Brain Modulation Treatments for Mild Traumatic Brain Injury
Non-Invasive Brain Modulation for Mild Traumatic Brain Injury: A Review
Non-invasive brain modulation has been rapidly growing as a therapeutic modality for various neurological disorders and diseases. Growing research on photobiomodulation, transcranial magnetic stimulation, and transcranial direct current stimulation show promising results in their ability to alter neuronal activity and neuroplasticity in specific brain regions, ultimately impacting broader cognitive or clinical outcomes. This review explores the applicability of such modulation techniques to mild traumatic brain injuries (mTBI). mTBIs can cause prolonged post-concussion symptoms, such as headache and dizziness, depression, and cognitive impairment- all which negatively impact an individual’s ability to work, play sports, and maintain relationships. While current treatment involves medications that aim to simply reduce symptoms, neuromodulation devices have the potential to offer a safe and effective treatment to eliminate the root neuropathology of post-concussion symptoms.
Mild Traumatic Brain Injury
There are an estimated 2.5 million cases of traumatic brain injuries (TBI) per year in the United States, making it one of the leading areas for research and development . Most of this research focuses on treating severe cases of TBI; however, around 70-85% of all TBI cases are classified as mild traumatic brain injury (mTBI). mTBI is defined as “a traumatically induced physiological disruption of brain function” associated with less severe loss of consciousness (<30mins), memory (<24hr), and neurological function as compared to moderate or severe TBI . mTBIs are often caused by vehicle accidents, falls, and sports injuries. In fact, increased diagnosis of sports concussions has raised several questions regarding optimal treatment protocols for athletes.
Despite being labeled as “mild”, mTBI is often associated with post-concussive symptoms (PCS) that can be debilitating and chronic. The average symptoms of an mTBI last around 2 weeks in adults, but in 40% of mTBI, symptoms will last over 3 months and 80% of this subset will have persistent symptoms following one year after injury . These symptoms include physical symptoms (headache, dizziness, fatigue), emotional symptoms (depression, anxiety), and cognitive symptoms (attention deficits, difficulty learning, poor working memory). These all have negative impacts on the individual’s quality of life and relationships with others.
Current treatments for mTBI
Current treatments for mTBI vary widely, but standard procedure involves simply monitoring and managing symptoms until they stabilize . This can be extremely frustrating to the affected individual, as they may be taking pharmacological drugs that only partially reduce symptoms. For individuals with mTBI depression, antidepressant medications can cause negative side effects and/or drug dependency . Furthermore, cognitive impairments reduce work efficiency at school or work.
Since there are no current effective treatments for PCS, it is important that researchers explore the use of neuromodulation, a noninvasive and non-pharmacological solution to treating the root causes of many mTBI symptoms. Unlike medications that aim to alleviate symptoms, neuromodulation can directly address the neuropathy and strengthen synaptic connections to promote recovery . Neuromodulation techniques vary widely in application, treatment location, power, duration, and other protocol factors. This review aims to analyze the efficacy and optimal protocols for three types of neuromodulation: photobiomodulation (PBM), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS). Each modality has a different mechanism of action and ability to modulate certain brain regions. Their effects have been shown to last beyond treatment periods. These prolonged effects have been believed to come from changes in neuroplasticity regarding long-term potentiation and depression .
Repetitive transcranial magnetic stimulation
Transcranial magnetic stimulation (TMS) is a method of noninvasive neuromodulation, and it uses repetitive magnetic fields to induce or suppress neuronal activity and facilitate cortical reorganization of neural networks . Studies use a mix of high frequency (>5Hz) and low frequency (~1 Hz) to induce and suppress neuronal excitability, respectively . TMS is currently FDA approved for treating treatment-resistant depression, obsessive-compulsive disorder (OCD), and migraine . Additionally, researchers are studying if TMS can treat Parkinson’s and Schizophrenia . Despite the location of injury, TBI often negatively impacts brain connectivity and cognitive functions, which are controlled by frontal regions . Thus, for treating post-concussive symptoms such as depression and reduced executive function, rTMS is usually targeted to the dorsolateral prefrontal cortex (dlPFC) of mTBI subjects .
