Visual stimuli that exhibit vertical symmetry are easier to remember than stimuli symmetric along other axes, an advantage that extends to the haptic modality as well. Critically, the vertical symmetry memory advantage has not been found in early blind individuals, despite their overall superior memory, as compared with sighted individuals, and the presence of an overall advantage for identifying symmetric over asymmetric patterns. The absence of the vertical axis memory advantage in the early blind may depend on their total lack of visual experience or on the effect of prolonged visual deprivation. To disentangle this issue, in this study, we measured the ability of late blind individuals to remember tactile spatial patterns that were either vertically or horizontally symmetric or asymmetric. Late blind participants showed better memory performance for symmetric patterns. An additional advantage for the vertical axis of symmetry over the horizontal one was reported, but only for patterns presented in the frontal plane. In the horizontal plane, no difference was observed between vertical and horizontal symmetric patterns, due to the latter being recalled particularly well. These results are discussed in terms of the influence of the spatial reference frame adopted during exploration. Overall, our data suggest that prior visual experience is sufficient to drive the vertical symmetry memory advantage, at least when an external reference frame based on geocentric cues (i.e., gravity) is adopted.

BACKGROUND/OBJECTIVE: Transcutaneous electrical stimulation has been proven to modulate nervous system activity, leading to changes in pain perception, via the peripheral sensory system, in a bottom up approach. We tested whether different sensory behavioral tasks induce significant effects in pain processing and whether these changes correlate with cortical plasticity. METHODOLOGY/PRINCIPAL FINDINGS: This randomized parallel designed experiment included forty healthy right-handed males. Three different somatosensory tasks, including learning tasks with and without visual feedback and simple somatosensory input, were tested on pressure pain threshold and motor cortex excitability using transcranial magnetic stimulation (TMS). Sensory tasks induced hand-specific pain modulation effects. They increased pain thresholds of the left hand (which was the target to the sensory tasks) and decreased them in the right hand. TMS showed that somatosensory input decreased cortical excitability, as indexed by reduced MEP amplitudes and increased SICI. Although somatosensory tasks similarly altered pain thresholds and cortical excitability, there was no significant correlation between these variables and only the visual feedback task showed significant somatosensory learning. CONCLUSIONS/SIGNIFICANCE: Lack of correlation between cortical excitability and pain thresholds and lack of differential effects across tasks, but significant changes in pain thresholds suggest that analgesic effects of somatosensory tasks are not primarily associated with motor cortical neural mechanisms, thus, suggesting that subcortical neural circuits and/or spinal cord are involved with the observed effects. Identifying the neural mechanisms of somatosensory stimulation on pain may open novel possibilities for combining different targeted therapies for pain control.

Current neuropsychological evidence demonstrates that damage to sensory-specific and heteromodal areas of the brain not only disrupts the ability of combining sensory information from multiple sources, but can also cause altered multisensory experiences. On the other hand, there is also evidence of behavioural benefits induced by spared multisensory mechanisms. Thus, crossmodal plasticity can be viewed in both an adaptive and maladaptive context. The emerging view is that different crossmodal plastic changes can result following damage to sensory-specific and heteromodal areas, with post-injury crossmodal plasticity representing an attempt of a multisensory system to reconnect the various senses and by-pass injured areas. Changes can be considered adaptive when there is compensation for the lesion-induced sensory impairment. Conversely, it may prove maladaptive when atypical or even illusory multisensory experiences are generated as a result of re-arranged multisensory networks. This theoretical framework posits new intriguing questions for neuropsychological research and places greater emphasis on the study of multisensory phenomena within the context of damage to large-scale brain networks, rather than just focal damage alone.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that delivers low-intensity, direct current to cortical areas facilitating or inhibiting spontaneous neuronal activity. In the past 10 years, tDCS physiologic mechanisms of action have been intensively investigated giving support for the investigation of its applications in clinical neuropsychiatry and rehabilitation. However, new methodologic, ethical, and regulatory issues emerge when translating the findings of preclinical and phase I studies into phase II and III clinical studies. The aim of this comprehensive review is to discuss the key challenges of this process and possible methods to address them. METHODS: We convened a workgroup of researchers in the field to review, discuss, and provide updates and key challenges of tDCS use in clinical research. MAIN FINDINGS/DISCUSSION: We reviewed several basic and clinical studies in the field and identified potential limitations, taking into account the particularities of the technique. We review and discuss the findings into four topics: (1) mechanisms of action of tDCS, parameters of use and computer-based human brain modeling investigating electric current fields and magnitude induced by tDCS; (2) methodologic aspects related to the clinical research of tDCS as divided according to study phase (ie, preclinical, phase I, phase II, and phase III studies); (3) ethical and regulatory concerns; and (4) future directions regarding novel approaches, novel devices, and future studies involving tDCS. Finally, we propose some alternative methods to facilitate clinical research on tDCS.

