New approaches to the study of neurorehabilitation protocols in dogs and cats with acute or chronic spinal cord injury with or without deep pain sensation and possible spinal shock signs

Tese de Doutoramento em Ciências Veterinárias na especialidade Clínica, área científica de ClínicaABSTRACT - Intensive neurorehabilitation protocols (INRP) with rehabilitation modalities and weight supported treadmill training (BWSTT), are suggested as treatment to obtain ambulation in dogs and cats with complete (DPP-), discomplete and incomplete (DPP+) compressive or non-compressive spinal cord injury (SCI), similarly to what is performed in human medicine.The first study is a cohort, prospective, controlled and blinded study that was performed in 22 dogs with T11-L3 Hansen type I, revealing ambulation in 100% of the BWSTT group, within a mean of 4.6 weeks. One other study, a retrospective controlled clinical study, was developed in 367 acute post-surgical dogs, with T10-L3 Hansen type I. A new functional neurorehabilitation scale (FNRS-DPP-) was performed to evaluate the DPP- or discomplete dogs, that were able to achieve spinal reflex locomotion (SRL). A strong significance between groups was verified in the DPP+ (p<0.001), with 99.4% of ambulation. The same difference was seen in the DPP- (p=0.007) with 58,5% of ambulation and a tendency (p=0.058) was observed in regard to DPP recovery, with 37.2% achieving SRL, within a maximum of 3 months. INRP was demonstrated to be safe and ambulation recovery achieved earlier. The same population was included in another study, on 16 dogs with incomplete recovery 3 months after surgery. DPP- were under INRP associated with 4-aminopyridine administration, achieving 78% of SRL at day 45 and automatic micturition within a mean of 62 days. Also, 100% of ambulation in the DPP+ within a mean of 47 days and positive follow-up evolution. Ambulatory status was achieved in 88%, establishing this INRP as a therapeutic option to reduce euthanasia. Non-compressive myelopathies with contusive patterns were also referred in a prospective study of 9 cats that revealed 56% (n=5) of ambulation and 44% (n=4) of SRL, showing that INRP should be considered to improve quality of life and the well-being of our patients. Some dogs may develop spinal shock following SCI, including in acute noncompressive nucleus pulposus extrusion. Thus, a cohort prospective study applied a spinal shock scale as a monitoring tool, suggesting spinal shock as a negative factor for a quick recovery. INRP was shown to be safe, tolerable and feasible, allowing 32% of ambulation within 7 days and 94% within 60 days. Follow-ups until 4 years revealed a positive evolution. These studies should be continued, considering each limitationRESUMO - Nova abordagem aos protocolos de neuroreabilitação em cães e gatos com lesão medular aguda ou crónica, com/sem sensibilidade à dor profunda e choque espinhal. - Os protocolos de neuroreabilitação intensiva (INRP), com as modalidades de reabilitação e o treino locomotor em tapete rolante com suporte de peso (BWSTT), são sugeridos como terapêutica para obter a ambulação em cães e gatos de lesão medular compressiva / não compressiva, completa (DPP-), “discompleta” e incompleta (DPP+), tal como na medicina humana. Assim, apresenta-se o primeiro artigo, estudo de coorte, prospetivo, controlado e cego, em 22 cães com lesão T11-L3 Hansen tipo I, que demonstrou 100% de ambulação no grupo BWSTT, em média de 4.6 semanas. O segundo artigo refere-se ao estudo controlado e retrospetivo de 367 cães pós-cirúrgicos com lesão aguda T10-L3 de Hansen tipo I. A escala de neuroreabilitação funcional (FNRS-DPP-) foi elaborada e aplicada nestes cães, DPP- ou incompletos, capazes de atingir a locomoção espinhal por reflexos (SRL). Verificaram-se diferenças significativas entre grupos, nos DPP+ (p<0,001) com 99,4% de ambulação, e nos DPP- (p=0,007) com 58,5%. Em relação à recuperação da sensibilidade profunda (p=0,058), ocorreu 37.3% de SRL, no máximo em 3 meses. O INRP demonstrou-se seguro e a recuperação foi atingida de forma mais precoce. O mesmo foi estudado em 16 cães com recuperação incompleta 3 meses após cirurgia, sendo associada a administração de 4- aminopiridina nos DPP- com 78% de SRL até 45 dias e micção automática em ~62 dias. Obteve-se 100% de ambulação nos cães DPP+, em ~47 dias, com evolução positiva nas consultas de seguimento. A ambulação total foi de 88%, estabelecendo este INRP como opção terapêutica, reduzindo o número de eutanásias em âmbito clínico. As mielopatias não compressivas foram, também, estudadas. Assim sendo, estudo propectivo em 9 gatos revelou 56% de ambulação e 44% de SRL, demostrando que o INRP poderá ser considerado, no sentido de melhorar a qualidade de vida e bem-estar destes doentes. Após a lesão medular, alguns cães podem desenvolver o choque espinhal, principalmente na extrusão aguda não compressiva do núcleo pulposo. Assim, foi desenvolvido estudo propectivo coorte que elaborou e aplicou escala de choque espinhal para monitorização, sugerindo o choque espinhal como fator negativo para a rápida recuperação. Este INRP revelou-se seguro, tolerável e viável, com 32% de ambulação em 7 dias e 94% em 60 dias. Consultas de seguimento até 4 anos revelaram evolução positiva. Estes estudos devem ser continuados considerando as suas limitações.N/