Transcranial direct current stimulation (tDCS)
Transcranial direct current stimulation (tDCS) applies low intensity electrical current pulses (1 - 2mA) through the scalp to alter neuronal excitability. This technique may involve a mix of anodal and cathodal tDCS to increase and decrease excitability, respectively, and using both at the same time is referred to as bilateral tDCS. Scientists think that anodal tDCS increases cortical excitability possibly by reducing GABA concentration, while cathodal tDCS inhibits cortical excitability possibly by reducing glutamate concentration. This theory comes from the fact that mTBI patients have higher GABA concentrations and decrease plasticity compared to healthy controls . Additional mechanistic explanations suggest that the cortical electrical stimulation facilitates cognitive reorganization and consolidation of learning in a given neural network . This has led to various attempts to target specific networks related to PCS by combining tDCS with specific cognitive training modules. Overall, tDCS is a safe, easy to use, and cheap neuromodulation technique with potential for treating PCS from mTBI.
Photobiomodulation or Low Level Laser Therapy
Photobiomodulation (PBM) is another noninvasive neuromodulation technique that uses red to near-infrared (NIR) light to stimulate cells, alter metabolism, and encourage blood flow. PBM treatment was accidentally discovered by Mester et al. 1968 in an attempt to treat cancer with low power lasers, however instead of destroying tumor cells, the researchers noticed improved skin healing and hair growth in treatment areas . Since then, researchers have been studying how PBM could promote healing in the brain, since mTBI is associated with cerebral atrophy.
The mechanism of PBM involves the absorption of photons by the enzyme cytochrome C oxidase. The photons displace non-covalently bound nitric oxide molecules, which are then released to increase blood flow and oxygen consumption. The effects of PBM involve increased production of adenosine triphosphate (ATP), increased cerebral blood flow (CBF), neurogenesis, and decreased inflammation . This provides direct neuroprotection against the reduced ATP levels and CBF associated with mTBI .
Search terms consisted of various combinations of “neuromodulation” “rTMS” “tDCS” “photobiomodulation” “mild” “TBI” “post-concussive symptoms.” For this analysis, only human studies were included, and studies were taken from the past decade (2012-2022). Research focused on finding papers treating mTBI, but if needed, moderate to severe TBI papers were also considered.
METHODS, RESULTS, AND DISCUSSION
Headache / Mental Fatigue / Dizziness
Some of the most common complaints of PCS involve frequent headaches, mental fatigue, and/or dizziness. Oftentimes, the cause of these symptoms are not revealed through standard brain imaging or blood tests (e.g. there are no intracranial lesions or microhemorrhages causing these symptoms). Stumped, researchers have recently turned to neuromodulation techniques to try and treat these symptoms, each with variable results and study reliability.
Paxman et al. 2018 presents a case study of a 61-year-old man with chronic dizziness following mTBI five years prior to the study . Despite lots of vestibular and vision therapy, the dizziness had not subsided. Researchers administered 10 45-minute rTMS sessions over the left dlPFC at 10 Hz and 70% resting motor threshold (RMT) over the course of 2 weeks. RMT is identified using electromyography (EMG) and was determined as the minimal stimulation intensity required to evoke a motor response of 50uV in the right hand while stimulating the left primary motor cortex. For this study, MRI imaging was used for target localization. Three months after treatment, researchers measured a 50% reduction in dizziness severity and frequency measured by the Dizziness Handicap Inventory. This sustained and significant improvement in symptoms offers a potential solution; however, since this study was unblinded, only tested on one person, and relied on self-reported symptoms, caution should be taken when interpreting results. Leung et al. 2017 employed similar protocols for 4 daily rTMS sessions at 10 Hz and 80% RMT over the left dlPFC in 29 mTBI subjects . Results of this randomized and sham-controlled study demonstrated a significant difference in headache symptoms between active and sham groups, with the active group seeing a 25% reduction in headache intensity and a 50% reduction in headache frequency 1 week and 4 weeks after treatment. Results of this study provide stronger evidence of rTMS efficacy in treating post-concussive headaches. Longer followup data should be collected to determine how long the effects last and if more treatment is warranted.
