Observations of Autonomic Variability following Central Neuromodulation for Chronic Neuropathic Pain in Spinal Cord Injury

Abstract

Background:

Spinal cord injury (SCI) persons with chronic neuropathic pain (NP) demonstrate maladaptive autonomic profiles compared to SCI counterparts without NP (SCI-NP) or able-bodied (AB) controls. These aberrations may be secondary to maladaptive neuroplasticity in the shared circuitry of the pain neuromatrix-central autonomic network interface (PNM-CAN). In this study, we explored the proposed PNM-CAN mechanism in SCI+NP and AB cohorts following centrally-directed neuromodulation to assess if the PNM and CAN are capable of being differentially modulated.

Methods:

Central neuromodulation was administered via breathing-controlled electrical stimulation (BreEStim), previously evidenced to operate at the PNM. To quantify CAN activity, conventional heart rate variability (HRV) recordings were used to gather time and frequency domain parameters of autonomic modulation. SCI+NP (n=10) and AB (n=13) cohorts received null and active BreEStim randomly in crossover fashion. HRV data were gathered pre-test and 30 minutes post-test. Pain modulation was quantified at both time-points by visual analog scale (VAS) for SCI+NP persons and electrical detection and pain threshold levels (EDT, EPT) for AB persons.

Results:

Following active BreEStim only, SCI+NP persons demonstrated increased parasympathetic tone (increased NN50, p=0.03, and pNN50, p=0.02, HRV parameters). This parasympathetic restoration was associated with analgesia (VAS reduction, p<0.01). Similarly, AB persons demonstrated increased noxious tolerance (increased EPT, p=0.03, with preserved EDL, p=0.78) only following active BreEStim. However, this increased pain threshold wasn’t associated with autonomic changes.

Conclusions:

Central modulation targeting the PNM produced autonomic changes in SCI+NP persons but not AB persons. These findings suggest that AB persons exhibit intact CAN mechanisms capable of compensating for PNM aberrations or simply that SCI+NP persons exhibit altered PNM-CAN machinery altogether. Our collective findings confirm the interconnectedness and maladaptive plasticity of PNM-CAN machinery in SCI+NP persons and suggest that the PNM and CAN circuitry can be differentially modulated.

INTRODUCTION

Neuropathic pain (NP) is well known to be a common and particularly distressing comorbidity in persons with chronic spinal cord injury (SCI) [1]. Despite its high prevalence, managing persons with SCI and NP is often clinically challenging, owing largely in part to our limited understanding of its precise pathophysiology [2,3]. A score of recent, innovative studies have presented increasing evidence for pathological neuromodulation at the supraspinal level as being responsible for post-SCI NP [4-7]. The neural structures implicated in this pathogenesis include the insula, anterior cingulate cortex (ACC), and the pre-frontal cortex, which collectively comprise part of the pain neuromatrix (PNM) [8,9]. These theories are further validated in the context of post-SCI NP by studies that show these areas as having undergone structural and functional changes in the chronic phase following injury [10,11]. Similarly, others have demonstrated that transcranial direct current stimulation interventions may confer analgesia in persons with SCI and NP by way of modulating descending pain pathways at the level of the ACC [12]. Furthermore, elegantly designed studies utilizing functional MRI found these cortical areas within the PNM to demonstrate increased activity specifically in persons with SCI+NP relative to able bodied persons (AB) upon pain induction [4]. These neural structures were also found to be highly interconnected in proximity and function to the central autonomic network (CAN) in persons with SCI relative to AB persons [4,5,13-15].