Novel mechanisms of DC and kilohertz electrical stimulation

Transcranial electrical stimulation is a promising technique where a weak electrical current is applied to the scalp with the goal of modulating brain activity. Understanding the cellular mechanism of direct current (DC) and kilohertz (kHz) electrical stimulation is of broad interest in neuromodulation. More specifically, there is a large mismatch between enthusiasm for clinical applications of the method and understanding of DC and kHz novel mechanisms of action. This dissertation is centered around two main fundamental aims: 1) systematic study of the acute and long-term effects of kilohertz electrical stimulation and amplitude-modulated waveform with kHz carrier frequency using a well-established animal model, hippocampal brain slice, 2) study the effect of tDCS on water exchange rate across the blood-brain barrier using an advanced MRI imaging technique in a healthy population to investigate effect of tDCS stimulation on neurovascular units. The neuronal membrane has a well-established low pass filtering characteristic. This feature attenuates the sensitivity of the nervous system to any waveforms with high-frequency components. On the contrary, kilohertz stimulation has recently revolutionized spinal cord stimulation and even generated promising results in transcranial electrical stimulation. Investigating the effect of low kilohertz stimulation for neuromodulation is of huge interest. In chapters 2 and 3, several experimental designs are used to systematically investigate the frequency and dose-response of neuronal activity to unmodulated and amplitude modulated waveforms in low kilohertz range. The results support the theory of membrane attenuation of high-frequency stimulation. This dissertation provides the first direct in vitro evidence on acute effects of kilohertz electrical stimulation on modulating gamma oscillation using both unmodulated and Amplitude-modulated waveforms. While supported by membrane characteristics of neurons, we uncovered that using low kilohertz stimulation diminishes the sensitivity of hippocampal neurons to electrical stimulation. Moreover, Amplitude-Modulated waveforms can generate a different pattern of modulation with even higher sensitivity to stimulation. However, the required electric field, in this case, is still significantly higher than low-frequency stimulation methods such as tACS. Effects of DC stimulation have been studied in neuronal depolarization/hyperpolarization, synaptic plasticity, and neuronal network modulation. Recent evidence suggests that DC stimulation can induce polarity-dependent water exchange rate across the blood-brain barrier (BBB) in cell culture experiments through a mechanism called electroosmosis. Modulating water exchange rate across BBB is of broad interest in neurological diseases such as dementia, Alzheimer’s, and stroke where the brain clearance system is disrupted. Investigating the effect of electrical stimulation on water exchange across BBB can potentially lead to complimentary treatment options. In chapter 4, an advanced MRI technique was used to investigate induced changes in cerebral blood flow (CBF) and water exchange rate across BBB during stimulation in areas under electrodes. Contrary to our hypothesis, we could not resolve an effect in the water exchange rate across BBB. In conclusion, in our efforts to investigate effects of high frequency stimulation we found that sensitivity of neuronal networks to oscillating electrical stimulation is governed by time constant of neuronal membrane. Moreover, neuronal networks are selective to different kilohertz waveforms (i.e., amplitude modulated) and this is governed by a nonlinear adaptive mechanism present in the network. For the effect of DC stimulation on neurovascular units, we hypothesized that stimulation affects water exchange rate across BBB through a mechanism known as electroosmosis which is a very small portion of a large water exchange across BBB in active transport. We believe that this may be the answer to our negative results in experiments

