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Objective: Two chronic, traumatic brain injury (TBI) cases, where cognition improved following treatment with red and near-infrared light-emitting diodes (LEDs), applied transcranially to forehead and scalp areas, are presented. Background: Significant benefits have been reported following application of transcranial, low-level laser therapy (LLLT) to humans with acute stroke and mice with acute TBI. These are the first case reports documenting improved cognitive function in chronic, TBI patients treated with transcranial LED. Methods: Treatments were applied bilaterally and to midline sagittal areas using LED cluster heads [2.1″ diameter, 61 diodes (9×633nm, 52×870nm); 12–15mW per diode; total power: 500mW; 22.2mW/cm2; 13.3J/cm2 at scalp (estimated 0.4J/cm2 to cortex)]. Results: Seven years after closed-head TBI from a motor vehicle accident, Patient 1 began transcranial LED treatments. Pre-LED, her ability for sustained attention (computer work) lasted 20 min. After eight weekly LED treatments, her sustained attention time increased to 3 h. The patient performs nightly home treatments (5 years); if she stops treating for more than 2 weeks, she regresses. Patient 2 had a history of closed-head trauma (sports/military, and recent fall), and magnetic resonance imaging showed frontoparietal atrophy. Pre-LED, she was on medical disability for 5 months. After 4 months of nightly LED treatments at home, medical disability discontinued; she returned to working full-time as an executive consultant with an international technology consulting firm. Neuropsychological testing after 9 months of transcranial LED indicated significant improvement (+1, +2SD) in executive function (inhibition, inhibition accuracy) and memory, as well as reduction in post-traumatic stress disorder. If she stops treating for more than 1 week, she regresses. At the time of this report, both patients are continuing treatment. Conclusions: Transcranial LED may improve cognition, reduce costs in TBI treatment, and be applied at home. Controlled studies are warranted.
Traumatic brain injury (TBI) is a significant socio-economic burden;1 1.4 million individuals are affected by TBI annually in the U.S.2 Closed-head, mild TBI does not show focal lesions on computed tomography or magnetic resonance imaging scans.3 Instead, diffuse axonal injury4 in the anterior corona radiata and frontotemporal regions is often seen.5 Brain positron emission tomography scans have shown low levels of regional glucose metabolism in bilateral frontal and temporal lobes in chronic TBI cases.6 Other studies have also shown abnormal frontal lobe activation.7–9 Two regions within the frontal lobes susceptible to damage during TBI are the prefrontal cortex and the anterior cingulate gyrus. The prefrontal cortex is involved in maintaining, monitoring, and manipulating information in working memory,10 and particularly in sustained attention.11,12 The anterior cingulate gyrus has been implicated in divided attention, novelty detection, working memory, memory retrieval, Stroop tasks (inhibition), evaluative judgment, motivation, and performance monitoring.11–16 The anterior cingulate gyrus is considered an initiating or inhibiting region, in that it initiates appropriate, and suppresses inappropriate, behavior.13,15,16
Chronic post-traumatic stress disorder (PTSD) cases share some of the same abnormality in neurocircuitry with chronic TBI cases, including medial prefrontal cortex dysfunction. This includes inadequate top-down governance of the amygdala by the medial prefrontal cortex.17
Low-level laser (light) therapy (LLLT, 500mW or less) using coherent lasers, or non-coherent light-emitting diodes (LEDs) has been shown to produce beneficial cellular and physiological effects in controlled trials (reviewed in Desmet et al., 2006).18 During LLLT, absorption of red or near infra-red (NIR) photons by cytochrome c oxidase in the mitochondrial respiratory chain19 causes an increase in cellular respiration that continues for much longer than the duration of exposure to the light, when light treatment is delivered at appropriate fluence and exposure durations. Primary cellular effects include changes in intracellular calcium,20 increases in ATP synthesis,20–22 increases in nerve cell proliferation and migration,23 and production of low levels of reactive oxygen species (ROS) in mitochondria, causing NF-kB activation via the redox sensitive sensor enzyme protein kinase D1.24 One of the most upregulated genes after NF-kB activation is the antioxidant, mitochondrial superoxide dismutase (MnSOD).25
Transcranial NIR light that penetrates the scalp and skull can significantly reduce damage from experimentally induced stroke in rats23 and rabbits,26 improve memory in middle-aged mice,27 reduce the amount of brain damage and sequelae stemming from acute TBI in mice,28 and significantly improve the outcome in human cases of acute stroke.29,30 A single transcranial, NIR LED application to the left (L) and right (R) lateral forehead areas (F3, F4 in the 10/20 EEG system) has been observed to significantly reduce depression and anxiety for 2 weeks, in patients diagnosed with chronic, major depression.31
Neurogenesis in the TBI-damaged brain is not the rare event it was once thought to be.32 LLLT has stimulated neuron repair in the spinal cord in an animal model,33 and could increase neurogenesis in TBI-damaged brain tissue. LLLT increases expression (and activation) of growth factors such as transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF), which may contribute to positive brain remodeling after TBI. In a rat stroke model, transcranial LLLT triggered the expression of TGF-β1 (in addition to reducing NO levels).34 In a rat heart infarcts model, LLLT significantly increased VEGF expression levels, which are correlated with increased angiogenesis.35
Two similar red/NIR LED devices were used. The first had three, square-shaped LED cluster heads, each with a dimension of 4.4×4.4cm (approximately 1.75×1.75 in). The treatment area was 19.39cm2; each cluster head contained 49 diodes (40 NIR 870nm diodes, 12.25mW each, and 9 red 633nm diodes, 1mW each). Total power was 500mW (±20%), continuous wave (CW); power density, 25.8mW/cm2 (+20%); 1J=2s, 1J/cm2=38.8s.
