Background

Disorders of the Central Nervous System

Various disorders involve abnormal brain activity, including autism spectrum disorder, insomnia and sleep disorders, learning disabilities, Tourette syndrome, traumatic brain injury, seizure disorders, premenstrual dysphoric disorder, menopausal hot flashes, depression, stress management, panic and anxiety disorders, posttraumatic stress disorder, substance abuse disorders, eating disorders, migraine headaches, stroke, Parkinson disease, fibromyalgia, tinnitus, and attention-deficit/hyperactivity disorder.

Treatment

Neurofeedback is being investigated for the treatment of a variety of disorders. Neurofeedback may be conceptualized as a type of biofeedback that has traditionally used the electroencephalogram (EEG) as a source of feedback data. Neurofeedback differs from established forms of biofeedback in that the information fed back to the patient (via EEG tracings, functional magnetic resonance imaging, near-infrared spectroscopy) is a direct measure of global neuronal activity, or brain state, compared with feedback of the centrally regulated physiologic processes, such as tension of specific muscle groups or skin temperature. The patient may be trained to increase or decrease the prevalence, amplitude, or frequency of specified EEG waveforms (eg, alpha, beta, theta waves), depending on the changes in brain function associated with the particular disorder. It has been proposed that training of slow cortical potentials (SCPs) can regulate cortical excitability and that using the EEG as a measure of central nervous system functioning can help train patients to modify or control their abnormal brain activity. Upregulating or downregulating neural activity with real-time feedback of functional magnetic resonance imaging signals is also being explored.

Two EEG-training protocols (training of SCPs, theta/beta training) are typically used in children with attention-deficit/hyperactivity disorder. For training of SCPs, surface-negative and surface-positive SCPs are generated over the sensorimotor cortex. Negative SCPs reflect increased excitation and occur during states of behavioral or cognitive preparation, while positive SCPs are thought to indicate a reduction of cortical excitation of the underlying neural networks and appear during behavioral inhibition. In theta/beta training, the goal is to decrease activity in the EEG theta band (4-8 Hz) and increase activity in the EEG beta band (13-20 Hz), corresponding to an alert and focused but relaxed state. Alpha-theta neurofeedback is typically used in studies on substance abuse. Neurofeedback protocols for depression focus on alpha interhemispheric asymmetry and theta/beta ratio within the left prefrontal cortex. Neurofeedback for epilepsy has focused on sensorimotor rhythm up-training (increasing 12-15 Hz activity at motor strip) or altering SCPs. It has been proposed that learned alterations in EEG patterns in epilepsy are a result of operant conditioning and are not conscious or voluntary. A variety of protocols have been described for treatment of migraine headaches.

Regulatory Status

A number of EEG feedback systems (EEG hardware and computer software programs) have been cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process. For example, the BrainMaster™ 2E (BrainMaster Technologies) is "…indicated for relaxation training using alpha EEG Biofeedback. In the protocol for relaxation, BrainMaster™ provides a visual and/or auditory signal that corresponds to the patient's increase in alpha activity as an indicator of achieving a state of relaxation." Although devices used during neurofeedback may be subject to FDA regulation, the process of neurofeedback itself is a procedure, and, therefore, not subject to FDA approval. FDA product codes: HCC, GWQ.

Related Policies

• Biofeedback (Policy #060 in the Treatment Section)
• Quantitative Electroencephalography as a Diagnostic Aid for Attention-Deficit/Hyperactivity Disorder (Policy #077 in the Medicine Section)

FIDE-SNP Coverage:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was created in 2010 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through May 11, 2020.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

This review was informed by a TEC Assessment (1997).^1, Literature published since that 1997 TEC Assessment consists of studies that have evaluated neurofeedback for a variety of clinical indications, with the greatest amount of scientific literature published on the treatment of attention-deficit/hyperactivity disorder (ADHD).

Attention-Deficit/Hyperactivity Disorder
Clinical Context and Therapy Purpose

The purpose of neurofeedback is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as behavioral therapy and pharmacologic therapy, in patients with ADHD.

