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Reversing Brain Damage in Former NFL Players: Implications for Traumatic Brain Injury and Substance Abuse Rehabilitation

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Brain injuries are common in professional American football players. Finding effective rehabilitation strategies can have widespread implications not only for retired players but also for patients with traumatic brain injury and substance abuse problems. An open label pragmatic clinical intervention was conducted in an outpatient neuropsychiatric clinic with 30 retired NFL players who demonstrated brain damage and cognitive impairment. The study included weight loss (if appropriate); fish oil (5.6 grams a day); a high-potency multiple vitamin; and a formulated brain enhancement supplement that included nutrients to enhance blood flow (ginkgo and vinpocetine), acetylcholine (acetyl-l-carnitine and huperzine A), and antioxidant activity (alpha-lipoic acid and n-acetyl-cysteine). The trial average was six months. Outcome measures were Microcog Assessment of Cognitive Functioning and brain SPECT imaging. In the retest situation, corrected for practice effect, there were statistically significant increases in scores of attention, memory, reasoning, information processing speed and accuracy on the Microcog. The brain SPECT scans, as a group, showed increased brain perfusion, especially in the prefrontal cortex, parietal lobes, occipital lobes, anterior cingulate gyrus and cerebellum. This study demonstrates that cognitive and cerebral blood flow improvements are possible in this group with multiple interventions.
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Amen et al. Enhancing rCBF, Cognition in NFL Players
Journal of Psychoactive Drugs 1 Volume 43 (1), March 2011
Journal of Psychoactive Drugs, 43 (1), (insert page range of article here), 2011
Copyright © Taylor & Francis Group, LLC
ISSN: 0279-1072 / 2159-9777 online
DOI: 10.1080/02791072.2011.566489
Reversing Brain Damage in
Former NFL Players: Implications
for Traumatic Brain Injury and
Substance Abuse Rehabilitation
Daniel G. Amen, M.D.*; Joseph C. Wu, M.D.**; Derek Taylor*** & Kristen Willeumier, Ph.D.****
Abstract—Brain injuries are common in professional American football players. Finding effective
rehabilitation strategies can have widespread implications not only for retired players but also for
patients with traumatic brain injury and substance abuse. An open label pragmatic clinical intervention
was conducted in an outpatient neuropsychiatric clinic with 30 retired NFL players who demonstrated
brain damage and cognitive impairment. The study included weight loss (if appropriate); sh oil (5.6
grams a day); a high-potency multiple vitamin; and a formulated brain enhancement supplement that
included nutrients to enhance blood ow (ginkgo and vinpocetine), acetylcholine (acetyl-l-carnitine
and huperzine A), and antioxidant activity (alpha-lipoic acid and n-acetyl-cysteine). The trial average
was six months. Outcome measures were Microcog Assessment of Cognitive Functioning and brain
SPECT imaging. In the retest situation, corrected for practice effect, there were statistically signicant
increases in scores of attention, memory, reasoning, information processing speed and accuracy on the
Microcog. The brain SPECT scans, as a group, showed increased brain perfusion, especially in the
prefrontal cortex, parietal lobes, occipital lobes, anterior cingulate gyrus and cerebellum. This study
demonstrates that cognitive and cerebral blood ow improvements are possible in this group with
multiple interventions.
Keywords—brain trauma, football, MicroCog, rehabilitation, SPECT
†Players were recruited with the help of the Los Angeles Chapter of
the Retired NFL Players Association, The Summit, and Dave Pears blog.
The authors wish to thank Anthony Davis, Marvin Smith, Reggie Berry,
Dave Pear, Robert Lee and all the retired players for their assistance. No
competing nancial interests exist for any of the authors.
*Assistant Clinical Professor, UC Irvine School of Medicine, Irvine, CA.
**Associate Professor, UC Irvine School of Medicine; Clinical Director,
Brain Imaging Center, UC, Irvine School of Medicine, Irvine, CA.
***Data Analysis, Amen Clinics, Inc., Newport Beach, CA.
****Research Director, Amen Clinics, Inc., Newport Beach, CA.
Please address correspondence and reprint requests to Daniel G.
