Itching Frequency and Neuroanatomic Correlates in Frontotemporal Lobar Degeneration.

Importance: Itching is common in geriatric populations and is frequently linked to dermatological or systemic conditions. Itching engages specific brain regions that are implicated in the pathogenesis of frontotemporal lobar degeneration spectrum disorders (FTLD-SD). Thus, itching of undetermined origin (IUO) may indicate the presence of a neurodegenerative process. Objective: To compare the frequency of itching in FTLD-SD and Alzheimer disease (AD) and to determine the neuroanatomical underpinnings of IUO. Design, Setting, and Participants: This case-control study evaluated data and brain magnetic resonance images (MRIs) for participants with FTLD-SD or AD. Participants of a research study on FTLD-SD at the University of California, San Francisco, Memory and Aging Center were evaluated from May 1, 2002, to December 31, 2021. The exposure group underwent structural brain MRI within 6 months of initial diagnosis. Research visit summaries were reviewed to validate qualitative details and accurately identify itching with undetermined origin (IUO). Exposures: Symptoms suggestive of FTLD-SD or AD. Main Outcomes and Measures: Frequency of itching in FTLD-SD and AD and neuroanatomic correlates. Results: A total of 2091 research visit summaries were reviewed for 1112 patients exhibiting symptoms indicative of FTLD-SD or AD. From 795 records where itching or a related phrase was endorsed, 137 had IUO. A total of 454 participants were included in the study: 137 in the itching group (mean [SD] age, 62.7 [9.9] years; 74 [54%] females and 63 males [46%]) and 317 in the nonitching group (mean [SD] age, 60.7 [10.8] years; 154 [49%] females and 163 males [51%]). Groups were similar in age, sex, and disease severity. More frequent itching was found in FTLD-SD (95/248 patients [38%], of which 44 [46%] had behavioral variant frontotemporal dementia [bvFTD]) compared with the AD group (14/77 patients [18%]; P = .001). The odds of itching were 2.4 (95% CI, 1.48-3.97) times higher for FTLD-SD compared with all other cases of dementia. Compared with healthy controls, the group with IUO exhibited greater gray matter atrophy bilaterally in the amygdala, insula, precentral gyrus, and cingulum, as well as in the right frontal superior gyrus and thalamus. Among patients with bvFTD and itching vs bvFTD without itching, itching was associated with right-lateralized gray matter atrophy affecting the insula, thalamus, superior frontal gyrus, and cingulum. Conclusions and Relevance: Among individuals with IUO, FTLD-SD was disproportionately represented compared with AD. In FTLD-SD, dysfunction in the right anterior insula and its connected regions, including the right precentral gyrus, cingulum, and bilateral amygdala, contribute to dysregulation of the itching-scratching networks, resulting in uncontrollable itching or skin picking. Awareness among physicians about the relationship between neurodegeneration and itching may help in the management of itch in older individuals. Further studies are needed to determine the best treatments for these symptoms in patients with neurodegenerative disorders.

Exploration of the effects of Yang's pricking-cupping therapy on eczema-induced pruritus based on rs-fMRI. / 基于rs-fMRI探讨杨氏絮刺火罐对湿疹瘙痒的影响.

OBJECTIVES: To explore the clinical effect of Yang's pricking-cupping therapy and its central mechanism in treatment of eczema-induced pruritus using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: Fifty patients with eczema-induced pruritus were enrolled in the observation group, and 50 healthy subjects were enrolled in the control group. No any intervention was delivered in the control group. Yang's pricking-cupping therapy was operated at Dazhui (GV 14) and bilateral Quchi (LI 11), Xuehai (SP 10) and Sanyinjiao (SP 6), once a week, lasting 6 weeks in the observation group. The scores of the 12-item pruritus severity scale (12-PSS), the eczema area and severity index (EASI), the dermatology life quality index (DLQI), the Pittsburgh sleep quality index (PSQI), and the self-rating anxiety scale (SAS) were compared before and after treatment in the observation group. The rs-fMRI scanning was conducted and the regional homogeneity (ReHo) analysis performed in all of the participants before and after treatment in the observation group, as well as at the time of subject enrollment in the control group. The correlation was analyzed between ReHo values in the different areas of the brain and the scores of the above scales. RESULTS: Compared with those before treatment, the scores of 12-PSS, EASI, DLQI, PSQI, and SAS were reduced after treatment in the observation group (P<0.01, P<0.05). ReHo values were increased in the right caudate nucleus, the right middle temporal gyrus, the right orbitofrontal gyrus, the right thalamus and the left angular gyrus before treatment in the observation group when compared with those in the control group (P<0.001); and ReHo values in the above areas of the brain were decreased after treatment when compared with those before treatment in the observation group (P<0.001). In comparison with the control group, ReHo values were reduced in the left middle temporal gyrus, the left superior parietal lobule and the left supplementary motor area in the observation group before treatment (P<0.001); while when compared with those before treatment, ReHo values in the above areas of the brain were elevated after treatment in the observation group (P<0.001). Before treatment, ReHo value in the left supplementary motor area was positively correlated with 12-PSS score (r=0.432, P=0.004), and the value in the right orbitofrontal gyrus was negatively correlated with PSQI score (r=-0.318, P=0.04) in the observation group. After treatment, ReHo value in the left superior parietal lobule was positively correlated with 12-PSS score (r=0.384, P=0.012) in the observation group. CONCLUSIONS: The abnormal cerebral functional activities are exhibited in multiple areas of the brain involved in stimulus response, emotional regulation, behavior control and attention in the patients with eczema-induced pruritus. Yang's pricking-cupping therapy can effectively relieve the pruritus symptoms and skin lesions of the patients, which may be related to reversing the abnormal cerebral functional activities induced by pruritus.