The second device had one (or three), circular-shaped cluster heads, each with a diameter of 5.35cm (2.1 in). Treatment area was 22.48cm2; each cluster head contained 61 diodes (52 NIR 870nm diodes, and 9 red 633nm diodes, 12–15mW each). Total optical output power was 500mW (±20%), CW; power density, 22.2mW/cm2 (±20%); 1J=2s, 1J/cm2=45s. The devices were FDA-approved for treatment of musculoskeletal pain. They were used off-label; informed consent was obtained.
P1 (59F, R-handed) sustained closed-head TBI in a motor vehicle accident (MVA) (April 1997). Her head snapped back, hitting a rigid head-rest. She was wearing a seatbelt and did not lose consciousness. Head X-rays and structural magnetic resonance imaging (MRI) scan were normal.
She had two Master's degrees, knew three languages, had written three books, and was a member of Mensa. She had been director of marketing for an internet marketing company, and taught web-design at a major university. At 5 months post-MVA, she was diagnosed by a neurologist as having post-concussive syndrome, was told she might never recover (even for 5 years), and resigned from all professional work due to cognitive dysfunction.
At 2 years post-MVA, her cognitive abilities were re-evaluated. Her divergent reasoning abilities were “significantly impaired across all verbal tasks,” and “executive functioning ability was severely impaired.” During years 2 and 4 post-MVA, she completed three cognitive training programs (20–40 days, each). She could then work on her computer for 20 min at a time, but was still unable to perform professional work. She suffered from depression, with a suicidal gesture.
At 7 years post-MVA, she received her first transcranial LED treatment (May 2004). The first LED device (described above) was used on the L and R forehead areas, 8J/cm2 to each area; treatment time, 5min, 10s per area. She drove herself home (30 min), then slept through dinner and most of the next day. On day 3 after the first LED treatment, she had “improved concentration and focus” and she was able to work at her computer for 40 min (compared with 20 min, previously).
Note, when 8J/cm2 is applied to the head, it is estimated that only 2–3% of the NIR photons reach brain cortex at depths of 1cm from the skin or scalp surface (on the basis of post-mortem studies).36 Only 0.2–0.3% are estimated to reach depths of 2cm (into white matter). Thus, the transcranial LED treatment with 8J/cm2 delivered to skin on the L and R forehead areas is estimated to deliver only 0.24J/cm2 to brain cortex (3%); and 0.024J/cm2 to white matter (0.3%).
One week later, the same LED treatment was repeated. She had no return of excessive sleepiness, and was able to work at her computer for 40 min at a time during the week. During weeks 3 to 8, she continued with weekly treatments, with the following areas undergoing treatment: bilateral forehead (targeting the frontal poles/prefrontal cortex); midline at hairline (targeting the anterior cingulate gyrus); and bilateral temples (targeting the anterior temporal lobes). The hair was carefully parted on the scalp under each LED cluster head to help reduce blockage of the red/NIR photons into the scalp from hair.
The treatment parameters were gradually increased from 8J/cm2 (5min, 10s) per area to 20J/cm2 (12min, 54s) per area. After 8 weeks, P1 was able to work at her computer for 3 h at a time.
