Reliability of resting-state functional connectivity in the human spinal cord: Assessing the impact of distinct noise sources

The investigation of spontaneous fluctuations of the blood-oxygen-level-dependent (BOLD) signal has recently been extended from the brain to the spinal cord, where it has also generated initial interest from a clinical perspective. A number of resting-state functional magnetic resonance imaging (fMRI) studies have demonstrated robust functional connectivity between the time-series of BOLD fluctuations in bilateral dorsal horns and between those in bilateral ventral horns, in line with the functional neuroanatomy of the spinal cord. A necessary step prior to extension to clinical studies is assessing the reliability of such resting-state signals, which we aimed to do here in a group of 45 healthy young adults at the clinically prevalent field-strength of 3T. When investigating connectivity in the entire cervical spinal cord, we observed fair to good reliability for dorsal-dorsal and ventral-ventral connectivity, whereas reliability was poor for within- and between-hemicord dorsal-ventral connectivity. Considering how prone spinal cord fMRI is to noise, we extensively investigated the impact of distinct noise sources and made two crucial observations: removal of physiological noise led to a reduction in functional connectivity strength and reliability – due to the removal of stable and participant-specific noise patterns – whereas removal of thermal noise considerably increased the detectability of functional connectivity without a clear influence on reliability. Finally, we also assessed connectivity within spinal cord segments and observed that while the pattern of connectivity was similar to that of whole cervical cord, reliability at the level of single segments was consistently poor. Taken together, our results demonstrate the presence of reliable resting-state functional connectivity in the human spinal cord even after thoroughly accounting for physiological and thermal noise, but at the same time urge caution if focal changes in connectivity (e.g. due to segmental lesions) are to be studied, especially in a longitudinal manner

Energetics and activation of the central nervous system by in vivo nuclear magnetic resonance

Stefano Pascarella, Mario Compiani, Staderin

CEREBRAL ACTIVATION DURING THERMAL STIMULATION OF BURNING MOUTH DISORDER PATIENTS: AN fMRI STUDY

Functional magnetic resonance imaging (fMRI) has been widely used to study cortical and subcortical mechanisms related to pain. The pathophysiology of burning mouth disorder (BMD) is not clearly understood. Central neuropathic mechanisms are thought to be main players in BMD. This study aimed to compare the location and extension of brain activation following thermal stimulation of the trigeminal nerve with fMRI blood oxygenation level dependent (BOLD) signal. This study included 8 female patients with BMD and 8 matched pain-free volunteers. Qualitative and quantitative differences in brain activation patterns between the two study groups were demonstrated. There were differences in the activation maps regarding the location of activation, with patients displaying greater BOLD signal changes in the right anterior cingulate cortex (ACC BA 32/24) and bilateral precuneus (pandlt;0.005). The control group showed larger BOLD signal changes in the bilateral thalamus, right middle frontal gyrus, right pre-central gyrus, left lingual gyrus and cerebellum (pandlt;0.005). It was also demonstrated that patients had far less volumetric activation throughout the entire brain compared to the control group. These data are discussed in light of recent findings suggesting brain hypofunction as a key player in chronic neuropathic pain conditions

Imaging of thoracolumbar spine traumas

Spine trauma is an ominous event with a high morbidity, frequent mortality, and significant psychological, social, and financial consequences for patients, their relatives and society. On average three out of four spinal fractures involve the thoracolumbar spine and up to one-third are complicated by spinal cord injury. Spinal cord injuries (SCI) are a significant cause of disability in US and in all western countries. Knowledge of the main principles of biomechanics is essential in understanding the patho-morphology of spinal injuries, and the evolution of the various classification systems. Classification systems should be able to create a common language between specialists in order to improve patients' prognosis, guide treatment and compare treatment outcomes. Imaging has always been crucial in the evaluation of the injury type and accompanied the development of different classification systems. Thoracolumbar spine (TLS) trauma has a wide spectrum ranging from minor isolated fractures to highly unstable fracture-dislocations. Early classification systems were based on the analysis of the pattern of bony injuries on radiographs and CT. Traditionally, conventional radiographs are performed to confirm the clinical suspicion and to depict the level and type of bone injury. However, because of their inherent limitations, radiographs are often more helpful in proving the existence of a suspected bony spinal injury rather than excluding it. Multidetector computed tomography (MDCT) is superior in evaluating bone anatomy and, especially in polytrauma patients, it is the first line imaging modality. Morphological bone damage may be accurately shown and classified on CT. the most recent classifications also incorporate the integrity of soft tissues structures, which is considered equally relevant to spinal stability. Injuries to ligaments and discs can only be suspected on radiographs and conventional CT, although dual-energy CT is offering new insights on collagen mapping of damaged discs. Magnetic resonance imaging (MRI) may directly assess disc and ligamentous injuries, but also subtle osseous injuries, playing a complementary role in defining the whole spinal damage and an eventual instability. MRI is the only valid modality to assess the spinal cord (SC) and is indicated whenever a neurologic injury is suspected. Advanced MRI techniques, such as diffusion weighted imaging (DWI) and tractography, may provide further information regarding the integrity of the white matter which may improve outcome prognostication. Despite challenges in terms of costs, availability, accessibility and specificity, MRI and advanced MRI techniques are increasingly being used in spinal injuries. We present a review on TLS traumas discussing on the development of different classification system used in their evaluation, the role of imaging for their detection and the correlation to the patients' outcomes and treatment options

