Quantitative Sensory Testing in Spinal Cord Stimulation: A Narrative Review

Objectives: Quantitative sensory testing (QST) has been used for decades to study sensory abnormalities in multiple conditions in which the somatosensory system is compromised, including pain. It is commonly used in pharmacologic studies on chronic pain but less so in conjunction with neuromodulation. This review aims to assess the utility of QST in spinal cord stimulation (SCS) protocols. Materials and Methods: For this narrative review, we searched PubMed for records of studies in which sensory testing has been performed as part of a clinical study on SCS from 1975 onward until October 2023. We focused on studies in which QST has been used to explore the effect of SCS on neuropathic, neuropathic-like, or mixed pain. Results: Our search identi ﬁ ed 22 useful studies, all small and exploratory, using heterogeneous methods. Four studies used the full battery of validated German Research Network on Neuropathic Pain QST. There is emerging evidence that assessment dynamic mechanical allodynia (eight studies), and mechanical/thermal temporal summation of pain (eight studies) may have a role in quantifying the response to various SCS waveforms. There also were sporadic reports of improvement of sensory de ﬁ cits in a proportion of patients with neuropathic pain that warrant further study. Conclusions: We recommend the adoption of QST into future clinical research protocols, using either the full QST protocol or a less time-demanding short-form QST.


INTRODUCTION
Spinal cord stimulation (SCS) is an established treatment option for many chronic pain conditions that do not respond adequately to pharmacotherapy or other conventional treatment.
The indications for which SCS is most used are persistent spinal pain syndrome (PSPS), complex regional pain syndrome (CRPS), and peripheral neuropathy.Although its mechanism of action is still not fully understood, SCS has been posited to have mechanisms involving peripheral, spinal, and supraspinal pathways.
Systematic reviews of placebo/sham-controlled studies of different SCS systems, conventional low-frequency, high-frequency (up to 5 kHz), and burst SCS confirm the efficacy and safety in the previously mentioned indications over the short to medium term. 1,2owever, overall pain relief remains relatively moderate, with a mean difference of −1.15 (95% CI −1.75, −0.55) on a scale of 1 to 10 and −8.73 (95% CI −15.67, −1.78) on a scale of 0 to 100. 1,24][5][6] Observational studies of low-frequency SCS extend beyond ten years. 7,8[15] Early loss of effect also is common.Observational studies suggest that of those who receive a permanent implant, 12% to 37% will report <50% pain relief in the first three months of therapy, ie, remaining under the threshold of improvement they reported during the screening trial. 16,17Controlled trials of novel SCS paradigms report similar early failure in 16% to 18% of patients (successfully trialed) achieving <50% relief after permanent implantation (the failure percentages for the comparator tonic SCS therapies are worse, up to 55%). 18,19A failure within months of implantation-with no evidence of device malfunction or stimulation-related discomfort-suggests an inadequate trial, a placebo response, early habituation, or simply a late exposure of patients' expectations at the time of the trial that were not met after permanent implantation.Overall, the existing data suggest that we still cannot very well predict who will be a responder and a nonresponder.
In today's clinical practice, a patient with chronic pain being considered for SCS will first undergo multidisciplinary assessment for their suitability and if eligible, will undergo a screening trial usually lasting one to two weeks or longer as recommended by most guidelines (although an on-table trial followed by permanent implantation also has been advocated 20 ).
2][23][24] The question arises whether current screening methods looking at generic clinical factors such as etiology, category of pain (nociceptive, neuropathic, nociplastic, mixed), effect of previous therapies, and psychosocial factors such as lack of engagement, unresolved psychiatric problems, maladaptive coping, unrealistic expectations, and drug and alcohol abuse as relative contraindications are sufficiently capable of distinguishing appropriate candidates.Current clinical guidelines do not address the role of clinical signs and symptoms as representations of putative pain-related mechanisms and consequently do not include them in their screening trial recommendations.Clinical trial protocols follow the same selection process.
The need to understand the mechanisms whereby neuromodulation brings about its effects has been underlined repeatedly.Not only will such information allow development of new neuromodulation techniques or more precise targeting of treatment, but it also will help encourage patients and clinicians to address the whole pain experience more comprehensively.In part, this can be achieved by symptom reporting.6][27][28] Multiple sensory descriptors within these tools can be grouped using cluster or factor analyses into subclasses, each characterizing a specific dimension of the pain experience, allowing pain-quality-based phenotyping.Limited applications of these PROMs in SCS trials have not shown any particular phenotypic responses to stimulation, with the descriptor subclass changes closely tracking changes in total pain intensity. 29,30n alternative method for capturing mechanistically relevant information may be provided by quantitative sensory testing (QST). 31,32QST is validated and standardized to measure sensory thresholds for pain, touch, vibration, and temperature sensations.It tests for sensory loss (hypoesthesia, hypoalgesia) and sensory gain (hyperesthesia, hyperalgesia, allodynia).It also provides the opportunity for testing temporal summation and conditioned pain modulation in the afferent and more central parts of the somatosensory system.Sensory abnormalities coupled with pain reflect underlying pathophysiological mechanisms within the somatosensory system.The latter, particularly the dorsal horn of the spinal cord, is a key target for SCS.Evidence of somatosensory dysfunction is present in all neuropathic pain but also is found or inferred in some nonneuropathic pain conditions.QST offers a relatively simple method for detecting and quantifying sensory abnormalities in a patient with pain and in so doing may potentially guide SCS therapy.
The aim of this narrative review is to summarize the current use of QST in studies of SCS effectiveness.We then discuss the potential utility of QST in three aspects, those being 1) to assist in patient selection, 2) to act as an outcome measure to assess SCS effects on particular sensory abnormalities, and 3) to inform clinical and preclinical researchers on mechanisms of action of SCS.We posit that the QST should be used routinely in clinical studies of SCS effects to inform the field on the eventual utility of such testing.

