Publications

2018
Bauer CM, Cattaneo Z, Merabet LB. Early Blindness is Associated with Increased Volume of the Uncinate Fasciculus. Eur J Neurosci. 2018.Abstract
Growing evidence demonstrates dramatic structural and functional neuroplastic changes in individuals born with early onset blindness. For example, crossmodal sensory processing at the level of the occipital cortex appears to be associated with adaptive behaviors in the blind. However, detailed studies examining the structural properties of key white matter pathways in other regions of the brain remain limited. Given that blind individuals rely heavily on their sense of hearing, we examined the structural properties of two important pathways involved with auditory processing namely, the uncinate and arcuate fasciculi. High angular resolution diffusion imaging (HARDI) tractography was used to examine structural parameters (i.e. tract volume and quantitative anisotropy, or QA) of these two fasciculi in a sample of 13 early blind individuals and 14 normally sighted controls. Compared to controls, early blind individuals showed a significant increase in the volume of the left uncinate fasciculus. A small area of increased QA was also observed half way along the right arcuate fasciculus in the blind group. These findings contribute to our knowledge regarding the broad neuroplastic changes associated with profound early blindness. This article is protected by copyright. All rights reserved.
2017
Bauer CM, Zajac LE, Koo B-B, Killiany RJ, Merabet LB. Age-related changes in structural connectivity are improved using subject-specific thresholding. J Neurosci Methods. 2017;288 :45-56.Abstract
BACKGROUND: Deterministic diffusion tractography obtained from high angular resolution diffusion imaging (HARDI) requires user-defined quantitative anisotropy (QA) thresholds. Most studies employ a common threshold across all subjects even though there is a strong degree of individual variation within groups. We sought to explore whether it would be beneficial to use individual thresholds in order to accommodate individual variance. To do this, we conducted two independent experiments. METHOD: First, tractography of the arcuate fasciculus and network connectivity measures were examined in a sample of 14 healthy participants. Second, we assessed the effects of QA threshold on group differences in network connectivity measures between healthy young (n=19) and old (n=14) individuals. RESULTS: The results of both experiments were significantly influenced by QA threshold. Common thresholds set too high failed to produce sufficient reconstructions in most subjects, thus decreasing the likelihood of detecting meaningful group differences. On the other hand, common thresholds set too low resulted in spurious reconstructions, providing deleterious results. COMPARISON WITH EXISTING METHODS: Subject specific thresholds acquired using our QA threshold selection method (QATS) appeared to provide the most meaningful networks while ensuring that data from all subjects contributed to the analyses. CONCLUSIONS: Together, these results support the use of a subject-specific threshold to ensure that data from all subjects are included in the analyses being conducted.
Ferrari C, Vecchi T, Merabet LB, Cattaneo Z. Blindness and social trust: The effect of early visual deprivation on judgments of trustworthiness. Conscious Cogn. 2017;55 :156-164.Abstract
Investigating the impact of early visual deprivation on evaluations related to social trust has received little attention to date. This is despite consistent evidence suggesting that early onset blindness may interfere with the normal development of social skills. In this study, we investigated whether early blindness affects judgments of trustworthiness regarding the actions of an agent, with trustworthiness representing the fundamental dimension in the social evaluation. Specifically, we compared performance between a group of early blind individuals with that of sighted controls in their evaluation of trustworthiness of an agent after hearing a pair of two positive or two negative social behaviors (impression formation). Participants then repeated the same evaluation following the presentation of a third (consistent or inconsistent) behavior regarding the same agent (impression updating). Overall, blind individuals tended to give similar evaluations compared to their sighted counterparts. However, they also valued positive behaviors significantly more than sighted controls when forming their impression of an agent's trustworthiness. Moreover, when inconsistent information was provided, blind individuals were more prone to revise their initial evaluation compared to controls. These results suggest that early visual deprivation may have a dramatic effect on the evaluation of social factors such as trustworthiness.