The question addressed in this policy is: Does neurofeedback reduce symptoms and improve functional outcomes in patients with ADHD or other psychiatric, central nervous system, or pain disorders?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals with ADHD.

Attention deficit hyperactivity disorder manifests in children as symptoms of hyperactivity, impulsivity, and/or inattention, and affects cognitive, academic, behavioral, emotional, and social function.^2, It is one of the most common neurobehavioral disorders of childhood.

Interventions

The therapy being considered is neurofeedback.

Neurofeedback describes techniques for providing feedback about neuronal activity, as measured by electroencephalogram (EEG) biofeedback, functional magnetic resonance imaging, or near-infrared spectroscopy, to teach patients to self-regulate brain activity. Neurofeedback may use several techniques to normalize unusual patterns of brain function in patients with various psychiatric and central nervous system disorders.

Patients with ADHD are actively managed by psychologists, psychiatrists, and primary care providers in an outpatient clinical setting.

Comparators

Guidelines for treatment of ADHD in children and adolescents generally recommend parent training in behavior management, FDA-approved medications (eg, stimulants), and educational interventions. Attention deficit hyperactivity disorder also occurs in adults, with a prevalence of approximately 3.4 to 4.4% of US adults. Guidelines for treatment of ADHD in adults include recommendations for psychoeducation, pharmacotherapy, and cognitive behavioral therapy.^3,

Comparators of interest include behavioral therapy and pharmacologic therapy. Treatment includes support groups, cognitive behavioral therapy, anger management, counseling psychology, psychoeducation, family therapy and applied behavior analysis. Medications for treatment include stimulants, cognition-enhancing medication, and antihypertensive drugs. Treatment is actively managed by psychologists, psychiatrists, and primary care providers in an outpatient clinical setting.

Outcomes

The general outcomes of interest are symptoms, functional outcomes, and quality of life.

Table 1. Outcomes of Interest for Individuals with attention-deficit/ hyperactivity disorder

Outcomes	Details
Symptoms	Outcomes as reported by assessors (parents most-often, or teachers, usually unblinded and with high risk of bias); Attention Deficit Hyperactivity Disorder-Rating Scale (ADHS-RS, domains of inattention, hyperactivity/impulsiveness, and combined scores); Conners scale; Fremdbeurteilungsbogen für Hyperkinetische Störungen (FBB-HKS) [Timing: greater than 1 year]

Table 2. Health Outcome Measures Relevant to ADHD in Children and Adolescents

Outcome	Measure (units)	Description	Clinically Meaningful Difference (If Known)
Attention-Deficit/Hyperactivity Disorder-Rating Scale (ADHD-RS)	Scale from 0 to 54 Higher scores indicate more symptoms 18 items are grouped into 2 subscales: hyperactivity/impulsivity and inattentiveness	Short scale that can be completed by parent, teacher, or investigator based on information provided by teacher or parent	Change between 5.2 and 7.7 points or 30% mean total score change between treatment groups4,
Conners Parent Rating Scale for ADHD	Scale from 0 to 144 Higher scores indicate more symptoms	Used by clinicians and researchers to assess parents' perception of children's behavior in classroom Assesses conduct problems, learning problems, psychometric problems, impulsivity and hyperactivity, and anxiety	Not defined4,
Conners 3rd Edition-Parent (Conners 3-P)	Scale with 9 subscales Higher scores indicate more symptoms	Used by parents to assess symptoms of ADHD and common comorbid problems	Not defined
Fremdbeurteilungsbogen für Hyperkinetische Störungen (FBB-HKS)	Scale with 20 items Higher scores indicate more symptoms	Items can be rated by parents or teacher	Not defined

ADHD: attention-deficit/hyperactivity disorder.

Follow-up duration

In studies of neurofeedback, duration of intervention was at least 1 month and ranged from 1 to 12 months.^5,6,7, Follow-up studies of RCTs that reported longer-term outcomes have reported results at 6 months.^8,9,

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Within each category of study design, studies with larger sample sizes and longer duration were preferred.
• Studies with duplicative or overlapping populations were excluded.