Altered resting-state functional connectivity of default mode network in brachioradial pruritus.

BACKGROUND: Patients with chronic pruritus (CP) have a low quality of life, thus it is important to gain a better understanding of the underlying processes. Previous functional magnetic resonance imaging studies at rest (rsfMRI) have shown that mainly areas associated with the default mode network (DMN), sensorimotor (SMN), frontoparietal (FPN) and salience networks (SN) are involved in the processing of itch in patients with chronic pruritus (CP), as well as the cortico-striatal circuit, which is involved in the motoric preparation of scratching. rsfMRI studies on functional connectivity (FC) patterns of resting-state networks (RSNs) in patients with inflammatory atopic dermatitis (AD) or with neuropathic brachioradial pruritus (BRP) compared with healthy controls (HC) are lacking. OBJECTIVES: The main goals of this study were to investigate whether functional connectivity within networks and areas associated with itch detection and processing are altered in patients with AD and BRP compared with matched healthy controls by rsfMRI, respectively. METHODS: Patients with AD (n = 28) and with BRP (n = 28) were compared with corresponding matched healthy controls by rsfMRI. Group-specific RSNs were identified by independent component analysis (ICA) and between-group differences in the RSNs were analysed by dual regression technique. Seed-based functional connectivity was analysed in several itch-related brain regions belonging to the DMN, SN and FPN, respectively. RESULTS: ICA and seed-based analyses revealed decreased functional connectivity in BRP compared with HC specially within the DMN including the precuneus and cingulate cortex. For AD patients in comparison with HC, as well as when BRP and AD patients were compared directly, no significant FC differences at rest were seen. CONCLUSIONS: Our findings point towards decreased FC particularly in the DMN at rest in patients with BRP. These results seem to indicate that central connectivity patterns at rest differentially encode itch in BRP and AD.

Specific Patterns of Spinal Metabolite Ratio Underlying α-Me-5-HT-evoked Pruritus Compared with Compound 48/80 Based on Proton Nuclear Magnetic Resonance Spectroscopy.

Mechanisms of pruritus are implicated in the dysregulation of the metabolites in the spinal cord. We investigated pruritus behavioral testing in three groups of young adult male C57Bl/6 mice, including one group treated with normal saline, while the other groups intradermally injected with α-Me-5-HT (histamine-independent pruritogen), compound 48/80 (histamine-dependent pruritogen) at the nape skin of the neck, respectively. Proton nuclear magnetic resonance spectroscopy (MRS) was used to compare spinal metabolites from the vertebral cervical among three groups, and to study the association of spinal metabolite ratio and pruritus intensity. The MRS-measured N-acetylaspartate-to-myoinositol ratio (NAA/Ins) was significantly correlated with the number of scratches between normal saline group and 48/80 group or α-Me-5-HT group (both P<0.0001), indicating that NAA/Ins may be a robust surrogate marker of histamine-independent/dependent pruritogen. There was significant difference in Glu/Ins between normal saline group and 48/80 group (P=0.017), indicating that Glu/Ins may be a surrogate marker of histamine-dependent pruritogen, while GABA/Ins was highly significantly different between normal saline group and α-Me-5-HT group (P=0.008), suggesting that GABA/Ins may be a surrogate marker of histamine-independent pruritogen. MRS may reflect the extent of pruritus intensity elicited by α-Me-5-HT and compound 48/80 with sensitivity similar to the number of scratches, and above potential markers need to be further validated in pre-clinical and clinical treatment trials.

