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. 2023 Apr 1;22(2):123–130. doi: 10.1016/j.jcm.2022.09.002

The Neurophysiological Lesion: A Scoping Review

David N Taylor 1,⁎
PMCID: PMC10280090  PMID: 37346242

Abstract

Objective

The purpose of this study was to examine the extent of the literature on the neurophysiological lesion as referenced in functional neurology.

Methods

A literature search was performed within the period from 2010 to March 2021. Search terms included central sensitization, central sensitivity syndrome, nociplastic pain, cold hyperalgesia, heat hyperalgesia, mechanical hyperalgesia, dynamic mechanical allodynia, temporal summation, spatial summation, and descending inhibition. A qualitative synthesis summarized the research findings, including clinical conditions and effect of spinal manipulation.

Results

There were 30 studies, which included 7 high-level studies (meta-analysis or systematic reviews), 22 randomized controlled studies, and 1 scoping review. The findings suggest the existence of the changes in the central integrated state of a population of neurons with various disorders, experimentally induced stimulation, and treatment. The current literature suggests plasticity of the central integrative state (CIS) with the onset of pathologies and the changes in the CIS with different conservative nonpharmacologic treatments.

Conclusions

This review suggests changes in the resting state of the CIS of a population of neurons that exist in the physiologic lesion may change in response to various therapies, including manipulative therapy. The findings from this review provide support of the hypothesis that nonpharmacologic conservative care may affect the neurophysiological lesion. However, studies were heterogeneous and evidence was lacking in the translation of targeting the therapies to distinct neuronal areas for clinical outcomes to treat specific disease states.

Key Indexing Terms: Chiropractic; Neuronal Plasticity; Manipulation, Spinal; Central Nervous System Sensitization; Models, Neurological

Introduction

The term neurophysiological lesion was used by Sir Charles Sherrington in 1906.1 He described the lesion as being determined by the central integrative state (CIS) of the individual neuron.1 This model was later described by Kandel et al2 and then by Beck,3 who extrapolated the concept from a single neuron to a distinct population of neurons, as the sum of excitatory and inhibitory action potential input to the population. A pathology would be described as a nonablative physiological lesion.3,4

The chiropractic definition of a functional neurological lesion could be differentiated from the medical definition as defined by the World Health Organization (WHO) in 2017. WHO defines it as a “dissociative disorder,” such as (nonepileptic) seizures or functional movement disorders that are genuinely experienced by the patient and can be positively identified as being internally inconsistent without a demonstrated pathology. For example, these disorders may show consistent tremor entrainment test, but is incongruent with a recognized disease process.5 These disorders have been classified as neuropsychological because they lack a structural abnormality. Both definitions describe an apparent functional pathophysiology; however, it is hypothesized that the chiropractic functional lesion may show signs during a neurologic exam.

It has been proposed that clinical assessment of the action potential responses, which may demonstrate abnormal function, may indicate pathophysiology or a functional neurological lesion.3,6 The resting physiologic state that determines the generation of action potentials is a normal function of the nervous system.2,4 The temporal and spatial summation of action potential input to a population of neurons in a specific locus of the central nervous system would indicate the probability of the output of action potentials.2 The CIS of the individual neuron is a neurophysiological phenomenon that determines the action of the individual neuron.2 The extension of this phenomenon from the individual neuron to a specific population of neurons and the ability to change that level of excitation within the population is a theory of functional neurology.

Up to this point in time, there has not been a thorough overview of this topic as it relates to the clinical application in chiropractic practice. Therefore, the purpose of this review was to provide a description of the scope of the overall literature on the neurophysiological lesion, specifically the evidence of the ability to change the CIS through nonpharmacologic treatment modalities, such as spinal manipulative therapy (SMT).

Methods

A literature-search of the Cumulative Index to Nursing and Allied Health Literature, PubMed, and Index to Chiropractic Literature electronic databases was performed. An initial search was conducted by an experienced librarian and then repeated by the author using the following terms: “central sensitization” or “central sensitivity syndrome” or “nociplastic pain” or “cold hyperalgesia” or “heat hyperalgesia” or “mechanical hyperalgesia” or “dynamic mechanical allodynia” or “temporal summation” or “spatial summation” or “descending inhibition.” A subsequent Medical Subject Headings (MeSH) search from the aforementioned keyword search results yielded the MeSH of “postsynaptic potential summation” and “central nervous system sensitization.” These MeSH terms were added to the search parameters, but no additional relevant papers were found. A hand search was also conducted of the references from reviewed articles. An initial search was performed on March 22, 2021, for the years 2010 to 2021. The reporting was modeled after the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (Supplemental Fig. 1),7, 8, 9 and the search strategy used STARLITE(Supplemental Table 1).10

