Development and Validation of a Novel Calibration Methodology and Control Approach for Robot-Aided Transcranial Magnetic Stimulation (TMS).

OBJECTIVE: This article presents the development and validation of a new robotic system for Transcranial Magnetic Stimulation (TMS), characterized by a new control approach, and an ad-hoc calibration methodology, specifically devised for the TMS application. METHODS: The robotic TMS platform is composed of a 7 dof manipulator, controlled by an impedance control, and a camera-based neuronavigation system. The proposed calibration method was optimized on the workspace useful for the specific TMS application (spherical shell around the subject's head), and tested on three different hand-eye and robot-world calibration algorithms. The platform functionality was tested on six healthy subjects during a real TMS procedure, over the left primary motor cortex. RESULTS: employing our method significantly decreases ( ) the calibration error by 34% for the position and 19% for the orientation. The robotic TMS platform achieved greater orientation accuracy than the expert operators, significantly reducing orientation errors by 46% ( ). No significant differences were found in the position errors and in the amplitude of the motor evoked potentials (MEPs) between the robot-aided TMS and the expert operators. CONCLUSION: The proposed calibration represents a valid method to significantly reduce the calibration errors in robot-aided TMS applications. Results showed the efficacy of the proposed platform (including the control algorithm) in administering a real TMS procedure, achieving better coil positioning than expert operators, and similar results in terms of MEPs. SIGNIFICANCE: This article spotlights how to improve the performance of a robotic TMS platform, providing a reproducible and low-cost alternative to the few devices commercially available.

Altered Proprioceptive Feedback Influences Movement Kinematics in a Lifting Task.

Movement control process can be considered to take place on at least two different levels: a high, more cognitive level and a low, sensorimotor level. On a high level processing a motor command is planned accordingly to the desired goal and the sensory afference, mainly proprioception, is used to determine the necessary adjustments in order to minimize any discrepancy between predicted and executed action. On a lower level processing, the proprioceptive feedback later employed in high level regulations, is generated by Ia sensory fibers positioned in muscle main proprioceptors: muscle spindles. By entraining the activity of these spindle fibers through 80Hz vibration of triceps distal tendon, we show the intriguing possibility of inducing kinematics adjustments due to negative feedback corrections, during a lifting task.

A virtual reality platform for multisensory integration studies.

A unique virtual reality platform for multisensory integration studies is presented. It allows to provide multimodal sensory stimuli (i.e. auditory, visual, tactile, etc.) ensuring temporal coherence, key factor in cross-modal integration. Four infrared cameras allow to real-time track the human motion and correspondingly control a virtual avatar. A user-friendly interface allows to manipulate a great variety of features (i.e. stimulus type, duration and distance from the participants' body, as well as avatar gender, height, arm pose, perspective, etc.) and to real-time provide quantitative measures of all the parameters. The platform has been validated on two healthy participants testing a reaction time task which combines tactile and visual stimuli, for the investigation of peripersonal space. Results proved the effectiveness of the proposed platform, showing a significant correlation (p=0.013) between the participant's hand distance from the visual stimulus and the reaction time to the tactile stimulus. More participants will be recruited to further investigate the other measures provided by the platform.

'Doublecheck: a sensory confirmation is required to own a robotic hand, sending a command to feel in charge of it'.

Over a lifetime of experience, the representation of the body is built upon congruent integration of multiple elements constituting the sensorimotor loop. To investigate its robustness against the rupture of congruency between senses and with motor command, we selectively manipulated in healthy subjects the binds between sight, proprioception, and efferent motor command. Two experiments based on the Moving Hand Illusion were designed employing Tendon Vibration Illusion to modulate proprioception and generate illusory altered feedback of movement. In Experiment A, visuomotor congruency was modulated by introducing adelay between complex multifingered movements performed by arobotic hand and real movement of each participant's hand. In the presence of the motor command, visuomotor congruency enhanced ownership, agency, and skin conductance, while proprioceptive-motor congruency was not effective, confirming the prevalence of vision upon proprioception. In Experiment B, the impact of visuo-proprioceptive congruency was tested in the absence of motor command because the robotic hand moved autonomously. Intersensory congruency compensated for the absence of motor command only for ownership. Skin conductance in Exp Band Proprioceptive Drift in both experiments did not change. Results suggest that ownership and agency are independently processed, and presence of the efferent component modulates sensory feedbacks salience. The brain seems to require the integration of at least two streams of congruent information. Bodily awareness can be generated from sensory information alone, but to feel in charge of the body, senses must be double-checked with the prediction generated from efference copy, which is treated as an additional sensory modality.

Non-invasive brain stimulation of motor cortex induces embodiment when integrated with virtual reality feedback.