Amen, M.D., Amen Clinics, Inc., 4019 Westerly Place Suite 100, Newport
Beach, CA 92660. Phone: 949-266-3717, fax: 949-266-3766, email:
docamen@amenclinic.com
Brain injuries are common in professional American
football players, and their incidence has been associated
with mild cognitive impairment, dementia and depression
(Guskiewicz et al. 2007, 2005). A study sponsored by the
National Football League (NFL) found that retired players
aged 30 to 49 receive a dementia-related diagnosis at a rate
of 1.9%, or 20 times the rate of age-matched populations,
while 6.1% of players over the age of 50 receive a dementia-
related diagnosis representing ve times the national average
of 1.2% (Weir, Jackson & Sonnega 2009). In a recent study
conducted on 100 active and retired NFL players the authors
found overall decreased cerebral perfusion and a higher in-
cidence of depression, obesity and memory and attentional
problems compared to the general population (Amen et al.
2011). In addition, brain injuries have also been found to
Amen et al. Enhancing rCBF, Cognition in NFL Players
Journal of Psychoactive Drugs 2 Volume 43 (1), March 2011
increase the risk of substance abuse (Olson-Madden et al.
2010; Graham & Caron 2008).
Brain injuries affect not only retired professional
football players, but also an estimated 1.7 million people
annually (CDC 2010) and many soldiers returning from Iraq
and Afghanistan. In addition, substance abusers also experi-
ence high levels of brain damage from the toxic effects of the
drugs or alcohol and the higher incidence of brain injuries
during intoxication (Gold et al. 2009).
Evaluating potential treatments to rehabilitate or reverse
brain damage is important in many clinical populations,
especially for patients with traumatic brain injury and sub-
stance abuse. Brain SPECT imaging is a standard, widely
available functional brain imaging tool that has been found to
help evaluate baseline brain function and the effect of treat-
ment interventions (Amen 2010). In this report we describe
our experience with 30 retired NFL players who took part
in a pragmatic open-label, clinical intervention to attempt
to reverse brain damage and cognitive dysfunction.
MATERIALS AND METHODS
Recruitment
As part of a larger study we recruited 100 retired NFL
players, representing 27 teams and all positions. Each player
met our inclusion criteria of being on an active NFL roster
for a minimum of three years. We excluded any subjects
who could not cease taking psychoactive medications (recre-
ational or otherwise) for an appropriate washout period prior
to scanning. All subjects signed informed consent as part of
an IRB protocol. The study started in 2009 and concluded
in 2010.
Evaluation Procedures
Each participant was interviewed by a physician and
completed a detailed medical and psychiatric history.
Weight, height and waist size were obtained on all partici-
pants and body mass index (BMI) and waist-to-height ratios
were calculated. As part of the evaluation each participant
took the Microcog Assessment of Cognitive Functioning
(MACF; Powell et al. 2004), which contains nine subtests:
general cognitive functioning, general cognitive prociency,
information processing speed, information processing ac-
curacy, attention, reasoning, memory, spatial processing and
reaction time. The MACF scores were compared to its own
standardized sample (n= 810) chosen to be representative of
the U.S. population of adults between the ages of 18 and 89
in regards to education, gender, and ethnicity. The MACF
was chosen because the means from test to retest were stable
over time and showed little practice effect (Powell et al.
1993).
In addition, each subject underwent high-resolution
brain SPECT imaging to measure regional cerebral blood
ow (rCBF). Each subject received an age/weight-appropri-
ate dose of Tc99m HMPAO intravenously. Subjects were
injected in normal lighting while they performed a go, no-
go, continuous performance task. The radiopharmaceutical
was injected three minutes after starting the 15-minute test.
All subjects completed the task. Subjects were then scanned
30 minutes later using a high-resolution Picker Prism 3000
triple-headed gamma camera with fan beam collimators,
acquiring data in 128x128 matrices, yielding 120 images
per scan with each image separated by 3 degrees spanning
360 degrees.
