ABSTRACT
Although manifesting contrasting phenotypes, Parkinson's disease and dystonia, the two most common movement disorders, can originate from similar pathophysiology. Previously, we demonstrated that lesioning (silencing) of a discrete dorsal region in the globus pallidus (rodent equivalent to globus pallidus externa) in rats and produced parkinsonism, while lesioning a nearby ventral hotspot-induced dystonia. Presently, we injected fluorescent-tagged multi-synaptic tracers into these pallidal hotspots (n = 36 Long Evans rats) and permitted 4 days for the viruses to travel along restricted connecting pathways and reach the motor cortex before sacrificing the animals. Viral injections in the Parkinson's hotspot fluorescent labeled a circumscribed region in the secondary motor cortex, while injections in the dystonia hotspot labeled within the primary motor cortex. Custom probability mapping and N200 staining affirmed the segregation of the cortical territories for Parkinsonism and dystonia to the secondary and primary motor cortices. Intracortical microstimulation localized territories specifically to their respective rostral and caudal microexcitable zones. Parkinsonian features are thus explained by pathological signaling within a secondary motor subcircuit normally responsible for initiation and scaling of movement, while dystonia is explained by abnormal (and excessive) basal ganglia signaling directed at primary motor corticospinal transmission.
Subject(s)
Basal Ganglia , Dystonia , Motor Cortex , Neural Pathways , Parkinsonian Disorders , Rats, Long-Evans , Animals , Motor Cortex/physiopathology , Motor Cortex/pathology , Parkinsonian Disorders/physiopathology , Parkinsonian Disorders/pathology , Rats , Neural Pathways/physiopathology , Dystonia/physiopathology , Dystonia/pathology , Dystonia/etiology , Basal Ganglia/pathology , Male , Globus Pallidus/pathology , Disease Models, AnimalABSTRACT
Background: Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has been preliminarily investigated as a potential treatment for dementia. The degeneration of NBM cholinergic neurons is a pathological feature of many forms of dementia. Although stimulation of the NBM has been demonstrated to improve learning, the ideal parameters for NBM stimulation have not been elucidated. This study assesses the differential effects of varying stimulation patterns and duration on learning in a dementia rat model. Methods: 192-IgG-saporin (or vehicle) was injected into the NBM to produce dementia in rats. Next, all rats underwent unilateral implantation of a DBS electrode in the NBM. The experimental groups consisted of i-normal, ii-untreated demented, and iii-demented rats receiving NBM DBS. The stimulation paradigms included testing different modes (tonic and burst) and durations (1-hr, 5-hrs, and 24-hrs/day) over 10 daily sessions. Memory was assessed pre- and post-stimulation using two established learning paradigms: novel object recognition (NOR) and auditory operant chamber learning. Results: Both normal and stimulated rats demonstrated improved performance in NOR and auditory learning as compared to the unstimulated demented group. The burst stimulation groups performed better than the tonic stimulated group. Increasing the daily stimulation duration to 24-hr did not further improve cognitive performance in an auditory recognition task and degraded the results on a NOR task as compared with 5-hr. Conclusion: The present findings suggest that naturalistic NBM burst DBS may offer a potential effective therapy for treating dementia and suggests potential strategies for the reevaluation of current human NBM stimulation paradigms.