Assessment of the impact of sex in intensity, skin flares and central processing of histaminergic itch-A pilot study.

Itch is the commonest skin-related symptom, and sex differences are increasingly recognised as important determinants in stratified medicine, but only little is known about sex differences in itch. Questionnaire-based studies indicated that women perceive itch as more intensive and bothersome in comparison with men. However, data of studies using standardised itch models to objectify sex differences are scarce and inconsistent. To determine sex differences in intensity, skin flares and central processing of histaminergic itch, we compared 15 female and 15 male healthy subjects in a double-blinded, within-subject, placebo-controlled study using a histamine skin prick itch model (histamine 1% applied onto the volar forearm) and functional MRI. We found trends in higher mean itch intensity (0.58 VAS, CI 95% 0.004-1.19, P = .056) and maximum itch intensity (men 3.93 VAS ± 0.39 SD at 3 minutes, women 4.73 VAS ± 0.31 SD at 4 minutes, P = .073) in women paralleled by a trend in a stronger positive correlation between itch intensity and blood oxygen level-dependent (BOLD) activity in brain structures identified during itch in comparison with men (rs in women: .46, P = .08, rs in men: .07, P = .79). The erythema and wheal following histamine skin pricking were (non-significantly) larger in men, indicating that higher mean itch intensities on the right volar forearm in women may not be explained by more intense flares. The comparison of the activation patterns between the sexes revealed increased activity in men compared to women in the left middle temporal gyrus (temporooccipital part)/lateral occipital cortex. Thus, our findings indicate that histaminergic itch perception and central itch processing differ between the sexes under standardised conditions.

Nocebo-induced modulation of cerebral itch processing - An fMRI study.

It has been shown repeatedly that perceiving itch-related pictures or listening to a lecture on itch can enhance itch sensation and scratching behaviour (Niemeier and Gieler, 2000; Holle et al., 2012; Lloyd et al., 2013), indicating that itch is strongly influenced by expectations. Using fMRI, we investigated the neural correlates of the itch-related nocebo effect in healthy male and female human subjects. Itch sensation on the left forearm was induced by cutaneous histamine application and thermally modulated, with cooling leading to higher itch. Nocebo-induced aggravation of histaminergic itch was achieved by ostensibly treating volunteers with "transcutaneous electrical nerve stimulation (TENS)" about which subjects were instructed that it would increase itch. During a conditioning phase subjects indeed experienced stronger itch due to slightly altered cooling and histamine concentrations, but attributed it to the alleged "TENS stimulation". Importantly, in the subsequent test phase where no "TENS" or electrical stimulation was applied, volunteers significantly reported stronger itch during the nocebo as compared to the control condition. Comparing BOLD responses during nocebo in contrast to control, we observed increased activity in contralateral (right) rolandic operculum. Opercular involvement was repeatedly reported in studies related to the expectation of stimulus intensification and might thus represent an early area integrating expectation information with somatosensory information. Finally, functional coupling between the insula and the periaqueductal gray (PAG) was enhanced specifically in the nocebo condition. This cortex-PAG interaction indicates that context-dependent top-down modulation during itch might represent a shared mechanism with other modalities such as pain.

Prevalence and Clinical Characteristics of Itch in Vitiligo and Its Clinical Significance.

OBJECTIVE: Vitiligo usually presented as asymptomatic depigmented macules and patches. Little is known regarding itch in vitiligo. This study aimed to evaluate the prevalence and characteristics of itch in vitiligo patients. PATIENTS AND METHODS: A cross-sectional study was conducted on vitiligo patients. Itch character and intensity were determined through questionnaires. Evaluation was also made by dermatologists to define vitiligo subtype, body surface area, Koebner phenomenon (KP), and so on. Data were assessed by computer software. Results were considered statistically significant if p < 0.05. RESULTS: Among 402 patients, itch on vitiliginous lesion presented in 20.2%. Prevalence of itch was most common in focal vitiligo (29.4%), followed by segmental vitiligo (20.3%) and nonsegmental vitiligo (19.6%), respectively. Tingling sensation was the most common itch-related symptom (82.7%). The median itch intensity is 5 by 10-point visual analog scale. Daily activity and sleep disturbance were observed in 60.5% and 39.5% of patients who experience itch. Itch occurred approximately 3 days prior to the development of lesions in 48.1% of patients. Thirty-two patients (78.1%) with both itch and KP type IIb had active disease. CONCLUSIONS: Itch in vitiligo is not uncommon. The presence of itch with KP type IIb may warrant the active vitiligo.

