Supraspinal pain perception consists of mainly three functional regions: 1) sensory discriminatory regions such as the primary and secondary somatosensory cortices (SSC1 and SSC2) and inferior parietal lobe (IPL); 2) affective regions such as anterior cingulate cortex (ACC) and insula (IN); and 3) modulatory regions involving motor and various regions of prefrontal cortices (PFCs).(18, 19) Additionally, the insula (IN) has been known to play a role in assessing the magnitude of pain, while the inferior parietal lobe (IPL) aids in distinguishing spatial discrimination in pain perception.(20–23) Chronic pain state is often associated with a mal-adaptation in the supraspinal pain processing, which is often accompanied with diminished modulatory functional connectivity from the prefrontal cortices with diminished motor cortex excitability as reflected by an elevated resting motor threshold.(24, 25)
Persian Gulf War veterans in this study demonstrated an increase in RMT level compared to their non-pain Gulf War veteran counterparts. The need for a higher level of stimulation in Gulf War veterans is consistent with other chronic pain conditions resulted from either direct or indirect neuronal traumas which resulted in impaired supraspinal pain modulation(26–34). Although the pathophysiology behind the headaches and diffuse body pain in this population has not been explicitly defined, the observed functional deficit in supraspinal cortical modulatory function serves as a significant step in understanding the pathophysiology underlying the high prevalence of chronic pain states in this patient population.(35–37)
While transcranial magnetic stimulation-evoked resting motor threshold has been demonstrated to be a reliable method for assessing cortical excitability, it may also be a viable solution for the chronic pain experienced by these veterans. TMS is approved by the United States Food and Drug Administration for treating depression and migraine headaches.(38–40) In addition, multiple meta-analyses and panel consensus review definitively supported a high level of evidence for treating central neuropathic states, such as in the management of chronic and debilitating headaches in mild Traumatic Brain Injury patients.(17, 41) High frequency (> 1 Hz) TMS works by evoking action potentials to directly excite the motor cortex and potentially regain cortical excitability, which cannot be accomplished with traditional pharmacological methods. Since Gulf War veterans with Gulf War Illness-associated headaches and pain present with a similarly increased RMT profile, it is possible they may also find relief with repetitive transcranial magnetic stimulation in the form of increased pain modulatory function.
Limitations to the study include those due to an all-male study population and recruitment from a single site. Although all subjects were successfully gender and age-matched to a counterpart in the other group of the study, all forty veterans were male which is not indicative of the true veteran population that was deployed to the Persian Gulf in 1990-91. While female veterans were screened for the study, they were far fewer in number compared to male veterans who met the criteria. This is most likely explained by the inherently male-dominated target population of 1990-91 Gulf War veterans, of which only 7% of the total deployed personnel consisted of females.(42) Furthermore, 70–78% of female veterans report pain symptoms, meaning only a small number of female veterans would meet the Control criteria while also living near the recruitment site.(43, 44) Other reasons that may have led to this all-male result include the current distribution of female to male veterans at Veteran Affairs San Diego Healthcare System. Since veterans with pain required a gender and age matched healthy counterpart, it became less likely that a female was included in the study. Additionally, recruitment occurred primarily in San Diego County, which is heavily dominated by Naval and Marine bases. Future studies would benefit from recruitment from multiple sites as it would provide a study population that is more representative of the 1990-91 Persian Gulf War veterans in terms of military branches and gender.
In short, the observed result from the current study suggests that the high prevalence of headaches and diffuse body pain in 1990-91 Persian Gulf War veterans is associated with impaired cortical excitability and pain modulation. This was expressed by a higher resting motor threshold in GWV-HAP veterans compared to control. The significance of transcranial magnetic stimulation in this study is two-fold. TMS was utilized as the primary modality in assessing resting motor threshold. In a clinical setting, the same TMS machine may also provide veterans potential benefit long-term pain relief that is currently lacking in the management of this multisymptom illness.