Cortical representations of phantom movements in lower limb amputees.

Understanding how sensorimotor cortex (SMC) organization relates to limb loss has major clinical implications, as cortical activity associated with phantom hand movements has been shown to predict phantom pain reports. Critically, earlier studies have largely focused on upper limb amputees; far less is known regarding SMC activity in lower limb amputees, despite the fact that this population comprises the majority of major limb loss cases. We aimed to characterize BOLD fMRI responses associated with phantom and sound limb movements to test the hypothesis that SMC organization is preserved in individuals with lower limb loss. Individuals with unilateral or bilateral lower limb loss underwent fMRI scans as they performed simple movements of their sound or phantom limbs. We observed that voluntary movements of the sound and phantom ankles were associated with BOLD signal changes in medial and superior portions of the precentral and postcentral gyri. In both hemispheres, contralateral limb movements were associated with greater signal changes compared to ipsilateral limb movements. Hand and mouth movements were associated with distinct activation patterns localized to more lateral SMC regions. We additionally tested whether activations associated with phantom movements related to self-report assessments indexing phantom pain experiences, nonpainful phantom sensations and phantom movement capabilities. We found that responses during phantom ankle movements did not correlate with any of the composite phantom limb indices in our sample. Our collective results reveal that SMC representations of the amputated limb persist and that traditional somatotopic organization is generally preserved in individuals suffering from lower limb loss.

Auditory and tactile frequency representations are co-embedded in modality-defined cortical sensory systems.

Sensory information is represented and elaborated in hierarchical cortical systems that are thought to be dedicated to individual sensory modalities. This traditional view of sensory cortex organization has been challenged by recent evidence of multimodal responses in primary and association sensory areas. Although it is indisputable that sensory areas respond to multiple modalities, it remains unclear whether these multimodal responses reflect selective information processing for particular stimulus features. Here, we used fMRI adaptation to identify brain regions that are sensitive to the temporal frequency information contained in auditory, tactile, and audiotactile stimulus sequences. A number of brain regions distributed over the parietal and temporal lobes exhibited frequency-selective temporal response modulation for both auditory and tactile stimulus events, as indexed by repetition suppression effects. A smaller set of regions responded to crossmodal adaptation sequences in a frequency-dependent manner. Despite an extensive overlap of multimodal frequency-selective responses across the parietal and temporal lobes, representational similarity analysis revealed a cortical "regional landscape" that clearly reflected distinct somatosensory and auditory processing systems that converged on modality-invariant areas. These structured relationships between brain regions were also evident in spontaneous signal fluctuation patterns measured at rest. Our results reveal that multimodal processing in human cortex can be feature-specific and that multimodal frequency representations are embedded in the intrinsically hierarchical organization of cortical sensory systems.

Principles of tactile search over the body.

Although we routinely experience complex tactile patterns over our entire body, how we selectively experience multisite touch over our bodies remains poorly understood. Here, we characterized tactile search behavior over the full body using a tactile analog of the classic visual search task. On each trial, participants judged whether a target stimulus (e.g., 10-Hz vibration) was present or absent anywhere on the body. When present, the target stimulus could occur alone or simultaneously with distractor stimuli (e.g., 30-Hz vibrations) on other body locations. We systematically varied the number and spatial configurations of the distractors as well as the target and distractor frequencies and measured the impact of these factors on tactile search response times. First, we found that response times were faster on target-present trials compared with target-absent trials. Second, response times increased with the number of stimulated sites, suggesting a serial search process. Third, search performance differed depending on stimulus frequencies. This frequency-dependent behavior may be related to perceptual grouping effects based on timing cues. We constructed linear models to explore how the locations of the target and distractor cues influenced tactile search behavior. Our modeling results reveal that, in isolation, cues on the index fingers make relatively greater contributions to search performance compared with stimulation experienced on other body sites. Additionally, costimulation of sites within the same limb or simply on the same body side preferentially influence search behavior. Our collective findings identify some principles of attentional search that are common to vision and touch, but others that highlight key differences that may be unique to body-based spatial perception.NEW & NOTEWORTHY Little is known about how we selectively experience multisite touch patterns over the body. Using a tactile analog of the classic visual target search paradigm, we show that tactile search behavior for flutter cues is generally consistent with a serial search process. Modeling results reveal the preferential contributions of index finger stimulation and two-site stimulus interactions involving ipsilateral patterns and within-limb patterns. Our results offer initial evidence for spatial and temporal principles underlying tactile search behavior over the body.

