Figure 3. Potential models underlying the inverted-U effect of VNS.

(A) In the one system model, low intensities fail to sufficiently activate the system, moderate intensities produce optimal activation and consequent efficacy, and high intensities overactive and desensitize the system, thus limiting effects. (B) In the two system model, moderate intensities engage the low-threshold system and generate efficacy. Higher intensities activate the overriding high-threshold system and limit efficacy. Together, these systems produce an inverted-U response. As shown in this example, a combination of α- and β-adrenergic receptors could exhibit this behavior.