BACKGROUND: Vision Restoration Therapy (VRT) aims to improve visual field function by systematically training regions of residual vision associated with the activity of suboptimal firing neurons within the occipital cortex. Transcranial direct current stimulation (tDCS) has been shown to modulate cortical excitability. OBJECTIVE: Assess the possible efficacy of tDCS combined with VRT. METHODS: The authors conducted a randomized, double-blind, demonstration-of-concept pilot study where participants were assigned to either VRT and tDCS or VRT and sham. The anode was placed over the occipital pole to target both affected and unaffected lobes. One hour training sessions were carried out 3 times per week for 3 months in a laboratory. Outcome measures included objective and subjective changes in visual field, recording of visual fixation performance, and vision-related activities of daily living (ADLs) and quality of life (QOL). RESULTS: Although 12 participants were enrolled, only 8 could be analyzed. The VRT and tDCS group demonstrated significantly greater expansion in visual field and improvement on ADLs compared with the VRT and sham group. Contrary to expectations, subjective perception of visual field change was greater in the VRT and sham group. QOL did not change for either group. The observed changes in visual field were unrelated to compensatory eye movements, as shown with fixation monitoring. CONCLUSIONS: The combination of occipital cortical tDCS with visual field rehabilitation appears to enhance visual functional outcomes compared with visual rehabilitation alone. TDCS may enhance inherent mechanisms of plasticity associated with training.

OBJECTIVES: Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that delivers low-intensity currents facilitating or inhibiting spontaneous neuronal activity. tDCS is attractive since dose is readily adjustable by simply changing electrode number, position, size, shape, and current. In the recent past, computational models have been developed with increased precision with the goal to help customize tDCS dose. The aim of this review is to discuss the incorporation of high-resolution patient-specific computer modeling to guide and optimize tDCS. METHODS: In this review, we discuss the following topics: 1) The clinical motivation and rationale for models of transcranial stimulation is considered pivotal in order to leverage the flexibility of neuromodulation; 2) the protocols and the workflow for developing high-resolution models; 3) the technical challenges and limitations of interpreting modeling predictions; and 4) real cases merging modeling and clinical data illustrating the impact of computational models on the rational design of rehabilitative electrotherapy. CONCLUSIONS: Though modeling for noninvasive brain stimulation is still in its development phase, it is predicted that with increased validation, dissemination, simplification, and democratization of modeling tools, computational forward models of neuromodulation will become useful tools to guide the optimization of clinical electrotherapy.

Computer based video games are receiving great interest as a means to learn and acquire new skills. As a novel approach to teaching navigation skills in the blind, we have developed Audio-based Environment Simulator (AbES); a virtual reality environment set within the context of a video game metaphor. Despite the fact that participants were naïve to the overall purpose of the software, we found that early blind users were able to acquire relevant information regarding the spatial layout of a previously unfamiliar building using audio based cues alone. This was confirmed by a series of behavioral performance tests designed to assess the transfer of acquired spatial information to a large-scale, real-world indoor navigation task. Furthermore, learning the spatial layout through a goal directed gaming strategy allowed for the mental manipulation of spatial information as evidenced by enhanced navigation performance when compared to an explicit route learning strategy. We conclude that the immersive and highly interactive nature of the software greatly engages the blind user to actively explore the virtual environment. This in turn generates an accurate sense of a large-scale three-dimensional space and facilitates the learning and transfer of navigation skills to the physical world.

