Neuropathy is a nerve injury that can lead to sensory A complicated web of neurons located outside the central nervous system (CNS) with intricate interaction of synapses, is known as the Peripheral nervous system (PNS). The PNS mainly consists of ganglions, sensory and motor neurons, and multiple synaptic junctions (1). This system acts as a bridge for transferring bilateral signals from external stimuli to CNS and reverses the signals through cranial (originated from the brain stem and forebrain), ventral, and dorsal (originated from the spinal cord) nerves. The ventral (motor axons) and dorsal (sensory axons) roots divide just next to the intervertebral foramina to innervate different parts of the body in a pattern in which the posterior (dorsal) supplies  muscles and  skin of the back, whereas the anterior (ventral) ramus is limited to limb muscles and the skin of the ventral part of the body. Subsequently, they are divided into smaller branches to innervate each muscle (2). Each division of these fibers may be supported by a myelin sheath or lack it. Besides, endoneurium, a specific connective tissue, surrounds axons. Since axons have close connectivity with each other before innervating targeted muscle fibers, another connective tissue layer is needed to support the structure of bundles known as perineurium. Besides its supportive role, this layer acts similar to the pia-arachnoid layer of the spinal cord, by providing blood-barrier properties for the axons (3). Moreover, protection of the nerve bundles can be supplemented by another layer containing dense connective tissue with larger diametral supports, named epineurium (4). Finally, two additional layers still exist, one with loose connective tissue outside of the epineurium and the other one with loose areolar connective tissue attributes, known as mesoneurium (5). The particular morphology of the PNS is a basis on which imaging techniques were manipulated to specify the PNS from adjacent tissues. Contrast agents are appropriate particles to differentiate PNS from similar tissue structures. Contrast agents are made of Fe particles with multiple limitations such as self-adhesion and low stability within in vivo conditions (6). As a compensation, there is a suggestion to utilize a combination of gold nanoparticles and Fe to boost the stability and signal quality of the tissue. Gold nanoparticles were formerly applied for therapeutic approaches that targeted tumors (7-9). Nevertheless, there are multiple obstacles, including determination of the optimum size of the nanoparticles and eliminating the unpredicted hazardous property of them (10, 11). Unfortunately, up to now, a comprehensive review article comprised of the traditional and novel imaging techniques, which  introduces the applicable imaging sequences in PNS imaging, has not been conducted, . Moreover, the role of USPIO and nanoparticles in enhancing the quality of PNS imaging has been neglected.  This study aimed to present proper imaging methods and devices for visualizing the PNS anatomy accurately, in order to provide an appropriate background for the specialists to make a better diagnosis.
 

