Monthly Archives: March 2025

Increased Plasma Serotonin 2A Receptor Autoantibodies Predicts Significant One-year Cognitive Decline in Middle-aged Adult Traumatic Brain Injury

DOI: 10.31038/EDMJ.2025914

Introduction

Traumatic brain injury (TBI) contributes to substantially increased global disability [1] and has been associated with major depressive disorder and dementia [2] through unknown mechanisms. Chronic inflammation increased autoantibodies to a serotonin 2A receptor from older adult TBI patients suffering with accelerated cognitive decline over a two-year period [3]. Because middle-age (post 9/11 military veterans) who were exposed to multiple TBIs can experience even more rapid cognitive decline, here we tested whether baseline plasma serotonin 2A receptor autoantibodies (AA) predicts 1-year rate of decline in global cognitive functions or in pattern separation, a dentate gyrus dependent behavior. Biomarker that could predict subset of younger adult TBI at higher risk for accelerated cognitive decline would be useful in future evaluation of candidate neuroprotective treatments.

Participants and Methods

TBI Patients

Informed consent for the local Institutional Review Board- approved study was obtained from all participants prior to blood drawing or cognitive testing. Thirty-four middle-aged, adult TBI patients (40-60, mean 49.9 years old) including 33 male and 1 female participant enrolled in the study. Many of the post-9/11 U.S. military veterans had experienced repeated TBI exposures including direct force, blast or both kinds of TBI injury. Only one patient had experienced moderately-severe TBI, most of the other injuries were mild TBI. Thirty-three of thirty-four participants had baseline blood drawing for determination of plasma autoantibodies.

Protein-A Affinity Chromatography

Protein-A affinity chromatography was used to isolate the IgG fraction of plasma [4] in thirty-three middle-aged adults who had experienced one or more TBI exposures. The IgG fraction (1/40th dilution=7.5 ug/mL) was stored at 0-4 degree C prior to determination of autoantibody level.

Peptide

A linear synthetic peptide corresponding to the second extracellular loop of the human 5HT2AR (QN..18) was synthesized at Lifetein, Inc (Hillsborough, NJ). The peptide had purity > 95% and was stored under desiccated conditions at −40 degrees C.. On the day of an enzyme-linked immunoassay experiment, an aliquot of lyophilized peptide was dissolved in sterile deionized water prior to immunoassay or bioassay.

Enzyme Linked Immunoassay

Enzyme Linked Immunoassay was performed as previously described using the QN..18 second extracellular loop of the 5HT2AR [5] as the target peptide antigen. Increased autoantibody binding in the QN..18 immunoassay was previously reported to correlate with neurotoxicity in a bioassay employing mouse N2A neuroblastoma cells [5] consistent with an agonist role for the circulating 5HT2A receptor autoantibodies.

Cognitive Tests

One year change in cognitive test performance was calculated as the [One year test score – baseline test score]. Higher one-year change in test score is indicative of improved performance with the exception of the Trail-making Part B in which longer time to task completion reflects worsening executive function.

Statistics

Statistical analysis was performed using unpaired Students’ t-test.

Results and Discussion

Baseline Plasma Serotonin 2A R Autoantibodies

Thirty-three TBI patients underwent baseline determination of plasma 5HT2AR AAB and completed baseline and one-year cognitive testing: St Louis University Mental Status Test (SLUMS) of working memory; digit symbol substitution test (DSST) of processing speed; and the behavioral pattern separation object task (BPS-O), a dentate gyrus hippocampal- dependent test.

Ten of thirty-three TBI patients (30.0%) had elevated plasma 5HT2AR AAB (i.e. binding of 1.5-fold background or higher; and 10/33 patients had no detectable plasma AAB (binding </= 1.25-fold background) (Figure 1). The mean one-year rate of change in SLUMs test declined significantly in AAB-positive vs AAB-negative TBI patients (-2.6 ± 2.47 vs 0.6 ± 1.62; P = 0.004) (Figure 2). Two of ten AAB-positive TBI patients experienced large one-year declines in SLUMs score to a level below the cut-off for dementia (not shown in Figure 2). The mean one-year rate of change in performance on the Trail-making Test, Part B (a measure of executive function) also worsened significantly in AAB- positive vs AAB-negative TBI patients (9.7 vs -13.4 sec; P = 0.04) (Figure 3). In the TMT-B test increased time (to task completion) is indicative of declining executive function. One-year change in performance on the DSST ( -1.5 vs 4.7; P = 0.02) also declined significantly in AAB-positive vs -negative TBI patients (Figure 4).