It is noted that there are no published studies for the use of tDCS for treating headache or dizziness in TBI patients; however, Shirvani et al. 2021 investigated the effect of tDCS on mental fatigue in TBI patients, which is often associated with headache . 48 subjects were split into 3 groups: tDCS treatment, tDCS sham, and mindfulness based stress reduction (MBSR) treatment. MBSR is a form of cognitive training focused on the awareness of thoughts, feelings, and perceptions. The tDCS group were assigned 10 20-minute sessions at 1.5 mA over the course of 3 weeks. Anodal tDCS was localized over the left frontal regions and cathodal tDCS was localized over the right dlPFC. The sham group had the same protocols but with ramp-in and ramp-out phases to stimulate treatment. Finally, the MBSR group underwent 9 2-hour treatment sessions and take-home exercises over the course of 8 weeks. Results demonstrate that both the tDCS and MBSR treatments caused sustained reductions (2 month post-treatment) in mental fatigue compared to sham tDCS. Measured by the mental fatigue scale (MFS) questionnaire, the mental fatigue of subjects in the MBSR treatment group had greater reductions than that in the tDCS group, suggesting that MBSR may be a more effective option. It is important to note, however, that the perceived self-efficacy of active training could skew the results of this study.
Studies have also looked into using LLLT for treating headache and dizziness following TBI. In one paper, Figueiro Longo et al. 2020 conducted a randomized and blinded study using LLLT on 68 moderate TBI patients at Massachusetts General Hospital . Treatment was administered to the entire scalp surface using a custom-built helmet with 18 clusters of 20 NIR LEDs, and treatment was begun within 72 hours of the TBI. The sham treatment used the same helmet just without the LEDs turned on. Both the treatment group and the sham group underwent 3 20-minute sessions, totaling an energy density of 43 J/cm^2. This amounts to 1.3 J/cm^2 reaching the brain since only 3% penetrates through the skull. Note that this treatment was much shorter than the rTMS treatments presented by Paxman et al. 2018. Additionally, Figueiro Longo et al. 2020 and Paxman et al. 2018 differ in their outcome measurements, with Figueiro Longo et al. 2020 measuring subject headache and dizziness with the Rivermead Post-Concussion Symptoms Questionnaire (RPQ). With the conditions outlined above, the researchers found lower but not significantly lower RPQ scores in LLLT treatment vs sham groups. They did, however, detect significant group differences in white matter diffusivity measured with MRI, suggesting that LLLT can modulate myelin repair pathways in moderate TBI patients. Further research is needed to generalize these results to mTBI since axonal damage and myelination can vary based on TBI severity.
Based on the studies by Paxman et al., Shirvani et al., and Longo et al., it seems that rTMS has the potential for the most effective treatment for head complaints following mTBI; however, it may be less studied than the other two neuromodulation techniques presented. On the other hand, tDCS was tested in a fairly large study and was shown to have some positive effects, though not as effective as alternative methods like MBSR. Finally, LLLT did not show significant effects on symptoms for the given treatment protocols, but it is possible that it could show effects if extended to longer periods, such as the 10-sessions presented in the other two studies.
Another major post-concussive symptom of research interest is depression. 50% of TBI cases will suffer from associated depression, compared to the 19% depression rate of the normal population . The development of depression depends on a wide variety of factors, including age, education level, injury severity, and various psychosocial factors. Pharmacological treatments can create a dependency on these medicines and can come with negative side effects. Finding an effective way to noninvasively treat depression could make a huge impact on mTBI subjects’ quality of life and could speed up their recovery processes .
Perhaps the most studied neuromodulation treatment for depression involves using rTMS to target the prefrontal cortex. Major depression has been associated with abnormally decreased activity in the left prefrontal cortex (PFC) and increased activity in the right PFC. Thus, researchers believe that anodal (increases activity) left-sided rTMS over the left PFC and/or cathodal (decreases activity) right-sided rTMS over the right PFC could directly treat the pathology . Two different studies, Rao et al. 2019 and Lee and Kim 2018, employed similar protocols for using 1Hz rTMS at 110% and 100% RMT, respectively, vs sham treatment over the right dlPFC to treat depression in TBI subjects [. Lee and Kim recruited 13 subjects for 10 daily sessions spanning 2 weeks, while Rao et al. recruited 30 subjects for 20 daily sessions spanning 5 weeks. Despite very similar protocols, the studies found very different results. Lee and Kim reported a reduction in depression by 29.29% using the Montgomery-Asberg Depression Rating Scale (MADRS), which was significantly different from sham treatment. They did not collect follow-up data. On the other hand, Rao et al. reported no significant group differences in depression measured using a 17-item Hamilton Depression Rating Scale (HAM-D) depression score. They confirmed no differences between groups at 4, 8, 12, and 16 week follow-ups. The differences in results could be explained by the depression measurement, since the two studies used different scoring systems. Even though Lee and Kim had a smaller sample size, they only recruited subjects who had been diagnosed with TBI within 6 months of the study. It is possible that treating subjects earlier has a better likelihood of treatment success.