Trials	Systematic Reviews
	Cortese et al (2016)10,	Van Doren (2019)6,	Yan et al (2019)7,	Lambez et al (2020)5,
Linden et al (1996)	●
Li et al (2001)		●
Heinrich et al (2004)	●	●		●
Klingberg et al (2005)				●
Bauregard et al (2006)	●			●
Zhang et al (2006)			●
Chen et al (2007)			●
Drechsler et al (2007)				●
Kong et al (2007)			●
Chen et al (2009)			●
Gevensleben et al (2009)	●
Holtmann et al (2009)	●
Ji et al (2009)			●
Zuo et al (2009)			●
Gevensleben et al (2010)		●
Virta et al (2010)				●
Bakhshayesh et al (2011)	●			●
Chen et al (2011)			●
Prins et al (2011)				●
Steiner et al (2011)	●			●
Chang et al (2012)				●
Fan et al (2012)			●
Zhou et al (2012)			●
Arnold et al (2013)	●	●
Li et al (2013)			●
Meisel et al (2013)		●	●
Miranda et al (2013)				●
VanDongen et al (2013)	●
Chang et al (2014)				●
Christiansen et al (2014)	●	●
Du et al (2014)			●
Maurizio et al (2014)	●
Steiner et al (2014)	●	●
Vollebregt et al (2014)	●
Bink et al (2015)	●	●
Choi et al (2015)				●
Gapin et al (2015)
Menezes et al (2015)				●
Miranda et al (2015)
Moreno et al (2015)			●
Salomone et al (2015)				●
Pan et al (2016)
Yang et al (2016)			●
Duric et al (2017)		●	●
Gelade et al (2017)		●	●	●
Tang et al (2017)			●
Sudnawa et al (2018)			●

Study	ADHD Total Symptoms	ADHD Inattention Symptoms	ADHD Hyperactivity/Impulsiveness Symptoms	Inhibition
Cortese et al (2016)10,
Total N	13 trials (n=NR)	11 trials (n=NR)	10 trials (n=NR)	NR
Pooled Effect (95% CI)	Parent-reported: SMD, 0.35 (0.11 to 0.59) Teacher-reported: SMD, 0.15 (-0.08 to 0.38)	Parent-reported: SMD, 0.36 (0.09 to 0.63) Teacher-reported: SMD, 0.06 (-0.24 to 0.36)	Parent-reported: SMD, 0.26 (0.08 to 0.43) Teacher-reported: SMD, 0.17 (-0.05 to 0.39)	NR
I2 (p)	41% (0.06)	43% (0.07)	0% (0.8)	NR
Van Doren et al (2019)6,
Total N	NR	11 trials (n=NR)	11 trials (n=NR)	NR
Pooled Effect (95% CI)	NR	SMD, 0.31 (-0.01 to 0.63)	0.32 (0.15 to 0.49)	NR
I2 (p)	NR	70% (0.06)	0% (0.0003)	NR
Yan et al (2019)7,
Total N	4 trials (n=228)	4 trials (n=228)	4 trials (n=228)	NR
Pooled Effect (95% CI)	SMD, −0.578 (−1.063 to –0.092)	SMD, -0.667 (-1.245 to -0.109)	SMD, -0.474 (-0.860 to 0.088)	NR
I2 (p)	59% (0.062)	70% (0.019)	38% (0.156)	NR
Lambez et al (2020)5,
Total N	NR	NR	NR	6 trials (n=203)
Pooled Effect (95% CI)	NR	NR	NR	SMD, 0.61 (-3.77 to 4.82)
I2 (p)	NR	NR	NR	0% (<0.05)

Several RCTs not included in the above systematic reviews are described below, which were published after the above meta-analyses.^11,8,