Nerve injury
Schwann cells have a vital role in myelin sheath formation along with conducting injured nerve axons to grow in a proper direction. After the nerve injury, there is a disruption in the axonal flow, resulting in axonal and myelin degradation due to the lack of energy support, nominated as Wallerian degeneration (12). Although there are different types of nerve damage from partial axonal damage to an unrecoverable cell body loss (13), all injuries are highlighted by inflammation and tissue clearance commenced by macrophages, as an inseparable post-traumatic compound (14). In this phenomenon, chemokines and cytokines are the mediator of cell signaling, in a way that neutrophils utilize them to attract macrophages derived from blood or resident monocytes, to the target area to infiltrate the nerve (15). Besides the devastating action of macrophages, they can involve in neuron regeneration by implementing two primary duties. One of them is neovasculature formation, and the other is helping Schwann cells to align in the correct direction for axonal growth (16). To perform this procedure, macrophages produce several growth factors like Brain-Derived Neurotrophic Factor (BDNF) (17), which could accelerate Schwann cells' maturation after nerve injury (18). During the retrieval of a peripheral nerve, if the Schwann cells migration fails to be implemented in the accurate line, or an inflammation occurs as a result of external long-term pressure, chronic pains may appear which could reduce the life quality of patients. Sometimes nerve recovery becomes impossible due to the high-intensity of the damage. In these conditions, we could apply two surgical techniques named neurolysis and neurorrhaphy.
In the Neurolysis method, chronic pain is alleviated by cutting the specific part of the nerve, implemented by neurosurgeons (19, 20). This method has positive results in patients who are suffering from carpal or peroneal tunnel syndrome in the case of ligament entrapment or Osteotendinous (21). By applying this method, nerve regeneration initiates, and after a while, the same condition as before treatment intervention, appears. In this case, to prolong the nerve recovery period, chemical substrates such as ethanol and ¹²⁵I radioactive seed are administered to the targeted area, (22). The second method called Neurorrhaphy is mainly used for the facial nerve, in which the disjoint fiber attaches to its neighboring nerve (23). This method was reported to restore muscle ability for contraction, in patients with flaccid or non-flaccid facial palsy (24). Advanced imaging techniques can be an applicable tool to monitor and follow up on the efficiency of therapeutic methods in order to establish a proper treatment strategy. 
Imaging related nanoparticle
Ultrasmall superparamagnetic particles of iron oxide (USPIO) nanoparticles are supplementary agents used in imaging research procedures, due to their low involvement in cellular reactions and high biocompatibility (25, 26). The USPIO nanoparticle or Iron oxide nanoparticles (IONs) consist of two main parts: A sheathing part containing organic compounds to protect the internal part, which commonly has a 4 to 10-nm diameter core of magnetite (Fe₃O₄) or maghemite (γ-Fe₂O₃ or α-Fe₂O₃) (27). As previously mentioned, among the advantages of this compound is its safety, which is justified in Maraloiu et al. research. In their study, P904 USPIOs were injected into mice to evaluate the atherosclerotic plaques. The results illustrated a nontoxicity property of P904 USPIOs in maghemite (Fe3+) form, even by increasing the dosage. In addition, the researcher claimed that in the preclinical studies, prescribing dose of 12 millimoles Fe/kg wt represented no toxicity. The study employed advanced techniques, including Two-Photon Laser Scanning Microscopy (TPLSM) and High-Resolution Transmission Electron Microscopy (HRTEM) to assess atherosclerotic plaque. The USPIOs provided effective magnetic contrast agents to execute in vivo TPLSM method. Nevertheless, this method has a penetrating limitation through gross tissue. Instead, utilizing nonlinear micro-endoscopy in the study of thick tissue, is applicable. In addition, some of the USPIO nanoparticles encountered phagolysosomal processing, in which the maghemite core changed to ferritin form, resulting in long-term storage (28). Although previous research administrates high doses of USPIO nanoparticles, it is possible to get sufficient signals from tissue with much lower doses. In a study conducted by Oghabian et al., the threshold dose to obtain proper contrast of lymph nodes was defined in the rat. The results clearly depicted that subcutaneous injection (0.028 mg Fe/kg) demands a much lower dose than intravenous injection (0.16 mg Fe/kg) (29). This data suggested that the subcutaneous injection method maximizes the effectiveness of obtaining images from different tissues, since the excretion rate decreased. Moreover, ten years after Oghabian et al. research, Nie and colleagues conducted a similar study with another form of USPIO nanoparticles called CS015. This nanoparticle has more advantages than the previous one, including a Poly Acrylic Acid (PAA) surface which provides multiple loading sites for drug delivery and drug tracking, even though some portions of them are endocytosed by tissue-resident macrophages. By utilizing Magnetic resonance (MR) lymphangiography to specify the CS015, similar to previous studies, there is an assumption on the priority of subcutaneous injection over intravenous injection (30). Based on the peripheral nerve structure, one of the challenging issues in detecting, especially in large nerve trunks, is the perineurium layer, which acts as a blood barrier. In a recent animal study, Wu et al. used a modified form of USPIO nanoparticle called USPIO- PEG-tLyP-1 which can cross the blood-brain barrier. The aim of developing this particle was to disclose tumor tissue because of its high binding affinity to neuropilin-1. Using an MRI system, the particle could easily be tracked, suggesting it as a potential candidate for glioma detection, as well as other research purposes like peripheral nerve imaging (31).
In another research, the USPIO was reorganized by Cy5.5 and PEG in order to construct a new probe, named USPIO-PEG-Cy5.5. The particle revealed relatively high stability and biocompatibility along with a wide excitation wavelength (32). Another advantage of USPIO nanoparticles is tracking either resident cells with no migration or mobile cells, in blood and tissue. This phenomenon helps researchers detect nerve inflammation with high efficiency. An in-vitro research on chimeric antigen receptors (CAR) T cells illustrated a new method in which immune cells could be signed. In this way, every tiny inflammatory site in the body could be detected through the MRI (33). It is also possible to adjust the USPIO nanoparticle to the morphological traits of the targeted tissue. In this regard, a specific sequence of peptides is conjugated with PEG-coated USPIO to make it adaptive to the brown adipose tissue (BAT). The particle could specifically bind to the targeted tissue to estimate the volume of the targeted area by the MRI (34). Finally, it is important to mention the role of the USPIO in tracking drug delivery. Tracking the effectiveness of drug delivery has a remarkable role in following up the patients who suffer from cancer. In addition to cancer, there is a possibility to study a wide range of diseases including peripheral nerve injuries. In animal research, the chemotherapeutic drugs with the admixture of the USPIO nanovesicles were employed to define the fate of the drug by the MRI (35) (Table 1).