Another study by Siddiqi et al. used a slightly different rTMS protocol from the previous two studies and found positive effects on MADRS depression scores . The first major difference in protocol was how they localized the target for treatment. Since research has pointed to large-scale brain network dysfunction in TBI patients, Siddiqi et al. utilized fMRI resting-state network mapping to target the area of the dlPFC for treatment. They targeted the location with maximal activation difference between the dorsal attention network (DAN) and the default mode network (DMN). In a sham-controlled, randomized, double-blind study, they recruited 15 subjects with mild to moderate TBI who had depression persisting after at least one pharmacotherapy attempt. The real treatment group underwent 20 daily sessions of bilateral rTMS, in which 10Hz excitatory pusles were applied to the left dlPFC location, and 1Hz inhibitory pulses were applied to the right dlPFC location at 120% RMT. Results of the study reveal significant differences in depression scores between the real and sham group, with the real group showing 56% improvement based on the MADRS scores. No follow-up data was collected, but a larger study is currently underway to compare rTMS targeting approaches, including this functional-connectivity method. This paper suggests that the individualized network mapping for bilateral rTMS treatment localization can improve post-concussive depression and that the variance of responses to treatment may be associated with heterogeneity of functional connectivity following TBI. If so, fMRI connectivity measurement could be used to screen for specific patients and optimize protocol factors.
Far less research has been done for treating post-concussion depression using tDCS or PBM. Quinn et al. 2020 reports a double-blind randomized control trial of tDCS over the left dlPFC . 24 individuals with mild to moderate TBI were split into active and sham treatment groups, undergoing 10 daily tDCS treatments combined with cognitive training. tDCS was administered at 2mA for 30 minutes per session. Results show a decrease in depression score, measured by the HAM-D and the Beck Depression Inventory-II (BDI), for both tDCS and sham groups; however, there were no significant differences between groups. These results suggest that the reduction in depression could have just been from cognitive training alone and that tDCS does not add any benefit.
Similarly, Naeser et al. 2014 found no significant or sustained improvement in BDI depression scores due to PBM treatment . They tested 11 mTBI patients using LED NIR over the DMN and dlPFC. 18 10-minute sessions were spread across 6 weeks and each treatment applied a total of 78 J/cm^2 among 6 LED clusters. Since 3% reaches the brain surface, this accounts to 2.4 J/cm^2 applied. It is noted that this energy density is twice the amount as applied by Figueiro Longo et al. 2020 when using PBM for post-concussive headache and dizziness. Neither study found beneficial results from using PBM.
Based on limited research using tDCS or PBM, it appears that these neuromodulation techniques are not as promising as rTMS for treating depression in mTBI patients. Since rTMS is already approved for treating depression in non-TBI subjects, it is believed that it could be extended to treat TBI subjects as well. The major limitation of rTMS involves the sham treatment and effective blindness of the studies. Since active rTMS can cause minor facial twitches, it is possible that the sham treatment can be distinguished by sensation. Additionally, some argue that depression can naturally improve over time following TBI; however, studies have shown that 60% of TBI patients have persisting symptoms 10 years after injury . Thus, researchers believe that any improvements in depression scores over the study period are due directly to the neuromodulation treatment, rather than spontaneous improvements over time. Quality sham groups can further help control for this confounding factor.
The final PCS that is often researched involves various aspects of cognitive impairment. This includes deficits in processing, attention, working memory, and executive functioning. Several studies have been conducted to test the efficacy of using neuromodulation devices to help improve these deficits following TBI. Two studies, Lee and Kim 2018 and Hoy et al. 2019, have demonstrated somewhat promising results for using rTMS on post-concussive subjects . Both studies used a randomized and sham controlled protocol on 13 and 21 subjects, respectively. Lee and Kim targeted the right dlPFC at 1Hz for 10 daily sessions over 2 weeks, while Hoy et al. applied bilateral rTMS over the dlPFC (localized with MRI) for 20 daily sessions over 4 weeks. Both studies found improvements in cognitive function in the active group vs sham group. Lee and Kim reported improvements in processing speed, attention, and executive function measured by the Trail Making Test (TMT) and the Stroop Color Word Test (SCWT). Hoy et al. demonstrated improved working memory and executive function, measured with the Wechsler Adult Intelligence Scale [WAIS] and TMT. Despite these promising results, neither study collected follow-up data, which seems to be a limitation for most of the neuromodulation studies.