Kim JS, Kanjlia S, Merabet LB, Bedny M. Development of the Visual Word Form Area Requires Visual Experience: Evidence from Blind Braille Readers. J Neurosci. 2017;37 (47) :11495-11504.Abstract
Learning to read causes the development of a letter- and word-selective region known as the visual word form area (VWFA) within the human ventral visual object stream. Why does a reading-selective region develop at this anatomical location? According to one hypothesis, the VWFA develops at the nexus of visual inputs from retinotopic cortices and linguistic input from the frontotemporal language network because reading involves extracting linguistic information from visual symbols. Surprisingly, the anatomical location of the VWFA is also active when blind individuals read Braille by touch, suggesting that vision is not required for the development of the VWFA. In this study, we tested the alternative prediction that VWFA development is in fact influenced by visual experience. We predicted that in the absence of vision, the "VWFA" is incorporated into the frontotemporal language network and participates in high-level language processing. Congenitally blind (n = 10, 9 female, 1 male) and sighted control (n = 15, 9 female, 6 male), male and female participants each took part in two functional magnetic resonance imaging experiments: (1) word reading (Braille for blind and print for sighted participants), and (2) listening to spoken sentences of different grammatical complexity (both groups). We find that in blind, but not sighted participants, the anatomical location of the VWFA responds both to written words and to the grammatical complexity of spoken sentences. This suggests that in blindness, this region takes on high-level linguistic functions, becoming less selective for reading. More generally, the current findings suggest that experience during development has a major effect on functional specialization in the human cortex.SIGNIFICANCE STATEMENT The visual word form area (VWFA) is a region in the human cortex that becomes specialized for the recognition of written letters and words. Why does this particular brain region become specialized for reading? We tested the hypothesis that the VWFA develops within the ventral visual stream because reading involves extracting linguistic information from visual symbols. Consistent with this hypothesis, we find that in congenitally blind Braille readers, but not sighted readers of print, the VWFA region is active during grammatical processing of spoken sentences. These results suggest that visual experience contributes to VWFA specialization, and that different neural implementations of reading are possible.
Merabet LB, Mayer LD, Bauer CM, Wright D, Kran BS. Disentangling How the Brain is "Wired" in Cortical (Cerebral) Visual Impairment. Semin Pediatr Neurol. 2017;24 (2) :83-91.Abstract
Cortical (cerebral) visual impairment (CVI) results from perinatal injury to visual processing structures and pathways of the brain and is the most common cause of severe visual impairment or blindness in children in developed countries. Children with CVI display a wide range of visual deficits including decreased visual acuity, impaired visual field function, as well as impairments in higher-order visual processing and attention. Together, these visual impairments can dramatically influence a child's development and well-being. Given the complex neurologic underpinnings of this condition, CVI is often undiagnosed by eye care practitioners. Furthermore, the neurophysiological basis of CVI in relation to observed visual processing deficits remains poorly understood. Here, we present some of the challenges associated with the clinical assessment and management of individuals with CVI. We discuss how advances in brain imaging are likely to help uncover the underlying neurophysiology of this condition. In particular, we demonstrate how structural and functional neuroimaging approaches can help gain insight into abnormalities of white matter connectivity and cortical activation patterns, respectively. Establishing a connection between how changes within the brain relate to visual impairments in CVI will be important for developing effective rehabilitative and education strategies for individuals living with this condition.
