Boosting the immune system via positive thinking

Mind over matter, the reinforcement learning way

This past Saturday was my mother’s birthday, so happy birthday to my amazing mom (that is why no article, I spent time with her, helping her too).

While I was working on my other articles, I suddenly stumbled upon the following (today) and decided to write this in a more stream-of-consciousness form. Of course, I will share older articles related to the subject.

On (building) resilience

The mind, and habits - Use it or lose it

Positive thinking and neurological health

I am a huge proponent and believer of “mind over matter”, not only observing it throughout my military life, but applying it myself. And to me, building resilience and achieving a state of mind over matter can form a positive feedback loop. This concept is incredibly important in the face of different aspects of life and the challenges it brings, but to me, it is strictly necessary for Long Covid patients, and part of my readership either has LC, deals with sequelae for months like myself on occasion (not necessarily LC, but damaged from the virus), or knows someone who is in one of these conditions.

Dealing with LC patients, or any patient with post-infection sequelae (the same applies to post-septic patients and how debilitated they become), or “long vaccine” is difficult, not only from the sheer complexity of their cases, but the slow uphill battle, and the endless invalidation of their condition by a myriad of doctors, until they find a good one.

You are put into a difficult position because telling someone struggling with their body or mind to build resilience, “embrace the suck”, or think more positively will imply that you are invalidating their experiences or condition, because of previous bad experiences. It is one of the reasons I don’t share my experiences because my approach is the one it was beaten into me. Become comfortable being miserable, and thus work through the recovery, but if there is interest, I may share lessons learned in this last infection.

Thus, the reason we are here. It is one thing to tell someone “think more positively, expect better outcomes from the future, and that will improve life and health”, it is another to demonstrate in a scientific, randomized trial. =) (this paper is sadly paywalled, but you can find the pre-print here)

Upregulation of reward mesolimbic activity and immune response to vaccination: a randomized controlled trial

Growing evidence points to a close neurophysiological link between brain and body. Recent rodent studies have shown that the dopaminergic mesolimbic pathway, which underlies expectations of positive outcomes, also modulates immune function. However, it remains unknown whether a similar brain-immune link exists in humans and whether it involves conscious positive expectations. In a preregistered, double-blind randomized controlled trial, we used fMRI neurofeedback (NF) to train healthy participants to increase reward mesolimbic activity through self-chosen mental strategies, followed by an immune challenge with the hepatitis B virus (HBV) vaccine and assessments of HBV antibody (HBVab) levels. Eighty-five participants were randomized to (1) reward mesolimbic upregulation (n = 34), (2) non-mesolimbic control upregulation (n = 34) or (3) no-NF control (n = 17). Prespecified primary outcomes were (1) differences in reward mesolimbic activation between NF groups, (2) correlation between reward mesolimbic upregulation and post-vaccination HBVab changes across both NF groups and (3) group differences in post-vaccination HBVab changes. Both NF groups showed significant increases in reward mesolimbic activation. Notably, greater ventral tegmental area (VTA) upregulation—but not nucleus accumbens or control region activation—was associated with larger post-vaccination increases in HBVab levels (r = 0.31, P = 0.018). Sustained VTA upregulation was further linked to mental strategies involving positive expectations. Post-vaccination antibody levels did not differ between groups, and no adverse effects occurred. Together, these findings suggest that consciously generated positive expectations can engage reward circuitry to influence immune function, a process that may be leveraged for non-invasive immune modulation. ClinicalTrials.gov identifier: NCT03951870.

This trial uses fMRI‑neurofeedback as a way to let participants voluntarily upregulate their own reward circuitry by watching their neural activity in real time and, through trial and error, learning what mental states reliably move it. The remarkable part is not simply that people can learn to modulate deep brain structures like the midbrain, but that doing so appears to have measurable downstream effects on the immune system, which is the premise of this research, if our mind can affect our body/immune system.

At the center of this experiment is the ventral tegmental area (VTA), a compact midbrain nucleus best known for its role in motivation, learning, and reward prediction. The VTA is densely populated by dopaminergic neurons, alongside GABAergic and glutamatergic populations, and sits at the origin of the mesolimbic pathway projecting to structures such as the nucleus accumbens.