Table 7. Characteristics of RCTs of Neurofeedback in ADHD

Study	Countries	Sites	Dates	Participants	Interventions
Lim et al (2019)11,	Singapore	1	January 20123 to June 2016	Children age 6 to 12 years diagnosed with ADHD	BCI-based neurofeedback attention training vs untreated waitlist control for 8 weeks followed by BCI-based neurofeedback attention training for 20 weeks
Aggensteiner et al (2019)8,	Germany	NR (multicenter)	September 2009 to January 2013	Children age 7 to 9 years diagnosed with ADHD	SCP-based neurofeedback vs EMG-based biofeedback

ADHD: attention-deficit/hyperactivity disorder; BCI:brain-computer interface; NR: not reported; SCP: slow cortical potential.

Table 8. Results of RCTs of Neurofeedback in ADHD

Study	ADHD-RS	FBB-HKS
Lim et al (2019)11,
N	172
BCI-based neurofeedback	8 weeks of intervention: 3.5 ± 3.87 20 weeks of intervention: 3.3 ± 5.55 4 weeks post-intervention: 4.7 ± 5.94	NR
Waitlist control	8 weeks of intervention: 1.9 ± 4.42 20 weeks of intervention: 1.4 ± 3.94 4 weeks post-intervention: 2.0 ± 4.26	NR
Difference [Neurofeedback - Control] (95% CI)	8 weeks of intervention: 1.6 points (0.3 to 0.29) 20 weeks of intervention: 2.4 points (1.6 to 3.2) 4 weeks post-intervention: 3.3 points (2.5 to 4.2)	NR
Aggensteiner et al (2019)8,
N	144	144
SCP-based neurofeedback	1.28	1.33
EMG-based biofeedback	1.30	1.38
Difference [Neurofeedback - Control] (95% CI)	NR	-0.04 (-0.27 to 0.14)

ADHD-RS: attention deficit-hyperactivity disorder-rating scale; CI: confidence interval; FBB-HKS: Fremdbeurteilungsbogen für Hyperkinetische Störungen; NR: nor reported

Table 9. Study Relevance Limitations of RCTs of Neurofeedback in ADHD

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Duration of Follow-upe
Lim et al (2019)11,	4. Included patients from a single site in Singapore				1. Follow-up occurred only 4 weeks after intervention
Aggensteiner et al (2019)8,	4. Included patients from Germany

ADHD: attention-deficit/hyperactivity disorder.
The evidence limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

^aPopulation key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^bIntervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
^cComparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^dOutcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^eFollow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Lim et al (2019)11,	3.	1.Patients, parents, and investigators were unblinded; outcome assessors and teachers were blinded
Aggensteiner et al (2019)8,	3.	1. Patients were unblinded; blinding of parents and teachers not reported			1.

^aAllocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^bBlinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^cSelective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^dData Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^ePower key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^fStatistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Several meta-analyses and at least 6 moderately sized RCTs (n range, 90-113 patients) have compared neurofeedback with methylphenidate, attention skills training, and/or cognitive therapy. These studies found either small to moderate or no benefit of neurofeedback, and sustained long-term benefit (eg, at 6 to 12 months) has not been consistently demonstrated. Studies using active controls have suggested that at least part of the effect of neurofeedback might be due to attention skills training, biofeedback, relaxation training, and/or other nonspecific effects. One RCT investigated neurofeedback in the right inferior prefrontal cortex. Another RCT assessed the utility of neurofeedback used to target the dorsal anterior cingulate cortex. All RCTs indicated that any beneficial effects were more likely to be reported by evaluators unblinded to treatment (parents), than by evaluators blinded (teachers) to treatment, which would suggest bias in the nonblinded evaluations. Moreover, a meta-analysis found no effect of neurofeedback on objective measures of attention and inhibition. Additional research with blinded evaluation of outcomes is needed to demonstrate an effect of neurofeedback on ADHD.

Disorders Other Than Attention Deficit-Hyperactivity Disorder
Clinical Context and Therapy Purpose

The purpose of neurofeedback is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as behavioral therapy and pharmacologic therapy, in patients with disorders other than ADHD.