The evidence was rated by the author into evidence levels as adapted from Fisher and Wood,11 The Oxford Centre,12 and Evidence-Based Medicine Consult (Supplemental Table 2).13 The inclusion criteria were scoping reviews, randomized and nonrandomized controlled studies, clinical cohorts, and systematic reviews. Animal or laboratory bench research was included only if it provided laboratory demonstration of the physiological response in the nervous system. Exclusion criteria were lack of relevant information or a failure of evidence of the state of the CIS of neurons. The search and selection were performed solely by the author. All data results were entered into an Excel spreadsheet.

Results

There were 7 high-level studies (meta-analysis or systematic reviews), 22 randomized controlled studies, and 1 relevant scoping review included in this review. See the supplemental file for studies included in this review.

Description of Findings

Various types of input from the external and internal environment to the nervous system may influence the ability of the neurons to create an action potential.1 The action potential relies upon factors including ionic cellular changes, depolarization/excitation, hyperpolarization/inhibition, temporal and spatial summation, and conductance changes of individual neurons and populations of neurons.1 Studies have looked at central neurologic changes and their ability to generate an excitatory or inhibitory action potential, which may influence the peripheral responses. The following studies suggest that the neurophysiological lesion may result from changes in the CIS of central neurons and authenticated plastic neuronal changes.

Changes in the resting state, or the potential excitability of neurons, have been researched using treatment, imaging, and functional activity technology. Repetitive transcranial magnetic stimulation evaluated a clinical effect by modulating central brain neuronal plasticity via functional reorganization of cortical and subcortical neurons, which affected the descending inhibitory pathways and resultant peripheral effects.14

Magnetic resonance imaging (MRI) demonstrated progressive loss of gray matter in the neocortex and the dorsolateral prefrontal cortex with chronic pain, especially with severe neuropathic pain.15 Differences in gray matter volume in specific brain regions were noted with chronic pain patients.16 Functional MRI identified increased pain sensitivity and enhanced central pain processing in patients with chronic low back pain (LBP).17 Imaging in fibromyalgia patients showed a decrease in brain grey matter and a change in the periaqueductal grey inhibitory area.18 Concurrent altered brain morphology was seen in brain regions not associated with pain processing resulting in frequent distal neurologic comorbidities.16 Excitatory changes existed in the CIS of supraspinal regions in fibromyalgia patients.19 There was functional MRI evidence of structural and functional brain abnormalities in chronic low back pain and evidence of global gray matter changes, both increased and decreased. In one study, the primary somatosensory cortex showed a decrease in gray matter, while there was an increase in grey matter that was somatotopically associated with the low back. An increase in the amygdala grey matter was present, which indicated the increasing emotional response to chronic pain.20

Diffuse tensor imaging showed progressive neurophysiological lesions in white matter,21 changes in the deep cortical neurons (ie, basal ganglia and thalamus), and decrease in activity in the periaqueductal gray matter of patients with chronic low back pain.17 One study showed disruption of functional connectivity during rest in patients with chronic LBP.20

A study that evaluated evidence from positron emission tomography scans with electroencephalogram revealed that electrical stimulation to the occipital nerve resulted in cortical changes in both excitatory and inhibitory populations of the neurons.22 Clinical correlation of the cortical changes were noted by concurrent numeric rating scale and Fibromyalgia Impact Questionnaire scores.

In another study, quantitative sensory testing and somatosensory evoked potential showed altered sensory function in the patient with LBP when compared with controls. 23 Some alterations included abnormal conditioned pain modulation and higher pain thresholds. This was present even in remote body parts, reflecting the central origin of changes in CIS.23 Other studies used somatosensory evoked potential to demonstrate changes in the CIS of the sensory cortex.24, 25, 26

Using transcranial magnetic stimulation and monitoring with motor evoked potentials for pre- and post-SMT confirmed facilitation with an increased amplitude of motor evoked potentials in cortical motor neuronal cells and the alpha motor neuronal pool.27 Chronic pain in patients with whiplash associated disorders were shown to have dysfunctional conditioned pain modulation due to disruption of endogenous pain inhibition. This correlated with the clinical outcome measures of pain and disability.28 This change in the CIS was similar to central sensitization increased temporal summation and decreased inhibition.

