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Ivana Vuka,1 Tihana Marciuš,1 Damir Kovačić,2 Antonio Šarolić,3 Livia Puljak,4,* Damir Sapunar1,* 1Laboratory for Pain Research, University of Split School of Medicine, Split, Croatia; 2Laboratory for Biophysics and Medical Neuroelectronics, University of Split Faculty of Science, Split, Croatia; 3Laboratory for Applied Electromagnetics (EMLab), FESB, University of Split, Split, Croatia; 4Centre for Evidence-Based Medicine and Health Care, Catholic University of Croatia, Zagreb, Croatia*These authors contributed equally to this workCorrespondence: Damir SapunarLaboratory for Pain Research, University of Split School of Medicine, Šoltanska 2, Split, 21000, CroatiaTel +385 21-557-809Email ds@mefst.hrObjective: This was a proof of concept study, based on systematic reviews of the efficacy and safety of the dorsal root ganglion (DRG) stimulation. The main objective was to develop an implantable, programmable, and wireless device for electrical stimulation of DRG and a methodology that can be used in translational research, especially to understand the mechanism of neuromodulation and to test new treatment modalities in animal models of pain.Methods: We developed and tested a stimulator that uses a battery-powered microelectronic circuit, to generate constant current square biphasic or monophasic pulsed waveform of variable amplitudes and duration. It is controlled by software and an external controller that allows radio frequency communication with the stimulator. The stimulator was implanted in Sprague–Dawley (SD) rats. The lead was positioned at the L5 DRG level, while the stimulator was placed in the skin pocket at the ipsilateral side. Forty-five animals were used and divided into six groups: spinal nerve ligation (SNL), chronic compression injury of the DRG (CCD), SNL + active DRG stimulation, intact control group, group with the implanted sham stimulator, and sham lead. Behavioral testing was performed on the day preceding surgery and three times postoperatively (1st, 3rd, and 7th day).Results: In animals with SNL, neurostimulation reduced pain-related behavior, tested with pinprick hyperalgesia, pinprick withdrawal test, and cold test, while the leads per se did not cause DRG compression. The rats well tolerated the stimulator. It did not hinder animal movement, and it enabled the animals to be housed under regular conditions.Conclusion: A proof-of-concept experiment with our stimulator verified the usability of the device. The stimulator enables a wide range of research applications from adjusting stimulation parameters for different pain conditions, studying new stimulation methods with different frequencies and waveforms to obtain knowledge about analgesic mechanisms of DRG stimulation.Keywords: neurostimulation, implantable stimulator, DRG, SNL, pain-related behavior

BackgroundWe systematically reviewed the evidence on the efficacy and safety of dorsal root ganglion (DRG) targeted pulsed radiofrequency (PRF) versus any comparator for treatment of non-neuropathic pain.MethodsWe searched MEDLINE, CINAHL, Embase, PsycINFO, clinicaltrials.gov and WHO clinical trial register until January 8, 2019. All study designs were eligible. Two authors independently conducted literature screening. Primary outcomes were pain intensity and serious adverse events (SAEs). Secondary outcomes were any other pain-related outcome and any other safety outcome that was reported. We assessed the risk of bias using the Cochrane tool and Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I). We conducted narrative evidence synthesis and assessed the conclusiveness of included studies regarding efficacy and safety.ResultsWe included 17 studies with 599 participants, which analyzed various pain syndromes. Two studies were randomized controlled trials; both included participants with low back pain (LBP). Non-randomized studies included patients with the following indications: LBP, postsurgical pain, pain associated with herpes zoster, cervicogenic headache, complex regional pain syndrome type 1, intractable vertebral metastatic pain, chronic scrotal and inguinal pain, occipital radiating pain in rheumatoid arthritis and chronic migraine. In these studies, the PRF was usually initiated after other treatments have failed. Eleven studies had positive conclusive statements (11/17) about efficacy; the remaining had positive inconclusive statements. Only three studies provided conclusiveness of evidence statements regarding safety – two indicated that the evidence was positive conclusive, and one positive inconclusive. The risk of bias was predominantly unclear in randomized and serious in non-randomized studies.ConclusionPoor quality and few participants characterize evidence about benefits and harms of DRG PRF in patients with non-neuropathic pain. Results from available studies should only be considered preliminary. Not all studies have reported data regarding the safety of the intervention, but those that did, indicate that the intervention is relatively safe. As the procedure is non-destructive and early results are promising, further comparative studies about PRF in non-neuropathic pain syndromes would be welcomed.

