TREATMENT FOR PARKINSON'S MAY BE EXTENDED TO OTHER BRAIN DISORDERS
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TREATMENT FOR PARKINSON'S MAY BE EXTENDED TO OTHER BRAIN DISORDERS.
ORLANDO, Tuesday, Nov. 5 - The use of "deep brain stimulation" has steadily increased for the surgical treatment of Parkinson's disease and tremor since its approval a few years ago by the Food and Drug Administration. It is now likely to be extended to other disorders, researchers say.
Deep brain stimulation (DBS) involves the introduction of electrodes into the brain through which small electrical currents are delivered in a way similar to how an implanted cardiac pacemaker controls the heartbeat.
"Indeed, the next few years are likely to see its application to various other neurological diseases from epilepsy to eating disorders," says Robert Gross, MD, PhD, of the Emory University School of Medicine and organizer of a symposium on the mechanisms of DBS at the 32nd annual meeting of the Society for Neuroscience.
DBS was developed to replace the surgical destruction of a small region of the thalamus, as stimulation was found to be as effective and without as many side effects. Subsequently, DBS has been applied to the globus pallidus and the subthalamic nucleus for the treatment of Parkinson's disease, on the presumption that DBS effects would mimic the effects of destructive surgery, and indeed clinical results support this presumption.
While these observations support the notion that DBS acts in a fashion similar to destructive surgery - by blocking or inhibiting the brain region being "stimulated" - in fact little is currently known about the true mechanisms by which DBS affects the brain.
Current thinking centers on the possibility that DBS (1) inhibits or activates the cell bodies of nerve cells themselves, at their cell bodies; (2) inhibits or activates the axonal processes from these neurons on their way to their target regions; and (3) inhibits or activates the afferent processes that "synapse" on these neurons.
In an effort to determine which of these mechanisms may play a role in the robust clinical effects observed, various investigators have been studying the response to DBS of (1) the "stimulated" regions themselves (i.e. thalamus, globus pallidus, and/or subthalamic nucleus), and (2) the target structures to which these stimulated regions project (i.e. cortex, thalamus, and globus pallidus, respectively).
The response to DBS is measured in a number of ways. In the studies presented at this symposium, the responses are measured by analyzing the "firing" rate and pattern of the stimulated and target structures, as well as the synthesis and release of neurotransmitters in the same structures. In addition, computers are used to model the effects of electrical stimulation on the various neural elements.
The results of the types of studies discussed in this symposium should result in an increased understanding of how DBS affects the brain. "This will allow engineers, biomedical scientists and clinicians to refine and advance the technology of DBS as it applies to the treatment of human neurological diseases, and - we hope - lead to improved quality of life for patients suffering from Parkinson's disease, as well as a plethora of other conditions from seizures to strokes," says Gross.
In recent studies during the past few years, a group led by Jonathan Dostrovsky, PhD, at the University of Toronto has shown for the first time that high frequency electrical stimulation in the human brain inhibits the firing of many of the brain cells in the vicinity of the stimulation electrode.
This depression of neuronal firing may be one of the mechanisms involved in producing the therapeutic benefits of DBS. These findings resulted from the development of an experimental technique that allows scientists to directly see the effects of electrical stimulation on the brain cells.
Prior to implanting the DBS electrode, Dostrovsky's team first uses a very fine tipped electrode to record the signals produced by the brain cells in order to find the appropriate target site for DBS electrode placement. However, in order to examine the effects of electrical stimulation on the nerve cells in the brain the group introduces a second electrode at a small distance from the recording electrode and delivers small current pulses at low and high frequency. Currently DBS electrodes are implanted in three regions of the brain - the globus pallidus, the subthalamic nucleus and the thalamus, and in all three regions it is found necessary to use continuous high frequency stimulation to produce good therapeutic effects.
In Dostrovsky's studies of low frequency and high frequency stimulation in all three regions, the most pronounced effects are found in the globus pallidus where both low frequency and high frequency stimulation are very effective in producing inhibition of neuronal firing. High frequency stimulation produces almost complete inhibition of firing. In the subthalamic nucleus low frequency stimulation is ineffective but high frequency stimulation inhibits the firing of many of the nerve cells. In the thalamus, low frequency stimulation sometimes excites the cells but high frequency stimulation inhibits many of the cells for a prolonged duration.
