Research
Themes
I. Mechanisms of action of neuromodulation therapies: deep brain stimulation (DBS) and focused ultrasound (FUS)
II. Clinical trials of surgery for movement, pain and psychiatric disorders
III. Neural prostheses
IV. Physiology of the human basal ganglia and thalamus
V. Neuroethics in neuromodulation
I. Mechanisms of action of neuromodulation therapies
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Our research aims are to understand how neuromodulation therapies work. DBS electrodes are placed in various deep brain nuclei for the treatment of movement disorders (essential tremor, Parkinson’s disease, dystonia), pain, epilepsy, depression, and obsessive-compulsive disorder. The clinical benefits of DBS are well recognized; however, its mechanism of action is less so. Our lab has developed a good understanding of mechanisms of thalamic DBS for tremor (Neurosci 2002, J Physiol 2004, J Neurosci 2006, J Neurophysiol 2006), others have dissected how subthalamic STN DBS works. While we have made inroads (PlosOne 2014, J Neurophysiol 2016, J Neurosci 2018), how DBS works for dystonia remains an open question. And mechanisms of benefit for depression are even more puzzling (Eur Neuropsychopharmacol 2021).
Focused ultrasound (FUS) is the newest treatment technique and at high intensity it can lesion brain targets. However at lower intensities and by applying different patterns, it may modulate neural tissue thereby non-invasively and focally altering neural function. How FUS neuromodulation works is also unknown.
Using a combined approach of direct examination of beneficial effects of DBS and FUS in patients, intra-operative microelectrode recording/stimulation, applying FUS / DBS to brain slices, and in behaving animal models, we hope to understand its mode of action. With a better understanding of how both these therapies work, we can optimize its application and apply them to novel brain nuclei to treat new conditions.
II. Clinical trials of surgery for movement, pain and psychiatric disorders
While DBS and FUS seems to help several neurological and psychiatric conditions, in order to prove benefit well-designed and controlled clinical studies are essential. Our group was the first to perform a multicentre clinical trial for DBS in Canada (Brain 2007). We have previously led a multicentre randomized controlled double-blind trial of hippocampal DBS for epilepsy, participated in a multicentre cross-over trial of motor cortex stimulation for neuropathic pain (Can J Neurol Sci 2015), and an industry-sponsored trial of occipital nerve region stimulation for migraine (Cephalalgia 2011). We performed a randomized trial of different DBS parameters for treatment-resistant depression (Lancet Psychiatry 2020), identifying several biomarkers of response (J Affective Disord 2020, Neuropsychopharmacology 2020, Brain Stim 2020 and 2022).
III. Smart neural prostheses to restore lost function
Smart prosthetics are in their infancy, but they are one of the newest fields of neuroscience. While there are many challenges faced in this arena we have focused on sensory restoration of touch and kinesthesis (J Neural Eng 2010 and 2018, Trans Neural Syst Rehabil Eng 2011). We continue to test various stimulation methods and ways to improve naturalness of electrical stimulation-induced percepts in patients undergoing surgery.
IV. Human systems physiology and disease pathophysiologyWhile smart prosthetics are exciting and novel, we still do not understand how the nervous system works well enough to interact with it in a meaningful manner.
We have been recording single and multiple neuronal firing in the human thalamus, pallidum, striatum, subthalamic regions and other subcortical regions with microelectrodes for more than two decades, as part of routine surgery to determine the optimal spot for DBS electrode placement. This provides a unique opportunity to study the firing rates, patterns and receptive fields of the neurons we encounter, thereby helping us understand the function of these nuclei and the sensorimotor system as a whole. We have identified electrophysiological markers of disease in depression (Biol Psychiatry 2016), dystonia (J Neurol Neurosurg Psychiatry 2014) and continue to explore the pathophysiology of PD and dystonia using multimodal imaging and electrophysiology.
V. Ethics in neuromodulation
Collaborative work with the UBC Centre for Neuroethics has reported on patents in neuromodulation therapies (Nature Biotechnol 2017, Neuromodulation 2019). We continue to examine the patent landscape and the flow of funding for neuromodulation intellectual property (IP).
PUBLICATIONS
CURRICULUM VITAE
Zelma Kiss, MD PhD FRCSC
Professor, Department of Clinical Neurosciences
Hotchkiss Brain Institute, University of Calgary
SELECTED PUBLICATIONS (* next to our lab trainees)
Noor MS*, Yu L, Murari K, Kiss ZHT: Neurovascular coupling during deep brain stimulation. Brain Stimul 13(3): 916-927, 2020. [PMID: 32289725]
Kim LH*, McLeod RS, Kiss ZHT: A new psychometric questionnaire for reporting of somatosensory percepts. J Neural Eng 15(1):013002, 2018. [PMID: 29076455]
Noor MS*, Murari K, McCracken CB*, Kiss ZHT: Spatiotemporal dynamics of cortical perfusion in response to thalamic deep brain stimulation. Neuroimage 126: 131-139, 2016. [PMID: 26578359] {*our figure was selected as the cover image for this volume}
Wile DJ, Ranawaya R, Kiss ZHT: Smart watch accelerometry for analysis and diagnosis of tremor. J Neurosci Methods. 230: 1-4, 2014. [PMID: 24769376]
Anderson TR*, Hu B, Pittman Q, Kiss ZHT: Mechanisms of deep brain stimulation: An intracellular study in rat thalamus. J Physiol 559(Pt 1):301-313, 2004. [PMID: 15218068]
ONGOING FUNDING
2018-2023: Canada Foundation for Innovation
MR Guided Focused Ultrasound Research Platform
PI: GB Pike; Co-Applicants: G Cairncross, J Dunn, R Frayne, A Kirton, Z Kiss, D. Martino, O Monchi, G Sutherland, P Whelan
2021-2024: ERA-NET (Research Projects on Ethical, Legal and Social Aspects of Neuroscience) NEURON (Network for European Funding for Neuroscience Research)
Canadian Institutes of Health Research contribution
International Neuroethics Patent Initiative
PIs: Spranger (Germany) and Illes (Canada); co-PI (Canada): Kiss
2022-2024: HBI/DCNS Pilot Research Fund Program
Title: Developing a new LIFU neuromodulation method to suppress tremor
2022-2025: CaPRI -HBI Movement disorders Neuroteam pilot project
Title: Electrophysiological markers of long-term benefit vs. early cognitive decline in PD patients treated with STN-DBS
2023-2024: Parkinson Canada Pilot Project Grant
Restoration of locomotor function following stimulation of the A13 region in Parkinson’s rat models.
PI: Whelan; co-I: Kiss, Murari, Park
2023-2028: Natural Sciences and Engineering Research Council of Canada (NSERC)
Discovery Grant Renewal: Mechanisms of low intensity focused ultrasound neural modulation