Somatosensory interactions reveal feature-dependent computations.

Our ability to perceive and discriminate textures is based on the processing of high-frequency vibrations generated on the fingertip as it scans across a surface. Although much is known about the processing of vibration amplitude and frequency information when cutaneous stimulation is experienced at a single location on the body, how these stimulus features are processed when touch occurs at multiple locations is poorly understood. We evaluated participants' ability to discriminate tactile cues (100-300 Hz) on one hand while they ignored distractor cues experienced on their other hand. We manipulated the relative positions of the hands to characterize how limb position influenced cutaneous touch interactions. In separate experiments, participants judged either the frequency or intensity of mechanical vibrations. We found that vibrations experienced on one hand always systematically modulated the perception of vibrations on the other hand. Notably, bimanual interaction patterns and their sensitivity to hand locations differed according to stimulus feature. Somatosensory interactions in intensity perception were only marked by attenuation that was invariant to hand position manipulations. In contrast, interactions in frequency perception consisted of both bias and sensitivity changes that were more pronounced when the hands were held in close proximity. We implemented models to infer the neural computations that mediate somatosensory interactions in the intensity and frequency dimensions. Our findings reveal obligatory and feature-dependent somatosensory interactions that may be supported by both feature-specific and feature-general operations. NEW & NOTEWORTHY Little is known about the neural computations mediating feature-specific sensory interactions between the hands. We show that vibrations experienced on one hand systematically modulate the perception of vibrations felt on the other hand. Critically, interaction patterns and their dependence on the relative positions of the hands differed depending on whether participants judged vibration intensity or frequency. These results, which we recapitulate with models, imply that somatosensory interactions are mediated by feature-dependent neural computations.

Auditory Frequency Representations in Human Somatosensory Cortex.

Recent studies have challenged the traditional notion of modality-dedicated cortical systems by showing that audition and touch evoke responses in the same sensory brain regions. While much of this work has focused on somatosensory responses in auditory regions, fewer studies have investigated sound responses and representations in somatosensory regions. In this functional magnetic resonance imaging (fMRI) study, we measured BOLD signal changes in participants performing an auditory frequency discrimination task and characterized activation patterns related to stimulus frequency using both univariate and multivariate analysis approaches. Outside of bilateral temporal lobe regions, we observed robust and frequency-specific responses to auditory stimulation in classically defined somatosensory areas. Moreover, using representational similarity analysis to define the relationships between multi-voxel activation patterns for all sound pairs, we found clear similarity patterns for auditory responses in the parietal lobe that correlated significantly with perceptual similarity judgments. Our results demonstrate that auditory frequency representations can be distributed over brain regions traditionally considered to be dedicated to somatosensation. The broad distribution of auditory and tactile responses over parietal and temporal regions reveals a number of candidate brain areas that could support general temporal frequency processing and mediate the extensive and robust perceptual interactions between audition and touch.

Auditory adaptation improves tactile frequency perception.

