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Chronic refractory central post-stroke pain (CPSP), one of the most disabling consequences of cerebral stroke, occurs in up to 10% of patients with CPSP. Because a considerable proportion of these patients with chronic pain remain resistant to pharmacological and behavioral therapies, adjunctive invasive and non-invasive brain stimulation therapies are needed. We performed a review of human studies applying burst and conventional motor cortex stimulation (burstMCS and cMCS, respectively) for chronic pain states, on the basis of data sources identified through searches of PubMed, MEDLINE/OVID, and SCOPUS, as well as manual searches of the bibliographies of known primary and review articles. Our aim was to review and discuss clinical data on the indications of burstMCS for various chronic pain states originating from central stroke (excluding trigeminal facial pain). In addition, we assessed the efficacy and safety of burst versus cMCS for central post-stroke pain with an extended follow-up of 5 years in a 60-year-old man. According to our review, uncontrolled observational human cohort studies and one RCT using cMCS waveforms have revealed a meaningful clinical response; however, these studies lacked placebo groups and extended observation periods. In our case report, we found that 3 months of adjunctive cMCS reduced pain levels [visual analog scale (VAS) pre: 9/10 versus VAS post 7/10], whereas the pain decreased further under burstMCS (VAS pre: 7/10 versus VAS post: 2/10); the study involved a follow-up of 5 years and the following parameters: burst rate 40 Hz (500 Hz), 1–1.75 mA, 1 ms, bipolar configuration. To date, only limited evidence exists for the efficacy and safety of burst motor cortex stimulation for the treatment of refractory chronic pain. BurstMCS resulted in significantly decreased post-stroke pain observed after 5 years of cMCS. The available literature suggests similar efficacy as that of conventional (tonic) motor cortex stimulation, although the results are preliminary. Mechanistically, the precise mechanism of action is not fully understood. However, burstMCS may interact with the nociceptive thalamic-cingulate and descending spinal pain networks. To determine the potential utility of this treatment, large-scale sham-controlled trials comparing cMCS and burstMCS are highly recommended.

Complex regional pain syndrome (CRPS) and associated comorbidities have been linked to a pro‐inflammatory state driven by different mediators. Targeted dorsal root ganglion stimulation (DRGSTIM) suppressed pain levels and improved functional capacity in intractable CRPS. However, clinical trials assessing the impact of DRG stimulation on the neuroimmune axis are lacking. This study enrolled 24 subjects (12 refractory CRPS patients plus suitably matched healthy controls) and performed immunoassays of inflammatory mediators in saliva and serum along with score‐based assessments of pain, mood, and sleep quality at baseline and after three months of selective L4‐DRGSTIM. After three‐month L4‐DRGSTIMCRPS associated pain significantly decreased. In addition, disturbed sleep and mood improved post‐DRGSTIM, although statistically not significant. Significantly increased serum values of pro‐inflammatory markers were detected pre‐ and post L4‐DRGSTIMfor high‐mobility group box 1, tumor‐necrosis factor α, interleukin (IL) 6, and leptin. IL‐1β was significantly elevated pre‐L4 DRGSTIM, but not posttreatment. Elevated anti‐inflammatory IL‐10 significantly decreased after three months in serum, while saliva oxytocin concentrations increased in CRPS subjects after L4‐DRGSTIM(p= 0.65). No severe implantation and stimulation associated adverse events were recorded. Selective L4‐DRGSTIMimproved neuropathic pain and functional impairment in CRPS as previously reported. CRPS patients displayed a pro‐inflammatory molecular pattern in serum. Serum anti‐inflammatory IL‐10 significantly declined, while saliva oxytocin nonsignificantly increased after L4‐DRGSTIM. An evidence‐based relational interpretation of our study is limited due to the uncontrolled study design. However, molecular profiling of biofluids (saliva, serum) represents a novel and experimental field in applied neuromodulation, which warrant further investigations to unveil mechanisms of neuroimmune modulation.

In our previous study, anti‐inflammatory IL‐10 serum levels were significantly elevated after burst spinal cord stimulation (SCS) in back pain patients and correlated with pain intensity. This current study extended cytokine analysis including metabolic‐associated adipokine/cytokine serum assessment in chronic back pain patients with co‐existing metabolic disorders such as diabetes, hypertension, and cardiovascular diseases. At baseline and after three months of burst SCS treatment, leptin (LP), adiponectin (AN), and ghrelin (GH) were recorded in non‐/pre‐obese chronic back pain patients with co‐existing metabolic disorders and compared to age‐/gender‐matched healthy controls (HC). Mean BMI was 22 ± 0.81 kg/m2in 12 (five male/seven female) participants with diabetes in 6/12 (50%), hypertension in 9 (75%), and CVD in five patients (42%). Pre‐ and post‐SCS LP levels were significantly higher compared to healthy controls: pre‐SCS, 30567 (12,996–58,821) vs. HC, 7952 (4932–12,583) pg/mL, p= 0.029; post‐SCS, 18,890 (7140–44,719) vs. HC, 7952 (4932–12,583) pg/mL, p= 0.035. Pre‐ and post‐SCS changes of GH (p= 0.18) and AN (p= 0.8) did not differ significantly. GH serum levels correlated with AN (Spearman r= 0.5; p= 0.012; 95 CI 0.11 to −0.76) and AN levels were significantly correlated with higher age (Pearson correlation r= 0.8; p= 0.002; 95 CI 0.41–0.94) at baseline. This study determined serum changes of metabolic‐associated cytokines/adipokines in non‐obese chronic back pain patients responsive to burst SCS suggesting that neuroinflammation assessment may consider pain‐associated mood, cognition, sleep, and metabolic state.