A 1/40th dilution of the protein-A eluate fraction from human TBI plasma was tested for binding to the second extracellular 5HT2A receptor peptide. Background absorbance was 0.04 AU. Undetectable binding was defined as 0-1.25 times background; increase binding was defined as 1.5 times or more above background. The solid lines indicate the upper limits of undetectable (5HT2AR AAB negative) and lower limit of high binding (5HT2AR AAB positive) in the immunoassay.
Figure 1: Distribution of binding to the human 5HT2A receptor second extracellular loop peptide (QN..18) in enzyme linked immunosorbent assay.

Results are mean ± SD.
Figure 2: Significant association between baseline presence of 5HT2AR autoantibodies and significant mean one-year decline in SLUMs score.

Results are mean ± SD.
Figure 3: Significant association between baseline presence of 5HT2AR AAB and one-year decline in Trail-making Part B test performance.

Results are mean ± SD.
Figure 4: Significant association between baseline presence of 5HT2AR AAB and one-year decline in digit symbol substitution test performance.

Behavioral pattern separation object task is a dentate gyrus, hippocampal- dependent component of working memory which was reported to be age-dependent [6] and decline significantly with mild cognitive dysfunction in a small subset of older (75 yr old) adults [6]. Dentate gyrus newborn neurons express 5HT2A receptor, and autoantibodies from diabetic depression patients inhibited dendrite extension and decreased survival in cultured rat DG neurons [7]. Here we tested for a possible association between baseline presence of plasma 5HT2AR autoantibodies and 1-year change in performance on the BPS object task. Bias on the BPS task is a measure of the ratio of correct responses to lure (similar object) vs similar responses to the foil (a completely new object). A bias ratio of 1 is indicative of complete pattern separation and a ratio of 0 is consistent with complete loss of pattern separation. In nineteen TBI patients who completed baseline and 1-year pattern separation tests, there was no significant difference in one-year rate of change in BPS-O in 5-HT2AR AAB-positive vs -negative TBI patients (5.7 ± 3 vs 3.0 ± 7); (P > 0.05) (Figure 5).

Results are mean ± SD.
Figure 5: Lack of significant association between baseline presence of 5HT2AR AAB and one-year change in behavioral pattern separation object task performance.

There was no significant association between one-year rate of change in BPS-O and one-year rate of change in SLUMS test (Figure 6). Baseline BPS-O scores were widely- ranging in middle-aged TBI patients consistent with prior report of high degree of individual differences on pattern separation, object task [6] (Figure 7). Many middle-aged TBI patients had relatively preserved one-year BPS scores even though they had already experienced significant declines in the other cognitive tests of memory recall, executive function and processing speed. This suggests that in younger adult TBI population age 40-60, pattern separation may be less useful as an indicator of early cognitive decline than the SLUMS, Trail-making Part B and digit symbol substitution tests.

Figure 6: Lack of significant association between one-year rate of change in behavioral pattern separation and SLUMS test performance.

Figure 7: Distribution of baseline behavioral pattern separation test scores in 34 middle aged adult TBI patients.

In summary, the current results suggest that middle-aged adult TBI patients (age 40-60 years) (including those exposed to repeated TBI) can experience significant cognitive decline after a relatively short time period (one year) and that baseline presence of plasma 5HT2AR AAB was a significant predictor of cognitive decline across three different cognitive domains.

Acknowledgments

The study was supported by a grant (CBIR22PIL016) from the New Jersey Commission on Brain Injury Research (Trenton, New Jersey) to Dr. Mark Zimering.

The authors report no competing interests with any products or techniques employed in this study.

References

  1. Ilie G, Adlaf EM, Mann RE, et al. (2018) Associations between self-reported lifetime history of traumatic brain injuries and current disability assessment in a population sample of Canadian adults, PLoS One. [crossref]
  2. Kaup AR, Peltz C, Kenney K, Kramer JH, Diaz-Arrastia R, Yaffe K (2017) Neuropsychological Profile of Lifetime Traumatic Brain Injury in Older Veterans. J Int Neuropsychol Soc. 2017 [crossref]
  3. Zimering MB, Grinberg M, Myers CE, Bahn G (2022) Plasma Serotonin 2A Receptor Autoantibodies Predict Rapid, Substantial Decline in Neurocognitive Performance in Older Adult Veterans with Endocrinol Diabetes Metab J. 2022 [crossref]
  4. Zimering MB (2018) Circulating Neurotoxic 5-HT2A Receptor Agonist Autoantibodies in Adult Type 2 Diabetes with Parkinson’s Disease. J Endocrinol Diabetes. 2018 [crossref]
  5. Zimering MB (2019) Autoantibodies in Type-2 Diabetes having Neurovascular Complications Bind to the Second Extracellular Loop of the 5-Hydroxytryptamine 2A Endocrinol Diabetes Metab J. 2019 [crossref]
  6. Stark SM, Yassa MA, Lacy JW, Stark CE (2013) A task to assess behavioral pattern separation (BPS) in humans: Data from healthy aging and mild cognitive impairment. Neuropsychologia. 2013 [crossref]
  7. Zimering MB, Behnke JA, Thakker-Varia S, Alder J (2015) Autoantibodies in Human Diabetic Depression Inhibit Adult Neural Progenitor Cells In vitro and Induce Depressive-Like Behavior in J Endocrinol Diabetes. 2015 [crossref]

Electromagnetic Psychiatry: A Proposed Paradigm Shift

DOI: 10.31038/JNNC.2025812

Abstract

Academic psychiatry is dominated by a biological approach to mental illness. Mental disorders are conceptualized as biological brain diseases, based primarily on abnormalities in genes and neurotransmitters. The author proposes that there should be a fundamental paradigm shift from biological psychiatry to electromagnetic psychiatry.