Table 1. The USPIO nanoparticle's role in disease detection and therapeutic purpose

Imaging techniques
In the clinical approach, Ultrasound and Magnetic resonance imaging (MRI) are conducted to take images of the PNS. Physicians mainly prefer to use ultrasound for their diagnostic aims, especially for tumor and entrapment syndromes, since it has lower cost and takes less time than MRI, while MRI still depicts a growth potential for experimental goals. It provides substantial information across the body with multiplanar abilities and high contrast resolution (1). In the following, multiple sequences and techniques of the MRI application are stated to help characterize the proper method in PNS imaging.
Conventional MRI
In the MRI technique, multiple sequences are available to obtain signals from the targeted area. In this section, conventional MRI sequences are compared to each other, to state the suitable method for peripheral nerve imaging. By utilizing T1-weighted spin-echo sequences, it can be possible to assess morphological properties along with high spatial resolution. Moreover, T2-weighted spin-echo sequences, are commonly employed to gain information on tissue, due to proper contrast resolution (36). To acquire detailed data about inflammatory diseases or even tumors, it is noteworthy to set long echo times of MRI, usually 100 ms, to take highly weighted T2 sequences. In addition, two to four-millimeter sections are required to set the spatial resolution at maximum value. These settings are used in combination with fat signal suppression, which is implemented by spin-echo (SE) or turbo spin-echo (TSE) sequences. Sometimes Short Tau Inversion Recovery (STIR) or T1 weighted sequences associated with gadolinium injection are a substitute for the previous method (37, 38). One of the challenges in T1 weighted sequences is the isointense signals of the nerves compared to the muscles. In this case, one of the ways to distinguish peripheral nerve is epineural fat, characterized by a hyperintense halo (39). On the contrary, by applying T2 weighted sequences, nerves appear somehow hyperintense with even higher intensity in large nerve trunks fascicles, mainly because of endoneurial fluid (36).
Yet, studies imply that MRI is the first candidate for nerve damage diagnostic approaches. In Mulkey et al. study, there was an increase in the cauda equina nerve root diameter, which was a diagnostic clue to detect inflammatory polyneuropathies (40). In T2 weighted sequences with or without fat suppression, detecting possible fascicular damages becomes possible and by applying gadolinium injection in T1 weighted sequences, some branches of the blood-nerve barrier could even be tracked (1). To evaluate the existence of Wallerian degeneration in the damage site, the T2 weighted sequences can be suitable (41). It generally requires a minimum of 24-hour interval to highlight a clear hyperintensity in signal illustration, after the injury happens (42). After a 48 hours interval, while the morphology properties of adjacent tissue depict a normal status like muscles, in T2 weighted sequences there is a clear wide hyperintensity defined as edema condition (43). In the final stage, in which the adjacent muscles suffer from denervation, their amyotrophic stage initiates, detected by a hyperintense T1 signal accompanied by long-time denervation persistence (44). Nevertheless, one of the challenges in conventional MRI is acquiring high-quality images to differentiate peripheral nerves from vessels, due to the same diameter and signal intensity in T2-weighted sequences. Even T2 weighted spectral adiabatic inversion recovery turbo spin echo (T2 SPAIR TSE) sequences, despite their high resolution, cannot differentiate two structures (45, 46). One of the suggested methods to define peripheral nerve is to put focus on normal or damaged nerve fascicular layer, through peri-mural and intra-mural fat (47).
Three-Dimensional Diffusion-Weighted PSIF (3D DW-PSIF)
Besides the mentioned techniques, MRI can obtain 3D volume data of the sample. By using this method, complex nerve pathways, such as the brachial plexus, could be analyzed with higher efficiency, since the neurography contains satisfying isotropic quality with curvilinear multiplanar reconstructions. Moreover, the physician could track the efficiency of treatment by applying Maximum intensity projection (MIP) (48, 49). Three-Dimensional Diffusion-Weighted PSIF Technique (3D DW-PSIF) provides a large field of view (FOV) and proper shimming, while some areas may reflect ghosting artifacts. Nonetheless, 3D DW-PSIF still provides high conspicuity scores compared to T2 weighted images (1.57±0.67 versus 0.74±0.76), when applied to peripheral nerves including: lumbosacral plexus, brachial plexus, and sciatic nerve. This MRI method offers more data and provides a more accurate diagnosis of pathological nerve conditions (50).
Gadofluorine M contrast agent