"Thus, these studies indicate that high frequency stimulation of the type used clinically for DBS inhibits the firing of many of the brain cells in the vicinity of the stimulation electrode, and suggest that this may be one of the mechanisms underlying its therapeutic effect," says Dostrovsky.
"Further studies are needed to determine whether the inhibitory effects persist with prolonged stimulation and to examine to what extent other mechanisms, such as direct excitation of the axons projecting out of the region stimulated may also be responsible for mediating the clinical effects of DBS. Such findings will lead to a better understanding of how and why the clinical benefits occur and should lead to improvements in the therapeutic technique and perhaps its application to the treatment of other brain disorders."
Jerrold Vitek, MD, PhD, also of Emory, notes that the comparable effect of stimulation to surgery in the thalamus on tremor, and in the subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) on the motor signs associated with Parkinson's disease, have led many researchers to conclude that DBS acts to suppress neuronal activity, decreasing output from the stimulated site.
Contrary to what one would expect if stimulation inhibits output from the stimulated structure, however, stimulation in the external segment of the globus pallidus (GPe) in humans, a site where lesions has been demonstrated in monkeys to worsen bradykinesia, has been demonstrated to improve bradykinesia. Thus, the effects of stimulation in deep brain structures do not always mirror that of lesions and may in fact produce opposite motor effects.
To further understand the mechanism underlying the effect of stimulation in deep brain structures, Vitek examined the effect of stimulation in the subthalamic nucleus on neuronal activity in GPi and correlated this with the effect of stimulation on bradykinesia and rigidity in an animal model of Parkinson's disease. During stimulation in the STN, coincident with improvement in bradykinesia and rigidity, the average firing rate of GPi neurons was significantly increased. In addition, the firing pattern of GPi neurons changed from an irregular bursting pattern to one that was more regular.
"These results suggest that activation of the STN efferent fibers and resultant changes in the temporal firing pattern of neurons in GPi underlie the beneficial effect of high frequency stimulation in the STN in Parkinson's disease," says Vitek.
The observation of improvement in the slowness of movement (bradykinesia) and rigidity in light of a further increase in mean discharge rate of GPi neurons supports a shift in our thinking from rate to pattern related changes in neuronal activity as a mechanism underlying the development of parkinsonian motor signs. Although arguments for increased output from the stimulated structure seem to conflict with the hypothesis that stimulation acts to inhibit neuronal activity, it is possible to explain these observations through a common mechanism - activation of fiber pathways.
Based on this mechanism, the effect of stimulation on cellular activity in the stimulated site would be increased or decreased dependent on the neurotransmitter of the afferent fibers projecting to that site, but the output of the stimulated structure would be increased due to activation of projection axons from neurons in the stimulated structure. These axons would also be activated and discharge independently of the soma, thereby increasing output from the structure during extracellular stimulation.
Thus, although high frequency stimulation may inhibit neurons at the site of stimulation via activation of inhibitory afferents, the output from that structure may be increased as the result of activation of axonal elements leaving the target structure. This hypothesis would explain the present experimental results, is consistent with excitability profiles of neuronal elements based on their biophysical properties, and fits with more recent models emphasizing the role of altered patterns of neuronal activity in the development of Parkinson's disease and other movement disorders.
Marc Savasta, PhD, of France's National Institute of Health and Medical Research and Hospital University of Grenoble, notes that one debate concerns the mechanisms by which DBS of the subthalamic nucleus (STN) provokes inhibition. Several theories attempt to explain this phenomenon.
In a recent study, Savasta used an in vivo functional approach in rats, by combining the techniques of electrical deep brain stimulation and intracerebral microdialysis (in which minute quantities of fluid are withdrawn from the brain and analyzed). The goal was to identify the neurochemical changes induced by STN-DBS in the related nuclei of the basal ganglia such as the globus pallidus, a section of the substantia nigra and striatum.