Pruritus may be a common symptom related to neuromyelitis optica spectrum disorders.

BACKGROUND: To evaluate pruritus in patients with neuromyelitis optica spectrum disorders (NMOSD) and to characterize the relationship between pruritus and lesions of NMOSD. METHODS: 61 patients with NMOSD were included in the study and their medical records were reviewed for pruritus, neurological symptoms and magnetic resonance imaging (MRI) images. We focused on the patients' history of pruritus, especially the severity, duration, region, and the relationship of pruritus with other symptoms of NMOSD. RESULTS: Of the 61 patients with NMOSD, 59 had longitudinally extensive transverse myelitis (LETM). 38 of these patients (64.4%) reported pruritus during the course of their illness, with 16 patients reporting pruritus as the initial symptoms followed by limb weakness. In 35 of 38 patients (92.1%), pruritus was located within the dermatomes innervated by the spinal nerves from the involved spinal cord. CONCLUSION: Our results show that pruritus is a common symptom of NMOSD and relates to the lesions in the spinal cord. Pruritus may indicate a new episode of myelitis in patients with NMOSD.

Spinal cord interneurons expressing the gastrin-releasing peptide receptor convey itch through VGLUT2-mediated signaling.

Itch is a sensation that promotes the desire to scratch, which can be evoked by mechanical and chemical stimuli. In the spinal cord, neurons expressing the gastrin-releasing peptide receptor (GRPR) have been identified as specific mediators of itch. However, our understanding of the GRPR population in the spinal cord, and thus how these neurons exercise their functions, is limited. For this purpose, we constructed a Cre line designed to target the GRPR population of neurons (Grpr-Cre). Our analysis revealed that Grpr-Cre cells in the spinal cord are predominantly excitatory interneurons that are found in the dorsal lamina, especially in laminae II-IV. Application of the specific agonist gastrin-releasing peptide induced spike responses in 43.3% of the patched Grpr-Cre neurons, where the majority of the cells displayed a tonic firing property. Additionally, our analysis showed that the Grpr-Cre population expresses Vglut2 mRNA, and mice ablated of Vglut2 in Grpr-Cre cells (Vglut2-lox;Grpr-Cre mice) displayed less spontaneous itch and attenuated responses to both histaminergic and nonhistaminergic agents. We could also show that application of the itch-inducing peptide, natriuretic polypeptide B, induces calcium influx in a subpopulation of Grpr-Cre neurons. To summarize, our data indicate that the Grpr-Cre spinal cord neural population is composed of interneurons that use VGLUT2-mediated signaling for transmitting chemical and spontaneous itch stimuli to the next, currently unknown, neurons in the labeled line of itch.

Brain mechanism of itch in atopic dermatitis and its possible alteration through non-invasive treatments.

Atopic dermatitis (AD) is a common chronic skin disease that is characterized by intense pruritus and has high impairment of quality of life. AD is often described as "the itch that rashes, rather than the rash that itches". Several studies suggest that mechanisms of central modulation play an important role in the development and maintenance of chronic itch. Therefore, treating the neurosensory aspects of itch is an important part in the management of chronic itch. However, little attention has been paid to the role of the central nervous system in the processing of itch in AD. Targeting itch-related anatomical structures in the brain with non-invasive treatments such as psychological interventions and transcranial Direct Current Stimulation (tDCS) could have an antipruritic effect in AD. Therefore, in this review article, we discuss the current progress in brain imaging research of itch, as well as the efficacy of non-invasive interventions for itch relief in this patient group.

Is pruritus an indicator of aquaporin-positive neuromyelitis optica?

BACKGROUND: Recently, pruritus has been recognised as an important association with neuromyelitis optica spectrum disorders (NMOSD). OBJECTIVE: To determine the clinical and radiological characteristics of patients with NMOSD and pruritus. METHODS AND RESULTS: Among 57 consecutive patients with NMOSD, 15 (26.3% women) reported pruritus. All had aquaporin-4 (AQP4) antibodies. The mean age was 34.5 ± 9.1 years, age at onset was 31.3 ± 11.0 years and the duration of illness was 3.9 ± 3.1 years. Pruritus preceded the neurological disturbances in all the patients. Predominant patients experienced pruritus in the cervical dermatome (66.7%) followed by cervicothoracic region (13.3%), trigeminal nerve (13.3%) and lumbar region (6.7%). Lesions extending from cervicomedullary junction up to the thoracic segment was the most common site of affection (40%) followed by cervicothoracic (26.7%), cervicomedullary junction to cervical cord (13.3%), cervical cord (6.7%) and thoracic segment (6.7%). CONCLUSION: This report is one of the largest series reporting the close association of pruritus with onset of neurological symptoms in NMOSD. It highlights the importance of recognising this rare symptom which may help in making a correct diagnosis in a patient with suspected demyelinating disorder. In a patient with NMOSD, early treatment with immunomodulation during pruritus may prevent or minimise occurrence of neurological dysfunction.

