Browsing by Author "Kiss, Zelma H. T."
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Item Metadata only Both 50 and 30 Hz continuous theta burst transcranial magnetic stimulation depresses the cerebellum(2018-08-16) Strzalkowski, Nicholas D. J.; Chau, Aaron D.; Gan, Liu Shi; Kiss, Zelma H. T.The cerebellum is implicated in the pathophysiology of numerous movement disorders, which makes it an attractive target for non-invasive neurostimulation. Continuous theta burst stimulation (cTBS) can induce long-lasting plastic changes in human brain; however, the efficacy of different simulation protocols has not been investigated at the cerebellum. Here, we compare a traditional 50-Hz and a modified 30-Hz cTBS protocols at modulating cerebellar activity in healthy subjects. Seventeen healthy adults participated in two testing sessions where they received either 50-Hz (cTBS50) or 30-Hz (cTBS30) cerebellar cTBS. Cerebellar brain inhibition (CBI), a measure of cerebello-thalamocortical pathway strength, and motor-evoked potentials (MEP) were measured in the dominant first dorsal interosseous muscle before and after (up to ~ 40 min) cerebellar cTBS. Both cTBS protocols induced cerebellar depression, indicated by significant reductions in CBI (P < 0.001). No differences were found between protocols (cTBS50 and cTBS30) at any time point (P = 0.983). MEP amplitudes were not significantly different following either cTBS protocol (P = 0.130). The findings show cerebellar excitability to be equally depressed by 50-Hz and 30-Hz cTBS in healthy adults and support future work to explore the efficacy of different cerebellar cTBS protocols in movement disorder patients where cerebellar depression could provide therapeutic benefits.Item Open Access Dopaminergic modulation of spinal circuits for walking in the adult mouse(2018-09-06) Mayr, Kyle Andrew; Whelan, Patrick J.; Bennett, Dave; Kiss, Zelma H. T.Walking is a stereotyped rhythmic behavior that consists of alternating contractions of flexor and extensor muscles, as well as the left and right hindlimbs. The basic rhythmic pattern underlying locomotion is generated by a central pattern generator network within the lumbar spinal cord. The role of many neurotransmitters and modulators have been studied extensively, but dopamine’s (DA) role in modulating movement at the level of the lumbar spinal cord, is still not fully understood, especially in adult mice. The decerebrate mouse preparation allows us to examine modulation of stepping behaviour in adult mice with reduced descending inputs to the spinal cord, while intrathecally manipulating the lumbar spinal cord. Locomotor activity was measured by recording weight bearing during locomotion and electromyograms (EMG) from the flexor (tibialis anterior) and extensor (gastrocnemius) muscles of the hindlimbs. Our results show that intrathecal application of DA at the lumbar spinal cord increased the duration of locomotor bouts. Intrathecal DA led to an increase in weight bearing, suggesting that DA may promote extensor biased walking. Furthermore, addition of D1-like agonists augmented weight bearing in the decerebrate animal, but not as much as DA alone. Using intact animals intrathecally injected with either DA, or DA antagonists we selectively activated or blocked DA receptor subtypes of the spinal cord. Using the open field test and ladder rung, we quantified the amount of activity, type of activity and scored the skilled steps during locomotion. Our findings show that DA decreased the amount of locomotor activity in the open field but did not have a significant effect on the ladder rung step score. Furthermore, we found that D1-like antagonists reduced locomotor activity (distance, velocity and bouts) while D2-like antagonists did not have a significant impact on open field activity, though there was an increase in errors while crossing the ladder rung. This thesis provides insight into the DAergic contribution to the modulation in adult mouse locomotion and bridges the gap from previous neonatal animal work. It shows that DA can have differential effects dependant on the state of the animal and provides a foundation for future work on DA neuromodulation.Item Metadata only Dosing of Electrical Parameters in Deep Brain Stimulation (DBS) for Intractable Depression: A Review of Clinical Studies(2018-07-11) Ramasubbu, Rajamannar; Lang, Stefan; Kiss, Zelma H. T.; lanBackground: The electrical parameters used for deep brain stimulation (DBS) in movement disorders have been relatively well studied, however for the newer indications of DBS for psychiatric indications these are less clear. Based on the movement disorder literature, use of the correct stimulation parameters should be crucial for clinical outcomes. This review examines the stimulation parameters used in DBS studies for treatment resistant depression (TRD) and their relevance to clinical outcome and brain targets. Methods: We examined the published studies on DBS for TRD archived in major databases. Data on stimulus parameters (frequency, pulse width, amplitude), stimulation mode, brain target, efficacy, safety, and duration of follow up were extracted from 29 observational studies including case reports of patients with treatment resistant