Another MRI technique for obtaining high-quality images of peripheral nerve, is using contrast agents. In novel animal research, a significant increase in signal intensity was observed among rats that took Gadofluorine M contrast agents for sciatic nerve data acquisition. By applying contrast agents, the reconstruction and retrieving stage of the peripheral nerve could be assessed. Strengthening the signal amplitude allows physicians to have deep insight into disease progression, along with justifying the clinical symptoms with the predicted illness, whereas contrast agents lack the ability to be applied in a wide range of nerve damages. For instance, Gadofluorine M can only reveal the inflammatory aspect of nerve lesions (51). Former research utilizes Gadofluorine M, similar to the USPIO, as a sign of the degeneration process triggered by macrophages, since it could bind to myelin-degraded particles (52, 53). Moreover, Gadofluorine M was reported to have the potential to detect several nerve damages, including demyelination and Wallerian degeneration. Regarding this fact that in the nerve injury process, the signal intensity is concentrated in the damaged area, it can be concluded that the blood-nerve barrier is responsible for the high influx of Gadofluorine M, reaching for the nerves (54-56).
Functional magnetic resonance imaging (fMRI)
It is noteworthy to mention a well-known MRI technique named Blood-oxygen-level-dependent (BOLD) fMRI and its application in peripheral nerve imaging. This method has a powerful ability to record brain function, in which there is facilitation in monitoring myelinated axonal activity for multiple aims, ranging from basic psychological research to clinical approaches. Its limitation in employment on gray matter tissue, makes it suitable to exclude unwanted signals, in peripheral nerve imaging. It was successfully implemented on bullfrog sciatic nerves to evaluate and visualize axonal stimulation. Diffusional fMRI also participates in the detection of microstructural changes occurred in myelin fiber, which are linearly correlated with electrical impulses (57). Besides mentioned methods and techniques, we could consider more specific methods in which detailed information could be obtained about the quality of fibers in nerve function, and possible denervation without any sign of inflammation (58). One of these methods is nominated as Diffusion-weighted imaging (DWI) which is mentioned in the following section.
Diffusion-weighted imaging (DWI)
The DWI is based on the key compound in biological processes called water molecules, in which quantitative data are obtained from tracking its movement (59). The different behavior of water molecules in the tissue encountered pathological conditions, results in significant differences in signal intensity of normal and damaged tissue (60). In human research conducted on a tiny sample size of five participants, Diffusion-weighted MR neurography (DW-MRN) sequences, based on DWI, were obtained to scrutinize the sacral plexus. The results defined a concept of the priority of unidirectional MPGs in peripheral nerve image acquisition. Moreover, utilizing soap-bubble MIP depicts better results in gaining detailed information compared to the conventional MIP method (61). While in the previous research, the small sample size is the overt limitation that decreases the reliability of the results, in another study with a larger sample size (N=65), the head and neck of the participants were evaluated with different methods of DWI. As the data illustrated, Multishot EPI spectral presaturation with inversion recovery (msEPI-SPIR) is superior to single-shot EPI (ssEPI), since it contains higher image quality and provides fewer artifacts. In the DWI neurography, massive fat suppression results in an increase in signal-to-noise ratio (SNR) as well as apparent diffusion coefficient (ADC) improvement (62). Although the previous study mainly focused on the central nervous system (CNS), Takahara et al.'s study on peripheral nerve injury, showed that DW-MR neurography could be considered as a suitable method for localizing nerve injury and determining the type of the disease (58, 63) (Table 2). Finally, in the most recent research conducted by Koike et al. in patients with malignant peripheral nerve sheath tumor (MPNST) and plexiform neurofibroma (pNF), the result of the study recommended the DWI method in discriminating these two diseases. Moreover, the combination of Wasa's score and ADC map is suggested to be implemented to increase the accuracy of diagnosis (64). In the next section, another well-known technique for gathering data on peripheral nerves, named Diffusion tensor imaging (DTI), is scrutinized.
Diffusion tensor imaging (DTI)
