a light ice cream) so far - one with mango and the other with frozen bananas (no sweetener added).  I would like to make some with cherries or peaches or papaya in the future. Strawberries are not recommended for consumption on RBTI because the tiny, hard seeds get stuck in the colon.  However, one of Vitamix's sales pitches is that it is so powerful it can grind the tiny seeds in strawberries and unlock the nutrition in them - making smoothies and ice cream made with strawberries more nutritious.  This is debatable, but I may try that one some day as well.     

Melatonin For Tinnitus Clinical Trial

Tinnitus, or persistent ear ringing, has no definitive treatment.  I had recently posted a summary of the status of this disorder based on a research review.

Since that post, a small but important placebo-controlled clinical trial examined the effect of melatonin on a group of subjects with tinnitus.

Here are the key elements of the study design from this clinical trial:
Subjects: Chronic tinnitus of at least 6 months duration as primary complaint (subjects ranged in age from 34 to 86)
Clinical Trial Design: 3 mg melatonin versus placebo for 30 days switchover to other assignment for an additional 30 days
Outcome Measure: Improvement defined as improvement in at least two tinnitus rating scales from 3 administered (Tinnitus Matching, Tinnitus Severity Index, Self-Rated Tinnitus)

In the analysis of the outcome of the trial, 57% of subjects were rated as improved during the melatonin phase while 25% were rated as improved during the placebo phase.   This was a statistically significant difference for the active drug.

Subjects who reported improvement with the melatonin trial were more likely to have the following clinical features:

• male gender
• bilateral tinnitus
• history of loud noise exposure
• no history of previous treatment for tinnitus
• no comorbid anxiety or depression
• higher Tinnitus Matching and Tinnitus Severity Index scores prior to the study

One of the problems with the design in this study is controlling for the potential confounding effect of improved sleep on tinnitus severity reporting.  Individuals who have improvement in sleep with melatonin may generally feel better and report improvement in a variety of domains.  An active non-melatonin comparator hypnotic, i.e. Ambien (zolpidem) would need to be included to determine if melatonin specifically contributes to reducing tinnitus.

The authors note potential mechanisms for melatonin in tinnitus include it's antioxidant effect, autonomic nervous system effects, effects on blood pressure or muscle tone. 

Larger multicenter studies confirming this study result are needed before a significant change in clinical practice can be recommended.  Since melatonin is a generic drug, such a study will likely need public research funding to be completed.

Molecular model of the compound melatonin from the Wikipedia Creative Commons authored by sbrools under the GNU Free Documentation License.

Hurtuk A, Dome C, Holloman CH, Wolfe K, Welling DB, Dodson EE, & Jacob A (2011). Melatonin: can it stop the ringing? The Annals of otology, rhinology, and laryngology, 120 (7), 433-40 PMID: 21859051

Inflammation, Depression and Heart Disease

Sunset in Santa Fe, New Mexico

Major depression appears linked to risk for coronary artery disease and an adverse outcome following myocardial infarction.  The mechanism for this association is unclear.

One proposed mechanism relates to systemic markers of inflammation.  Elevated serum blood levels of inflammatory markers such as interleukin-6 and C-reactive protein are risk factors for heart disease.  Some research point to higher inflammatory markers levels in samples of individuals with depression.

Duivis and colleagues from the Netherlands and the United States recently published an informative study on this issue in the American Journal of Psychiatry.  Their study prospectively examined a series of patients with heart disease with measurements of depression and markers of inflammation.  The key elements of the design of their study included:

Subjects: 667 individuals with documented coronary artery disease interviewed yearly for 5 years
Depression Assessment: 9-item Patient Health Questionnaire corresponding to the 9 items making up the criteria for major depression in DSM-IV.  Subjects were grouped into three categories: never scoring 10 or more on the PHQ, scoring 10 or more at one time, scoring 10 or more at 2 or more interviews
Inflammatory Markers: Fasting blood samples measured for high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and fibrinogen.

Subjects with two or more periods with significant depressive symptoms showed statistically higher levels of hsCRP and IL-6 than the other two subject groups (fibrinogen levels showed a trend for higher levels, p=.06)

Subjects with two or more periods with significant depressive symptoms tended to be younger, have a diagnosis of myocardial infarction, use aspirin daily and have lower levels of good (HDL) cholesterol.
They also were more likely to be physically inactive, be a current smoker and have higher levels of obesity (BMI).  This association appeared to occur in only one direction--depression predicted later higher inflammatory markers, high inflammatory markers did not predict subsequent development of depression.

When potential key inflammatory confounding variables were controlled (BMI, smoking and inactivity), the association of depression and higher inflammatory biomarkers washed out.    The authors note that this finding suggests the inflammation linked to depression in heart disease may be amenable to increased efforts to "improve health behaviors".