ObjectivePulsed radiofrequency (PRF) is a nonablative pain treatment that uses radiofrequency current in short high-voltage bursts, resulting in interruption of nociceptive afferent pathways. We conducted a systematic review with the aim to create a synthesis of evidence about the efficacy and safety of PRF applied to the dorsal root ganglion (DRG) for the treatment of neuropathic pain.MethodsWe searched MEDLINE, CINAHL, Embase, and PsycINFO through January 8, 2019, as well as ClinicalTrials.gov and the clinical trial register of the World Health Organization. All study designs were eligible. We assessed risk of bias using the Cochrane tool for randomized controlled trials and the Risk Of Bias In Non-Randomized Studies of Interventions (ROBINS-I). We assessed level of evidence using the Oxford tool and quality of evidence with GRADE.ResultsWe included 28 studies with participants suffering from lumbosacral, cervical, or thoracic radicular pain, post-herpetic neuralgia, neuropathicbone pain in cancer patients, or carpal tunnel syndrome. Only five studies were randomized controlled trials (RCTs), while others were of nonrandomized designs, predominantly before and after comparisons. A total of 991 participants were included, with a median number (range) of 31 (1–101) participants. Only 204 participants were included in the RCTs, with a median number (range) of 38 (23–62) participants. The overall quality of evidence was low, as the majority of the included studies were rated as evidence level 4 or 5. The quality of evidence was very low.ConclusionsEvidence about the efficacy and safety of PRF of the DRG for the treatment of neuropathic pain is based mainly on results from very small studies with low evidence quality. Current research results about the benefits of PRF of the DRG for the treatment of neuropathic pain should be considered preliminary and confirmed in high-quality RCTs with sufficient numbers of participants.

Ivana Vuka,1 Tihana Marciuš,1 Svjetlana Došenović,2 Lejla Ferhatović Hamzić,3 Katarina Vučić,4 Damir Sapunar,1,5,* Livia Puljak5,* 1Laboratory for Pain Research, University of Split School of Medicine, 21000 Split, Croatia; 2Department of Anesthesiology, Reanimatology and Intensive Care, University Hospital Split, 21000 Split, Croatia; 3Department for Proteomics, Center for Translational and Clinical Research, University of Zagreb School of Medicine, 10000 Zagreb, Croatia; 4Department for Safety and Efficacy Assessment of Medicinal Products, Agency for Medicinal Products and Medical Devices, 10000 Zagreb, Croatia; 5Center for Evidence-Based Medicine and Health Care, Catholic University of Croatia, 10000 Zagreb, Croatia *These authors contributed equally to this work Objective: We conducted a systematic review about patient selection, efficacy, and safety of neuromodulation with electrical field stimulation (EFS) of dorsal root ganglion (DRG) in various painful conditions. We also analyzed conclusion statements as well as conflict of interest and financing of the included studies.Methods: All study designs were eligible for inclusion. We searched MEDLINE, CINAHL, Embase, PsycINFO, and clinical trial registries until September 7, 2018. We assessed risk of bias by using Cochrane tool for randomized controlled trials (RCTs).Results: Among the 29 included studies, only one was RCT, majority being case series and case reports. The evidence is based on studies with small number of participants (median: 6, range 1–152) with various painful conditions. Neuromodulation with EFS of DRG was mostly performed in participants who have failed other treatment modalities. Most of the authors of the included studies reported positive, but inconclusive, evidence regarding efficacy of neuromodulation with EFS of DRG. Meta-analysis was not possible since only one RCT was included.Conclusion: Available evidence suggest that neuromodulation with EFS of DRG may help highly selected participants with various pain syndromes, who have failed to achieve adequate pain relief with other pharmacological and nonpharmacological interventions. However, these findings should be confirmed in high-quality RCTs with sufficient numbers of participants. Keywords: DRG, pain, neuropathic pain, chronic pain, neurostimulation, electrical stimulation &nbsp

We present the novel method for machine learning- based image processing of optically detected neurons, grown as in-vitro cultures on top of the patterned high-density micro-pillar substrates and chips. We first validated the method with the control images of in-vitro cultures of dorsal root ganglion neurons grown on glass coverslips. Then, we showed that the method is able to reveal morphological differences between neonatal and adult dorsal root ganglion neurons, as well as the estimation of their in-vitro age. The method was optimized for fast image analysis of large image datasets of neurons.