Nasobiliary Drainage for Benign Recurrent Intrahepatic Cholestasis in Patients Refractory to Standard Therapy.

PURPOSE: Benign recurrent intrahepatic cholestasis (BRIC) is characterized by episodic cholestasis and pruritus without anatomical obstruction. The aim of this study was to evaluate the safety and efficacy of nasobiliary drainage (NBD) in patients with BRIC refractory to medical therapy and to determine whether the use of NBD prolongs the episode duration. METHODS: This was a multicenter retrospective study consisting of 33 patients suffering from BRIC. All patients were administrated medical treatment and 16 patients who were refractory to standard medical therapies improved on treatment with temporary endoscopic NBD. Duration of treatment response and associated complications were analyzed. RESULTS: Sixteen patients (43% females) underwent 25 NBD procedures. The median duration of NBD was 17 days. There were significant improvements in total and direct bilirubin and alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and gamma-glutamyl transpeptidase on the 3rd day of NBD. Longer clinical remission was monitored in the NBD group. Post-endoscopic retrograde cholangiopancreatography pancreatitis was observed in one of 16 cases. CONCLUSION: NBD effectively eliminates BRIC in all patients and improves biomarkers of cholestasis. It can be suggested that patients with attacks of BRIC can be treated with temporary endoscopic NBD; however, the results of this study should be confirmed by prospective studies in the future.

PIACS: A System for the Automatic Detection, Categorization and Comparison of Scratch-Related Skin Lesions in Dermatology.

OBJECTIVE: In the treatment of chronic pruritus-related, scratch-induced skin lesions the categorization, counting and temporal comparison are common methodologies. The observation requires a good memory and expertise in this field to gain comparable findings for this time-consuming process. Digital image processing aims at supporting such manual detections. The objective is to develop a software tool for automatic image detection and comparison. The new photographic setting implies the usage of markers to derive the brightness and size of lesions. MATLAB has been used for the software development. The newly defined setting allows taking standardized images of pruritus-associated cutaneous lesions for detection and comparison. The tool named PIACS (Prurigo Image Analyzing and Comparing System) allows automatically detecting, categorizing and comparing lesions based on digital images.

Sex differences in itch perception and modulation by distraction--an FMRI pilot study in healthy volunteers.

BACKGROUND: Even though itch is a common syndrome of many diseases there is only little knowledge about sex and gender differences in pruritus, especially in central itch perception and modulation. To our knowledge, this is the first fMRI study examining sex differences in perception and its modulation by distraction. METHODS: Experimental itch was induced by application of histamine (0.1 mM) via microdialysis fibers twice at the left forearm and twice at the left lower leg in 33 healthy volunteers (17 females, 16 males). The brain activation patterns were assessed by fMRI during itch without and with distraction (Stroop task). Between the various conditions, subjects were asked to rate itch intensity, desire to scratch and pain intensity. In a second experiment in 10 of the 33 volunteers histamine was replaced by saline solution to serve as control for the 'Stroop' condition. RESULTS: Women generally presented higher itch intensities compared to men during itch over the course of the experiment. A more specific analysis revealed higher itch intensities and desire to scratch in women during experimental induced itch that can be reduced by distraction at the lower legs when itch is followed by 'Stroop'. In contrast, men depicted significant reduction of 'itch' by 'Stroop' at the forearms. Women depicted higher brain activation of structures responsible for integration of sensory, affective information and motor integration/planning during 'itch' and 'Stroop' condition when compared to men. No sex differences were seen in the saline control condition. CONCLUSION: Women and men exhibited localisation dependent differences in their itch perception with women presenting higher itch intensities and desire to scratch. Our findings parallel clinical observations of women reporting higher itch intensities depending on itch localisation and suffering more from itch as compared to men.

Itch and the brain.

The sensation of itch - defined as unpleasant sensation inducing the urge to scratch - is processed by a network of different brain regions contributing to the encoding of sensory, emotional, attention-dependent, cognitive-evaluative and motivational patterns. Patients with atopic eczema show different activation patterns and kinetics compared to healthy volunteers. This review summarizes current studies investigating itch in the brain.