Browsing by Author "Martino, Davide"
Now showing 1 - 6 of 6
Results Per Page
Sort Options
- ItemEmbargoCharacterizing the cerebello-thalamo-cortical tracts in the pathophysiology of adult-onset idiopathic dystonia(2023-07) Sondergaard, Rachel Elisa; Kiss, Zelma; Martino, Davide; Condliffe, Elizabeth; Cluff, TylerAdult-onset idiopathic dystonia (AOID) is a movement disorder causing painful and disabling muscular contractions. The pathophysiology of AOID has evolved over time from original consideration as a purely functional neurological condition to its present understanding as a disorder of the motor network. What is presently unknown within the network model is the relative contribution of specific cerebellar outflow pathways, despite several lines of evidence in support of a role for these tracts. In this thesis, I attempt to characterize the anatomy, function, and response to intervention of the cerebello-thalamo-cortical pathway, a cerebellar outflow pathway subserving motor processes, in AOID. First, tractographic measures of the bilateral dentato-rubro-thalamic tracts were computed in patients with cervical dystonia (CD) and healthy controls. We identified bilateral reductions in diffusion tractography metrics in CD metrics relative to controls. We also computed the degree of lateralization of these tractographic measures and found that it was related to the severity of CD in subgroups of patients with similar motor phenotype. Second, I sought evidence that functions subserved by the cerebello-thalamo-cortical tracts may also be abnormal. Using a transcranial magnetic stimulation (TMS) protocol called cerebellar brain inhibition (CBI) I found that CD severity increased in association with a breakdown in normal CBI. I suspected that proprioception, another function subserved by this pathway might be abnormal and could be rescued by changing activity along this pathway using repetitive TMS. I was unable to find evidence of either in a small pilot study. I was also unable to find evidence that a single session of repetitive TMS targeting the cerebellar cortex induced changes in local field potential activity at the level of the thalamus in movement disorder patients treated with deep brain stimulators for their movement disorders. Third, I indirectly examined the response to intervention subserved by the cerebello-thalamo-cortical tracts by comparing TMS motor maps of hand representations in focal hand dystonia patients produced at peak botulinum toxin treatment effect and following washout. I examined technical factors contributing to the modest or absent changes in hand representation between conditions in these patients in an additional pilot study and structured review. Overall, I found evidence supporting abnormal anatomy and function of the cerebello-thalamo-cortical tracts in dystonia. Taken together, the findings establish structural and functional features of the cerebello-thalamo-cortical tracts in the pathophysiology of dystonia. The specific pattern of microstructural abnormalities observed and its relationship with severity also provides a plausible new target for non-invasive repetitive TMS targeting the cerebellum for therapeutic effect in AOID.
- ItemOpen AccessDeveloping a provincial patient support network for children and families affected by Tourette syndrome and/or obsessive–compulsive disorder: results of a stakeholder consultation(2021-06-16) Fletcher, Julian; Dimitropoulos, Gina; Martino, Davide; Wilcox, Gabrielle; MacMaster, Frank; Arnold, Paul; Pringsheim, TamaraAbstract Background Tourette syndrome and OCD are disorders that frequently occur in children and cause a high level of disability. In Alberta there is a huge delivery gap in providing healthcare services for children with TS and OCD. A stakeholder consultation was performed to ascertain how service delivery could be improved across the province and to inform the development of a provincial information and support organization, the Tourette OCD Alberta Network. Methods A mixed-methods study was employed: 10 parents were recruited for interview and 140 parents responded to a survey. Results Qualitative data showed there was often an absence of a clear pathway to access healthcare for people with TS and OCD. The negative impact of not receiving treatment, information, and resources in a timely and prompt manner was also revealed. Good clinical practice existed across the province but too often it was hindered by a shortage of knowledge about TS and OCD. In schools, learning for students with TS and OCD was also impaired by educators’ lack of knowledge and preparedness in relation to the disorders. Conclusions This study identified ways that challenges with healthcare access, school learning, and seeking information can be overcome. Skills-based training webinars, educational outreach in schools, and peer support were recognized as actions for improving healthcare outcomes for people with TS and OCD. The aim of the Tourette OCD Alberta Network is to provide services and support that directly address the healthcare service delivery shortfalls shown in this study.