MATERIALS AND METHODS
We searched PubMed for records of studies in which sensory testing has been performed as part of a clinical study on SCS from 1975 onward until August 2023.Only studies that were prospective, included patients with neuropathic, neuropathic-like, or mixed pain, and used generally accepted sensory testing methods were considered."Neuropathic-like" in this context refers to conditions in which there are signs and symptoms of sensory abnormalities without stated evidence of presence of a somatosensory lesion (eg, CRPS type 1) or symptoms compatible with neuropathic pain but without clear sensory abnormalities (probable radicular pain)."Mixed pain" refers to conditions with combined neuropathic and nociceptive pain, typically PSPS, in which the presence of a neuropathic component is reported by the authors or can be reasonably inferred from the text.No restrictions were set for sample size or study design, so both observational and controlled studies were included.The search string used to identify relevant articles was ("spinal cord stimulation" OR "dorsal column stimulation") AND perception OR "sensory profile" OR "quantitative sensory testing" NOT pharmacol* NOT animal.In addition, we manually searched biographies of key original articles and systematic reviews.

RESULTS
The search yielded 3540 articles, of which, after assessment of relevance and removal of reviews and duplications, we identified 20 in which the target populations were people with PSPS, CRPS, or neuropathic pain or neuropathic-like pain of other origin.The manual search identified two further studies (Table 1).  Theras a noticeable difference in investigated QST parameters between older and newer studies.Articles published before 2015 concentrated on sensory detection thresholds, whereas newer articles were more comprehensive and included "dynamic" QST, such as mechanical and thermal allodynia and hyperalgesia, temporal summation, and conditioned pain modulation (CPM) as tests.In four studies, the investigators used the full battery of 13 tests according to the protocol developed by the German Research Network on Neuropathic Pain (DFNS). 31,55Most studies (18/22) evaluated the effect of low-frequency SCS (LF SCS) alone.In four studies, either 10-kHz high frequency SCS (HF SCS) or burst SCS (Table 1) were compared with LF SCS.
Since the first QST study in SCS in 1975 by Lindblom and Meyerson, who reported an increase in vibratory thresholds and disappearance of evoked pain during SCS, 29 QST has occasionally been studied to see whether any sensory features are predictive of short-or long-term analgesia in SCS.Mironer and Somerville (2000)  reported that patients who showed 60% pain relief during the screening trial and an increase in two different electrically induced pain tolerance thresholds after they had undergone three to five days of SCS continued to experience >50% pain relief at six months   after permanent SCS, whereas those whose tolerance thresholds at the end of the trial phase remained unaltered did not. 35n 24 patients with low back pain, leg pain, or CRPS, Campbell et al (2015) found a differential response to thermal temporal summation between responders and nonresponders to trial SCS. 46he authors went on to generate a composite score for central sensitization (mechanical and thermal temporal summation of pain and mechanical hyperalgesia combined) together with low (less efficient) CPM and reduction of pain at three months of SCS.In total, eight studies evaluated the impact of SCS on temporal (mechanical and/or thermal) summation of pain.Four showed a significant reduction.Of note, in all of those, SCS reduced overall pain by >50%.In contrast, in studies not showing any change in temporal summation of pain, SCS reduced overall pain between 2% and 43%.The association was bidirectional: In studies that showed a strong (>50%) analgesic response during SCS, levels of allodynia and temporal summation of pain were consistently attenuated.In one study, the pain levels remained very low throughout, making it difficult to judge the value of the lack of modulation of temporal summation. 