Federal Practitioner

Traumatic brain injury (TBI) is the signature injury of post-9/11 military operations, impacting > 441,000 combat veterans from 2001 to 2021 and 87% diagnosed with mild TBI (mTBI).^1,2 The most common cause of mTBI during these operations was blast exposures stemming from improvised explosive devices, rocket-propelled grenades, or land mines. mTBI was once thought to be self-limiting, lasting hours or days postinjury, but is now recognized as a complex focal and diffuse injury causing a cascade of molecular and biochemical responses with significant physiologic effects lasting for a longer duration. A significant number of combat veterans with mTBI (23%-48%) experience long-standing postconcussive symptoms (PCSs) for many years postinjury.^3-5

Developing and implementing strategies to reduce persistent symptoms associated with mTBI is of critical importance. Veterans diagnosed with mTBI and experiencing PCSs present ongoing treatment challenges to the health care system due to limited or suboptimal treatment options.^6,7 According to the 2021 US Department of Veterans Affairs (VA) and US Department of Defense (DoD) clinical guidelines for postacute mTBI, treatment for PCSs should be symptom focused. ^8,9 For instance, veterans with migraine headaches associated with mTBIs are often treated with abortive agents (eg, triptans) and preventive medications (eg, anticonvulsants and tricyclics).¹⁰ Cognitive dysfunction and insomnia are treated with cognitive rehabilitation programs, cognitive behaviorial therapy, occupational therapy, and medications (eg, hypnotics for insomnia).^11,12 The 2021 VA/DoD guidelines note that veteran and military focus groups described greater success with nonpharmacologic treatments than with pharmacologic treatments.⁸ The VA launched an enterprise-wide Whole Health Service program with the requirement that complementary and integrative health approaches must be available to veterans.¹³ As a nonpharmacologic, integrative, and noninvasive modality, neurofeedback (NFB) supports the VA Whole Health initiative and veterans’ preferences for integrative treatments.¹⁴

Neurofeedback

Rather than a symptom management approach, Defina et al described the possibilities of brain repair in TBI by treatments to enhance neuroplasticity, thereby establishing a more normalized or stable brain environment and enabling the brain to reorganize itself and function more normally.¹⁵ NFB has been shown to influence neuroplasticity,¹⁶ as evident in microstructural changes in white and gray matter¹⁷ and its ability to contribute to functional rehabilitation by restoring connectivity in specific areas of the brain that may have been impaired.¹⁸ The benefits of neuroenhancement strategies include potentially reduced pain for patients with mTBI and improved quality of life (QOL).¹⁹

NFB assists individuals by helping them become more aware of and self-regulate their physiology.^20,21 Because there are several types of NFB (eg, quantitative electroencephalography, Z-scored, α-θ) that differ in terms of equipment, mechanism of action, focus, and patient and clinician procedures, it is important to note that this study used a novel technologically advanced form of NFB, referred to as infra-low frequency (ILF) NFB. It works by reflecting a person’s brain wave activity via conventional electroencephalography back to the person through the visual cortex, thus providing relevant information to which the brain responds to improve core state regulation.²²

In 2006, ILF NFB developers sought to extend NFB capability into the slow cortical potential domain (< 0.1 Hz) and then gradually extended to lower frequencies on the basis of favorable clinical responses.^22,23 In 2017, the technology reached an ILF capacity that appeared to be helpful for several clinical issues. These developments depended on instrumentation capable of low noise signal detection down to the lowest frequency of interest. Instrumentation was developed for the purpose (eg, Bee Medic Cygnet NFB).

Although mTBI has been a clinical focus in NFB since the 1980s, there are few published studies demonstrating the efficacy of ILF NFB relating to the PCSs of interest in this study, and 2 suggested ILF NFB positively affected change in PCS severity.^24,25 Other studies found that ILF NFB decreased incidence of migraines and tension type headaches.^26,27 However, the findings of these studies had limited generalizability due to methodologic limitations, such as selection bias and small sample sizes.^24-27 Of importance to this article, there are also several publications on the efficacy of ILF NFB in clinical settings.^28-33

This article presents the second analysis of data from veterans who completed ILF NFB intervention and control group procedures during a 5-year randomized controlled trial (RCT). The RCT included veterans who experienced an mTBI while participating in post-9/11 military operations to evaluate the impact of ILF NFB on chronic PCSs, including headache, insomnia, and attention dysfunction. Initial results of this trial demonstrated significant differences between the intervention and control groups with strong effect sizes on all outcome measures at the end of treatment.³⁴

Methods

Participants included male and nonpregnant female veterans with a diagnosed mTBI during post-9/11 military operations; aged 18 to 65 years; reports of persistent (ie, > 3 months in duration) headaches, insomnia, and attention difficulties; and able to read and write English, comprehend what is read, and follow directions. mTBI diagnosis was verified for each veteran via the electronic health record. Patients were excluded if they had a severe TBI diagnosis or impaired decision-making capacity; were unable to comply with study visit schedule; or endorsed active suicidal intent on the Columbia-Suicide Severity Rating Scale.³⁵

Recruitment efforts included: (1) letters sent to eligible veterans with mTBI who were identified by clinical informatics data after waiver of Health Insurance Portability and Accountability Act was obtained; veterans could contact the research team directly or the research team would call the veteran 2 weeks after the letter was sent; (2) veterans could be referred by a clinician; and (3) veterans could self-refer based on flyers and other study marketing materials.

The study was conducted from 2019 to 2024 at Spark M. Matsunaga VA Medical Center, in Honolulu, Hawaii. Four private research spaces in compliance with human research standards were used for consent, treatment, and assessment.

Consenting Procedure and Randomization

The privacy rights of potential participants were observed, and interested veterans who met the eligibility criteria underwent an informed consent procedure and were administered the Columbia-Suicide Severity Rating Scale.³⁵ Those veterans not indicating active suicidal intent were randomized into the intervention or control group. Once randomized, the participant was enrolled and scheduled for baseline assessment.

All procedures of this study were performed in adherence with relevant laws and institutional guidelines. The study was reviewed and approved by the VA Pacific Islands Health Care System Institutional Review Board (#2019-06-JC/Promise 0003).

Outcome Measures

The outcome measures were administered at baseline, midpoint (3-7 weeks), end of treatment (6-12 weeks), and at a 2-month follow-up appointment with the research assistant or project coordinator.

The primary outcome measures include the Headache Impact Test (HIT-6), TBIQOL Headache Pain item short form, Insomnia Severity Index (ISI), Quality of Life in Neurological Disorders (Neuro-QOL) Sleep Disturbance short form, and attention measure: QIKtest Continuous Performance Test (QIKtest) (Table 1).^36-44

Secondary outcome measures included QOL After Brain Injury (QOLIBRI), Neuro- QOL Satisfaction With Roles/Activities short form (Neuro-QOL Satisfaction), Neuro-QOL Ability to Participate in Roles/Activities short form (Neuro-QOL Participate), Depression Anxiety Stress Scales (DASS-21), Patient Health Questionnaire-9 (PHQ-9), Posttraumatic Stress Disorder (PTSD) Checklist for DSM-5 (PCL-5), and the General Symptom Inventory (eAppendix 1).^39,42,45-52

Sample

Seventy-two participants (36 in each group) were needed to have adequate statistical power for the analysis. Presuming attrition, the goal was to recruit 100 veterans. Literature on NFB studies of patients with mTBI have reported dropout rates ranging from 10% to 30%.^53,54 Assuming a dropout rate of 28% and a moderate autocorrelation of 0.6 among repeated measures, this sample size ensured the detection of an average difference of at least 0.49 SDs with a power of 80% in the NFB intervention group compared with the control group using a 2-tailed significance level of 0.05.

Control Group

Following baseline assessment, control group participants received 8 phone calls (1 call/wk) from 1 of 4 clinical investigators over 8 to 10 weeks. During each 15-minute call, 1 of the following health topics was discussed: sleep hygiene, basic nutritional concepts, beverage choices, positive thinking, thought reframing, fitness, daily calming activity, and enhancement of focus strategies. A script for each topic was used to guide each call.

Intervention Group

Following baseline assessment, intervention group participants completed 20 half-hour ILF NFB sessions, typically receiving 3 sessions per week over an 8- to 10-week period. ILF NFB treatments were administered by 1 of 4 licensed health care employees who had received substantial ILF NFB training and achieved a skill reliability index score of 0.95, ensuring the skill level of the ILF NFB providers was equal. A script was used by the ILF NFB providers during the ILF NFB sessions to keep the interaction approach consistent with all participants.

All procedures were explained in advance to participants and voluntary participation affirmed. At the first session, participants filled out a clinical symptom checklist of 5 symptoms (eAppendix 1).^39,42,45-49 The initial rating on the symptom checklist was reflective of their experience over the past month, while in each subsequent session, participants indicated their experience of those symptoms that day. ILF NFB providers were never privy to participants’ primary or secondary outcome measures data during the study, so these recurring clinical symptom checklist ratings, as well as other feedback provided by participants on their experience within and between sessions, were the clinical data used to make decisions about ILF NFB treatment protocol.

The Othmer Optimal Response Frequency (ORF) protocol was used for participants in this study.⁵⁵ Through an iterative process, ORF protocol establishes the specific frequency point along the 0.000001 mHz to 0.1 Hz continuum, which is optimal to diminish symptoms experienced in real-time during the session (eg, tension or pain in shoulders; racing thoughts).

During each ILF NFB session, participants were seated comfortably and encouraged to look at the feedback screen. The moving images on the game screen provided almost instantaneous feedback (within 500 ms) to participants about their brain functioning, as ascertained by electrodes placed on the scalp as dictated by study protocol.⁵⁶ A standardized protocol for site placement was used beginning with T3-T4, followed by the weekly addition of a site as tolerated in the following sequence: T4-P4, FP2-T4, and FP1-T4. More information about the ILF NFB procedures are outlined in the report of the pilot study and RCT initial results.^22,34

Statistical Analysis

Eighty-seven participants were randomized, with 43 assigned to the intervention group and 44 to the control group to achieve the enrollment goal of ≥ 36 participants in each group. This report is the second analysis of data from this RCT that employed a per-protocol approach, analyzing a subset of participants who fully adhered to the study protocol and completed all study procedures. Outcome scores at baseline, midpoint, end of treatment, and 2-month follow-up were summarized as means with corresponding 95% CIs. Group comparisons at the end of treatment and 2-month follow-up time points were conducted using 2-sample t tests. All statistical tests were 2-sided with a significance level of .05 (Type I error rate). SAS software version 9.4 Maintenance 8 was used for statistical analysis. Cohen d analyses were used for effect sizes.

Results

Seventy-four participants fully adhered to the study protocol and were included in the present analyses, with 38 in the control group and 36 in the intervention group. eAppendix 2 depicts the flow of participants through this study. There were no adverse events related to treatment, and the 13 participants who withdrew typically reported difficulty with scheduling or transportation as the primary reason. This study also took place during the COVID-19 pandemic, which likely had some impact on enrollment; participants were differentially impacted by changes in employment and moves to the continental United States.

Participants were aged 30 to 60 years (mean [SD], 45.4 [8.0]). Most participants (90.5%) were male, and multiracial and White were the most common racial identities (Table 2). Participant characteristics were largely balanced across randomized groups. Similarly, test scores on the primary variables of interest in this study and secondary clinical variables assessed were comparable across participants (Table 3).

Primary Variables of Interest Analyses

This study’s hypothesis was that those who completed ILF NFB treatment per protocol would demonstrate statistically significant improvement in symptoms related to headaches, sleep disturbance, and difficulty with attention when compared with veterans in the control group. This hypothesis was partially supported. A 2-sample t test showed that veterans in the intervention group demonstrated significant improvement in headache symptoms compared with veterans in the control group on the HIT-6 at the end-of-treatment (P < .001, d = 1.53) and 2-month follow-up assessment (P < .001, d = 1.14). This pattern also was consistent with the TBI-QOL Headache Pain item short form, with veterans in the intervention group showing improvement beyond those in the control group at the end-of-treatment (P < .001, d = 0.89) and 2-month follow-up assessment (P < .001, d = 0.83). Two-sample t tests also demonstrated significant improvement in subjective reports of sleep; those in the intervention group had significantly lower scores on the ISI at the end-of-study (P < .001, d = 1.53) and 2-month follow-up assessment (P < .001, d = 0.97). This pattern also held true for the Neuro-QOL Sleep Disturbance short form subtest, which demonstrated significantly more improvement in the intervention group compared with the control group at the end-of-study (P < .001, d = 0.97) and 2-month follow- up assessment (P < .001, d = 0.92). improvement in attention was not supported by the present results. A 2-sample t test found no significant difference between performance on the QIKtest for veterans in the intervention group vs the control group at the end-of-study (P = .40, d = 0.19) or the 2-month follow-up (P = .43, d = 0.20) (eAppendix 3).

