Background/Objectives: Chronic pain is associated with autonomic nervous system (ANS) dysfunction, which can be indexed by heart rate variability (HRV). This cross-sectional study examined associations between ANS dysregulation and phantom limb pain (PLP) intensity in amputees and explored related clinical and psychosocial variables. Methods: Fifty-three adults with chronic PLP (mean age 57.7 ± 15.4; 60% male) were enrolled. Primary exposure was PLP intensity concurrent with HRV time- and frequency-domain metrics. Additional variables included residual limb pain, phantom limb sensations (PLS), telescoping and PLP–PLS index. Results: PLP intensity was not significantly associated with frequency-domain HRV measures. Time-domain parameters RMSSD (root mean square of successive differences) and pNN50 (percentage of successive normal RR intervals >50 ms) were lower in the positive PLP–PLS group. In multivariate models, depression (range of βs:−1.36 to −58.16), pain-medication use (range of βs: −12.3 to −953.4), and body mass index (range of βs: 0.55 to 45.8) were significantly associated with lower SDNN (standard deviation of NN intervals), RMSSD, pNN50, low-frequency (LF), and high-frequency (HF) power. Female sex and pre-amputation pain correlated with higher LF, whereas traumatic etiology correlated with lower LF. Poor sleep quality correlated with elevated HF. No predictors related to the LF/HF ratio. Conclusions: HRV alterations in PLP were associated with depression and pain-medication use rather than pain intensity. Findings support HRV dysfunction as a marker of brain compensatory failure within the autonomic circuit, and maladaptive plasticity, highlighting utility for identifying central dysfunction even when pain severity does not vary.

The rising prevalence of neuroimmune disorders such as multiple sclerosis and fibromyalgia has renewed interest in the hygiene hypothesis, which posits that reduced early-life microbial exposure deprives the immune system of formative “noise” that calibrates thresholds of tolerance. We extended this framework by introducing stochastic resonance (SR), a system phenomenon in which optimally tuned noise enhances weak-signal detection in nonlinear networks, as a potential surrogate for missing microbial variability. As electrical noise and subthreshold stimulation have been shown to modulate cortical excitability and enhance perception, microbial noise may be necessary for sustaining immune plasticity. Conversely, a lack of stimulation, whether microbial or electrical, can lead to maladaptive states characterized by dysregulated signaling and heightened vulnerability to chronic inflammation. Evidence from immunology highlights noise-aware processes, such as T-cell receptor proofreading, NF-κB pulsatility, and cytokine quorum sensing, all of which exploit stochastic fluctuations. Computational tumor–immune models similarly suggest that tuned noise can optimize immune surveillance. Clinical data from neuroscience demonstrate that subsensory electrical noise improves motor excitability and sensory perception, whereas vagus nerve stimulation modulates inflammatory pathways, underscoring translational feasibility. We propose that SR reframes noise from a biological error to a therapeutic resource capable of recalibrating dysregulated neuroimmune thresholds. This conceptual synthesis positions microbial and electrical noise as parallel modulators of tolerance and outlines testable predictions with translational potential for neuroimmune disorders.

Background/Objectives: Chronic pain is associated with autonomic nervous system (ANS) dysfunction. Heart rate variability (HRV) indexes sympathetic–parasympathetic balance and autonomic adaptability. Phantom limb pain (PLP) is prevalent after limb loss, but evidence of ANS dysregulation in chronic PLP is limited. This cross-sectional study examined associations between ANS dysregulation and PLP intensity in amputees and explored links with clinical and psychosocial variables. Methods: Fifty-three adults with chronic PLP (mean age 57.7±15.4; 60% male) were enrolled. Primary exposure was PLP intensity concurrent with HRV time- and frequency-domain metrics. Additional variables included residual limb pain, phantom limb sensations (PLS), and telescoping. The PLP–PLS index was also evaluated. Results: PLP intensity was not significantly associated with frequency-domain HRV measures. Time-domain parameters RMSSD (root mean square of successive differences) and pNN50 (percentage of successive normal RR intervals >50 ms) were lower in the positive PLP–PLS group. In multivariate models, depression, pain-medication use, and body mass index were associated with lower SDNN (standard deviation of NN intervals), RMSSD, pNN50, low-frequency (LF), and high-frequency (HF) power. Female sex and pre-amputation pain correlated with higher LF, whereas traumatic etiology correlated with lower LF. Poor sleep quality correlated with elevated HF. No predictors related to the LF/HF ratio. Conclusions: HRV alterations in PLP were associated with depression and pain-medication use rather than pain intensity. Findings support HRV dysfunction as a marker of brain compensatory failure and central neurophysiological disruption within circuits governing autonomic regulation and maladaptive plasticity, highlighting utility for identifying central dysfunction even when pain severity does not vary.