We and others have also further substantiated this PNM-CAN interface by demonstrating that persons with SCI+NP exhibited maladaptive autonomic profiles at baseline compared to their SCI counterparts without NP or even AB controls [5,16]. Most importantly, it was found that this difference was independent of the level of SCI-induced neurological impairments. In a subsequent study, we further explored PNM and CAN interconnectedness by neuromodulation via breathing controlled electrical stimulation (BreEStim), which has centrally-mediated analgesic effects [14]. We found that BreEStim modulation of SCI+NP persons confers a resultant increase in their diminished baseline parasympathetic tone concomitantly with analgesic effect. Interestingly, we also found that this degree of autonomic restoration by increasing parasympathetic activity made the autonomic system of the SCI+NP persons comparable to that of the SCI-NP and AB persons at baseline.

The degree of PNM to CAN association and their capacity to be differentially modulated, however, has yet to be clearly investigated. As a whole, there currently exists limited evidence correlating post-SCI NP and autonomic irregularities in the course of recovery after SCI [17-19]. Epidemiological findings suggest that the prevalence of NP, although variable in the sub-acute stages, stabilizes in the chronic stages of injury where some data suggest that up to 80% of persons are affected [17]. In regards to autonomic dysreflexia (AD), the most threatening autonomic aberrancy characterized by excessive sympathetic outflow in response to peripheral stimuli, the prevalence is well documented in the chronic phase in persons with chronic SCI affecting the T6 or above [18]. The extensive concordant prevalence of AD and NP, both of which are secondary sequela of autonomic dysfunction in the chronic phase of SCI suggests that there may be a unifying underlying etiology driving both NP and autonomic dysfunction.

Central sensitization following SCI may be sequela of maladaptive central nervous reorganization, and has been implicated as an important pathophysiological mechanism underlying both chronic NP and autonomic dysregulation [19,20]. It is thought that chronic and sustained inflammatory states confer a reorganization of ascending neural networks, which in turn produces resultant sensitization to noxious input and sympathetic reflexes. From a compensatory perspective, it stands to reason that survival benefit and physiological preservation would be best attained by sensitizing afferent noxious stimuli and decreasing the threshold for reactive sympathetic responses.

As post-SCI central sensitization may result in maladaptive reorganization of both the somatosensory and autonomic networks, it is of particular interest if and how the PNM and CAN systems correlate post-injury. Also of interest is if and whether the PNM and CAN circuitry can be differentially modulated given that they share a degree of anatomical proximity and functional association. To truly explore these phenomena, we utilized an innovative investigational approach to explore the role of the proposed PNM-CAN network in neurologically pathological and healthy cohorts, as represented by SCI+NP and AB cohorts, respectively. We hypothesized that the PNM and CAN mechanisms could be differentially modulated in pathological and healthy states.

METHODS

Subject Population

The necessary approval and recommendations of our institutional review board was obtained before initiating our study. Inclusion criteria for all study subjects were: (1) persons above between 18 and 75 years of age, (2) cognitively capable of providing consent, (3) without any self-reported clinically significant or unstable medical or neuropsychiatric disorders, (4) without a history of cranial pathology, such as but not limited to traumatic brain injury, stroke, multiple sclerosis, brain tumors, or prior intracranial interventions, (5) without a history of arrhythmias or associated heart diseases, namely those requiring implanted pacemakers, inotropic, or chronotropic medications such as beta-blockers, that may artificially alter the heart rate and/or rhythm. Additional inclusion criteria for SCI+NP subjects were persons (1) with chronic SCI, defined as >6 months, (2) with chronic NP, defined as >3 months, (3) without reported autonomic dysreflexia episodes in the preceding 24 hours, and (4) without changes in their baseline pain levels or pain medication regiment for at least 2 weeks prior to the experiment. Recruitment for our SCI+NP cohort took place at an outpatient SCI rehabilitation clinic, which is located in a large rehabilitation facility in an urban setting, under the guidance of a board-certified SCI rehabilitation physician. The presence of NP was determined using the LANNS pain scale – a patient questionnaire assessing for NP symptoms that has been evidenced in the literature [21].

