Opinion
VIEWPOINT
Maxime W. C. Rousseaux, PhD Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; and Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston. Huda Y. Zoghbi, MD Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston; and Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas.
Deep Brain Stimulation for Parkinson Disease The 2014 Lasker-DeBakey Clinical Medical Research Award This year’s Lasker-DeBakey Clinical Medical Research Award honors Mahlon R. DeLong, MD, at Emory University in Atlanta, Georgia, and Alim-Louis Benabid, MD, PhD, at Université Joseph Fourier in Grenoble, France, for their development of deep brain stimulation of the subthalamic nucleus (STN) for patients with advanced Parkinson disease (PD). This surgical technique reduces tremors and restores motor function in patients with PD and allows for lower doses of levodopa, thus reducing its toxic effects. This approach, both effective and reversible through a pacemaker switch, has culminated in the treatment of more than 100 000 patients and is likely the most significant advance in PD-based therapeutics since the discovery of levodopa more than 40 years ago. The neurosurgeon Alim-Louis Benabid discovered that the higher-frequency electrical stimulation, originally used to map anatomical targets in the brain for ablation to eliminate a tremor, in fact mimicked lesioning. In parallel, the neurologist Mahlon R. DeLong demonstrated that the parkinsonian symptoms in the 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model were due to increased neuronal activity in the STN and that lesioning this nucleus alleviated parkinsonian symptoms in this model. Building on DeLong’s results, Benabid began to apply deep brain stimulation to the STN of patients with PD. These combined efforts led to a new and effective therapy that alleviates some parkinsonian motor symptoms, allowing for diminished doses of dopamine in dopamine replacement therapy and a subsequent reduction in its associated complications. The discovery of deep brain stimulation dramatically improved the quality of life for many patients with PD.
DeLong: Drugs, Monkeys, and Neuronal Circuits
Corresponding Author: Huda Y. Zoghbi, MD, Howard Hughes Medical Institute, Baylor College of Medicine, 1250 Moursund St, Ste 1350, Mail Stop NR-1350, Houston, TX 77030 (hzoghbi@bcm .edu). jamaneurology.com
Delong, originally an astrophysics student at Stanford University in Stanford, California, attended medical school at Harvard Medical School in Boston, Massachusetts, where clinical encounters spurred his interest in movement disorders. He pursued further scientific training at the National Institute of Mental Health in Bethesda, Maryland, where he learned to perform single cell recordings in the basal ganglia of behaving primates and associated the resulting neural activity with specific behavioral readouts. A decade of further research led him to propose that the neurons of the basal ganglia belong to multiple parallel but segregated circuits, each of which is specific for a particular region and projects back to one of the cortical areas providing input to the circuit to form a partially closed loop.1 This work had a large impact given
that the prevailing thought at the time was that these nuclei were only involved in movement. Although DeLong did not expect these studies to have any direct clinical impact, the identification of MPTP as a parkinsonism-inducing agent in both humans and nonhuman primates allowed him and others to delve into the pathophysiology of basal ganglia dysfunction. It was generally thought at that time that PD symptoms arose from impaired activity in the globus pallidus, which represents the major output of the basal ganglia motor circuit (Figure). Much to everyone’s surprise, DeLong and colleagues found that, in MPTP-treated monkeys, the tonic neuronal discharges of the internal globus pallidus and the STN that projects to it were actually increased. Conversely, the tonic neuronal discharges of the external segment of the globus pallidus were decreased. These findings are consistent with evidence that loss of striatal dopamine results in increased transmission through the indirect pathway and decreased transmission through the direct pathway. The net result from such altered transmission would be excessive inhibition of the thalamic-cortical pathway, thus explaining some of the “negative” signs of PD, such as akinesia and rigidity (Figure). These findings pinpointed the STN as a key node in the circuit dysfunction underlying the disorder. From here, he reasoned that lesioning the STN should improve MPTP-induced parkinsonism. The DeLong team injected ibotenic acid into the STN of 2 African green monkeys and noted a remarkable finding: within minutes, both monkeys moved their contralateral extremities, purposeful movements ensued, and the tremors disappeared.2 The effect of STN lesions on the tremor was quite unexpected and suggested that this symptom results from basal ganglia circuit dysfunction. Nevertheless, lesioning the STN in humans did not appear to be a reasonable therapeutic approach because of the STN’s small size, and this is where Benabid’s contribution comes into play.