In the DTI technique similar to Diffusion tensor imaging (DWI), image analysis is based on water molecules. In Haakma et al. research, a three-tesla magnetic field is utilized to acquire a 3D image of the sacral plexus with a sample size of ten patients. The result is depicted by detailed information across the L4-L3 area of the participants. By scrutinizing the study result, it could be perceived that S1 in the mean diffusivity (MD) and Radial Diffusivity (RD) parameters have a meaningful alternation in comparison to normal and patients, while L4 and L5 were not depicted at any significant rate. Based on the results, The MD parameter could be considered as an accurate parameter in the detection of PNS pathological states. Since this method of MRI is rarely implemented in clinical studies to finally, the study suggested using a combination of methods, including the 3D Turbo spin echo (3D-TSE), DTI, and Fiber tractography (FT) (65). One way to increase the confidential ratio of the image acquisition to determine what happened during nerve injury, is increasing the magnetic field strength (MFS). In recent animal research, the sciatic nerve of rats was put into focus. Animals were divided into three groups, sham, crush, and cut. All groups were taken on DTI imaging techniques with 7 T MFS. The data collection was based on a specific timeline to define the most suitable time for nerve injury detection. The results suggested that a four weeks interval was the best for distinguishing between multiple nerve injury types. This issue is mainly because of the influence of inflammation. After four weeks, the inflammation dwindles, then the nerve begins to regenerate. Moreover, in this condition, in which proximal nerves are involved, the golden time for detection becomes even shorter, compared to distal nerves. In this study, unlike the previous one, the researcher suggested the FA parameter for nerve injury detection. In transection cut at one and 4 weeks after injury, a remarkable reduction in FA parameter could be revealed (66). By measuring FA over time, an overall period of 12 weeks for complete recovery, could be conclude. Nevertheless, the main challenge of image distortion still remains and even exacerbates with higher MFS. To cope with the unpleasant issue of artifacts and distortion which are mainly due to B0 inhomogeneity as well as eddy currents, in a human study, the author suggested a method named TOPUP for image recovery. This study was conducted on humans with 7 T MFS to obtain detailed information on the peripheral nerve of the arm and carpal tunnel, by utilizing the Steady-state free precession MRI (SSFP) sequence to minimize the slice thickness to 0.2 x 0.2mm and 0.4 mm. With the aid of this method, several structures of the peripheral nerve could be visualized, including single fascicles of the median nerve, branches of the superficial radial nerve, and the sheaths of the flexor tendons. Nevertheless, there are particular difficulties, especially with high MFS, including low spatial resolution when the echo-planar (EPI) method is performed for image acquisition, which leads to less assurance to discern peripheral nerve compounds. Besides, the DTI method has the potential to diagnose neuropathies with an entanglement of small-diameter trunks. Similar to Farinas et al. (2020), Schmid et al. (2018) study revealed FA as the most proper parameter for peripheral nerve imaging. Finally, the time-consuming procedure to acquire proper signal ratio images, remains the major challenge for high MFS applications (67).
Formerly, DTI was one of the methods to assess white matter integrity, with reliable implementation in the demonstration of inflammation or possible edema (68). A similar methodology can be applied to the peripheral nerve to evaluate the type of injury and treatment rate. It is worthy to indicate the contrary attitude of FA and RD in the diagnosis of nerve injury, in which reduced FA is illustrated as a clue for myelin and axon degeneration while an increase in RD could be concluded as the same result, however, RD is not recommended for nerve injury prognosis. In these two studies, first, Sun et al. conducted animal research on rabbits with 1.5 T MFS in healthy and nerve injury model groups. The data suggested approximately 10 weeks for nerve recovery, detected by FA (69). Secondly, Yamasaki et al. collected data over time from the sciatic nerve injury model of rabbits, which found significant changes in FA during the second and fourth week after the injury. In this research, a more powerful MFS (7 T) is utilized compared to previous research (70). In another research, all the DTI parameters were compared to each other in order to clarify the most sensitive parameter in nerve injury diagnosis, in which by the aid of 3 T MFS, numerous data across the median nerve was obtained. The results highlighted FA and RD as an appropriate indicator of the quality of myelin sheath. However, FA could indicate the myelin sheath integrity better. Among other parameters, MD lacks the minimum criteria to be considered as a diagnostic value, while AD could still be perceived as an additional data provider for the RD and FA. The pros of this method compared to other sequences of MRI, is its ability to provide detailed data on the nerve, by which we could detect small lesions in peripheral nerves and even peripheral neuropathies (71). Eventually, it is noteworthy to briefly mention that the Diffusion basis spectrum imaging (DBSI) method could provide a larger amount of data compared to DTI, even though still the DTI data acquisition produces enough information on  the condition of the peripheral nerve (57) (Table 2) (Figure1).

