Limbic Connectivity Underlies Pain Treatment Response in Small-Fiber Neuropathy.

OBJECTIVE: Small-fiber neuropathy (SFN) is characterized by neuropathic pain due to degeneration of small-diameter nerves in the skin. Given that brain reorganization occurs following chronic neuropathic pain, this study investigated the structural and functional basis of pain-related brain changes after skin nerve degeneration. METHODS: Diffusion-weighted and resting-state functional MRI data were acquired from 53 pathologically confirmed SFN patients, and the structural and functional connectivity of the pain-related network was assessed using network-based statistic (NBS) analysis. RESULTS: Compared with age- and sex-matched controls, the SFN patients exhibited a robust and global reduction of functional connectivity, mainly across the limbic and somatosensory systems. Furthermore, lower functional connectivity was associated with skin nerve degeneration measured by reduced intraepidermal nerve fiber density and better therapeutic response to anti-neuralgia medications, particularly for the connectivity between the insula and the limbic areas including the anterior and middle cingulate cortices. Similar to the patterns of functional connectivity changes, the structural connectivity was robustly reduced among the limbic and somatosensory areas, and the cognition-integration areas including the inferior parietal lobule. There was shared reduction of structural and functional connectivity among the limbic, somatosensory, striatal, and cognition-integration systems: (1) between the middle cingulate cortex and inferior parietal lobule and (2) between the thalamus and putamen. These observations indicate the structural basis underlying altered functional connectivity in SFN. INTERPRETATION: Our findings provide imaging evidence linking structural and functional brain dysconnectivity to sensory deafferentation caused by peripheral nerve degeneration and therapeutic responses for neuropathic pain in SFN. ANN NEUROL 2023;93:655-667.

Temporal shifts of the microbiome associated with antibiotic treatment of purpuric drug eruptions related to epidermal growth factor receptor inhibitors.

BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors are selective and effective treatments for cancers with relevant mutations. Purpuric drug eruptions are an uncommon but clinically significant dermatological side effect related to EGFR inhibitor use that are associated with positive bacterial cultures and responsive to antibiotic treatment. However, the longitudinal temporal shifts in the skin microbiome that occur before and after antibiotic treatment of purpuric drug eruptions remain largely unknown. OBJECTIVES: To characterize temporal changes in the skin and mucosal microbiomes before and after antibiotic treatment of EGFR inhibitor-related purpuric drug eruptions. METHODS: Twelve patients who experienced EGFR inhibitor-related purpuric drug eruptions were recruited from a dermato-oncology clinic in Taiwan from May 2017 to April 2018. Swabs were obtained from skin lesions and the nasal mucosa before and after antibiotic treatment of purpuric drug eruptions. After the amplification and sequencing of bacterial 16S rRNA genes, the diversity and compositions of microbiomes sampled at different time points were compared. RESULTS: The alpha diversity (represented by the Shannon index) of the skin microbiome increased significantly in the recovered phase of purpuric drug eruptions compared with that of the active phase. By contrast, the nasal microbiome showed no significant change in alpha diversity. The relative abundance of Staphylococcus significantly decreased in samples from skin of the recovered phase, which was confirmed by analysis of compositions of microbiomes (ANCOM) and the ALDEx2 analysis packages in R. CONCLUSIONS: The cutaneous microbiome of purpuric drug eruptions showed a significant increase in alpha diversity and a decrease in the relative abundance of Staphylococcus following antibiotic treatment. These findings may help guide antimicrobial therapy of this EGFR inhibitor-related condition.

Impaired brain network architecture as neuroimaging evidence of pain in diabetic neuropathy.