Common Clinical Conditions

The following conditions are examples of neurophysiological lesions, sometimes referred to as a functional lesion. Central sensitization is defined as enhancement of excitation of the pain-related neurons and pathways or a decrease in excitability of the inhibitory neurons or pathways.29 This is a physiological plastic change in the response to a previous nociceptor excitation from injury or inflammation. It has been proposed that ongoing excitability of the pain-related tracts may be a result of augmented action potentials in the absence of nociception.30 A pathological sensory response from normal sensory input without anatomic change may evoke hypersensitivity, hyperalgesia or allodynia, which might be plastic in nature with a physiological change in the neurons, receptors, and synapses of primary, secondary, or tertiary neurons. These neurons could then be recruited with subthreshold stimuli. One study described the expansion of the receptive fields peripherally and in the dorsal horn, which further aggravated the condition and resulted in nonnociceptive receptors provoking pain.31 The change in the CIS may be in the central neurons of the dorsal horn, brainstem, or superficial and deep cortical nuclei. These changes are proposed to be nonanatomic and may be ionic or biochemical, affecting cellular permeability and subsequent action potentials. Neuropathic pain may be present, creating abnormal action potentials of Type A and C fibers with ectopic-generated spontaneous action potentials presenting as a plastic change in CIS of the neurons.30 The CIS of both central and peripheral neurons by various pain neuromodulation methods with electrical stimulation could be the result of changes from spinal cord stimulation, dorsal root ganglion stimulation, transcutaneous electrical stimulation, invasive brain stimulation via repetitive transcranial magnetic stimulation, or transcranial direct current stimulation with excitatory and inhibitory effect.32

Mild traumatic brain injuries may result in dysfunctional neurons, in which the CIS of cortical neurons may be disrupted because of cellular changes, excitotoxicity, oxidative stress, and mitochondrial dysfunction. In brain injury, there may be disruption of normal metabolism, decreased glucose metabolism, and sympathetic relaxation,33 thus a change in the resting physiologic state of a population of neurons.

Cases of carpal tunnel syndrome that showed vascular ischemia to the median nerve have been shown to result in reorganization at the primary motor and sensory cortex. This reorganization is a change in the CIS of central neurons, while the changes in the CIS of distal neuron synapsing in the dorsal horn can result in demyelination and apoptosis.34 Inflammatory radiculitis may occur without impingement of the nerve root and could present with radicular symptoms due to a hyperexcitatory state of the neuron. The patient may have mechanical and thermal sensitivities without motor loss.35

Treatment Modalities and the CIS of the Neurophysiological Lesion

Neuroplastic changes to the CIS after 2 bouts of eccentric exercise have been shown to result in a neuroprotective effect.36 High-frequency spinal cord stimulation (10 Khz) used on failed back surgery syndrome and monitored with functional MRI found a significant increase in connectivity of supraspinal cortical areas. This also correlated with numerous clinical outcome measures.37 Conflicting studies revealed that repetitive transcranial magnetic stimulation can allow recovery from muscle soreness, pain, or mechanical hyperalgesia, without changes in cortical CIS.38

Transcranial direct current stimulation was able to provide evidence of change in the CIS of a population of cortical neurons, which correlated with analgesia and subsequent neuroplastic changes in the pain pathways.39 This conservative nonpharmacologic treatment was found to correlate with clinical changes in pain and ranges of motion in myofascial pain syndrome patients.40

Repetitive muscle tasks performed for 20 minutes caused cortical and subcortical SEP amplitude attenuation in uninvolved muscles lasting for 30-minute post-task. This showed changes in the CIS in the somatosensory system from this activity. The inhibition of uninvolved muscles indicated the change in CIS of a population of central neurons.41

Even exercise seemed to influence inhibition of nociceptor transmission, likely via proprioceptive input.42 Overall, the search revealed multiple instances of evidence that supported the ability to change the CIS of neurologic physiological lesions through some conservative treatment modalities.