unipolar, bipolar, and co-morbid depression. Results: The algorithms commonly used to optimize efficacy were increasing amplitude followed by changing the electric contacts or increasing pulse width. High frequency stimulation (>100 Hz) was applied in most cases across brain targets. Keeping the high frequency stimulation constant, three different combinations of parameters were mainly used: (i) short pulse width (60-90 us) and low amplitude (0-4 V), (ii) short pulse width and high amplitude (5-10 V), (iii) long pulse width (120-450 us) and low amplitude. There were individual variations in clinical response to electrical dosing and also in the time of clinical recovery. There was no significant difference in mean stimulation parameters between responders and non-responders suggesting a role for stimulation unrelated factors in response. Conclusions: Although limited by open trials and small sample size, three optimal stimulation parameter combinations emerged from this review. Studies are needed to assess the comparative efficacy and safety of these combinations, such as a registry of data from patients undergoing DBS for TRD with individual data on stimulation parameters.Item Open Access Dosing of Electrical Parameters in Deep Brain Stimulation (DBS) for Intractable Depression: A Review of Clinical Studies(Frontiers, 2018-01) Ramasubbu, Rajamannar; Lang, Stefan; Kiss, Zelma H. T.Background: The electrical parameters used for deep brain stimulation (DBS) in movement disorders have been relatively well studied, however for the newer indications of DBS for psychiatric indications these are less clear. Based on the movement disorder literature, use of the correct stimulation parameters should be crucial for clinical outcomes. This review examines the stimulation parameters used in DBS studies for treatment resistant depression (TRD) and their relevance to clinical outcome and brain targets. Methods: We examined the published studies on DBS for TRD archived in major databases. Data on stimulus parameters (frequency, pulse width, amplitude), stimulation mode, brain target, efficacy, safety, and duration of follow up were extracted from 29 observational studies including case reports of patients with treatment resistant unipolar, bipolar, and co-morbid depression. Results: The algorithms commonly used to optimize efficacy were increasing amplitude followed by changing the electric contacts or increasing pulse width. High frequency stimulation (>100 Hz) was applied in most cases across brain targets. Keeping the high frequency stimulation constant, three different combinations of parameters were mainly used: (i) short pulse width (60-90 us) and low amplitude (0-4 V), (ii) short pulse width and high amplitude (5-10 V), (iii) long pulse width (120-450 us) and low amplitude. There were individual variations in clinical response to electrical dosing and also in the time of clinical recovery. There was no significant difference in mean stimulation parameters between responders and non-responders suggesting a role for stimulation unrelated factors in response. Conclusions: Although limited by open trials and small sample size, three optimal stimulation parameter combinations emerged from this review. Studies are needed to assess the comparative efficacy and safety of these combinations, such as a registry of data from patients undergoing DBS for TRD with individual data on stimulation parameters.Item Open Access Instrumentation for Functional Brain Monitoring with Intrinsic Optical Signals(2019-12-05) Yu, Linhui; Murari, Kartikeya; Dunn, Jeff F.; Fear, Elise C.; Kiss, Zelma H. T.; Curiel, Laura; Côté, Daniel C.Intrinsic optical signals are widely used in functional brain imaging techniques for measuring hemodynamic parameters, such as oxygen saturation and blood volume. These parameters indicate brain metabolism and serve as an indirect measurement of neural activity. In this thesis, I describe two techniques for hemodynamic monitoring from freely-moving animals. The first technique is single fiber spectroscopy, which enables measurements from a highly-localized volume in deep brain structures. I describe the optical system design for measuring reflectance spectra, Monte Carlo simulations for estimating the sampling volume, phantom experiments for rating the accuracy of hemodynamic parameter quantification, and finally, animal experiments for evaluating system performance in in-vivo experiments. I demonstrate that the single fiber spectroscopic system is capable of measuring spontaneous and stimulus-evoked hemodynamic response through a small diameter multimode fiber from non-line-of-sight brain regions in anesthetized and freely-moving animals. The second system is a miniaturized intrinsic optical sensing system (MiniIOS), a cost-effective, integrated system for measurement from the brain surface. The thesis covers the design and characterization of two versions of MiniIOS, the development of an empirical model for extracting hemodynamic parameters from the measured reflectance, as well as system validation in optical phantoms and animal experiments. The final system has a dimension of 5.5 mm×4.7 mm×1.8 mm and weight of 0.12 g. The system can be powered with a battery and operated as a stand-alone