Savasta's team had previously reported that STN-DBS induces, in intact rats, an increase of the neurotransmitter glutamate in the globus pallidus and substantia nigra and a selective increase of the neurotransmitter GABA in the substantia nigra. The researchers have carried on this study by investigating whether such changes could also be detected in rats bearing a destruction of the dopamine nigral cell population, an animal model of Parkinson's disease. The results obtained in such rats reveal that: 1) basal values of glutamate, both in the globus pallidus and substantia nigra, are higher than in intact controls, consistent with the view that dopamine depletion leads to hyperactivity of the STN; 2) glutamate in both the globus pallidus and substantia nigra is not affected by STN-DBS but remains at the high baseline levels; 3) interestingly, as in intact rats, STN-DBS induces an increase of GABA in the substantia nigra but not in the globus pallidus.
Another aim of Savasta's work, was to investigate the role of the globus pallidus in mediating the stimulation-induced increase in GABA in the substantia nigra. His team examined the effects of STN-DBS in rats bearing a globus pallidus lesion or in combination with total dopamine denervation. In rats with the globus pallidus lesion: 1) basal levels of glutamate in the substantia nigra were not significantly different from those detected in intact rats whereas GABA levels were dramatically decreased; 2) STN-DBS still increased glutamate levels in the substantia nigra.
In double lesioned animals, Savasta observed that: 1) the basal value of glutamate in the substantia nigra was higher than in intact rats but lower than in hemiparkinsonian rats and that 2) STN-DBS did not affect glutamate or GABA in the substantia nigra.
"All these results suggest that STN-DBS interferes with GABA in basal ganglia output structures and could provide a mechanism for normalizing their excessive activity in parkinsonism which may contribute to the therapeutic efficacy of STN-DBS," says Savasta.
His team previously reported that DBS induces a significant increase of striatal dopamine in the striatum in normal and partially dopamine denervated rats. In experimental rats, STN-DBS induces a significant increase of striatal glutamate and GABA. However, the increase in hemiparkisonian rats was much higher than in normal animals. These observations suggest that striatal amino acids could be modulated directly or indirectly by STN-DBS through the nigro-striatal dopamine pathway.
Better understanding of the neurochemistry will provide insight into the complex interactions within the basal ganglia network during DBS-STN suggesting functional alternatives which might elucidate the mechanisms underlying the effectiveness of this new therapeutic in Parkinsonian patients. In addition, the outcomes of these neurochemical studies related to DBS could lead to the development of new surgical targets in movement disorders or in other neurological diseases such as epilepsy and of new, less invasive, therapies.
In other work, Warren Grill, PhD, of the department of bioengineering at Case Western Reserve University notes that implanted DBS electrodes are surrounded by a diversity of neural elements including local cells, fibers of passage, and presynaptic terminals. In addition, previous studies indicate that different neural elements respond at similar stimulation thresholds. This lack of selectivity of the neural response complicates the understanding of the mechanisms of action of DBS, and limits our ability to maximally exploit DBS for therapy.
Grill's computer-based modeling of the electric fields generated in the brain by DBS and the neuronal elements affected by DBS provides a tractable method to determine what neural elements are activated by DBS and a tool to design methods to activate selectively different neuronal elements. Grill is the inventor on a pending patent, assigned to Case Western Reserve University, which protects intellectual property of novel stimulus pulses discussed in his presentation.
Computational models of extracellular stimulation of CNS neurons show that DBS has varied effects on local neurons dependent on the distance between the electrode and the neuron and the stimulus parameters. These results enable the refutation of several proposed mechanisms of DBS, and support changes in network synchronization as a key factor in the clinical effectiveness of DBS. Further, computer-based modeling has been used in the design of novel stimulation waveform that enable selective stimulation of different neuronal elements around the electrode. These waveforms enable the responsive neural elements could be controlled selectively, and their differential effects may be used to expand the applications of DBS and minimize undesirable side effects.
"The outcomes of this research are an understanding of what neuronal elements are affected by DBS and novel methods to activate selectively targeted populations of neuronal elements," says Grill. "These developments will enable us to define the populations of neurons that produce desired and undesired effects during DBS, and to specify the next generation of implantable electrodes and stimulators. Collectively, these results will improve the efficacy and expand the range of applications for deep brain stimulation."