SPECT data was processed and attenuation correction
performed using general linear (Chang) methods. All images
were reconstructed and resliced using an oblique reformat-
ting program, according to anterior-posterior commissure
line so nal images were similarly aligned for analysis.
Intervention
All subjects were offered the opportunity to participate
in a pragmatic interventional phase. Pragmatic interventions
are ones that participants might experience in a “real-world”
clinical situation. The interventions included education on a
brain-healthy lifestyle, such as proper nutrition, regular ex-
ercise, limiting alcohol, eliminating drug abuse and cigarette
smoking, getting appropriate sleep, and having sleep apnea
assessed if symptoms were endorsed. As obesity has been as-
sociated with dementia and a smaller brain (Raji et al. 2010),
TABLE 1
Before and After Percentile Scores on the Microcog Assessment of Cognitive Functioning in 30 NFL Players
MicroCog Before After Number of Players with
Domains Mean (Std. Dev) Mean (Std. Dev) p Value > 50% improvement
General Cognitive Functioning 31.8 (24.1) 43.4 (25.7) <0.000 14
General Cognitive Prociency 24.7 (20.1) 35.2 (23.5) <0.000 14
Processing Speed 33.1 (24.8) 39.3 (25.5) 0.026 12
Processing Accuracy 40.9 (28.7) 48.5 (29.1) 0.012 13
Attention 38.4 (26.2) 48.7 (27.6) 0.025 9
Reasoning 32.7 (25.7) 41.6 (28.0) 0.006 11
Memory 33.8 (27.4) 42.9 (28.4) 0.022 17
Spatial Processing 69.0 (21.8) 74.3 (13.2) 0.154 3
Reaction Time 70.2 (24.5) 74.67 (22.9) 0.669 6
Amen et al. Enhancing rCBF, Cognition in NFL Players
Journal of Psychoactive Drugs 3 Volume 43 (1), March 2011
we encouraged overweight or obese players to lose weight.
Forty-eight percent of players in the initial study were over-
weight or obese, even taking into account their large body
frames. Author KW ran an optional weight-loss group for
players. In addition, players were given 5.6 grams of sh oil
a day, containing 1720mg of EPA and 1160mg of DHA, as
omega-three fatty acid supplementation has shown benets
with memory, mood and cognition (Michael-Titus 2009;
Conklin et al. 2007) and a high-potency multiple vitamin,
which has been shown to enhance mental performance (Ken-
nedy et al. 2010). Participants in the interventional study also
received a brain enhancement supplement that contained
clinically effective dosages of nutrients to enhance blood
ow: ginkgo (Santos et al. 2003) and vinpocetine (Gulyás
et al. 2002); decrease cortisol: phosphatidylserine (Monte-
leone et al. 1990); enhance acetylcholine: acetyl-l-carnitine
(Jones, McDonald & Borum 2010) and huperzine A (Zhang,
Yan & Tang 2008); and enhance antioxidants: alpha-lipoic
acid (Arguelles et al. 2010) and n-acetyl-cysteine (Dodd et
al. 2008). The trial for each participant ranged from two to
12 months, with the average being six months, depending
on the participant’s ability to travel to the study location in
Southern California.
In the follow-up evaluation, participants underwent
a clinical interview, completed a questionnaire on their
progress, had a follow-up brain SPECT scan, and retook
the MACF.
SPECT Image Analysis
Differences in HMPAO uptake were analyzed using
SPM8 software (Wellcome Department of Cognitive Neu-
rology, London, UK) implemented on the Matlab platform
(MathWorks Inc., Sherborn, MA). Statistical parametric
maps (SPMs) are spatially extended statistical processes that
are constructed to test hypotheses about regionally specic
effects in neuroimaging data. Statistical parametric map-
ping combines the general linear model and the theory of
Gaussian random elds to make statistical inferences about
regional effects (Friston, Holmes & Worsley 1995). The
images were spatially normalized using a twelve parameter
afne transformation followed by nonlinear deformations
(Ashburner & Friston 1999) to minimizing the residual
sum of squares between each scan and a reference or tem-
plate image conforming to the standard space dened by
the Montreal Neurological Institute (MNI) template. The
original image matrix obtained at 128x128x29 with voxel
sizes of 2.16mm x 2.16mm x 6.48mm were transformed
and resliced to a 79x95x68 matrix with voxel sizes of 2mm
x 2mm x 2mm consistent with the MNI template. Images
were smoothed using an 8mm FWHM isotropic Gaussian
kernel.