Spinal Manipulation and CIS Change in the Physiological Lesion

In one study, high-velocity low-amplitude SMT improved motor function through a decrease in inhibition of the cortical motor strip in patients with neck pain.43 Qualitative sensory testing (QST) documented the change in the CIS of the population of neurons of a subgroup of patients with chronic low back pain with central sensitization. This suggested that treatment may influence central neurologic dysfunction (ie, the descending inhibitory pathways) instead of addressing peripheral pathologies.44 This correlates with preliminary and post-SMT changes in cortical maps of the blind spot after SMT is applied to C2.45

A clinical study on SMT showed a lack of change in H-reflex with SMT but an increase in the V-wave. This ruled out segmental input, and the electromyogram (EMG) indicated a measured increase in maximum voluntary contraction reflecting a change in supraspinal cortical neurons.46 The V-wave response was previously considered as an index of cortical neural drive.47 This finding suggests that SMT may have caused some neuroplastic changes in corticospinal excitability.46 Cervical spinal manipulation was also shown to alter sensorimotor integration.24 There were changes in cortical intrinsic inhibitory interactions in patients with chronic neck pain. After experimentally induced evoked potentials in the motor cortex, premotor cortex, and deeper cortical nuclei, 12 weeks of SMT improved the suppression of the potentials.48 It has been suggested that spinal dysfunction may have altered afferent input resulting in ongoing central plastic changes.26 This altered sensorimotor integration of the abnormal afferent input can result in abnormal feedback, which is normalized by high-velocity low-amplitude.49 SMT was noted to cause changes that were seen with the amplitude differences in somatosensory evoked potentials, revealing a normalization.24,26 There was a change with low back pain patients with a loss of central neurologic “feed forward” trunk muscle stabilization for limb movements such as throwing a ball,50,51 but sacroiliac manipulation seemed to result in plastic central changes.50 There have been observations of SMT-induced neuronal changes such as enlarged cortical blind-spot map,45 corticospinal excitability,46 alpha motor neuronal pool inhibition,52,53 cortical motor neurons excitation,54 segmental changes with H-reflex and V-waves,55 improved motor unit recruitment, decreased intracortical inhibition,56 temporal changes in functional connectivity of areas of the brain,57 and effects on numerous other supraspinal structures including the cerebellar vermis, temporal gyrus, basal ganglia, and anterior cingulate cortex.58

Clinical studies with cervical spine manipulation showed a plastic change in the neuronal population of the somatosensory cortex, motor cortex, and basal ganglia that were previously showing changes from chronic pain. Cervical SMT resulted in changes in the cortical integration of the sensory input.24

The type of SMT applied has been found to be significant to evoke the central neuronal response. The most common type that used provoked responses was high-velocity low-amplitude SMT. In some instances, there was demonstration of detrimental changes in the cortical CIS affecting the corticospinal tract after distal injuries and repair. This was shown with quantifiable hemispheric differences after anterior cruciate surgical repair.59 Laboratory studies found noxious inhibitory responses from SMT resulting in a prolong decrease in nociceptive spontaneous activity.60,61 Transcranial magnetic stimulation of patients with minor neck pain who had not yet sought care showed that their type c neurons were effected, dependent upon force and preload duration of the SMT.62 Related preliminary clinical outcomes showed a significant decrease in reading time of patients with attention-deficit/hyperactivity disorder post-SMT, demonstrating cortical excitation.63

Discussion

This literature review offers a broad summary of the neurophysiological lesion and points to possibilities of areas for future research. Some may question whether there are sufficient changes and whether it is sufficiently long term to have clinical implications for the neurophysiological lesion.58,64,65 At present, there are insufficient studies to answer this question. In his systematic review, Meyer, rated most of the studies to be low to median quality and noted the frequent methodological weakness in many of the studies previously done, including the lack of certainty of blinding of participants or investigators.64 However, many studies have demonstrated pathologically induced changes in the CIS of the central neurons. This included chronic pain effecting central brain connections and descending inhibitory pathways,66 pain sensitization,67 induced neuroplastic long-term potentiation,68 changes in CIS with shoulder pain,69 psychobehavioral changes as a result of central nociplastic changes without tissue damage,70 catastrophizing,71 anesthesia-induced short-term cortical and subcortical changes,72 and long-term neuroplastic changes.73

Sir Charles Scott Sherrington1,74 originally proposed an hypothesis about the integrative action of the nervous system as unidirectional synapses that are dependent upon sensory input and that all actions result in the same final common pathway through the alpha motor neuron.75 These early hypotheses provided evidence on the probability of an action potential. In more recent years, high technology stimulation therapies and diagnostic tests have suggested that the neurophysiological lesion exists in different conditions and in various supraspinal areas. For example, chronic pain plastic changes were noted in central grey matter and connectivity was disrupted between different brain regions.21