Previous evidence highlighted the multisensory-motor origin of embodiment - that is, the experience of having a body and of being in control of it - and the possibility of experimentally manipulating it. For instance, an illusory feeling of embodiment towards a fake hand can be triggered by providing synchronous visuo-tactile stimulation to the hand of participants and to a fake hand or by asking participants to move their hand and observe a fake hand moving accordingly (rubber hand illusion). Here, we tested whether it is possible to manipulate embodiment not through stimulation of the participant's hand, but by directly tapping into the brain's hand representation via non-invasive brain stimulation. To this aim, we combined transcranial magnetic stimulation (TMS), to activate the hand corticospinal representation, with virtual reality (VR), to provide matching (as contrasted to non-matching) visual feedback, mimicking involuntary hand movements evoked by TMS. We show that the illusory embodiment occurred when TMS pulses were temporally matched with VR feedback, but not when TMS was administered outside primary motor cortex, (over the vertex) or when stimulating motor cortex at a lower intensity (that did not activate peripheral muscles). Behavioural (questionnaires) and neurophysiological (motor-evoked-potentials, TMS-evoked-movements) measures further indicated that embodiment was not explained by stimulation per se, but depended on the temporal coherence between TMS-induced activation of hand corticospinal representation and the virtual bodily feedback. This reveals that non-invasive brain stimulation may replace the application of external tactile hand cues and motor components related to volition, planning and anticipation.

Control de la lepra en Venezuela después de más de cinco décadas de desarrolo

La lucha antileprosa se incia en Venezuela en el siglo XIX, y se refuerza a comienzos del siglo XX. Con la creación del Ministerio de Sanidad en 1936 se inicia el servicio de lucha antileprosa y en 1946 se crea la División de Lepra, que se convertirá después en el Departamento de Dermatología, el cual actualmente forma parte del Instituto de Biomedicina, que es organismo rector de esta actividad a nivel estatal, y cuyas actividades a nivel operativo se realizan a través de los 31 servicios regionales de Dermatología Sanitaria. En 1985 se inició la aplicación de la poliquimioterapia supervisada como tratamiento de elección. La evolución de la lepra en Venezuela desde 1946 se caracteriza por un aumento de la detección y la prevalencia en los años inmediatos a esta fecha, con un descenso posterior desde la década del 60, estabilizándose la deteción desde inicios de la década del 80, con tasas alrededor de 0'25 (algo más de 500 casos) por 10.000 habitantes por año. Para este período de ha mantenido el descenso de la prevalencia, la cual mostró cambios bruscos en 1982 y 1995, por actuatualización de los registros. En nivel de eliminación de la lepra como problema de salud (de acuerdo al criterio de la OMS de una tasa de prevalencia inferior a uno ano por 10.000 habitantes), se alcanzó en Venezuela en 1997. En las entidadades federales, soleamente cuatro de las 23 (Apure, Barinas, Dojedes y Portuguesa) mantienen tasas de prevalencia por encima del nivel de eliminación. Dado el hecho de haber alcanzado el nivel de eliminación, manteniéndose relaticamente estables el número de casos nuevos y la tasa de detección, se propone que el criterio para clasificar a un país como "en fase de eliminación) sea más estricto e incluya, además de la tasa de prevaelncia, datos relativos a la detección de casos. El tipo clínico predominante es el multibacilar. Las tasas de detección por edade muestran un aumento gradual al avanzar en edad. La racón masculino/femenino se mantiene alrededor de 2. Un 10% de los casos presentaron algún grado de discapacidad, aunque discreta en la mayoría de los casos. Existe un porcentaje de casos nacidos en el ixterior que es superior a la proporción de población con esta característica en el país. La mayor proporción de casos proviene del área urbana, especialmente de las zonas marginales, aun cuando las tasas son mayores para la zona...

Coexistence of two species of Leishmania in the digestive tract of the vector Lutzomyia ovallesi.

Leishmania isolated from the digestive tract of a naturally infected Lutzomyia ovallesi sand fly were cultured in blood agar for rapid growth, cloning, and subsequent identification through schizodeme analysis, dot-blot hybridization, use of monoclonal antibodies with various specificities and absorbed polyclonal antibodies. Twenty-three clones isolated from the primary culture were identified. The results showed that parasites belonging to some clones corresponded to the L. mexicana complex, while others belonged to the L. braziliensis complex. These results clearly establish the coexistence of two Leishmania species in the digestive tract of a single Lu. ovallesi sand fly.

Leprosy in women: characteristics and repercussions.