Non-invasive multi-channel electrophysiology of the human spinal cord: Assessing somatosensory processing from periphery to cortex

The spinal cord is of fundamental importance for somatosensory processing and plays a significant role in various pathologies, such as chronic pain. However, knowledge on spinal cord processing in humans is limited due to the vast technical challenges involved in its investigation via non-invasive recording approaches. Here, we aim to address these challenges by developing an electrophysiological approach – based on a high-density electrode-montage – that allows for characterizing spinal cord somatosensory evoked potentials (SEPs) and combining this with concurrent recordings of the spinal cord’s input (peripheral nerve action potentials) and output (SEPs in brainstem and cortex). In two separate experiments, we first methodologically validate the approach (including replication and robustness analyses) and then assess its application in the context of a neuroscientific question (integrative processes along the neural hierarchy). Critically, we demonstrate the benefits of multi-channel recordings in terms of enhancing sensitivity via spatial filtering, which also allows for obtaining spinal cord SEPs at the single-trial level. We make use of this approach to demonstrate the feasibility of recording spinal cord SEPs in low-signal scenarios (single-digit stimulation) and – most importantly – to provide evidence for bottom-up signal integration already at the level of the spinal cord. Taken together, our approach of concurrent multi-channel recordings of evoked responses along the neural hierarchy allows for a comprehensive assessment of the functional architecture of somatosensory processing at a millisecond timescale

Management of Degenerative Cervical Myelopathy and Spinal Cord Injury

The present Special Issue is dedicated to presenting current research topics in DCM and SCI in an attempt to bridge gaps in knowledge for both of the two main forms of SCI. The issue consists of fourteen studies, of which the majority were on DCM, the more common pathology, while three studies focused on tSCI. This issue includes two narrative reviews, three systematic reviews and nine original research papers. Areas of research covered include image studies, predictive modeling, prognostic factors, and multiple systemic or narrative reviews on various aspects of these conditions. These articles include the contributions of a diverse group of researchers with various approaches to studying SCI coming from multiple countries, including Canada, Czech Republic, Germany, Poland, Switzerland, United Kingdom, and the United States

An investigation into central nervous system involvement in distal symmetrical diabetic neuropathy in type 1 diabetes mellitus.

Diabetes is a leading cause of peripheral neuropathy. It is the main initiating factor for foot ulceration and amputation resulting in considerable morbidity and remarkable consumption of scarce medical resources. Relatively little is known about the pathophysiology underlying DPN. Research into DPN has focused mainly on the peripheral nervous system (PNS) with central nervous system (CNS) involvement relatively overlooked. The studies undertaken have been designed to investigate CNS involvement in DPN. 1. Before embarking on spinal cord studies, I reviewed and modified the techniques employed in the pilot study to improve the precision and accuracy of cord cross sectional area measurements. These modifications were patiented to quality control studies, which are reported in Chapter 2. 2. I performed in-vivo cross-sectional magnetic resonance imaging of the cervical spine and reported evidence of spinal cord shrinkage (atrophy) in Painless DPN (Chapter 3). This study showed spinal cord atrophy to be an early phenomenon, present even in subclinical DPN. As the spinal cord is the caudal portion of the CNS, its involvement made us question whether the brain too may be involved. 3. Using MR spectroscopy I examined thalamic involvement in Painless DPN (Chapter 4). This deep brain nucleus is considered the gateway to all somatosensory information entering the brain, and responsible for modulation of sensory information prior to presentation to the cerebral cortex. I demonstrated thalamic biochemical abnormalities consistent with possible neuronal dysfunction in patients with Painless DPN. 4. The demonstration of thalamic neuronal dysfunction in DPN suggests that CNS involvement is not limited to the spinal cord but other important areas, responsible for somatosensory perception, may also be involved. Although the pathogenesis of thalamic involvement is unknown, it is likely that both vascular and metabolic factors that have been implicated in the pathogenesis of DPN are involved. In Chapter 4, I examined the possible role of metabolic factors in the pathogenesis of thalamic neuronal dysfunction in DPN. Using MR spectroscopy, I demonstrated a significant elevation in thalamic glutamine/glutamate in patients with diabetes. Glutamate is the most abundant excitatory neurotransmitter and implicated in various models of neuronal cell death. Astrocytes, which play an important role in glutamate/glutamine metabolism, were impaired in the thalamus of diabetic patients in this study. The combination of elevated glutamate and impaired thalamic astrocytes may provide a pathophysiological explanation for thalamic dysfunction in DPN. 5. In Chapter 5, an alternative hypothesis for thalamic neuronal dysfunction in DPN was tested. Using dynamic contrast enhanced MR perfusion imaging, I demonstrated that Painful DPN is associated with unique thalamic perfusion abnormalities. Intriguingly, these abnormalities were present in patients with Painful but not Painless DPN. 6. Finally, in Chapter 6, I conducted a randomised, double blind and placebo-control trial (RCT) comparing the efficacy and tolerability of sativex, a cannabis based medicinal extract (CBME), with placebo in the symptomatic treatment of painful DPN. This is the first ever RCT using a CBME in painful DPN. We report no significant difference in the primary outcome measure due to a massive placebo effect and that depression is a potential major confounder in such clinical trials