In contrast to the rTMS studies that solely applied the neuromodulation technique, most tDCS studies seek to improve post-concussive cognitive impairment by combining neuromodulation sessions with cognitive training modules. It is believed that the electrical stimulation can facilitate cognitive reorganization and learning within the activated neural network during cognitive training . Another unique factor for tDCS is that it can be administered at-home with remote supervision. This convenient option allows for more feasible long-term studies. Eliam-Stock et al. 2021 reports a case study of a 29-year-old male with PCS 4 years following his mTBI . Using the Soterix Medical mini-CT device, he underwent 20 20-minute tDCS sessions over 4 weeks. During each session, the device delivered 2mA bilateral tDCS over the dlPFC, while the subject completed an online adaptive cognitive training using Posit Science’s BrainHQ algorithm. Results demonstrate improvements in attention, working memory, and processing speed measured by several tests, including the common WAIS-IV and the Trail Making Test. Since this study only employed one subject, there was no blinding or sham control to strengthen the results. As a result, changes in cognitive function cannot be directly attributed to tDCS or cognitive training alone.
The only tDCS study that involved multiple subjects looked primarily at divided attention (DA) in severe TBI patients. Sacco et al. 2016 combined 10 tDCS sessions with computer-assisted training in 32 subjects with severe TBI . The subjects were divided into an active group and a control group. While the control group just completed the DA cognitive training alone, the active group received 2 20 minute-sessions per day of bilateral tDCS at 2 mA over the dlPFC followed by 30 minutes of DA training. The study continued for 5 days for a total of 10 sessions. It is noted that unlike the previous study by Eliam-Stock et al, this study employed tDCS prior to cognitive training. More research is needed to determine the best protocol for combining the two treatments. With outcomes measured by the DA subtest of the Test for the Examination of Attention, the tDCS group significantly improved DA over time and also improved significantly more than the control group. This improvement, measured by faster reaction times and fewer errors, was sustained 1 month after treatment. Comparing pre- and post-treatment fMRI scans indicated a decrease in cerebral activations in areas that are linked to pathological hyperactivity in TBI patients during attentional tasks. The authors hypothesize that tDCS decreases the attentional cost of dual tasks in TBI patients, thus normalizing the pathology. Current studies are underway to further analyze the effects of combining cognitive telerehabilitation with at-home tDCS systems.
Finally, several studies have been conducted to analyze the effects of PBM on cognitive function. The first major study was conducted by Naeser et al. 2014, testing PBM over the DMN in 11 mTBI patients (not sham-controlled). LED clusters applied an energy density of 13 J/cm^2 each 10 minute sessions for 18 sessions over 6 weeks. Results demonstrate an improvement in executive function and learning measured by the Stroop test and California Verbal Learning Test CVLT-II. Another study published in 2022 by Santiago et al. supports the findings of Naeser et al. and demonstrates that PBM treatment in 35 mTBI subjects leads to cognitive improvements in visual motor speed and reaction time . PBM was applied 3 times a week for 4 weeks, with a variable dosing schedule to increase power dosage every week in the 180 LED array set. Cognitive outcomes were measured using the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT), a widely recognized computer neurocognitive assessment tool that measures cognitive performance and symptoms after concussion. Neither study by Maeser et al. or Santiago et al. employed sham control groups, and thus, results must be taken cautiously. Finally, Chao et al. 2020 presents a case study for using at-home PBM treatment for 8 weeks . Since there was only one subject, the details of the paper will not be discussed; however, the results of the paper demonstrate feasibility and effectiveness of at-home PBM treatment over longer time periods.
Compared to other post-concussive symptoms, it seems that neuromodulation has the greatest potential to promote cognitive recovery following TBI. This hypothesis is based on the relative amounts of literature available, the outcomes of those studies, and the fact that there is no pharmacological drug to improve cognitive impairment following mTBI. Alternative treatments include various forms of online cognitive training; however, the studies by Eliam Stock et al. and Sacco et al. demonstrate that adding tDCS sessions to cognitive training can help increase effectiveness . Further research is needed to quantify the added benefits of cognitive training to tDCS or other neuromodulation techniques. Limitations of these studies include a lack of standardization of outcome measurements. Different researchers use different tests for measuring cognitive functions, making it difficult to compare across studies. Furthermore, it is also difficult to demonstrate that changes in these test scores translate into real-life cognitive improvements.
