Multifidus dysfunction and restorative neurostimulation: a scoping review

Abstract Objective Chronic low back pain (CLBP) is multifactorial in nature, with recent research highlighting the role of multifidus dysfunction in a subset of nonspecific CLBP. This review aimed to provide a foundational reference that elucidates the pathophysiological cascade of multifidus dysfunction, how it contrasts with other CLBP etiologies and the role of restorative neurostimulation. Methods A scoping review of the literature. Results In total, 194 articles were included, and findings were presented to highlight emerging principles related to multifidus dysfunction and restorative neurostimulation. Multifidus dysfunction is diagnosed by a history of mechanical, axial, nociceptive CLBP and exam demonstrating functional lumbar instability, which differs from other structural etiologies. Diagnostic images may be used to grade multifidus atrophy and assess other structural pathologies. While various treatments exist for CLBP, restorative neurostimulation distinguishes itself from traditional neurostimulation in a way that treats a different etiology, targets a different anatomical site, and has a distinctive mechanism of action. Conclusions Multifidus dysfunction has been proposed to result from loss of neuromuscular control, which may manifest clinically as muscle inhibition resulting in altered movement patterns. Over time, this cycle may result in potential atrophy, degeneration and CLBP. Restorative neurostimulation, a novel implantable neurostimulator system, stimulates the efferent lumbar medial branch nerve to elicit repetitive multifidus contractions. This intervention aims to interrupt the cycle of dysfunction and normalize multifidus activity incrementally, potentially restoring neuromuscular control. Restorative neurostimulation has been shown to reduce pain and disability in CLBP, improve quality of life and reduce health care expenditures.


Introduction
Low back pain (LBP) is the leading cause of years lived with disability globally with a prevalence of an estimated 568 million people worldwide.LBP is the most common musculoskeletal condition with a lifetime prevalence as high as 65%-80%, affecting 52 million people in the United States.5][6] While most acute LBP events are self-limited, an average of 35% can lead to subacute and/or chronic pain. 710][11][12] Management of LBP can be challenging, and unfortunately, treatment outcomes are variable.4][11][12] As such, we must understand distinctive features of pain neurobiology, such as neuropathic, nociceptive, and nociplastic pain to try to customize individual treatment and optimize outcomes.
The International Association for the Study of Pain (IASP) defines neuropathic pain as central or peripheral pain "caused by a lesion or disease of the somatosensory nervous system" and occurs as a result of abnormal neural activity.It is commonly characterized as burning, electric, and/or shooting pain, which follows a neuroanatomically plausible distribution with or without motor or sensory deficits.[14][15][16] The IASP has defined nociplastic pain as "pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain."In turn, this may elicit central sensitization or widespread hypersensitivity, which may not be directly associated to tissue damage.][15][16][17] CLBP is a nebulous symptom and often the underlying etiology is nonspecific, complex, and multifactorial with combined pain generators that may lead to challenging treatments and limited success.[10] Functional spinal instability resulting from multifidus muscle dysfunction secondary to arthrogenic muscle inhibition (AMI) and loss of neuromuscular control has emerged as an important functional etiology.[29][30][31][32][33][34][35][36] Yet there is a gap in the literature comprehensively discussing the scientific background on this potential link between loss of neuromuscular control, AMI, multifidus dysfunction, functional instability, and CLBP.Furthermore, there is a current need in the literature discussing how restorative neurostimulation differs from other neuromodulation therapies, their anatomical targets and mechanisms of action (MOA).
Therefore, in this scoping review we aim to define the functional pathophysiological cascade of how multifidus dysfunction may play a role in LBP recurrence and chronicity, contrasting to other CLBP etiologies.Then we discuss treatment options by exploring the distinctions between traditional and restorative neurostimulation therapy.

