Foxa1 is essential for development and functional integrity of the subthalamic nucleus.
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ABSTRACT:
SUBMITTER: Gasser E
PROVIDER: S-EPMC5146925 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The subthalamic nucleus (STN) is successfully used as a surgical target for deep brain stimulation in the treatment of movement disorders. Interestingly, the internal structure of the STN is still incompletely understood. The objective of the present study was to investigate three-dimensional (3D) immunoreactivity patterns for 12 individual protein markers for GABA-ergic, serotonergic, dopaminergic as well as glutamatergic signaling. We analyzed the immunoreactivity using optical densities and created a 3D reconstruction of seven postmortem human STNs. Quantitative modeling of the reconstructed 3D immunoreactivity patterns revealed that the applied protein markers show a gradient distribution in the STN. These gradients were predominantly organized along the ventromedial to dorsolateral axis of the STN. The results are of particular interest in view of the theoretical underpinning for surgical targeting, which is based on a tripartite distribution of cognitive, limbic and motor function in the STN.
| S-EPMC6875153 | biostudies-literature
Project description:A typical feature of Parkinson's disease (PD) is pathological activity in the subthalamic nucleus (STN). Here, we tested whether in patients with PD under dopaminergic treatment functional connectivity of the STN differs from healthy controls (HC) and whether some brain regions show (anti-) correlations between functional connectivity with STN and motor symptoms. We used functional magnetic resonance imaging to investigate whole-brain resting-state functional connectivity with STN in 54 patients with PD and 55 HC matched for age, gender, and within-scanner motion. Compared to HC, we found attenuated negative STN-coupling with Crus I of the right cerebellum and with right ventromedial prefrontal regions in patients with PD. Furthermore, we observed enhanced negative STN-coupling with bilateral intraparietal sulcus/superior parietal cortex, right sensorimotor, right premotor, and left visual cortex compared to HC. Finally, we found a decline in positive STN-coupling with the left insula related to severity of motor symptoms and a decline of inter-hemispheric functional connectivity between left and right STN with progression of PD-related motor symptoms. Motor symptom related uncoupling of the insula, a key region in the saliency network and for executive function, from the STN might be associated with well-known executive dysfunction in PD. Moreover, uncoupling between insula and STN might also induce an insufficient setting of thresholds for the discrimination between relevant and irrelevant salient environmental stimuli, explaining observations of disturbed response control in PD. In sum, motor symptoms in PD are associated with a reduced coupling between STN and a key region for executive function.
| S-EPMC6867311 | biostudies-literature
Project description:ObjectivesUnilateral subthalamic nucleus (STN) deep brain stimulation (DBS) for Parkinson's disease (PD) improves ipsilateral symptoms, but how this occurs is not well understood. We investigated whether unilateral STN DBS suppresses contralateral STN beta activity in the local field potential (LFP), since previous research has shown that activity in the beta band can correlate with the severity of contralateral clinical symptoms and is modulated by DBS.Materials and methodsWe recorded STN LFPs from 14 patients who underwent bilateral STN DBS for PD. Following a baseline recording, unilateral STN stimulation was delivered at therapeutic parameters while LFPs were recorded from the contralateral (unstimulated) STN.ResultsUnilateral STN DBS suppressed contralateral beta power (p = 0.039, relative suppression = -5.7% ± [SD] 16% when averaging across the highest beta peak channels; p = 0.033, relative suppression = -5.2% ± 13% when averaging across all channels). Unilateral STN DBS produced a 17% ipsilateral (p = 0.016) and 29% contralateral (p = 0.002) improvement in upper limb hemi-body bradykinesia-rigidity (UPDRS-III, items 3.3-3.6). The ipsilateral clinical improvement and the change in contralateral beta power were not significantly correlated.ConclusionsUnilateral STN DBS suppresses contralateral STN beta LFP. This indicates that unilateral STN DBS modulates bilateral basal ganglia networks. It remains unclear whether this mechanism accounts for the ipsilateral motor improvements.
| S-EPMC7299664 | biostudies-literature
Project description:Previous research has indicated increased functional connectivity between subthalamic nucleus (STN) and sensorimotor cortex in off-medication Parkinson's disease (PD) compared with control subjects. It is not clear if the increase in functional connectivity between STN and sensorimotor cortex occurs in de novo PD, which is before patients begin dopamine therapy. Resting-state functional magnetic resonance imaging was carried out in 20 de novo (drug naïve) patients with PD (Hoehn and Yahr stage: I-II), 19 patients with moderate PD (Hoehn and Yahr stage: II-III), and 19 healthy controls. The functional connectivity analysis in de novo and moderate PD patients focused on the connectivity of the more affected STN and the sensorimotor cortex. Using resting-state functional connectivity analysis, we provide new evidence that people with de novo PD and off-medicated moderate PD have increased functional connectivity between the more affected STN and different regions within the sensorimotor cortex. The overlapping sensorimotor cortex found in both de novo and moderate PD had functional connectivity values that correlated positively with the Unified Parkinson's Disease Rating Scale part III. This key finding suggests that changes in functional connectivity between STN and sensorimotor cortex occur early in the disease following diagnosis and before dopamine therapy.