The question addressed in this policy is: Does neurofeedback reduce symptoms and improve functional outcomes in patients with psychiatric, central nervous system, or pain disorders other than ADHD?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals with disorders other than ADHD.

Interventions

The therapy being considered is neurofeedback.

Comparators

Comparators of interest include behavioral therapy and pharmacologic therapy. Treatment is actively managed by psychologists, psychiatrists, and primary care providers in an outpatient clinical setting.

Outcomes

The general outcomes of interest are symptoms, functional outcomes, and quality of life.

Table 11. Outcomes of Interest for Individuals with Disorders Other than ADHD

Outcomes	Details
Reduction of Symptoms as Observed by Parents and Patients	Attention Switching Task; Impact of Pediatric Epilepsy Scale; PTSD symptoms [Timing: 6 weeks]

ADHD: attention-deficit/hyperactivity disorder; PTSD: post-traumatic stress disorder.

Table 12. Health Outcome Measures Relevant to Disorders other than ADHD

Outcome	Measure (units)	Description	Clinically Meaningful Difference (If Known)
Attention Switching Task	msec Longer duration indicates more symptoms	Computerized task measuring ability to adjust behavior in accordance with changing task goals	Not defined12,
Impact of Pediatric Epilepsy Scale	Scale from 0 to 33 Higher scores indicate more symptoms	Questionnaire administered to parent or guardian measuring domains of academic improvement, social adaptation, and self-esteem	Not defined12,
PTSD symptoms	Various questionnaires Higher scores indicate more symptoms	Various questionnaires administered to patients measuring frequency and intensity of PTSD symptoms	Not defined13,
Sleep efficiency	Percentage Lower values indicate more symptoms	Measure of percentage of total time in bed spent asleep	Not defined14,
Sleep fragmentation	Occurrences Higher values indicate more symptoms	Measure of number of awakening episodes by polysomnography or patient diary	Not defined14,
Total sleep time	Minutes Lower values indicate more symptoms	Measure of time spent asleep among total recording time	Not defined14,

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Within each category of study design, studies with larger sample size and longer duration were preferred.
• Studies with duplicative or overlapping populations were excluded.

A systematic review by Melo (2019) reviewed 7 RCTs of biofeedback techniques, including neurofeedback, in the treatment of chronic insomnia.^15, The authors identified conflicting results in comparisons of neurofeedback with other cognitive behavioral therapy techniques, placebo, and no treatment; a majority of outcomes demonstrated no significant differences between comparison groups. A majority of studies were at high risk of bias related to blinding of participants and personnel and incomplete outcome data.

Systematic Reviews with Meta-Analysis
Table 13. Characteristics of Systematic Reviews and Meta-analyses of Neurofeedback for Chronic Insomnia

Study	Dates	Trials	Participants	N (Range)	Design	Duration
Melo et al (2019)15,	To 2019	7	Adults with chronic insomnia	224 (18-48)	7 RCTs of biofeedback techniques	10 days to 36 months

RCT: randomized controlled trial

Table 14. Results of Systematic Reviews and Meta-analyses of Neurofeedback for Chronic Insomnia

Study	Total Sleep Time	Sleep Fragmentation	Sleep Efficiency
Melo et al (2019)15,
Total N	2 Trials (n=NR)	2 Trials (n=NR)	2 Trials (n=NR)
Pooled Effect (95% CI)	No significant difference between biofeedback and placebo (effect estimate NR)	Mean difference in number of awakenings, -4.5 (-8.33 to -0.67)	No significant difference between biofeedback and placebo as measured by either polysomnography or sleep diaries (effect estimates NR)
I2 (p)	NR	NR	NR

CI: confidence interval; NR: not reported; SMD: standardized mean difference
Epilepsy

An RCT by Morales-Quezada (2019) randomized children with focal epilepsy to sensorimotor rhythm neurofeedback, SCP neurofeedback, or sham neurofeedback for 25 sessions over 5 weeks.^12, At the end of the intervention period, only the sensorimotor rhythm neurofeedback group demonstrated significant improvement in the activity switching task and all groups demonstrated significant improvements in quality of life.