50In the eight studies in which dynamic mechanical allodynia was assessed, improvement was reported in four and strong trend toward improvement in three, whereas one was inconclusive (with very low levels of pain).CPM was performed in six studies; in three, there was positive response (reduction in the intensity of the test stimulus induced pain during or after SCS), whereas three showed no change (Table 1).][49] Threshold determinations were methodologically diverse and yielded highly variable results.One or more pain detection/pain tolerance threshold changes within the pain areas were measured in 20 studies; 13 studies reported threshold elevations during or immediately after SCS and seven no change.From the data, it is not always clear whether the changes were toward normal values or more pathological (with the original already being abnormal owing to the neuropathy).Nonpainful detection thresholds were reported in 19 studies; ten showed threshold increase, three decrease, whereas six failed to show a single abnormality.Vibratory threshold was measured in ten studies, showing an increase in three and no change in seven.No study was found in which QST-based sensory phenotyping (ie, combining QST results across multiple modalities) in relation to SCS was evaluated, although in one small study, questionnaire-based profiling was used. 49The authors reported a postimplantation reduction in six of the seven painDETECT-derived descriptors at 18 months but do not discuss the correlation with change in total pain. 49The painDETECT is a self-administered questionnaire of pain qualities, designed to identify whether the patient's pain is neuropathic or has a neuropathic component. 56omparison studies involving patients with neuropathic pain have shown that sensory profiles constructed exclusively on the basis of painDETECT do not adequately mirror those derived from physical QST measurements, which excludes its use as a QST replacement. 57,58 phenomenon that has attracted less attention is an improvement in abnormal sensory thresholds within the affected area toward normal in patients with neuropathy receiving SCS.In two small case series (Cata et al 2004, 38 Rasche et al 2006 40 ), an improvement in sensory detection thresholds was found at one and six hours after their LF SCS system had been switched on, listed in Table 1. 38,40Morgalla and Domay 53 showed a trend toward normalization of altered baseline mechanical detection thresholds during burst SCS and cold pain threshold during LF SCS (Table 1). 53f note, in a large randomized controlled trial on the efficacy of HF SCS on painful diabetic neuropathy, clinical neurologic assessment by trained investigators revealed improvement in neurologic deficits, recorded at baseline, in 72% at three months and 62% at six months after implantation. 14Most of these changes were in the mechanical sensory domain, determined using von Frey filaments and pinprick. 14In a small open-label study on painful neuropathy of diverse etiologies, neurologic improvement was observed clinically in 14 of 25 patients at three months and eight of 15 patients at 12 months.Notably, in seven of 18 patients tested, an improvement in sensitivity to pinprick had been maintained until end of study. 29None of the authors provided a specific hypothesis about the mechanism behind sensory improvement.