El masaje eléctrico en la acromioplastia. Ensayo clínico

OBJETIVOS: Establecer y validar un procedimiento de electroterapia consistente en la aplicación de masaje eléctrico con corrientes interferenciales (CIF) en sujetos intervenidos quirúrgicamente de acromioplastia. Evaluar el aumento del balance articular, la disminución del dolor y el grado de funcionalidad tras la intervención fisioterapéutica. MATERIAL Y MÉTODO: Estudio de ensayo clínico aleatorizado con grupo control. Muestra constituida por 56 sujetos de 49.61±12.46 años de edad, [23-76] de ambos sexos (26 hombres y 30 mujeres), distribuidos en 2 grupos: grupo experimental n=28 y grupo control n=28 pacientes. Ambos grupos recibieron un protocolo de tratamiento de Fisioterapia durante 6 sesiones. El grupo experimental recibió además, un tratamiento mediante masaje eléctrico, con la aplicación bipolar de CIF en modo CV (constant voltage), corriente portadora a 4000Hz y AMF de 100 Hz. Se utilizaron 2 electrodos de 48 cm2, siendo de 10 minutos el tiempo de tratamiento. A toda la muestra se le midió previamente el grado de aprensión psicológica mediante la escala de aprensión psicológica personal, (EAPP®) para asegurar su la validez interna. Se midió su percepción dolorosa mediante la escala visual analógica (EVA), la movilidad articular mediante goniometría y el grado de funcionalidad mediante la escala de Constant, antes y después del tratamiento. RESULTADOS: La medición de la EVA reveló que existen diferencias estadísticamente significativas tras el tratamiento entre ambos grupos (p=0.005 para p<0.05), analizado mediante el estadístico T de Welch. El grupo experimental pasó de una EVA de 6.98±1.67 pre-tratamiento a una EVA 3.26±1.36 post-tratamiento, mientras el grupo control pasó de una EVA 6.57±2.08 pre-tratamiento a una EVA 4.75±2.29 post-tratamiento. Los resultados de la escala de Constant revelaron que existen diferencias estadísticamente significativas tras el tratamiento entre ambos grupos (p=0.006 para p<0.05), analizado mediante el estadístico U de Mann-Whitney. En el grupo experimental pasó de 29.68±10.42 pre-tratamiento a 56.07±10.96 posttratamiento, mientras en el grupo control pasó de 29.71±12.24 pre-tratamiento a 45.39±13.82 post-tratamiento. Existen diferencias estadísticamente significativas tras el tratamiento en el balance articular entre ambos grupos en los parámetros de flexión (p=0.023 para p<0.05) y rotación interna (p=0.017 para p<0.05) analizados mediante el estadístico U de Mann-Whitney. El procedimiento de electroterapia consistente en la aplicación mediante masaje eléctrico de corrientes interferenciales (CIF) en sujetos intervenidos quirúrgicamente de acromioplastia es válido y fiable, con un alfa de Cronbach de 0.944. CONCLUSIONES: La aplicación del masaje eléctrico propuesta en el presente estudio es clínicamente significativa para la reducción del dolor medida a través de la EVA, con una reducción de 3.72 puntos, (p=0.005) para el aumento del grado de funcionalidad medido a través de la escala de Constant, con un aumento de 26.39 puntos, (p=0.006) y para el aumento del balance articular en los parámetros de flexión (p=0.023) y rotación interna (p=0.017). El procedimiento es válido y fiable, con un alfa de Cronbach de 0.944

Brain and Human Body Modeling

This open access book describes modern applications of computational human modeling with specific emphasis in the areas of neurology and neuroelectromagnetics, depression and cancer treatments, radio-frequency studies and wireless communications. Special consideration is also given to the use of human modeling to the computational assessment of relevant regulatory and safety requirements. Readers working on applications that may expose human subjects to electromagnetic radiation will benefit from this book’s coverage of the latest developments in computational modelling and human phantom development to assess a given technology’s safety and efficacy in a timely manner. Describes construction and application of computational human models including anatomically detailed and subject specific models; Explains new practices in computational human modeling for neuroelectromagnetics, electromagnetic safety, and exposure evaluations; Includes a survey of modern applications for which computational human models are critical; Describes cellular-level interactions between the human body and electromagnetic fields

Brain and Human Body Modeling

This open access book describes modern applications of computational human modeling with specific emphasis in the areas of neurology and neuroelectromagnetics, depression and cancer treatments, radio-frequency studies and wireless communications. Special consideration is also given to the use of human modeling to the computational assessment of relevant regulatory and safety requirements. Readers working on applications that may expose human subjects to electromagnetic radiation will benefit from this book’s coverage of the latest developments in computational modelling and human phantom development to assess a given technology’s safety and efficacy in a timely manner. Describes construction and application of computational human models including anatomically detailed and subject specific models; Explains new practices in computational human modeling for neuroelectromagnetics, electromagnetic safety, and exposure evaluations; Includes a survey of modern applications for which computational human models are critical; Describes cellular-level interactions between the human body and electromagnetic fields