Our ability to process temporal frequency information by touch underlies our capacity to perceive and discriminate surface textures. Auditory signals, which also provide extensive temporal frequency information, can systematically alter the perception of vibrations on the hand. How auditory signals shape tactile processing is unclear; perceptual interactions between contemporaneous sounds and vibrations are consistent with multiple neural mechanisms. Here we used a crossmodal adaptation paradigm, which separated auditory and tactile stimulation in time, to test the hypothesis that tactile frequency perception depends on neural circuits that also process auditory frequency. We reasoned that auditory adaptation effects would transfer to touch only if signals from both senses converge on common representations. We found that auditory adaptation can improve tactile frequency discrimination thresholds. This occurred only when adaptor and test frequencies overlapped. In contrast, auditory adaptation did not influence tactile intensity judgments. Thus auditory adaptation enhances touch in a frequency- and feature-specific manner. A simple network model in which tactile frequency information is decoded from sensory neurons that are susceptible to auditory adaptation recapitulates these behavioral results. Our results imply that the neural circuits supporting tactile frequency perception also process auditory signals. This finding is consistent with the notion of supramodal operators performing canonical operations, like temporal frequency processing, regardless of input modality.NEW & NOTEWORTHY Auditory signals can influence the tactile perception of temporal frequency. Multiple neural mechanisms could account for the perceptual interactions between contemporaneous auditory and tactile signals. Using a crossmodal adaptation paradigm, we found that auditory adaptation causes frequency- and feature-specific improvements in tactile perception. This crossmodal transfer of aftereffects between audition and touch implies that tactile frequency perception relies on neural circuits that also process auditory frequency.

Feeling form: the neural basis of haptic shape perception.

The tactile perception of the shape of objects critically guides our ability to interact with them. In this review, we describe how shape information is processed as it ascends the somatosensory neuraxis of primates. At the somatosensory periphery, spatial form is represented in the spatial patterns of activation evoked across populations of mechanoreceptive afferents. In the cerebral cortex, neurons respond selectively to particular spatial features, like orientation and curvature. While feature selectivity of neurons in the earlier processing stages can be understood in terms of linear receptive field models, higher order somatosensory neurons exhibit nonlinear response properties that result in tuning for more complex geometrical features. In fact, tactile shape processing bears remarkable analogies to its visual counterpart and the two may rely on shared neural circuitry. Furthermore, one of the unique aspects of primate somatosensation is that it contains a deformable sensory sheet. Because the relative positions of cutaneous mechanoreceptors depend on the conformation of the hand, the haptic perception of three-dimensional objects requires the integration of cutaneous and proprioceptive signals, an integration that is observed throughout somatosensory cortex.

Myocardial iron load and fibrosis in long term survivors of childhood leukemia.

BACKGROUND: We sought to assess myocardial iron load and fibrosis, which may potentially affect cardiac function, in adult survivors of childhood leukemias and their relationships with left (LV) and right ventricular (RV) function. PROCEDURE: Fifty-eight (33 males) adult survivors, aged 24.5 ± 4.4, underwent cardiac magnetic resonance (CMR) at 16.6 ± 5.8 years after completion of treatment. Myocardial iron load and fibrosis were quantified using respectively T2* scan and late gadolinium enhancement. Right and left ventricular ejection fraction (EF) was measured by CMR, while myocardial function was assessed using tissue Doppler imaging. RESULTS: None of the survivors had significant myocardial iron overload (T2*<20 msec). The prevalence of LV and RV fibrosis was 9% (5/58) and 38% (22/58), respectively. Left ventricular EF was subnormal (EF 45-<55%) in 9% (5/58), while RV EF was abnormal (EF <45%) in 12% (7/58) and subnormal in 34% (20/58) of survivors. Patients with LV fibrosis had significantly lower mitral annular early diastolic velocity (P = 0.01) and smaller LV end-systolic volume (P = 0.02), while those with RV fibrosis had significantly lower tricuspid late diastolic annular velocity (P = 0.02) and early to late diastolic annular velocity ratio (P = 0.02) compared to those without. Cumulative anthracycline dose correlated with early diastolic mitral (r = -0.28, P = 0.038) and tricuspid (r = -0.40, P = 0.002) annular velocities, but not LV and RV EF or fibrosis (all P > 0.05). CONCLUSION: Ventricular fibrosis may occur in long term survivors of childhood leukemias and is related to diastolic function in the absence of significant myocardial iron overload.

Feeling better: separate pathways for targeted enhancement of spatial and temporal touch.