Rinaldi L, Vecchi T, Fantino M, Merabet LB, Cattaneo Z. The Ego-Moving Metaphor of Time Relies on Visual Experience: No Representation of Time Along the Sagittal Space in the Blind. J Exp Psychol Gen. 2017.Abstract
In many cultures, humans conceptualize the past as behind the body and the future as in front. Whether this spatial mapping of time depends on visual experience is still not known. Here, we addressed this issue by testing early-blind participants in a space-time motor congruity task requiring them to classify a series of words as referring to the past or the future by moving their hand backward or forward. Sighted participants showed a preferential mapping between forward movements and future-words and backward movements and past-words. Critically, blind participants did not show any such preferential time-space mapping. Furthermore, in a questionnaire requiring participants to think about past and future events, blind participants did not appear to perceive the future as psychologically closer than the past, as it is the case of sighted individuals. These findings suggest that normal visual development is crucial for representing time along the sagittal space. (PsycINFO Database Record
Occelli V, Lacey S, Stephens C, Merabet LB, Sathian K. Enhanced verbal abilities in the congenitally blind. Exp Brain Res. 2017;235 (6) :1709-1718.Abstract
Numerous studies have found that congenitally blind individuals have better verbal memory than their normally sighted counterparts. However, it is not known whether this reflects superiority of verbal or memory abilities. In order to distinguish between these possibilities, we tested congenitally blind participants and normally sighted control participants, matched for age and education, on a range of verbal and spatial tasks. Congenitally blind participants were significantly better than sighted controls on all the verbal tasks but the groups did not differ significantly on the spatial tasks. Thus, the congenitally blind appear to have superior verbal, but not spatial, abilities. This may reflect greater reliance on verbal information and the involvement of visual cortex in language processing in the congenitally blind.
Bauer CM, Hirsch GV, Zajac L, Koo B-B, Collignon O, Merabet LB. Multimodal MR-imaging reveals large-scale structural and functional connectivity changes in profound early blindness. PLoS One. 2017;12 (3) :e0173064.Abstract
In the setting of profound ocular blindness, numerous lines of evidence demonstrate the existence of dramatic anatomical and functional changes within the brain. However, previous studies based on a variety of distinct measures have often provided inconsistent findings. To help reconcile this issue, we used a multimodal magnetic resonance (MR)-based imaging approach to provide complementary structural and functional information regarding this neuroplastic reorganization. This included gray matter structural morphometry, high angular resolution diffusion imaging (HARDI) of white matter connectivity and integrity, and resting state functional connectivity MRI (rsfcMRI) analysis. When comparing the brains of early blind individuals to sighted controls, we found evidence of co-occurring decreases in cortical volume and cortical thickness within visual processing areas of the occipital and temporal cortices respectively. Increases in cortical volume in the early blind were evident within regions of parietal cortex. Investigating white matter connections using HARDI revealed patterns of increased and decreased connectivity when comparing both groups. In the blind, increased white matter connectivity (indexed by increased fiber number) was predominantly left-lateralized, including between frontal and temporal areas implicated with language processing. Decreases in structural connectivity were evident involving frontal and somatosensory regions as well as between occipital and cingulate cortices. Differences in white matter integrity (as indexed by quantitative anisotropy, or QA) were also in general agreement with observed pattern changes in the number of white matter fibers. Analysis of resting state sequences showed evidence of both increased and decreased functional connectivity in the blind compared to sighted controls. Specifically, increased connectivity was evident between temporal and inferior frontal areas. Decreases in functional connectivity were observed between occipital and frontal and somatosensory-motor areas and between temporal (mainly fusiform and parahippocampus) and parietal, frontal, and other temporal areas. Correlations in white matter connectivity and functional connectivity observed between early blind and sighted controls showed an overall high degree of association. However, comparing the relative changes in white matter and functional connectivity between early blind and sighted controls did not show a significant correlation. In summary, these findings provide complimentary evidence, as well as highlight potential contradictions, regarding the nature of regional and large scale neuroplastic reorganization resulting from early onset blindness.
Rossi A, Gnesi M, Montomoli C, Chirico G, Malerba L, Merabet LB, Fazzi E. Neonatal Assessment Visual European Grid (NAVEG): Unveiling neurological risk. Infant Behav Dev. 2017;49 :21-30.
