neurodex tm palliates pseudobulbar affect:
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Neurodex TM Palliates Pseudobulbar Affect: An Overview of the Pathogenesis of Pseudobulbar Affect and the Pharmacologic Mechanism of Action of Neurodex. Ursula Hess, PhD Torre Lazur McCann West. Neural Circuits Hypothesized to Mediate Emotional Motor Expression. Cortico-Bulbar Circuit. - PowerPoint PPT PresentationTRANSCRIPT
NeurodexTM Palliates Pseudobulbar Affect:
An Overview of the Pathogenesis of Pseudobulbar Affect
and the Pharmacologic Mechanism of Action of Neurodex
Ursula Hess, PhDTorre Lazur McCann West
Neural Circuits Hypothesized to MediateEmotional Motor Expression
• Cortico-Bulbar Circuit
• Cortico-Pontine-Cerebellar Circuit
Cortex controls bulbar-generated laughing/crying and inhibitsinvoluntary affective motor displays
Cerebellum communicates with cortical association areas and adjusts laughing/crying responses to appropriate cognitive/social context
Monoamine Centers in Brainstem Regulate Networks That Mediate Emotional Motor Expression
• Brainstem monoamine (5-HT, NE, DA) centers send diffuse projections throughout the brain
• Monoamines are neuromodulators and may cause physiological state changes that raise or lower the threshold of activation of neural networks that trigger emotional expression
Brain Pathways Commonly Damaged in PBA Patients
Disconnection Hypothesis Lesions of cortico-bulbar tracts mayrelease bulbar-generated laughing/cryingfrom cortical control
Cerebellar HypothesisLesions that interrupt cerebellar communication with cortex or effector regions may disrupt adjustment of emotional responses to context
Monoamine HypothesisDamage to monoamine centers or theirascending projections is proposed to correlatewith PBA severity. Dysfunction of modulatory pathsmay lower the threshold for laughing/crying
DM Primarily Targets Brain RegionsBelieved to Mediate Emotional Motor Expression
and Modulates NT Systems Implicated in PBA
DM 1DM 1o o Targets Brainstem and CerebellumTargets Brainstem and CerebellumLikely Due to Its Sigma PropertiesLikely Due to Its Sigma Properties• Sigma 1 agonist
DM Modulates Glutamatergic and DM Modulates Glutamatergic and Monoaminergic SignalingMonoaminergic Signaling• Decreases excitatory Glu signaling (NMDA antagonist, sigma 1 agonist)• DM modulates DA and 5-HT release in some brain systems
DM may palliate PBA via1) Targeted action on sigma Rs in brainstem2) Distributed action on monoamine systems that raises threshold of laughing/crying
Brain Circuits Mediating Laughing and Crying
• Motor cortex pyramidal neurons control bulbar motor neurons that mediate facio-respiratory functions associated with laughing/crying
— Direct cortical signals are Excitatory, Glu+
• Monoamine centers in brainstem can modulate facio-respiratory functions by raising/lowering threshold at which cortical neurons can evoke brainstem motor neuron responses
— Monoamines set Inhibitory (-) Tone
A SIMPLE HYPOTHESIS
Brain Pathology That Disturbs Integrity of These Circuits May Result in PBA
A SIMPLE HYPOTHESIS
• Damage to cortico-bulbar or cerebellar-motor cortex paths results in
Excess Cortical Excitation (Glu+) of bulbar motor neurons and triggers involuntary laughing/crying
• Damage to brainstem monoamine centers or their ascending/descending tracts
Decreases Inhibitory (-) Tone on cortico-bulbar circuits and lowers threshold for laughing/crying
Sigma Modulation of Excitatory Neurotransmission
Excitatory Cortico-Bulbar Synapse
• Neurotransmitter: Glutamate (Glu )
• Glu Receptors: NMDA and AMPA
• Influx of Na+ and Ca2+ excites neuron
• Presynaptic sigma 1 Rs may modulate Glu release via effects on Ca2+ flux
• Postsynaptic sigma 1 Rs may indirectly modulate NMDA responses, via effects on intracellular Ca2+ homeostasis
DM May Decrease Excess BS Motor Neuron Excitationand Raise Low Threshold for Laughing/Crying
• Targeted, concerted action to decrease cortico-bulbar excitatory signaling
— DM inhibits Glu release via sigma activity— DM weakly blocks NMDA responses
• Diffuse, indirect action to raise low threshold for laughing/crying
— DM may increase inhibitory tone
Neuropharmacology of DM
• Sigma 1 R agonist
• Weak, noncompetitive NMDA R antagonist that binds PCP site
• Decreases K+-stimulated glutamate release
• Reduces KCl and NMDA-induced increases in intracellular Ca2+ concentration via voltage- and receptor-gated Ca2+ channels
• Noncompetitive 34 nicotinic R antagonist; thereby proposed to modulate DA release in the mesolimbic pathway
• Increases 5-HT release in the brainstem nucleus of the solitary tract (NTS)