Some studies have shown a correlation of therapies with CIS changes via clinical outcome measures, including numerical rating scales, visual analogue scales, and disability outcome measures. Spinal manipulation has shown changes in pain pressure thresholds76 (which may differ with sensitization)76,77 and an increase in cortical inhibition.78 Spinal cord stimulation is known to affect the central cortical neuron for pain management.79 In fact, there are current proposals that chronic pain treatment should target the central neurons80 vs the injured tissue; some have even proposed neurosurgical bypass when there is decreased function of an area.81 However, it is not surprising that there is a lack of clarity in targeting a specific neuronal population with this treatment. The evidence ascertained that manipulative therapy may be able to initiate a change in the CIS of a physiological lesion, but there is a gap in the literature regarding the ability to target a specific population of neurons with any conservative nonpharmacologic therapy. There is also a gap in dosage variables and the presence of long-term duration of the changes made in the CIS. The variable forces and preload duration for SMT and subsequent variable change in CIS reinforced the importance of the type of SMT and the type of technique. More work needs to be done to bridge the transition from the laboratory to defined implementation in clinical practice.

This review suggests the changes in the central integrated state of a population of neurons with various disorders, experimentally induced stimulation, and treatment. The current literature suggests plasticity of the CIS with the onset of pathologies and the changes in the CIS with different conservative nonpharmacologic treatments. The most researched conservative therapy found in this review was SMT.17 This is notable in treatment of chronic pain, but more clinical studies need to be performed to better correlate the changes in the CIS with the manipulation.

Future Studies

Further research should measure the changes in the CIS of a population of neurons, such as the changes in CIS that have been seen in various situations at a sufficient frequency, greater than chance frequency. Studies are needed that measure the difference between a normal physiological response and clinical applications of conservative treatments to those changes in the physiological lesion. The transition from theory to established practice requires more clinical documentation of the applications. Observational studies need to address the specific targeting of different central neuronal populations for the specific condition. Clinical studies need to investigate the logistics of how to target these neuronal populations with nonpharmacologic therapies such as SMT, electrical therapies, exercise therapies, light therapies, mechanical therapies, and other afferent stimulation. Other studies need to be conducted to assess the long-term plastic effects on the supraspinal population of neurons. Future research that combines the evaluation of the CIS with clinical outcome measures for specific conditions should be considered.

Limitations

This review was performed by a solo author; thus, it was interpreted through only 1 lens and the studies selected may have experienced selection bias. It is possible that some studies were not identified by the search parameters. The review did not include a critical appraisal of the studies that were included. Such appraisal of the literature would be appropriate to determine the rigor of the study and whether there were sources of bias. The studies reviewed were of diverse quality and had diverse levels of evidence and thus showed great heterogeneity.

Conclusion

This review examined and synthesized the current literature on the neurophysiological lesion. This review suggests that changes in the resting state of the CIS of a population of neurons, which exist in the physiologic lesion, may change in response to various therapies, including manipulative therapy. The findings from this review support the hypothesis that nonpharmacologic conservative care may affect the neurophysiological lesion. However, the extent of the evidence was found to be lacking in the translation of targeting the therapies to distinct neuronal areas for long-term clinical outcomes to treat specific disease states.

Acknowledgments

I thank Dr Cheryl Hawk for her input and advice and Claire Noll for her aid in the literature search.

Funding Sources and Conflicts of Interest

No funding sources or conflicts of interest were reported for this study.

Contributorship Information

Concept development (provided idea for the research): D.N.T.

Design (planned the methods to generate the results): D.N.T.

Supervision (provided oversight, responsible for organization and implementation, writing of the manuscript): D.N.T.

Data collection/processing (responsible for experiments, patient management, organization, or reporting data): D.N.T.

Analysis/interpretation (responsible for statistical analysis, evaluation, and presentation of the results): D.N.T.

Literature search (performed the literature search): D.N.T.

Writing (responsible for writing a substantive part of the manuscript): D.N.T.

Critical review (revised manuscript for intellectual content, this does not relate to spelling and grammar checking): D.N.T.

Practical Applications.

  • •

    The central integrative state of a population of neurons may change in response to various therapies, including manipulative therapy.

  • •

    It is hypothesized that nonpharmacologic conservative care may affect the neurophysiological lesion.

  • •

    However, studies were heterogeneous and evidence was lacking for treatment of specific diseases.

Alt-text: Unlabelled box

Footnotes

Supplementary material associated with this article can be found in the online version at doi:10.1016/j.jcm.2022.09.002.

Appendix. Supplementary materials

mmc1.pdf (613.9KB, pdf)

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