Methods
This scoping reviewed followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis for scoping reviews (PRISMA-ScR) (Figure 1) and the step-by-step process for scoping review based on Peters et al.8] The scoping review protocol was registered on the Open Science Framework.A scoping review is a type of literature review that aims to map the evidence available with key concepts on a particular topic.8] Our first step was to formulate clear objectives and specific research questions to guide the scoping review process to address the gaps in the literature, followed by a framework design to identify the population, context, and concept approach of eligibility criteria.Then, we conducted a comprehensive search strategy to identify relevant studies in electronic databases, and later proceeded to screen the identifiable studies based on predetermined inclusion and exclusion criteria in a nonbiased fashion.Data were extracted from the eligible studies, synthesized, and presented in a clear and concise manner using a descriptive format into specific themes within this review.

Search strategy and terms
A comprehensive search of electronic databases (MEDLINE, PubMed, Embase, and Cochrane Library) was conducted for studies published in English language since inception to February 2023 with the first search performed in June 2022 and a repeat search in April 2023.We searched for metaanalysis, systematic reviews, narrative, and clinical reviews, randomized and non-randomized trials, prospective and retrospective studies, and case series.Case reports, letters, editorials, conference abstracts and commentaries were excluded.The following combination of subject headings and keyword search terms were utilized: "multifidus," "restorative neurostimulation." "lumbar medial branch nerve," "neuromodulation," peripheral nerve stimulation," "sensorimotor control," "neuromuscular control," and "chronic low back pain."The search strategy was developed by the authors in consultation with a research librarian.

Eligibility criteria
A population, concept, and context approach was followed.No patient data were involved in this scoping review.The population of interest was subjects with CLBP associated with multifidus dysfunction.The core concept of importance was to define how neuromuscular control loss and AMI may lead to multifidus dysfunction and functional lumbar instability, which in turn is theoretically presumed to contribute to CLBP, while contrasting with other LBP etiologies.Furthermore, we summarized how restorative neurostimulation may address this etiology, briefly comparing with traditional neuromodulation therapies.The context of interest was to provide a state-of-the-art comprehensive review of the literature to serve as a foundational reference on multifidus dysfunction and restorative neurostimulation to help enhance comprehension of this complex functional pathophysiological process and optimize practitioners' understanding on why and when to utilize this intervention.Thereby, improved awareness of this theme may lead to optimal selection and therapy application, thus avoiding overutilization, reimbursement reduction, and sustaining long-term durable outcomes with exemplary safety.

Article selection and inclusion
We conducted a comprehensive search of electronic databases stated above.After the initial search, duplicates were removed, and titles and abstracts of articles were screened.All eligible studies identified in the search were independently appraised by two reviewers in a standardized, unblinded fashion, using the same strategy to ensure proper cross-checking of the results with the PRISMA-ScR method/ checklist to reduce selection bias and standardize inclusion and exclusion criteria.Any disagreement between the two screeners was flagged for resolution, mediated by a third and fourth author independently.Eligible full-text articles of potential interest were fully reviewed following the population, concept, and context eligibility criteria.Studies that investigated the relationship between the multifidus muscle and CLBP, studies that assessed multifidus function and structure in subjects with CLBP, studies that evaluated multifidus assessment in CLBP, studies that examined interventions aimed at improving multifidus function in individuals with and without CLBP were included.Other studies were included to supplement the core concept and answer the research questions.

Data extraction
Data extraction focused on capturing key information to answer the research questions and the study objectives.The data from the selected studies were comprehensively reviewed and organized into subsections within the results section of this scoping review.As designated by scoping review methodology, the data extracted were utilized to map the literature on this subject area, identifying key principles to answer  37 current gaps in the literature.

Results
We found 671 citations through our initial online database search.After removal of duplicates, 420 records remained and were screened as per our selection criteria.Of these, 218 were excluded because of lack of relevance to the topic of interest to answer the proposed research questions and study objectives.An additional 8 studies were excluded due to language other than English and unable to retrieve full text.The remaining 194 full-text articles were included, comprising of meta-analysis, systematic reviews, clinical and narrative reviews, randomized clinical trials, prospective, retrospective, observational clinical studies, population based and basic science studies.Key findings were presented along the results section in a thematic organization with figures and in a descriptive format contrasting the literature to highlight critical and emerging principles related to multifidus dysfunction and restorative neurostimulation.