device integrating light source, detector, power supply, data acquisition and storage. Phantom experiments showed that the system was sensitive to both changes in oxygen saturation and blood volume fraction. A pilot animal experiment showed the system can be mounted on the head of a mouse without affecting its movement.Item Open Access Intrinsic Optical Imaging of Cortex During Deep Brain Stimulation: Parameters, Spatiotemporal Dynamics and Neurovascular Coupling(2018-04-23) Noor, Muhammad Sohail; Kiss, Zelma H. T.; Murari, Kartikeya; Frayne, Richard; Hu, BinDeep brain stimulation (DBS) is clinically used to treat various movement disorders and has a potential to ameliorate other conditions such as depression, epilepsy etc. However, the mechanism through which DBS alleviates symptoms is not clear which prevents its efficient application and expansion to new conditions. Modulation of motor cortex due to DBS is thought to be imperative in this therapy. Recent electrophysiology and imaging studies investigating the effects of DBS on motor cortex have reported contradictory results. One reason of this disagreement is that functional imaging techniques (functional magnetic resonance imaging and positron imaging tomography) commonly used to study DBS are neither suited for mechanistic understanding nor for chronic measurements. In this thesis, I tested a similar functional imaging technique, called intrinsic optical imaging (IOI), which can be used to better probe the functioning of DBS in animals models because it allows simultaneous imaging and electrophysiology, neurochemical manipulations, and long-term recording over months. I established that IOI can measure DBS-induced cortical perfusion consistently and using this technique I studied how various parameters of DBS, which are critical to its therapeutic effect, modulate motor cortex perfusion in rodents. The temporal and spatial dynamics of perfusion were dependent on the parameters of DBS. 'Maximum change in reflectance' and its spatial spread (two measures of hemodynamic response) increased linearly with increases in current amplitude or pulse width and had a non-linear relationship with frequency. Using simultaneous imaging and electrophysiology, I studied the relationship between DBS-induced neural and vascular response — neurovascular coupling, understanding which is necessary to interpret the data acquired with functional imaging techniques used in patients. Neurovascular coupling relationship was developed between 'maximum change in reflectance' (MCR, a measure of vascular response) and 'integrated evoked potential (IEP)' or 'multiunit broadband power' (two measures of neural response). The relationship between MCR and IEP was maintained to a stimulation frequency of 60 Hz: both increased with the frequency of stimulation. However, above 60 Hz MCR saturated while IEP increased linearly to the maximum frequency tested of 100 Hz. The relationship between MCR and multi-unit power remained coupled for the whole range of stimulation frequency applied. These relationships will help researchers in the interpretation of functional imaging studies during DBS. The technique established here and my results will further our understanding of DBS, help to improve this therapy and provide an opportunity to expand it to treat new neurologic and psychiatric conditions.Item Metadata only Long-lasting electrophysiological after-effects of high frequency stimulation in the globus pallidus: human and rodent slice studies(2018-10-29) Luo, Feng; Kim, Linda H.; Magown, Philippe; Sohail Noor, M.; Kiss, Zelma H. T.Deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) is a highly effective therapy for movement disorders, yet its mechanism of action remains controversial. Inhibition of local neurons due to release of GABA from afferents to the GPi is a proposed mechanism in patients. Yet, high frequency stimulation (HFS) produces prolonged membrane depolarization mediated by cholinergic neurotransmission in endopeduncular neurons (EP, GPi-equivalent in rodent). We applied HFS while recording neuronal firing from an adjacent electrode during microelectrode mapping of GPi in awake patients (both male and female) with Parkinson disease (PD) and dystonia. Aside from after-suppression and no change in neuronal firing, high frequency microstimulation induced after-facilitation in 38% (26/69) of GPi neurons. In neurons displaying after-facilitation, 10-s HFS led to an immediate decrease of bursting in PD, but not dystonia patients. Moreover, the changes of bursting patterns in neurons with after-suppression or no change after HFS, were similar in both patient groups. To explore the mechanisms responsible, we applied HFS in EP brain slices from rats of either sex. As in humans, HFS in EP induced two subtypes of after-excitation: excitation or excitation with late inhibition. Pharmacological experiments determined that the excitation subtype, induced by lower charge density, was dependent on glutamatergic transmission. HFS with higher charge density induced excitation with late inhibition, which involved cholinergic modulation. Therefore HFS with different charge density may affect the local neurons through multiple synaptic mechanisms. The cholinergic system