Zajac L, Koo B-B, Bauer CM, Killiany R, Behalf of the Alzheimer’s Disease Neuroimaging Initiative. Seed Location Impacts Whole-Brain Structural Network Comparisons between Healthy Elderly and Individuals with Alzheimer’s Disease. Brain Sciences [Internet]. 2017;7 (4}, ARTICLE NUMBER = 7). Publisher's VersionAbstract
Whole-brain networks derived from diffusion tensor imaging (DTI) data require the identification of seed and target regions of interest (ROIs) to assess connectivity patterns. This study investigated how initiating tracts from gray matter (GM) or white matter (WM) seed ROIs impacts (1) structural networks constructed from DTI data from healthy elderly (control) and individuals with Alzheimer’s disease (AD) and (2) between-group comparisons using these networks. DTI datasets were obtained from the Alzheimer’s disease Neuroimaging Initiative database. Deterministic tractography was used to build two whole-brain networks for each subject; one in which tracts were initiated from WM ROIs and another in which they were initiated from GM ROIs. With respect to the first goal, in both groups, WM-seeded networks had approximately 400 more connections and stronger connections (as measured by number of streamlines per connection) than GM-seeded networks, but shared 94% of the connections found in the GM-seed networks. With respect to the second goal, between-group comparisons revealed a stronger subnetwork (as measured by number of streamlines per connection) in controls compared to AD using both WM-seeded and GM-seeded networks. The comparison using WM-seeded networks produced a larger (i.e., a greater number of connections) and more significant subnetwork in controls versus AD. Global, local, and nodal efficiency were greater in controls compared to AD, and between-group comparisons of these measures using WM-seeded networks had larger effect sizes than those using GM-seeded networks. These findings affirm that seed location significantly affects the ability to detect between-group differences in structural networks.
Occelli V, Lacey S, Stephens C, Merabet LB, Sathian K. Enhanced verbal abilities in the congenitally blind. Experimental Brain Research [Internet]. 2017;235 (6) :1709-1718. Publisher's VersionAbstract
Numerous studies have found that congenitally blind individuals have better verbal memory than their normally sighted counterparts. However, it is not known whether this reflects superiority of verbal or memory abilities. In order to distinguish between these possibilities, we tested congenitally blind participants and normally sighted control participants, matched for age and education, on a range of verbal and spatial tasks. Congenitally blind participants were significantly better than sighted controls on all the verbal tasks but the groups did not differ significantly on the spatial tasks. Thus, the congenitally blind appear to have superior verbal, but not spatial, abilities. This may reflect greater reliance on verbal information and the involvement of visual cortex in language processing in the congenitally blind.
Bauer CM, Zajac LE, Koo B-B, Killiany RJ, Merabet LB. Age-related changes in structural connectivity are improved using subject-specific thresholding. Journal of Neuroscience Methods [Internet]. 2017;288 :45 - 56. Publisher's VersionAbstract
Deterministic diffusion tractography obtained from high angular resolution diffusion imaging (HARDI) requires user-defined quantitative anisotropy (QA) thresholds. Most studies employ a common threshold across all subjects even though there is a strong degree of individual variation within groups. We sought to explore whether it would be beneficial to use individual thresholds in order to accommodate individual variance. To do this, we conducted two independent experiments. First, tractography of the arcuate fasciculus and network connectivity measures were examined in a sample of 14 healthy participants. Second, we assessed the effects of QA threshold on group differences in network connectivity measures between healthy young (n=19) and old (n=14) individuals. The results of both experiments were significantly influenced by QA threshold. Common thresholds set too high failed to produce sufficient reconstructions in most subjects, thus decreasing the likelihood of detecting meaningful group differences. On the other hand, common thresholds set too low resulted in spurious reconstructions, providing deleterious results. Subject specific thresholds acquired using our QA threshold selection method (QATS) appeared to provide the most meaningful networks while ensuring that data from all subjects contributed to the analyses. Together, these results support the use of a subject-specific threshold to ensure that data from all subjects are included in the analyses being conducted.
Rossi A, Gnesi M, Montomoli C, Chirico G, Malerba L, Merabet LB, Group NAVEGS, Fazzi E. Neonatal Assessment Visual European Grid (NAVEG): Unveiling neurological risk. Infant Behavior and Development [Internet]. 2017;49 :21-30. Publisher's VersionAbstract
Evaluation of visual function in newborns is of utmost importance. A tailored non invasive evaluation of visual function in newborns is proposed (NAVEG). NAVEG’s discriminating capability as a marker of brain lesions is evaluated. NAVEG provides information on the early functioning of the visual system.Visualfunction assessment could integrate ophthalmologic and neurologic evaluation. 