Secondary Variables of Interest Analysis

Secondary variables examined differences in QOL, PTSD, depressive symptoms, and general symptoms reported between veterans in the intervention and control groups. Results demonstrated that veterans in the intervention group showed improvement above and beyond those in the control group on all measures. In regard to QOL, veterans in the intervention group had significantly higher scores on the Neuro-QOL Participate subtest than those in the control group at the end-of-study (P = .01, d = 0.89) and 2-month follow-up assessment (P < .001, d = 0.62). A similar pattern was found for the Neuro-QOL Satisfaction subtest, with veterans in the intervention group showing significantly higher scores than those in the control group at the end-of-study (P = .001, d = 0.95) and 2-month follow-up assessment (P < .001, d = 0.62). This also held true on the QOLIBRI, with veterans in the intervention group demonstrating significantly higher scores than those in the control group at the end-of-study (P = .001, d = 0.92) and 2-month follow-up assessment (P < .001, d = 0.66).

Veterans in the intervention group had significantly lower scores on the PCL-5 than those in the control group at the end-of- study (P = .003, d = 0.78) and 2-month follow-up assessment (P = .001, d = 0.72). Veterans in the intervention group also had significantly lower scores on the PHQ-9 than those in the control group at the end-of-study (P < .001, d = 0.98) and 2-month follow-up assessment (P < .001, d = 0.83). Veterans in the intervention group had significantly lower scores on the DASS- 21 than those in the control group at the end-of-study (P = .002, d = 0.80) and 2-month follow-up assessment (P = .001, d = 0.77). They also had significantly lower scores on the General Symptom Inventory than those in the control group at the end-of-study (P = .02, d = 0.75) and 2-month follow-up assessment (P = .002, d = 0.57). A clinically significant shift of score occurred for each of the measures except DASS-21 (eAppendix 3). eAppendix 4 depicts the change in scores for the intervention group at the end of treatment and the clinically significant shift score of each measure.

Discussion

The results of this RCT revealed a promising impact of ILF NFB on the commonly experienced persistent PCSs of headaches and disrupted sleep. Veterans in the intervention group demonstrated statistically significant improvement in headache symptoms compared with veterans in the control group when assessed at the end of treatment and during a 2-month follow-up. The statistical significance of these improvements was also supported by large or very large effect sizes. In addition to these primary variables of interest, veterans in the intervention group notably demonstrated significant improvement compared with those in the control group in a number of secondary clinical measures, including QOL, traumatic stress-related symptoms, depressive symptoms, and general symptom report. The clinical impact was further supported by the clinically relevant shift in scores in the intervention group.

The data did not support the hypothesis that attention concerns would show significant improvement following ILF NFB. Performance on an attention measure did not differ significantly between groups at either the end-of-treatment or 2-month follow up assessment. The QIKtest, a continuous performance test used to measure attention, was a go/no-go task and calculated based on a combination of various types of errors and outlier responses. The stimulus for this task is a series of computerized, blinking lights, for which participants are tasked with discriminating targets and nontargets under time pressure. However, the order of the stimuli are consistent across administrations, rather than being randomized, introducing a potential confound of practice effects on this task since patients were administered the QIKtest 3 times in a 2-month period and again 2 months later. Veterans in the control group notably improved in their average performance of this task from baseline to the endpoint of their treatment participation and demonstrated further improvement at the 2-month follow-up assessment; this pattern would be consistent with potential practice effects and warrants caution in its interpretation for both groups.

Previously published ILF NFB clinical studies that used the QIKtest and found positive results were mostly conducted among children and teen populations across longer treatment periods. This research may indicate the QIKtest is not an appropriate measure to assess adults who have specialized training in responding to stimuli (ie, trained military personnel). This suggests the concept of attention dysfunction experienced by veterans and the best method to measure it may need to be explored further. This construct may not be related to the focus and skill in prolonged attention needed in selecting go/ no-go tasks, but rather related to a broader conceptual basis involving memory, recall, clarity of rational thought, and decision making impacted by the mTBI. For instance, a study among combat veterans with mTBI and PTSD found that performance on objective cognitive measures did not significantly correlate with their subjective reports of cognitive difficulties.⁵⁷ This reflects the pattern of the present study, in which subjective reports of attention improved over time on the clinical symptom checklist filled out by participants at each session, but the objective measure did not. The mean attention dysfunction score was 6 at session 1 and 1 to 2 at session 20 (lower scores are better on a 10-point scale).

Strengths and Limitations

This study presents results stemming from the first RCT examining clinical effectiveness of ILF NFB in a VA setting for veterans with diagnoses of mTBI. The study design shows promising external validity. Veterans were able to participate in a treatment consisting of 20 sessions over a period of typically 8 to 10 weeks, entailing 2 to 3 sessions per week, with an attrition of only 18% over the course of the study. Notably, attrition rates may have been impacted by the time course of the study, which was recruiting and running participants throughout the COVID-19 pandemic (March 2020 to May 2023). No attrition was due to the intervention itself, and no adverse reactions to ILF NFB were reported during the course of the study. Other strengths of the study include the ethnically and racially diverse participants, representative of the population of veterans in Hawaii. Additionally, all ILF NFB providers underwent supervised ILF NFB training and achieved a skill reliability index score of 0.95 prior to providing ILF NFB to the intervention group.

This study was not blinded. Neither veterans nor ILF NFB providers were blinded and were therefore aware of the randomly assigned groups. Research assistants administering the periodic assessments were meant to be blinded to condition by design; however, as the study progressed, a research assistant became unintentionally aware of each study participant's condition based on required documentation in the veteran’s health records; more notes were present for those in the intervention group (20 specialist notes) than the control group (8 notes). While the presence of a control group represents a strength relative to much of the existing ILF NFB literature, the control group in this case did not account for the total time spent with the researchers. Participants in the intervention group met with researchers for 20 total sessions as opposed to 8 telephone calls. Therefore, the study design cannot fully rule out the differential impact of demand characteristics between the 2 groups, nor can it fully address or rule out the impact of differential motivation and expectations between groups. There is also evidence that technological innovation can influence the expectations of research participants, meaning that the intervention group may have been unduly influenced by the novelty of the ILF NFB technology, to which the control group did not have exposure.⁵⁸

A second attention measure for this study would have been beneficial, perhaps in identifying true change in attention ability or providing more insight into finding better methods to assess attention among veterans with mTBI. ILF NFB demonstrated significant impact across multiple outcome measures of clinical relevance for veterans diagnosed with mTBI, including the primary outcome variables of headache and sleep. The strength of the improvements seen in these areas, supported by large practical effects as well as veterans’ subjective reports, indicates much promise. Follow-up studies may also focus on the potential effectiveness of ILF NFB as a treatment of the secondary concerns measured in this study, including traumatic stress-related and depressive symptoms, and may explore the added benefit, if any, of ILF NFB alongside other evidence-based treatments for traumatic stress-related and mood disorders (eg, cognitive behavioral therapy). Using functional magnetic resonance imaging before and after assessments to determine actual brain enhancement with ILF NFB for certain disorders in which a brain signature exists (ie, migraine) should be explored. Further examination of ILF NFB as an intervention for attention may also be warranted, using more effective measures of attention in the population of veterans with mTBI, given the concerns noted earlier. Future research on this topic will need to clearly define attention in relation to the veteran experience and use relevant measures.

Conclusions

This study supports ILF NFB as a safe, noninvasive, nonpharmacologic treatment that may be effective in addressing the complex clinical concerns of veterans diagnosed with mTBI, a population for whom effective treatments have been difficult to identify. This intervention can provide veterans with a desirable and effective nonpharmacologic alternative in their care.

Traumatic brain injury (TBI) is the signature injury of post-9/11 military operations, impacting > 441,000 combat veterans from 2001 to 2021 and 87% diagnosed with mild TBI (mTBI).^1,2 The most common cause of mTBI during these operations was blast exposures stemming from improvised explosive devices, rocket-propelled grenades, or land mines. mTBI was once thought to be self-limiting, lasting hours or days postinjury, but is now recognized as a complex focal and diffuse injury causing a cascade of molecular and biochemical responses with significant physiologic effects lasting for a longer duration. A significant number of combat veterans with mTBI (23%-48%) experience long-standing postconcussive symptoms (PCSs) for many years postinjury.^3-5

Developing and implementing strategies to reduce persistent symptoms associated with mTBI is of critical importance. Veterans diagnosed with mTBI and experiencing PCSs present ongoing treatment challenges to the health care system due to limited or suboptimal treatment options.^6,7 According to the 2021 US Department of Veterans Affairs (VA) and US Department of Defense (DoD) clinical guidelines for postacute mTBI, treatment for PCSs should be symptom focused. ^8,9 For instance, veterans with migraine headaches associated with mTBIs are often treated with abortive agents (eg, triptans) and preventive medications (eg, anticonvulsants and tricyclics).¹⁰ Cognitive dysfunction and insomnia are treated with cognitive rehabilitation programs, cognitive behaviorial therapy, occupational therapy, and medications (eg, hypnotics for insomnia).^11,12 The 2021 VA/DoD guidelines note that veteran and military focus groups described greater success with nonpharmacologic treatments than with pharmacologic treatments.⁸ The VA launched an enterprise-wide Whole Health Service program with the requirement that complementary and integrative health approaches must be available to veterans.¹³ As a nonpharmacologic, integrative, and noninvasive modality, neurofeedback (NFB) supports the VA Whole Health initiative and veterans’ preferences for integrative treatments.¹⁴

Neurofeedback

Rather than a symptom management approach, Defina et al described the possibilities of brain repair in TBI by treatments to enhance neuroplasticity, thereby establishing a more normalized or stable brain environment and enabling the brain to reorganize itself and function more normally.¹⁵ NFB has been shown to influence neuroplasticity,¹⁶ as evident in microstructural changes in white and gray matter¹⁷ and its ability to contribute to functional rehabilitation by restoring connectivity in specific areas of the brain that may have been impaired.¹⁸ The benefits of neuroenhancement strategies include potentially reduced pain for patients with mTBI and improved quality of life (QOL).¹⁹

NFB assists individuals by helping them become more aware of and self-regulate their physiology.^20,21 Because there are several types of NFB (eg, quantitative electroencephalography, Z-scored, α-θ) that differ in terms of equipment, mechanism of action, focus, and patient and clinician procedures, it is important to note that this study used a novel technologically advanced form of NFB, referred to as infra-low frequency (ILF) NFB. It works by reflecting a person’s brain wave activity via conventional electroencephalography back to the person through the visual cortex, thus providing relevant information to which the brain responds to improve core state regulation.²²

In 2006, ILF NFB developers sought to extend NFB capability into the slow cortical potential domain (< 0.1 Hz) and then gradually extended to lower frequencies on the basis of favorable clinical responses.^22,23 In 2017, the technology reached an ILF capacity that appeared to be helpful for several clinical issues. These developments depended on instrumentation capable of low noise signal detection down to the lowest frequency of interest. Instrumentation was developed for the purpose (eg, Bee Medic Cygnet NFB).