As a group, we compared participants’ original SPECT
scans with their follow-up scans using a paired t-test with
ANCOVA. Based on our prior study (Amen et al. 2011),
our hypothesis was that we would see increased rCBF in the
prefrontal cortex, anterior cingulate gyrus, temporal lobes,
parietal lobes, occipital lobes and cerebellum. SPM(z) score
differences for a-priori regions of interest (Table 2) were
computed using the WFU PickAtlas toolbox within the
SPM8 framework (Maldjian et al. 2003, Maldjian, Laurienti
& Burdette 2004).
RESULTS
In the retest situation, corrected for practice effect, there
were statistically signicant increases in MACF scores in
general cognitive functioning, general cognitive prociency,
attention, memory, reasoning, information processing speed
and accuracy (see Table 1). There were also increases in
spatial processing and reaction time, although these were not
statistically signicant. Many of the participants had robust
increases in performance. Table 1 also lists the number of
participants in each category who had greater than a 50%
increase in percentile scores.
The brain SPECT scans also showed signicant in-
creases in brain perfusion at p < 0.001, especially in the
prefrontal cortex, anterior cingulate gyrus, parietal lobes,
occipital lobes, and cerebellum (see Table 2 for specic areas
of signicant increases and Figure 1 for a visual represen-
tation of the areas of signicant increase). No signicant
TABLE 2
Signicant Areas of Increased Perfusion After Treatment at p < 0.001
AAL Areas Cluster Size Location Z
Prefrontal Infer-Mid-Sup Lt 473 -24 62 16 4.69
Prefrontal Mid Sup Rt 2064 36 50 24 3.58
Inferior Orbital Lt 244 -2 52 -32 4.05
Anterior Cingulate Rt 79 12 40 24 3.68
Parietal/Angular Lt 77 -60 -54 48 4.49
Parietal/Precuneus Lt 205 -12 -56 74 4.32
Parietal/Precuneus Rt 188 20 -54 78 4.35
Occipital/Cuneus Lt 136 2 -102 18 4.30
Occipital/Cuneus Rt 197 26 -104 8 3.89
Cerebellum Crus Rt 104 48 -78 -22 4.01
Amen et al. Enhancing rCBF, Cognition in NFL Players
Journal of Psychoactive Drugs 4 Volume 43 (1), March 2011
decreases were seen. These ndings were consistent with our
hypothesis, except at this level we did not see increases in
temporal lobe perfusion. When the threshold was lowered to
p < 0.05 there were signicant increases in the left and right
fusiform gyrus and lateral temporal lobes. Symptomatically,
participants reported increases in memory (69%), attention
(53%), mood (38%), motivation (38%), and sleep (25%).
CONCLUSIONS
This clinical study targeted retired professional football
players who had experienced traumatic brain injuries as a
result of numerous impacts over extended periods of time.
Our goal was to design an interventional strategy that would
improve cognitive function by enhancing cerebral blood
ow, acetylcholine and antioxidant activity. We utilized a
standard brain imaging tool (SPECT) and a standard com-
puterized neuropsychological test (MACF) to determine if
improvement could be obtained. Our ndings on this unique
population are encouraging as we observed signicant im-
provements in general cognitive functioning, information
processing speed, attention and memory in close to half of
the participants. Plus, there were signicant increases in
regional cerebral blood ow seen on SPECT.
FIGURE 1
Areas of Increased Perfusion on SPECT with Treatment at p < 0.001 are Highlighted
Amen et al. Enhancing rCBF, Cognition in NFL Players
Journal of Psychoactive Drugs 5 Volume 43 (1), March 2011
The implications of this study directly apply to the larger
traumatic brain injury and substance abuse communities. We
were able to demonstrate improvement in brain function and
cognitive performance in retired players who sustained brain
injuries often decades previously, demonstrating brain plas-
ticity. This is an area where much more research is needed.
