Publications

Evidence for a task-dependent switch in subthalamo-nigral basal ganglia signaling
Nature Communications, 2017


Basal ganglia (BG) can either facilitate or inhibit movement through excitatory and inhibitory pathways; however whether these opposing signals are dynamically regulated during healthy behavior is not known. Here, we present compelling neurophysiological evidence from three complimentary experiments in non-human primates, indicating task-specific changes in tonic BG pathway weightings during saccade behavior with different cognitive demands. First, simultaneous local field potential recording in the subthalamic nucleus (STN; BG input) and substantia nigra pars reticulata (SNr; BG output) reveals task-dependent shifts in subthalamo-nigral signals. Second, unilateral electrical stimulation of the STN, SNr, and caudate nucleus results in strikingly different saccade directionality and latency biases across the BG. Third, a simple artificial neural network representing canonical BG signaling pathways suggests that pathway weightings can be altered by cortico-BG input activation. Overall, inhibitory pathways (striato-pallidal-subthalamo-nigral) dominate during goal-driven behavior with instructed rewards, while facilitatory pathways (striato-nigral and subthalamo-pallidal-nigral) dominate during unconstrained (free reward) conditions.



A brain-computer interface for extended reality control
Proc. SIGGRAPH '17 VR Village, Los Angeles, CA, USA, 2017


Extended reality (XR) technologies, such as augmented reality (AR) and virtual reality (VR), remain limited in their interaction modalities. Prevailing interaction methods such as hand gestures and voice recognition prove awkward in XR environments, even when performing common tasks (e.g., object selection, menu navigation, and others). In contrast, an ideal interaction method would robustly and naturally translate a user's intention into both 2D and 3D environmental controls. A direct brain-computer interface (BCI) system is ideally situated to accomplish this. Neurable's technology provides a solution to maximize XR's potential, affording users real-time mental selection via dry electroencephalography (EEG).



Role of the frontal eye field, superior colliculus, and basal ganglia in flexible saccade behavior
Diss. QSpace, Queen's University, 2016


A distributed network of cortical and subcortical brain regions mediates the control of voluntary behavior, but it is unclear how this complex system may flexibly shift between different behavioral events. We examined five nuclei critical for saccade initiation and modulation: the frontal eye field (FEF) in the cerebral cortex, the subthalamic nucleus (STN), caudate nucleus (CD), and substantia nigra pars reticulata (SNr) in the basal ganglia (BG), and the superior colliculus (SC) in the midbrain. The studies presented here demonstrate that the conditions for saccade initiation by the FEF and SC vary according to behavioral condition, while simultaneously, large-scale task dependent shifts occur in BG signaling consistent with the observed modulation of FEF and SC activity. Taken together, these describe a mechanistic framework by which the cortico-BG loop may contribute to the flexible control of behavior.[truncated]



Pallidal deep brain stimulation modulates afferent fibers, efferent fibers, and glia
Journal of Neuroscience, 2013


INTRODUCTION: Deep brain stimulation (DBS) of the basal ganglia is an effective treatment option for intractable symptoms of neurological and psychiatric disorders. For example, movement deficits in Parkinson’s disease and dystonia are improved by DBS of the internal segment of the globus pallidus (GPi), a major output structure of the basal ganglia. Despite its increasing prevalence, however, there remains substantial disagreement over the therapeutic mechanisms of DBS (Miocinovic et al., 2013). Because there is potential for adverse side effects depending on DBS parameters and location, further elucidating the mechanism of DBS of the basal ganglia may improve treatment. In a recent report published in The Journal of Neuroscience, Chiken and Nambu (2013) address this issue in the globus pallidus of normal monkeys. It is known that the GPi is inhibited by afferent GABAergic projections from the striatum and the external segment of the globus pallidus (GPe), and it is activated by a glutamatergic projection from the subthalamic nucleus. Chiken and Nambu (2013) suggest that DBS of the GPi blocks cortical and basal ganglia signals by increasing GABA release from afferent fibers to the GPi, thereby suppressing GPi activity.
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Threshold mechanism for saccade initiation in the frontal eye field and superior colliculus
Journal of Neurophysiology, March 13 2013

Jantz JJ, Watanabe M, Everling S, Munoz DP (2013) Threshold mechanism for saccade initiation in the frontal eye field and superior colliculus. J Neurophysiol 109(11): 2767-80. PMID: 23486198