Although mTBI has been a clinical focus in NFB since the 1980s, there are few published studies demonstrating the efficacy of ILF NFB relating to the PCSs of interest in this study, and 2 suggested ILF NFB positively affected change in PCS severity.^24,25 Other studies found that ILF NFB decreased incidence of migraines and tension type headaches.^26,27 However, the findings of these studies had limited generalizability due to methodologic limitations, such as selection bias and small sample sizes.^24-27 Of importance to this article, there are also several publications on the efficacy of ILF NFB in clinical settings.^28-33

This article presents the second analysis of data from veterans who completed ILF NFB intervention and control group procedures during a 5-year randomized controlled trial (RCT). The RCT included veterans who experienced an mTBI while participating in post-9/11 military operations to evaluate the impact of ILF NFB on chronic PCSs, including headache, insomnia, and attention dysfunction. Initial results of this trial demonstrated significant differences between the intervention and control groups with strong effect sizes on all outcome measures at the end of treatment.³⁴

Methods

Participants included male and nonpregnant female veterans with a diagnosed mTBI during post-9/11 military operations; aged 18 to 65 years; reports of persistent (ie, > 3 months in duration) headaches, insomnia, and attention difficulties; and able to read and write English, comprehend what is read, and follow directions. mTBI diagnosis was verified for each veteran via the electronic health record. Patients were excluded if they had a severe TBI diagnosis or impaired decision-making capacity; were unable to comply with study visit schedule; or endorsed active suicidal intent on the Columbia-Suicide Severity Rating Scale.³⁵

Recruitment efforts included: (1) letters sent to eligible veterans with mTBI who were identified by clinical informatics data after waiver of Health Insurance Portability and Accountability Act was obtained; veterans could contact the research team directly or the research team would call the veteran 2 weeks after the letter was sent; (2) veterans could be referred by a clinician; and (3) veterans could self-refer based on flyers and other study marketing materials.

The study was conducted from 2019 to 2024 at Spark M. Matsunaga VA Medical Center, in Honolulu, Hawaii. Four private research spaces in compliance with human research standards were used for consent, treatment, and assessment.

Consenting Procedure and Randomization

The privacy rights of potential participants were observed, and interested veterans who met the eligibility criteria underwent an informed consent procedure and were administered the Columbia-Suicide Severity Rating Scale.³⁵ Those veterans not indicating active suicidal intent were randomized into the intervention or control group. Once randomized, the participant was enrolled and scheduled for baseline assessment.

All procedures of this study were performed in adherence with relevant laws and institutional guidelines. The study was reviewed and approved by the VA Pacific Islands Health Care System Institutional Review Board (#2019-06-JC/Promise 0003).

Outcome Measures

The outcome measures were administered at baseline, midpoint (3-7 weeks), end of treatment (6-12 weeks), and at a 2-month follow-up appointment with the research assistant or project coordinator.

The primary outcome measures include the Headache Impact Test (HIT-6), TBIQOL Headache Pain item short form, Insomnia Severity Index (ISI), Quality of Life in Neurological Disorders (Neuro-QOL) Sleep Disturbance short form, and attention measure: QIKtest Continuous Performance Test (QIKtest) (Table 1).^36-44

Secondary outcome measures included QOL After Brain Injury (QOLIBRI), Neuro- QOL Satisfaction With Roles/Activities short form (Neuro-QOL Satisfaction), Neuro-QOL Ability to Participate in Roles/Activities short form (Neuro-QOL Participate), Depression Anxiety Stress Scales (DASS-21), Patient Health Questionnaire-9 (PHQ-9), Posttraumatic Stress Disorder (PTSD) Checklist for DSM-5 (PCL-5), and the General Symptom Inventory (eAppendix 1).^39,42,45-52

Sample

Seventy-two participants (36 in each group) were needed to have adequate statistical power for the analysis. Presuming attrition, the goal was to recruit 100 veterans. Literature on NFB studies of patients with mTBI have reported dropout rates ranging from 10% to 30%.^53,54 Assuming a dropout rate of 28% and a moderate autocorrelation of 0.6 among repeated measures, this sample size ensured the detection of an average difference of at least 0.49 SDs with a power of 80% in the NFB intervention group compared with the control group using a 2-tailed significance level of 0.05.

Control Group

Following baseline assessment, control group participants received 8 phone calls (1 call/wk) from 1 of 4 clinical investigators over 8 to 10 weeks. During each 15-minute call, 1 of the following health topics was discussed: sleep hygiene, basic nutritional concepts, beverage choices, positive thinking, thought reframing, fitness, daily calming activity, and enhancement of focus strategies. A script for each topic was used to guide each call.

Intervention Group

Following baseline assessment, intervention group participants completed 20 half-hour ILF NFB sessions, typically receiving 3 sessions per week over an 8- to 10-week period. ILF NFB treatments were administered by 1 of 4 licensed health care employees who had received substantial ILF NFB training and achieved a skill reliability index score of 0.95, ensuring the skill level of the ILF NFB providers was equal. A script was used by the ILF NFB providers during the ILF NFB sessions to keep the interaction approach consistent with all participants.

All procedures were explained in advance to participants and voluntary participation affirmed. At the first session, participants filled out a clinical symptom checklist of 5 symptoms (eAppendix 1).^39,42,45-49 The initial rating on the symptom checklist was reflective of their experience over the past month, while in each subsequent session, participants indicated their experience of those symptoms that day. ILF NFB providers were never privy to participants’ primary or secondary outcome measures data during the study, so these recurring clinical symptom checklist ratings, as well as other feedback provided by participants on their experience within and between sessions, were the clinical data used to make decisions about ILF NFB treatment protocol.

The Othmer Optimal Response Frequency (ORF) protocol was used for participants in this study.⁵⁵ Through an iterative process, ORF protocol establishes the specific frequency point along the 0.000001 mHz to 0.1 Hz continuum, which is optimal to diminish symptoms experienced in real-time during the session (eg, tension or pain in shoulders; racing thoughts).

During each ILF NFB session, participants were seated comfortably and encouraged to look at the feedback screen. The moving images on the game screen provided almost instantaneous feedback (within 500 ms) to participants about their brain functioning, as ascertained by electrodes placed on the scalp as dictated by study protocol.⁵⁶ A standardized protocol for site placement was used beginning with T3-T4, followed by the weekly addition of a site as tolerated in the following sequence: T4-P4, FP2-T4, and FP1-T4. More information about the ILF NFB procedures are outlined in the report of the pilot study and RCT initial results.^22,34

Statistical Analysis

Eighty-seven participants were randomized, with 43 assigned to the intervention group and 44 to the control group to achieve the enrollment goal of ≥ 36 participants in each group. This report is the second analysis of data from this RCT that employed a per-protocol approach, analyzing a subset of participants who fully adhered to the study protocol and completed all study procedures. Outcome scores at baseline, midpoint, end of treatment, and 2-month follow-up were summarized as means with corresponding 95% CIs. Group comparisons at the end of treatment and 2-month follow-up time points were conducted using 2-sample t tests. All statistical tests were 2-sided with a significance level of .05 (Type I error rate). SAS software version 9.4 Maintenance 8 was used for statistical analysis. Cohen d analyses were used for effect sizes.

Results

Seventy-four participants fully adhered to the study protocol and were included in the present analyses, with 38 in the control group and 36 in the intervention group. eAppendix 2 depicts the flow of participants through this study. There were no adverse events related to treatment, and the 13 participants who withdrew typically reported difficulty with scheduling or transportation as the primary reason. This study also took place during the COVID-19 pandemic, which likely had some impact on enrollment; participants were differentially impacted by changes in employment and moves to the continental United States.

Participants were aged 30 to 60 years (mean [SD], 45.4 [8.0]). Most participants (90.5%) were male, and multiracial and White were the most common racial identities (Table 2). Participant characteristics were largely balanced across randomized groups. Similarly, test scores on the primary variables of interest in this study and secondary clinical variables assessed were comparable across participants (Table 3).

Primary Variables of Interest Analyses

This study’s hypothesis was that those who completed ILF NFB treatment per protocol would demonstrate statistically significant improvement in symptoms related to headaches, sleep disturbance, and difficulty with attention when compared with veterans in the control group. This hypothesis was partially supported. A 2-sample t test showed that veterans in the intervention group demonstrated significant improvement in headache symptoms compared with veterans in the control group on the HIT-6 at the end-of-treatment (P < .001, d = 1.53) and 2-month follow-up assessment (P < .001, d = 1.14). This pattern also was consistent with the TBI-QOL Headache Pain item short form, with veterans in the intervention group showing improvement beyond those in the control group at the end-of-treatment (P < .001, d = 0.89) and 2-month follow-up assessment (P < .001, d = 0.83). Two-sample t tests also demonstrated significant improvement in subjective reports of sleep; those in the intervention group had significantly lower scores on the ISI at the end-of-study (P < .001, d = 1.53) and 2-month follow-up assessment (P < .001, d = 0.97). This pattern also held true for the Neuro-QOL Sleep Disturbance short form subtest, which demonstrated significantly more improvement in the intervention group compared with the control group at the end-of-study (P < .001, d = 0.97) and 2-month follow- up assessment (P < .001, d = 0.92). improvement in attention was not supported by the present results. A 2-sample t test found no significant difference between performance on the QIKtest for veterans in the intervention group vs the control group at the end-of-study (P = .40, d = 0.19) or the 2-month follow-up (P = .43, d = 0.20) (eAppendix 3).

Secondary Variables of Interest Analysis

Secondary variables examined differences in QOL, PTSD, depressive symptoms, and general symptoms reported between veterans in the intervention and control groups. Results demonstrated that veterans in the intervention group showed improvement above and beyond those in the control group on all measures. In regard to QOL, veterans in the intervention group had significantly higher scores on the Neuro-QOL Participate subtest than those in the control group at the end-of-study (P = .01, d = 0.89) and 2-month follow-up assessment (P < .001, d = 0.62). A similar pattern was found for the Neuro-QOL Satisfaction subtest, with veterans in the intervention group showing significantly higher scores than those in the control group at the end-of-study (P = .001, d = 0.95) and 2-month follow-up assessment (P < .001, d = 0.62). This also held true on the QOLIBRI, with veterans in the intervention group demonstrating significantly higher scores than those in the control group at the end-of-study (P = .001, d = 0.92) and 2-month follow-up assessment (P < .001, d = 0.66).

Veterans in the intervention group had significantly lower scores on the PCL-5 than those in the control group at the end-of- study (P = .003, d = 0.78) and 2-month follow-up assessment (P = .001, d = 0.72). Veterans in the intervention group also had significantly lower scores on the PHQ-9 than those in the control group at the end-of-study (P < .001, d = 0.98) and 2-month follow-up assessment (P < .001, d = 0.83). Veterans in the intervention group had significantly lower scores on the DASS- 21 than those in the control group at the end-of-study (P = .002, d = 0.80) and 2-month follow-up assessment (P = .001, d = 0.77). They also had significantly lower scores on the General Symptom Inventory than those in the control group at the end-of-study (P = .02, d = 0.75) and 2-month follow-up assessment (P = .002, d = 0.57). A clinically significant shift of score occurred for each of the measures except DASS-21 (eAppendix 3). eAppendix 4 depicts the change in scores for the intervention group at the end of treatment and the clinically significant shift score of each measure.

Discussion

The results of this RCT revealed a promising impact of ILF NFB on the commonly experienced persistent PCSs of headaches and disrupted sleep. Veterans in the intervention group demonstrated statistically significant improvement in headache symptoms compared with veterans in the control group when assessed at the end of treatment and during a 2-month follow-up. The statistical significance of these improvements was also supported by large or very large effect sizes. In addition to these primary variables of interest, veterans in the intervention group notably demonstrated significant improvement compared with those in the control group in a number of secondary clinical measures, including QOL, traumatic stress-related symptoms, depressive symptoms, and general symptom report. The clinical impact was further supported by the clinically relevant shift in scores in the intervention group.

The data did not support the hypothesis that attention concerns would show significant improvement following ILF NFB. Performance on an attention measure did not differ significantly between groups at either the end-of-treatment or 2-month follow up assessment. The QIKtest, a continuous performance test used to measure attention, was a go/no-go task and calculated based on a combination of various types of errors and outlier responses. The stimulus for this task is a series of computerized, blinking lights, for which participants are tasked with discriminating targets and nontargets under time pressure. However, the order of the stimuli are consistent across administrations, rather than being randomized, introducing a potential confound of practice effects on this task since patients were administered the QIKtest 3 times in a 2-month period and again 2 months later. Veterans in the control group notably improved in their average performance of this task from baseline to the endpoint of their treatment participation and demonstrated further improvement at the 2-month follow-up assessment; this pattern would be consistent with potential practice effects and warrants caution in its interpretation for both groups.