This circuitry is foundational to reinforcement learning. When an outcome is better than expected, dopaminergic firing increases, reinforcing the neural and behavioral patterns that preceded it. It is critical for learning, motivation, and pleasure, involved in complex decision-making.

Participants underwent three to four fMRI‑neurofeedback sessions over roughly two weeks. During each session, they alternated between rest and an “upregulate” phase, during which they attempted to increase their neural activity in a targeted manner, in specific regions, and they did this by using a specific approach.

They were free to choose their own mental strategies, such as recalling meaningful memories, imagining positive future events, focusing on feelings of anticipation or success, and received immediate feedback scoring of such strategies, indicating how successful each attempt was the fMRI-neuralfeedback system.

Strategies that reliably increased the target signal were reinforced and reused, and the ineffective, weaker ones were discarded. Over time, participants converged on mental states that consistently drove activity in the targeted regions. Both the experimental and the control group showed significant VTA increases across training, because neurofeedback itself is inherently rewarding.

When you see a highcore, the brain releases dopamine, which strengthens the neural pathway that produced the state, gaining a sense of control over your own brain engages the same reinforcement machinery that the task is attempting to train.

This matters because the central biological question of the paper is not whether people can learn to control VTA activity, but whether doing so is meaningfully related to immune function. Immediately after the final neurofeedback session, all participants received a hepatitis B vaccination. Antibody levels were measured before vaccination, two and four weeks afterward, and again at three months in a subset of participants. Hepatitis B vaccination is known to have a considerable number of non-responders, so it is a very good way to measure the effects of VTA on immune responses.

Across both neurofeedback groups, individuals who showed stronger increases in VTA activity during training mounted a significantly higher antibody response to the vaccine. This relationship was not observed for the nucleus accumbens, nor for control brain regions used in the control neurofeedback condition. Nor could it be explained by general task engagement, reward sensitivity, or baseline motivational traits measured independently. The immune effect tracked to VTA regulation itself.

This mirrors earlier animal work showing that activation of VTA dopaminergic neurons can enhance both innate and adaptive immune responses, improve bacterial clearance, and slow tumor growth (cited by the authors).

By carefully characterizing the strategies participants used, the authors show that elevated VTA activity just before vaccination was selectively associated with mental strategies involving positive expectation, anticipation, excitement about future outcomes, and a sense that something good is about to happen. Other affective features, such as calmness, pleasure, or social warmth, were more strongly associated with nucleus accumbens activity, but did not predict immune enhancement.

Positive expectation is a defining antecedent of placebo effects. The placebo response is not merely about feeling good in the present, but about predicting improvement. In reinforcement learning terms, it is about anticipated reward rather than consummatory pleasure. The data suggest that the VTA may be a neural hinge connecting expectation to immune readiness, priming the body to invest resources when the brain predicts future benefit.

The same circuitry that drives learning, motivation, and attention also coordinates bodily preparedness, tuning immune function in anticipation of future demands. In an environment where reward often predicts effort, injury, or exposure, such coupling makes evolutionary sense. Using this strategy, you can reinforce learn your own mind towards improvement, boosting immune function.

If you read the older articles, you will now possess a wider knowledge on how the brain, and especially positive thinking affects not only your general wellbeing, but critically can positively modulate your cognition, neurological health and here, by indirect effects (dopamine specifically) modulate your systemic immune response, with glimpses of true evidence that you can boost your immune system by thought alone, let alone improving the “placebo effects”.

To attempt to provide you with a wider, broader perspective, this also applies to muscle growth. One of the most cited papers among gym bros is the “brains over gains” paper, by which the authors observed strength gains by merely activating muscles via mental training, leading to stronger contractions and an increase in strength. A more recent pilot study observed similar effects. By doing motor imagery training (vizualizing and simulating actual movements without doing them), the older adults experienced a 22% increase in muscle strength. Improvement in muscle strength and gait (walking) performance was also observed in stroke patients going through recovery.

Or by shifting Aristotle’s famous quote.

As I sometimes advise friends and people closer to me, the best way to make a consistent, lasting change is to form a new habit, often a subconscious one, where the habit becomes muscle memory, and I believe this applies to the findings in this paper and the matter discussed here. You can biohack yourself into shifting your body towards recovery, thus allowing the needle to move and improvements to finally occur. Physical activity, grounding comes second, and supplementation comes a close third.

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