It is unclear from this study how many subjects received pharmacotherapy or psychotherapy for a diagnosis of depression.  Primary treatment of depression may be necessary to engage and motivate those with depression and heart disease to improve their lifestyle choices and behaviors.

Photo of sunset in Santa Fe, New Mexico from the author's collection.

Duivis, H., de Jonge, P., Penninx, B., Na, B., Cohen, B., & Whooley, M. (2011). Depressive Symptoms, Health Behaviors, and Subsequent Inflammation in Patients With Coronary Heart Disease: Prospective Findings From the Heart and Soul Study American Journal of Psychiatry, 168 (9), 913-920 DOI: 10.1176/appi.ajp.2011.10081163

Ulcerative Colitis Diet

This is a funny video with Challen Waychoff.  One of the attendees mentions something about the RBTI beliefs surrounding how cancer develops, and he stiffens up so as not to reveal anything too libelous on camera.

But he goes on to tell an anecdote of a man basically on his deathbed due to a severe case of ulcerative colitis - an inflammatory and "incurable" bowel disease.  Something was obviously quite off in his "chemistry," but it was something that Challen was able to guide the man to sorting out and fix in short order, like he so often does.  I did not ask him specifically the details of the case, and what was causing the problem, but obviously following one of the simple rules of the RBTI in particular was enough to sort it out (as he hints at in the video).   

Real-Time fMRI Psychotherapy

Old World Psychotherapy: Sofa of Sigmund Freud

There has been a series of interesting research studies examining the effect of psychotherapy on brain structure and function.  These studies have typically shown that effective psychotherapy results in reduction of brain deficits or abnormalities associated with a specific neuropsychiatric disorder.

Now a study published in Plos One summarizes the results of study examining the use of real-time fMRI to provide neurofeedback during an amygdala activation task.

This research was completed by neuroscientists affiliated with the Laureate Institute of Brain Research in Tulsa, Oklahoma and George Mason University in Fairfax, Virginia. (Disclosure: The author of Brain Posts is employed by Laureate Institute of Brain Research but was not involved in the study reviewed in this post.)

The authors of this study noted the key role of the amygdala in the processing of emotions.   They developed a experimental paradigm to train control subjects to increase the activation of the brain left amygdala.  A group of young male subjects were instructed in a happy autobiographical memory task and provided real-time feedback on how successful they were in increasing blood flow to the left amygdala.

Subjects identified three key happy memories from their past.  During the experimental phase, they were instructed to recall these specific memories while being scanned using an fMRI scanner. They were provided real-time feedback on a monitor screen on the changes in left amygdala BOLD signal.  (Subjects were told prior to scanning that fMRI neurofeedback is delayed by a few seconds due to the brain hemodynamic process).

Subjects provided real-time feedback were more successful at increasing the left amygdala activation than those in a control group.  This increase in the experimental group correlated with increases in other brain areas known to have functional connectivity with the amygdala (fronto-temporo-limbic network).

New World Psychotherapy: Real Time fMRI

Additionally, the study identified six specific regions where functional connectivity identified correlations with the left amygdala activation:

• right medial frontal cortex
• bilateral dorsomedial prefrontal cortex
• left anterior cingulate cortex
• bilateral superior frontal gyrus

Subjects were selected based on being free of a history of neuropsychiatric disorders including anxiety and depression.  However, there was some variability in the level of change in left amygdala activation with neurofeedback training.  Subjects who scored high on the Difficulty Identifying Feelings scale had less increase in the left amygdala.  Additionally, subjects with higher scores on a scale of being susceptible to anger showed less increase.

This research is an very important advance in understanding the amygdala and regions connected with the amygdala.  Additionally, it raises the possibility that real-time fMRI may emerge as a tool to understand processes associated with psychotherapy and to be an emerging model for providing therapy under real-time neurofeedback conditions.  

The site of psychotherapy might be moving from the sofa model of Sigmund Freud to the fMRI scanner.  Both methods have subjects that lie down, but only the fMRI method provides real-time feedback of brain effects related to a psychotherapy intervention.

The authors note that this study was a type of "proof-of-concept" study since it focused on healthy control subjects.  They suggest that this type of model might be particularly relevant to cognitive behavioral treatment of conditions such as PTSD and major depression.

Photo of Sigmund Freud sofa from the Freud Museum in London from Wikipedia distributed under the GNU Free Documentation License.


Photo of Functional Magnetic Research Imaging device courtesy of the Laureate Institute for Brain Research. 

Zotev, V., Krueger, F., Phillips, R., Alvarez, R., Simmons, W., Bellgowan, P., Drevets, W., & Bodurka, J. (2011). Self-Regulation of Amygdala Activation Using Real-Time fMRI Neurofeedback PLoS ONE, 6 (9) DOI: 10.1371/journal.pone.0024522