Keywords

Biological psychiatry, Electromagnetic fields, Scanning the human body

The current research focus in psychiatry is on the biology of mental illness and that is predominantly the type of research that is funded by the National Institutes of Mental Health. Yet, after decades of effort and tens of billions of dollars spent, biological psychiatry research has not yielded a single finding of direct clinical relevance. For example, despite repeated efforts to measure neurotransmitters in the cerebrospinal fluid of individuals meeting criteria for DSM mental disorders, no consistent abnormality in dopamine, serotonin, noradrenalin or any other neurotransmitter has ever been demonstrated. The chemical imbalance theory of mental illness has been disproven by a large, replicated body of null findings. The same is true in psychiatric genetics: no consistent set of genetic abnormalities in individuals with mental disorders has ever been demonstrated. This was the case when an analysis of biological psychiatry was published 30 years ago. Nothing has changed since [1,2].

Biological psychiatry continues to maintain pervasive influence over grant funding, academic and federal appointments, publications in leading journals, and academic promotions. The ideology of biological psychiatry is supported and endorsed by big pharma, hospital corporations, insurance companies and academic psychiatry. The core idea is that there is an underlying pathophysiology to mental illness that, once understood, will lead to effective treatments. Rather than calling to give up on a bio-reductionist model that has yielded nothing of clinical relevance, academic psychiatry promises major breakthroughs coming in the near future.

In my opinion, there is only one logical conclusion to reach: for mental health, biology is the wrong level of analysis. That is why biological research in psychiatry is a scientific dead end. This statement is not an example of anti-psychiatry or anti-science, in fact the opposite is true. My goal is to contribute to a paradigm shift that will yield real scientific findings and real clinical applications in psychiatry. There will be multiple levels of resistance to the paradigm shift: for example, biological researchers will be replaced by physicists, electrical engineers and tech experts.

The idea that the conscious mind can be fully explained by biology is absurd, but nevertheless it dominates bio-reductionist psychiatry. The idea gets couched in vocabulary that disguises the reductionism – for example, the mind is said to be an emergent property of brain function, or, more blatantly, the mind is an epiphenomenon of brain activity. How the mind “emerges” from atoms and electrical currents in the brain is a complete mystery, since atoms and electricity are not allowed to be conscious in bio-reductionist models [3].

Mental illness, I propose, is primarily a disturbance at the electromagnetic (EM) level, which is where the mind – the psyche – is located. There are likely causal interactions in both directions between biology and the electromagnetic field of the human body, but the underlying pathophysiology is primarily electromagnetic. There is likely a small number of cases in which genetics and biology are predominant, but these are outliers from a public health perspective. Disturbances in the EM field of the human body can be caused by a large array of environmental factors including EM pollution, psychological trauma, social conditions, and insufficient exposure to sunlight.

The pandemic of worldwide vitamin D deficiencies illustrates the logic of the EM model. We know that photons are captured by plants to drive biological processes that support the entire biosphere – without photosynthesis there would be no biosphere. Similarly, we know that receptors in the retina can capture photons and use them to drive a series of transductions that result in conscious visual perception. Receptors in the skin capture photons to drive the synthesis of vitamin D and getting a suntan. Excessive electrical input to the human body in industrial accidents can result in burns, cardiac arrest and death, while mild input causes a slight tingling sensation. All these interactions are dose-dependent and have thresholds that vary across individuals: some people burn easily when out in the sun for too long, others do not. There are vitamin D receptors in every cell in the human body and low vitamin D levels correlate strongly with numerous physical and mental health problems. This is driven entirely by insufficient EM exposure in the form of sunlight.

The purpose of mentioning vitamin D is to illustrate the logic of the EM model – vitamin D illustrates how EM fields can have an impact on the human body.

I have met people with bipolar disorder who are floridly manic. It is very obvious to me that more than just their brain is in a manic state. They are euphoric, hyper-active, talkative, amused, hyper-sexual, grandiose, full of energy and require much less sleep than usual. They are glowing with radiant energy which shows in their complexion, their behavior and their speech. Conversely, the same person in the depressed phase has a much different complexion – no glow, pale, unhealthy looking, and sallow.