Benabid: High-Frequency Stimulations in the Brain Alim-Louis Benabid, both a neurosurgeon and a physicist, earned his medical degree in 1970 and his physics doctorate in 1978 at Université Joseph Fourier. As a staff neurosurgeon there, Benabid used electrical stimulation during stereotaxic surgery to identify the precise sites for lesioning. For instance, patients with severe, treatment-resistant tremors could be treated via thalamotomy of the thalamic nucleus ventralis intermedius, an irreversible procedure with many possible adverse effects. Benabid noticed that, upon using electrical stimu-
(Reprinted) JAMA Neurology March 2015 Volume 72, Number 3
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 05/19/2015
259
Opinion Viewpoint
Figure. Neural Circuits Affected in Parkinson Disease A Health
B
Parkinson disease after inactivation of STN
Cortex
Cortex
Cortex
Putamen
Putamen
Putamen
SNC
SNC
SNC
GPe
VL thalamus
STN
GPe
VL thalamus
STN GPi
GPe
VL thalamus
STN GPi
GPi
Schematic depicting direct and indirect pathways of the basal ganglia thalamocortical circuit (A), the effect of its disruption in Parkinson disease via loss of substantia nigra pars compacta (SNC) cells (B), and the rectifying effect of inhibiting the subthalamic nucleus using deep brain stimulation (C). The blue arrows represent excitatory connections, and the orange block lines represent inhibitory connections. Line thickness represents strength of neural
connectivity (with thicker lines representing stronger connectivity), and the dashed lines represent disruption of connectivity. GPe indicates external segment of the globus pallidus; GPi, internal segment of the globus pallidus; STN, subthalamic nucleus; and VL, ventrolateral (adapted from Bergman et al2 and Zoghbi3 and published with permission from Elsevier).
lation to locate this thalamic target in the patient, it could halt the tremor even before lesioning. Through a systematic approach, he found that stimulation of the ventralis intermedius nucleus at 100 Hz consistently suppressed tremors.4 A larger scale study of patients with both PD and essential tremor demonstrated a high rate of complete relief from the tremor, reliable safety, and reversibility (in case of mild adverse effects), making thalamic stimulation superior to thalamotomy.5 The next logical step was exploring this approach beyond the thalamus. If lesions of the STN proved to reverse parkinsonism in DeLong’s MPTP-treated monkeys, could bilateral STN stimulation benefit human patients? Indeed, Benabid performed a key study6 that demonstrated the benefits of STN stimulation for 24 patients with advanced PD; 20 of these patients were followed over the course of a year. This approach was remarkably successful, reducing gait difficulties, rigidity, tremor, and akinesia and allowing the dose of dopaminergic medication to be halved. This study6 not only validated DeLong’s predictions that were made almost a decade before but proved the relative safety, reliability, and efficacy of this adjunct therapy for patients with advanced PD. Indeed, longitudinal follow-up of treated patients revealed improved motor function over
5 years, particularly for those who were not receiving dopamine replacement therapy.7
ARTICLE INFORMATION Published Online: January 5, 2015. doi:10.1001/jamaneurol.2014.4109. Conflict of Interest Disclosures: None reported. REFERENCES 1. Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 1986;9:357-381.
260
C
Parkinson disease
Deep Brain Stimulation: Beyond PD Since US Food and Drug Administration approval in 2002, deep brain stimulation is now widely performed, particularly for patients who no longer respond to levodopa. By implanting electrode leads and precisely mapping the stimulation target, together with using a subcutaneous pulse generator, DeLong and Benabid found that patients can get much needed relief. More than 100 000 patients with PD have undergone deep brain stimulation of the STN, and several clinical trials comparing deep brain stimulation in conjunction with medication with medication alone have established that deep brain stimulation significantly improves motor symptoms, functionality, and quality of life. The collective work from these seminal studies—recognized by this award—leaves the neurology, psychiatry, and neurobiology communitieswith2gifts.First,thetransitionfromablationtodeepbrainstimulation has revived functional neurosurgery for several neuropsychiatric disorders. Second, the power of deep brain stimulation lies not only in its use as an effective therapy for altering neurological symptoms but also in its potential to probe neural circuits.
2. Bergman H, Wichmann T, DeLong MR. Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science. 1990;249(4975): 1436-1438.
5. Benabid AL, Pollak P, Gervason C, et al. Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet. 1991;337(8738):403-406.