Developing a Brain‐Based, Non‐Invasive Treatment for Pain

Chronic pain cost society more than $500 billion each year and contributes to the ongoing opioid overdose crisis. Substantial risks and low efficacy are associated with opiate usage for chronic pain. This dissertation seeks to fill the urgent need for a new pain treatment using a neural-circuit based approach in healthy controls and chronic pain patients. First, we performed a single-blind study examining the causal effects of transcranial magnetic stimulation (TMS), compared to a well-matched control condition. Using interleaved TMS/fMRI we explored brain activation in response to dorsolateral prefrontal cortex (DLPFC) stimulation in 20 healthy controls. This study tested the hypothesis that the TMS evoked responses would be in frontostriatal locations. Consistent with this hypothesis active TMS, compared to the control, led to significantly greater activity in the caudate, thalamus and anterior cingulate cortex (ACC). Building on these findings, we developed a single-blind, sham-controlled study examining two TMS strategies for analgesia in 45 healthy controls. We completed an fMRI thermal pain paradigm before and after modulatory repetitive TMS at either the DLPFC or the medial prefrontal cortex (MPFC). Despite a role in pain processing, the MPFC has not yet been explored as a target for analgesia. Only MPFC stimulation significantly improved behavioral pain measures. These effects were associated with increased motor and parietal cortex activity during the pain task. We then supplement these findings by testing the hypothesis that chronic pain patients who use opioids (n=14) would have elevated brain responses to thermal pain relative to healthy controls (n=14). Despite indistinguishable self-report measures, we found increased brain activity in the ACC and sensory areas in patients which were positively correlated with opioid dose. We conclude by evaluating the feasibility of these approaches in chronic pain patients, reporting preliminary findings from a pilot study examining the two treatment strategies tested previously in controls. Collectively, our findings support a circuits-first approach to pain treatment. Though MPFC stimulation was effective in reducing pain in healthy controls, further work is required to confirm these results in a chronic pain population, as chronic pain and opioid usage alter how the brain processes the pain experience

Computational Model of Electroconvulsive Therapy Considering Electric Field Dependent Skin Conductivity

Improvements in electroconvulsive therapy (ECT) outcomes have followed refinement in device electrical output and electrode montage. The physical properties of the ECT stimulus, together with those of the patient’s head, determine the impedances measured by the device and govern current delivery to the brain and ECT outcomes. However, the precise relations among physical properties of the stimulus, patient head anatomy, and patient-specific impedance to the passage of current are long-standing questions in ECT research and practice. In this thesis, we develop a computational framework based on diverse clinical data sets. We developed anatomical MRI-derived models of transcranial electrical stimulation (tES) that included changes in tissue conductivity due to local electrical current flow. These “adaptive” models simulate ECT both during therapeutic stimulation using high current and when dynamic impedance is measured, as well as prior to stimulation when low current is used to measure static impedance. We modeled two scalp layers: a superficial scalp layer with adaptive conductivity that increases with electric field up to a subject-specific maximum, and a deep scalp layer with a subject-specific fixed conductivity. We demonstrated that variation in these scalp parameters may explain clinical data on subject-specific static impedance and dynamic impedance, their imperfect correlation across subjects, their relationships to seizure threshold, and the role of head anatomy. Adaptive tES models demonstrated that current flow changes local tissue conductivity which in turn shapes current delivery to the brain in a manner not accounted for in fixed tissue conductivity models. Our predictions that variation in individual skin properties, rather than other aspects of anatomy, largely govern the relationship between static impedance, dynamic impedance, and ECT current delivery to the brain, themselves depend on assumptions about tissue properties. Broadly, our novel modeling pipeline opens the door to explore how adaptive-scalp conductivity may impact transcutaneous electrical stimulation (tES). Lastly, we incorporate the (device specific) role of frequency with a single overall assumption allowing quasi-static stimulations of ECT: appropriately parametrizing effective resistivity at single representative frequency (e.g., at 1 kHz), including subject-specific and adaptive skin resistivities. We only stipulate that our functions for (adaptive) resistivity at 1 kHz explain local tissue resistivity as they impact the static and dynamic impedance measures by specific ECT devices (e.g., Thymatron)