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

Abstract

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.

Neural correlates of aversive anticipation: An activation likelihood estimate meta-analysis across multiple sensory modalities

“…Limitations, strengths, and future directions Some caveats and limitations to these results need to be considered. First, the nature of our analyses indicate that these structures are involved in aversive anticipation but do not provide information about the functional significance of these structures or the dynamic communication between these structures during anxious anticipation (Mujica-Parodi, Carlson, Cha, & Rubin, 2014;Mujica-Parodi, Cha, & Gao, 2017). Additionally, the studies included in the multi-study voxelwise analyses all contained anticipation periods with a one second fixation cue followed by a sixteen second anticipatory countdown.…”

Making Sense of Computational Psychiatry

“…If the full spectrum of regulation is represented along an axis designated for each circuit, then-in principle-we can position each psychiatric disorder at precise coordinates within such a phase space. For example, we have shown that the anxious-to-reckless spectrum tracks feedback dynamics within the threat-detection and perceptual circuits (Mujica-Parodi et al, 2017). In contrast, depression likely implicates feedback dynamics with the reward circuit, and complex disorders such as paranoid schizophrenia and addiction are likely to implicate all three circuits and potentially others as well.…”

Quantifying control circuit regulation in the human brain

“…Two reasons to suspect that at least some psychiatric disorders implicate allostatic disruption 9 are their vulnerability to perturbation in the form of emotional stress (commonly seen in first-break psychosis and relapse) and trajectories with prominent oscillating features (e.g., bipolar disorder and addiction). Candidate circuits that have been consistently implicated in psychiatrically relevant symptoms include the prefrontal-limbic circuit 10,11 (threat processing, as per anxiety and paranoia), the meso-corticolimbic circuit 12,13 (reward processing, as per anhedonia and addiction), the cortico-thalamic loop 14,15 (sensory processing, as per attentional deficits and hallucinations), and combinations thereof. As evident even from the nomenclature, all three circuits have significant overlap as well as mutual feedback.…”