Subthalamic deep brain stimulation sweet spots and hyperdirect cortical connectivity in Parkinson’s disease

Objectives Firstly, to identify subthalamic region stimulation clusters that predict maximum improvement in rigidity, bradykinesia and tremor, or emergence of side-effects; and secondly, to map-out the cortical fingerprint, mediated by the hyperdirect pathways which predict maximum efficacy. Methods High angular resolution diffusion imaging in twenty patients with advanced Parkinson’s disease was acquired prior to bilateral subthalamic nucleus deep brain stimulation. All contacts were screened one-year from surgery for efficacy and side-effects at different amplitudes. Voxel-based statistical analysis of volumes of tissue activated models was used to identify significant treatment clusters. Probabilistic tractography was employed to identify cortical connectivity patterns associated with treatment efficacy. Results All patients responded well to treatment (46% mean improvement off medication UPDRS-III [p<0.0001]) without significant adverse events. Cluster corresponding to maximum improvement in tremor was in the posterior, superior and lateral portion of the nucleus. Clusters corresponding to improvement in bradykinesia and rigidity were nearer the superior border in a further medial and posterior location. The rigidity cluster extended beyond the superior border to the area of the zona incerta and Forel-H2 field. When the clusters where averaged, the coordinates of the area with maximum overall efficacy was X=-10(-9.5), Y=-13(-1) and Z=-7(-3) in MNI(AC-PC) space. Cortical connectivity to primary motor area was predictive of higher improvement in tremor; whilst that to supplementary motor area was predictive of improvement in bradykinesia and rigidity; and connectivity to prefrontal cortex was predictive of improvement in rigidity. Interpretation These findings support the presence of overlapping stimulation sites within the subthalamic nucleus and its superior border, with different cortical connectivity patterns, associated with maximum improvement in tremor, rigidity and bradykinesia

Investigating early functional alteration in a human iPSC-based model of Parkinson’s Disease

[eng] Dopaminergic neurons (DAn) were efficiently differentiated from 6 different iPSC lines derived from a 2 control, 3 PD lines, and an isogenic PD line. We characterize the culture at different time point in order to verify the composition of the culture. At day 35 almost 50% of the cells expressed the neuronal marker TUJ1, of which 20% were of DA lineage as judged by TH expression. No astrocytes were found in the culture. Interestingly at day 50 of differentiation the amount of DAn increased up to 25-35% of which 35% were expressing Girk2, a midbrain DA neuronal marker that was not expressed at day 35 and 45-60% of the DA neurons express FOXA2, another important transcription factor that confirm the midbrain fate. Even more importantly, at day 80 of the differentiation process, the amount of DAn that expressed Girk2 increased up to 50%, while the expression of FOXA2 in DA remain stable, confirming the ventral midbrain phenotype. We then test for each line the neuronal activity by calcium imaging assay. Comparing the two groups of controls and isogenic PD line versus PD lines, interestingly we identify two distinct patterns of activity: controls lines display a mixed mode, oscillatory activity normally associated with healthy networks while PD lines display a two-state dynamics, with strong bursting combined with intervals of almost no activity that suggest an impairment in the communication between the neurons. These dynamic differences suggest a more in depth analysis of the functional network that controls and PD create. Using a custom algorithm we demonstrate that just the PD lines were functionally impaired because their neurons, especially at day 80, were not able to form a homogeneous network like the controls one that can be described as a scale-free like systems. Analyzing separately TH and non TH neurons we were able to conclude that the functional connectivity of PD1 lines shows a higher departure from the controls lines along maturation, which indicates poor information flow efficiency. Particularly, PD TH+ neurons connectomes display abnormal network organization that occurs primarily before the general alteration of the network, suggesting that TH+ are leading to general neural connectome alteration. Due to the biophysical simulation analysis we were able to identify as a cause of the functional impairment the reduction in the neurite arborization TH specific just in the PD lines and confirm this phenotype in our biological samples. We then used our in vitro model to take a step backwards and examine the biological and molecular behavior before the functional alteration manifests. We analyzed the culture at D50, when the data suggests that the functional alteration has not yet developed fully, using gene expression profile analysis to identify possible deregulations in pathways that can be connected to the altered functionality. Bioinformatics analysis focused on differentially expressed genes, selected with a pAdjValue of 0.05 and a fold change ≤-2 and ≥ 2. Within these strict selection criteria, we were unable to highlight any gene related to LRRK2 PD and isogenic PD. This confirms the validity of the in vitro model and the robustness of the differentiation protocol and shows that the functional phenotype is not due to macroscopic neurodegenerative conditions.[spa] La enfermedad de Parkinson (EP) es una enfermedad incurable, crónica y progresiva que conduce a la invalidez prematura y la muerte. Se espera que el diagnóstico temprano de la EP mejore dramáticamente el resultado de las terapias actuales. Para ello, empleamos un modelo de EP basado en células neuronales humanas, para detectar alteraciones funcionales tempranas que nos den un diagnostico de la enfermedad antes de la aparición de síntomas motores. Utilizando neuronas derivadas de células madre pluripotentes inducidas (iPSC) de individuos sanos y pacientes con EP asociados con la mutación familiar en el gen LRRK2, hemos comprobado que los dos grupos forman redes complejas y muestran signos evidentes de maduración funcional a lo largo del tiempo. Sin embargo, las redes neuronales de la EP desarrollaron una híper-sincronía anormal, en comparación con las redes de los controles y de la línea isogénica de LRRK2. En esto estudio combinamos análisis de la actividad neuronal a lo largo de tiempo utilizando la técnica del “calcium imaging”, un modelo in silico de “network”, líneas reporteras de neuronas dopaminérgicas, y el análisis del perfil de expresión génica. Con estos experimentos, encontramos que una disminución en la longitud de la neurita de neuronas dopaminérgicas es, entre otras causas, una de las primeras alteraciones funcionales presentes en la red de neuronas derivada de EP. Por lo tanto, nuestros resultados identifican alteraciones tempranas en la función neuronal de la EP que son anteriores al inicio de la degeneración neuronal, resaltando la extraordinaria ventaja que ofrece este modelo de iPSC en la evaluación pre sintomática de las enfermedades degenerativas crónicas