Gamond L, Vecchi T, Ferrari C, Merabet LB, Cattaneo Z. Emotion processing in early blind and sighted individuals. Neuropsychology [Internet]. 2017;31 (5) :516-524. Publisher's VersionAbstract
OBJECTIVE: Emotion processing is known to be mediated by a complex network of cortical and subcortical regions with evidence of specialized hemispheric lateralization within the brain. In light of prior evidence indicating that lateralization of cognitive functions (such as language) may depend on normal visual development, we investigated whether the lack of prior visual experience would have an impact on the development of specialized hemispheric lateralization in emotional processing. METHOD: We addressed this issue by comparing performance in early blind and sighted controls on a dichotic listening task requiring the detection of specific emotional vocalizations (i.e., suggestive of happiness or sadness) presented independently to either ear. RESULTS: Consistent with previous studies, we found that sighted individuals showed enhanced detection of positive vocalizations when presented in the right ear (i.e., processed within the left hemisphere) and negative vocalizations when presented in the left ear (i.e., right hemisphere). It is interesting to note that although blind individuals were as accurate as sighted controls in detecting the valance of the vocalization, performance was not consistent with any pattern of specialized hemispheric lateralization. CONCLUSIONS: Overall, these results suggest that although the lack of prior visual experience may not lead to impaired emotion processing performance, the underlying neurophysiological substrate (i.e., degree of special hemispheric lateralization) may depend on normal visual development. (PsycINFO Database Record
Occelli V, Lacey S, Stephens C, Merabet LB, Sathian K. Enhanced verbal abilities in the congenitally blind. Experimental Brain Research [Internet]. 2017 :1–10. Publisher's VersionAbstract
Numerous studies have found that congenitally blind individuals have better verbal memory than their normally sighted counterparts. However, it is not known whether this reflects superiority of verbal or memory abilities. In order to distinguish between these possibilities, we tested congenitally blind participants and normally sighted control participants, matched for age and education, on a range of verbal and spatial tasks. Congenitally blind participants were significantly better than sighted controls on all the verbal tasks but the groups did not differ significantly on the spatial tasks. Thus, the congenitally blind appear to have superior verbal, but not spatial, abilities. This may reflect greater reliance on verbal information and the involvement of visual cortex in language processing in the congenitally blind.
Bauer CM, Hirsch GV, Zajac L, Koo B-B, Collignon O, Merabet LB. Multimodal MR-imaging reveals large-scale structural and functional connectivity changes in profound early blindness. PLOS ONE [Internet]. 2017;12 (3) :1-26. Publisher's VersionAbstract
In the setting of profound ocular blindness, numerous lines of evidence demonstrate the existence of dramatic anatomical and functional changes within the brain. However, previous studies based on a variety of distinct measures have often provided inconsistent findings. To help reconcile this issue, we used a multimodal magnetic resonance (MR)-based imaging approach to provide complementary structural and functional information regarding this neuroplastic reorganization. This included gray matter structural morphometry, high angular resolution diffusion imaging (HARDI) of white matter connectivity and integrity, and resting state functional connectivity MRI (rsfcMRI) analysis. When comparing the brains of early blind individuals to sighted controls, we found evidence of co-occurring decreases in cortical volume and cortical thickness within visual processing areas of the occipital and temporal cortices respectively. Increases in cortical volume in the early blind were evident within regions of parietal cortex. Investigating white matter connections using HARDI revealed patterns of increased and decreased connectivity when comparing both groups. In the blind, increased white matter connectivity (indexed by increased fiber number) was predominantly left-lateralized, including between frontal and temporal areas implicated with language processing. Decreases in structural connectivity were evident involving frontal and somatosensory regions as well as between occipital and cingulate cortices. Differences in white matter integrity (as indexed by quantitative anisotropy, or QA) were also in general agreement with observed pattern changes in the number of white matter fibers. Analysis of resting state sequences showed evidence of both increased and decreased functional connectivity in the blind compared to sighted controls. Specifically, increased connectivity was evident between temporal and inferior frontal areas. Decreases in functional connectivity were observed between occipital and frontal and somatosensory-motor areas and between temporal (mainly fusiform and parahippocampus) and parietal, frontal, and other temporal areas. Correlations in white matter connectivity and functional connectivity observed between early blind and sighted controls showed an overall high degree of association. However, comparing the relative changes in white matter and functional connectivity between early blind and sighted controls did not show a significant correlation. In summary, these findings provide complimentary evidence, as well as highlight potential contradictions, regarding the nature of regional and large scale neuroplastic reorganization resulting from early onset blindness.