AIMS: To investigate alterations in structural brain networks due to chronic diabetic neuropathic pain. METHODS: The current study recruited 24 patients with painful diabetic neuropathy (PDN) to investigate the influences of chronic pain on the brain. Thirteen patients with painless diabetic neuropathy (PLDN) and 24 healthy adults were recruited as disease and healthy controls. White matter connectivity of the brain networks constructed by diffusion tractography was compared across groups using the Network-based statistic (NBS) method. Graph theoretical analysis was further applied to assess topological changes of the brain networks. RESULTS: The PDN patients had a significant reduction in white matter connectivity compared with PLDN and controls in the limbic and temporal regions, particularly the insula, hippocampus and parahippocampus, the amygdala, and the middle temporal gyrus. The PDN patients also exhibited an altered topology of the brain networks with reduced global efficiency and betweenness centrality. CONCLUSION: The current findings indicate that topological alterations of brain networks may serve as a biomarker for pain-induced maladaptive reorganization of the brain in PDN. Given the high prevalence of diabetes worldwide, novel insights from network sciences to investigate the central mechanisms of diabetic neuropathic pain are warranted.

Brain Mechanisms of Pain and Dysautonomia in Diabetic Neuropathy: Connectivity Changes in Thalamus and Hypothalamus.

CONTEXT: About one-third of diabetic patients suffer from neuropathic pain, which is poorly responsive to analgesic therapy and associated with greater autonomic dysfunction. Previous research on diabetic neuropathy mainly links pain and autonomic dysfunction to peripheral nerve degeneration resulting from systemic metabolic disturbances, but maladaptive plasticity in the central pain and autonomic systems following peripheral nerve injury has been relatively ignored. OBJECTIVE: This study aimed to investigate how the brain is affected in painful diabetic neuropathy (PDN), in terms of altered structural connectivity (SC) of the thalamus and hypothalamus that are key regions modulating nociceptive and autonomic responses. METHODS: We recruited 25 PDN and 13 painless (PLDN) diabetic neuropathy patients, and 27 healthy adults as controls. The SC of the thalamus and hypothalamus with limbic regions mediating nociceptive and autonomic responses was assessed using diffusion tractography. RESULTS: The PDN patients had significantly lower thalamic and hypothalamic SC of the right amygdala compared with the PLDN and control groups. In addition, lower thalamic SC of the insula was associated with more severe peripheral nerve degeneration, and lower hypothalamic SC of the anterior cingulate cortex was associated with greater autonomic dysfunction manifested by decreased heart rate variability. CONCLUSION: Our findings indicate that alterations in brain structural connectivity could be a form of maladaptive plasticity after peripheral nerve injury, and also demonstrate a pathophysiological association between disconnection of the limbic circuitry and pain and autonomic dysfunction in diabetes.

Brain imaging signature of neuropathic pain phenotypes in small-fiber neuropathy: altered thalamic connectome and its associations with skin nerve degeneration.

ABSTRACT: Small-fiber neuropathy (SFN) has been traditionally considered as a pure disorder of the peripheral nervous system, characterized by neuropathic pain and degeneration of small-diameter nerve fibers in the skin. Previous functional magnetic resonance imaging studies revealed abnormal activations of pain networks, but the structural basis underlying such maladaptive functional alterations remains elusive. We applied diffusion tensor imaging to explore the influences of SFN on brain microstructures. Forty-one patients with pathology-proven SFN with reduced skin innervation were recruited. White matter connectivity with the thalamus as the seed was assessed using probabilistic tractography of diffusion tensor imaging. Patients with SFN had reduced thalamic connectivity with the insular cortex and the sensorimotor areas, including the postcentral and precentral gyri. Furthermore, the degree of skin nerve degeneration, measured by intraepidermal nerve fiber density, was associated with the reduction of connectivity between the thalamus and pain-related areas according to different neuropathic pain phenotypes, specifically, the frontal, cingulate, motor, and limbic areas for burning, electrical shocks, tingling, mechanical allodynia, and numbness. Despite altered white matter connectivity, there was no change in white matter integrity assessed with fractional anisotropy. Our findings indicate that alterations in structural connectivity may serve as a biomarker of maladaptive brain plasticity that contributes to neuropathic pain after peripheral nerve degeneration.

Biomarkers of neuropathic pain in skin nerve degeneration neuropathy: contact heat-evoked potentials as a physiological signature.