People perceive spatial form and temporal frequency through touch. Although distinct somatosensory neurons represent spatial and temporal information, these neural populations are intermixed throughout the somatosensory system. Here, we show that spatial and temporal touch can be dissociated and separately enhanced via cortical pathways that are normally associated with vision and audition. In Experiments 1 and 2, we found that anodal transcranial direct current stimulation (tDCS) applied over visual cortex, but not auditory cortex, enhances tactile perception of spatial orientation. In Experiments 3 and 4, we found that anodal tDCS over auditory cortex, but not visual cortex, enhances tactile perception of temporal frequency. This double dissociation reveals separate cortical pathways that selectively support spatial and temporal channels. These results bolster the emerging view that sensory areas process multiple modalities and suggest that supramodal domains may be more fundamental to cortical organization.

Curvature processing dynamics in macaque area V4.

We have previously analyzed shape processing dynamics in macaque monkey posterior inferotemporal cortex (PIT). We described how early PIT responses to individual contour fragments evolve into tuning for multifragment shape configurations. Here, we analyzed curvature processing dynamics in area V4, which provides feedforward inputs to PIT. We contrasted 2 hypotheses: 1) that V4 curvature tuning evolves from tuning for simpler elements, analogous to PIT shape synthesis and 2) that V4 curvature tuning emerges immediately, based on purely feedforward mechanisms. Our results clearly supported the first hypothesis. Early V4 responses carried information about individual contour orientations. Tuning for multiorientation (curved) contours developed gradually over ∼50 ms. Together, the current and previous results suggest a partial sequence for shape synthesis in ventral pathway cortex. We propose that early orientation signals are synthesized into curved contour fragment representations in V4 and that these signals are transmitted to PIT, where they are then synthesized into multifragment shape representations. The observed dynamics might additionally or alternatively reflect influences from earlier (V1, V2) and later (central and anterior IT) processing stages in the ventral pathway. In either case, the dynamics of contour information in V4 and PIT appear to reflect a sequential hierarchical process of shape synthesis.

Efficient and robust identification of cortical targets in concurrent TMS-fMRI experiments.

Transcranial magnetic stimulation (TMS) can be delivered during fMRI scans to evoke BOLD responses in distributed brain networks. While concurrent TMS-fMRI offers a potentially powerful tool for non-invasively investigating functional human neuroanatomy, the technique is currently limited by the lack of methods to rapidly and precisely localize targeted brain regions - a reliable procedure is necessary for validly relating stimulation targets to BOLD activation patterns, especially for cortical targets outside of motor and visual regions. Here we describe a convenient and practical method for visualizing coil position (in the scanner) and identifying the cortical location of TMS targets without requiring any calibration or any particular coil-mounting device. We quantified the precision and reliability of the target position estimates by testing the marker processing procedure on data from 9 scan sessions: Rigorous testing of the localization procedure revealed minimal variability in coil and target position estimates. We validated the marker processing procedure in concurrent TMS-fMRI experiments characterizing motor network connectivity. Together, these results indicate that our efficient method accurately and reliably identifies TMS targets in the MR scanner, which can be useful during scan sessions for optimizing coil placement and also for post-scan outlier identification. Notably, this method can be used generally to identify the position and orientation of MR-compatible hardware placed near the head in the MR scanner.

Representation of tactile curvature in macaque somatosensory area 2.

Tactile shape information is elaborated in a cortical hierarchy spanning primary (SI) and secondary somatosensory cortex (SII). Indeed, SI neurons in areas 3b and 1 encode simple contour features such as small oriented bars and edges, whereas higher order SII neurons represent large curved contour features such as angles and arcs. However, neural coding of these contour features has not been systematically characterized in area 2, the most caudal SI subdivision in the postcentral gyrus. In the present study, we analyzed area 2 neural responses to embossed oriented bars and curved contour fragments to establish whether curvature representations are generated in the postcentral gyrus. We found that many area 2 neurons (26 of 112) exhibit clear curvature tuning, preferring contours pointing in a particular direction. Fewer area 2 neurons (15 of 112) show preferences for oriented bars. Because area 2 response patterns closely resembled SII patterns, we also compared area 2 and SII response time courses to characterize the temporal dynamics of curvature synthesis in the somatosensory system. We found that curvature representations develop and peak concurrently in area 2 and SII. These results reveal that transitions from orientation tuning to curvature selectivity in the somatosensory cortical hierarchy occur within SI rather than between SI and SII.

