Impairment of Decision Making in Chronic Trigeminal Neuropathic Pain Is Associated with Desynchrony in the Anterior Cingulate Cortex-amygdala Neural Network


Student thesis: Doctoral Thesis

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Award date4 Dec 2018


Infraorbital nerve chronic constriction injury (ION-CCI) has become the most popular chronic trigeminal neuropathic pain (TNP) injury animal model which causes prolonged mechanical allodynia. Accumulative evidence suggests that TNP interferes with cognitive functions, however the underlying mechanisms are not known. Clinical research in human and rodents consistently suggest that chronic pain affects cognitive function. Brain fMRI studies have shown enhanced activation of spinal trigeminal nucleus (SpV), anterior cingulate cortex(ACC), thalamus and basolateral amygdala(BLA) in the patients with trigeminal neuropathic pain (TNP), suggesting a dysfunction of the brainstem sensory components and higher brain regions. It is surprising that there has been no experimental animal model to study chronic oral facial pain related and cognitive deficits, and little is known about the underlying mechanisms.

The aim of this study was to investigate decision making performance as well as synaptic and large-scale neural synchronized alterations on spinal trigeminal nucleus (SpV) circuitry and in higher brain regions BLA-ACC circuitry in rats with TNP. The rat gambling task showed that ION-CCI led to a decrease in the proportion of good decision-makers and increase in the proportion of poor decision-makers. Electrophysiological recordings showed long-lasting synaptic potentiation of local field potentials (LFP) in the trigeminal ganglia (TG)-SpV caudalis (SpVc) synapses in TNP rats. High frequency electrical stimulation (HFS) of the TG induces long-term potentiation (LTP) in the TG-SpVc pathway in normal rats, which was occluded in the TNP state. Multiple-channel electrode recordings revealed that spike-field coherence and phase locking were reduced within the SpVc, meanwhile theta synchronization between SpVc and SpV oralis (SpVo) was disrupted in ION-CCI rats. These findings provide the first documentation that orofacial allodynia and decision-making deficit are associated with alteration of synaptic plasticity on TG-SpVc synapses, as well as disruptions of spike-field coherence within SpVc and synchronization between SpVc-SpVo in rats following trigeminal nerve injury.

Large-scale electrophysiological recordings in BLA-ACC circuitry in freely moving animals during a decision-making task indicate that chronic TNP reduces the phase locking and synchronization, thus affecting the information flow between the higher brain regions necessary for cognitive functions.

To suppress the pain sensation, ELVAX embedded tetrodotoxin (Elvax-TTX) was implanted close to the injured nerve immediately after nerve constriction to block the peripheral inputs during the early phase of pain development. Directly implanting an Elvax-TTX immediately at the ION lesion site completely suppressed the lesion-induced allodynia, and rescued the decision-making deficits induced by chronic TNP. However, the same nerve blockade used at a later phase, 30 days after ION-CCI surgery, couldn’t suppress the mechanical allodynia nor rescue from decision-making deficits.

I also used systemic application of riluzole, an approved neuroprotective agent activating glutamate reuptake, to block the central inputs during the late phase of somatic pain. TNP causes reduction in glial excitatory amino acid transporter (EAAT)-1. Administration of riluzole at the late phase suppressed mechanical allodynia but failed to rescue the decision-making deficits.

These studies collectively show that decision-making deficits is associated with pain sensation in the early phase of TNP, however in the late phase, it becomes independent to the pain sensation per se. Chronic TNP affects TG-SpV circuitry and later affects higher brain regions BLA-ACC circuitry, aided by myelin damage in the ACC region. Hence, early pain relief treatment is important for recovering from pain related cognitive impairments.

    Research areas

  • decision making, spike-field phase locking, spinal trigeminal nucleus, anterior cingulate cortex, basolateral amygdala, synaptic plasticity, trigeminal neuropathic pain