Surgical treatment of degenerative lumbosacral stenosis in the dog : a critical appraisal

Dissertação de Mestrado Integrado em Medicina VeterináriaDegenerative lumbosacral stenosis (DLSS) is the compression of the cauda equina caused by protrusion of supportive tissues into the vertebral canal. Young adult, male, and large-breed dogs seem to be predisposed to this condition, although it can also affect cats. When medical treatment fails to provide adequate relief of clinical signs associated with DLSS, surgical treatment is often performed. Although several surgical modalities to treat DLSS have been reported, definitive criteria for surgical technique preference are currently lacking. Critical appraisal is the process of systematically examining research evidence to judge its trustworthiness, its value and relevance in a particular context. Therefore it is essential to make informed decisions in clinical practice. The main objective of this study was to critically appraise the literature reporting the results of surgical treatment of DLSS; to identify gaps in current knowledge and ensure there is justification for future research on the subject; and to propose study characteristics that would enrich the conduct and reporting of these studies. A critical appraisal tool that examined the conduct and reporting of each study was designed. After a systematic search and screening of the literature, 17 papers were critically appraised. Results showed that 94% of included studies did not clearly report inclusion and exclusion criteria and in 71% it was unclear whether consecutive inclusion of participants was applied. 94% of studies reported age, breed, and sex of the participants, and 65% did not report duration and prevalence of clinical signs. In 76% of studies, the condition was not measured in a standard and reliable way. Identification of the condition was performed using radiography in 88% of studies, CT in 29%, and MRI in 53%. It was considered that 47% of included studies did not clearly describe the intervention. Objective outcome measures were used in 35% of studies and clinical practical guidance was provided by all included studies. Although case series rank relatively low in the evidence hierarchy and have several limitations, results demonstrate that there is room for improvement of the conduct and reporting quality of case series so that rigorous data can be generated and analysed, to inform research design, guide clinical practice, and improve veterinary healthcare delivery.RESUMO - A estenose lombossagrada degenerativa é a compressão da cauda equina causada pela protusão de tecidos de suporte no canal vertebral. Apesar de também poder afetar gatos, cães de raça grande, machos e jovens adultos parecem ter predisposição para esta doença. Quando o tratamento médico não promove o alívio dos sinais clínicos associados à estenose lombossagrada degenerativa, o tratamento cirúrgico é uma escolha frequente. Apesar de já terem sido descritas diversas técnicas cirúrgicas para o tratamento de estenose lombossagrada degenerativa, não há critérios definitivos para a escolha de uma ou outra técnica. A análise crítica é o exame sistemático da evidência científica para verificar a sua fiabilidade, o seu valor e relevância em determinado contexto. É, portanto, essencial para a tomada de decisões fundadas em prática clínica. Os principais objetivos deste estudo foram os de apreciar criticamente a literatura que relata os resultados do tratamento cirúrgico de estenose lombossagrada degenerativa, de identificar lacunas no conhecimento e justificar a necessidade de mais investigação acerca do tema e ainda propôr elementos que poderão valorizar a execução e o relato de informação destes estudos. Foi construída uma ferramenta de análise crítica que examina a execução e o relato de informação de cada estudo e, após uma pesquisa sistemática e seleção da literatura, 17 artigos foram analisados criticamente. Os resultados mostraram que 94% dos estudos incluídos não relataram claramente critérios de inclusão e exclusão e em 71% não foi claro se a inclusão dos participantes foi feita de forma consecutiva. 94% dos estudos relatou a idade, a raça e o sexo dos participantes e 65% não relatou a duração e prevalência dos sinais clínicos. Em 76% dos estudos, a doença não foi medida de forma padronizada e repetível. O diagnóstico da doença foi auxiliado por radiografia em 88% dos estudos, tomografia computorizada em 29%, e ressonância magnética em 53%. Foi considerado que 47% dos estudos incluídos não descreveram claramente a intervenção cirúrgica. Em 35% dos estudos foram usadas medidas objetivas para avaliação dos resultados e todos os estudos incluídos forneceram orientação clínica prática ao leitor. Apesar de se situarem numa posição relativamente baixa na hierarquia da evidência e possuírem diversas limitações, os resultados demonstram que há lugar para melhorar a execução e o relato de informação em séries de caso, de forma a que se possam gerar e analisar dados rigorosos, para informar a investigação científica, guiar a prática clínica e, acima de tudo, melhorar a prestação de cuidados de saúde em medicina veterinária.N/