plays a role in mediating the after-facilitatory effects in GPi neurons, and because of their modulatory nature, may provide a basis for both the immediate and delayed effects of GPi-DBS. We propose a new model to explain the mechanisms of DBS in GPi.SIGNIFICANCE STATEMENTDeep brain stimulation (DBS) in the globus pallidus pars interna (GPi) improves Parkinson disease (PD) and dystonia, yet its mechanisms in GPi remain controversial. Inhibition has been previously described and thought to indicate activation of GABAergic synaptic terminals, which dominate in GPi. Here we report that 10-s high frequency microstimulation induced after-facilitation of neural firing in a substantial proportion of GPi neurons in humans. The neurons with after-facilitation, also immediately reduced their bursting activities after high frequency stimulation in PD, but not dystonia patients. Based on these data and further animal experiments, a mechanistic hypothesis involving glutamatergic, GABAergic and cholinergic synaptic transmission is proposed to explain both short- and longer-term therapeutic effects of DBS in GPi.Item Open Access Mapping and Modulating Brain-Behavior Relationships in Parkinson’s Disease(2020-07-27) Lang, Stefan Thomas; Monchi, Oury; Kirton, Adam; Kiss, Zelma H. T.; Pike, G. BruceWhile Parkinson’s disease (PD) is primarily known as a movement disorder, non-motor symptoms are increasingly recognized as having a significant impact on quality of life. In particular, cognitive impairment and neuropsychiatric symptoms are common and debilitating. These symptoms likely arise from dysfunction in distributed brain networks, which can result from diverse molecular, cellular, and synaptic pathology. Development of effective treatments for these non-motor symptoms will benefit from a detailed understanding of the relationship between the symptomatology and the functional architecture of the brain. These brain networks can be investigated with resting-state functional MRI (rs-fMRI), and can be modulated with non-invasive brain stimulation (NIBS). In the first part of the thesis, using rs-fMRI, we provide novel descriptions of the relationship between cognitive and neuropsychiatric symptoms and functional brain architecture in PD. First, we show that the dysexecutive and posterior cortical profiles of cognitive impairment are related to distinct brain networks. Next, we show that mild behavioral impairment (as a measure of global neuropsychiatric symptoms) is related to altered corticostriatal connectivity. Finally, we develop a novel brain mapping analytical method to investigate the networks underlying the interface of cognitive, neuropsychiatric, and motor symptoms in PD. In the second part of the thesis, we investigate the use of NIBS for cognitive enhancement, both in PD and in healthy subjects. In the first project, subjects with PD and mild cognitive impairment are randomized to receive real or sham intermittent theta-burst transcranial magnetic stimulation of the left dorsolateral prefrontal cortex. Neuropsychological assessments and rs-fMRI are administered before and after the treatment sessions. We show that this treatment paradigm can alter corticostriatal connectivity and may improve executive functioning one-month following stimulation. In the final project, using healthy subjects, we show that it may be possible to improve associative memory performance by targeting theta rhythm high-definition transcranial alternating current stimulation to posterior cortical regions. In sum, this thesis contributes novel descriptions of the relationship between macroscale functional brain networks and the non-motor symptoms of PD, while also describing efforts to modulate these networks using NIBS. This work provides novel targets for neuromodulation, demonstrates the challenges in developing treatments for cognitive impairment, and suggests promising directions for future efforts.Item Metadata only A new psychometric questionnaire for reporting of somatosensory percepts(2018-01-16) Kim, Linda H.; McLeod, R. S.; Kiss, Zelma H. T.There have been remarkable advances over the past decade in neural prostheses to restore lost motor function. However, restoration of somatosensory feedback, which is essential for fine motor control and user acceptance, has lagged behind. With an increasing interest in using electrical stimulation to restore somatosensory sensations within the peripheral (PNS) and central nervous systems (CNS), it is critical to characterize the percepts evoked by electrical stimulation in a standardized manner with a validated psychometric questionnaire. This will allow comparison of results from applications at various nervous system levels in multiple settings.Item Open Access Outcomes of occipital nerve stimulation for craniofacial pain syndromes(2020-11-25) Magown, Philippe; Becker, Werner J.; Kiss, Zelma H. T.Item Metadata only Situating brain regions among patent rights and moral risks(2017-01) Roskams-Edris, Dylan; Anderson-Redick, Stacey; Kiss, Zelma H. T.; Illes, JudyItem Open Access Time and Frequency-Dependent Modulation of Local Field Potential Synchronization by Deep Brain Stimulation(Public Library of Science (PLoS), 2014-07-16) McCracken, Clinton B.; Kiss, Zelma H. T.