Previously published ILF NFB clinical studies that used the QIKtest and found positive results were mostly conducted among children and teen populations across longer treatment periods. This research may indicate the QIKtest is not an appropriate measure to assess adults who have specialized training in responding to stimuli (ie, trained military personnel). This suggests the concept of attention dysfunction experienced by veterans and the best method to measure it may need to be explored further. This construct may not be related to the focus and skill in prolonged attention needed in selecting go/ no-go tasks, but rather related to a broader conceptual basis involving memory, recall, clarity of rational thought, and decision making impacted by the mTBI. For instance, a study among combat veterans with mTBI and PTSD found that performance on objective cognitive measures did not significantly correlate with their subjective reports of cognitive difficulties.⁵⁷ This reflects the pattern of the present study, in which subjective reports of attention improved over time on the clinical symptom checklist filled out by participants at each session, but the objective measure did not. The mean attention dysfunction score was 6 at session 1 and 1 to 2 at session 20 (lower scores are better on a 10-point scale).

Strengths and Limitations

This study presents results stemming from the first RCT examining clinical effectiveness of ILF NFB in a VA setting for veterans with diagnoses of mTBI. The study design shows promising external validity. Veterans were able to participate in a treatment consisting of 20 sessions over a period of typically 8 to 10 weeks, entailing 2 to 3 sessions per week, with an attrition of only 18% over the course of the study. Notably, attrition rates may have been impacted by the time course of the study, which was recruiting and running participants throughout the COVID-19 pandemic (March 2020 to May 2023). No attrition was due to the intervention itself, and no adverse reactions to ILF NFB were reported during the course of the study. Other strengths of the study include the ethnically and racially diverse participants, representative of the population of veterans in Hawaii. Additionally, all ILF NFB providers underwent supervised ILF NFB training and achieved a skill reliability index score of 0.95 prior to providing ILF NFB to the intervention group.

This study was not blinded. Neither veterans nor ILF NFB providers were blinded and were therefore aware of the randomly assigned groups. Research assistants administering the periodic assessments were meant to be blinded to condition by design; however, as the study progressed, a research assistant became unintentionally aware of each study participant's condition based on required documentation in the veteran’s health records; more notes were present for those in the intervention group (20 specialist notes) than the control group (8 notes). While the presence of a control group represents a strength relative to much of the existing ILF NFB literature, the control group in this case did not account for the total time spent with the researchers. Participants in the intervention group met with researchers for 20 total sessions as opposed to 8 telephone calls. Therefore, the study design cannot fully rule out the differential impact of demand characteristics between the 2 groups, nor can it fully address or rule out the impact of differential motivation and expectations between groups. There is also evidence that technological innovation can influence the expectations of research participants, meaning that the intervention group may have been unduly influenced by the novelty of the ILF NFB technology, to which the control group did not have exposure.⁵⁸

A second attention measure for this study would have been beneficial, perhaps in identifying true change in attention ability or providing more insight into finding better methods to assess attention among veterans with mTBI. ILF NFB demonstrated significant impact across multiple outcome measures of clinical relevance for veterans diagnosed with mTBI, including the primary outcome variables of headache and sleep. The strength of the improvements seen in these areas, supported by large practical effects as well as veterans’ subjective reports, indicates much promise. Follow-up studies may also focus on the potential effectiveness of ILF NFB as a treatment of the secondary concerns measured in this study, including traumatic stress-related and depressive symptoms, and may explore the added benefit, if any, of ILF NFB alongside other evidence-based treatments for traumatic stress-related and mood disorders (eg, cognitive behavioral therapy). Using functional magnetic resonance imaging before and after assessments to determine actual brain enhancement with ILF NFB for certain disorders in which a brain signature exists (ie, migraine) should be explored. Further examination of ILF NFB as an intervention for attention may also be warranted, using more effective measures of attention in the population of veterans with mTBI, given the concerns noted earlier. Future research on this topic will need to clearly define attention in relation to the veteran experience and use relevant measures.

Conclusions

This study supports ILF NFB as a safe, noninvasive, nonpharmacologic treatment that may be effective in addressing the complex clinical concerns of veterans diagnosed with mTBI, a population for whom effective treatments have been difficult to identify. This intervention can provide veterans with a desirable and effective nonpharmacologic alternative in their care.

Traumatic brain injury (TBI) is the signature injury of post-9/11 military operations, impacting > 441,000 combat veterans from 2001 to 2021 and 87% diagnosed with mild TBI (mTBI).^1,2 The most common cause of mTBI during these operations was blast exposures stemming from improvised explosive devices, rocket-propelled grenades, or land mines. mTBI was once thought to be self-limiting, lasting hours or days postinjury, but is now recognized as a complex focal and diffuse injury causing a cascade of molecular and biochemical responses with significant physiologic effects lasting for a longer duration. A significant number of combat veterans with mTBI (23%-48%) experience long-standing postconcussive symptoms (PCSs) for many years postinjury.^3-5

Developing and implementing strategies to reduce persistent symptoms associated with mTBI is of critical importance. Veterans diagnosed with mTBI and experiencing PCSs present ongoing treatment challenges to the health care system due to limited or suboptimal treatment options.^6,7 According to the 2021 US Department of Veterans Affairs (VA) and US Department of Defense (DoD) clinical guidelines for postacute mTBI, treatment for PCSs should be symptom focused. ^8,9 For instance, veterans with migraine headaches associated with mTBIs are often treated with abortive agents (eg, triptans) and preventive medications (eg, anticonvulsants and tricyclics).¹⁰ Cognitive dysfunction and insomnia are treated with cognitive rehabilitation programs, cognitive behaviorial therapy, occupational therapy, and medications (eg, hypnotics for insomnia).^11,12 The 2021 VA/DoD guidelines note that veteran and military focus groups described greater success with nonpharmacologic treatments than with pharmacologic treatments.⁸ The VA launched an enterprise-wide Whole Health Service program with the requirement that complementary and integrative health approaches must be available to veterans.¹³ As a nonpharmacologic, integrative, and noninvasive modality, neurofeedback (NFB) supports the VA Whole Health initiative and veterans’ preferences for integrative treatments.¹⁴

Neurofeedback

Rather than a symptom management approach, Defina et al described the possibilities of brain repair in TBI by treatments to enhance neuroplasticity, thereby establishing a more normalized or stable brain environment and enabling the brain to reorganize itself and function more normally.¹⁵ NFB has been shown to influence neuroplasticity,¹⁶ as evident in microstructural changes in white and gray matter¹⁷ and its ability to contribute to functional rehabilitation by restoring connectivity in specific areas of the brain that may have been impaired.¹⁸ The benefits of neuroenhancement strategies include potentially reduced pain for patients with mTBI and improved quality of life (QOL).¹⁹

NFB assists individuals by helping them become more aware of and self-regulate their physiology.^20,21 Because there are several types of NFB (eg, quantitative electroencephalography, Z-scored, α-θ) that differ in terms of equipment, mechanism of action, focus, and patient and clinician procedures, it is important to note that this study used a novel technologically advanced form of NFB, referred to as infra-low frequency (ILF) NFB. It works by reflecting a person’s brain wave activity via conventional electroencephalography back to the person through the visual cortex, thus providing relevant information to which the brain responds to improve core state regulation.²²

In 2006, ILF NFB developers sought to extend NFB capability into the slow cortical potential domain (< 0.1 Hz) and then gradually extended to lower frequencies on the basis of favorable clinical responses.^22,23 In 2017, the technology reached an ILF capacity that appeared to be helpful for several clinical issues. These developments depended on instrumentation capable of low noise signal detection down to the lowest frequency of interest. Instrumentation was developed for the purpose (eg, Bee Medic Cygnet NFB).

Although mTBI has been a clinical focus in NFB since the 1980s, there are few published studies demonstrating the efficacy of ILF NFB relating to the PCSs of interest in this study, and 2 suggested ILF NFB positively affected change in PCS severity.^24,25 Other studies found that ILF NFB decreased incidence of migraines and tension type headaches.^26,27 However, the findings of these studies had limited generalizability due to methodologic limitations, such as selection bias and small sample sizes.^24-27 Of importance to this article, there are also several publications on the efficacy of ILF NFB in clinical settings.^28-33

This article presents the second analysis of data from veterans who completed ILF NFB intervention and control group procedures during a 5-year randomized controlled trial (RCT). The RCT included veterans who experienced an mTBI while participating in post-9/11 military operations to evaluate the impact of ILF NFB on chronic PCSs, including headache, insomnia, and attention dysfunction. Initial results of this trial demonstrated significant differences between the intervention and control groups with strong effect sizes on all outcome measures at the end of treatment.³⁴

Methods

Participants included male and nonpregnant female veterans with a diagnosed mTBI during post-9/11 military operations; aged 18 to 65 years; reports of persistent (ie, > 3 months in duration) headaches, insomnia, and attention difficulties; and able to read and write English, comprehend what is read, and follow directions. mTBI diagnosis was verified for each veteran via the electronic health record. Patients were excluded if they had a severe TBI diagnosis or impaired decision-making capacity; were unable to comply with study visit schedule; or endorsed active suicidal intent on the Columbia-Suicide Severity Rating Scale.³⁵

Recruitment efforts included: (1) letters sent to eligible veterans with mTBI who were identified by clinical informatics data after waiver of Health Insurance Portability and Accountability Act was obtained; veterans could contact the research team directly or the research team would call the veteran 2 weeks after the letter was sent; (2) veterans could be referred by a clinician; and (3) veterans could self-refer based on flyers and other study marketing materials.

The study was conducted from 2019 to 2024 at Spark M. Matsunaga VA Medical Center, in Honolulu, Hawaii. Four private research spaces in compliance with human research standards were used for consent, treatment, and assessment.

Consenting Procedure and Randomization

The privacy rights of potential participants were observed, and interested veterans who met the eligibility criteria underwent an informed consent procedure and were administered the Columbia-Suicide Severity Rating Scale.³⁵ Those veterans not indicating active suicidal intent were randomized into the intervention or control group. Once randomized, the participant was enrolled and scheduled for baseline assessment.

All procedures of this study were performed in adherence with relevant laws and institutional guidelines. The study was reviewed and approved by the VA Pacific Islands Health Care System Institutional Review Board (#2019-06-JC/Promise 0003).

Outcome Measures

The outcome measures were administered at baseline, midpoint (3-7 weeks), end of treatment (6-12 weeks), and at a 2-month follow-up appointment with the research assistant or project coordinator.

The primary outcome measures include the Headache Impact Test (HIT-6), TBIQOL Headache Pain item short form, Insomnia Severity Index (ISI), Quality of Life in Neurological Disorders (Neuro-QOL) Sleep Disturbance short form, and attention measure: QIKtest Continuous Performance Test (QIKtest) (Table 1).^36-44

Secondary outcome measures included QOL After Brain Injury (QOLIBRI), Neuro- QOL Satisfaction With Roles/Activities short form (Neuro-QOL Satisfaction), Neuro-QOL Ability to Participate in Roles/Activities short form (Neuro-QOL Participate), Depression Anxiety Stress Scales (DASS-21), Patient Health Questionnaire-9 (PHQ-9), Posttraumatic Stress Disorder (PTSD) Checklist for DSM-5 (PCL-5), and the General Symptom Inventory (eAppendix 1).^39,42,45-52

Sample

Seventy-two participants (36 in each group) were needed to have adequate statistical power for the analysis. Presuming attrition, the goal was to recruit 100 veterans. Literature on NFB studies of patients with mTBI have reported dropout rates ranging from 10% to 30%.^53,54 Assuming a dropout rate of 28% and a moderate autocorrelation of 0.6 among repeated measures, this sample size ensured the detection of an average difference of at least 0.49 SDs with a power of 80% in the NFB intervention group compared with the control group using a 2-tailed significance level of 0.05.

