STN Deep Brain Stimulation and Neuroprotection
Director: Caryl E. Sortwell, Ph.D.
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become the most often practiced neurosurgery for treatment of the cardinal motor features of Parkinson’s disease (PD), specifically bradykinesia, rigidity and resting tremor.
Despite the symptomatic efficacy of DBS, our understanding of its impact on ongoing nigral degeneration remains limited. This is in part due to the fact that STN DBS is currently practiced as a treatment of last resort in late stage PD when the overwhelming majority of substantia nigra pars compacta (SNc) degeneration has already occurred. In recent years interest in whether STN DBS should be applied to early PD as well as its neuroprotective potential has escalated. The increased focus on early DBS and its possible disease-modifying effects illustrate the significance of preclinical studies aimed at investigating these phenomena.
In our laboratory, we have developed a rodent model of STN DBS that incorporates the following features:
- STN DBS initiated at a time when the denervation status of the nigrostriatal system was known to be partial and progressing
- Current spread minimized and optimized to closely approximate the clinical situation
- STN DBS that occurred over long (two-week) intervals
- STN DBS that includes the critical control conditions as well as post mortem verification of the stimulator placement target
- STN stimulation parameters that provide functional improvements in the parkinsonian motor behaviors induced by dopamine denervation
Our rat model of functionally-relevant long term STN DBS provides a useful preclinical experimental platform in which to conduct these studies.
|Long Term STN-DBS Platform. A. Schematic of an individual stimulation setup, including an Accupulser Signal Generator (World Precision Instruments, WPI) connected to a Constant Current Bipolar Stimulus Isolator (WPI) that is connected to the concentric bipolar stimulating electrode implanted into the rat STN and secured using dental cement and bone screws. The rat is housed in a Raturn System Bowl (BioAnalytical Systems, Inc., BASi). The stimulator cable is routed through a commutator to allow the rat to move freely during the two week stimulation interval. B. Photograph of an individual rat undergoing STN-DBS during the two week stimulation interval.|
|Long term STN DBS reverses 6-OHDA induced deficits in forepaw akinesia. Rats were videotaped and analyzed for the number of spontaneous number of weight bearing forepaw placements on the cylinder wall (red plus = unlesioned paw, green plus = lesioned paw) prelesion, 2 weeks following intrastriatal 6-OHDA, during STN DBS and 24 hours after the cessation of stimulation. STN DBS was associated with increased use of the lesioned forepaw (green plus) compared to rats that received no stimulation. Twenty-four hours after cessation of stimulation, stimulation-associated improvement was no longer apparent.|
Spieles-Engemann AL, Collier TJ, Sortwell CE (2010) A functionally relevant and long term model of deep brain stimulation of the rat subthalamic nucleus: Advantages and considerations. Eur J Neurosci 32:1092-1099. PMID: 21039948
We have used our rat model of long-term STN DBS to investigate the following questions:1. Is STN DBS neuroprotective following significant nigrostriatal degeneration?Studies in rats and monkeys indicate that STN DBS significantly protects SNc dopamine (DA) neurons from degeneration induced by dopaminergic neurotoxins. However, what was not known is whether STN DBS can halt ongoing SNc DA neuron loss after significant degeneration had already occurred, analogous to the degree of nigral DA neuron loss in PD patients at the time of diagnosis. To examine the neuroprotective potential of STN DBS after nigrostriatal degeneration we first characterized the time course and magnitude of nigral DA neuron following unilateral intrastriatal 6-hydroxydopamine (6-OHDA) injection in rats. Our lesion parameters resulted in a loss of 46% tyrosine hydroxylase immunoreactive (THir) neurons at two weeks, progressing further to 75% THir nigral neuron loss at four weeks. Using this identical lesion paradigm, rats were assigned to receive active STN DBS between weeks two and four or no stimulation. We observed significantly more THir neurons in the SNc of rats receiving active stimulation compared to the number of THir neurons in both the inactive stimulator control animals and animals who received stimulation but stimulators were found to be located outside the STN. In summary, these data suggest that STN-DBS can halt ongoing nigral degeneration in the face of previous large-scale dopamine neuron loss. This effect is not due to inadvertent lesioning of the STN and is dependent upon proper electrode placement. The suggestion that STN-DBS has neuroprotective properties would indicate that this therapy should be offered to PD patients in early and moderate stages of the disease. Our present results strongly suggest a need for a clinical trial to investigate whether STN-DBS can modify the progression of PD. Ongoing studies are currently examining the long term impact of STN DBS on nigrostriatal patency and motor function after 6-OHDA. Additional studies are investigating whether stimulation of the internal globus pallidus, another structure targeted in DBS for PD, has neuroprotective potential. Future studies will explore whether STN DBS can provide neuroprotection against alpha-synuclein mediated toxicity.
