Systematic review of in-vivo neuro magnetic resonance spectroscopy for the assessment of posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a trauma and stressor-related disorder that results in complex somatic, cognitive, affective and behavioural effects, after exposure to traumatic event(s). Conventional imaging (T1 and T2 weighted magnetic resonance imaging) has little to offer in the way of diagnosis of mental health conditions such as PTSD and there is currently no objective diagnostic test available. Magnetic resonance spectroscopy (MRS) allows for non-invasive measurement of metabolites and neurochemicals in the brain using a conventional MRI scanner and offers the potential to predict, diagnose and monitor PTSD. This systematic review summarises the results of 24 MRS studies, performed between 1998 and 2017, to measure neurochemical differences, occurring as a consequence of PTSD. The most consistent finding in subjects with PTSD is lower N-acetylaspartate levels in the hippocampus and anterior cingulate cortex, with and without atrophic change. More recent studies, using more advanced techniques and modern hardware, have shown evidence of glutamatergic dysfunction and differences in gamma-aminobutyric acid levels in the brain of patients with PTSD. Conflicting results have been reported in choline-containing metabolites and there is emerging evidence of glutathione being affected. Myo-inositol and creatine are unchanged in the majority of studies

Neuro magnetic resonance spectroscopy using wavelet decomposition and statistical testing identifies biochemical changes in people with spinal cord injury and pain

Spinal cord injury (SCI) can be accompanied by chronic pain, the mechanisms for which are poorly understood. Here we report that magnetic resonance spectroscopy measurements from the brain, collected at 3 T, and processed using wavelet-based feature extraction and classification algorithms, can identify biochemical changes that distinguish control subjects from subjects with SCI as well as subdividing the SCI group into those with and without chronic pain. The results from control subjects (n = 10) were compared to those with SCI (n = 10). The SCI cohort was made up of subjects with chronic neuropathic pain (n = 5) and those without chronic pain (n = 5). The wavelet-based decomposition of frequency domain MRS signals employs statistical significance testing to identify features best suited to discriminate different classes. Moreover, the features benefit from careful attention to the post-processing of the spectroscopy data prior to the comparison of the three cohorts. The spectroscopy data, from the thalamus, best distinguished control subjects without SCI from those with SCI with a sensitivity and specificity of 0.9 (Percentage of Correct Classification). The spectroscopy data obtained from the prefrontal cortex and anterior cingulate cortex both distinguished between SCI subjects with chronic neuropathic pain and those without pain with a sensitivity and specificity of 1.0. In this study, where two underlying mechanisms co-exist (i.e. SCI and pain), the thalamic changes appear to be linked more strongly to SCI, while the anterior cingulate cortex and prefrontal cortex changes appear to be specifically linked to the presence of pain

Advances in proton MR spectroscopy for quantifying pain associated metabolic changes in the human brain

In this work non-invasive in vivo detection of excitatory neurotransmitter glutamate andother cortical metabolites and their changes in the presence of acute and chronic pain wasperformed in the human brain with proton magnetic resonance spectroscopy (1H-MRS).This information can be used to better understand biochemical processes of cerebral painprocessing. Following introductory material, the first part of this thesis describes theimplemented method for post-processing of MR spectroscopic data to estimate absoluteconcentrations of the brain metabolites by considering the heterogeneous tissue compositionin the spectroscopic voxel. Phantom and in vivo brain studies demonstrated theadvantage of this method by reduced inter-individual variation of calculated metabolicconcentrations as well as enhanced quantitation accuracy. The second part of this workpresents the implemented method for the stimulus triggered data sampling permittingthe acquisition of in vivo 1H-MR spectra with a time resolution of few seconds. It wasshown that this method enables detection of changes of the neurotransmitter glutamateinduced by short acute pain stimuli. Considering these data, it was possible to characterisechanges of the glutamatergig neurotransmission associated with the sensation ofthe acute pain. The third part describes in vivo measurements on chronic pain patientsand healthy controls aiming to evaluate the changes of several brain metabolites in thedifferent cerebral pain processing regions associated with chronic pain. Patients revealeddecreased concentrations of the metabolic cell density markers and neurotransmitters indicatingthe degenerative processes as well as neurotransmitter dysfunctions, respectively.Results of this thesis indicate that pain induced metabolic changes in the human brainare traceable with the 1H-MRS by using experimental environment as it is used in clinicalroutine. This offers a broad spectrum of further applications aiming to explore thecerebral pain processing as well as to improve the specificity of the diagnostic assessmentof the chronic pain disease.Die vorliegende Arbeit beschreibt die Anwendung der Protonenmagnetresonanzspektroskopie(1H-MRS) zum nicht invasiven Nachweis von schmerzinduzierten Änderungen des erregenden Neurotransmitters Glutamat sowie anderer Metaboliten im menschlichen Gehirn. Diese Informationen könnten zu einem tieferen Verständnis der biochemischen Prozesse während der zerebralen Schmerzverarbeitung beitragen. Nach einer kurzen Einführung in die Problematik der Schmerzforschung sowie in die Grundlagen der MRSTechnikwird eine im Rahmen dieser Arbeit implementierte Methode zur Berechnung absoluter Metabolitenkonzentrationen unter Berücksichtigung der heterogenen Gewebezusammensetzung im spektroskopischen Volumen beschrieben. Der Vorteil dieses Verfahrens in Bezug auf die Verbesserung der Quantifizierungsgenauigkeit wird anhand von Ergebnissen spektroskopischer Messungen in einem Phantom sowie in Gehirnen gesunder Probanden belegt. Der zweite Teil befasst sich mit der Implementierung einer Technik zur reizgetriggerten Akquisition von MR Spektren, welche eine Abtastung verschiedener Stimulationszustände mit einer zeitlichen Auflösung von wenigen Sekunden zulässt und somit die Detektion dynamischer Änderungen von Metaboliten im Gehirn ermöglicht. Durch die Anwendung dieser Methode bei Messungen an gesunden Probanden konnten Änderungen im Glutamatstoffwechsel infolge einer Stimulation mit kurzen akuten Schmerzreizen nachgewiesen werden. Im dritten Teil der Arbeit wird schließlich eine an gesunden Probanden und Patienten mit chronischen Schmerzen durchgeführte Studievorgestellt, innerhalb derer die Auswirkungen der Schmerzchronifizierung auf den Metabolismus in schmerzverarbeitenden kortikalen Regionen untersucht wurden. Die Ergebnisse dieser Studie belegen die Hypothese, dass chronischer Schmerz mit Veränderungen imNeurotransmitterstoffwechsel sowie mit degenerativen Prozessen auf zellulärer Ebene einhergeht. Zusammenfassend lässt sich sagen, dass es mit der 1H-MRS möglich ist, schmerzinduzierte Änderungen der Metaboliten im menschlichen Gehirn unter Verwendung von klinischen Standartverfahren zu quantifizieren. Dies wiederum eröffnet ein breites Feld für weitere Untersuchungen, welche zur Erforschung der zerebralen Schmerzverarbeitung sowie zur Verbesserung der Spezifität diagnostischer Verfahren bei chronischen Schmerzen beitragen könnten