Control Group

Following baseline assessment, control group participants received 8 phone calls (1 call/wk) from 1 of 4 clinical investigators over 8 to 10 weeks. During each 15-minute call, 1 of the following health topics was discussed: sleep hygiene, basic nutritional concepts, beverage choices, positive thinking, thought reframing, fitness, daily calming activity, and enhancement of focus strategies. A script for each topic was used to guide each call.

Intervention Group

Following baseline assessment, intervention group participants completed 20 half-hour ILF NFB sessions, typically receiving 3 sessions per week over an 8- to 10-week period. ILF NFB treatments were administered by 1 of 4 licensed health care employees who had received substantial ILF NFB training and achieved a skill reliability index score of 0.95, ensuring the skill level of the ILF NFB providers was equal. A script was used by the ILF NFB providers during the ILF NFB sessions to keep the interaction approach consistent with all participants.

All procedures were explained in advance to participants and voluntary participation affirmed. At the first session, participants filled out a clinical symptom checklist of 5 symptoms (eAppendix 1).^39,42,45-49 The initial rating on the symptom checklist was reflective of their experience over the past month, while in each subsequent session, participants indicated their experience of those symptoms that day. ILF NFB providers were never privy to participants’ primary or secondary outcome measures data during the study, so these recurring clinical symptom checklist ratings, as well as other feedback provided by participants on their experience within and between sessions, were the clinical data used to make decisions about ILF NFB treatment protocol.

The Othmer Optimal Response Frequency (ORF) protocol was used for participants in this study.⁵⁵ Through an iterative process, ORF protocol establishes the specific frequency point along the 0.000001 mHz to 0.1 Hz continuum, which is optimal to diminish symptoms experienced in real-time during the session (eg, tension or pain in shoulders; racing thoughts).

During each ILF NFB session, participants were seated comfortably and encouraged to look at the feedback screen. The moving images on the game screen provided almost instantaneous feedback (within 500 ms) to participants about their brain functioning, as ascertained by electrodes placed on the scalp as dictated by study protocol.⁵⁶ A standardized protocol for site placement was used beginning with T3-T4, followed by the weekly addition of a site as tolerated in the following sequence: T4-P4, FP2-T4, and FP1-T4. More information about the ILF NFB procedures are outlined in the report of the pilot study and RCT initial results.^22,34

Statistical Analysis

Eighty-seven participants were randomized, with 43 assigned to the intervention group and 44 to the control group to achieve the enrollment goal of ≥ 36 participants in each group. This report is the second analysis of data from this RCT that employed a per-protocol approach, analyzing a subset of participants who fully adhered to the study protocol and completed all study procedures. Outcome scores at baseline, midpoint, end of treatment, and 2-month follow-up were summarized as means with corresponding 95% CIs. Group comparisons at the end of treatment and 2-month follow-up time points were conducted using 2-sample t tests. All statistical tests were 2-sided with a significance level of .05 (Type I error rate). SAS software version 9.4 Maintenance 8 was used for statistical analysis. Cohen d analyses were used for effect sizes.

Results

Seventy-four participants fully adhered to the study protocol and were included in the present analyses, with 38 in the control group and 36 in the intervention group. eAppendix 2 depicts the flow of participants through this study. There were no adverse events related to treatment, and the 13 participants who withdrew typically reported difficulty with scheduling or transportation as the primary reason. This study also took place during the COVID-19 pandemic, which likely had some impact on enrollment; participants were differentially impacted by changes in employment and moves to the continental United States.

Participants were aged 30 to 60 years (mean [SD], 45.4 [8.0]). Most participants (90.5%) were male, and multiracial and White were the most common racial identities (Table 2). Participant characteristics were largely balanced across randomized groups. Similarly, test scores on the primary variables of interest in this study and secondary clinical variables assessed were comparable across participants (Table 3).

Primary Variables of Interest Analyses

This study’s hypothesis was that those who completed ILF NFB treatment per protocol would demonstrate statistically significant improvement in symptoms related to headaches, sleep disturbance, and difficulty with attention when compared with veterans in the control group. This hypothesis was partially supported. A 2-sample t test showed that veterans in the intervention group demonstrated significant improvement in headache symptoms compared with veterans in the control group on the HIT-6 at the end-of-treatment (P < .001, d = 1.53) and 2-month follow-up assessment (P < .001, d = 1.14). This pattern also was consistent with the TBI-QOL Headache Pain item short form, with veterans in the intervention group showing improvement beyond those in the control group at the end-of-treatment (P < .001, d = 0.89) and 2-month follow-up assessment (P < .001, d = 0.83). Two-sample t tests also demonstrated significant improvement in subjective reports of sleep; those in the intervention group had significantly lower scores on the ISI at the end-of-study (P < .001, d = 1.53) and 2-month follow-up assessment (P < .001, d = 0.97). This pattern also held true for the Neuro-QOL Sleep Disturbance short form subtest, which demonstrated significantly more improvement in the intervention group compared with the control group at the end-of-study (P < .001, d = 0.97) and 2-month follow- up assessment (P < .001, d = 0.92). improvement in attention was not supported by the present results. A 2-sample t test found no significant difference between performance on the QIKtest for veterans in the intervention group vs the control group at the end-of-study (P = .40, d = 0.19) or the 2-month follow-up (P = .43, d = 0.20) (eAppendix 3).

Secondary Variables of Interest Analysis

Secondary variables examined differences in QOL, PTSD, depressive symptoms, and general symptoms reported between veterans in the intervention and control groups. Results demonstrated that veterans in the intervention group showed improvement above and beyond those in the control group on all measures. In regard to QOL, veterans in the intervention group had significantly higher scores on the Neuro-QOL Participate subtest than those in the control group at the end-of-study (P = .01, d = 0.89) and 2-month follow-up assessment (P < .001, d = 0.62). A similar pattern was found for the Neuro-QOL Satisfaction subtest, with veterans in the intervention group showing significantly higher scores than those in the control group at the end-of-study (P = .001, d = 0.95) and 2-month follow-up assessment (P < .001, d = 0.62). This also held true on the QOLIBRI, with veterans in the intervention group demonstrating significantly higher scores than those in the control group at the end-of-study (P = .001, d = 0.92) and 2-month follow-up assessment (P < .001, d = 0.66).

Veterans in the intervention group had significantly lower scores on the PCL-5 than those in the control group at the end-of- study (P = .003, d = 0.78) and 2-month follow-up assessment (P = .001, d = 0.72). Veterans in the intervention group also had significantly lower scores on the PHQ-9 than those in the control group at the end-of-study (P < .001, d = 0.98) and 2-month follow-up assessment (P < .001, d = 0.83). Veterans in the intervention group had significantly lower scores on the DASS- 21 than those in the control group at the end-of-study (P = .002, d = 0.80) and 2-month follow-up assessment (P = .001, d = 0.77). They also had significantly lower scores on the General Symptom Inventory than those in the control group at the end-of-study (P = .02, d = 0.75) and 2-month follow-up assessment (P = .002, d = 0.57). A clinically significant shift of score occurred for each of the measures except DASS-21 (eAppendix 3). eAppendix 4 depicts the change in scores for the intervention group at the end of treatment and the clinically significant shift score of each measure.

Discussion

The results of this RCT revealed a promising impact of ILF NFB on the commonly experienced persistent PCSs of headaches and disrupted sleep. Veterans in the intervention group demonstrated statistically significant improvement in headache symptoms compared with veterans in the control group when assessed at the end of treatment and during a 2-month follow-up. The statistical significance of these improvements was also supported by large or very large effect sizes. In addition to these primary variables of interest, veterans in the intervention group notably demonstrated significant improvement compared with those in the control group in a number of secondary clinical measures, including QOL, traumatic stress-related symptoms, depressive symptoms, and general symptom report. The clinical impact was further supported by the clinically relevant shift in scores in the intervention group.

The data did not support the hypothesis that attention concerns would show significant improvement following ILF NFB. Performance on an attention measure did not differ significantly between groups at either the end-of-treatment or 2-month follow up assessment. The QIKtest, a continuous performance test used to measure attention, was a go/no-go task and calculated based on a combination of various types of errors and outlier responses. The stimulus for this task is a series of computerized, blinking lights, for which participants are tasked with discriminating targets and nontargets under time pressure. However, the order of the stimuli are consistent across administrations, rather than being randomized, introducing a potential confound of practice effects on this task since patients were administered the QIKtest 3 times in a 2-month period and again 2 months later. Veterans in the control group notably improved in their average performance of this task from baseline to the endpoint of their treatment participation and demonstrated further improvement at the 2-month follow-up assessment; this pattern would be consistent with potential practice effects and warrants caution in its interpretation for both groups.

Previously published ILF NFB clinical studies that used the QIKtest and found positive results were mostly conducted among children and teen populations across longer treatment periods. This research may indicate the QIKtest is not an appropriate measure to assess adults who have specialized training in responding to stimuli (ie, trained military personnel). This suggests the concept of attention dysfunction experienced by veterans and the best method to measure it may need to be explored further. This construct may not be related to the focus and skill in prolonged attention needed in selecting go/ no-go tasks, but rather related to a broader conceptual basis involving memory, recall, clarity of rational thought, and decision making impacted by the mTBI. For instance, a study among combat veterans with mTBI and PTSD found that performance on objective cognitive measures did not significantly correlate with their subjective reports of cognitive difficulties.⁵⁷ This reflects the pattern of the present study, in which subjective reports of attention improved over time on the clinical symptom checklist filled out by participants at each session, but the objective measure did not. The mean attention dysfunction score was 6 at session 1 and 1 to 2 at session 20 (lower scores are better on a 10-point scale).

Strengths and Limitations

This study presents results stemming from the first RCT examining clinical effectiveness of ILF NFB in a VA setting for veterans with diagnoses of mTBI. The study design shows promising external validity. Veterans were able to participate in a treatment consisting of 20 sessions over a period of typically 8 to 10 weeks, entailing 2 to 3 sessions per week, with an attrition of only 18% over the course of the study. Notably, attrition rates may have been impacted by the time course of the study, which was recruiting and running participants throughout the COVID-19 pandemic (March 2020 to May 2023). No attrition was due to the intervention itself, and no adverse reactions to ILF NFB were reported during the course of the study. Other strengths of the study include the ethnically and racially diverse participants, representative of the population of veterans in Hawaii. Additionally, all ILF NFB providers underwent supervised ILF NFB training and achieved a skill reliability index score of 0.95 prior to providing ILF NFB to the intervention group.

This study was not blinded. Neither veterans nor ILF NFB providers were blinded and were therefore aware of the randomly assigned groups. Research assistants administering the periodic assessments were meant to be blinded to condition by design; however, as the study progressed, a research assistant became unintentionally aware of each study participant's condition based on required documentation in the veteran’s health records; more notes were present for those in the intervention group (20 specialist notes) than the control group (8 notes). While the presence of a control group represents a strength relative to much of the existing ILF NFB literature, the control group in this case did not account for the total time spent with the researchers. Participants in the intervention group met with researchers for 20 total sessions as opposed to 8 telephone calls. Therefore, the study design cannot fully rule out the differential impact of demand characteristics between the 2 groups, nor can it fully address or rule out the impact of differential motivation and expectations between groups. There is also evidence that technological innovation can influence the expectations of research participants, meaning that the intervention group may have been unduly influenced by the novelty of the ILF NFB technology, to which the control group did not have exposure.⁵⁸

A second attention measure for this study would have been beneficial, perhaps in identifying true change in attention ability or providing more insight into finding better methods to assess attention among veterans with mTBI. ILF NFB demonstrated significant impact across multiple outcome measures of clinical relevance for veterans diagnosed with mTBI, including the primary outcome variables of headache and sleep. The strength of the improvements seen in these areas, supported by large practical effects as well as veterans’ subjective reports, indicates much promise. Follow-up studies may also focus on the potential effectiveness of ILF NFB as a treatment of the secondary concerns measured in this study, including traumatic stress-related and depressive symptoms, and may explore the added benefit, if any, of ILF NFB alongside other evidence-based treatments for traumatic stress-related and mood disorders (eg, cognitive behavioral therapy). Using functional magnetic resonance imaging before and after assessments to determine actual brain enhancement with ILF NFB for certain disorders in which a brain signature exists (ie, migraine) should be explored. Further examination of ILF NFB as an intervention for attention may also be warranted, using more effective measures of attention in the population of veterans with mTBI, given the concerns noted earlier. Future research on this topic will need to clearly define attention in relation to the veteran experience and use relevant measures.