Because of the high incidence of traumatic brain injury and
the long-term damaging effects of substance abuse, focus-
ing on brain health and brain rehabilitation strategies in
addiction treatment programs could potentially signicantly
improve patient outcomes.
This clinical study is limited by its nonrandomized,
open-label, multifaceted design and the results must be
interpreted with caution. Our hope is to use this trial as a
starting point to more rigorously study the individual parts
of the treatment protocol and to extend the study to include
other types of brain damage, including blast injuries, single-
incident brain traumas, and substance abuse.
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... 1,32,42,55,61,62,79,84 Additionally, impact location and direction of rotation has been shown to affect functional outcome. 4,6,10,11 While many brain injury metrics have been developed over the years, none fully characterize the influence of impact direction. ...
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... Similarly, Baicalein inhibits ferroptosis and improves post-TBI behavioral outcomes (Andersen et al., 2019;Kenny et al., 2019). Additionally, N-acetylcysteine has a protective effect on GSH in adult, but not pediatric, patients with TBI (Amen et al., 2011;Hoffer et al., 2013). (TABLE 1) Different cell death mechanisms, apoptosis, necrosis, autophagy and ferroptosis occur in neurological diseases (Guiney et al., 2017). ...
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Ferroptosis is mechanism for non-apoptotic, iron-dependent, oxidative cell death that is characterized by glutathione consumption and lipid peroxides accumulation. Ferroptosis is crucially involved in neurological diseases, including neurodegeneration, stroke and neurotrauma. This review provides detailed discussions of the ferroptosis mechanisms in these neurological diseases. Moreover, it summarizes recent drugs that target ferroptosis for neurological disease treatment. Furthermore, it compares the differences and relationships among the various cell death mechanisms involved in neurological diseases. Elucidating the ferroptosis role in the brain can improve the understanding of neurological disease mechanism and provide potential prevention and treatment interventions for acute and chronic neurological diseases.
... The first study by Harch and colleagues 76 examined 13 patients who were exposed to blast injury 1 to 5 years before treatment, and the second study by Boussi-Gross et al 77 examined 56 patients at 1 to 5 years after mild TBI. Finally, a multifactorial lifestyle program in a cohort of retired NFL players by Amen and colleagues 78 showed that interventions such as reducing body tissue adiposity as reflected by reducing body mass index produced increases in SPECT cerebral blood flow, particularly in the frontal lobes. 69 These studies are significant as they highlight the importance of SPECT scans as contributing to the personalized medicine of TBI by identifying biomarkers that predict treatment response. ...
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Obesity is associated with increased risk for cardiovascular health problems including diabetes, hypertension, and stroke. These cardiovascular afflictions increase risk for cognitive decline and dementia, but it is unknown whether these factors, specifically obesity and Type II diabetes, are associated with specific patterns of brain atrophy. We used tensor-based morphometry (TBM) to examine gray matter (GM) and white matter (WM) volume differences in 94 elderly subjects who remained cognitively normal for at least 5 years after their scan. Bivariate analyses with corrections for multiple comparisons strongly linked body mass index (BMI), fasting plasma insulin (FPI) levels, and Type II Diabetes Mellitus (DM2) with atrophy in frontal, temporal, and subcortical brain regions. A multiple regression model, also correcting for multiple comparisons, revealed that BMI was still negatively correlated with brain atrophy (FDR <5%), while DM2 and FPI were no longer associated with any volume differences. In an Analysis of Covariance (ANCOVA) model controlling for age, gender, and race, obese subjects with a high BMI (BMI > 30) showed atrophy in the frontal lobes, anterior cingulate gyrus, hippocampus, and thalamus compared with individuals with a normal BMI (18.5-25). Overweight subjects (BMI: 25-30) had atrophy in the basal ganglia and corona radiata of the WM. Overall brain volume did not differ between overweight and obese persons. Higher BMI was associated with lower brain volumes in overweight and obese elderly subjects. Obesity is therefore associated with detectable brain volume deficits in cognitively normal elderly subjects.