NEW ORLEANS -- Brain scans of persons whose symptoms improve significantly after surgery for Parkinson's disease show a clear reversal in aberrant patterns of brain activity, report Emory University researchers at this week's Society for Neuroscience meeting.
"These results provide new insight into the brain mechanisms responsible for symptomatic improvement following surgery for Parkinson's disease," says Robert S. Turner, Ph.D., assistant professor of Neurology at the Emory University School of Medicine.
The researchers sought to determine via the brain imaging technique known as positron emission tomography (PET), whether pallidotomy surgery for Parkinson's disease has the predicted effect of restoring a normal pattern of movement-related brain activity. Indeed, improvements in physical symptoms after pallidotomy such as tremor and rigidity corresponded with improvements in brain activity, as the Emory University neurologists showed with PET scans. Activity increased in brain regions that are normally responsible for controlling movement and decreased in cerebral areas that showed abnormally high activation with the movement disorder.
One of the next steps in this research will be to discover the significance of the unexpected increased activity observed in the brains of Parkinson's disease subjects, Dr. Turner says. Are these activations evidence of compensatory neural mechanisms working to overcome the primary deficits of Parkinson's? Or are they part of the primary pathology of Parkinson's and as such actually cause some of the symptoms of Parkinson's? The fact that clinically effective pallidotomy caused a marked reduction in these activations suggests, at least, that these abnormal activations are closely linked to the pathological processes that give rise to the symptoms of Parkinson's disease, he says.
Although brain imaging techniques have been used previously to study Parkinson's disease and the effects of pallidotomy on movement-related brain activity, the current study is unique in that the Emory team focused on activations correlated with speed of movement. One of the cardinal symptoms of Parkinson's disease is a marked slowness of movement. By focusing on brain areas involved in the control of movement speed, the team hoped to discover why this specific aspect of the control of movement is impaired in Parkinson's disease and why pallidotomy is an effective treatment. In addition, this approach allowed the group to identify changes in brain activity that might have actually caused the improvement in task performance after pallidotomy and distinguish those from changes in activity that were merely caused by changes in performance.
Researchers have established that Parkinson's disease is caused by degeneration of the dopamine neurons that innervate the basal ganglia (a group of interconnected brain areas that lie below the cerebral cortex) and that this loss of dopamine causes output neurons of the basal ganglia to send excessive and abnormal inhibitory signals to large portions of the frontal cortex. Most if not all of the symptoms of Parkinson's, including slowness of movement, are thought to arise from the excessive inhibition of frontal cortical circuits.
In support of this concept, a group at Emory headed by Mahlon DeLong, M.D., chairman of Neurology at Emory, and Jerrold Vitek, M.D., Ph.D., director of the department?s Functional Neurosurgery Section, along with groups at a number of other research centers has shown that most parkinsonian symptoms can be alleviated by pallidotomy -- a neurosurgical ablation of neurons in the globus pallidus, the main output nucleus of the basal ganglia. Pallidotomy is thought to work because it eliminates the source of abnormal inhibition of the frontal cortex, thereby allowing the patterns of neural activity needed to perform normal movements.
Pallidotomy as a treatment for Parkinson's disease has gained a great deal of attention recently because of its potential for addressing some of the shortcomings of traditional therapies, Dr. Turner says.
The most common drug treatments for Parkinson's, which work by providing an artificial supply of dopamine to the basal ganglia, are usually very effective when first administered. After years of use, however, these drugs may lose their effectiveness and begin to produce serious side effects such as excessive unwanted movement and hallucinations.
Pallidotomy has been advocated as a therapy for patients whose symptoms are inadequately controlled or have adverse reactions to drug therapies. Although the clinical effectiveness of pallidotomy is well established, the mechanisms underlying its effectiveness are only now being discovered. The present work contributes substantially to that understanding, he says.