Burst spinal cord stimulation (SCS) has been reported to reduce back pain and improve functional capacity in Failed Back Surgery Syndrome (FBSS). However, its mechanism of action is not completely understood. Systemic circulating cytokines have been associated with the development of chronic back pain. This prospective, feasibility study enrolled 12 refractory FBSS patients with predominant back pain (70% of overall pain) suitable for Burst SCS. Back and leg pain intensity (back pain [VASB]/leg pain [VASL]), functional capacity (sleep quality [PSQI]), depressive symptoms (BDI), body weight, stimulation parameters, and plasma levels of pro‐inflammatory (Il‐1b; TNF; HMGB1)/anti‐inflammatory (Il‐10) cytokines were collected at baseline and after three months of Burst SCS and compared to healthy controls. Pain intensity (pre VASB: 8.25 ± 0.75 vs. post 1.42 ± 1.24) and functional capacity (PSQI: pre 7.92 ± 3.92 vs. post 3.42 ± 1.24; BDI: pre 20.83 ± 3.56 vs. post 10.92 ± 0.75) significantly improved compared to baseline. Pro‐inflammatory HMGB1 remained unchanged (preburst: 3.35 ± 3.25 vs. postburst: 3.78 ± 3.83 ng/mL; p= 0.27; W= −30) versus the HC group (2.53 ± 2.6 ng/mL; p= 0.47; U= 59), while anti‐inflammatory IL‐10 levels were significantly elevated after burst SCS as compared to baseline (preburst 12.54 ± 22.95 vs. postburst 43.16 ± 74.71 pg/mL; p= 0.03; W = −48) and HC group (HC: 7.03 ± 11.6 vs. postburst 43.16 ± 74.71 pg/mL; p= 0.03; W= −48; p= 0.04). Baseline preburst IL‐10 values and preburst VASBsignificantly correlated (Spearman correlation r= −0.66; p= 0.05; 95 CI −0.86 to −0.24), while correlation was not significant between postburst IL‐10 values and postburst VASB(Spearman correlation r= −0.49; p= 0.18; 95 CI −0.83 to −0.15). Postburst IL‐10 values correlated significantly with postburst PSQI scores (Spearman correlation r= −0.66; p= 0.05; 95 CI −0.86 to −0.24), while no correlation was found between preburst and postburst changes related to the BDI. Burst SCS increased systemic circulating anti‐inflammatory IL‐10, improved FBSS back pain and back pain associated co‐morbidities like disrupted sleep architecture and depressive symptoms in FBSS patients. Thus, suggesting a possible relationship between burst SCS and burst‐evoked modulation of peripheral anti‐inflammatory cytokine IL‐10 in chronic back pain.

During a routine long-term drug safety study, lasting approximately 2½ yr, male Wistar rats, treated with a prolactin-inhibiting compound, developed an excess of Leydig cell tumors (LCTs). Most tumors were typical for the rat but a small number showed an unusual variation and some appeared malignant. The variation consisted of glandular and/or tubular structures within the tumor mass which occasionally anastomosed and contained an eosinophilic periodic-acid Schiff (PAS) positive material. In a few of these variants, malignant features such as cellular atypia, capsular, and lymphatic invasion and necrosis were seen. No metastases were detected. Detailed morphological and immunohistochemical investigations were conducted in order to establish the cell of origin of these variants. Glandular/tubular structures were found to stain with varying intensity for vimentin and cytokeratin, but were always negative for β-tubulin. The results indicated that the cell of origin of these LCT variants was indeed the Leydig cell and that glandular and/or tubular structures within LCTs represented a form of Leydig cell metaplasia.

Macroscopic and histologic evaluation of animal studies for general toxicity and carcinogenicity are cornerstones of the risk assessment of new chemical entities. Standard toxicopathologic evaluation is mainly based on the study of paraffin sections stained with hematoxylin and eosin. There are, however, a number of new approaches and techniques which have improved the objectivity of evaluation and the accuracy of cell identification, and provided deeper insight into the molecular biological mechanisms of toxicity and carcinogenicity. Such approaches include the standardization of the nomenclature, the creation of data banks for morphological alterations, the use of computers to register pathological findings in toxicity studies and to statistically evaluate incidences, and the use of morphometry. Other modern techniques are immunohistochemistry, in situ hybridization, and the assessment of cell kinetics.