| S-EPMC4268125 | biostudies-literature
Project description:Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is the most common neurosurgical treatment for Parkinson's disease motor symptoms. In preclinical models, STN DBS provides neuroprotection for substantia nigra (SN) dopamine neurons and increases BDNF in the nigrostriatal system and primary motor cortex. However, whether BDNF signaling in the SN participates in the neuroprotective effects of DBS remains unknown. We demonstrate that STN DBS in male rats activates signaling downstream of tropomyosin receptor kinase type B (trkB), namely, phosphorylation of Akt and ribosomal protein S6, in SN neurons. Long-term trkB blockade abolished STN DBS-mediated neuroprotection of SN neurons following progressive 6-hydroxydopamine lesion and was associated with decreased phosphorylated ribosomal protein S6 immunoreactivity. Acute trkB blockade in rats with stable nigrostriatal denervation attenuated the forelimb akinesia improvement normally induced by STN DBS. These results suggest that STN DBS increases BDNF-trkB signaling to contribute to the neuroprotective and symptomatic efficacy of STN DBS.SIGNIFICANCE STATEMENT Subthalamic nucleus deep brain stimulation (STN DBS) is increasingly used in mid- to late-stage Parkinson's disease (PD) but with an incomplete knowledge of its molecular mechanisms. STN DBS is neuroprotective against neurotoxicants in animal models and increases BDNF. This study is the first to show that BDNF signaling through the cognate tropomyosin receptor kinase type B (trkB) receptor occurs in substantia nigra pars compacta neurons and is required for neuroprotection. In addition, blockade of trkB unexpectedly reduced the functional benefit of STN DBS on a short timescale that is inconsistent with canonical trkB signaling pathways, suggesting a noncanonical role for trkB in STN DBS-mediated behavioral effects. Together, these data implicate trkB signaling in the symptomatic efficacy and disease-modifying potential of STN DBS.
| S-EPMC5508259 | biostudies-literature
Project description:Flexible instrumental learning is required to harness the appropriate behaviors to obtain rewards and to avoid punishments. The precise contribution of dopaminergic midbrain regions (substantia nigra/ventral tegmental area [SN/VTA]) to this form of behavioral adaptation remains unclear. Normal aging is associated with a variable loss of dopamine neurons in the SN/VTA. We therefore tested the relationship between flexible instrumental learning and midbrain structural integrity. We compared task performance on a probabilistic monetary go/no-go task, involving trial and error learning of: "go to win," "no-go to win," "go to avoid losing," and "no-go to avoid losing" in 42 healthy older adults to previous behavioral data from 47 younger adults. Quantitative structural magnetization transfer images were obtained to index regional structural integrity. On average, both some younger and some older participants demonstrated a behavioral asymmetry whereby they were better at learning to act for reward ("go to win" > "no-go to win"), but better at learning not to act to avoid punishment ("no-go to avoid losing" > "go to avoid losing"). Older, but not younger, participants with greater structural integrity of the SN/VTA and the adjacent subthalamic nucleus could overcome this asymmetry. We show that interindividual variability among healthy older adults of the structural integrity within the SN/VTA and subthalamic nucleus relates to effective acquisition of competing instrumental responses.
| S-EPMC3713434 | biostudies-literature
Project description:An android, i.e., a realistic humanoid robot with human-like capabilities, may induce an uncanny feeling in human observers. The uncanny feeling about an android has two main causes: its appearance and movement. The uncanny feeling about an android increases when its appearance is almost human-like but its movement is not fully natural or comparable to human movement. Even if an android has human-like flexible joints, its slightly jerky movements cause a human observer to detect subtle unnaturalness in them. However, the neural mechanism underlying the detection of unnatural movements remains unclear. We conducted an fMRI experiment to compare the observation of an android and the observation of a human on which the android is modelled, and we found differences in the activation pattern of the brain regions that are responsible for the production of smooth and natural movement. More specifically, we found that the visual observation of the android, compared with that of the human model, caused greater activation in the subthalamic nucleus (STN). When the android's slightly jerky movements are visually observed, the STN detects their subtle unnaturalness. This finding suggests that the detection of unnatural movements is attributed to an error signal resulting from a mismatch between a visual input and an internal model for smooth movement.