Representational Similarity Analysis for Tracking Neural Correlates of Haptic Learning on a Multimodal Device.

A goal of wearable haptic devices has been to enable haptic communication, where individuals learn to map information typically processed visually or aurally to haptic cues via a process of cross-modal associative learning. Neural correlates have been used to evaluate haptic perception and may provide a more objective approach to assess association performance than more commonly used behavioral measures of performance. In this article, we examine Representational Similarity Analysis (RSA) of electroencephalography (EEG) as a framework to evaluate how the neural representation of multifeatured haptic cues changes with association training. We focus on the first phase of cross-modal associative learning, perception of multimodal cues. A participant learned to map phonemes to multimodal haptic cues, and EEG data were acquired before and after training to create neural representational spaces that were compared to theoretical models. Our perceptual model showed better correlations to the neural representational space before training, while the feature-based model showed better correlations with the post-training data. These results suggest that training may lead to a sharpening of the sensory response to haptic cues. Our results show promise that an EEG-RSA approach can capture a shift in the representational space of cues, as a means to track haptic learning.

Oral arsenic trioxide for relapsed acute promyelocytic leukemia in pediatric patients.

Four patients (age 3-11 years at diagnosis) with relapsed acute promyelocytic leukemia (APL), 12-38 months from diagnosis, were treated with oral arsenic trioxide (As(2) O(3) ). One patient was treated with oral As(2) O(3) monotherapy and chemotherapy. Three patients failed initial oral or intravenous As(2) O(3) monotherapy were treated with oral As(2) O(3) plus ATRA followed by long-term oral maintenance (cumulative As(2) O(3) dose 280-2,100 mg). All patients achieved molecular remission, at a median follow up of 122 (10-132) months with no adverse effects. Oral As(2) O(3) , particularly in prolonged maintenance with oral ATRA may obviate the need of stem cell transplantation in relapsed pediatric APL.

Analogous intermediate shape coding in vision and touch.

We recognize, understand, and interact with objects through both vision and touch. Conceivably, these two sensory systems encode object shape in similar ways, which could facilitate cross-modal communication. To test this idea, we studied single neurons in macaque monkey intermediate visual (area V4) and somatosensory (area SII) cortex, using matched shape stimuli. We found similar patterns of shape sensitivity characterized by tuning for curvature direction. These parallel tuning patterns imply analogous shape coding mechanisms in intermediate visual and somatosensory cortex.

A neurocomputational analysis of visual bias on bimanual tactile spatial perception during a crossmodal exposure.

Vision and touch both support spatial information processing. These sensory systems also exhibit highly specific interactions in spatial perception, which may reflect multisensory representations that are learned through visuo-tactile (VT) experiences. Recently, Wani and colleagues reported that task-irrelevant visual cues bias tactile perception, in a brightness-dependent manner, on a task requiring participants to detect unimanual and bimanual cues. Importantly, tactile performance remained spatially biased after VT exposure, even when no visual cues were presented. These effects on bimanual touch conceivably reflect cross-modal learning, but the neural substrates that are changed by VT experience are unclear. We previously described a neural network capable of simulating VT spatial interactions. Here, we exploited this model to test different hypotheses regarding potential network-level changes that may underlie the VT learning effects. Simulation results indicated that VT learning effects are inconsistent with plasticity restricted to unisensory visual and tactile hand representations. Similarly, VT learning effects were also inconsistent with changes restricted to the strength of inter-hemispheric inhibitory interactions. Instead, we found that both the hand representations and the inter-hemispheric inhibitory interactions need to be plastic to fully recapitulate VT learning effects. Our results imply that crossmodal learning of bimanual spatial perception involves multiple changes distributed over a VT processing cortical network.

Androgen deprivation induces rapid involution and recovery of human prostate vasculature.