OBJECTIVES: We have previously reported that transcranial direct current stimulation (tDCS) delivered to the occipital cortex enhances visual functional recovery when combined with three months of computer-based rehabilitative training in patients with hemianopia. The principal objective of this study was to evaluate the temporal sequence of effects of tDCS on visual recovery as they appear over the course of training and across different indicators of visual function. METHODS: Primary objective outcome measures were 1) shifts in visual field border and 2) stimulus detection accuracy within the affected hemifield. These were compared between patients randomized to either vision restoration therapy (VRT) combined with active tDCS or VRT paired with sham tDCS. Training comprised two half-hour sessions, three times a week for three months. Primary outcome measures were collected at baseline (pretest), monthly interim intervals, and at posttest (three months). As secondary outcome measures, contrast sensitivity and reading performance were collected at pretest and posttest time points only. RESULTS: Active tDCS combined with VRT accelerated the recovery of stimulus detection as between-group differences appeared within the first month of training. In contrast, a shift in the visual field border was only evident at posttest (after three months of training). tDCS did not affect contrast sensitivity or reading performance. CONCLUSIONS: These results suggest that tDCS may differentially affect the magnitude and sequence of visual recovery in a manner that is task specific to the type of visual rehabilitative training strategy employed.

Objectives: We have previously reported that transcranial direct current stimulation (tDCS) delivered to the occipital cortex enhances visual functional recovery when combined with three months of computer-based rehabilitative training in patients with hemianopia. The principal objective of this study was to evaluate the temporal sequence of effects of tDCS on visual recovery as they appear over the course of training and across different indicators of visual function. Methods: Primary objective outcome measures were 1) shifts in visual field border and 2) stimulus detection accuracy within the affected hemifield. These were compared between patients randomized to either vision restoration therapy (VRT) combined with active tDCS or VRT paired with sham tDCS. Training comprised two half-hour sessions, three times a week for three months. Primary outcome measures were collected at baseline (pretest), monthly interim intervals, and at posttest (three months). As secondary outcome measures, contrast sensitivity and reading performance were collected at pretest and posttest time points only. Results: Active tDCS combined with VRT accelerated the recovery of stimulus detection as between-group differences appeared within the first month of training. In contrast, a shift in the visual field border was only evident at posttest (after three months of training). tDCS did not affect contrast sensitivity or reading performance. Conclusions: These results suggest that tDCS may differentially affect the magnitude and sequence of visual recovery in a manner that is task specific to the type of visual rehabilitative training strategy employed.

BACKGROUND: Vision Restoration Therapy (VRT) aims to improve visual field function by systematically training regions of residual vision associated with the activity of suboptimal firing neurons within the occipital cortex. Transcranial direct current stimulation (tDCS) has been shown to modulate cortical excitability. OBJECTIVE: Assess the possible efficacy of tDCS combined with VRT. METHODS: The authors conducted a randomized, double-blind, demonstration-of-concept pilot study where participants were assigned to either VRT and tDCS or VRT and sham. The anode was placed over the occipital pole to target both affected and unaffected lobes. One hour training sessions were carried out 3 times per week for 3 months in a laboratory. Outcome measures included objective and subjective changes in visual field, recording of visual fixation performance, and vision-related activities of daily living (ADLs) and quality of life (QOL). RESULTS: Although 12 participants were enrolled, only 8 could be analyzed. The VRT and tDCS group demonstrated significantly greater expansion in visual field and improvement on ADLs compared with the VRT and sham group. Contrary to expectations, subjective perception of visual field change was greater in the VRT and sham group. QOL did not change for either group. The observed changes in visual field were unrelated to compensatory eye movements, as shown with fixation monitoring. CONCLUSIONS: The combination of occipital cortical tDCS with visual field rehabilitation appears to enhance visual functional outcomes compared with visual rehabilitation alone. TDCS may enhance inherent mechanisms of plasticity associated with training.

Once the topic of folklore and science fiction, the notion of restoring vision to the blind is now approaching a tractable reality. Technological advances have inspired numerous multidisciplinary groups worldwide to develop visual neuroprosthetic devices that could potentially provide useful vision and improve the quality of life of profoundly blind individuals. While a variety of approaches and designs are being pursued, they all share a common principle of creating visual percepts through the stimulation of visual neural elements using appropriate patterns of electrical stimulation. Human clinical trials are now well underway and initial results have been met with a balance of excitement and cautious optimism. As remaining technical and surgical challenges continue to be solved and clinical trials move forward, we now enter a phase of development that requires careful consideration of a new set of issues. Establishing appropriate patient selection criteria, methods of evaluating long-term performance and effectiveness, and strategies to rehabilitate implanted patients will all need to be considered in order to achieve optimal outcomes and establish these devices as viable therapeutic options.

