Preventing Depression Following Brain Injury

Depression is a common feature following traumatic brain injury (TBI). Post-TBI depression may be difficult to treat and evolve into a chronic depression syndrome.

A recent published study demonstrates that prophylactic SSRI antidepressant treatment may reduce the incidence of depression following TBI.

This study was conducted by investigators affiliated with Baylor College of Medicine and the Department of Psychiatry at the University of Iowa.

Ninety four subjects were recruited to this randomized control trial.

Active drug treatment was provided by the selective serotonin reuptake inhibitor sertraline. Subjects were dosed up to 100 mg per day of sertraline and followed for 24 weeks.

The primary findings of the study included the following:

• Sertraline was well-tolerated with few adverse events in the study population
• By 24 weeks approximately 25% of control subjects met criteria for depression while only about 7% of sertraline subjects met criteria for depression
• The number of subjects needed to treat to prevent one person developing depression post-TBI was 5.9

The authors note in the discussion that sertraline and the SSRI class may be linked to:

"enhanced neuroplasticity in mood regulation areas, such as the hippocampus and prefrontal cortex"

The authors had previously noted an enhanced neuropsychological performance following TBI with the SSRI escitalopram. They were unable to replicate that finding in the current study.

This is an important study that deserves wider replication. If confirmed, SSRI primary prevention of depression following TBI may become a common practice.

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Photo of monarch butterfly depositing egg on milkweed plant is from the author's files.

Jorge RE, Acion L, Burin DI, & Robinson RG (2016). Sertraline for Preventing Mood Disorders Following Traumatic Brain Injury: A Randomized Clinical Trial. JAMA psychiatry PMID: 27626622

How Learning Braille Changes the Brain

Learning a new skill provides the opportunity to study brain neuroplasticity.

The Daily Mail recently highlighted research examining the effects of learning Braille language in a group of 29 sighted individuals.

The authors noted that changes in the the somatosensory cortex related to the tactile nature of Braille were found as expected.

However, the research team also found activation in a region of the lateral occipital lobe known as the visual word form area. This finding was unexpected and suggests new mechanisms in learning brain.

The study used sighted individuals and blind individuals may have distinct mechanisms for learning Braille. An informative study would use sighted and blind individuals with fMRI before and after a period of Braille training.

You can access the story on the Daily Mail HERE.

The free full text manuscript by the Polish research team can be found HERE.

Brain figure highlighting occipital cortex is mine from an iPad screen shot using the 3D Brain app.

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Neuroplasticity and Training the Older Brain

Neuroplasticity is the brain and nervous systems ability to evolve and to repair deficits.

At a basic level it represents the ability to learn and develop a structural and functional system to interact with the environment.

The brain's neuroplasticity is maximized during childhood and adolescence. This adaptability wanes with age. However, some neuroplasticity ability persists in the older brain.

This persistence was highlighted in a study from Hong Kong recently published in the journal Neural Plasticity.

Natalie Leung and colleagues studied a group of older adults with an average age of 70 years. Two hundred nine older adults were randomized to a cognitive training protocol or a control video education intervention.

The cognitive training protocol involved three one-hour training sessions for 13 weeks (39 hours total cognitive training). The training in this protocol was adapted from the Brain Fitness Program of Posit Science. Elements including tasks focusing on reaction time, visual discrimination, verbal memory, attention and working memory. All subjects completed neuropsychological assessment at baseline and at the end of the 13 week trial.

The active training groups demonstrated significant improvement in a variety of cognitive domains compared to the control group including:

• Higher sustained attention scores on the Seashore Rhythm Test
• Better performance on working memory digit span tasks
• Better performance on visual spatial cognition 

This study did not include a brain imaging component. However, the author's note their findings suggest sensitive imaging tools might complement their results and provide better understanding of structural and functional elements of neuroplasticity in the older brain.

The role of brain training in modifying the effects of aging on the brain is still in early stages of research. However, the current study supports the ability of elderly individuals to respond to cognitive training interventions.

Individuals with more interest in this study can access the full free-text manuscript by clicking on the PMID link below.

Screenshot of frontal lobes in brain is from the iPad Brain Tutor app.

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Leung NT, Tam HM, Chu LW, Kwok TC, Chan F, Lam LC, Woo J, & Lee TM (2015). Neural Plastic Effects of Cognitive Training on Aging Brain. Neural plasticity, 2015 PMID: 26417460

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

How Golf Practice Changes the Brain

Neuroscience research provides increased understanding of how behavior and specific activities change the brain.  This type of research underscores the concept of neuroplasticity--that our brains change in response to how it is used on a daily basis.