After 7 months of weekly LED treatments, in January 2005 (7 years, 9 months post-MVA) she obtained a home treatment unit, the second LED device (single LED cluster head) (Fig. 1). She treated 6 forehead/scalp areas per night (10min per area; 13.3J/cm2 per area; 0.4J/cm2 to cortex). The areas included were: bilateral forehead, temples, posterior-superior to the ears (likely angular gyrus areas, which she reports helped her to “remember what she read”), base of occiput (which “removed the extreme sensitivity of the L scalp area that had bothered her when her hair was being cut”), midline at front hairline, and the center, vertex of her head (which “improved her ability to do math”). She has not been formally tested.
She prefers to treat at bedtime because this LED protocol “improves her sleep.” The 6 areas treated vary from night to night. After 3.5 years, she also added an acupuncture point on the sole of the foot, Kidney 1, a point used historically to reverse coma and improve mentation,37 or top, base of toes - Ba Feng. At the time of this report (March 2010), she has continued to treat herself with this basic home treatment protocol for 5 years. She sometimes treats for 3 weeks in a row, then stops for 1 week.
If she stops the transcranial LED treatments for more than 2 weeks, she slowly regresses; her focus and attention become compromised. As is common with chronic TBI patients, she has fallen occasionally since the MVA. This includes two falls at home since acquiring the home treatment unit. She feels that using the LED cluster head, transcranially, as soon as possible after a fall, helps her to recover faster. (Note: because transcranial LED may increase cerebral blood flow, it would be contra-indicated if acute cerebral hemorrhage was present; see Discussion.)
After 6 years of transcranial LED treatments, she continues to perform computer work for 3 h at a time. She reports “improved self-awareness of both limitations and successes, as well as improved inhibition of inappropriate behavior and angry outbursts.” She also uses the LED unit to help manage her osteoarthritis knee pain. She notes there are some remaining cognitive problems; she cannot multi-task as well as she would like. She still needs to make notes, to be sure all things are accomplished; her overall quality of life, however, is much improved (now age 72, and 13 years post-MVA). She continues to take the drug, Concerta, which she had begun several years before starting the transcranial LED treatments.
P2 (52F, R-handed) referred herself for neuropsychological evaluation (March 2009) due to changes in her cognitive functioning over the preceding 2 years, particularly the last 4–5 months. She holds a Bachelor's degree and had a distinguished military career as a high-ranking officer. After 20 years of service, she retired and was working full-time as an executive consultant for an international, technology consulting firm.
She had a history of multiple concussions without loss of consciousness (LOC) during civilian traumas (rugby, sky diving), and military deployment. In 2007, she fell backwards from a swing, hitting the back of her head on concrete (with LOC, likely several minutes). Soon after, she noticed changes in cognition (could not concentrate, stay on task, or multi-task). In October 2008, she stopped working and required medical disability due to cognitive dysfunction.
In December 2008, an EEG showed right temporal lobe slowing (monorhythmic) without epileptiform activity. Structural MRI showed a slightly larger left frontal horn compared with the right frontal horn; and bilateral, deep prominent sulci were present throughout, especially in high frontal and parietal cortical areas (Fig. 2). No enhancing lesions were demonstrated with contrast. A toxicology screen was carried out, and a high mercury level of 1.2μg/g (reference <0.80) was observed. The nickel level was 0.40μg/g (reference <0.30).
Neuropsychological testing was performed in March 2009, prior to any LED treatments. This evaluation showed deficits in executive functioning, including working memory, processing speed, and cognitive flexibility, all of which are consistent with frontal lobe dysfunction. The scores from March 2009 are described later, in the context of comparison with those following 9 months of transcranial LED treatments (December 2009).
In March 2009, P2 began transcranial LED treatments (second LED device, three LED cluster heads). Each night, the cluster heads were placed on the skin/scalp over the bilateral forehead, high-frontal, high-parietal, and temporoparietal areas (areas with prominent cortical atrophy on her MRI).
The duration of treatment for each area was gradually increased over a 4-week period. During the first week, the LED cluster heads were applied daily for 7min/area (9.3J/cm2 at scalp, 0.28J/cm2 to cortex). Following the first treatment (performed in the afternoon) she was sleepy for the next several hours. During the second week, the LED cluster heads were applied nightly (at bedtime) for 8min/area (10.6J/cm2, 0.32J/cm2); during the third week, for 9min/area (12J/cm2, 0.36J/cm2); and thereafter, for 10min/area (13.3J/cm2, 0.4J/cm2). In addition to the transcranial LED areas, one additional area was treated on the sole of the foot, acupuncture point Kidney 1.37 See Fig. 3.