Conclusions

This study supports ILF NFB as a safe, noninvasive, nonpharmacologic treatment that may be effective in addressing the complex clinical concerns of veterans diagnosed with mTBI, a population for whom effective treatments have been difficult to identify. This intervention can provide veterans with a desirable and effective nonpharmacologic alternative in their care.

Medication regimens may require adjustment in acute care settings due to dysphagia and/or enteral feeding tubes. When a patient has dysphagia and/or a feeding tube, the health care team must review the pharmacotherapy regimen to assess the appropriateness of medication formulations. Patient anatomy, the type of feeding tube in place, pharmacokinetic and pharmacodynamic properties of medications, risk of feeding tube obstruction, and potential for interactions between enteral nutrition and medications should be considered when clinicians administer medications through feeding tubes. The risk of feeding tube obstruction and clogging rises with increasing tube length and decreasing tube lumen. Incidence of obstructed percutaneous endoscopic gastrotomy tubes is reported to be 23% to 35%.¹

A coordinated effort by all members of the health care team is essential to provide safe and effective care to patients with dysphagia and/or enteral feeding tubes. To decrease the risk of feeding tube obstruction, medications should be dissolved in water or administered in liquid form, saline fluids should be avoided, and the tube should be flushed with water before and after administering medications.

The pharmacokinetics of medications can be altered when tablets are crushed or capsules are opened. The bioavailability of dabigatran, for example, increases by 75% when the capsules are opened and pellets are taken orally.² Medications may become intolerable after manipulation due to taste.³ Others may also increase the risk of feeding tube obstruction, such as omeprazole granules that increase the risk of small-bore feeding tube obstruction.⁴

Prior assessments of drug administration for patients with dysphagia and/or enteral feeding tubes has shown medication errors are prevalent.^5-7 The Institute for Safe Medication Practices (ISMP) issued a Medication Safety Alert that provides a framework for preventing medication errors when preparing and administering medications via enteral feeding tubes.⁸ Other resources, such as monographs, are also available to guide pharmacotherapy decisions when oral medications require manipulation for administration to patients with dysphagia and/or enteral feeding tubes.^9-11

In 2021, the Kansas City Veterans Affairs Medical Center (KCVAMC) was recognized as a Veterans Health Administration (VHA) Shark Tank finalist for improving the safety of medication administration for patients with enteral feeding tubes.¹² This involved the addition of a Computerized Patient Record System (CPRS), clinical reminder order check (CROC), and a comprehensive medication review by a pharmacist. After implementing the CROC alert and pharmacy e-consultation workflow, the KCVAMC team reported that the number of inappropriate medications (ie, drugs on the ISMP do not crush list) was reduced from 41 to 6 in 1 year, resulting in an 85.4% reduction in potential medication errors.¹³

In 2014, the Richard L. Roudebush VAMC (RLRVAMC) created a pharmacy consultation process for patients with dysphagia and/or enteral feeding tubes. Any clinician could place a pharmacy consultation in CPRS. A pharmacist then reviewed patient charts, medication information resources, the VA formulary, and RLRVAMC pharmacy inventory. The pharmacist conferred with the patient’s care team to adjust pharmacotherapy, completed a consultation note, and updated medication order comments in Veterans Health Information Systems and Technology Architecture (VistA). These comments interfaced with the barcode medication administration software for the health care professional administering medications.

Despite the 2014 quality improvement (QI) process, medication errors involving the inappropriate ordering, preparation, and administration of medications for patients with dysphagia and/or enteral feeding tubes continued to be reported. Additionally, anonymous feedback revealed that only 3 of 10 responding pharmacists were satisfied with the existing medication use process for patients with dysphagia and/or enteral feeding tubes. Pharmacists expressed concerns that (1) clinicians were inappropriately crushing and/or manipulating new medications that were ordered after pharmacy consultations; (2) there was a lack of comprehensive documentation in CPRS; and (3) there were too many manual steps in the process. In response, RLRVAMC initiated a new QI initiative to improve the medication use process for patients with dysphagia and/or enteral feeding tubes in the acute care setting.

Quality Improvement Project

This multidisciplinary RLRVAMC QI project began November 2024 to improve pharmacotherapy care for patients with dysphagia and/or enteral feeding tubes in acute care. It was approved by the RLRVAMC Pharmacy Service. This intervention addressed the pharmacy consultation template, standardization of equipment, standardization of language, creation of clinical alerts, and sustainment (Table 1).

RLRVAMC has about 8600 annual inpatient admissions and 159 acute care beds.¹⁴ The project charter was drafted, and local stakeholders were identified including pharmacy technicians, pharmacists, nurses, speech language pathologists, and acute care clinicians. Pharmacy consultation workload was retrospectively reviewed to describe the scope of the existing state.

A workshop with 12 QI project stakeholders in December 2024 used A3 methodology to define the current process and the target state, barriers and solutions, prioritize interventions on an impact-effort matrix, perform a gap analysis, identify rapid plan-do-study-act (PDSA) experiments, and develop a completion plan (Figure). Five postworkshop PDSA experiments engaged additional stakeholders, clinical application coordinators, and medical supply representatives to ascertain the feasibility of the tools implemented.

About 3% of RLRVAMC admissions involve a pharmacy consultation to review medications for dysphagia and/or enteral feeding tubes. Clinicians reviewed 30 preimplementation inpatient pharmacy consultations involving 200 oral medications. Pharmacists were more frequently consulted for inpatients with dysphagia (19 [63%]) than for patients with enteral feeding tubes (11 [37%]) (Table 2).

Pharmacy Consultation Template

The pharmacy consultation was updated in CPRS. Prior to this QI project, the ordering clinician was prompted to select 1 option for the indication: dysphagia or enteral feeding tube. The type of enteral feeding tube was not prompted by the consultation text nor required to be specified in the consultation. The ordering clinician could provide free-text comments. Of 11 preimplementation consultations, the type of enteral feeding tube was specified in 5 (45%). The consultation template entry was updated to include an option to check a box for the consultation indication from 3 options: dysphagia, enteral feeding, or other patient- specific condition/request. If enteral feeding tube is selected, then the clinician is prompted to select the type of enteral feeding tube. Since the completion of the project, there have been no patient safety reports concerning an erroneous or incomplete consultation entry (Supplemental Material).

The note template was updated to import the list of active inpatient medications and provide sections for the adjudicating pharmacist to document which medications can be crushed (or opened), which require adjustment, and which are hazardous and require special handling. Additionally, the revised template added a statement clarifying that the documented recommendations apply only to the medication regimen at the time of the consultation (Supplemental Material).

Standardizations

There are multiple pill-crushing devices used at RLRVAMC that vary in crushing mechanism, corresponding medication pouches, and degree of protection when manipulating hazardous medications. Prior to this QI project, RLRVAMC used 3 pill-crushing devices (about 30 total devices in inpatient care areas). Only 1 device with corresponding closed pouches for preparation of hazardous medications was available, which was stored in the RLRVAMC inpatient pharmacy. This workflow resulted in waste and posed potential risks for delays in care. This project incorporated a standard pill-crushing system with the corresponding medication pouches in all inpatient care areas, which provided safeguards for clinicians to prepare and administer hazardous medications (Supplemental Material).

Patients requiring medications to be crushed or opened on discharge should receive education, written instruction, and have care plans documented in CPRS. RLRVAMC patients receive education and a printed medication list. Prior to this QI project, the instructions for crushing or opening medications could only be entered by free text in the electronic medication reconciliation tool, allowing for the potential for inconsistent language or omissions.

This QI project included an update to the electronic medication reconciliation tool. An optional checkbox selection was added for patients requiring medications to be manipulated. When checked, a radial selection for individual medications is displayed, prompting the clinician and pharmacist to indicate either do not crush tablet or OK to crush tablet. These selections appear in clinical care notes and on the printed medication list provided to the patient (Supplemental Material).

Clinical Alerts

As part of the RLRVAMC QI initiative, a CROC alert was implemented, based on the KCVAMC intervention for patients with enteral feeding tubes.¹³ The RLRVAMC CROC alert also included patients with dysphagia. A nursing text order was made available in CPRS for patients requiring medications and remains active throughout the duration of the patient’s admission or until discontinued. It generates CROC alerts in CPRS and VistA when new medication orders are entered and reviewed by pharmacists.

Clinicians used clinical decision support systems to create daily lists of patients receiving medications by feeding tube and patients receiving crushed/opened medications due to dysphagia. This allows pharmacists to perform a census review of all inpatients to confirm appropriateness of medication orders. Clinical alerts for patients with enteral feeding tubes are advised by the ISMP and have data demonstrating a reduction in medication errors (Supplemental Material).^14,15

Sustainment

During the sustainment phase, process owners were identified and a Pharmacy Service standard operating procedure (SOP) was written. The development of an institutional do not crush medication list was discussed; however, it was determined to be difficult to develop and maintain. An institutional tertiary resource list was selected in favor of a locally developed resource. These resources include the Handbook of Drug Administration via Enteral Feeding Tubes, Third Edition, the Pharmacist’s Letter list, “Meds that Should Not be Crushed,” and the Up- ToDate Lexidrug list, “Oral Medications That Should Not Be Crushed or Altered.”^9-11 Links to the resources were added to the RLRVAMC pharmacy service SharePoint. In addition to defining the preferred tertiary resources, the SOP defined the process for reviewing inventory and the process for reviewing medication orders for hazard risk.

Discussion

Continued patient safety reports and low satisfaction rates among pharmacists prompted this QI project to improve safety for patients with dysphagia and/or enteral feeding tubes at RLRVAMC. The project engaged stakeholders and also identified and addressed gaps with potential for patient harm.

The tools implemented by this initiative drew from previous work by the KCVAMC and from framework provided by the ISMP.^8,13 We expanded the QI intervention to include acute care patients with dysphagia.

RLRVAMC did not take steps to track the impact of the interventions on medication errors. However, no patient safety reports concerning an erroneous or incomplete pharmacy consultation entry have been reported. We also think that it is reasonable to assume that the adoption of the safety tools described here will have a positive impact on patient safety. RLRVAMC pharmacists have noted an increased appreciation for medication safety when processing medication orders for patients with dysphagia and/or enteral feeding tubes. While the workflow took time to adopt and integrate, clinical pharmacists perceived it as an improvement in patient safety. Our future focus is aimed at translating the process improvement into the Oracle/Cerner electronic health record, which is scheduled to be deployed at the RLRVAMC in August 2026.

Limitations

This QI project did not aim to quantify or compare medication errors before and after the intervention. An accurate number of unreported errors in the medication use process for patients with dysphagia and/or enteral feeding tubes would be challenging to quantify without direct observation. Multiple clinicians are engaged in the medication use process and individual steps may not be documented at all, or documented properly. In addition, medication errors are often underreported and may not reflect the total number of errors and/or potential for errors. That said, reported medication errors in the medication use process for patients with dysphagia and/or enteral feeding tubes are reviewed on a monthly basis by the RLRVAMC Multidisciplinary Medication Safety committee to continuously improve patient safety.

Another potential limitation is the extent to which the project can be adapted at other VHA sites. For example, RLRVAMC uses CPRS; the framework and tools to improve medication safety may not translate to sites using the Oracle/Cerner electronic health record. Furthermore, this QI project included a pharmacy consultation workflow that relied on pharmacists who are available at any hour. Other facilities may not have continuous consultation coverage to review medications for patients with dysphagia and/or enteral feeding tubes.

Conclusions

This QI project drew from ISMP recommendations, previous work within the VHA, local practice, and insight from multiple disciplines on the health care team to revise and create tools to improve medication safety for patients with dysphagia and/or enteral feeding tubes in the acute care setting. These tools included a revised pharmacy consultation workflow with improvements to the pharmacy consultation template, standardization of the pill-crushing devices and language used for patient medication lists, implementation of CROC alerts within the EHR, and development of an SOP.