DISCUSSION
On the basis of our findings, we conclude that QST in association with SCS research is possible and that there are consistent trends showing a measurable impact of SCS on sensory abnormalities.We do acknowledge that much of the present data come from pilots or other exploratory studies that were underpowered and some methodologically weak, so the results must be interpreted with caution, but nevertheless, they warrant further exploration. 59ost patients included in the studies we reviewed had PSPS (previously termed failed back surgery syndrome), CRPS, or "pure" neuropathic pain.In a few studies, the patient population was varied and would have included some with nociceptive pain.Apart from studies solely focusing on peripheral neuropathic pain, the mechanistic categorization of patients was not straightforward.The common criterion for patient recruitment of "low back and leg pain" likely allowed inclusion of patients with mixed nociceptive and neuropathic pain.In the case of CRPS, the presence or not of nerve injury was hardly ever discussed.A recent consensus panel on appropriateness of SCS for pain acknowledged a similar problem and chose to apply a category of "neuropathic-like pain," defined by lack of sensory abnormalities as opposed to neuropathic pain. 60We adopted the same approach and included studies irrespective of whether the participants had neuropathic pain or neuropathic-like pain because the purpose was to discuss the utility of QST in conjunction with SCS.

Using QST as a Screening Tool
Although the heterogeneous results of the identified studies, together with common methodologic weaknesses, do not provide a definite answer, they do suggest potential utility for predictive QST as part of the pretrial assessment of SCS candidates.50,54 Support for the findings comes from another, retrospective study in 244 patients with pain with diverse etiologies, which showed that presence of mechanical allodynia or hyperalgesia at the pretrial assessment was associated with a positive trial outcome in addition to a positive outcome at six months (also defined as >50% pain relief). 61In contrast, a small retrospective study argued that absence of brushevoked allodynia in CRPS type 1 was associated with a good outcome after one year of SCS treatment measured on a patient global impression of change questionnaire. 62Using the comprehensive QST protocol, Kriek et al (2023), in contrast, found that CRPS-associated mechanical allodynia and hyperalgesia are ameliorated by SCS. 54our studies showed that thermal or mechanical summation of pain is modulated by SCS that robustly controlled spontaneous pain. 44,46,47,51Both reflect central sensitization maintained by neuroplastic changes in the dorsal horn of the spinal cord that may be positively modulated by SCS.These observations justify additional data from adequately powered clinical trials and may open research avenues toward personalized treatment.
Generally, single sensory detection thresholds appear to have little predictive value in discriminating responders and nonresponders before a trial.However, sensory phenotyping, combining QST results across multiple modalities, has not yet been used in SCS trials. 63There is evidence from pharmacologic research that some phenotypes may be predictive of treatment success. 32his approach merits dedicated research in the context of SCS with the aim of identifying phenotypes that combine elements of static and dynamic QST.

QST as an Outcome Measure
That QST has been successfully used to study the effects of SCS raises the question whether in future clinical research, especially clinical trials of efficacy, it should be added as a measure to assess outcome.There are several points to consider.First, as published studies show, it is feasible to complete QST assessments in a clinical setting albeit requiring more time and resources.This is true even for the most comprehensive protocol described by the DFNS.Second, the methods have been validated and standardized so could be set up and used in practically all units in which SCS is provided as a clinical service.Short QST protocols also have been validated (later); both allow collaborative work between any number of centers. 31,55Third, QST adds a semiobjective dimension to the quantification of pain, especially evoked pain, that oral reports or questionnaires cannot fully capture; it could help to settle the question of any difference in perceived effectiveness between different SCS waveforms.Fourth, QST allows testing new hypotheses regarding the potential of SCS to normalize altered sensation in neuropathic pain. 14,29,53lthough the studies identified in this review are small and lack homogeneity in design, we argue that they constitute sufficient evidence for hypothesis-testing research projects aimed to establish whether QST or some parts of it constitute a meaningful outcome measure.If so, the results would be immediately applicable to clinical practice and be useful for developing new SCS techniques.Advances in clinical neurophysiology and neuroimaging will benefit from data beyond the report of pain.