- ItemOpen AccessFunctional Changes in the Motor Network Following Thalamotomy in Essential Tremor Patients using Seed-Based Resting-State Functional Magnetic Resonance Imaging(2022-07-18) Specht, Jacinta Lee; Pike, G. Bruce; Kiss, Zelma; Martino, DavideMotor network changes following magnetic resonance guided resonance imaging surgery (MRgFUS) in essential tremor (ET) are still poorly understood. The motor network dysfunction found in ET is hypothesized to originate from within the cortico-thalamo-cerebellar (CTC) network. Several methodologies of resting-state functional magnetic resonance imaging (rsfMRI) have been used to compare functional connectivity within these regions between ET patients and controls. Such methodologies include seed-based region of interest (ROI) analysis, independent component analysis and graph theory. To my knowledge, this is the first study to use seed-based rs-fMRI analysis to compare between longitudinal time-points in ET patients before and after MRgFUS thalamotomy and age- and sex-matched controls. Seed-to-voxel and ROI-to-ROI analysis were both used to study rs-fMRI in these groups. Although limited statistically significant differences were found between longitudinal time-points, more differences were observed when comparing between ET patients, pre- and post-surgery, and controls. It was found that pre-surgery ET patients had significantly increased functional connectivity between motor areas and occipital regions associated with visuospatial planning, compared to controls. This connectivity decreased immediately after surgery. A reduction in functional connectivity between basal ganglia regions and the motor cortices was also observed. These changes were transient however, because motor regions returned to increased connectivity with the occipital region, except for the left supplementary motor area (SMA), which continued to demonstrate decreased connectivity with the putamen at 3 months, compared to controls. These findings demonstrate that the motor network within ET may also entrain visual processing areas as well as the basal ganglia and that MRgFUS thalamotomy may alter functional connectivity to these areas.
- ItemOpen AccessInhibitory Control Deficits in Children with Tic Disorders Revealed by Object-Hit-and-Avoid Task(2021-07-02) Cothros, Nicholas; Medina, Alex; Martino, Davide; Dukelow, Sean P.; Hawe, Rachel L.; Kirton, Adam; Ganos, Christos; Nosratmirshekarlou, Elaheh; Pringsheim, TamaraBackground. Tic disorders may reflect impaired inhibitory control. This has been evaluated using different behavioural tasks, yielding mixed results. Our objective was to test inhibitory control in children with tics through simultaneous presentation of multiple, mobile stimuli. Methods. Sixty-four children with tics (mean age 12.4 years; 7.5-18.5) were evaluated using a validated robotic bimanual exoskeleton protocol (Kinarm) in an object-hit-and-avoid task, in which target and distractor objects moved across a screen and participants aimed to hit only the targets while avoiding distractors. Performance was compared to 146 typically developing controls (mean age 13 years; 6.1-19.9). The primary outcome was the percentage of distractors struck. Results. ANCOVA (age as covariate) showed participants struck significantly more distractors (participants without comorbid ADHD, 22.71% [SE 1.47]; participants with comorbid ADHD, 23.56% [1.47]; and controls, 15.59% [0.68]). Participants with comorbid ADHD struck significantly fewer targets (119.74 [2.77]) than controls, but no difference was found between participants without comorbid ADHD (122.66 [2.77]) and controls (127.00 [1.28]). Participants and controls did not differ significantly in movement speed and movement area. Just over 20% of participants with tics fell below the age-predicted norm in striking distractors, whereas fewer than 10% fell outside age-predicted norms in other task parameters. Conclusions. In children with tics (without comorbid ADHD), acting upon both targets and distractors suggests reduced ability to suppress responses to potential triggers for action. This may be related to increased sensorimotor noise or abnormal sensory gating.