The RLRVAMC Pharmacy Service intends to continue reviewing patient safety reports, assessing staff perspectives, and refining (and potentially adding) tools for medication safety. Future QI initiatives may focus on improving medication safety for outpatients with dysphagia and/or enteral feeding tubes. We also hope that these tools can be adapted at other VAMCs to promote medication safety for patients with dysphagia and/or enteral feeding tubes.

Medication regimens may require adjustment in acute care settings due to dysphagia and/or enteral feeding tubes. When a patient has dysphagia and/or a feeding tube, the health care team must review the pharmacotherapy regimen to assess the appropriateness of medication formulations. Patient anatomy, the type of feeding tube in place, pharmacokinetic and pharmacodynamic properties of medications, risk of feeding tube obstruction, and potential for interactions between enteral nutrition and medications should be considered when clinicians administer medications through feeding tubes. The risk of feeding tube obstruction and clogging rises with increasing tube length and decreasing tube lumen. Incidence of obstructed percutaneous endoscopic gastrotomy tubes is reported to be 23% to 35%.¹

A coordinated effort by all members of the health care team is essential to provide safe and effective care to patients with dysphagia and/or enteral feeding tubes. To decrease the risk of feeding tube obstruction, medications should be dissolved in water or administered in liquid form, saline fluids should be avoided, and the tube should be flushed with water before and after administering medications.

The pharmacokinetics of medications can be altered when tablets are crushed or capsules are opened. The bioavailability of dabigatran, for example, increases by 75% when the capsules are opened and pellets are taken orally.² Medications may become intolerable after manipulation due to taste.³ Others may also increase the risk of feeding tube obstruction, such as omeprazole granules that increase the risk of small-bore feeding tube obstruction.⁴

Prior assessments of drug administration for patients with dysphagia and/or enteral feeding tubes has shown medication errors are prevalent.^5-7 The Institute for Safe Medication Practices (ISMP) issued a Medication Safety Alert that provides a framework for preventing medication errors when preparing and administering medications via enteral feeding tubes.⁸ Other resources, such as monographs, are also available to guide pharmacotherapy decisions when oral medications require manipulation for administration to patients with dysphagia and/or enteral feeding tubes.^9-11

In 2021, the Kansas City Veterans Affairs Medical Center (KCVAMC) was recognized as a Veterans Health Administration (VHA) Shark Tank finalist for improving the safety of medication administration for patients with enteral feeding tubes.¹² This involved the addition of a Computerized Patient Record System (CPRS), clinical reminder order check (CROC), and a comprehensive medication review by a pharmacist. After implementing the CROC alert and pharmacy e-consultation workflow, the KCVAMC team reported that the number of inappropriate medications (ie, drugs on the ISMP do not crush list) was reduced from 41 to 6 in 1 year, resulting in an 85.4% reduction in potential medication errors.¹³

In 2014, the Richard L. Roudebush VAMC (RLRVAMC) created a pharmacy consultation process for patients with dysphagia and/or enteral feeding tubes. Any clinician could place a pharmacy consultation in CPRS. A pharmacist then reviewed patient charts, medication information resources, the VA formulary, and RLRVAMC pharmacy inventory. The pharmacist conferred with the patient’s care team to adjust pharmacotherapy, completed a consultation note, and updated medication order comments in Veterans Health Information Systems and Technology Architecture (VistA). These comments interfaced with the barcode medication administration software for the health care professional administering medications.

Despite the 2014 quality improvement (QI) process, medication errors involving the inappropriate ordering, preparation, and administration of medications for patients with dysphagia and/or enteral feeding tubes continued to be reported. Additionally, anonymous feedback revealed that only 3 of 10 responding pharmacists were satisfied with the existing medication use process for patients with dysphagia and/or enteral feeding tubes. Pharmacists expressed concerns that (1) clinicians were inappropriately crushing and/or manipulating new medications that were ordered after pharmacy consultations; (2) there was a lack of comprehensive documentation in CPRS; and (3) there were too many manual steps in the process. In response, RLRVAMC initiated a new QI initiative to improve the medication use process for patients with dysphagia and/or enteral feeding tubes in the acute care setting.

Quality Improvement Project

This multidisciplinary RLRVAMC QI project began November 2024 to improve pharmacotherapy care for patients with dysphagia and/or enteral feeding tubes in acute care. It was approved by the RLRVAMC Pharmacy Service. This intervention addressed the pharmacy consultation template, standardization of equipment, standardization of language, creation of clinical alerts, and sustainment (Table 1).

RLRVAMC has about 8600 annual inpatient admissions and 159 acute care beds.¹⁴ The project charter was drafted, and local stakeholders were identified including pharmacy technicians, pharmacists, nurses, speech language pathologists, and acute care clinicians. Pharmacy consultation workload was retrospectively reviewed to describe the scope of the existing state.

A workshop with 12 QI project stakeholders in December 2024 used A3 methodology to define the current process and the target state, barriers and solutions, prioritize interventions on an impact-effort matrix, perform a gap analysis, identify rapid plan-do-study-act (PDSA) experiments, and develop a completion plan (Figure). Five postworkshop PDSA experiments engaged additional stakeholders, clinical application coordinators, and medical supply representatives to ascertain the feasibility of the tools implemented.

About 3% of RLRVAMC admissions involve a pharmacy consultation to review medications for dysphagia and/or enteral feeding tubes. Clinicians reviewed 30 preimplementation inpatient pharmacy consultations involving 200 oral medications. Pharmacists were more frequently consulted for inpatients with dysphagia (19 [63%]) than for patients with enteral feeding tubes (11 [37%]) (Table 2).

Pharmacy Consultation Template

The pharmacy consultation was updated in CPRS. Prior to this QI project, the ordering clinician was prompted to select 1 option for the indication: dysphagia or enteral feeding tube. The type of enteral feeding tube was not prompted by the consultation text nor required to be specified in the consultation. The ordering clinician could provide free-text comments. Of 11 preimplementation consultations, the type of enteral feeding tube was specified in 5 (45%). The consultation template entry was updated to include an option to check a box for the consultation indication from 3 options: dysphagia, enteral feeding, or other patient- specific condition/request. If enteral feeding tube is selected, then the clinician is prompted to select the type of enteral feeding tube. Since the completion of the project, there have been no patient safety reports concerning an erroneous or incomplete consultation entry (Supplemental Material).

The note template was updated to import the list of active inpatient medications and provide sections for the adjudicating pharmacist to document which medications can be crushed (or opened), which require adjustment, and which are hazardous and require special handling. Additionally, the revised template added a statement clarifying that the documented recommendations apply only to the medication regimen at the time of the consultation (Supplemental Material).

Standardizations

There are multiple pill-crushing devices used at RLRVAMC that vary in crushing mechanism, corresponding medication pouches, and degree of protection when manipulating hazardous medications. Prior to this QI project, RLRVAMC used 3 pill-crushing devices (about 30 total devices in inpatient care areas). Only 1 device with corresponding closed pouches for preparation of hazardous medications was available, which was stored in the RLRVAMC inpatient pharmacy. This workflow resulted in waste and posed potential risks for delays in care. This project incorporated a standard pill-crushing system with the corresponding medication pouches in all inpatient care areas, which provided safeguards for clinicians to prepare and administer hazardous medications (Supplemental Material).

Patients requiring medications to be crushed or opened on discharge should receive education, written instruction, and have care plans documented in CPRS. RLRVAMC patients receive education and a printed medication list. Prior to this QI project, the instructions for crushing or opening medications could only be entered by free text in the electronic medication reconciliation tool, allowing for the potential for inconsistent language or omissions.

This QI project included an update to the electronic medication reconciliation tool. An optional checkbox selection was added for patients requiring medications to be manipulated. When checked, a radial selection for individual medications is displayed, prompting the clinician and pharmacist to indicate either do not crush tablet or OK to crush tablet. These selections appear in clinical care notes and on the printed medication list provided to the patient (Supplemental Material).

Clinical Alerts

As part of the RLRVAMC QI initiative, a CROC alert was implemented, based on the KCVAMC intervention for patients with enteral feeding tubes.¹³ The RLRVAMC CROC alert also included patients with dysphagia. A nursing text order was made available in CPRS for patients requiring medications and remains active throughout the duration of the patient’s admission or until discontinued. It generates CROC alerts in CPRS and VistA when new medication orders are entered and reviewed by pharmacists.

Clinicians used clinical decision support systems to create daily lists of patients receiving medications by feeding tube and patients receiving crushed/opened medications due to dysphagia. This allows pharmacists to perform a census review of all inpatients to confirm appropriateness of medication orders. Clinical alerts for patients with enteral feeding tubes are advised by the ISMP and have data demonstrating a reduction in medication errors (Supplemental Material).^14,15

Sustainment

During the sustainment phase, process owners were identified and a Pharmacy Service standard operating procedure (SOP) was written. The development of an institutional do not crush medication list was discussed; however, it was determined to be difficult to develop and maintain. An institutional tertiary resource list was selected in favor of a locally developed resource. These resources include the Handbook of Drug Administration via Enteral Feeding Tubes, Third Edition, the Pharmacist’s Letter list, “Meds that Should Not be Crushed,” and the Up- ToDate Lexidrug list, “Oral Medications That Should Not Be Crushed or Altered.”^9-11 Links to the resources were added to the RLRVAMC pharmacy service SharePoint. In addition to defining the preferred tertiary resources, the SOP defined the process for reviewing inventory and the process for reviewing medication orders for hazard risk.

Discussion

Continued patient safety reports and low satisfaction rates among pharmacists prompted this QI project to improve safety for patients with dysphagia and/or enteral feeding tubes at RLRVAMC. The project engaged stakeholders and also identified and addressed gaps with potential for patient harm.

The tools implemented by this initiative drew from previous work by the KCVAMC and from framework provided by the ISMP.^8,13 We expanded the QI intervention to include acute care patients with dysphagia.

RLRVAMC did not take steps to track the impact of the interventions on medication errors. However, no patient safety reports concerning an erroneous or incomplete pharmacy consultation entry have been reported. We also think that it is reasonable to assume that the adoption of the safety tools described here will have a positive impact on patient safety. RLRVAMC pharmacists have noted an increased appreciation for medication safety when processing medication orders for patients with dysphagia and/or enteral feeding tubes. While the workflow took time to adopt and integrate, clinical pharmacists perceived it as an improvement in patient safety. Our future focus is aimed at translating the process improvement into the Oracle/Cerner electronic health record, which is scheduled to be deployed at the RLRVAMC in August 2026.

Limitations

This QI project did not aim to quantify or compare medication errors before and after the intervention. An accurate number of unreported errors in the medication use process for patients with dysphagia and/or enteral feeding tubes would be challenging to quantify without direct observation. Multiple clinicians are engaged in the medication use process and individual steps may not be documented at all, or documented properly. In addition, medication errors are often underreported and may not reflect the total number of errors and/or potential for errors. That said, reported medication errors in the medication use process for patients with dysphagia and/or enteral feeding tubes are reviewed on a monthly basis by the RLRVAMC Multidisciplinary Medication Safety committee to continuously improve patient safety.

Another potential limitation is the extent to which the project can be adapted at other VHA sites. For example, RLRVAMC uses CPRS; the framework and tools to improve medication safety may not translate to sites using the Oracle/Cerner electronic health record. Furthermore, this QI project included a pharmacy consultation workflow that relied on pharmacists who are available at any hour. Other facilities may not have continuous consultation coverage to review medications for patients with dysphagia and/or enteral feeding tubes.

Conclusions

This QI project drew from ISMP recommendations, previous work within the VHA, local practice, and insight from multiple disciplines on the health care team to revise and create tools to improve medication safety for patients with dysphagia and/or enteral feeding tubes in the acute care setting. These tools included a revised pharmacy consultation workflow with improvements to the pharmacy consultation template, standardization of the pill-crushing devices and language used for patient medication lists, implementation of CROC alerts within the EHR, and development of an SOP.