Pertinent clinical variables in SCI+NP persons were gathered from the electronic health record and the most recent International Standards for Neurological Classification of SCI exam documented by a board certified SCI rehabilitation physician. Gathered variables included the time since injury, neurologic injury level, severity of injury, and the dosage and frequency of active medications for NP. Of note, the SCI+NP cohort from this study is the same as that from a previously published study exploring neuromodulation in SCI+NP vs. SCI-NP persons [5].

Experimental Overview

Subjects in the SCI+NP and AB cohorts received both null and active phases of a centrally directed pain intervention conducted randomly in a crossover fashion, following a 2 week washout period. Simple randomization using a two sided coin flip was used to randomize the order of experiments for each patient. Additionally, CAN activity and pain profiles were measured in all subjects at baseline and at 30 minutes post-intervention during each experiment. A centrally directed neuromodulation intervention was delivered via BreEStim, which has been evidenced in the literature to both operate at the level of the PNM and provide effective analgesia for persons with SCI+NP [22,23]. To quantify CAN activity, heart rate variability (HRV) was used to measure autonomic changes. Pain profiles involved quantifying a subject’s pain using the visual analog scale (VAS) scoring system or measuring their electric pain threshold levels in SCI+NP and AB persons, respectively.

BreEStim intervention

To conduct the BreEStim intervention, subjects were fitted with an airflow mask apparatus to measure respiratory flow and placed with surface electrodes along the median nerve at the level of the wrist. In the null “Breathing-only” experiments, 120 voluntary and paced breaths using sharp, deep inhalations were conducted. In the active “BreEStim” experiments, the paced breathing was accompanied by pulsatile transcutaneous electrical stimulation, which was dosed to a VAS pain level of 7/10. These settings and protocols were similar to our recent series of BreEStim experiments, which include studies evidencing BreEStim as an effective analgesic intervention of NP associated with SCI [5]. Further technical details of BreEStim are available online in a methodology video article: http://www.jove.com/video/50077/[22].

HRV data collection

HRV data collection involved a 5 minute electrocardiogram (ECG) recording gathered at resting baseline and at 30 minutes post-intervention. After the subject was instructed to remain seated and relaxed, a heart rhythm scanner (Biocom 5000 Wireless ECG Recorder, Biocom Technologies, Poulsbo, Washington) was used to record the ECG via a standard three electrode lead-II placement approach. A conventional heart rhythm software (Kubios HRV, University of Eastern Finland; Joensuu, Finland) was then utilized to analyze the millisecond variances in the R-R intervals across the ECG recording and produce groupings of time- and frequency-domain HRV parameters [24].

The time-domain parameters include SDNN: standard deviation in N-N intervals, RMSSD: root mean squared of successive differences, NN50: pairs of successive R-R beat lengths varying by greater than 50 milliseconds, and pNN50: proportion of NN50 for total number of pNN50. SDNN reflects overall HRV, while RMSSD, NN50, and pNN50 reflect parasympathetic tone. The frequency-domain parameters include LF: low frequency band, HF: high frequency band, Total Power, and LF/HF: low to high frequency ratio. Standard frequency stratification designating LF as 0.04 – 0.15 Hertz and HF as 0.15 – 0.40 Hertz, as determined by the fast Fourier transformation algorithm, was utilized. LF reflects overall HRV- a combination of sympathetic and parasympathetic influences, HF reflects parasympathetic tone, and Total Power reflects overall HRV, while LF/HF reflects degree of autonomic balance. These HRV parameters represent standard and established metrics reflective of autonomic modulations [13-16,24]. The capacity for HRV variables to reflect autonomic changes and differentiate various pain conditions has been widely demonstrated in the literature [25-30].