Definition of concepts
0][41] The deep multifidus is a group of medially oriented, short fibers that provide compression to maintain intersegmental spinal control by attaching superiorly to the laminae of L1-L5 and inferiorly to the mamillary process of vertebrae one level below. 39,42The intermediate multifidus fascicle is longer, spanning across three to four spinal segments and carries mixed stabilizing and mobilizing functions.6][47][48] Importantly, a unique feature of MM architecture is that it possesses a greater crosssectional area than the other spinal muscles.As such, the bilateral multifidi exert large compressive force over a small excursion, yielding stabilization of spinal segments rather than gross spinal movement.[41][42][43][44] Spinal stability Spinal instability is a clinical term that may encompass structural and functional components. 26 Sensorimotor and neuromuscular control The sensorimotor system incorporates all the afferent, efferent, central integration and processing components involved in maintaining functional joint stability during movement. 57ynamic contributions arise from feedforward and feedback neuromuscular control over skeletal muscles adjacent to joints.6][57] Neuromuscular control is a term related to sensorimotor control that refers to the neuromusculoskeletal kinetic chain collectively functioning in harmony to enable dynamic stability and movement patterns under control of the central nervous system. 55,57Specifically, from a joint stability perspective, neuromuscular control has been defined as the unconscious activation of dynamic restraints occurring in preparation for and in response to joint motion and joint loading for the purpose of maintaining and restoring functional joint stability. 57tered neuromuscular control Altered neuromuscular control has been proposed one potential contributing factor in the pathophysiological process of CLBP.This theory suggests that disruptions in the somatosensory feedback between muscles and joints afferents can lead to loss of neuromuscular control.[18][19][22][23][24][57][58][59] However, it is important to note that altered neuromuscular control is just one of many proposed contributors of nonspecific CLBP and often other structural pathologies may be present.4,9,[18][19]22,[58][59] Arthrogenic muscle inhibition Arthrogenic muscle inhibition (AMI) is defined as altered muscle activity due to neural inhibition secondary to a change in articular sensory discharge.[60][61] AMI can be a protective mechanism via spinal reflex pathway proposed to take effect in altered sensorimotor control from spinal joint mechanoreceptors acting on the motor pool Ib inhibitory interneurons resulting in adjacent muscle inhibition.[62][63][64] AMI is a wellrecognized phenomenon clinically confirmed under ultrasonography and electromyography (EMG).AMI has been shown to result in decreased muscle activity, fatigue, and spasm in adjacent muscles.[62][63][65][66][67][68] Multifidus dysfunction Multifidus dysfunction is a clinical diagnosis that manifests as impaired multifidus activity/muscle inhibition, resulting in loss of spinal stiffness in the neutral zone, which may enhance an environment of relatively functional instability.19,[24][25] MM dysfunction has been proposed to result from spinally induced arthrogenic inhibition in the setting of altered neuromuscular control. 19,24,66 When theM is inhibited, it yields reduced voluntary recruitment and limited motor units on EMG with replacement of tonic activation with phasic bursts of activity and muscle fibers transformation (slow type I to fast type II), which may ultimately result in muscle atrophy, aberrant co-contraction, and fatigue-spasm cycles.[69][70][71][72][73][74][75][76] MM dysfunction may continue even after the symptom of back pain have resolved, and the persistent loss of neuromuscular control may contribute to the high recurrence rate of LBP.19,25,41,[77][78][79][80] Multifidus dysfunction and loss of neuromuscular control Over time, these changes observed in the structure and function of the MM are believed to result in altered movement behaviors leading to cortical reorganization and neuromuscular control loss.19,[58][59][81][82][83][84] At first, changing movement patterns may be protective to prevent worsening pain and reaggravation of injury.These may be beneficial in the shortterm but might carry negative consequences over time, potentially resulting in fear-avoidance behavior that may contribute to LBP chronicity.hese reflect neuroplastic changes in neuromuscular control loss, which have been associated to chronic pain states supporting the hypothesis that it might play a key role in LBP chronicity.[81][82][83][84][85][86][87][88][91][92][93][94]
provide temporary symptom relief to facilitate participation in an active physical therapy program. 146When conservative therapies are insufficient to offer durable symptom relief, restorative neurostimulation of the LMBN may be considered.