Table 15. Characteristics of Recent RCTs of Neurofeedback in Epilepsy

Study	Countries	Sites	Dates	Participants	Interventions
Morales-Quezada et al (2019)12,	Mexico	1	NR	Children and adolescents with focal epilepsy responsive to antiepileptic pharmacotherapy and cognitive difficulties in school	Sensorimotor rhythm neurofeedback, SCP neurofeedback, or sham neurofeedback over 5 weeks

NR: not reported; SCP: slow cortical potential; SMR: sensorimotor rhythm

Table 16. Results of RCTs of Neurofeedback in Epilepsy

Study	Attention Switching Task	Impact of Pediatric Epilepsy Scale
Morales-Quezada et al (2019)12,
N	44	44
SMR neurofeedback	Significant improvement from baseline to postintervention (-757 msec; p=0.015) and follow-up (-644; p=0.04)	1.5-point change from baseline (p=0.002)
SCP neurofeedback	Not significant (effect estimate, NR)	1.9-point change from baseline (p=0.001)
Sham neurofeedback	Not significant (effect estimate, NR)	1.3-point change from baseline (p=0.006)
Difference [Neurofeedback - Control] (95% CI)	NR	NR

NR: not reported; SCP: slow cortical potential; SMR: sensorimotor rhythm

Table 17. Study Relevance Limitations of RCTs of Neurofeedback

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Duration of Follow-upe
Morales-Quezada et al (2019)12,	4. Included patients from a single site in Mexico

The evidence limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

^aPopulation key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^bIntervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
^cComparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^dOutcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^eFollow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Morales-Quezada et al (2019)12,	3.				1.

A systematic review by Sokhadze et al (2008) of neurofeedback as a treatment for substance abuse disorders described difficulties in assessing the efficacy of this and other substance abuse treatments.^16, Study shortcomings included a lack of clearly established outcome measures, differing effects of the various drugs, the presence of comorbid conditions, the absence of a criterion standard treatment, and use as an add-on to other behavioral treatment regimens. Reviewers concluded that alpha-theta training, when combined with an inpatient rehabilitation program for alcohol dependency or stimulant abuse, would be classified as level 3 or "probably efficacious." This level is based on beneficial effects shown in multiple observational studies, clinical studies, wait-list control studies, or within-subject or between-subject replication studies. Reviewers also noted that few large-scale studies of neurofeedback in addictive disorders have been reported and that the evidence for alpha-theta training has not been shown to be superior to sham treatment.

Pediatric Brain Tumor Survivors

De Ruiter et al (2016) reported on a multicenter, triple-blinded RCT of neurofeedback in 80 pediatric brain tumor survivors who had cognitive impairments.^17, The specific neurofeedback module was based on individual EEG, and participants, parents, trainers, and researchers handling the data were blinded to assignment to the active or sham neurofeedback module. At the end of training and 6-month follow-up, there were no significant differences between the neurofeedback and sham feedback groups on the primary outcome measures for cognitive performance, which included attention, processing speed, memory, executive functioning, visuomotor integration, and intelligence.

Post-Traumatic Stress Disorder

A meta-analysis by Steingrimsson (2020) evaluated 4 RCTs of adults with post-traumatic stress disorder (PTSD) treated with neurofeedback.^13, Compared with sham neurofeedback, no treatment or other treatment, neurofeedback was associated with significant improvement in PTSD symptoms. Other primary outcomes were only reported in one trial each, and the authors concluded there was uncertainty regarding the ability of neurofeedback to improve PTSD symptoms, self-rated suicidality, executive cognitive functioning, and medication use. All studies were at moderate to high risk for bias, and were assessed as having some indirectness and imprecision.

