Q: You’ve spent much of your long career studying the basal ganglia (BG). Why has this cluster of brain structures captured your attention, and how has scientific understanding of the basal ganglia progressed in recent years?
DeLong: The brain structures that comprise the basal ganglia—the putamen, caudate nucleus, globus pallidus, substantia nigra, and subthalamic nucleus—have long been an enigma to researchers, and they remain so. Even today, with all of the sophisticated methods we have for studying the anatomy and physiology of the brain, we have much yet to learn about what role these structures play in normal brain function. In fact, we have more information about how the basal ganglia contribute to movement disorders than about what they do in the normal brain.
That said, our understanding of the basal ganglia has progressed significantly in recent years, driven by a number of major research advances that have elucidated their anatomic organization and their functional significance both to normal motor function and to a spectrum of movement and neuropsychiatric disorders. These findings come from anatomical studies and recordings of neural firing patterns in animal models of disease (especially the primate model of Parkinson’s disease); from functional brain imaging studies of patients and animal models; from observations seen in the operating room during neurosurgical procedures on patients; and from physiologic studies that map the rates, patterns, and frequencies of nerve signals both within the BG and between the BG and interconnected brain regions, especially the cortex and thalamus.
Q: What have we learned about the basal ganglia’s role in motor control as a result of this ongoing research?
A: From this growing body of research has evolved an ever-clearer picture of the brain’s “motor circuit.” As my colleagues and I first proposed a decade ago, the BG are not merely “funnels” that relay information from the cortex to the thalamus. Rather, the structures of the BG form parallel segregated pathways for neural signals traveling to and from the cortex, essentially forming a loop that both feeds information to and receives information from the cortex. In fact, virtually every part of the cortex projects to some piece of the basal ganglia.
One can, therefore, think of the basal ganglia as key components of circuits, with the cortex and thalamus at either ends. Nerve signals traversing this circuit originate in the motor and sensory fields of the cortex, located in the pre- and post-central gyri of the frontal cerebral cortex—an area long known to be crucial for normal movement and somatosensory processing. (This area is often depicted in brain illustrations as distorted maps of the body that represent the neural real estate devoted to motor and somatosensory functions of each body part.) From this cortical starting gate, nerve signals travel to the putamen, where they activate striatal output neurons. The signals then take one of two routes on their journey to the thalamus: an indirect route that circuits through the rear parts of the striatum, the external pallidum and subthalamic nucleus, then on to the internal pallidum; or a more direct route to the internal pallidum that bypasses the first two stops. Once signals reach the thalamus, they project back to the cortex. Thus, the thalamocortical circuit consists not of a single loop, but of a series of subcircuits. Importantly, the output signals from the BG are inhibitory—meaning they quell, rather than activate, neural firing in their target neurons— giving the BG a powerful inhibitory drive. This fact has been critical to applying therapeutic approaches to the treatment of motor disorders.
Q: How have these understandings about the basal ganglia contributed to new therapies for people with movement disorders?
A: The study of motor circuits in the brain, particularly in the basal ganglia, is a good example of how fundamental basic science contributes to our understanding and treatment of neurodegenerative diseases. Over the past decade there has been a renaissance in neurosurgical approaches to the treatment of movement disorders such as Parkinson’s disease. In general, it appears that many movement disorders, including Parkinson’s, Huntington’s, dystonia and Tourette’s syndrome, result from disturbances in specific circuits that connect the cerebral cortex, basal ganglia and thalamus—in other words, they can be viewed as “circuit disorders.” In Parkinson’s disease, for example, physiologic studies in primate models and functional neuroimaging studies in patients have revealed distinctive widespread alterations in the activity of neurons in this motor circuit, including changes in the rate of neuronal discharge, changes in the pattern of discharge, such as signal “bursts” or abnormally synchronous nerve firing, and signal oscillations in low-frequency ranges (i.e., beta waves vs. the usual gamma waves). Together, these changes disrupt information processing in the motor circuit and result in the clinical features of Parkinson’s.
The study of motor circuits in the brain...is a good example of how basic science contributes to our understanding and treatment of neurodegenerative diseases.
Interrupting the motor circuit at the level of the subthalamic nucleus or the internal pallidum by surgical ablation can dramatically reduce the abnormal motor disturbances. But ablative surgery has significant drawbacks: it is non-modifiable; it carries a risk of functional loss as well as permanent complications in movement or vision, and it may interfere with or render future treatments less effective.
Deep Brain Stimulation (DBS), a therapy that applies chronic high-frequency stimulation to the same subcortical structures that have been the targets of surgical ablative approaches, can also ameliorate the abnormal movements associated with Parkinson’s and other movement disorders. DBS, however, has the advantage of being less invasive and destructive, and of being adjustable and reversible. Although DBS was initially believed to block the activity of neurons at the site of stimulation, it now appears that it acts by stimulating axons and replacing the abnormal basal ganglia output with a more tolerable pattern of nerve signaling.
Q: Deep Brain Stimulation has been most widely applied to Parkinson’s disease, but is being increasingly applied to other neurologic disorders as well. What are the prospects for wider application of DBS?
A: The success in treating Parkinson’s with DBS has led to successful treatment of other disorders, most notably dystonia, a devastating disorder of abnormal sustained muscle contractions. Unlike Parkinson’s, no neuronal degeneration occurs in dystonia; instead, the disorder appears to result from abnormal neuronal plasticity. Both surgical ablation and DBS are highly effective treatments for dystonia, but, in contrast to DBS for Parkinson’s, it may take weeks to months for dystonia patients to realize the maximal benefit. This suggests that the mechanism of action of these procedures in dystonia is a slow “re-tuning” of the neuronal circuits.
Recently, DBS has also been employed with some success as treatment for Tourette’s syndrome and obsessive compulsive disorder, and is also being studied as a therapy for depression and epilepsy. While more work is needed to better define the optimal protocols for these conditions and to show concrete, consistent benefits, in my view DBS remains one of the most promising and intriguing approaches for the treatment of the major movement and other neurologic disorders.