Contact heat-evoked potentials (CHEPs) have become an established method of assessing small-fiber sensory nerves; however, their potential as a physiological signature of neuropathic pain symptoms has not been fully explored. To investigate the diagnostic efficacy in examining small-fiber sensory nerve degeneration, the relationship with skin innervations, and clinical correlates with sensory symptoms, we recruited 188 patients (115 men) with length-dependent sensory symptoms and reduced intraepidermal nerve fiber (IENF) density at the distal leg to perform CHEP, quantitative sensory testing, and nerve conduction study. Fifty-seven age- and sex-matched controls were enrolled for comparison of CHEP and skin innervation. Among patients with neuropathy, 144 patients had neuropathic pain and 64 cases had evoked pain. Compared with quantitative sensory testing and nerve conduction study parameters, CHEP amplitudes showed the highest sensitivity for diagnosing small-fiber sensory nerve degeneration and exhibited the strongest correlation with IENF density in multiple linear regression. Contact heat-evoked potential amplitudes were strongly correlated with the degree of skin innervation in both patients with neuropathy and controls, and the slope of the regression line between CHEP amplitude and IENF density was higher in patients with neuropathy than in controls. Patients with evoked pain had higher CHEP amplitude than those without evoked pain, independent of IENF density. Receiver operating characteristic analysis showed that CHEP had better performance in diagnosing small-fiber sensory nerve degeneration than thermal thresholds. Furthermore, CHEPs showed superior classification accuracy with respect to evoked pain. In conclusion, CHEP is a sensitive tool to evaluate pathophysiology of small-fiber sensory nerve and serves as a physiological signature of neuropathic pain symptoms.

dBRWD3 Regulates Tissue Overgrowth and Ectopic Gene Expression Caused by Polycomb Group Mutations.

To maintain a particular cell fate, a unique set of genes should be expressed while another set is repressed. One way to repress gene expression is through Polycomb group (PcG) proteins that compact chromatin into a silent configuration. In addition to cell fate maintenance, PcG proteins also maintain normal cell physiology, for example cell cycle. In the absence of PcG, ectopic activation of the PcG-repressed genes leads to developmental defects and malignant tumors. Little is known about the molecular nature of ectopic gene expression; especially what differentiates expression of a given gene in the orthotopic tissue (orthotopic expression) and the ectopic expression of the same gene due to PcG mutations. Here we present that ectopic gene expression in PcG mutant cells specifically requires dBRWD3, a negative regulator of HIRA/Yemanuclein (YEM)-mediated histone variant H3.3 deposition. dBRWD3 mutations suppress both the ectopic gene expression and aberrant tissue overgrowth in PcG mutants through a YEM-dependent mechanism. Our findings identified dBRWD3 as a critical regulator that is uniquely required for ectopic gene expression and aberrant tissue overgrowth caused by PcG mutations.

Pathophysiology of Small-Fiber Sensory System in Parkinson's Disease: Skin Innervation and Contact Heat Evoked Potential.

Sensory symptoms are frequent nonmotor complaints in patients with Parkinson's disease (PD). However, few investigations integrally explored the physiology and pathology of the thermonociceptive pathway in PD. We aim to investigate the involvement of the thermonociceptive pathway in PD.Twenty-eight PD patients (16 men, with a mean age and standard deviation of 65.6 ±â€Š10.7 years) free of neuropathic symptoms and systemic disorders were recruited for the study and compared to 23 age- and gender-matched control subjects (12 men, with a mean age and standard deviation of 65.1 ±â€Š9.9 years). We performed skin biopsy, contact heat-evoked potential (CHEP), and quantitative sensory tests (QST) to study the involvement of the thermonociceptive pathway in PD.The duration of PD was 7.1 ±â€Š3.2 (range 2-17 years) years and the UPDRS part III score was 25.6 ±â€Š9.7 (range 10-48) during the off period. Compared to control subjects, PD patients had reduced intra-epidermal nerve fiber (IENF) density (2.48 ±â€Š1.65 vs 6.36 ±â€Š3.19 fibers/mm, P < 0.001) and CHEP amplitude (18.02 ±â€Š10.23 vs 33.28 ±â€Š10.48 µV, P < 0.001). Twenty-three patients (82.1%) had abnormal IENF densities and 18 (64.3%) had abnormal CHEP. Nine patients (32.1%) had abnormal thermal thresholds in the feet. In total 27 patients (96.4%) had at least 1 abnormality in IENF, CHEP, or thermal thresholds of the foot, indicating dysfunctions in the small-fiber nerve system. In control subjects, CHEP amplitude linearly correlated with IENF density (P < 0.001). In contrast, this relationship disappeared in PD (P = 0.312) and CHEP amplitude was negatively correlated with motor severity of PD independent of age, gender, and anti-PD medication dose (P = 0.036), suggesting the influences of central components on thermonociceptive systems in addition to peripheral small-fiber nerves in PD.The present study suggested impairment of small-fiber sensory system at both peripheral and central levels is an intrinsic feature of PD, and skin biopsy, CHEP, and QST provided an integral approach for assessing such dysfunctions.

