From Anxious to Reckless: A Control Systems Approach Unifies Prefrontal-Limbic Regulation Across the Spectrum of...

Here we provide an integrative review of basic control circuits, and introduce techniques by which their regulation can be quantitatively measured using human neuroimaging. We illustrate the utility of the control systems approach using four human neuroimaging threat detection studies (N = 226), to which we applied circuit-wide analyses in order to identify the key mechanism underlying individual variation. In so doing, we build upon the canonical prefrontal-limbic control system to integrate circuit-wide influence from the inferior frontal gyrus (IFG). These were incorporated into a computational control systems model constrained by neuroanatomy and designed to replicate our experimental data. In this model, the IFG acts as an informational set point, gating signals between the primary prefrontal-limbic negative feedback loop and its cortical information-gathering loop. Along the cortical route, if the sensory cortex provides sufficient information to make a threat assessment, the signal passes to the ventromedial prefrontal cortex (vmPFC), whose threat-detection threshold subsequently modulates amygdala outputs. However, if signal outputs from the sensory cortex do not provide sufficient information during the first pass, the signal loops back to the sensory cortex, with each cycle providing increasingly fine-grained processing of sensory data. Simulations replicate IFG (chaotic) dynamics experimentally observed at both ends at the threat-detection spectrum. As such, they identify distinct types of IFG disconnection from the circuit, with associated clinical outcomes. If IFG thresholds are too high, the IFG and sensory cortex cycle for too long; in the meantime the coarse-grained (excitatory) pathway will dominate, biasing ambiguous stimuli as false positives. On the other hand, if cortical IFG thresholds are too low, the inhibitory pathway will suppress the amygdala without cycling back to the sensory cortex for much-needed fine-grained sensory cortical data, biasing ambiguous stimuli as false negatives. Thus, the control systems model provides a consistent mechanism for IFG regulation, capable of producing results consistent with our data for the full spectrum of threat-detection: from fearful to optimal to reckless. More generally, it illustrates how quantitative characterization of circuit dynamics can be used to unify a fundamental dimension across psychiatric affective symptoms, with implications for populations that range from anxiety disorders to addiction.