Microneurography and Intraneural Microstimulation for Upper Limb Sensory Investigation in Healthy and Amputee Subjects (MICROAMP)

Experimental Study to Investigate Sensory Control of the Upper Limb Through Microneurography and to Restore Near-natural Tactile Sensations Through Intraneural Microstimulation in Healthy and Amputee Subjects

The goal of this experimental study is to investigate the somatosensory system through intraneural recording and stimulation of the median nerve in healthy volunteers and participants with upper-limb amputation. The main questions it aims to answer are:

• How does median nerve activity encode tactile perception during different types of mechanical tactile stimulation in healthy subjects?
• How can tactile information be artificially encoded and restored through intraneural microstimulation in both healthy subjects and upper-limb amputee participants? How rich and functionally meaningful is the restored sensory information?
• What are the neurophysiological mechanisms underlying tactile stimulus processing and the associated patterns of brain activation during tactile stimulation?

Participants will undergo median nerve recordings using microneurography during controlled mechanical tactile stimulation, as well as intraneural microstimulation with specific patterns to evoke near-natural tactile sensations. They will perform perceptual reporting tasks related to stimulus type, intensity, and localization, as well as psychophysical tests under different stimulation conditions. When possible, they will also undergo non-invasive recordings of brain activity using electroencephalography during sensory stimulation.

Study Overview

• Status: Recruiting
• Conditions: Healthy Subjects; Upper Limb Amputation
• Intervention / Treatment: Procedure: Microneurography; Procedure: Intraneural Microstimulation

Detailed Description

Participants will attend the laboratory where the entire research protocol will be conducted in a single visit lasting up to 4 hours.

Medical history and a physical examination will be collected. In participants with amputation, additional clinical information from previous neurological assessments will be reviewed (including medical records, nerve conduction velocity data, and ultrasound or MRI examinations required to verify inclusion/exclusion criteria). Psychometric tests will also be administered to assess language abilities, visuospatial skills, and general intelligence, ensuring that participants are able to understand and perform the experimental tasks. If inclusion and exclusion criteria are met, participants will undergo microneurography and/or intraneural microstimulation procedures. Participants will be seated comfortably, with the dominant arm (healthy volunteers) or the residual limb (participants with amputation) supported. A trained medical operator will identify the median nerve using external stimulation and/or ultrasound guidance to assist electrode insertion. The active electrode will be inserted into the nerve, while a reference electrode will be placed in the subcutaneous tissue a few centimeters away. Correct electrode placement will then be refined using intraneural stimulation. Once the nerve fascicle is reached, tactile stimulation of the hand will be used to identify single mechanoreceptive units. Final electrode placement will be confirmed by visual and auditory inspection of the neural signal. The median nerve activity must be clearly distinguishable from background activity when mechanical stimuli are applied to the skin. During electrode insertion, participants will be instructed to remain still until the procedure is completed. The intraneural microstimulation session, performed in both healthy volunteers and participants with upper-limb amputation, is preceded by peripheral neural recordings using microneurography during the presentation of tactile stimuli (e.g., Von Frey filaments). This step is used for accurate nerve localization and preliminary assessment of the receptors and their receptive fields. Once the neural target is identified, participants undergo intraneural stimulation involving the perception and recognition of artificially generated tactile stimuli. These stimuli are delivered via intraneural microstimulation and are derived from mechanoneural transduction, using a sensorized artificial finger interacting with different surfaces to encode surface-dependent tactile information. Participants will be asked to recognize different properties of the presented stimuli. During the tests, electroencephalographic (EEG) activity may be recorded using a 128-channel EEG system, synchronized with the onset of stimulation.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Stefano Taddei; Phone Number: +39 050993699; Email: stefano.taddei@unipi.it
• Study Contact Backup: Name: Calogero Maria Oddo; Phone Number: +39 050 883111; Email: calogero.oddo@santannapisa.it

Study Locations

• Italy
  • Pisa
    • Pisa, Pisa, Italy, 56127
      • Recruiting
      • Laboratorio Congiunto di Microneurografia e Microneurostimolazione
      • Contact: Calogero Maria Oddo, PhD; Phone Number: +39 050 883111; Email: calogero.oddo@santannapisa.it
      • Principal Investigator: Calogero Maria Oddo, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Healthy participants