Imaging signatures of altered brain responses in small-fiber neuropathy: reduced functional connectivity of the limbic system after peripheral nerve degeneration.

Small-fiber neuropathy (SFN) is hallmarked by degeneration of small unmyelinated peripheral nerve fibers in the skin. Traditionally, it has been considered as a pure disorder of the peripheral nervous system. Nevertheless, previous work found that dysfunction of skin nerves led to abnormal recruitment of pain-related regions, suggesting that the brain may be affected in SFN. This report combined structural and functional magnetic resonance imaging to identify structural and functional changes in the brain of 19 patients with SFN compared with 17 healthy controls. We applied tensor-based morphometry to detect brain structural alterations in SFN. Greater volume reduction in pain-processing regions, particularly the bilateral anterior cingulate cortices (ACCs), was associated with greater depletion of intraepidermal nerve fibers, a pathological biomarker of skin nerve degeneration. Based on the hypothesis that structural alterations in the pain-processing regions might impair their functional connectivity, we further applied psychophysiological interaction analysis to assess functional connectivity of the ACCs during noxious heat stimulation. There was significant reduction in functional connectivity from the ACCs to the limbic areas (the parahippocampal gyrus and the posterior cingulate cortex), pain-processing area (the insula), and visuospatial areas (the cuneus). Moreover, the degree of reduction in functional connectivity for the ACC to the amygdala and the precuneus was linearly correlated with the severity of intraepidermal nerve fiber depletion. Our findings suggest that SFN is not a pure peripheral nervous system disorder. The pain-related brain networks tend to break into functionally independent components, with severity linked to the degree of skin nerve degeneration.

Effect of glycemic control on sudomotor denervation in type 2 diabetes.

OBJECTIVE: Sudomotor symptoms are a common component of diabetic autonomic neuropathy, but the pathology of sudomotor innervation and its relationship with glycemic control have remained obscured. RESEARCH DESIGN AND METHODS: We enrolled 42 patients (26 males and 16 females aged 56.64 ± 12.67 years) with diabetic neuropathy defined by symmetric distally predominant sensory symptoms, abnormal nerve conduction studies, and reduced intraepidermal nerve fiber density in the leg. Skin biopsies of the distal leg were immunostained with antiprotein gene product 9.5 for nerve fibers and counterstained with Congo red for sweat glands. Sweat gland innervation index (SGII) was quantified with a new computerized area-based morphometric system. RESULTS: Protein gene product 9.5(+) nerve terminals surrounded secretory coils of the sweat glands in the skin of control subjects. Sudomotor denervation was present in diabetic patients, manifesting as depletion of periglandular nerve fibers with lower SGII compared with 42 age- and sex-matched control subjects (2.54 ± 1.87 vs. 4.68 ± 1.51%, P < 0.001). The SGII was correlated with HbA(1c) (P = 0.011) and was lower in patients with anhidrosis of the feet compared with those with normal sweating of the feet (0.82 ± 0.69 vs. 3.00 ± 1.81%, P = 0.001). Sudomotor denervation was concordant with cardiac autonomic dysfunction as assessed with reduced heart rate variability (P = 0.003). CONCLUSIONS: Sudomotor denervation is a significant presentation of diabetic neuropathy, and the SGII was associated with HbA(1c). A skin biopsy offers a structural assessment of sudomotor innervation.