QST to Identify Mechanisms of Action of SCS
Multiple lines of evidence from preclinical studies point to several networks of the spinal dorsal horn as having a key role in mediating the analgesic effects of SCS.Experimental studies in rodents that use microelectrode recordings or microinfusions of pharmacologic agents to study cellular-level activity cannot be replicated in humans for obvious reasons.However, testing the behavioral response to SCS in neuropathic animals can be emulated in human patients as part of their QST.The primary behavioral assays used in preclinical models are withdrawal thresholds to von Frey filaments (a mimic of mechanical pain threshold testing), paw withdrawal latency when exposed to a heat source (a mimic of heat pain threshold), and paw withdrawal duration after the administration of acetone (a mimic of cold pain threshold). 64Lower thresholds and reduced withdrawal latencies are signs of neuronal disinhibition in the dorsal horn, part of the process of central sensitization.Other end points have been used in experimental pharmacologic studies that have their counterparts in dynamic QST such as brush (a mimic of dynamic mechanical allodynia) and windup (a mimic of temporal summation of pain), both of which are linked to central sensitization, in addition to diffuse noxious inhibitory controls (a mimic of CPM). 65All these tests are applicable to SCS-related preclinical research, irrespective of the anatomical focus of investigation (spinal cord, thalamus, and brainstem nuclei, for example).The downside, in addition to species difference, is that many of these tests will have to be performed under general anesthesia in the test animals.In general, dedicated preclinical laboratories have the capacity to test hypotheses based on human QST studies.The critical issue remains that of availability of sufficient clinical QST data from human subjects at various stages of SCS.Equally, discoveries from preclinical studies can be translated to the clinic more accurately through the QST link, provided the clinical unit has a QST setup.This type of bench-to-bedside-and-back translational research has the advantage of using comparable interventions and outcomes.Hypotheses regarding, eg, the association between certain parameters of dynamic QST (allodynia, hyperalgesia) in patients with neuropathic pain and altered excitatory-inhibitory balance, or disinhibition, in the dorsal horn that characterizes the condition and is ameliorated by SCS, are more easily tested if preclinical and clinical units use the same testing method.
That QST in clinical research is not mainstream is, we believe, mainly due to concerns of time and effort needed, experience from pharmacologic studies of failure of translation of laboratory-tested analgesic drugs, and the complexity of the dorsal horn physiology that prohibits meaningful implementation of any clinical data.We suggest that these concerns can be allayed with recent advances in the methods to investigate in preclinical models the complex circuitry of the dorsal horn, including optical and chemokinetic manipulations of neuronal populations, gene editing, and singlecell profiling, in addition to improved in vivo models. 66An example of a successful translation of a finding established in a preclinical model is H-reflex rate dependent depression (HRDD), a measure of spinal cord disinhibition first studied in diabetic rats. 67RDD is impaired in patients with painful diabetic neuropathy (but normal in nonpainful neuropathy).Using HRDD methods in conjunction with QST and basic pain questionnaires, Marshall et al (2023) were able to identify within their study population a subgroup of patients with highest levels of burning pain, greatest impairment of HRDD, relative heat hyperalgesia, and increased mechanical sensitivity. 68HRDD is an example of a simple neurophysiological test with potential to become an objective scalable marker of spinal disinhibition, suitable for SCS-related mechanistic research.Another exciting development is that of computational modeling of the human spinal cord.These models are based on clinical magnetic resonance imaging-derived three-dimensional volume conductor models that serve to simulate electromagnetic fields generated by SCS to predict fiber activations.Patient-specific models can predict the sensory threshold for perceived SCSinduced paresthesia and the threshold for discomfort that resemble those measured clinically. 69,70These computational models can be rendered more sophisticated by coupling them with clinical measurements, such as QST, to explore the direct effects of SCS on the spinal cord. 69he time and resources needed to invest in QST are commonly presented as an obstacle that prevents its use in clinical practice or clinical research studies.The comprehensive DFNS protocol-based QST takes more than hour to complete and requires a dedicated setup.Numerous research-active neurophysiological laboratories in major hospitals in North America, Europe, Japan, and Australia with trained staff can provide the service.For quality assurance, the German Pain Society and the DFNS provide a certification procedure any laboratory can apply for. 71The DFNS QST setup is best suited for mechanistic research, both for hypothesis-generating and hypothesis-testing projects.Smaller centers providing SCS may prefer to adopt one of the recently validated short form QSTs 72 that enable the collection of some simple QST data simply and quickly.Comprising selected bedside tests, they yield data that show acceptable test-retest reliability and a good correlation with laboratory-based comprehensive DFNS QST protocols. 73Sensory profiling also is possible; eg, three clusters based on the short Kiel Bedside QST protocol will yield comparable results to those obtained from the full DNFS QST, with sensitivities ranging from 0.91 to 0.76 and specificities 0.85 to 0.63 depending on the cluster in question. 73Such short-form QSTs could be an important addition to certain clinical research studies and suitable for public SCSrelated data bases and registries.