SUMMARY AND CONCLUSION
A multitude of studies have been conducted concussive symptoms in individuals who have had a mTBI. As detailed previously, there are no effective treatments for chronic mTBI symptoms, encouraging researchers to test non-invasive neuromodulation techniques to directly address the associated neuropathology. This review paper has aimed to synthesize the field of research, along with comparing and contrasting the different neuromodulation methods for treating each symptom group.
For treating physical symptoms, such as headache and dizziness, rTMS has the greatest potential as treatment based on positive findings from two studies. tDCS also showed positive results; however, it was not shown to outperform mindfulness based stress reduction (MBSR). Ideally, a study would directly compare the three neuromodulation therapies, but perhaps more realistically, future studies could compare rTMS and longer periods of PBM to MBSR therapy. If the same outcome measurements are used, then a meta-study could compare the performance of each therapy.
Similarly, rTMS also seems to be the best neuromodulation technique for treating post-concussion depression, though this could be a direct effect of the increased number of studies using rTMS for general depression. Specifically, these studies employ right-sided low frequency rTMS, sometimes mixed with high frequency left-sided rTMS, for optimal results measured by either the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D). Again, a major limitation to studies using rTMS is that the sham treatment can be distinguished from active treatment due to the sensation of twitching felt with the active treatment.
Finally, for treating cognitive symptoms, all three techniques have shown promise in improving attention, working memory, processing speed, divided attention, executive function, and learning, though many studies were not sham controlled. Additionally, many studies tested the subjects on multiple cognitive tests, including the popular Trail Making Test (TMT) and Wechsler Adult Intelligence Scale (WAIS). When employing several tests, results should be corrected for multiple comparisons, as there is an increase in likelihood that the treatment group will randomly improve in some of the tests after treatment.
Given that the mechanistic explanations of the neuromodulation treatments are still widely unknown, it is difficult to speculate why certain technologies seem to have more promising results for certain symptoms. rTMS is perhaps the most studied of the three neurotechnologies, so it is possible that it simply has a more optimized protocol for inducing long-lasting changes in brain connectivity. Additionally, due to its electromagnetic properties and repetitive nature, rTMS may penetrate deeper or more focused to a treatment location, making it beneficial for specific targeted symptoms, such as headache and depression. On the other hand, cognitive impairments may involve more widespread networks and connectivity that can also be treated with tDCS and PBM. Finally, rTMS and tDCS have the advantage over PBM of being able to modulate excitatory or inhibitory effects using either high or low frequency (rTMS) or anode or cathode placement (tDCS), respectively. Because of this ability to tune modulation, rTMS and tDCS seem to have more potential for treating specific neuropathologies.
There are several limitations to these techniques and studies up to date. The technology itself is non-invasive, which benefits the patients, but makes it hard to localize treatment to certain areas of the brain. The treatment will get scattered and distorted by the skull, limiting localization to cortical regions of the brain. Other limitations to the technology include steep prices for use; however, this could definitely decrease as the field advances. Limitations to the studies presented in this review involve small sample sizes, and thus low-powered results, lack of blinding or sham-control, variation in TBI severity, and a lack of standardized protocols and outcome measurements. Additionally, many of the outcome measurements were based on self-reported symptoms, which can be biased by the subject. Robust measures must be developed to assess treatment results. This may, however, come as a double-edged sword. Studies that use an objective test to measure symptoms (ex. Trail making test for cognitive impairment) now have to prove that changes in these test scores translate into real-life improvements. Maybe future studies can employ a mix of self-reported surveys, doctor assessments, and online objective tests to comprehensively quantify treatment outcomes.
Future studies need to recruit more subjects and need to include blinded and sham-control groups. Additionally, follow-up studies need to be conducted to analyze how long beneficial effects last. For study methods, research should be done to determine the optimal localization method (neural network based vs anatomic) and treatment protocol (power, length, etc). Naeser et al. 2014 revealed that cognitive improvements were higher in patients with greater deficits, suggesting a relationship between severity and treatment outcome . Studies should evaluate these differences in treatment timing to determine the optimal timing and target patient population.