Table 2. Implementation of DTI and DWI in clinical and animal research

Computed tomography (CT) scan
There is a wide range of methods for nerve disease diagnosis, which two of them commonly utilized in clinical approaches, are computed tomography (CT) scan and ultrasonic sound. The CT scan similar to the MRI, has a high spatial resolution in which different tissues take different contrasts (72). Hence, tiny lesions as well as nerve tumors, can be detected in the peripheral nerves (73). Furthermore, spinal nerve compression status known as intraforaminal, extraforaminal, and intradural, along with type 1 neurofibromatosis, can be easily detected (74-76). Nevertheless, this method unlike DTI, has a limitation in detecting and tracking nerve microstructural changes, mainly due to inadequate contrast resolution (77).
Ultrasound (US)
Similar to DWI in the ultrasound method some nerve injuries like MPNST and benign peripheral nerve sheath tumors (BPNSTs), could be detected (78). In animal research on rabbits, the sciatic nerve encountered a blunt dissection in combination with an iodine solution to simulate a nerve injury. Subsequently, the regeneration process and drug administration efficiency could be monitored. Moreover, this method is successfully performed to detect nerve injury and quantitatively calculate microcirculation in injured peripheral nerves (79). In addition to mentioned diseases, high-resolution ultrasound is an appropriate device to determine Schwannomas, solid tumors in peripheral nerve, with the sign of hypoechoic signals and neurofibromas, mainly in the subcutaneous tissue, with the hyperechoic area along with neurofibromatosis 1 and 2 (80). The US combined with MR neurography resulted in high-resolution peripheral nerve imaging, which covers the detection of a wide range of nerve lesions as well as (non)focal neuropathies (81) (Figure 2).

Figure 1. The suggested application of the USPIO nanoparticles in peripheral nerve imaging and tracking is depicted along with potential imaging techniques such as DWI, DTI, and T₂* mapping


Figure 2. An overview of the nerve injury diagnosis, using some practical MRI sequences and Ultrasound

Discussion

In the current review, there was a particular focus on the clinical approaches in PNS imaging, along with discussing contrast agents and introducing MRI sequences. Our study's main finding and novelty is synopsized into the applicable role of the DTI method, especially the FA value in evaluating the structural health of the PNS. These results suggest a new candidate for diagnostic approaches that benefits surgeons and physicians, while currently PNS evaluation is implemented with the aid of electromyography (EMG) and nerve conduction studies (NCS) (82).
In a recent review article conducted by Endo et al., the MRI was signified as a mighty method in detecting the denervation of the superficial and deep nerves (83). Accordingly, in our study, the DTI method as one of the MRI sequences, was suggested as the suitable option to make an accurate diagnosis of denervation and other types of physical nerve injuries. Furthermore, in a systematic review evaluating the role of DTI in acquiring data about the brachial plexus, the results mentioned two values of FA and MD as the diagnostic parameters for detecting the changes in the quality of the nerves (84). Likewise, in our study, the value of FA was sensitive to denervation, while the value of MD was a proper parameter in monitoring nerve regeneration. More specifically, in a review article written by Martín et al., the FA value in revealing neuropathy in which the FA value reduces, was on the debate. The author continued by pointing out the downward trend of the FA value in the PNS injury. To provide supplementary information regarding the previous result, the role of RD in evaluating the myeline sheath integrity of the nerves, along with the quality of the connective tissue was commented on, in which the remyelination procedure could be validated by observing a reduction in the RD value. In addition to the DTI property in the detection of nerve malformations, the cited review article briefly mentioned the role of the conventional MRI in the detection of nerve injuries, by stating fast spin-echo and TSE sequences along with fat suppression, as the validated methods to evaluate PNS (58). Accordingly, the main deduction of our study consisting of six original articles evaluating the DTI methods, was in line with Martín et al. study. In addition, Martín explanation of the role of conventional MRI was similar to our interpretation as well as Filler et al. (37) and Moser et al. (38) results. In addition to the beneficial role of MRI, it is worth mentioning the controversial issues about MRI corresponding to the DWI roles, in detecting MPNST and pNF. Accordingly, in a review article conducted by Donaldson et al., the author reported that MRI cannot determine MPNST since among the MRI taken from three patients, only one was suspected of tumor presence, without providing data about tumor type (85).
Besides the MRI technique, in a review article mentioning the role of ultrasonography in PNS imaging, multiple benefits were indicated. Accordingly, the ability of the ultrasound to track and rate the grade of the nerve injury, was supposed to be a practical technique for surgery operations (86). Similarly, in the current study, the role of ultrasonography and its accuracy in the detection of MPNST and BPNSTs has been briefly mentioned. Although the role of ultrasonography was highlighted in monitoring the nerve regeneration process, MRI advanced techniques have superiority over its in demonstrating nerve injury. The declaration of the priority of the MRI technique over ultrasonography, relies on the low contrast of ultrasonography. In support of this issue, Jerban et al. systematic review could be mentioned, which specified the low contrast and artifact as the main limitations of ultrasonography (87). Correspondingly, in a review article demonstrating the advances in MRI technology, DTI has been introduced as a potent method in determining the grade of nerve injury with a high spatial resolution (88).

