The following was submitted as an Essay to the Science PINS Prize 2026 competition for developments in neuromodulation. The award is intended for young investigators, so the essay cannot qualify for the award. It was submitted merely to insert endogenous neuromodulation into the conversation among the reviewers in the competition.
On December 12, 2025, a pre-proof manuscript titled “Disassembling Infra-Low-Frequency Neurofeedback: A neurophysiological investigation of its feedback components” was published on-line in the Journal NeuroImage (de Matos NMP, Staempfli P, Seifritz E, Bruegger M, 2025). This was a double-blind, sham-controlled crossover study involving 40 participants in each of three arms to investigate two protocol constituents individually and jointly. Alterations in functional connectivity measures were reported after a single 30-minute training session with feedback on a target frequency of 0.1 micro-Hz, with a signal derived from the differential surface potential at two cortical sites, {T4 – P4}. Such a low frequency cannot be discerned directly by the human brain; rather, it is the dynamics observable at that frequency, in the frequency range of 1-200 mHz, that engages the trainee’s brain.
The publication of this manuscript is roughly a three-year story, but the rationale for its existence takes us back some forty years. In connection with the neurofeedback training of our epileptic son in 1985, my wife and I learned that the training efficiency of the standard operant conditioning design could be significantly enhanced by engaging the brain with the dynamics of the training band.
Further, by the mere expedient of being more generous with the discrete rewards of the operant conditioning design, the brain also had access to the low-frequency dynamics of the training band that were more directly related to core state regulation. The discrete rewards had lost their special significance, as the brain simply engaged with the unfolding real-time dynamics, both fast and slow, in the process of Endogenous Neuromodulation.
This had the effect of a paradigm reversal. Instead of the clinician prescribing the protocol to effect explicit targeting of identified deficits, the clinician was now placed largely in the role of observer, as the brain took charge of its own recovery based on the rich source of information afforded by way of access to its own dynamics in real time. Early results were obtained with the ADHD population, with training in the mid-beta range (Kaiser DA, Othmer S, 2000).
In the late nineties, we discovered that certain EEG frequencies were particularly effective. The first burden on the clinician became that of identifying the optimal response frequency (ORF) in each client. These turned out to be the key to the remediation of cerebral instabilities in particular, ranging from migraines, panic and seizures to asthmatic episodes and restless leg syndrome, when utilized in inter-hemispheric placement at homotopic sites. In application to Bipolar Disorder, the ORF was the balance point between mania and depression that could yield system stability with extended training.
The distribution of ORF’s was strongly biased toward the lower EEG frequencies, which were preferentially populated by the more severely dysregulated nervous systems. This drove our agenda into the infra-low frequency (ILF) regime in 2006. The ILF application was first introduced in the neurology literature in 2011 (Legarda SB, McMahon D, Othmer S, Othmer SF, 2011; Othmer S, Othmer SF, Legarda, SB. 2011), and the frequency domain organization was fully described there in 2013 (Othmer S, Othmer SF, Kaiser DA, Putman J, 2013).
The migration to ever lower target frequencies continued episodically to the range of micro-Hz and below. The operative model for this is Hermann Haken’s Synergetics. The ORFs serve as order parameters that organize the higher frequency spectrum. Training their ‘behavior’ is our most efficient means of training the whole spectrum. At the lowest-frequency ORFs we are training the homeostatic mechanism that governs the realm of homeodynamics that we observe in the ‘fMRI’ spectral regime.
We are training core state regulation. In the perspective of control system theory, the ‘prime directive’ is unconditional system stability. Next is the setpoint of activation, i.e. central arousal, which is in turn conditioned by affect regulation, autonomic regulation, and interoception. By training the foundations of the frequency hierarchy, we are also targeting the foundations of the regulatory hierarchy, which yields to a parsimonious set of protocols. It was found most efficient to target the multi-modal association areas, which feature the highest connectivity gradient in cortex. Within the frame of intrinsic connectivity networks, we are training hubs of the Default Mode Network that are accessible to us at the cortical surface.
The last three years have seen the publication of a Special Topics Issue on Endogenous Neuromodulation in the Infra-Low Frequency Regime in Frontiers of Human Neuroscience, for which the writer was invited to serve as Special Topics Editor. Some eighteen papers were published (Othmer S, Kropotov J, Ioannides A, editors, 2023). Our latest contribution, a methods and mechanisms paper, is presently available only as preprint (Othmer S, Othmer SF, 2024). A more clinically focused treatment of the same material is to be found in our latest book chapter (Othmer, S., 2023).
The publication of a controlled study on recovery from treatment-resistant combat-related PTSD, with emphasis on headache, insomnia, and attentional deficits appeared last year (Carlson J, Ross GW, Tyrell C et al, 2025). Participants had at least a ten-year history of prior treatment failure. Also reported were clinical outcomes of 256 cases that fell into four symptom categories: mood disorders; neurotic, stress-related, and somatoform disorders; developmental disorders; and childhood/adolescent behavioral disorders. Progress was comparable in all categories (Theis T, Bolduan U, Seuss S et al, 2025). Additionally, a case report on the remediation the sleep dysregulation and seizure susceptibility in Dravet Syndrome has been published (Schmidt C, Laugesen H, 2023). A study involving some 250 participants documented outcomes for the ADHD population (Schneider H, Riederle J, Seuss S (2022).