One area of research in neuroplasticity is the effect of specific cognitive and motor behavior on brain structure.  A novel study published in The Journal of Neuroscience examined the effect of golf practice on brain structure.  Bezzola and colleagues from Switzerland and Germany in this study proposed that golf practice is likely to effect the following brain regions based on their known functions:

• Dorsal stream--development of visuomotor skills
• Subcortical and cerebellar regions--motor learning
• Frontal association areas--cognitive aspects of skill development

A group of relatively novice golfers had brain scan before and after a period of 40 hours of golf practice.  This study used a real world type of design.  The golfer intervention group were directed to complete their practice under a golf instructor at their own course at their own pace.  The experimental group and control groups in this study were between the ages of 40 and 60 years of age as the goal was to examine the effect in those who were likely to begin experiencing some decline in brain cognitive function.

The brain imaging in this study was completed using magnetic resonance imaging or MRI.  This technique allows for examination of small changes in brain gray and white matter volumes.

The golf practice intervention group demonstrated significant brain volume increases in a variety of brain regions including the:

• ventral premotor cortex
• several regions in the parietal cortex including the inferior parietal cortex (area demonstrated in the attached Brain Tutor HD screen shot)
• parietal-occipital junction

The golfers in the study took up to five months to complete the 40 hours of practice.  Interestingly, those who completed their practice in the least number of days showed the greatest increase in brain volumes in at the parietal occipital junction.

The authors note their study is important because it shows brain neuroplasticity occurs not just in strictly controlled motor exercise protocols but in the real world of structured leisure activity like golf.  The note structured leisure exercise activities "may be considered an additional therapeutic setting in the process of neuro-rehabilitation.

This study also suggests middle-aged individuals have a new excuse for taking up a new physical activity like golf.  If their spouse objects to heading out to the golf course to practice, a scientific response might be: "Honey, I'm just going out to work out my brain parietal-occipital junction".

Photo of Steve Williams assisting Tiger Woods practice golf at the 2010 PGA Championship from the author's private collection.

Screen shot of the inferior parietal lobe from Brain Tutor HD iPad app.

Bezzola L, Mérillat S, Gaser C, & Jäncke L (2011). Training-induced neural plasticity in golf novices. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31 (35), 12444-8 PMID: 21880905

Fluoxetine (Prozac) Boosts Motor Recovery After Stroke

Antidepressant drugs are being used for multiple non-depression indications including chronic pain, peripheral neuropathy, migraine prophylaxis, irritable bowel syndrome, hot flashes, premature ejaculation and insomnia (list not inclusive).   I had previously posted results of research looking at the effect of antidepressants after stroke on cognitive recovery.  This study from the University of Iowa College of Medicine, Department of Psychiatry found that escitalopram was linked to improved cognitive recovery following stroke compared to placebo.

Now on a related note, a study has been randomized placebo controlled study of fluoxetine has been published looking at recovery of motor function following acute ischemic stroke.   Here are the key elements of the design of this study:

• Subjects:  113 patients with acute ischemic stroke ages 18-85 suffering hemiplegia or hemiparesis
• Baseline motor deficit: Fugl-Meyer motor scale (FMMS) score of 55 or less
• Intervention: Fluoxetine 20 mg daily for 3 months or placebo
• Key outcome measure: FMMS score at day 90

The raters on the key outcome measure were blinded to the assigned treatment.  The findings from the study were impressive—mean (standard deviation) FMSS scores for the fluoxetine group was 54(28) compared to only 35.1 (22) in the placebo group.  As might be expected, rates of post-stroke depression were lower in the fluoxetine group (7% vs 29%).    Adverse events included nausea and diarrhea in the fluoxetine group—a typical selective serotonin reuptake inhibitor side effect.  One subject in each group died during the follow up period.  More patients in the fluoxetine group were more independent suggesting that motor recovery is an important contributor to global function after stroke.  The motor recovery effect appeared independent of lower depression rates in the fluoxetine group.

So why would a drug used typically for depression potentially have a role in post-stroke motor recovery?  The authors note animal studies have shown that drugs affecting brain neurotransmitters can modulate the rate and extent of recovery following brain injury.   Rats given fluoxetine after ischemic brain injury appear to have enhanced hippocampal neurogenesis.  These studies support a potential role for selective serotonin reuptake inhibitors like fluoxetine to have a neuroplasticity effect that may aid brain healing from a variety of insults.  This is not a magic bullet—it appears necessary to pair the drug treatment with active rehabilitation efforts.   But when used together, the combination appears to result in a better motor recovery after stroke.  I think we are likely to see more active research in this area and search for novel neuroprotective compounds that my provide better outcomes for stroke and other brain injury patients. 


Molecular model of fluoxetine molecule from Wikipedia Creative Commons, author Benjah-bmmj27.

Chollet F, Tardy J, Albucher JF, Thalamas C, Berard E, Lamy C, Bejot Y, Deltour S, Jaillard A, Niclot P, Guillon B, Moulin T, Marque P, Pariente J, Arnaud C, & Loubinoux I (2011). Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet neurology, 10 (2), 123-30 PMID: 21216670