2016
Martín MBC, Santos-Lozano A, Martín-Hernández J, López-Miguel A, Maldonado M, Baladrón C, Bauer CM, Merabet LB. Cerebral versus Ocular Visual Impairment: The Impact on Developmental Neuroplasticity. Front Psychol. 2016;7 :1958.Abstract
Cortical/cerebral visual impairment (CVI) is clinically defined as significant visual dysfunction caused by injury to visual pathways and structures occurring during early perinatal development. Depending on the location and extent of damage, children with CVI often present with a myriad of visual deficits including decreased visual acuity and impaired visual field function. Most striking, however, are impairments in visual processing and attention which have a significant impact on learning, development, and independence. Within the educational arena, current evidence suggests that strategies designed for individuals with ocular visual impairment are not effective in the case of CVI. We propose that this variance may be related to differences in compensatory neuroplasticity related to the type of visual impairment, as well as underlying alterations in brain structural connectivity. We discuss the etiology and nature of visual impairments related to CVI, and how advanced neuroimaging techniques (i.e., diffusion-based imaging) may help uncover differences between ocular and cerebral causes of visual dysfunction. Revealing these differences may help in developing future strategies for the education and rehabilitation of individuals living with visual impairment.
Merabet LB, Devaney KJ, Bauer CM, Panja A, Heidary G, Somers DC. Characterizing Visual Field Deficits in Cerebral/Cortical Visual Impairment (CVI) Using Combined Diffusion Based Imaging and Functional Retinotopic Mapping: A Case Study. Front Syst Neurosci. 2016;10 :13.
Pinto CB, Saleh Velez FG, Bolognini N, Crandell D, Merabet LB, Fregni F. Optimizing Rehabilitation for Phantom Limb Pain Using Mirror Therapy and Transcranial Direct Current Stimulation: A Randomized, Double-Blind Clinical Trial Study Protocol. JMIR Res Protoc. 2016;5 (3) :e138.Abstract
BACKGROUND: Despite the multiple available pharmacological and behavioral therapies for the management of chronic phantom limb pain (PLP) in lower limb amputees, treatment for this condition is still a major challenge and the results are mixed. Given that PLP is associated with maladaptive brain plasticity, interventions that promote cortical reorganization such as non-invasive brain stimulation and behavioral methods including transcranial direct current stimulation (tDCS) and mirror therapy (MT), respectively, may prove to be beneficial to control pain in PLP. Due to its complementary effects, a combination of tDCS and MT may result in synergistic effects in PLP. OBJECTIVE: The objective of this study is to evaluate the efficacy of tDCS and MT as a rehabilitative tool for the management of PLP in unilateral lower limb amputees. METHODS: A prospective, randomized, placebo-controlled, double-blind, factorial, superiority clinical trial will be carried out. Participants will be eligible if they meet the following inclusion criteria: lower limb unilateral traumatic amputees that present PLP for at least 3 months after the amputated limb has completely healed. Participants (N=132) will be randomly allocated to the following groups: (1) active tDCS and active MT, (2) sham tDCS and active MT, (3) active tDCS and sham MT, and (4) sham tDCS and sham MT. tDCS will be applied with the anodal electrode placed over the primary motor cortex (M1) contralateral to the amputation side and the cathode over the contralateral supraorbital area. Stimulation will be applied at the same time of the MT protocol with the parameters 2 mA for 20 minutes. Pain outcome assessments will be performed at baseline, before and after each intervention session, at the end of MT, and in 2 follow-up visits. In order to assess cortical reorganization and correlate with clinical outcomes, participants will undergo functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) before and after the intervention. RESULTS: This clinical trial received institutional review board (IRB) approval in July of 2015 and enrollment started in December of 2015. To date 2 participants have been enrolled. The estimate enrollment rate is about 30 to 35 patients per year; thus we expect to complete enrollment in 4 years. CONCLUSIONS: This factorial design will provide relevant data to evaluate whether tDCS combined with MT is more effective than each therapy alone, as well as with no intervention (sham/sham) in patients with chronic PLP after unilateral lower limb amputation. In addition, this randomized clinical trial will help to investigate the neurophysiological mechanisms underlying the disease, which could potentially provide relevant findings for further management of this chronic condition and also help to optimize the use of this novel intervention. TRIAL REGISTRATION: Clinicaltrials.gov NCT02487966; https://clinicaltrials.gov/ct2/show/NCT02487966 (Archived by WebCite at http://www.webcitation.org/6i3GrKMyf).