Collective clinical experience supports the case for targeting core state regulation in considerable generality, confirming the observation by Russian neurologist A. A. Ponomarenko that “there are no discrete mental disorders; their diversity is a reflection of malfunctions in central regulatory systems.” The method offers recourse for our greatest brain fitness challenges, the category of cerebral instabilities in first instance, as well as the challenge of neurodevelopmental disorders and of early childhood emotional and physical brain trauma. The method works well with infants to promote homeostatic regulation, laying the foundation for the move toward a prevention model. It is more efficient to target conditions that are latent rather than manifest.
Siegfried Othmer, writing also on behalf of my late wife and professional partner Susan FitzGerald Othmer, the creative mind responsible for these developments, and in remembrance of our son Brian, whose epilepsy drew us into this field in 1985. Progress throughout has rested on the labors of software writers Edward Dillingham, Howard Lightstone, and instrument developer Bernhard Wandernoth, respectively, in our three generations of system design.
References:
Carlson J, Ross GW, Tyrrell C, Fiame B, Nunokawa C, Siriwardhana C, Schaper K, Infra-Low Frequency Neurofeedback Impact on Post-Concussive Symptoms of Headache, Insomnia and Attention Disorder: Results of a Randomized Control Trial, EXPLORE (2025),
doi: https://doi.org/10.1016/j.explore.2025.103137
de Matos NMP, Staempfli P, Seifritz E, Bruegger M, Disassembling Infra-Low-Frequency Neurofeedback: A neurophysiological investigation of its feedback
components, NeuroImage (2025),
doi: ttps://doi.org/10.1016/j.neuroimage.2025.121647
Dobrushina, Olga R.; Vlasova, Roza M.; Rumshiskaya, Alena D.; Litvinova, Liudmila D.;
Mershina, Elena A.; Sinitsyn, Valentin E.; Pechenkova, Ekaterina V. (2020): Modulation of Intrinsic Brain Connectivity by Implicit Electroencephalographic Neurofeedback. In: Front Hum Neurosci 14, S. 192. DOI: 10.3389/fnhum.2020.00192
Kaiser, D.A., Othmer, S. (2000). Effect of Neurofeedback on Variables of Attention in a Large Multi-Center Trial (2000), Journal of Neurotherapy, 4(1) 2000 https://www.researchgate.net/publication/233060756_Effect_of_Neurofeedback_on_Variables_of_Attention_in_a_Large_Multi-Center_Trial
Legarda SB, McMahon D, Othmer S, Othmer SF (2011): Clinical neurofeedback: case studies, proposed mechanism, and implications for pediatric neurology practice. In: J. Child Neurol. 26 (8), S. 1045–1051.
DOI: 10.1177/0883073811405052.
https://www.researchgate.net/publication/51130738_Clinical_Neurofeedback_Case_Studies_Proposed_Mechanism_and_Implications_for_Pediatric_Neurology_Practice
Othmer S, Othmer SF, Legarda SB (2011): Clinical Neurofeedback: Training Brain Behavior. In: Treatment Strategies – Pediatric Neurology and Psychiatry (2(1)), S. 67– 73. https://www.researchgate.net/publication/284506346_Clinical_neurofeedback_Training_brain_behavior
Othmer S, Othmer SF, Kaiser DA, Putman J (2013): Endogenous Neuromodulation at Infralow Frequencies. In: Seminars in Pediatric Neurology 20 (4), S. 246 – 257.
DOI: 10.1016/j.spen.2013.10.006.
https://www.researchgate.net/publication/259455519_Endogenous_Neuromodulation_at_Infralow_Frequencies
Othmer S, Kropotov J, Ioannides A, editors (2023). Endogenous Neuromodulation in the Infra-Low Frequency Regime, Special Topics Edition, Frontiers of Human Neuroscience (2023) https://www.frontiersin.org/research-topics/24349/endogenous-neuromodulation-in-the-infra-low-frequency-regime#articles
Othmer S, Othmer SF (2023) Endogenous Neuromodulation at Infra-Low Frequency: Method and Theory
DOI: 10.20944/preprints202310.1085.v2
Schmidt C, Laugesen H, Infra-low frequency neurofeedback training in Dravet
syndrome: a case study, Epilepsy & Behavior Reports (2023),
doi: https://doi.org/10.1016/j.ebr.2023.100606
Schneider H, Riederle J, Seuss S (2022): Therapeutic Effect of Infra-Low-
Frequency Neurofeedback Training on Children and Adolescents with ADHD. In: Vahid
Asadpour (Hg.): Brain-Computer Interface, Bd. 9: IntechOpen (Artificial Intelligence, 9).
Theis T, Bolduan U, Seuß S, Spallek J, Wandernoth B and Mayer-Pelinski R (2025)
ILF-neurofeedback in clinical practice: examining symptom change and performance metrics across diagnostic groups. Front. Hum. Neurosci. 19:1601187.
doi: 10.3389/fnhum.2025.1601187