Pain profile measurements

In the SCI+NP cohort, pain measurements at each time point were gathered using VAS pain scores with a range of 0 to 10. In AB persons, who do not have pain at baseline, electrical detection level (EDL) and electrical pain threshold levels (EPT) were gathered at both time points. To measure the EDL and EPT, subjects were placed with two electrodes in parallel along the median nerve, through which transcutaneous voltage (in milliamps) was slowly and incrementally administered. EDL was defined as that voltage level at which the subject was first able to detect an electric sensation and EPT was defined as that voltage level at which the subject reported a VAS score of 7. In pain experimentation of AB persons, the use of EDL and EPT variables has been extensively substantiated for measuring differences in sensory and painful stimuli. Due to diminished peripheral sensation present in many persons with cervical SCI, as in our cohort, EDL and EPT levels were unable to be gathered in our SCI+NP cohort.

Statistical Analysis

The major dependent variables were VAS scores and heart rhythm and HRV parameters. We chose to analyze differences between SCI+NP and AB groups (1) in demographics, (2) in response across time (baseline and post-intervention) and, (3) across treatment. For use in statistical analysis, all HRV parameters, expect SDNN, are non-normally distributed. For two group comparisons of similar groups, paired t-tests and Wilcoxon signed-rank tests were used for parametric and non-parametric variables, respectively. Two-way ANOVA tests and the Kruskal Wallis tests with Scheirer-Ray-Hare extension were conducted to measure the interaction of time (baseline and post-intervention) and treatment (null and active) factors in producing changes in parametric and non-parametric variables, respectively. Statistical analysis was performed using the STATA Version 12.1 (StataCorp LP, College Station, TX). An alpha level of 0.05 was used as threshold for significance for all statistical tests. Data were reported as mean ± standard error of the mean in the figures. Only the significant main effects were presented, unless otherwise noted.

RESULTS

Study Subjects

The AB cohort was comprised of 13 subjects, who were an average of 34 years old and 69% male. The SCI+NP cohort was comprised of 10 subjects who were an average of 48 years old and 100% male. Relative to our AB cohort, our SCI+NP cohort was older (p<0.01) but no statistical differences in sex prevalence were appreciated. Additional demographic parameters specific to our SCI+NP population include an average 13.3 year injury chronicity, with 70% cervical injuries, and 20% complete injuries, as determined by the American Spinal Injury Association Impairment Scale A designation. Pain medications utilized included GABA analogs (80%), opioids (20%), and atypical antidepressants (10%).

Neuromodulation of SCI+NP persons

The VAS pain score significantly decreased across time following active intervention (pre-test:4.30±0.51 to post-test:1.63±0.44, p=<0.01) but remained unchanged following null intervention (pre-test:4.15±0.65 to post-test:3.90±0.68, p=0.79) (Figure 1). Likewise, there was no difference in average heart rate in beats per minute across time in null (pre-test:78.94±4.62 to post-test:77.05±5.14, p=0.57) or active (pre-test:78.53±4.97 to post-test:75.83±5.67, p=0.46) interventions. Similarly, there were no differences in R-R length appreciated across time in null (pre-test:783.82±42.93 to post-test:808.93±47.95, p=0.57) or active (pre-test:790.24±44.76 to post-test:826.31±51.11, p=0.46) interventions.

Figure 1:

Visual analog scale (VAS) pain scores along with NN50 and pNN50 time domain HRV parameters across time (Pre-Test to Post-Test) and across treatment (Null and Active) for persons with spinal cord injury and chronic neuropathic pain (SCI+NP, N=10)

Similar patterns of results were also found in HRV parameters. SCI+NP subjects exhibited an increased parasympathetic tone, via increased NN50 in count, for active intervention (pre-test:7.50±3.14 to post-test:30.22±8.33, p=0.03) but remained unchanged following null intervention (pre-test:11.20±4.46 to post-test:9.56±4.29, p=0.93). This increase in parasympathetic tone was also noted for pNN50 in percentage which increased for active intervention (pre-test:2.29±0.96 to post-test:9.88±2.70, p=0.02) but remained unchanged following null intervention (pre-test:2.86±1.20 to post-test:2.99±1.44, p=0.93). Data for changes of other HRV parameters in response to null and active BreEStim are also presented in Table 1 and Figure 1

TABLE 1.