Pinto BC, Saleh Velez GF, Bolognini N, Crandell D, Merabet BL, Fregni F. Optimizing Rehabilitation for Phantom Limb Pain Using Mirror Therapy and Transcranial Direct Current Stimulation: A Randomized, Double–Blind Clinical Trial Study Protocol. JMIR Res Protoc [Internet]. 2016;5 (3) :e138. Publisher's VersionAbstract
Background: Despite the multiple available pharmacological and behavioral therapies for the management of chronic phantom limb pain (PLP) in lower limb amputees, treatment for this condition is still a major challenge and the results are mixed. Given that PLP is associated with maladaptive brain plasticity, interventions that promote cortical reorganization such as non-invasive brain stimulation and behavioral methods including transcranial direct current stimulation (tDCS) and mirror therapy (MT), respectively, may prove to be beneficial to control pain in PLP. Due to its complementary effects, a combination of tDCS and MT may result in synergistic effects in PLP. Objective: The objective of this study is to evaluate the efficacy of tDCS and MT as a rehabilitative tool for the management of PLP in unilateral lower limb amputees. Methods: A prospective, randomized, placebo-controlled, double-blind, factorial, superiority clinical trial will be carried out. Participants will be eligible if they meet the following inclusion criteria: lower limb unilateral traumatic amputees that present PLP for at least 3 months after the amputated limb has completely healed. Participants (N=132) will be randomly allocated to the following groups: (1) active tDCS and active MT, (2) sham tDCS and active MT, (3) active tDCS and sham MT, and (4) sham tDCS and sham MT. tDCS will be applied with the anodal electrode placed over the primary motor cortex (M1) contralateral to the amputation side and the cathode over the contralateral supraorbital area. Stimulation will be applied at the same time of the MT protocol with the parameters 2 mA for 20 minutes. Pain outcome assessments will be performed at baseline, before and after each intervention session, at the end of MT, and in 2 follow-up visits. In order to assess cortical reorganization and correlate with clinical outcomes, participants will undergo functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) before and after the intervention. Results: This clinical trial received institutional review board (IRB) approval in July of 2015 and enrollment started in December of 2015. To date 2 participants have been enrolled. The estimate enrollment rate is about 30 to 35 patients per year; thus we expect to complete enrollment in 4 years. Conclusions: This factorial design will provide relevant data to evaluate whether tDCS combined with MT is more effective than each therapy alone, as well as with no intervention (sham/sham) in patients with chronic PLP after unilateral lower limb amputation. In addition, this randomized clinical trial will help to investigate the neurophysiological mechanisms underlying the disease, which could potentially provide relevant findings for further management of this chronic condition and also help to optimize the use of this novel intervention. Trial Registration: Clinicaltrials.gov NCT02487966; https://clinicaltrials.gov/ct2/show/NCT02487966 (Archived by WebCite at http://www.webcitation.org/6i3GrKMyf)

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