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NeurodexTM 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 Cortex controls bulbar-generated laughing/crying and inhibits involuntary affective motor displays • Cortico-Pontine-Cerebellar Circuit 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 may release bulbar-generated laughing/crying from cortical control Cerebellar Hypothesis Lesions that interrupt cerebellar communication with cortex or effector regions may disrupt adjustment of emotional responses to context Monoamine Hypothesis Damage to monoamine centers or their ascending projections is proposed to correlate with PBA severity. Dysfunction of modulatory paths may lower the threshold for laughing/crying DM Primarily Targets Brain Regions Believed to Mediate Emotional Motor Expression and Modulates NT Systems Implicated in PBA DM 1o Targets Brainstem and Cerebellum Likely Due to Its Sigma Properties • Sigma 1 agonist DM Modulates Glutamatergic and Monoaminergic 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 via 1) Targeted action on sigma Rs in brainstem 2) Distributed action on monoamine systems that raises threshold of laughing/crying Brain Circuits Mediating Laughing and Crying A SIMPLE HYPOTHESIS • 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 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 Excitation and 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 a3b4 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)