Table 19. Characteristics of Systematic Reviews and Meta-analyses of Neurofeedback for ADHD

Study	Dates	Trials	Participants	N (Range)	Design	Duration
Steingrimsson et al (2020)13,	To 2019	4	Adults with PTSD	123 (12-52)	4 RCTs of EEG-based neurofeedback for PTSD vs sham neurofeedback, other treatment, or no treatment	Follow-up: 4 weeks to 30 months

ADHD: attention-deficit/hyperactivity disorder; EEG: electroencephalography; PTSD: post-traumatic stress disorder
Table 20. Results of Systematic Reviews and Meta-analyses of Neurofeedback for ADHD

Study	Self-Harm	PTSD Symptoms
Steingrimsson et al (2020)13,
Total N	1 Trial (n=NR)	4 Trials (n=123)
Pooled Effect (95% CI)	1.4-point improvement with neurofeedback (p=0.002)	SMD, 2.3 (-4.37 to -0.24)
I2 (p)	89% (<0.0001)	NR

ADHD: attention-deficit/hyperactivity disorder; NR: not reported; PTSD: post-traumatic stress disorder; SMD: standardized mean difference
Other Disorders

Literature searches and a systematic review by Schoenberg et al (2014) assessing biofeedback for psychiatric and neurologic disorders^18, have identified small studies (case reports, case series, comparative cohorts, small RCTs) of neurofeedback for the following conditions:

• Anxiety^18,
• Asperger syndrome^18,
• Autism spectrum disorder^19,20,
• Cigarette cravings^21,
• Cognitive impairment^22,
• Depression^23,24,25,
• Depression, pain, or fatigue in patients with multiple sclerosis^26,
• Depression in alcohol addiction^18,
• Dissociative identity disorder^18,
• Fall risk^27,
• Fibromyalgia^28,
• Insomnia^29,
• Headache^30,31,
• Lower back pain^32,
• Multiple sclerosis^33,
• Overweight and obesity^34,35,
• Obsessive-compulsive disorder^36,37,
• Parkinson disease^38,
• Posttraumatic stress disorder^39,18,40,
• Schizophrenia^41,42,18,
• Stroke^43,44,
• Tinnitus^45,
• Tourette syndrome^46,47,

The evidence for neurofeedback in individuals with disorders other than ADHD includes case reports, case series, comparative cohorts, small RCTs, and systematic reviews of these studies. For these disorders, the evidence is poor, and a number of questions regarding clinical efficacy remain unanswered. Larger RCTs that include either a sham or active control are needed to evaluate the effect of neurofeedback for these conditions.

Summary of Evidence

For individuals who have attention-deficit/hyperactivity disorder who receive neurofeedback, the evidence includes randomized controlled trials (RCTs) and a meta-analysis. Relevant outcomes are symptoms, functional outcomes, and quality of life. At least 6 moderately sized RCTs (n range, 90- 172 patients) have compared neurofeedback with methylphenidate, attention skills training, and/or cognitive therapy. These trials found either small or no benefit of neurofeedback. Studies that used active controls have suggested that, at least part of the effect of neurofeedback may be due to attention skills training, relaxation training, and/or other nonspecific effects. Also, the beneficial effects are more likely to be reported by evaluators unblinded to treatment (parents) than by evaluators blinded (teachers) to treatment, suggesting bias in the nonblinded evaluations. A meta-analysis also found no effect of neurofeedback on objective measures of attention and inhibition. Additional research with blinded evaluation of outcomes is needed to demonstrate an effect of neurofeedback on attention-deficit/hyperactivity disorder. The completion dates for some registered trials of neurofeedback in attention-deficit/hyperactivity disorder have passed without publication of results, suggesting the potential for publication bias. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have disorders other than attention-deficit/hyperactivity disorder (eg, epilepsy, substance abuse, pediatric brain tumors) who receive neurofeedback, the evidence includes case reports, case series, comparative cohorts, and small RCTs. Relevant outcomes are symptoms, functional outcomes, and quality of life. For these other disorders, including psychiatric, neurologic, and pain syndromes, the evidence is poor, and several questions concerning clinical efficacy remain unanswered. Larger RCTs that include either a sham or active control are needed to evaluate the effect of neurofeedback for these conditions. The completion dates for some registered trials of neurofeedback in disorders other than attention-deficit/hyperactivity disorder have passed without publication of results, suggesting the potential for publication bias. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION
Practice Guidelines and Position Statements
American Academy of Pediatrics