• Age between 18-60 years, of any sex
• Signed informed consent
• No neurological diseases
• Presence of both intact upper limbs
• Normal language, visuospatial, and general intellectual abilities, assessed using the Wechsler Adult Intelligence Scale-Revised (WAIS-R) (Appendix 1)

Amputee participants

• Age between 18-60 years, of any sex
• Signed informed consent
• Upper-limb amputation (transradial or hand amputation)
• Stable amputation for at least one year
• Normal language, visuospatial, and general intellectual abilities, assessed using the Wechsler Adult Intelligence Scale-Revised (WAIS-R) (Appendix 1)
• Evidence of residual peripheral nerve function in the stump, based on nerve conduction studies as documented in clinical records

Exclusion Criteria:

Healthy participants

• Conditions affecting perceptual abilities
• Inability to provide informed consent
• Pregnancy or breastfeeding (self-reported)
• Clinical conditions that, in the judgment of the investigator responsible for recruitment, may interfere with microneurography, microstimulation, and EEG procedures
• Current or past substance abuse
• Brain injury with residual motor impairment
• Depression
• Presence of neurological or musculoskeletal disorders
• Diabetes mellitus
• Current or previous dermatological conditions
• Morphological nerve abnormalities, as indicated by ultrasound or MRI findings in clinical records
• Upper-limb amputation

Amputee participants

• Psychological and/or cognitive disorders
• Inability to provide informed consent
• Pregnancy or breastfeeding (self-reported)
• Clinical conditions that, in the judgment of the investigator responsible for recruitment, may interfere with microneurography, microstimulation, and EEG procedures
• Current or past substance abuse
• Brain injury with residual motor impairment
• Depression
• Presence of neurological or musculoskeletal disorders
• Diabetes mellitus
• Current or previous dermatological conditions
• Morphological nerve abnormalities, as indicated by ultrasound or MRI findings in clinical records
• Bilateral upper-limb amputation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Microneurographic Session; During MNG session, microneurographic signals are recorded while mechanical tactile stimuli (e.g., Von Frey filaments) are applied. This recording-only task is used to characterize the mechanoreceptor properties, including receptive field mapping, response type, and firing behavior.	Procedure: Microneurography; Microneurography is a minimally invasive neurophysiological technique that allows direct recording of the electrical activity of single peripheral nerve fibers using specific microelectrodes inserted into the nerve.
Experimental: Intraneural Microstimulation Session; During INMS session, intraneural microstimulation is delivered via the microelectrode to evoke tactile sensations. Stimulation patterns are generated from sensor-based interactions with different surfaces and are used to assess tactile perception, including stimulus recognition, intensity, and localization in both healthy and amputee participants.	Procedure: Intraneural Microstimulation; Intraneural microstimulation is a minimally invasive neurophysiological technique in which small electrical currents are delivered through a microelectrode inserted into a peripheral nerve to selectively activate nerve fibers and evoke sensory perceptions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mechanoreceptor identification success rate	The proportion of experimental sessions in which a single mechanoreceptive afferent is successfully isolated and identified using MNG during controlled mechanical tactile stimulation, expressed as the percentage of successful recordings (%).	During the experimental protocol (up to 3 hours)
Mechanoreceptor classification accuracy	The accuracy of mechanoreceptor type classification (e.g., SA1, SA2, RA, PC) based on MNG recordings during mechanical tactile stimulation, expressed as the percentage of correctly classified receptors (%).	During the experimental session (up to 3 hours)
Peripheral afferent firing rate during tactile stimulation	The mean firing rate (spikes/s) of mechanoreceptive afferents recorded by MNG during controlled mechanical tactile stimulation.	During the experimental session (up to 3 hours)
Tactile mechanical detection threshold	The minimum stimulus intensity (expressed in grams of calibrated Von Frey Hairs) required to evoke a consistent neural response during mechanical tactile stimulation.	During the experimental session (up to 3 hours)
Receptive field size of mechanoreceptive afferents	The spatial extent of skin area (mm²) eliciting neural responses during mechanical tactile stimulation mapped via MNG.	During the experimental session (up to 3 hours)
Perceived sensory perception during intraneural microstimulation	Participant-reported sensory percepts will be classified into predefined categories (e.g., pressure, vibration, tingling, tapping) and summarized as the frequency and percentage of each sensory class across stimulation conditions.	During the experimental protocol (up to 3 hours)
Perceived intensity of tactile sensations elicited during intraneural microstimulation	Participants will rate the perceived intensity of each evoked sensation using a numerical rating scale from 0 (no sensation) to 10 (maximum imaginable intensity). Mean and standard deviation (or median and interquartile range) will be reported for each stimulation condition.	During the experimental protocol (up to 3 hours)
Perceived location of tactile sensations elicited during intraneural microstimulation	Participants will indicate the anatomical location of each evoked sensation on a standardized hand map. Responses will be summarized as frequencies and percentages for each anatomical region.	During the experimental protocol (up to 3 hours)
Tactile discrimination performance	Discrimination performance will be assessed using a two-alternative forced-choice (2AFC) psychophysical paradigm during intraneural microstimulation. Performance will be quantified using the Elo rating system, a continuous score derived from pairwise stimulus comparisons. The Elo rating has no predefined minimum or maximum value. Higher Elo scores indicate greater discrimination performance.	During the experimental session (up to 3 hours)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-related potential amplitude during intraneural microstimulation	Event-related potentials (ERPs) elicited by intraneural microstimulation and recorded using 128-channel EEG will be quantified by peak amplitude (µV) of stimulus-locked cortical responses.	During the experimental protocol (up to 3 hours)
Event-related potential latency during intraneural microstimulation	Event-related potentials (ERPs) elicited by intraneural microstimulation and recorded using 128-channel EEG will be quantified by peak latency (ms) of stimulus-locked cortical responses.	During the experimental protocol (up to 3 hours)
EEG spectral power modulation during intraneural microstimulation	Changes in EEG spectral power recorded using 128-channel EEG during intraneural microstimulation expressed as spectral power (µV²) or percentage change from baseline (%)	During the experimental session (up to 3 hours)
Decoding accuracy of tactile stimulation conditions from EEG signals	Machine learning-based classification of tactile stimulation conditions using EEG-derived features (classification accuracy %)	During the experimental session (up to 3 hours)