 

Conclusion

Peripheral nerve injuries have many subunits, which cause difficulty in proper diagnosis and using suitable therapeutic methods. These difficulties are due to the complicated procedure of imaging and several issues in implementing the traditional MRI method, including the isointense signal of muscles, nerves, and vessels in T1 weighted sequences as well as the same appearance in diameter of the vessels and nerves (39, 45, 46). Nonetheless, thanks to advanced imaging techniques, most of these challenges have been overcome. To compensate for the isointense issue, contrast agents and USPIOs particles are applied to the targeted tissue. Accordingly, USPIO nanovesicles, nanoparticles, and P904 USPIOs could be utilized to provide suitable contrast, in order to differentiate nerves from adjacent tissue (33, 35). Moreover, with the aid of USPIOs, drug delivery could be tracked, and immune cells could be marked to visualize minor nerve inflammation (30, 31). In addition to USPIOs, the image contrast in specifying PNS is improved by some basic manipulation on echo time, TR, and TE, resulting in gathering of different sequences like SE or TSE sequences. Alternatively, a combination of methods including STIR and T1 weighted sequences, along with gadolinium injection may be applied to get high-quality images (37, 38). Apart from the contrast issue, in the PNS image acquisition, artifacts that deteriorate in high MFS, mislead the physician for making a reasonable deduction. For instance, in the DTI and 3D DW-PSIF sequences, artifacts disrupt some proportion of the PNS details. As an alternative, the msEPI-SPIR sequence and TOPUP image recovering tool for DTI sequencing, could be applied to decrease the artifact effects (62, 67). Another challenge in the clinical application of PNS is the conflicting interpretation of the data. In this regard, some hallmarks would be utilized in signified malady conditions, such as an increase in nerve root diameter that is as an indication of inflammatory polyneuropathies (40). Besides, in the DTI sequence, a reduction in the FA parameter, illustrated the myelin and axon degeneration and the alternation in the MD value, provided a quantitative scale for nerve recovery (69).
Finally, the dynamic and live evaluation of the PNS is one of the requirements for the accurate diagnosis of PNS diseases. Among imaging instruments, fMRI and sonography are gathering dynamics images. Sonography lacks the minimum contrast quality to visualize details, while by utilizing fMRI, even microstructural changes could be revealed (57, 79) (Fig2).

 

Acknowledgements

This work is supported by Iran University of Medical Sciences.

 

Funding

The authors did not receive any funding.

 

Authors' contributions

Auob Rustamzadeh contributes to the study concept and design. Armin Ariaei contributes to data acquisition and writing. Mehran Ebrahimi Shah-abadi, Arash Shabani, Hossein Mohammadi, Rastegar Rahmani Tanha, Vahid Tavakolian Ferdousie, and Mohsen Marzban contribute to reviewing and editing. Abdolmajid Taheri and Mahdi Heydari contribute to revising the article. All authors read and approved the final manuscript.

 

Data availability

This review article contains no supplementary or raw data.

 

Conflicts of Interest

There is no conflict of interest.