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)