"Health is often measured in terms of low mortality; nevertheless, merely being alive is not a measure of the quality of life" H. Méndez Castellanos. Physiological, socioeconomic and cultural factors play important roles in the response of women to Mycobacterium leprae and in the impact of leprosy on their lives. They appear to develop stronger immunological responses to M. leprae than men, as suggested by lower incidence and less severe clinical forms of disease in most areas of the world, as well as stronger reactions of cell-mediated immunity after prophylactic vaccination. Genetic factors and physiological status including pregnancy, intercurrent infection and malnutrition might be among the factors which modulate this response. Women in leprosy-endemic areas of the world, with few exceptions, suffer from marked economic and social dependency and inferiority which can only be heightened by the social stigma associated with leprosy. Nevertheless, they bear an enormous responsibility for the health of their families, often as head of the household, and they often possess a unique capacity to influence community opinion. With the introduction of multidrug therapy, leprosy control throughout the world is no longer an unrealistic goal. Active vaccination may constitute the other factor necessary for eventual eradication of the disease. The incorporation of women at all levels into active roles in health care programs may constitute one of the decisive factors in the success or failure of leprosy control.

Immunoprophylactic trial with combined Mycobacterium leprae/BCG vaccine against leprosy: preliminary results.

In an attempt to find a vaccine that gives greater and more consistent protection against leprosy than BCG vaccine, we compared BCG with and without killed Mycobacterium leprae in Venezuela. Close contacts of prevalent leprosy cases were selected as the trial population since they are at greatest risk of leprosy. Since 1983, 29,113 contacts have been randomly allocated vaccination with BCG alone or BCG plus 6 x 10(8) irradiated, autoclaved M leprae purified from the tissues of infected armadillos. We excluded contacts with signs of leprosy at screening and a proportion of those whose skin-test responses to M leprae soluble antigen (MLSA) were 10 mm or more (positive reactions). By July, 1991, 59 postvaccination cases of leprosy had been confirmed in 150,026 person-years of follow-up through annual clinical examinations of the trial population (31 BCG, 28 BCG/M leprae). In the subgroup for which we thought an effect of vaccination was most likely (onset more than a year after vaccination, negative MLSA skin-test response before vaccination), leprosy developed in 11 BCG recipients and 9 BCG/M leprae recipients; there were 18% fewer cases (upper 95% confidence limit [CL] 70%) in the BCG/M leprae than in the BCG alone group. For all cases with onset more than a year after vaccination irrespective of MLSA reaction the relative efficacy was 0% (upper 95% CL 54%; 15 cases in each vaccine group). Retrospective analysis of data on the number of BCG scars found on each contact screened suggested that BCG alone confers substantial protection against leprosy (vaccine efficacy 56%, 95% CL 27-74%) and there was a suggestion that several doses of BCG offered additional protection. There is no evidence in the first 5 years of follow-up of this trial that BCG plus M leprae offers substantially better protection against leprosy than does BCG alone, but the confidence interval on the relative efficacy estimate is wide.

Immunotherapy of localized, intermediate, and diffuse forms of American cutaneous leishmaniasis.

The clinical efficacy of immunotherapy for localized American cutaneous leishmaniasis with a combination of heat-killed Leishmania mexicana amazonensis promastigotes and viable BCG (bacille Calmette Guérin) has been compared with meglumine antimoniate chemotherapy and with BCG alone in a controlled clinical study in 217 patients. The results in the first two groups were comparable, with greater than 90% clinical cures with an average time of 16-18 w required for healing. The cure rate was considerably lower (42%) and more prolonged in the group receiving BCG alone. Secondary effects were observed in less than 5% of the patients receiving combined immunotherapy or BCG alone. In contrast, 49% of the patients receiving chemotherapy showed side effects. High therapeutic efficacy was also observed using combined immunotherapy in patients with intermediate and diffuse cutaneous leishmaniasis who were previously unresponsive to chemotherapy. Cure or clinical improvement was seen in all 11 patients with intermediate forms of the disease, and marked clinical improvement was observed in 9 of 10 patients with diffuse disease. The results on the efficacy of the combined vaccine in immunotherapy for American cutaneous leishmaniasis provide a strong rationale for studying its effectiveness in prophylactic trials.

Situación actual en inmunoterapia de Leishmania / Current situation in inmunotherapy of the Leishmaniasis

En un ensayo clínico controlado, con evaluación a ciegas y asignación al azar, se ha evaluado la eficacia terapéutica de una combinación de B.C.G. con promastigotes de L.Mexicana amazonensis muertos por calor (Inmunoterapia) en comparación con Antimoniaco de Meglumine (Quimioterapia) y un tercer grupo vacunado con B.C.G. solamente, con un total de 171 pacientes de Leishmaniasis Cutánea localizada (99 Inmunoterapia, 46 Quimioterapia y 26 con BCG). Los resultados obtenidos son comparables en los dos primeros grupos, tanto en el porcentaje de curación (más del 95% a las 32 semanas) como en el tiempo promedio de curación (alrededor de 17 semanas, en cambio en el grupo con BCG solamente los porcentajes de curación son muy bajos (38,5% a las 32 semanas) y el tiempo promedio de curación mucho más prolongado (26 semanas). Los efectos secundarios fueron leves e infrecuentes (menos del 5%) en inmunoterapia y con BCG solo, pero muy frecuente (48%) y severos en quimioterapia. Resultados preliminares indican así mismo buena eficacia terapéutica de la inmunoterapia en pacientes cutáneos y mucosos del área intermedia del espectro clínico-inmunológico y en pacientes con L.Cutánea Difusa (LCD). en este trabajo se discuten los fundamentos de la inmunoterapia en Leishmaniasis en base al espectro de deficiencias de inmunidad celular y se plantean las perspectivas de la inmunoprofilaxis en base a estos conceptos

Immunotherapy versus chemotherapy in localised cutaneous leishmaniasis.