Recommendations for Practice
We suggest that in future clinical trials, QST should be included in the study protocols as additional pretrial and on-trial predictors.
Research questions along these lines could ask the following: 1. whether, in a patient with neuropathic (-like) pain, allodynia/ hyperalgesia/hyperpathia (as putative manifestations of central sensitization) predict the outcome from trial or permanent SCS, 2. whether a sensory phenotype/phenotypes (combining all lossof-function and gain-of-function measurements obtained during QST) have similar predictability, 3. whether SCS can alter (positively or negatively) any sensory abnormalities detected pretrial, 4. whether, and to what extent, QST-based data can be exploited by preclinical research.
Some of these research questions can be answered using a short-form QST whereas others require adoption of the full DFNS protocol and a large trial.The latter method is standardized, allowing multicenter collaboration including in-industry or publicsponsored clinical trials or upgrading of existing SCS registries.

CONCLUSIONS
In this narrative review, we highlight opportunities for sensory phenotype-based research regarding SCS.We join those who argue that the utility of QST should be incorporated into any research project on efficacy and/or mechanisms of interventions for neuropathic pain, 14,49,69,74 and, in our opinion, neuropathic-like pain.Within the domain of SCS, the utility of these measures in assessing patient suitability for an SCS trial, prediction of outcome, mechanisms of SCS, loss of short-and long-term effect, and salvage therapy should be subjected to rigorous research.We encourage forward translation and back translation to a much greater extent than is happening today.We suggest such an approach would facilitate steps toward less trial and error and more individualized SCS applications.

COMMENTS
Spinal cord stimulation has been shown to be an effective treatment for many neuropathic pain conditions.The diagnosis of neuropathic pain has a defined algorithm, with the research on altered sensation as a mandatory step.QST is a valid instrument to detect alterations of the somatosensory system, including small-fiber functionality; unfortunately, it needs a dedicated neurophysiological laboratory and is time consuming.Before any surgical decision, neuropathic pain should be confirmed at least with clinical instruments for bedside evaluation documenting sensitive alterations, whereas for research purposes, a complete QST should be recommended.The same instruments should be applied in follow-up to better understand SCS mechanisms of action.
Laura Demartini, MD Pavia, Italy *** Overall, this manuscript provides a good review of using basic science to further clarify the mechanisms of spinal cord stimulation action.It provides good suggestions for patient selection and exploring mechanisms of action.

Table 1 .
Somatosensory Changes Measured Using QST in Patients With Implantable SCS.