|Time Course and Magnitude of Nigrostriatal Degeneration Following Intrastriatal 6-OHDA. Micrographs of tyrosine hydroxylase immunoreactive (THir) neurons in the SNc and THir terminals in the striatum at 2 (A), 4 (B) and 6 (C) weeks after unilateral intrastriatal 6-OHDA (left). Progressive degeneration of nigral THir neurons is illustrated by comparing nigral the number of THir neurons evident in the left hemisphere with the normal complement of THir nigral neurons in the contralateral mesencephalon.|
|Continuous Long Term STN DBS Halts Ongoing Nigral DA Neuron Degeneration. Representative micrographs of THir neurons four weeks after 6-OHDA. Note higher magnification or neurons from the area of the SN pars lateralis delineated by the black box. Rats received unilateral intrastriatal injections of 6-OHDA and stimulation was initiated 2 weeks later (corresponding to 50% nigral DA neuron loss) and continued for a period of 2 weeks (normally associated with significant nigral degeneration to 70% loss). A, D. STN DBS; B, E. No Stimulation; C, F. Misplaced Stimulation Note the presence of more THir nigral neurons (A,D) in rats that received two weeks of STN-DBS appropriately located in the STN whereas rats receiving no stimulation (B, E) or stimulation outside of the STN (C, F) display fewer surviving THir neurons. STN DBS completely halted the progression of nigral DA neuron degeneration normally observed between two and four weeks after 6-OHDA. Scale bar in A = 500 µM, scale bar in D = 50 µM.|
Spieles-Engemann AL, Behbehani MM, Collier TJ, Wohlgenant SL, Steece-Collier K, Paumier K, Daley BF, Gombash S, Madhavan L, Mandybur GT, Lipton JW, Terpstra BT, Sortwell CE (2010) Stimulation of the rat subthalamic nucleus is neuroprotective following significant nigral dopamine neuron loss. Neurobiol Dis 39(1):105-15. PMID: 203076682. What impact does STN DBS have on the trophic environment of the brain? How does STN DBS impact brain derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF)?Growing preclinical and clinical evidence suggests that STN HFS drives and synchronizes the STN instead of inhibiting it. Therefore, it is unlikely that decreased excitotoxicity is involved in STN HFS-mediated neuroprotection. Given that trophic factors promote neuron survival we examined whether functionally effective, long-term STN DBS modulates GDNF and/or BDNF in both unlesioned and unilateral 6-hydroxydopamine lesioned rats. Lesioned rats that received two weeks of continuous unilateral STN DBS exhibited significant improvements in parkinsonian motor behaviors. Unilateral STN DBS did not increase GDNF in the nigrostriatal system, primary motor cortex (M1), or hippocampus of unlesioned rats. In contrast, unilateral STN DBS increased BDNF protein 2-3 fold bilaterally in the nigrostriatal system with the location (substantia nigra vs. striatum) dependent upon lesion status. Further, BDNF protein was bilaterally increased in M1 cortex by as much as 2 fold regardless of lesion status. STN DBS did not impact cortical regions that receive less input from the STN. STN DBS also was associated with bilateral increases in BDNF mRNA in the substantia nigra (SN) and internal globus pallidus (GPi). The increase observed in GPi was completely blocked by pretreatment with 5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), suggesting that the activation of N-methyl-D-aspartate (NMDA) receptors was involved in this phenomenon. The upregulation of BDNF associated with long term STN DBS suggest that this therapy may exert pronounced and underappreciated effects on plasticity in the basal ganglia circuitry that may play a role in the symptomatic effects of this therapy as well as support the neuroprotective effect of stimulation documented in this rat model. Ongoing studies using Low Density PCR Based Arrays will examine whether the expression of additional trophic factors is altered in response to STN DBS. Future studies will examine whether blockade of BDNF upregulation attenuates STN DBS mediated neuroprotection.
Spieles-Engemann AL, Steece-Collier K, Behbehani MM, Collier TJ, Wohlgenant SL, Kemp CJ, Cole-Strauss A, Levine ND, Gombash SE, Thompson VB, Lipton JW, Sortwell CE (2011) Subthalamic nucleus stimulation increases brain derived neurotrophic factor in the nigrostriatal system and primary motor cortex. J Parkinsons Dis 1(1):123-136. PMID 22328911
3. Does STN DBS provide neuroprotection for the aged nigrostriatal system? Does STN DBS in the aged brain upregulate BDNF expression?
In future experiments we will examine the impact of STN DBS on the aged nigrostriatal system and test the hypothesis that STN DBS will provide little to no neuroprotection in the aged brain. We speculate that STN DBS may not be neuroprotective due to limited trophic plasticity of the aged brain. The proposed studies will determine whether STN DBS can slow the progression of DA neuron degeneration and whether this outcome is compromised by advancing age. The results of these studies will provide insight into the optimal therapeutic timing for intervention with STN DBS in PD patients.
Udall Projects & Services
Director: Kathy Steece-Collier, Ph.D.
Director: Caryl E. Sortwell, Ph.D.
Director: Jack W. Lipton, Ph.D.
Director: Timothy J. Collier, Ph.D
Director: Fredric P. Manfredsson, Ph.D.
Director: Timothy J. Collier, Ph.D