If mania and depression have anything to do with serotonin, we know that 90% of the body’s serotonin is in the gut and the periphery. Maybe that’s where SSRI antidepressants have their clinical effect. Maybe, even at the level of biology, the brain is the wrong place to look.

We currently measure the EM emissions of the heart and brain in mainstream medicine in the form of EEGs and EKGs. There is nothing mystical or extra-scientific about this. All physical objects in the universe emit an EM field, from stars to human bodies to single atoms. We know that the EM field of the human body can be mined for clinically relevant information. I propose that this is true for the body as a whole, not just the heart and brain, or nerve transmission in the periphery (electromyography).

Using an array of non-contact electrodes I call the whole body electromagnetic scanner [4-6], one could scan the whole body of a person while manic and then again when depressed. The EM state in the two conditions would be markedly different – this would be evident in the amplitude and frequencies of the whole body’s EM field and in a color-coded visual display on a computer screen. Bipolar disorder is a disorder of the whole body, not just of the brain. As is true of EKG’s for some cardiac conduction defects and arrythmias, the whole body EM scanner could potentially detect EM disease processes before they trickle down to the biological level. That could include metabolic disorders, cancers and a wide range of diseases.

It follows from this line of thinking that there could be a wide- ranging set of psychiatric interventions targeting the EM field of the body. These could modulate mania, but also fight, flight and freeze reactions. Transcranial magnetic stimulation (TMS) is FDA-approved for the treatment of depression: I see this as the primitive beginning of EM psychiatry. I see electroconvulsive therapy (ECT) as a blunt and often toxic form of EM psychiatry. One can fix a software problem in a computer without hitting it with a sledgehammer.

Our bodies have evolved in the biosphere over millions of years – hundreds of millions if we track enzymes and genes that have been conserved in evolution. My theory of human energy fields [7] states that, rather than being background noise, EM signals from rocks, trees, lakes, plants and animals contain information that has evolutionary meaning and purpose. Human beings are like biological cell phones – we receive, process and transmit information back and forth between ourselves and our environment. These signaling processes have been highly disturbed by EM pollution and EM disconnection from the magnetic field of the earth.

If we assume that the human spirit and the EM field of the body are the same thing, viewed through different paradigms, vocabulary and beliefs, then the Earth Mother is subjective language for the EM field of our planet. EM disconnection from the Earth Mother may have serious spiritual and physical health consequences – this can happen due to EM-insulated shoes, concrete and general EM pollution. Living on Mars might cause stresses on the human body that lie outside the current biological paradigm in medicine, or it might not. We should at least be conscious of the possibility and study the EM field of the body in health and medicine so that we can monitor it on Mars.

An example of how the EM model might change the perception, study and treatment of “subjective” patient complaints is brain zaps [8,9]. I have talked to quite a few people who have experienced brain zaps and also body zaps. These are dismissed as invalid subjective illusions or misperceptions by mainstream medicine and science. Well, maybe not. Maybe brain zaps are a real EM phenomenon that does not follow anatomical pathways. Maybe there is an evolutionarily relevant set of direct EM transmissions within the human body that links tissues and organs by mechanisms other than hormones, nerve impulses and blood-borne biological signals. I propose that the whole body EM scanner might be able to detect, measure and validate chakras and chi meridians and a variety of treatments like therapeutic touch. The scanner might be able to detect the response of the client’s EM field to EM transmissions from the healer’s hands. Rather than being mysticism this is an experimentally testable scientific hypothesis – the EM paradigm offers a way to unify eastern and western medicine.

A final thought: “Where’s your evidence?” is a statement never heard in the field of theoretical physics.

References

  1. Ross CA (2025) Reform of the National Institute of Mental Health: A Journal of Neurology and Neurocritical Care, 8: 1-4.
  2. Ross CA, Pam A (1995) Pseudoscience in Biological Blaming the Body. John Wiley & Sons, New York.
  3. Ross CA (2017) Psychiatry’s illogical model of mind. Ethical Human Psychology & Psychiatry 19: 81-90.
  4. Ross CA (2010) Electrophysiological properties of human ocular Subtle Energies and Energy Medicine 21: 21-27.
  5. Ross CA (2013) Recent patents on non-contact electrodes for measuring EEG and Recent Patents on Electrical and Electronic Engineering 6: 2-6.
  6. rossenergysystems.com
  7. Ross CA (2009) Human Energy A New Science and Medicine. Richardson, Texas, Manitou Communications.
  8. Papp A, Onton JA (2018) Brain zaps: an underappreciated symptom of antidepressant Primary Care Companion to CNS Disorders, 20(6); 18m02311. [crossref]
  9. Papp A, Onton JA (2022) Triggers and characteristics of brain zaps according to the findings of an internet Primary Care Companion to CNS Disorders, 4(1): 21m02972. [crossref]