- ItemOpen AccessMitochondrial dysfunction and steroidogenesis in Parkinson disease(2023-09-06) Lee-Glover, Laurie Patricia; Shutt, Timothy; Pfeffer, Gerald; Martino, DavidePatients with Parkinson disease (PD), one of the most common neurodegenerative disorders, have elevated levels of the glucocorticoid cortisol, a stress-related steroid hormone. Increased stress or glucocorticoids in experimental models of PD worsens neurodegeneration, implicating elevated glucocorticoids in disease pathogenesis. However, the mechanism behind dysregulated glucocorticoid levels is unclear. The rate-limiting step of steroidogenesis, cholesterol import into the mitochondria, is mediated by steroidogenic acute regulatory protein (STARD1). STARD1 transports cholesterol while transiently localized to the outer mitochondrial membrane. Impairments in mitochondrial protein import, a key aspect of cellular dysfunction linked to PD, increase STARD1-mediated mitochondrial cholesterol import, providing a potential mechanism connecting PD with increased steroidogenesis. To test how steroidogenesis is affected by mitochondrial function in PD, we used PD-related toxins and genetic variants to model the effects of PD. We looked at the import of STARD1 overexpressed in HEK293 cells and steroid production in steroidogenic adrenocortical cell lines. We found that the PD toxin rotenone slowed STARD1 import and increased cholesterol import. Cortisol production increased only under lower levels of rotenone-induced mitochondrial stress. This is intriguing as milder mitochondrial stress may be more relevant to the progressive nature of PD. Additionally, overexpression of PD pathogenic variant alpha synuclein A53T upregulated basal production of pregnenolone and cortisol in steroidogenic cells. To explore further connections between steroidogenesis and PD, we also looked for miRNA biomarkers related to steroidogenesis in PD patients. We found expression of hsa-mir-320a in PD patient serum exosomes was negatively correlated with disease duration. As this miRNA negatively regulates expression of certain enzymes involved in cortisol synthesis, dysregulation of this miRNA could contribute to elevated cortisol levels in PD. Overall, our findings are consistent with cellular dysfunction in PD upregulating cortisol production. We delineated a novel pathway where mitochondrial dysfunction in PD activates cholesterol import by STARD1 to promote steroidogenesis. STARD1 may be a novel therapeutic target in PD. Additionally, as steroid signalling can be acutely protective against cellular stress, we propose this could be a stress response mechanism that couples steroid production to mitochondrial status, but which can be detrimental upon prolonged activation.
- ItemOpen AccessThe relationship of genetics with cognitive and behavioral impairments in idiopathic Parkinson’s disease patients(2021-06-10) Ramezani, Mehrafarin; Monchi, Oury; Pfeffer, Gerald; Pike, Bruce; Martino, Davide; Arnold, PaulParkinson’s disease (PD) is currently characterized by cardinal motor symptoms of rigidity, tremor and bradykinesia. However, this disease is far from a mere movement disorder, and non-motor symptoms have a substantial adverse effect on the quality of life for PD patients. PD patients suffer from a broad range of non-motor symptoms but two of them are the focus of this thesis, neuropsychiatric and cognitive impairments. The true cause of these symptoms’ manifestation is still unknown, but it is speculated that they might originate from the extensive neuronal damage due to PD. The investigation of genetic variants associated with these non-motor symptoms can provide valuable information on the possible causes of non-motor symptoms, their prevention, and even their treatment. In this thesis, the association of some specified genetic variants were investigated with neuropsychiatric symptoms and cognitive impairments in idiopathic PD patients (iPD). In the 1st part, mild behavioral impairment (MBI) in iPD patients was investigated using the mild behavioral impairment checklist (MBI-C). In chapter 3, the association of MBI and rs6265 in the Brain-Derived-Neurotrophic-Factor (BDNF) was studied and it was shown that the Met allele for this variant was linked to higher risk of MBI. It was observed that the Met allele was associated with specific neuropsychiatric symptoms related to emotional dysregulation and distorted thoughts. In chapter 4, the relationship between rs4680 in Catechol-O-methyltransferase (COMT) and rs28363170 in Solute carrier family 3 member 6 (SLC6A3) with MBI was explored in iPD patients. These two variants are both pertinent in the regulation of dopamine availability in the frontal lobe. No association was found for either of these variants with MBI in iPD patients. In the second part, the association of a specific variant rs894280 in Synuclein-alpha (SNCA) and mild cognitive impairment (MCI) in iPD patients was explored. In chapter 5, a machine learning analysis was used to predict cognition in iPD patients. rs894280 was ranked as the second most important feature for prediction of cognition in PD patients. The post-hoc analysis demonstrated a connection between this variant and overall cognition, attention and visual-spatial abilities in iPD patients. This variant was further investigated in chapter 6 using longitudinal data from the Parkinson’s Progression Marker Initiative (PPMI) dataset. It was shown that rs894280 was linked to the cognitive status of drug-naïve iPD patients at baseline. This variant was associated with the rate of MCI conversion in iPD patients longitudinally, but no association was found between the variant and neuropsychiatric symptoms. In conclusion, this thesis presents genetic association with two prominent non-motor symptoms in iPD patients. These findings can be used to assist identification of PD patients at risk of cognitive decline or neuropsychiatric impairments. Nonetheless, further studies should be conducted to elucidate and validate the results of this thesis further. Limitations of the present projects and a framework for future studies are discussed in the last chapter.