Insights into Parkinson’s disease from computational models of the basal ganglia

Movement disorders arise from the complex interplay of multiple changes to neural circuits. Successful treatments for these disorders could interact with these complex changes in myriad ways, and as a consequence their mechanisms of action and their amelioration of symptoms are incompletely understood. Using Parkinson's disease as a case study, we review here how computational models are a crucial tool for taming this complexity, across causative mechanisms, consequent neural dynamics and treatments. For mechanisms, we review models that capture the effects of losing dopamine on basal ganglia function; for dynamics, we discuss models that have transformed our understanding of how beta-band (15-30?Hz) oscillations arise in the parkinsonian basal ganglia. For treatments, we touch on the breadth of computational modelling work trying to understand the therapeutic actions of deep brain stimulation. Collectively, models from across all levels of description are providing a compelling account of the causes, symptoms and treatments for Parkinson's disease

Neuroimaging biomarkers associated with clinical dysfunction in Parkinson disease

Parkinson disease (PD) is the second most common neurodegenerative disorder in the world, directly affecting 2-3% of the population over the age of 65. People diagnosed with the disorder can experience motor, autonomic, cognitive, sensory and neuropsychiatric symptoms that can significantly impact quality of life. Uncertainty still exists about the pathophysiological mechanisms that underlie a range of clinical features of the disorder, linked to structural as well as functional brain changes. This thesis thus aimed to uncover neuroimaging biomarkers associated with clinical dysfunction in PD. A 'hubs-and-spokes' neural circuit-based approach can contribute to this aim, by analysing the component elements and also the interconnections of important brain networks. This thesis focusses on structures within basal ganglia-thalamocortical neuronal circuits that are linked to a range functions impacted in the disorder, and that are vulnerable to the consequences of PD pathology. This thesis investigated neuronal 'hubs' by studying the morphology of the caudate nucleus, putamen, thalamus and neocortex. The caudate nucleus, putamen and thalamus are all vital subcortical 'hubs' that play important roles in a number of functional domains that are compromised in PD. The neocortex, on the other hand, has a range of 'hubs' spread across it, regions of the brain that are crucial for neuronal signalling and communication. The interconnections, or 'spokes', between these hubs and other brain regions were investigated using seed-based resting-state functional connectivity analyses. Finally, a morphological analysis was used to investigate possible structural changes to the corpus callosum, the major inter-hemispheric white matter tract of the brain, crucial to effective higher-order brain processes. This thesis demonstrates that the caudate nucleus, putamen, thalamus, corpus callosum and neocortex are all atrophied in PD participants with dementia. PD participants also demonstrated a significant correlation between volumes of the caudate nuclei and general cognitive functioning and speed, while putamina volumes were correlated with general motor function. Cognitively unimpaired PD participants demonstrated minimal morphological alterations compared to control participants, however they demonstrated significant increases in functional connectivity of the caudate nucleus, putamen and thalamus with areas across the frontal lobe, and decreases in functional connectivity with parietal and cerebellar regions. PD participants with mild cognitive impairment and dementia show decreased functional connectivity of the thalamus with paracingulate and posterior cingulate cortices, respectively. This thesis contributes a deeper understanding of the relationship between structures of basal ganglia-thalamocortical neuronal circuits, corpus callosal and neocortical morphology, and the clinical dysfunction associated with PD. This thesis suggests that functional connectivity changes are more common in early stages of the disorder, while morphological alterations are more pronounced in advanced disease stages