Transcranial direct current stimulation (tDCS) has recently emerged as a promising approach to enhance neurorehabilitative outcomes. However, little is known about how the local electrical field generated by tDCS relates to underlying neuroplastic changes and behavior. To address this question, we present a case study analysis of an individual with hemianopia due to stroke and who benefited from a combined visual rehabilitation training and tDCS treatment program. Activation associated with a visual motion perception task (obtained by functional magnetic resonance imaging; fMRI) was used to characterize local changes in brain activity at baseline and after training. Individualized, high-resolution electrical field modeling reproducing precise cerebral and lesioned tissue geometry, predicted distortions of current flow in peri-lesional areas and diffuse clusters of peak electric fields. Using changes in fMRI signal as an index of cortical recovery, correlations to the electrical field map were determined. Significant correlations between the electrical field and change in fMRI signal were region specific including cortical areas under the anode electrode and peri-lesional visual areas. These patterns were consistent with effective tDCS facilitated rehabilitation. We describe the methodology used to analyze tDCS mechanisms through combined fMRI and computational modeling with the ultimate goal of developing a rationale for individualized therapy.

OBJECTIVE: To standardize a protocol for promoting visual rehabilitative outcomes in post-stroke hemianopia by combining occipital cortical transcranial direct current stimulation (tDCS) with Vision Restoration Therapy (VRT). DESIGN: A comparative case study assessing feasibility and safety. SETTING: A controlled laboratory setting. PATIENTS: Two patients, both with right hemianopia after occipital stroke damage. METHODS AND OUTCOME MEASUREMENTS: Both patients underwent an identical VRT protocol that lasted 3 months (30 minutes, twice a day, 3 days per week). In patient 1, anodal tDCS was delivered to the occipital cortex during VRT training, whereas in patient 2 sham tDCS with VRT was performed. The primary outcome, visual field border, was defined objectively by using high-resolution perimetry. Secondary outcomes included subjective characterization of visual deficit and functional surveys that assessed performance on activities of daily living. For patient 1, the neural correlates of visual recovery were also investigated, by using functional magnetic resonance imaging. RESULTS: Delivery of combined tDCS with VRT was feasible and safe. High-resolution perimetry revealed a greater shift in visual field border for patient 1 versus patient 2. Patient 1 also showed greater recovery of function in activities of daily living. Contrary to the expectation, patient 2 perceived greater subjective improvement in visual field despite objective high-resolution perimetry results that indicated otherwise. In patient 1, visual function recovery was associated with functional magnetic resonance imaging activity in surviving peri-lesional and bilateral higher-order visual areas. CONCLUSIONS: Results of preliminary case comparisons suggest that occipital cortical tDCS may enhance recovery of visual function associated with concurrent VRT through visual cortical reorganization. Future studies may benefit from incorporating protocol refinements such as those described here, which include global capture of function, control for potential confounds, and investigation of underlying neural substrates of recovery.

OBJECTIVE: To standardize a protocol for promoting visual rehabilitative outcomes in post-stroke hemianopia by combining occipital cortical transcranial direct current stimulation (tDCS) with Vision Restoration Therapy (VRT). DESIGN: A comparative case study assessing feasibility and safety. SETTING: A controlled laboratory setting. PATIENTS: Two patients, both with right hemianopia after occipital stroke damage. METHODS AND OUTCOME MEASUREMENTS: Both patients underwent an identical VRT protocol that lasted 3 months (30 minutes, twice a day, 3 days per week). In patient 1, anodal tDCS was delivered to the occipital cortex during VRT training, whereas in patient 2 sham tDCS with VRT was performed. The primary outcome, visual field border, was defined objectively by using high-resolution perimetry. Secondary outcomes included subjective characterization of visual deficit and functional surveys that assessed performance on activities of daily living. For patient 1, the neural correlates of visual recovery were also investigated, by using functional magnetic resonance imaging. RESULTS: Delivery of combined tDCS with VRT was feasible and safe. High-resolution perimetry revealed a greater shift in visual field border for patient 1 versus patient 2. Patient 1 also showed greater recovery of function in activities of daily living. Contrary to the expectation, patient 2 perceived greater subjective improvement in visual field despite objective high-resolution perimetry results that indicated otherwise. In patient 1, visual function recovery was associated with functional magnetic resonance imaging activity in surviving peri-lesional and bilateral higher-order visual areas. CONCLUSIONS: Results of preliminary case comparisons suggest that occipital cortical tDCS may enhance recovery of visual function associated with concurrent VRT through visual cortical reorganization. Future studies may benefit from incorporating protocol refinements such as those described here, which include global capture of function, control for potential confounds, and investigation of underlying neural substrates of recovery.