Importantly, a study comparing the different modulation treatments would be game changing, in that it could identify the best treatment method for a given set of symptoms and thus direct future research in that area. Comparing the different methods involves analyzing their efficacy, such as the length of treatment required compared to the magnitude of change over time post-treatment. These changes should be then compared to results from other therapies, such as mindfulness based stress reduction, medications, cognitive training, and other current treatments. Additional considerations involve the ability to treat different age groups, such as adolescents or senior citizens. Furthermore, the field is already pushing towards methods to administer treatment sessions at home. tDCS and PBM have been shown to be feasible for at-home treatment, offering more convenient options for subjects. Finally, as researchers learn more about the specific neuropathology of TBI, neuromodulation treatments can be adjusted to promote neurorecovery.
 Naeser, M. A., Zafonte, R., Krengel, M. H., Martin, P. I., Frazier, J., Hamblin, M. R., Knight, J. A., Meehan, W. P., & Baker, E. H. (2014a). Significant Improvements in Cognitive Performance Post-Transcranial, Red/Near-Infrared Light-Emitting Diode Treatments in Chronic, Mild Traumatic Brain Injury: Open-Protocol Study. Journal of Neurotrauma, 31(11), 1008–1017. https://doi.org/10.1089/neu.2013.3244
 Buhagiar, F., Fitzgerald, M., Bell, J., Allanson, F., & Pestell, C. (2020). Neuromodulation for Mild Traumatic Brain Injury Rehabilitation: A Systematic Review. Frontiers in Human Neuroscience, 14. https://www.frontiersin.org/articles/10.3389/fnhum.2020.598208
 Rao, V., Bechtold, K., McCann, U., Roy, D., Peters, M., Vaishnavi, S., Yousem, D., Mori, S., Yan, H., Leoutsakos, J., Tibbs, M., & Reti, I. (2019). Low-Frequency Right Repetitive Transcranial Magnetic Stimulation for the Treatment of Depression After Traumatic Brain Injury: A Randomized Sham-Controlled Pilot Study. The Journal of Neuropsychiatry and Clinical Neurosciences, 31(4), 306–318. https://doi.org/10.1176/appi.neuropsych.17110338
 Lee, S. A., & Kim, M.-K. (2018). Effect of Low Frequency Repetitive Transcranial Magnetic Stimulation on Depression and Cognition of Patients with Traumatic Brain Injury: A Randomized Controlled Trial. Medical Science Monitor : International Medical Journal of Experimental and Clinical Research, 24, 8789–8794. https://doi.org/10.12659/MSM.911385
 Paxman, E., Stilling, J., Mercier, L., & Debert, C. T. (2018). Repetitive transcranial magnetic stimulation (rTMS) as a treatment for chronic dizziness following mild traumatic brain injury. BMJ Case Reports, 2018, bcr2018226698, bcr-2018–226698. https://doi.org/10.1136/bcr-2018-226698
 Mollica, A., Greben, R., Oriuwa, C., Siddiqi, S. H., & Burke, M. J. (2022). Neuromodulation Treatments for Mild Traumatic Brain Injury and Post-concussive Symptoms. Current Neurology and Neuroscience Reports, 22(3), 171–181. https://doi.org/10.1007/s11910-022-01183-w
 Eilam-Stock, T., George, A., & Charvet, L. E. (2021). Cognitive Telerehabilitation with Transcranial Direct Current Stimulation Improves Cognitive and Emotional Functioning Following a Traumatic Brain Injury: A Case Study. Archives of Clinical Neuropsychology, 36(3), 442–453. https://doi.org/10.1093/arclin/acaa059
 Rudroff, T., & Workman, C. D. (2021). Transcranial Direct Current Stimulation as a Treatment Tool for Mild Traumatic Brain Injury. Brain Sciences, 11(6), Art. 6. https://doi.org/10.3390/brainsci11060806