In 2011, the American Academy of Pediatrics (AAP) published clinical practice guidelines on the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents.³⁶The AAP stated that although electroencephalogram biofeedback is used clinically, it is not approved by the U.S. Food and Drug Administration (FDA) for the treatment of ADHD and requires further research.The AAP (2012) revised its position on biofeedback, designating it as a "Level 1 - Best Support" treatment for children with ADHD.^48,The AAP (2014) further supported its position, stating that neurofeedback "can contribute to lasting improvements" for children with ADHD,^49, citing the Steiner et al (2014)⁵ article.The AAP (2019) published a guideline update to the 2011 guideline for treatment of ADHD in children and adolescents.^50, The guideline states that EEG biofeedback is one of several nonmedication treatments that have either too little evidence to support their recommendation or have little or no benefit.

The AAP (2018), in a clinical report on mind-body therapies in children and youth, stated that research suggests benefits of peripheral forms of biofeedback, including EEG biofeedback (neurofeedback) in ADHD.^51, The report noted no significant contraindications to use of biofeedback, with the only barriers potentially being financial in nature.

National Institute for Health and Care Excellence

In 2013, the National Institute for Health and Care Excellence issued guidance on management and support of children on the autism spectrum.^52, The Institute stated that e a number of treatments were considered but are not recommended, including neurofeedback.

International Society for Neurofeedback & Research

In 2011, the International Society for Neurofeedback & Research published a position paper on standards of practice for neurofeedback and neurotherapy.^53, Issues discussed mostly addressed professional issues.

American Psychological Association

The American Psychological Association has provided general information on biofeedback (including neurofeedback) on its website, stating that "Biofeedback helps treat some illness, may boost performance, helps people relax and is even used to help children with Attention Deficit-Hyperactivity Disorder."^54,

American Academy of Child and Adolescent Psychiatry and American Psychiatric Association

No information on neurofeedback was identified from the American Academy of Child and Adolescent Psychiatry or the American Psychiatric Association.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this policy are listed in Table 21. The completion date for various registered trials of neurofeedback have passed without publication of results, suggesting the potential for publication bias.

Table 21. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT04097522	The Effectiveness of Neurofeedback for the Treatment of Chronic Pain	102	Oct 2020
NCT04220112	Comparing Real-time fMRI Neurofeedback Versus Sham for Altering Limbic and Eating Disturbances in Anorexia Nervosa	47	Sep 2022
NCT02251743	Double-Blind 2-Site Randomized Clinical Trial of Neurofeedback for ADHD	142	Apr 2020
Unpublished
NCT02146495	Pain and Sleep Quality Measures Before and After a Course of EEG Neurofeedback in Fibromyalgia Patients	200	Oct 2016 (unknown)
NCT02397161	Improving Mental Attention, Timing of Muscle Activation and Reactive Balance Control in Children With Developmental Coordination Disorder: A Randomized Controlled Trial	172	Jul 2017 (unknown)
NCT02778360a	Effectiveness of a Personalized Neurofeedback Training Device (ADHD@Home) as Compared With Methylphenidate in the Treatment of Children and Adolescents With Attention-Deficit/ Hyperactivity Disorder: A Multicentre Randomized Clinical Study	179	Sep 2017 (unknown)
NCT02991781	Multidisciplinary Tools for Improving the Efficacy of Public Prevention Measures Against Smoking	140	Jun 2019
NCT01841151	Does Neurofeedback and Working Memory Training Improve Core Symptoms of ADHD in Children and Adolescents? A Comparative, Randomized and Controlled Study	220	Dec 2018
NCT01879644	Neurofeedback Study ADHD	120	Dec 2018

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.nsored trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Neurofeedback
Biofeedback, EEG
EEG Biofeedback

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