In July 2009, after 4 months of transcranial LED treatments, her medical disability was discontinued; she returned to work full-time, as executive consultant with the international, technology consulting firm (employer prior to October 2008). She continues with this full-time employment as of March 2010.
Post-LED neuropsychological testing showed significant improvement (+1, +2 SD) on tests of executive function and inhibition, and on memory. On the Stroop test, a test for executive function (color-word interference test),38 there was significant improvement in condition 3, showing improved inhibition. This task requires naming the ink color in which discrepant color words are printed. There was a change of +2 SD from a score of −1.5 SD below the mean for this test (9th percentile, March 2009) to a score of +0.5 SD above the mean (63rd percentile, December 2009). There was also a significant improvement in condition 4, showing improved inhibition accuracy. This task requires switching back and forth between naming the ink colors and reading the words. There was a change of +2 SD from a score of −1.5 SD below the mean for this test (9th percentile, March 2009) to a score of +0.5 SD above the mean (63rd percentile, December 2009). These scores reflect significant improvement (+2 SD) in executive functioning, inhibition, and inhibition accuracy (Fig. 4).
On the Wechsler Memory Scale - Revised39 there was significant improvement in logical memory passages, where the examinee repeats information in two paragraphs (one at a time) read aloud by the examiner, both immediately, and after a 30-min delay. In addition, inquiry regarding recognition of facts within each story follows the delayed recall. In March 2009, immediate recall was in the 83rd percentile, and in December 2009, in the 95th percentile, reflecting a +1 SD improvement. In March 2009, delayed recall was in the 83rd percentile, and in December 2009, in the 99th percentile, reflecting a +2 SD improvement. These scores show a +1, +2 SD improvement in memory.
In December 2009 (9 months post-LED treatments), P2 participated in an interview with a co-author (JK), a clinical neuropsychologist specializing in PTSD. As is true for many people who suffer a physical injury with TBI, the index event also qualifies diagnostically for PTSD as a psychological trauma. Clinical effects can manifest in difficulties modulating memories, emotions, and physiological reactivity that develop from personal internal as well as from environmental cues. Managing these reactions can be further impaired by an overlapping TBI, or multiple overlapping TBIs.40
Prior to the LED treatments, P2 was having noticeable difficulties employing appropriate levels of social behavior, with appropriate levels of emotional intensity in social and work milieus. Her sleep was disrupted and less regular than before the injury. After a few months of transcranial LED treatments, she noticed improved levels of self-awareness, self-monitoring, and self-regulation in social and work settings. Her sleep was improved and impulsivity to react with irritation and anger were reduced. Her medications include Lexapro (since 2002, but discontinued in June, 2009), Provigil, Ritalin (30mg per day, initiated in June, 2009), Armour thyroid replacement, liquid glutathione, and twice weekly vitamin B injections.
The mechanisms of action underlying the observed improved cognition through the use of transcranial, red/NIR LEDs in these two mild TBI cases are unknown. Five possible mechanisms are reviewed briefly, below.
Results from the two chronic TBI cases described here, along with those from previous transcranial LLLT/LED studies with acute stroke patients and chronic, major depression cases, suggest that further, controlled research with this methodology is warranted. Further study is required to determine the optimal treatment parameters. Transcranial red/NIR LED may be an inexpensive, noninvasive treatment, suitable for home treatments, to improve cognitive function in TBI patients, as well as to reduce symptom severity in PTSD patients. It is recommended that future studies include pre- and post-neuropsychological testing, as well as functional brain imaging and diffusion tensor imaging scans, to better understand the possible physiological changes that may take place with transcranial LLLT/LED treatments.
A preliminary version of this paper was published as a proceedings paper.56
The authors thank Charles Foltz for the graphics art in Figure 5; Carole Palumbo, Ph.D. for assistance with MRI analysis; Paula Martin, Anna Kharaz, Michael Ho, Ph.D., and Ethan Treglia, M.S., for manuscript assistance; and Michael and Winter Robinson for photography. M. Naeser was supported by Merit Review Funding, Department of Veterans Affairs. M. Hamblin was supported by the NIH (grant RO1AI050875), US Air Force MFEL program (contract FA9550-04-1-0079), Center for Integration of Medicine and Innovative Technology (DAMD17-02-2-0006), and Congressionally Directed Medical Research Program (W81XWH-09-1-0514).
No competing financial interests exist.