Collaborators and Investigators

• Sponsor: Azienda Ospedaliero, Universitaria Pisana
• Collaborators: Scuola Superiore di Studi Universitari e di Perfezionamento Sant'Anna

Publications and helpful links

General Publications

• Oddo CM, Raspopovic S, Artoni F, Mazzoni A, Spigler G, Petrini F, Giambattistelli F, Vecchio F, Miraglia F, Zollo L, Di Pino G, Camboni D, Carrozza MC, Guglielmelli E, Rossini PM, Faraguna U, Micera S. Intraneural stimulation elicits discrimination of textural features by artificial fingertip in intact and amputee humans. Elife. 2016 Mar 8;5:e09148. doi: 10.7554/eLife.09148.
• Vallbo AB. Microneurography: how it started and how it works. J Neurophysiol. 2018 Sep 1;120(3):1415-1427. doi: 10.1152/jn.00933.2017. Epub 2018 Jun 20.
• Ackerley R, Watkins RH. Microneurography as a tool to study the function of individual C-fiber afferents in humans: responses from nociceptors, thermoreceptors, and mechanoreceptors. J Neurophysiol. 2018 Dec 1;120(6):2834-2846. doi: 10.1152/jn.00109.2018. Epub 2018 Sep 26.
• Statache M, Filosa M, Ballanti S, D'Alesio G, Di Salvo G, Camboni D, Oddo CM. Neuromorphic Touch Sensors for Pleasantness Encoding via Spike Patterns: A Bio-Inspired Artifical Fingertip for Restoring Affective Sensations. IEEE Sensors, 2024, Kobe, Japan. doi: 10.1109/SENSORS60989.2024.10784624.

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: May 21, 2026
• First Submitted That Met QC Criteria: July 7, 2026
• First Posted (Actual): July 9, 2026

Study Record Updates

• Last Update Posted (Actual): July 9, 2026
• Last Update Submitted That Met QC Criteria: July 7, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Microneurography; Upper limb amputation; Somatosensory System; Intraneural Microstimulation
• Other Study ID Numbers: 18385_TADDEI; TUNEBEAM_MICROAMP (Other Identifier: Tuscany Region)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Upon publication of results, anonymized data and analysis code will be shared to ensure reproducibility.
• IPD Sharing Time Frame: Upon publication of results
• IPD Sharing Access Criteria: Data and code will be available for research purposes upon request to authors.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No