At the 1996 Society for Neuroscience meeting, the Emory team presented data from a study that used PET to compare brain activations related to the speed of movement in normal and parkinsonian subjects. Subjects (11 parkinsonian patients and nine age-matched controls) performed a video game-like task in which they performed smooth, alternating movements with a handheld joystick in order to track the movements of a target presented on a computer monitor. PET scans of the brain were captured while subjects performed tracking at three different speeds of target movement. The three-dimensional images resulting from the PET scans reflected local cerebral blood flow -- an indirect yet reliable measure of local neural activity. Brain areas were identified where there was significant correlation between local blood flow and speed of movement. As predicted by current models, the group observed that brain activity in areas correlated with movement speed in normal subjects (the primary motor cortex, globus pallidus and cerebellum) was abnormally low in parkinsonian patients.
"We were surprised, however, to find a number of other cortical areas strongly related to the speed of movement in the parkinsonian patients but not activated in normal subjects," Dr. Turner says. "These additional areas (including cortical areas involved in motor control on both sides of the brain) might have been activated in an attempt to compensate for the loss of function of the areas normally used. Or, another possibility is that the abnormally enhanced activation seen in some brain areas may actually contribute to one or more of the symptoms of Parkinson's disease."
In the past year, the Emory researchers studied a subgroup of the same parkinsonian subjects again, three months after they received a pallidotomy, and compared those results with the pre-pallidotomy scans. Of the five parkinsonian subjects who received a pallidotomy, four showed clear improvement in their parkinsonian symptoms. In these four, the most obvious effect of pallidotomy was a decrease in the movement speed-related activation of cortical motor areas on both sides of the brain. Most of the cortical areas that had abnormally high activations in the Parkinson's subjects showed significantly reduced activations after pallidotomy. Pallidotomy-related increases in activity were observed in the cerebellum and the thalamus, both areas that were underactivated in the parkinsonian subjects compared to normals. As expected, activations were not seen in the globus pallidus after pallidotomy because of the lesion placed there.
The current study was supported by the Dana Foundation.
THE REORGANIZATION OF MOVEMENT RATE-RELATED CEREBRAL ACTIVATION FOLLOWING PALLIDOTOMY FOR PARKINSON'S DISEASE.
R.S. Turner*, J.M. Hoffman, S.T. Grafton, R.A.E. Bakay, J.L. Vitek and M.R.DeLong. Dept. of Neurology, Emory Univ. Sch. of Med., Atlanta, GA 30322
In Parkinson's disease (PD) patients, regional cerebral blood flow (rCBF) is correlated with the rate of smooth pursuit tracking movements of the arm in a variety of motor control structures that are not modulated with rate in normal controls.* Posteriolateral pallidotomy ameliorates the cardinal symptoms of PD including the slowing of rapidly alternating movements. How does pallidotomy affect the abnormal distribution of rate-related activity observed in PD?
H215O PET activation techniques were used to study 6 unmedicated right-handed PD subjects (to date) before and 3 months after a microelectrode-guided left posterior pallidotomy. During 6 activation scans, subjects moved a joystick held in the right hand to match with a cursor the sinusoidal movement of a visual target at 0.1, 0.4 or 0.7 Hz along a horizontal movement extent of 20 cm. Two control scans required visual tracking of the target alone. Comparisons of mean rCBFs were performed using linear contrasts to detect brain regions with activity related to treatment, movement rate, and the interaction of these two factors (P<0.01).
Four of the 6 PD subjects showed a marked improvement in motor performance after pallidotomy. Following pallidotomy in these subjects, there was a significant reduction and sometimes an inversion of the effect of rate on the rCBF of multiple cortical motor control sites (left hemisph.: M1/S1, SMA, CMA, PMv, and ant. insula, right hemisph.: M1/S1 and PMv). Increases in rate-related modulation following pallidotomy were found only in left VA and VL thalamus and right cerebellum.
Neural reorganization following clinically effective pallidotomy may allow an increased activation of the few areas that are normally modulated with movement rate (thalamus and cerebellum). Secondary to that normalization and the reduced effort required to rapidly modulate muscle activation patterns, fewer additional cortical areas need be recruited to increase the rate and/or velocity of movement after pallidotomy.
*Turner et al, 1996, Soc. Neurosci. Abstr.22:2038. Supported by the Dana Foundation