1. 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

2. Neural Circuits Hypothesized to Mediate Emotional Motor Expression Cortico-Bulbar Circuit Cortico-Pontine-Cerebellar Circuit Cortex controls bulbar-generated laughing/crying and inhibits involuntary affective motor displays Cerebellum communicates with cortical association areas and adjusts laughing/crying responses to appropriate cognitive/social context

3. 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

4. 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

5. DM Primarily Targets Brain Regions Believed to Mediate Emotional Motor Expression and Modulates NT Systems Implicated in PBA DM 1 o 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

6. 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

7. 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

8. Sigma Modulation of Excitatory Neurotransmission Excitatory Cortico-Bulbar Synapse Neurotransmitter: Glutamate (Glu ) Glu Receptors: NMDA and AMPA Influx of Na + and Ca 2+ excites neuron Presynaptic sigma 1 Rs may modulate Glu release via effects on Ca 2+ flux Postsynaptic sigma 1 Rs may indirectly modulate NMDA responses, via effects on intracellular Ca 2+ homeostasis

9. 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

10. 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 Ca 2+ concentration via voltage- and receptor-gated Ca 2+ channels Noncompetitive  3  4 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)