Progressive Supranuclear Palsy (PSP) is an unusual degenerative disease in that it primarily targets the brain stem. Patients with PSP experience severe difficulty with balance, voluntary (vertical greater than horizontal) eye movements, fixation, and visual attention, however initially intellect is preserved. The neuropathologic changes of PSP are found primarily in the basal ganglia and reticular structures including the paramedian zone of the pontine reticular formation (PPRF) and rostral interstitial nucleus of the MLF (riMLF), the premotor regions for the control of horizontal and vertical saccade eye movements, respectively. Since vestibularly induced eye movements remain intact, damage to the PPRF and riMLF alone cannot account for the observed clinical deficits of patients with PSP. The current study examines the idea that: The Mesencephalic Reticular Formation (MRF) provides feedback of the current displacement of the eyes to the superior colliculus (SC) via a mathematical integration of an eye velocity signal provided by neurons from the PPRF.
Three aims are proposed: 1) Determine the oculomotor attributes of neurons in the MRF. 2) Characterize the effects of reversibly activating, inactivating, or permanently lesioning physiologically identified subregions of the MRF using the GABA active substances bicuculline and muscimol or the excitotoxin ibotenic acid. Damage to the velocity to position integrator which is essential in oculomotor feedback control should generate hypermetric saccades. 3)Determine if the map of saccade amplitude in the intermediate and deep layers of the SC is modified following inactivation or lesions of the MRF. Preliminary data demonstrate striking hypermetria of contraversive saccades and macro-saccadic square wave jerks following both reversible inactivation and excitotoxic lesions of the primate MRF. Visually guided saccades partially recover, while saccades to remembered targets do not. These oculomotor changes suggest that the MRF does participate in feedback. These results also imply that examining the remembered saccades of patients with PSP may lead to earlier and more reliable diagnosis and permit better monitoring of therapeutic interventions.