Discussion
This is the first study to comprehensively review the scientific literature and to assemble the current state of knowledge to delineate how the principles of altered neuromuscular control and AMI may lead to multifidus dysfunction, functional lumbar instability and CLBP.As such, this study aimed to provide a foundational reference to illustrate the complex functional disease-process proposedly addressed with restorative neurostimulation (Figure 4).
CLBP is often multifactorial and categorized as nociceptive, neuropathic or nociplastic. 4,13However, such narrowed categorization to one type does not represent the true prevalence in clinical practice.In fact, the majority of CLBP is a mixed pain syndrome with an overlap of pain types and a constellation of symptoms that might occur in a continuum cycle.7 For decades there has been a focus in exploring, understanding and identifying this clinical picture.98,158 By way of illustration, consider a clinical scenario with a nonspecific event that triggers a noxious insult to spinal joint mechanoreceptors and/or paraspinal muscle spindles that can result in joint or muscle overload.In turn, this can lead to an influx of aberrant mechanoreceptive input towards the spinal cord interneurons.Automatically within the spinal pathway, a spinally-induced AMI reflex may occur to subconsciously protect the spinal joint by limiting segmental spinal motion.This limitation in movement further decreases mechanoreceptive discharge to surrounding muscles leading to reflexive tonic contraction and potentially a painful cycle of muscle spasm and muscle overload.Usually, such acute events are self-limiting, and the deleterious effects may be lessened with maintenance of physical activity, despite acute pain.However, if altered sensorimotor feedback persist beyond normal healing time, it may lead to loss of neuromuscular control.Over time if uncorrected, this may lead to persistent multifidus inhibition/dysfunction and the inability to maintain spinal stiffness in the neutral zone, resulting in an augmented environment for functional lumbar instability.Consequently, this may express symptomatologically as nonspecific LBP.

1346
][83][84][85][86] Multifidus dysfunction may present primarily with a nociceptive-mechanical pain pattern, with pain usually movement or position related, and aggravated by trivial activities and small movement tasks, such as returning to an erect posture from bending, leaning over a sink, unloading the dishwasher, reaching out for an item, lower extremity dressing, and so forth.4 As previously mentioned, most CLBP have a mixed pain picture. 157ultifidus dysfunction may present similarly with a mixed pain syndrome depending on the time-to-effect of neuroplastic changes secondary to the loss of neuromuscular control, however ideally pain is primarily of mechanonociceptive without neuropathic or with limited nociplastic features.As a proposed functional etiology, it is imperative to assess CLBP beyond structural changes on diagnostic images and shift thinking to a functional perspective.][133][134]170 However, the finding of muscle atrophy on MRI alone does not establish multifidus dysfunction diagnosis (since this is a functional etiology) and by itself should never be relied upon as a sole criterion for the indication for restorative neurostimulation. 30 Commonly, these patients are not surgical candidates and a have limited response to conservative management without longitudinal improvement in pain and function.[31][171][172] This is an innovative neurostimulation system that has emerged as a disease-modifying therapy to restore neuromuscular control through a rehabilitative MOA rooted in the previous discussion of the pathophysiology of multifidus dysfunction and loss of neuromuscular control.[30][31][32][33][34]171 Thereby, the therapeutic goal is restorative in nature to first normalize neuromuscular function, and subsequently reduce disability and pain.[31][32][33][34][35][36] Because of the MOA and clinical benefits that accumulate over time, it is thought that a short trial period is unlikely to yield optimized patient selection and predict future responders. 29mportantly, restorative neurostimulation distinguishes itself from traditional neuromodulation in a way that treats a different etiology, targets a different anatomical site, and has a distinctive MOA.0][181][182][183][184][185] Furthermore, lumbar radiofrequency ablation is traditionally utilized for symptomatic management of facet arthropathy, a well-identifiable structural etiology of axial LBP, and offers immediate analgesia by creating a temporary ablative destruction of the LMBN. 171,186However, this has been hypothesized to have deleterious effects on structures supplied by the LMBN, such as the multifidus muscle. CLBP associated with multifidus dysfunction and loss of neuromuscular control must be treated with a multidisciplinary approach, given that 1 therapy alone is less beneficial in scenarios of sustained neuroplastic changes, cortical remodeling and kinesiophobia.These factors have been linked to limited and/or negative treatment outcomes.3][191][192][193][194] Restorative neurostimulation may be beneficial earlier in the treatment algorithm (as an escalation to augment physical therapy program) to restore neuromuscular control, before the presence of cortical neuroplastic changes seen in chronic pain states, which have been associated to poor outcomes.In turn, this could lead to decreased need for additional interventions, reduced opioid consumption, lower psychological burden, and perhaps reduce LBP recurrence and chronicity, thereby limiting healthcare expenditures.

