SAN DIEGO-The idea that Parkinson disease (PD) and dystonia are circuit disorders involving the basal ganglia-thalamocortical circuit - which influences motor activity - is supported by the success of deep brain stimulation in reversing motor symptoms, said one leading expert in movement disorders here in the Robert Wartenberg Lecture at the AAN Annual Meeting.
The evolving concepts of basal ganglia circuitry and how these concepts have clarified how surgical approaches such as pallidotomy and deep brain stimulation might work were described by Mahlon R. DeLong, MD, William Timmie Chair of Neurology at the Emory University School of Medicine.
Dr. DeLong said that, historically, the basal ganglia were thought to be pathways that funneled the output from the entire cortex, via the thalamus, to the motor cortex. The model, proposed by Dr. DeLong and colleagues in the mid-80s, viewed the basal ganglia as components of parallel segregated pathways that originate from specific areas of the cortex and return to those same areas via specific regions of the basal ganglia and thalamus, Dr. DeLong explained. Broadly, the circuits can be divided into motor, oculomotor, associative, and limbic circuits. This model made it possible to better understand the varied clinical expressions of basal ganglia diseases. Each circuit is comprised of subcircuits that are centered on specific cortical areas. Motor subcircuits include those from the motor cortex itself and the different premotor fields, such as the supplemental motor area and premotor cortex. Each subcircuit is organized somatotopically with maintained face, arms, and leg representations in each of the component nuclei.
CHANGING CONCEPTS OF BRAIN ORGANIZATION
Dr. DeLong noted that the concepts of the extrinsic and intrinsic organization are changing. In addition to the intrinsic pathways, which include direct and indirect striatal-pallidal pathways, the direct pathway is directly linked to the output nuclei, whereas the indirect pathway has stations in the external pallidum and subthalamic nucleus. Attention is now focused on a hyperdirect pathway to the subthalamic nucleus (STN) with a net excitatory effect on the indirect pathway. These concepts affect our understanding of Parkinson disease, Dr. DeLong said. The fact that PD is a dopaminergic disorder is just the tip of the iceberg. 'Below the water,' we know there are non-motor features [depression, anxiety, autonomic dysfunction, sleep disorders, and cognitive impairment] that respond poorly to dopamine, Dr. DeLong continued.
Figure. Dr. Mahlon D...Image Tools
He described early studies in MPTP-induced parkinsonism in monkeys as animal models of nigral dopamine deficiency. In these animals, neuronal firing rates were increased in the (inhibitory) output from the globus pallidus interna (GPi), the major output nucleus of the basal ganglia - considered the cause of hypokinetic features of Parkinson disease.
In subsequent experiments, Dr. DeLong and colleagues found that inactivation (by surgical lesions) of the STN led to immediate abolition of bradykinesia, tremor, and rigidity in the contralateral limbs. And it provided evidence for the key role of the STN and the indirect pathway in Parkinson disease, which led to a reconsideration of surgical approaches.
These and subsequent experiments indicated that the sensorimotor part of the subthalamic nucleus and pallidum are critical for the development of Parkinson disease, he noted.
Subsequent experiments showed that, in addition to changes in neuronal discharge rates, changes in pattern, synchronization, and oscillations of discharge occur in animal models of PD and in patients with the disease. These discharge abnormalities are thought to disrupt cortical processing and cause the clinical features.
This is strongly supported by the finding that ablation or deep brain stimulation in the motor portions of the subthalamic nucleus or GPi result in dramatic and immediate improvement in parkinsonism and at the same time normalize cortical motor activity in these areas, he explained.
RATIONALE FOR SURGERY
The rationale for surgical intervention is that patients who initially respond to levodopa become resistant to the drug in time. Pallidotomy (by lesions in the GPi) abolishes features of PD on the contralateral side of the body. Parkinson bradykinesia is also ameliorated post-pallidotomy, he said.
Neuroimaging in patients with PD have demonstrated that many areas of the brain are activated by motor tasks that are not activated in normals, he said.
Deep brain stimulation has now replaced pallidotomy as the surgical procedure of choice for PD, Dr. DeLong said, because it seems to restore more normal functioning and to abolish parkinsonian signs by replacing or modulating the abnormal circuit activity, which is fundamental to recovery.
A study (awaiting publication) by Dr. DeLong and his colleagues shows that deep brain stimulation corrects the abnormalities in circuitry that are present at rest and also in movement. In addition, deep brain stimulation normalizes the abnormal patterns of cortical activity, as well as activity in individual cortical areas.
DEEP BRAIN STIMULATION FOR DYSTONIA
Dystonia also seems to be related to abnormal neuronal activity in motor circuitry that includes cortical reorganization and abnormal sensory processing, because ablation or deep brain stimulation of the same areas used to treat patients with PD also relieve dystonia. However, patients with dystonia take much longer to respond to deep brain stimulation - weeks or months - whereas the response is immediate in Parkinson disease. This suggests that dystonia results from abnormal motor learning or neuroplasticity.
Dr. DeLong showed a video clip of a patient with severe dystonia who had to walk bent over and eat off the floor because his trunk was contorted. Following deep brain stimulation, he could walk, talk, eat normally, and hold his pets - none of which could he do before surgery. The patient said that the most painful part of the disorder was being ridiculed because of his appearance.
Dr. DeLong noted that deep brain stimulation is being studied in other basal ganglia circuit disorders, such as Tourette syndrome and obsessive compulsive disorder. And, he said, he expects there will be other refinements and improvements for applying deep brain stimulation to other circuit disorders.
Figure. Dr. Robert C...Image Tools
ANOTHER PERSPECTIVE
Dr. DeLong's talk provided a solid historical context for models of basal ganglia circuitry, said Robert Chen, MD, Associate Professor of Neurology at the University of Toronto. Parkinson disease patients are slow, Dr. Chen said, not only because of the rate but also because of the pattern, frequency, and dyssynchrony of neural impulses.
This understanding explains how deep brain stimulation works, Dr. Chen continued. Originally, we thought it worked by creating a lesion as we did with pallidotomy. Now we know it is not that simple. Deep brain stimulation seems to activate downstream areas, affect oscillation frequencies, and change the synchrony of neural structures, he said.
Deep brain stimulation has several advantages over pallidotomy, Dr. Chen continued. It doesn't produce a lesion, so there is less chance of surgical morbidity. It is also adjustable, allowing change of stimulation characteristics such as frequency and intensity. Each electrode has four contact points, and the surgeon or neurologist can choose one or two of those points. Additionally, the creation of a lesion with pallidotomy may not allow patients to benefit from new restorative neuronal treatments that may be developed, whereas deep brain stimulation would not interfere with response to those treatments.
ARTICLE IN BRIEF
✓ Dr. Mahlon DeLong described the evolving concepts of basal ganglia circuitry and how these concepts have clarified how surgical approaches such as pallidotomy and deep brain stimulation might work.
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