The RLRVAMC Pharmacy Service intends to continue reviewing patient safety reports, assessing staff perspectives, and refining (and potentially adding) tools for medication safety. Future QI initiatives may focus on improving medication safety for outpatients with dysphagia and/or enteral feeding tubes. We also hope that these tools can be adapted at other VAMCs to promote medication safety for patients with dysphagia and/or enteral feeding tubes.

Medication regimens may require adjustment in acute care settings due to dysphagia and/or enteral feeding tubes. When a patient has dysphagia and/or a feeding tube, the health care team must review the pharmacotherapy regimen to assess the appropriateness of medication formulations. Patient anatomy, the type of feeding tube in place, pharmacokinetic and pharmacodynamic properties of medications, risk of feeding tube obstruction, and potential for interactions between enteral nutrition and medications should be considered when clinicians administer medications through feeding tubes. The risk of feeding tube obstruction and clogging rises with increasing tube length and decreasing tube lumen. Incidence of obstructed percutaneous endoscopic gastrotomy tubes is reported to be 23% to 35%.¹

A coordinated effort by all members of the health care team is essential to provide safe and effective care to patients with dysphagia and/or enteral feeding tubes. To decrease the risk of feeding tube obstruction, medications should be dissolved in water or administered in liquid form, saline fluids should be avoided, and the tube should be flushed with water before and after administering medications.

The pharmacokinetics of medications can be altered when tablets are crushed or capsules are opened. The bioavailability of dabigatran, for example, increases by 75% when the capsules are opened and pellets are taken orally.² Medications may become intolerable after manipulation due to taste.³ Others may also increase the risk of feeding tube obstruction, such as omeprazole granules that increase the risk of small-bore feeding tube obstruction.⁴

Prior assessments of drug administration for patients with dysphagia and/or enteral feeding tubes has shown medication errors are prevalent.^5-7 The Institute for Safe Medication Practices (ISMP) issued a Medication Safety Alert that provides a framework for preventing medication errors when preparing and administering medications via enteral feeding tubes.⁸ Other resources, such as monographs, are also available to guide pharmacotherapy decisions when oral medications require manipulation for administration to patients with dysphagia and/or enteral feeding tubes.^9-11

In 2021, the Kansas City Veterans Affairs Medical Center (KCVAMC) was recognized as a Veterans Health Administration (VHA) Shark Tank finalist for improving the safety of medication administration for patients with enteral feeding tubes.¹² This involved the addition of a Computerized Patient Record System (CPRS), clinical reminder order check (CROC), and a comprehensive medication review by a pharmacist. After implementing the CROC alert and pharmacy e-consultation workflow, the KCVAMC team reported that the number of inappropriate medications (ie, drugs on the ISMP do not crush list) was reduced from 41 to 6 in 1 year, resulting in an 85.4% reduction in potential medication errors.¹³

In 2014, the Richard L. Roudebush VAMC (RLRVAMC) created a pharmacy consultation process for patients with dysphagia and/or enteral feeding tubes. Any clinician could place a pharmacy consultation in CPRS. A pharmacist then reviewed patient charts, medication information resources, the VA formulary, and RLRVAMC pharmacy inventory. The pharmacist conferred with the patient’s care team to adjust pharmacotherapy, completed a consultation note, and updated medication order comments in Veterans Health Information Systems and Technology Architecture (VistA). These comments interfaced with the barcode medication administration software for the health care professional administering medications.

Despite the 2014 quality improvement (QI) process, medication errors involving the inappropriate ordering, preparation, and administration of medications for patients with dysphagia and/or enteral feeding tubes continued to be reported. Additionally, anonymous feedback revealed that only 3 of 10 responding pharmacists were satisfied with the existing medication use process for patients with dysphagia and/or enteral feeding tubes. Pharmacists expressed concerns that (1) clinicians were inappropriately crushing and/or manipulating new medications that were ordered after pharmacy consultations; (2) there was a lack of comprehensive documentation in CPRS; and (3) there were too many manual steps in the process. In response, RLRVAMC initiated a new QI initiative to improve the medication use process for patients with dysphagia and/or enteral feeding tubes in the acute care setting.

Quality Improvement Project

This multidisciplinary RLRVAMC QI project began November 2024 to improve pharmacotherapy care for patients with dysphagia and/or enteral feeding tubes in acute care. It was approved by the RLRVAMC Pharmacy Service. This intervention addressed the pharmacy consultation template, standardization of equipment, standardization of language, creation of clinical alerts, and sustainment (Table 1).

RLRVAMC has about 8600 annual inpatient admissions and 159 acute care beds.¹⁴ The project charter was drafted, and local stakeholders were identified including pharmacy technicians, pharmacists, nurses, speech language pathologists, and acute care clinicians. Pharmacy consultation workload was retrospectively reviewed to describe the scope of the existing state.

A workshop with 12 QI project stakeholders in December 2024 used A3 methodology to define the current process and the target state, barriers and solutions, prioritize interventions on an impact-effort matrix, perform a gap analysis, identify rapid plan-do-study-act (PDSA) experiments, and develop a completion plan (Figure). Five postworkshop PDSA experiments engaged additional stakeholders, clinical application coordinators, and medical supply representatives to ascertain the feasibility of the tools implemented.

About 3% of RLRVAMC admissions involve a pharmacy consultation to review medications for dysphagia and/or enteral feeding tubes. Clinicians reviewed 30 preimplementation inpatient pharmacy consultations involving 200 oral medications. Pharmacists were more frequently consulted for inpatients with dysphagia (19 [63%]) than for patients with enteral feeding tubes (11 [37%]) (Table 2).

Pharmacy Consultation Template

The pharmacy consultation was updated in CPRS. Prior to this QI project, the ordering clinician was prompted to select 1 option for the indication: dysphagia or enteral feeding tube. The type of enteral feeding tube was not prompted by the consultation text nor required to be specified in the consultation. The ordering clinician could provide free-text comments. Of 11 preimplementation consultations, the type of enteral feeding tube was specified in 5 (45%). The consultation template entry was updated to include an option to check a box for the consultation indication from 3 options: dysphagia, enteral feeding, or other patient- specific condition/request. If enteral feeding tube is selected, then the clinician is prompted to select the type of enteral feeding tube. Since the completion of the project, there have been no patient safety reports concerning an erroneous or incomplete consultation entry (Supplemental Material).

The note template was updated to import the list of active inpatient medications and provide sections for the adjudicating pharmacist to document which medications can be crushed (or opened), which require adjustment, and which are hazardous and require special handling. Additionally, the revised template added a statement clarifying that the documented recommendations apply only to the medication regimen at the time of the consultation (Supplemental Material).

Standardizations

There are multiple pill-crushing devices used at RLRVAMC that vary in crushing mechanism, corresponding medication pouches, and degree of protection when manipulating hazardous medications. Prior to this QI project, RLRVAMC used 3 pill-crushing devices (about 30 total devices in inpatient care areas). Only 1 device with corresponding closed pouches for preparation of hazardous medications was available, which was stored in the RLRVAMC inpatient pharmacy. This workflow resulted in waste and posed potential risks for delays in care. This project incorporated a standard pill-crushing system with the corresponding medication pouches in all inpatient care areas, which provided safeguards for clinicians to prepare and administer hazardous medications (Supplemental Material).

Patients requiring medications to be crushed or opened on discharge should receive education, written instruction, and have care plans documented in CPRS. RLRVAMC patients receive education and a printed medication list. Prior to this QI project, the instructions for crushing or opening medications could only be entered by free text in the electronic medication reconciliation tool, allowing for the potential for inconsistent language or omissions.

This QI project included an update to the electronic medication reconciliation tool. An optional checkbox selection was added for patients requiring medications to be manipulated. When checked, a radial selection for individual medications is displayed, prompting the clinician and pharmacist to indicate either do not crush tablet or OK to crush tablet. These selections appear in clinical care notes and on the printed medication list provided to the patient (Supplemental Material).

Clinical Alerts

As part of the RLRVAMC QI initiative, a CROC alert was implemented, based on the KCVAMC intervention for patients with enteral feeding tubes.¹³ The RLRVAMC CROC alert also included patients with dysphagia. A nursing text order was made available in CPRS for patients requiring medications and remains active throughout the duration of the patient’s admission or until discontinued. It generates CROC alerts in CPRS and VistA when new medication orders are entered and reviewed by pharmacists.

Clinicians used clinical decision support systems to create daily lists of patients receiving medications by feeding tube and patients receiving crushed/opened medications due to dysphagia. This allows pharmacists to perform a census review of all inpatients to confirm appropriateness of medication orders. Clinical alerts for patients with enteral feeding tubes are advised by the ISMP and have data demonstrating a reduction in medication errors (Supplemental Material).^14,15

Sustainment

During the sustainment phase, process owners were identified and a Pharmacy Service standard operating procedure (SOP) was written. The development of an institutional do not crush medication list was discussed; however, it was determined to be difficult to develop and maintain. An institutional tertiary resource list was selected in favor of a locally developed resource. These resources include the Handbook of Drug Administration via Enteral Feeding Tubes, Third Edition, the Pharmacist’s Letter list, “Meds that Should Not be Crushed,” and the Up- ToDate Lexidrug list, “Oral Medications That Should Not Be Crushed or Altered.”^9-11 Links to the resources were added to the RLRVAMC pharmacy service SharePoint. In addition to defining the preferred tertiary resources, the SOP defined the process for reviewing inventory and the process for reviewing medication orders for hazard risk.

Discussion

Continued patient safety reports and low satisfaction rates among pharmacists prompted this QI project to improve safety for patients with dysphagia and/or enteral feeding tubes at RLRVAMC. The project engaged stakeholders and also identified and addressed gaps with potential for patient harm.

The tools implemented by this initiative drew from previous work by the KCVAMC and from framework provided by the ISMP.^8,13 We expanded the QI intervention to include acute care patients with dysphagia.

RLRVAMC did not take steps to track the impact of the interventions on medication errors. However, no patient safety reports concerning an erroneous or incomplete pharmacy consultation entry have been reported. We also think that it is reasonable to assume that the adoption of the safety tools described here will have a positive impact on patient safety. RLRVAMC pharmacists have noted an increased appreciation for medication safety when processing medication orders for patients with dysphagia and/or enteral feeding tubes. While the workflow took time to adopt and integrate, clinical pharmacists perceived it as an improvement in patient safety. Our future focus is aimed at translating the process improvement into the Oracle/Cerner electronic health record, which is scheduled to be deployed at the RLRVAMC in August 2026.

Limitations

This QI project did not aim to quantify or compare medication errors before and after the intervention. An accurate number of unreported errors in the medication use process for patients with dysphagia and/or enteral feeding tubes would be challenging to quantify without direct observation. Multiple clinicians are engaged in the medication use process and individual steps may not be documented at all, or documented properly. In addition, medication errors are often underreported and may not reflect the total number of errors and/or potential for errors. That said, reported medication errors in the medication use process for patients with dysphagia and/or enteral feeding tubes are reviewed on a monthly basis by the RLRVAMC Multidisciplinary Medication Safety committee to continuously improve patient safety.

Another potential limitation is the extent to which the project can be adapted at other VHA sites. For example, RLRVAMC uses CPRS; the framework and tools to improve medication safety may not translate to sites using the Oracle/Cerner electronic health record. Furthermore, this QI project included a pharmacy consultation workflow that relied on pharmacists who are available at any hour. Other facilities may not have continuous consultation coverage to review medications for patients with dysphagia and/or enteral feeding tubes.

Conclusions

This QI project drew from ISMP recommendations, previous work within the VHA, local practice, and insight from multiple disciplines on the health care team to revise and create tools to improve medication safety for patients with dysphagia and/or enteral feeding tubes in the acute care setting. These tools included a revised pharmacy consultation workflow with improvements to the pharmacy consultation template, standardization of the pill-crushing devices and language used for patient medication lists, implementation of CROC alerts within the EHR, and development of an SOP.

The RLRVAMC Pharmacy Service intends to continue reviewing patient safety reports, assessing staff perspectives, and refining (and potentially adding) tools for medication safety. Future QI initiatives may focus on improving medication safety for outpatients with dysphagia and/or enteral feeding tubes. We also hope that these tools can be adapted at other VAMCs to promote medication safety for patients with dysphagia and/or enteral feeding tubes.