Neuroimmune change has been proposed as a tractable indicator of target engagement during neuromodulation for anxiety and depression, yet the evidence spans different organisms, anatomical targets, biological compartments, and sampling times. This study asked whether the direction of immune change remains consistent across those sources of heterogeneity and whether apparently favorable modality profiles withstand deliberate perturbation. A 27-comparison in vivo corpus covering transcranial magnetic stimulation (TMS), transcranial electrical stimulation (TES), electroconvulsive therapy (ECT), photobiomodulation (PBM), transcranial ultrasound stimulation (TUS), deep brain stimulation (DBS), and vagus nerve stimulation (VNS) was analyzed with Directional Immune Concordance Analysis. Every comparison received a signed value of \(+1\) for neuroimmune normalization, \(0\) for no detectable or mixed change, and \(-1\) for inflammatory activation. Group means were paired with 20,000-resample intervals, Jeffreys-posterior probabilities among directionally decisive comparisons, 100,000-draw randomization tests, and a sign-fragility experiment. Nineteen comparisons indicated normalization, five indicated activation, and three were null or mixed. The overall directional mean was 0.519 (95% bootstrap interval 0.222–0.815). VNS and TUS each had a mean of 1.000, whereas ECT and PBM had means of 0; however, modality heterogeneity was not supported by randomization (\(p=0.478\)). Direct affective comparisons had a mean of 0.333, compared with 0.611 in indirect disease models (\(p=0.454\)). Human and rodent means were nearly identical (0.500 and 0.526), as were peripheral and central estimates (0.500 and 0.471). Three favorable VNS reports, two TUS or TES reports, and one TMS or DBS report had to reverse sign before their respective aggregate values became nonpositive. The evidence therefore supports a general homeostatic immune direction but does not justify choosing a device solely from modality-level immune rankings. For anxiety and depression, the decisive next test is temporally matched measurement of symptoms, peripheral cytokines, and circuit-proximal neuroimmune activity within the same participants.
Neuroimmune change has been proposed as a tractable indicator of target engagement during neuromodulation for anxiety and depression, yet the evidence spans different organisms, anatomical targets, biological compartments, and sampling times. This study asked whether the direction of immune change remains consistent across those sources of heterogeneity and whether apparently favorable modality profiles withstand deliberate perturbation. A 27-comparison in vivo corpus covering transcranial magnetic stimulation (TMS), transcranial electrical stimulation (TES), electroconvulsive therapy (ECT), photobiomodulation (PBM), transcranial ultrasound stimulation (TUS), deep brain stimulation (DBS), and vagus nerve stimulation (VNS) was analyzed with Directional Immune Concordance Analysis. Every comparison received a signed value of \(+1\) for neuroimmune normalization, \(0\) for no detectable or mixed change, and \(-1\) for inflammatory activation. Group means were paired with 20,000-resample intervals, Jeffreys-posterior probabilities among directionally decisive comparisons, 100,000-draw randomization tests, and a sign-fragility experiment. Nineteen comparisons indicated normalization, five indicated activation, and three were null or mixed. The overall directional mean was 0.519 (95% bootstrap interval 0.222–0.815). VNS and TUS each had a mean of 1.000, whereas ECT and PBM had means of 0; however, modality heterogeneity was not supported by randomization (\(p=0.478\)). Direct affective comparisons had a mean of 0.333, compared with 0.611 in indirect disease models (\(p=0.454\)). Human and rodent means were nearly identical (0.500 and 0.526), as were peripheral and central estimates (0.500 and 0.471). Three favorable VNS reports, two TUS or TES reports, and one TMS or DBS report had to reverse sign before their respective aggregate values became nonpositive. The evidence therefore supports a general homeostatic immune direction but does not justify choosing a device solely from modality-level immune rankings. For anxiety and depression, the decisive next test is temporally matched measurement of symptoms, peripheral cytokines, and circuit-proximal neuroimmune activity within the same participants.