Time and frequency domain HRV parameters across time (Pre-test to Post-test) and treatment (Null and Active) for persons with spinal cord injury and chronic neuropathic pain (SCI+NP, N=10).

	NULL			ACTIVE			Two Way ANOVA
	Pre-Test	Post-Test	p-value	Pre-Test	Post-Test	p-value	p-value, F-value
TIME DOMAIN PARAMETERS
SDNN (milliseconds)	32.73	42.76	0.870	28.77	39.47	0.165	0.967, F=0.00
RMSSD (milliseconds)	18.78	39.66	0.897	20.44	30.31	0.153	0.655, F=0.20
NN50 (count)	11.20	9.56	0.931	7.50	30.22	0.030	0.033, F=4.92*
pNN50 (percentage)	2.86	2.99	0.931	2.29	9.88	0.023	0.040, F=4.57*
FREQUENCY DOMAIN PARAMETERS
LF (power ms2)	162.20	279.67	0.327	115.80	181.67	0.369	0.649, F=0.21
HF (power ms2)	129.20	107.89	0.935	212.00	230.11	0.935	0.747, F=0.11
Total Power (ms2)	729.30	620.56	0.959	695.30	1275.11	0.253	0.133, F=2.37
LF/HF	2.00	4.75	0.121	2.25	2.67	0.369	0.307, F=1.08

Neuromodulation of AB persons

AB persons demonstrated a marked increase in noxious tolerance, as determined by an increased EPT in milliamps, for active intervention (pre-test:35.38±4.23 to post-test:41.37±4.32, p=0.03) but not for null intervention (pre-test:36.11±4.33 to post-test:37.52±4.51, p=0.54). This increase in EPT was accompanied by an unchanged EDL in milliamps for active (pre-test:4.88±0.31 to post-test:4.86±0.35, p=0.79) and also null interventions (pre-test:4.88±0.34 to post-test:5.13±0.38, p=0.26), which serves to suggest preservation of sensation sensitivity. This modulation of EPT was not associated with any changes in baseline heart rate for null (pre-test:75.09±2.23 to post-test:73.84±1.51, p=0.76) or active (pre-test:75.42±2.25 to post-test:73.25±1.69, p=0.62) interventions. Likewise, there were no appreciable differences in R-R interval lengths across null (pre-test:811.20±24.34 to post-test:821.47±17.13, p=0.88) or active (pre-test:807.16±23.22 to post-test:828.62±20.09, p=0.62) interventions. Additionally, EPT modulation did not affect autonomic profiles across time and treatment, as determined across all time and frequency domain HRV parameters, despite reflecting analgesic effects for experimentally induced pain (Table 2 and Figure 2).

TABLE 2.

Time and frequency domain HRV parameters across time (Pre-test to Post-test) and treatment (Null and Active) for able bodied persons (AB, N=13).

	NULL			ACTIVE			Two Way ANOVA
	Pre-Test	Post-Test	p-value	Pre-Test	Post-Test	p-value	p-value, F-value
TIME DOMAIN PARAMETERS
SDNN (milliseconds)	52.8	57.46	0.818	48.23	54.35	0.555	0.888, F=0.02
RMSSD (milliseconds)	39.08	43.62	0.841	40.28	41.41	0.575	0.808, F=0.06
NN50 (count)	66.67	64.00	0.772	61.54	59.69	0.780	1.000, F=0.00
pNN50 (percentage)	20.28	20.03	0.772	17.35	17.45	0.719	1.000, F=0.00
FREQUENCY DOMAIN PARAMETERS
LF (power ms2)	1310.33	1146.92	0.638	943.69	1208.92	0.384	0.462, F=0.55
HF (power ms2)	702.33	892.83	0.989	854.92	775.54	0.974	0.599, F=0.28
Total Power (ms2)	2988	3484.75	0.478	2540.77	3117.15	0.610	1.000, F=0.00
LF/HF	3.15	2.92	0.872	2.68	2.56	0.795	0.921, F=0.01