In a randomised trial a combination vaccine consisting of live BCG together with killed leishmania promastigotes was compared with a standard antimonial regimen in 94 patients with localised cutaneous leishmaniasis. Three vaccinations over 32 weeks gave a similar cure rate (94%) to three 20-day courses of meglumine antimonate. In the immunotherapy group side-effects were few (5.8%) and slight whereas in the chemotherapy group they were frequent (52.4%) and often serious. Immunotherapy is a low-cost, low-risk alternative to chemotherapy in localised cutaneous leishmaniasis, applicable by primary health services in rural areas.

Immunotherapy with a mixture of Mycobacterium leprae and BCG in different forms of leprosy and in Mitsuda-negative contacts.

A total of 529 weak or non-reactors to M. leprae, including Mitsuda-negative contacts and patients with leprosy, were vaccinated once or repeatedly, as necessary, with a mixture of 6 x 10(8) purified, heat-killed M. leprae and 0.01 mg to 0.2 mg of viable BCG. Clinical, histopathological and immunological criteria were used to evaluate the response of these individuals. Clinical changes, including sharper definition of borders and progressive flattening and regression of lesions, were observed in 57% of the active LL cases and 76% of the active BL cases. Histopathological study revealed infiltration of the lesions by mononuclear cells, appearance of epithelioid differentiation, and fragmentation of the microorganisms. Delayed-type skin tests with soluble antigen from purified M. leprae became positive in significant numbers of each group studied. These results demonstrate the efficacy of combined immunotherapy in low-resistance forms of leprosy and potential utility in the immunoprophylaxis of the disease.

In vitro activation of neutrophils by suspensions of Mycobacterium leprae.

Activation, defined as an increase in the proportion of cells that reduce nitroblue-tetrazolium in vitro, is present in neutrophils from patients with reactional lepromatous leprosy but not in neutrophils from patients with non-reactional lepromatous leprosy. Neutrophils from patients with all forms of leprosy are equally well activated by endotoxin in vitro. We have now shown that in vitro activation induced by Mycobacterium leprae suspensions is of comparable magnitude in neutrophils from patients with all forms of leprosy (including lepromatous and reactional lepromatous leprosy). There is no intrinsic neutrophil anergy in patients with lepromatous leprosy vis-à-vis M. leprae as pertains to activation. Spontaneous activation in reactional lepromatous leprosy is likely due to an indirect mechanism, probably of immunologic nature, and not simply to the presence of circulating Mycobacterium leprae in the blood.

Immunological changes observed in indeterminate and lepromatous leprosy patients and Mitsuda-negative contacts after the inoculation of a mixture of Mycobacterium leprae and BCG.

This investigation was carried out to study the possibility of eliciting favourable immunological changes in small groups of Mitsuda-negative patients with indeterminate leprosy, lepromatous patients who were bacteriologically negative after prolonged treatment with sulphones, and in Mitsuda-negative contacts by means of stimulation with a mixture of autoclaved tissues from Mycobacterium leprae-infected armadillos and living BCG. A radical change was observed in the specific immunological activity of the indeterminate group, all of whom initially had occasional bacilli in cutaneous nerves in biopsies taken from hypopigmented spots, and in the persistently Mitsuda-negative contacts. The 48 hr and 30 day reactions to lepromin, the 48 hr reaction to supernatant antigen from lepromin, the test for bacillary clearence and in vitro lymphocyte transformation (LTT) to M. leprae from human and armadillo lesions all became positive. Of the lepromatous patients studied, only one became positive to all the criteria mentioned above. In the others, the 48 hr reaction to supernatant antigen, the LTT to antigen from a humn source, and the clearance test remained negative, while the Fernandez and Mitsuda reactions became positive. These results are discussed in terms of the possible use of this stimulation procedure in the prevention and immunotherapy of leprosy.

Immunological changes observed in indeterminate and lepromatous leprosy patients and Mitsuda-negative contacts after the inoculation of a mixture of Mycobacterium leprae and BCG

This investigation was carried out to study the possibility of eliciting favourable immunological changes in small groups of Mitsuda-negative patients...