Limitations
Although we followed the journal's guidelines on scoping reviews, including the PRISMA-ScR and Peter et al. 38 framework, this scoping review has limitations that should be considered when interpreting the discussion of the results section.Assessment of the quality of the studies was not performed due to the heterogenicity of included studies.Data synthesis and key summary of findings was presented in a descriptive format, rather than a quantitative format since this scoping review highlights a conceptual framework and does not compare the same intervention and outcomes within the same or populations.It was outside the scope of this study to extensively review procedural techniques, safety profile, and comparative clinical results since other studies have covered these topics in detail.Selection bias in the extraction process cannot be excluded; however, this was mitigated by using a systematic transparent approach following the above-cited guidelines.

Conclusion
Multifidus dysfunction has been proposed to result from spinally induced AMI in the setting of loss of neuromuscular control.Multifidus dysfunction is a clinical diagnosis that manifests as muscle inhibition resulting in impaired muscle activity leading to loss of spinal stiffness, which may enhance an environment for relatively functional instability.Multifidus dysfunction is diagnosed by a clinical history of primarily mechanical, positional related, predominantly axial nociceptive CLBP without neuropathic and with limited or without nociplastic components.Physical exam demonstrates functional lumbar instability, which conceptually differs from other structural etiologies of CLBP (discovertebral pain, facetogenic pain, stenotic pain).Ultrasonography and EMG may be helpful to assess multifidus activity with functional movements, while MRI is used to grade multifidus atrophy and assess for other structural pathologies that may be present concurrently with multifidus dysfunction and could be amenable to surgery and not to restorative neurostimulation.
Restorative neurostimulation is the only FDA-approved PNS device to treat CLBP associated with multifidus dysfunction and loss of neuromuscular control resulting in functional lumbar instability.Importantly, restorative neurostimulation distinguishes itself from traditional neurostimulation in a way that treats a different etiology, targets a different anatomical site, and has a distinctive MOA.Restorative neurostimulation is a novel disease-modifying therapy that through a rehabilitative MOA with efferent neurostimulation of the dorsal rami of the LMNB elicits repetitive multifidus contraction that with a gradual and longitudinal accrual time to effect has been proposed to override underlying AMI and restore mechanonociceptive feedback, which may normalize neuromuscular control and functional spinal stability.This therapy has been shown to reduce pain and disability in CLBP, improve quality of life and reduce health care expenditures.

Figure 1 .
Figure 1.PRISMA-ScR methodology and results flowchart with identification, screening, eligibility and inclusion and exclusion process.Adapted from: Tricco et al 2018.37

Figure 3 .
Figure 3. Magnetic resonance images demonstrating progressive multifidus fat infiltration from normal to moderate to severe.

Figure 4 .
Figure 4. Diagram illustrating the complex interplay between altered sensorimotor control, arthrogenic muscle inhibition, multifidus dysfunction, functional spinal instability, and neuroplastic changes that may result in loss of neuromuscular control contributing to low back pain recurrency and chronicity.