| S-EPMC5736650 | biostudies-literature
Project description:Background:Directional deep brain stimulation (DBS) technology aims to address the limitations, such as stimulation-induced side effects, by delivering selective, focal modulation via segmented contacts. However, DBS programming becomes more complex and time-consuming for clinical feasibility. Local field potentials (LFPs) might serve a functional role in guiding clinical programming. Objective:In this pilot study, we investigated the spectral dynamics of directional LFPs in subthalamic nucleus (STN) and their relationship to motor symptoms of Parkinson's disease (PD). Methods:We recorded intraoperative STN-LFPs from 8-contact leads (Infinity-6172, Abbott Laboratories, Illinois, United States) in 8 PD patients at rest. Directional LFPs were referenced to their common average and time-frequency analysis was computed using a modified Welch periodogram method. The beta band (13-35 Hz) features were extracted and their correlation to preoperative UPDRS-III scores were assessed. Results:Normalized beta power (13-20 Hz) and normalized peak power (13-35 Hz) were found to be higher in anterior direction despite lack of statistical significance (p > 0.05). Results of the Spearman correlation analysis demonstrated positive trends with bradykinesia/rigidity in dorsoanterior direction (r = 0.659, p = 0.087) and with axial scores in the dorsomedial direction (r = 0.812, p = 0.072). Conclusion:Given that testing all possible combinations of contact pairs and stimulation parameters is not feasible in a single clinic visit, spatio-spectral LFP dynamics obtained from intraoperative recordings might be used as an initial marker to select optimal contact(s).
| S-EPMC7198898 | biostudies-literature
Project description:Deep brain stimulation therapy is an effective symptomatic treatment for Parkinson's disease, yet the precise mechanisms responsible for its therapeutic effects remain unclear. Although the targets of deep brain stimulation are grey matter structures, axonal modulation is known to play an important role in deep brain stimulation's therapeutic mechanism. Several white matter structures in proximity to the subthalamic nucleus have been implicated in the clinical benefits of deep brain stimulation for Parkinson's disease. We assessed the connectivity patterns that characterize clinically beneficial electrodes in Parkinson's disease patients, after deep brain stimulation of the subthalamic nucleus. We evaluated 22 patients with Parkinson's disease (11 females, age 57 ± 9.1 years, disease duration 13.3 ± 6.3 years) who received bilateral deep brain stimulation of the subthalamic nucleus at the National Institutes of Health. During an initial electrode screening session, one month after deep brain stimulation implantation, the clinical benefits of each contact were determined. The electrode was localized by coregistering preoperative magnetic resonance imaging and postoperative computer tomography images and the volume of tissue activated was estimated from stimulation voltage and impedance. Brain connectivity for the volume of tissue activated of deep brain stimulation contacts was assessed using probabilistic tractography with diffusion-tensor data. Areas most frequently connected to clinically effective contacts included the thalamus, substantia nigra, brainstem and superior frontal gyrus. A series of discriminant analyses demonstrated that the strength of connectivity to the superior frontal gyrus and the thalamus were positively associated with clinical effectiveness. The connectivity patterns observed in our study suggest that the modulation of white matter tracts directed to the superior frontal gyrus and the thalamus is associated with favourable clinical outcomes and may contribute to the therapeutic effects of deep brain stimulation. Our method can be further developed to reliably identify effective deep brain stimulation contacts and aid in the programming process.
| S-EPMC5006230 | biostudies-literature
Project description:PurposeTo assess quantitative susceptibility mapping (QSM) in the depiction of the subthalamic nucleus (STN) by using 3-T magnetic resonance (MR) imaging.Materials and methodsThis study was HIPAA compliant and institutional review board approved. Ten healthy subjects (five men, five women; mean age, 24 years ± 3 [standard deviation]; age range, 21-33 years) and eight patients with Parkinson disease (five men, three women; mean age, 57 years ± 14; age range, 25-69 years) who were referred by neurologists for preoperative navigation MR imaging prior to deep brain stimulator placement were included in this study. T2-weighted (T2w), T2*-weighted (T2*w), R2* mapping (R2*), phase, susceptibility-weighted (SW), and QSM images were reconstructed for STN depiction. Qualitative visualization scores of STN and internal globus pallidus (GPi) were recorded by two neuroradiologists on all images. Contrast-to-noise ratios (CNRs) of the STN and GPi were also measured. Measurement differences were assessed by using the Wilcoxon rank sum test and the signed rank test.ResultsQualitative scores were significantly higher on QSM images than on T2w, T2*w, R2*, phase, or SW images (P < .05) for STN and GPi visualization. Median CNR was 6.4 and 10.7 times higher on QSM images than on T2w images for differentiation of STN from the zona incerta and substantia nigra, respectively, and was 22.7 and 9.1 times higher on QSM images than on T2w images for differentiation of GPi from the internal capsule and external globus pallidus, respectively. CNR differences between QSM images and all other images were significant (P < .01).ConclusionQSM at 3-T MR imaging performs significantly better than current standard-of-care sequences in the depiction of the STN.
| S-EPMC3781358 | biostudies-literature