Figure 2:

Electrical detection threshold (EDT) and electrical pain threshold (EPT) along with NN50 and pNN50 time domain HRV parameters across time (Pre-Test to Post-Test) and across treatment (Null and Active) for able bodied persons (AB, N=13)

DISCUSSION

In this current study, we aimed to further explore differential modulation of PNM and CAN mechanisms by providing null and active forms of BreEStim to SCI+NP and AB persons in a crossover fashion. We found that in SCI+NP persons, only active BreEStim produced both analgesia and concomitantly autonomic restoration by increasing parasympathetic tone. However, the same intervention in AB persons increased their pain threshold but without any associated autonomic changes. These findings confirmed analgesic effects of BreEStim in both healthy and SCI+NP subjects. The novel findings of modulation of autonomic function in SCI+NP subjects and differential modulation of autonomic function between AB subjects and SCI+NP subjects provide new insights into understanding the PNM-CAN machinery and the pathophysiology of NP post-SCI.

The pathogenesis of NP after SCI has been increasingly associated with autonomic dysregulation in recent years [2,4,5,10,14,31]. As aforementioned, our own group published findings first demonstrating that persons with SCI+NP demonstrate altered baseline autonomic profiles and that centrally directed pain intervention produced analgesia and conferred an increase in parasympathetic tone [5,14]. These collective findings suggest that maladaptive neuroplasticity, by way of the PNM-CAN interconnectedness, may be responsible to mediating NP after SCI.

Central Sensitization correlates to Chronic Pain and Autonomic Dysregulation

Functional neuroimaging studies have shown that, in both humans and animal models, sensory cortex remodeling occurs following SCI [32-34]. This deafferentation of large cortical networks is possibly a response to unregulated stimulation by the remaining intact spinothalamic pathways below the neurological level of injury. This neural reorganization may be an appropriate structural response intended to accommodate for post-injury sensory processing. However, it may also propagate the dysregulation of sensory input and lead to inappropriate efferent responses including NP.

Central sensitization likely exists beyond the somatosensory system [19,32,34,35]. Following traumatic injury, there exists an appropriate sensitization to spinal sympathetic reflexes in response to diminished descending neural transmission [35,36,19,36]. This reorganization of sympathetic circuitry is thought to drive the pathophysiology of autonomic dysreflexia (AD) – sympathetic overactivity in response to noxious stimuli ranging from bladder distention to constipation to peripheral pain [19,36]. AD pathophysiology, thought to be secondary to diminished inhibition of efferent sympathetic responses, also represents the complex interconnectedness between chronic pain and autonomic dysfunction [19,36,37].

Chronic pain conditions and mood disorders, such as anxiety, have been extensively correlated to one another [38]. The high degree of correlation of these two processes even seems to suggest that they may propagate one another. Interestingly, several studies have found that anxiety is strongly associated with triggering AD [31,39,40]. It was also shown that the prevalence of AD in SCI persons is much higher in those with anxiety disorders [31,41]. Consequently, it has been suggested that AD may be resultant, albeit indirectly, to chronic pain status, by way of anxiety [31,41]. Interestingly, the anterior insula, which is strongly incorporated into the PNM machinery, has been implicated across numerous studies to modulate anxiety responses [42,43]. These findings collectively serve to suggest that chronic neuropathic pain, similar to these listed consequences after SCI, may share a similar underlying pathogenesis of autonomic dysregulation, given their concordance in the chronic state and their anatomical correlates.

Evidence for Autonomic Modulation of Post-SCI NP

Our findings in this study serve to confirm the interconnectedness of the PNM and CAN networks as PNM modulations produced autonomic restorations in association with analgesia in persons with SCI and NP. However, the nature of the PNM-CAN interface has yet to be precisely identified, especially in healthy and pathological states. A possible explanation for the varying effects on BreEStim on healthy, AB persons, and neurologically pathological, SCI+NP persons may involve the degree of PNM-CAN association.

