A regulatory pathway model of neuropsychological disruption in Havana syndrome

Abstract

Introduction: In 2016 diplomatic personnel serving in Havana, Cuba, began reporting audible sensory phenomena paired with onset of complex and persistent neurological symptoms consistent with brain injury. The etiology of these Anomalous Health Incidents (AHI) and subsequent symptoms remains unknown. This report investigates putative exposure-symptom pathology by assembling a network model of published bio-behavioral pathways and assessing how dysregulation of such pathways might explain loss of function in these subjects using data available in the published literature. Given similarities in presentation with mild traumatic brain injury (mTBI), we used the latter as a clinically relevant means of evaluating if the neuropsychological profiles observed in Havana Syndrome Havana Syndrome might be explained at least in part by a dysregulation of neurotransmission, neuro-inflammation, or both.

Method: Automated text-mining of >9,000 publications produced a network consisting of 273 documented regulatory interactions linking 29 neuro-chemical markers with 9 neuropsychological constructs from the Brief Mood Survey, PTSD Checklist, and the Frontal Systems Behavior Scale. Analysis of information flow through this network produced a set of regulatory rules reconciling to within a 6% departure known mechanistic pathways with neuropsychological profiles in N = 6 subjects.

Results: Predicted expression of neuro-chemical markers that jointly satisfy documented pathways and observed symptom profiles display characteristically elevated IL-1B, IL-10, NGF, and norepinephrine levels in the context of depressed BDNF, GDNF, IGF1, and glutamate expression (FDR < 5%). Elevations in CRH and IL-6 were also predicted unanimously across all subjects. Furthermore, simulations of neurological regulatory dynamics reveal subjects do not appear to be "locked in" persistent illness but rather appear to be engaged in a slow recovery trajectory.

Discussion: This computational analysis of measured neuropsychological symptoms in Havana-based diplomats proposes that these AHI symptoms may be supported in part by disruption of known neuroimmune and neurotransmission regulatory mechanisms also associated with mTBI.

Keywords: Havana syndrome; anomolous health incidents; computational model; mild traumatic brain injury; neuroimmunology; neuropsychology; neurotransmission; regulatory pathways.

Figure 1

A text-mined bio-behavioral regulatory network. A network of documented neurotransmission and neuro-inflammation pathways associated with mTBI consisting of 29 molecular mediators, 9 mood function measures and an external stressor connected through 273 directed regulatory interactions supported 9,032 peer-reviewed citations. A green interaction indicates that a source node upregulates a downstream target. Conversely a red interaction indicates that a downstream target is down-regulated by its upstream mediator.

Figure 2

A regulatory logic program. In this network MAOA is part of a negative feedback through PTSD severity and a positive feedback through Depression severity. A putative regulatory program where Depression is only detectable by MAOA at high severity (+2) while PTSD is more readily detectable at moderate severity (+1), would result in a PTSD driven decrease in MAOA expression (left panel). If Depression increased to high severity (+2) it would become detectable making MAOA subject to the opposing actions of both upstream nodes. In this example a regulatory program might assign more influence to Depression over PTSD thereby driving an increase in MAOA (right panel).

Figure 3

A qualitative neuropsychological description. A description of N = 6 subjects with indications of Havana Syndrome described in terms of 9 neuropsychological constructs where severity is scaled onto a discrete qualitative scale from 0 or minimal to 3 or most severe. The reference control condition was defined as a stable resting state with minimal severity and maximum function.

Figure 4

Predicted dysregulation of neurological biomarkers. Predictions based on a regulatory network model of known neurotransmission and neuro-inflammatory pathways indicate that 8 of 29 neurological markers might be differentially expressed at FDR ≤ 5% in the group of N = 6 Havana Syndrome subjects compared to a minimum severity control reference profile (Ctrl). The model-based co-expression profile characteristic of Havana Syndrome would consist of depressed neurotrophic factors BDNF, GDNF, IGF1, and glutamate in the context of over-expression of IL-10, IL-1B, NGF, and norepinephrine.

Figure 5

Predicting the current course of illness. The decisional logic rules that allow the regulatory network to support the symptom severity and functional profiles observed in the N = 6 subjects implicitly determine the profiles that must have preceded the current cross-sectional observation as well as the next state to which the network is expected to progress. As in subject 4 (above), severity scores decrease monotonically, with exception of suicidal ideation score and apathy, with function improving or remaining high suggesting a trend towards a slow partial recovery in this group.