In an influential model of frontal eye field (FEF) and superior colliculus (SC) activity, saccade initiation occurs when the discharge rate of either single neurons or a population of neurons encoding a saccade motor plan reaches a threshold level of activity. Conflicting evidence exists for whether this threshold is fixed, or can change under different conditions. We tested the fixed threshold hypothesis at the single-neuron and population levels to help resolve the inconsistency between previous studies. Two rhesus monkeys performed a randomly interleaved pro- and anti-saccade task in which they must look either toward (pro) or 180º away (anti) from a peripheral visual stimulus. We isolated visuomotor (VM) and motor (M) neurons in the FEF and SC, and tested three specific predictions of a fixed threshold hypothesis. We found little support for fixed thresholds. First, correlations were never totally absent between pre-saccadic discharge rate and saccadic reaction time when examining a larger (plausible) temporal period. Second, pre-saccadic discharge rates varied markedly between saccade tasks. Third, visual responses exceeded pre-saccadic motor discharges for FEF and SC VM neurons. We calculated that only a remarkably strong bias for M neurons in downstream projections could render the fixed threshold hypothesis plausible at the population level. Also, comparisons of gap vs. overlap conditions indicate that increased inhibitory tone may be associated with stability of thresholds. We propose that fixed thresholds are the exception rather than the rule in FEF and SC, and that stabilization of an otherwise variable threshold depends on task-related, inhibitory modulation.



DKK-1, a Secreted Wnt Antagonist, Activates the WNT5A Receptor, Ror2, to Stimulate Non-Canonical Wnt Signaling in the Intestine
Gastroenterology, May 2010


BACKGROUND: Dkk-1 prevents canonical Wnt signaling by binding a transmembrane receptor, Kremen1/2, which then complexes with LRP6 and reduces LRP6-Frizzled-Wnt multimers. Dkk-1 expression is lost in colon cancer but increased in colitis. Ror2 is a tyrosine kinase expressed from the crypt base to villus tip in the small intestine but only on surface epithelia of normal colon. Wnt5a stimulates Ror2 by interacting with the Ror2 Cysteine rich domain (CRD). AIM: To understand how Ror2 overexpression in Dkk-1 secreting epithelia signals CDX2, villin, and SGLT1 and show recombinant human (rh) Dkk-1 interacts with Ror2 using epithelial cells which do not secrete Dkk-1 constitutively. METHODS: PCR cloning was used to construct His and Myc-tagged full length Dkk-1. Transient transfection of wild type Ror2 (Flag-tagged) or CRD-Ror2 in Dkk-1 secreting adenocarcinoma cells (HT-29) or non-Dkk-1 secreting intestinal epithelial cells, RKO, expressing wild type APC and β-catenin. Western blotting was used to quantitate increases in CDX2, villin and SGLT1. Co-immunoprecipitation was performed using standard His, Myc and Flag antibodies. Inhibition of Casein-kinase 1, p38 MAP kinase and JNK was accomplished pharmacologically. Transient transfection of siRNA duplex against Ror2 or Kremen2 was used to knockdown expression. RESULTS: Overexpression of Ror2 increased CDX2 (3 fold), villin (2 fold) and SGLT1 (5 fold) protein expression in HT-29 cells. Wnt5a conditioned medium or rhWnt5a (200 ng/ml) further increased CDX2 expression, with maximal effect after 2h, then reduced CDX2 expression until it was absent by 6h. Wnt5a addition did not further increase SGLT1 protein. The increase in CDX2 protein observed with Ror2 overexpression was prevented by inhibitors of p38, CK1 and Src family kinases while Wnt5a stimulated increases were blocked by inhibition of JNK, CK1 and Src kinases. Addition of rhDkk-1 (25 ng/ml) to RKO cells increased CDX2. Ror2 knockdown by siRNA duplex prevented this increase. In Ror2 overexpressing RKO cells rhDkk-1 dose responsively (0.5-100 ng/ml) increased CDX2 protein with maximal stimulation at 2.5 ng/ml after 24h. Comparable results were observed in RKO cells overexpressing CRD-Ror2. Co-immunoprecipitation of His or Myc-tagged Dkk- 1 with Flag-tagged Ror2 revealed interaction, co-localization was observed with immunoflurescence microscopy. CONCLUSIONS: Dkk-1 at physiological concentrations will activate intestinal epithelial Ror2. Dkk-1 stimulation of Ror2 does not require the cysteine-rich region of the receptor. Dkk-1 interaction with Ror2 may explain β-catenin independent effects of Dkk-1.



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