The response of the prostate tissue microenvironment to androgen deprivation (AD) represents a critical component in the treatment of benign prostatic hyperplasia and prostate cancer (CaP). Primary xenografts of human benign and CaP tissue transplanted to immunocompromized SCID mice were used to characterize the response of the prostate vasculature during the initial 14 days of AD. Microvessel density and vascular lumen diameter in the prostate xenografts decreased rapidly after AD, reached a nadir on days 2-4, and recovered between days 4 and 14. The number of apoptotic endothelial cells peaked on day 2 after AD and decreased to precastration levels over days 4-7. Leakage of vascular contents in the interstitial space was apparent between days 1 and 3 after AD; however, the vascular permeability barrier reestablished between days 7 and 14. Expression of vascular endothelial growth factor (VEGF)-A, VEGF receptor-2, and basic fibroblast growth factor protein increased in endothelial cells between days 2 and 4 after AD, which preceded vascular recovery and appeared to be a direct and specific response of the endothelial cells to AD. Lack of comparable upregulation of these genes in primary cultures of human prostate endothelial cells in response to AD suggests a role for paracrine signaling mediated through stromal or epithelial cells. VEGF-A expression by prostate endothelial cells appears to represent a key facilitator of the vascular rebound in human prostate tissue induced by removal of circulating testicular androgens.

A synopsis of current haemophilia care in Hong Kong.

OBJECTIVE: To provide a synopsis of current haemophilia care in Hong Kong. DESIGN: Retrospective survey. SETTING: All haematology units of the Hospital Authority in Hong Kong. PATIENTS: All patients with haemophilia A and haemophilia B. RESULTS: To date, there were 222 mild-to-severe haemophilia patients (192 type A, 30 type B) under regular public care in Hong Kong (43% were considered severe, 33% moderate, and 24% mild), which gave a crude prevalence of 6.8/100 000 male inhabitants. A total of 12.8 million units of Factor VIII and 3 million units of Factor IX were prescribed annually. This amounts to 1.83 units of FVIII per capita of the population, which is comparable to that of other developed countries. Leading causes of mortality were human immunodeficiency virus-related complications (10 cases) and cerebral bleeding (2 cases). The life expectancy of patients with severe haemophilia in Hong Kong is improving; currently the oldest patient is 60 years old. Such improved survival may be due to enhanced factor availability, prompt treatment of bleeding episodes at home, safer factor products, and better antiviral treatment. Primary prophylaxis is the accepted standard of care for severe and moderate cases, and "Factor First" has become hospital policy. However, 12 patients continue to present treatment challenges, due to the documented presence of factor inhibitors. In all, 28, 100, and 14 cases respectively were positive for human immunodeficiency virus, hepatitis C virus, and hepatitis B virus; the youngest patients with the corresponding infections being 28, 13, and 22 years old. Comprehensive care with dedicated physiotherapy, surgical support, and radionucleotide synovectomy may reduce morbidity further. CONCLUSION: A multidisciplinary approach can further improve the future care for haemophilia patients in Hong Kong.

Evaluating the Effect of Stimulus Duration on Vibrotactile Cue Localizability With a Tactile Sleeve.

Vibrotactile arrays are appealing as wearable haptic devices, since designers can vary parameters including cue location and duration to create distinct haptic icons to represent a wide range of information. Vibrotactile sleeves have typically used cues that vary in duration from 100 to 400 ms, but it is not well understood how cue duration might affect localizability of stimuli. Using an experimental protocol typically employed to understand how our visual system can localize stimuli, we examined localization of tactile cues for tactors spaced at fixed locations along the forearm while we varied cue duration between 100 and 400 ms. To validate our experimental methods and hardware, we also evaluated visual cue localization performance. Our visual cue localization results were in agreement with prior experiments showing that varying noise in visual cues affects cue localization. More importantly, this experimental paradigm allowed us to verify that participants could successfully localize tactile cues regardless of duration. Response variance in tactile localizability was much greater than the visual case. There was also an effect of stimulus location on tactile localization performance. Our findings support the variation of tactile cue duration in the 100 to 400 ms range for tactile arrays positioned on the forearm.