Modulación de la nocicepción mediante condicionamiento térmico heterotópico y estimulación magnética espinal repetitiva en voluntarios sanos y en pacientes con lesión medular

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Anatomía, Histología y Neurociencia. Fecha de lectura: 16 de Diciembre de 201

Animal models of neuropathic pain after spinal cord injury

Approximately 70% of spinal cord injured patients suffer from pain and it is estimated that in 40-50% of these, the pain is of central neuropathic origin. This pain can be perceived to originate at, or below the level of injury and both evoked and spontaneous pain can occur. Neuropathic pain after spinal cord injury (SCI) is difficult to treat and often poorly controlled by the currently available analgesics so that development of better treatments is an important need. Current ideas about the treatment of SCI pain are that different approaches may be needed to treat the different types of pain (e.g. evoked and spontaneous, at level and below level) as they may have different mechanisms. However, this mechanistic approach to treatment is hampered by a poor understanding of the underlying mechanisms. This in turn depends on development of animal models and pain assessment techniques suitable for mechanistic studies. In this thesis, several rodent SCI models have been investigated using a range of assessment techniques some of which were developed in the course of the study. Contusion injuries at a low thoracic level are currently the most popular model used to investigate central neuropathic pain in rodents. However this model and the assessments used with it are subject to a number of limitations. We therefore began by re-evaluating this model using a relatively severe (200 kdyn) injury since this is indicated in the literature as being necessary for the development of robust signs of neuropathic pain. We found that this model showed robust signs of tactile allodynia and thermal hyperalgesia of the forepaws and in addition by developing new tests, were able to demonstrate cold allodynia and hyperalgesia. Although the hindpaws also showed responses that would normally be interpreted as mechanical allodynia and thermal hyperalgesia, the absence of accompanying supraspinally mediated behaviours (including licking following heat stimuli) indicated that the enhanced responsiveness to these stimuli might not give rise to pain. Further investigation using operant testing supported this idea and tract tracing suggested that this may be due to substantial interruption of ascending nociceptive pathways. Testing over the back at locations confirmed electrophysiologically to involve sensory processing at, above and below the injury level supported the idea that increased sensitivity in this model developed at and above, but not below level. In addition, observations on the forepaws suggested evidence of spontaneous pain which has never been described in SCI models previously and provides an important opportunity for studying the underlying mechanisms. Because the 200 kdyn low thoracic model proved unsuitable for the study of below level pain we next investigated whether a less severe injury at this level would provide a better model. Injuries of 150 kdyn were found to result in most of the same indicators of pain following forelimb testing as were seen following 200 kdyn injuries but all signs were less pronounced, in particular, indicators of evoked pain. Testing over the back led to increased sensitivity below level which had not been evident in the 200 kdyn model, providing an opportunity for below level testing. However, interpretation of hindpaw tests remained equivocal. Because the low thoracic model showed features that suggested forelimb assessments were particularly useful for the assessment of above level pain of different modalities as well as spontaneous pain, we investigated the effect of moving the injury closer to the segments assessed by such tests. Injuries at the T3/T4 level were found to lead to enhancement of all of the behavioural signs seen in the 200 kdyn low thoracic injury animals, especially signs of spontaneous pain. This model may therefore be optimum for the assessment of above/at level pain. The work presented in this thesis provides the clearest and most comprehensive data yet on the utility of models of SCI for the investigation of central neuropathic pain and represents a significant advance in the field. The finding that injuries at low thoracic levels may (depending on injury severity) be unsuitable for assessment of below level pain has implications for previous studies of the mechanisms of post SCI pain, many of which have used exclusively hindlimb assessments in these models. The hope is that an improved understanding of the models used here and an improved ability to investigate different modalities of evoked pain, and in addition spontaneous pain, will enhance the quality of future research in this area and lead to both a better understanding of central neuropathic pain mechanisms and the development of more effective analgesics for this type of pain