The PNM-CAN interface does not truly depict to scale the degree of overlap between the two networks. Rather, it is possible that the overlap and/or functional interconnectedness varies in healthy and pathological states. Deafferentation is a compensatory phenomenon that follows SCI in an attempt to appropriate cortical and subcortical structures for new neurological demands and afferent inputs [32-34]. Consequently, it is possible that PNM-CAN overlap and/or interconnectedness increases in response to SCI and results in dysregulated pain and autonomic processing, which manifest as chronic post-SCI NP. This increase in central sensitization across time serves to explain how autonomic dysregulation manifests chronically via disease states like neuropathic pain and AD propensity. Likewise, a possibly lower degree of PNM-CAN association that may exist in AB persons may explain how they are capable of processing pain inputs independent of autonomic associations. Or simply, their intact neural circuitry provides them the capacity to withstand PNM directed supraspinal interventions with appropriate compensation by their healthy CAN mechanisms. However, these theories require additional exploration by way of functional neuroimaging.

Limitations

Our study was largely limited by small sample sizes for both cohorts. Consequently, several of our analyses may have been underpowered. Additionally, our SCI+NP cohort was older than our AB cohort; thus, age related cardiac differences might have possibly conferred HRV differences. Of note, we also utilized a 5-minute ECG recording for HRV analysis, which although evidenced as capable, is less sensitive compared to a 24 hour ECG recording. Moreover, many of the patients in the SCI+NP cohort were utilizing GABA analog medications with some also using opiate and atypical antidepressant medications. It is possible that medications may have secondary effects that may have been masking any potential for autonomic changes in response to central neuromodulation stimuli. Future studies may consider larger and better matched sample sizes and longer ECG recordings to improve yield of subtle autonomic variations. Also, advanced methods of autonomic measurements such as microneurography could be utilized to fully characterize autonomic dysfunction.

CONCLUSION

The analgesic effects produced by active BreEStim intervention in SCI+NP persons were associated with acute autonomic restoration, by way of increased parasympathetic tone. These findings serve to suggest an interconnectedness of the PNM-CAN machinery in persons with SCI+NP, possibly due to maladaptive plasticity as centrally directed PNM interventions were able to produce modulations in CAN activity.. When exploring this PNM-CAN machinery in AB persons, we found that the same PNM modulations failed to produce CAN modulations. These findings suggest that intact CAN mechanisms, which are presumably evident in AB persons, may be able to compensate for acute PNM aberrations or that chronic SCI+NP persons may exhibit altered PNM-CAN machinery altogether. It can also be considered that the extent of PNM-CAN overlap is greater in pathological states, as present in chronic SCI+NP persons, compared to healthy states, as present in AB persons. Nonetheless, these collective findings serve to suggest that the PNM and CAN networks share a level of interconnectedness and may be differentially modulated.. Findings from this study and our recent studies provide evidence of maladaptive changes in the CAN network in chronic SCI+NP patients. They also suggest that central neuromodulation interventions could provide analgesic effects and help restore autonomic dysfunction.

ABBREVIATIONS

NP

neuropathic pain

SCI

spinal cord injury

ACC

anterior cingulate cortex

PNM

pain neuromatrix

CAN

central autonomic network

AB

able bodied

BreEStim

breathing controlled electrical stimulation

AD

autonomic dysreflexia

VAS

visual analog scale

ECG

electrocardiogram

HRV

heart rate variability

SDNN

standard deviation in R-R interval length

RMSSD

root mean squared of successive differences

NN50

pairs of successive R-R beat lengths that differ by more than 50 milliseconds

pNN50

the proportion of NN50 for total number of beats

LF

low frequency

HF

high frequency

LF/HF

ratio of low to high frequency

EDL

electric detection level

EPT

electrical pain threshold

SD

standard deviation

SEM

standard error of the mean