Once the topic of folklore and science fiction, the notion of restoring vision to the blind is now approaching a tractable reality. Technological advances have inspired numerous multidisciplinary groups worldwide to develop visual neuroprosthetic devices that could potentially provide useful vision and improve the quality of life of profoundly blind individuals. While a variety of approaches and designs are being pursued, they all share a common principle of creating visual percepts through the stimulation of visual neural elements using appropriate patterns of electrical stimulation. Human clinical trials are now well underway and initial results have been met with a balance of excitement and cautious optimism. As remaining technical and surgical challenges continue to be solved and clinical trials move forward, we now enter a phase of development that requires careful consideration of a new set of issues. Establishing appropriate patient selection criteria, methods of evaluating long-term performance and effectiveness, and strategies to rehabilitate implanted patients will all need to be considered in order to achieve optimal outcomes and establish these devices as viable therapeutic options.

Transcranial direct current stimulation (tDCS) has recently emerged as a promising approach to enhance neurorehabilitative outcomes. However, little is known about how the local electrical field generated by tDCS relates to underlying neuroplastic changes and behavior. To address this question, we present a case study analysis of an individual with hemianopia due to stroke and who benefited from a combined visual rehabilitation training and tDCS treatment program. Activation associated with a visual motion perception task (obtained by functional magnetic resonance imaging; fMRI) was used to characterize local changes in brain activity at baseline and after training. Individualized, high-resolution electrical field modeling reproducing precise cerebral and lesioned tissue geometry, predicted distortions of current flow in peri-lesional areas and diffuse clusters of peak electric fields. Using changes in fMRI signal as an index of cortical recovery, correlations to the electrical field map were determined. Significant correlations between the electrical field and change in fMRI signal were region specific including cortical areas under the anode electrode and peri-lesional visual areas. These patterns were consistent with effective tDCS facilitated rehabilitation. We describe the methodology used to analyze tDCS mechanisms through combined fMRI and computational modeling with the ultimate goal of developing a rationale for individualized therapy.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that delivers low-intensity, direct current to cortical areas facilitating or inhibiting spontaneous neuronal activity. In the past 10 years, tDCS physiologic mechanisms of action have been intensively investigated giving support for the investigation of its applications in clinical neuropsychiatry and rehabilitation. However, new methodologic, ethical, and regulatory issues emerge when translating the findings of preclinical and phase I studies into phase II and III clinical studies. The aim of this comprehensive review is to discuss the key challenges of this process and possible methods to address them. METHODS: We convened a workgroup of researchers in the field to review, discuss, and provide updates and key challenges of tDCS use in clinical research. MAIN FINDINGS/DISCUSSION: We reviewed several basic and clinical studies in the field and identified potential limitations, taking into account the particularities of the technique. We review and discuss the findings into four topics: (1) mechanisms of action of tDCS, parameters of use and computer-based human brain modeling investigating electric current fields and magnitude induced by tDCS; (2) methodologic aspects related to the clinical research of tDCS as divided according to study phase (ie, preclinical, phase I, phase II, and phase III studies); (3) ethical and regulatory concerns; and (4) future directions regarding novel approaches, novel devices, and future studies involving tDCS. Finally, we propose some alternative methods to facilitate clinical research on tDCS.

We present the design, development and initial cognitive evaluation of an Audio-based Environment Simulator (AbES). This software allows a blind user to navigate through a virtual representation of a real space for the purposes of training orientation and mobility skills. Our findings indicate that users feel satisfied and self-confident when interacting with the audio-based interface, and the embedded sounds allow them to correctly orient themselves and navigate within the virtual world. Furthermore, users are able to transfer spatial information acquired through virtual interactions into real world navigation and problem solving tasks.

We present the design, development and an initial study changes and adaptations related to navigation that take place in the brain, by incorporating an Audio-Based Environments Simulator (AbES) within a neuroimaging environment. This virtual environment enables a blind user to navigate through a virtual representation of a real space in order to train his/her orientation and mobility skills. Our initial results suggest that this kind of virtual environment could be highly efficient as a testing, training and rehabilitation platform for learning and navigation.