 Sacco, K., Galetto, V., Dimitri, D., Geda, E., Perotti, F., Zettin, M., & Geminiani, G. C. (2016a). Concomitant Use of Transcranial Direct Current Stimulation and Computer-Assisted Training for the Rehabilitation of Attention in Traumatic Brain Injured Patients: Behavioral and Neuroimaging Results. Frontiers in Behavioral Neuroscience, 10, 57. https://doi.org/10.3389/fnbeh.2016.00057
 You, J., Bragin, A., Liu, H., & Li, L. (2021). Preclinical studies of transcranial photobiomodulation in the neurological diseases. Translational Biophotonics, 3(2), e202000024. https://doi.org/10.1002/tbio.202000024
 Chao, L. L., Barlow, C., Karimpoor, M., & Lim, L. (2020). Changes in Brain Function and Structure After Self-Administered Home Photobiomodulation Treatment in a Concussion Case. Frontiers in Neurology, 11, 952. https://doi.org/10.3389/fneur.2020.00952
 Santiago, R., Ozsarfati, J., Shulman, H., Valenzuela, R., & Zitney, M. (2022). ImPACT® Assessment of Photobiomodulation Therapy for Post-Concussion Syndrome. Journal of Spine Research and Surgery, 04(01). https://doi.org/10.26502/fjsrs0037
 Leung, A., Metzger-Smith, V., He, Y., Cordero, J., Ehlert, B., Song, D., Lin, L., Shahrokh, G., Tsai, A., Vaninetti, M., Rutledge, T., Polston, G., Sheu, R., & Lee, R. (2018). Left Dorsolateral Prefrontal Cortex rTMS in Alleviating MTBI Related Headaches and Depressive Symptoms. Neuromodulation: Journal of the International Neuromodulation Society, 21(4), 390–401. https://doi.org/10.1111/ner.12615
 Shirvani, S., Davoudi, M., Shirvani, M., Koleini, P., Hojat Panah, S., Shoshtari, F., & Omidi, A. (2021). Comparison of the effects of transcranial direct current stimulation and mindfulness-based stress reduction on mental fatigue, quality of life and aggression in mild traumatic brain injury patients: A randomized clinical trial. Annals of General Psychiatry, 20, 33. https://doi.org/10.1186/s12991-021-00355-1
 Figueiro Longo, M. G., Tan, C. O., Chan, S., Welt, J., Avesta, A., Ratai, E., Mercaldo, N. D., Yendiki, A., Namati, J., Chico-Calero, I., Parry, B. A., Drake, L., Anderson, R., Rauch, T., Diaz-Arrastia, R., Lev, M., Lee, J., Hamblin, M., Vakoc, B., & Gupta, R. (2020). Effect of Transcranial Low-Level Light Therapy vs Sham Therapy Among Patients With Moderate Traumatic Brain Injury. JAMA Network Open, 3(9), e2017337. https://doi.org/10.1001/jamanetworkopen.2020.17337
 Siddiqi, S. H., Trapp, N. T., Hacker, C. D., Laumann, T. O., Kandala, S., Hong, X., Trillo, L., Shahim, P., Leuthardt, E. C., Carter, A. R., & Brody, D. L. (2019). Repetitive Transcranial Magnetic Stimulation with Resting-State Network Targeting for Treatment-Resistant Depression in Traumatic Brain Injury: A Randomized, Controlled, Double-Blinded Pilot Study. Journal of Neurotrauma, 36(8), 1361–1374. https://doi.org/10.1089/neu.2018.5889
 Quinn, D. K., Upston, J., Jones, T., Brandt, E., Story-Remer, J., Fratzke, V., Wilson, J. K., Rieger, R., Hunter, M. A., Gill, D., Richardson, J. D., Campbell, R., Clark, V. P., Yeo, R. A., Shuttleworth, C. W., & Mayer, A. R. (2020). Cerebral Perfusion Effects of Cognitive Training and Transcranial Direct Current Stimulation in Mild-Moderate TBI. Frontiers in Neurology, 11. https://www.frontiersin.org/articles/10.3389/fneur.2020.545174
 Hoy, K. E., McQueen, S., Elliot, D., Herring, S. E., Maller, J. J., & Fitzgerald, P. B. (2019). A Pilot Investigation of Repetitive Transcranial Magnetic Stimulation for Post-Traumatic Brain Injury Depression: Safety, Tolerability, and Efficacy. Journal of Neurotrauma, 36(13), 2092–2098. https://doi.org/10.1089/neu.2018.6097
 Mester, E., Ludany, G., Selyei, M., Szende, B., & Total, G. J. (1968). THE STIMULATING EFFECT OF LOW POWER LASER RAYS ON BIOLOGICAL SYSTEMS. Laser Rev., 1: 3(Mar. 1968). https://www.osti.gov/biblio/4836455