3. Zoghbi HY. From anatomy to electrophysiology: clinical Lasker goes deep. Cell. 2014;158(6):1225-1229.
6. Limousin P, Krack P, Pollak P, et al. Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med. 1998;339(16):1105-1111.
4. Benabid AL, Pollak P, Louveau A, Henry S, de Rougemont J. Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease. Appl Neurophysiol. 1987;50(1-6):344-346.
7. Krack P, Batir A, Van Blercom N, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med. 2003;349(20):1925-1934.
JAMA Neurology March 2015 Volume 72, Number 3 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 05/19/2015
jamaneurology.com
VIEWPOINT
Maxime W. C. Rousseaux, PhD Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; and Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston. Huda Y. Zoghbi, MD Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston; and Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas.
Deep Brain Stimulation for Parkinson Disease The 2014 Lasker-DeBakey Clinical Medical Research Award This year’s Lasker-DeBakey Clinical Medical Research Award honors Mahlon R. DeLong, MD, at Emory University in Atlanta, Georgia, and Alim-Louis Benabid, MD, PhD, at Université Joseph Fourier in Grenoble, France, for their development of deep brain stimulation of the subthalamic nucleus (STN) for patients with advanced Parkinson disease (PD). This surgical technique reduces tremors and restores motor function in patients with PD and allows for lower doses of levodopa, thus reducing its toxic effects. This approach, both effective and reversible through a pacemaker switch, has culminated in the treatment of more than 100 000 patients and is likely the most significant advance in PD-based therapeutics since the discovery of levodopa more than 40 years ago. The neurosurgeon Alim-Louis Benabid discovered that the higher-frequency electrical stimulation, originally used to map anatomical targets in the brain for ablation to eliminate a tremor, in fact mimicked lesioning. In parallel, the neurologist Mahlon R. DeLong demonstrated that the parkinsonian symptoms in the 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model were due to increased neuronal activity in the STN and that lesioning this nucleus alleviated parkinsonian symptoms in this model. Building on DeLong’s results, Benabid began to apply deep brain stimulation to the STN of patients with PD. These combined efforts led to a new and effective therapy that alleviates some parkinsonian motor symptoms, allowing for diminished doses of dopamine in dopamine replacement therapy and a subsequent reduction in its associated complications. The discovery of deep brain stimulation dramatically improved the quality of life for many patients with PD.
DeLong: Drugs, Monkeys, and Neuronal Circuits
Corresponding Author: Huda Y. Zoghbi, MD, Howard Hughes Medical Institute, Baylor College of Medicine, 1250 Moursund St, Ste 1350, Mail Stop NR-1350, Houston, TX 77030 (hzoghbi@bcm .edu). jamaneurology.com
Delong, originally an astrophysics student at Stanford University in Stanford, California, attended medical school at Harvard Medical School in Boston, Massachusetts, where clinical encounters spurred his interest in movement disorders. He pursued further scientific training at the National Institute of Mental Health in Bethesda, Maryland, where he learned to perform single cell recordings in the basal ganglia of behaving primates and associated the resulting neural activity with specific behavioral readouts. A decade of further research led him to propose that the neurons of the basal ganglia belong to multiple parallel but segregated circuits, each of which is specific for a particular region and projects back to one of the cortical areas providing input to the circuit to form a partially closed loop.1 This work had a large impact given
that the prevailing thought at the time was that these nuclei were only involved in movement. Although DeLong did not expect these studies to have any direct clinical impact, the identification of MPTP as a parkinsonism-inducing agent in both humans and nonhuman primates allowed him and others to delve into the pathophysiology of basal ganglia dysfunction. It was generally thought at that time that PD symptoms arose from impaired activity in the globus pallidus, which represents the major output of the basal ganglia motor circuit (Figure). Much to everyone’s surprise, DeLong and colleagues found that, in MPTP-treated monkeys, the tonic neuronal discharges of the internal globus pallidus and the STN that projects to it were actually increased. Conversely, the tonic neuronal discharges of the external segment of the globus pallidus were decreased. These findings are consistent with evidence that loss of striatal dopamine results in increased transmission through the indirect pathway and decreased transmission through the direct pathway. The net result from such altered transmission would be excessive inhibition of the thalamic-cortical pathway, thus explaining some of the “negative” signs of PD, such as akinesia and rigidity (Figure). These findings pinpointed the STN as a key node in the circuit dysfunction underlying the disorder. From here, he reasoned that lesioning the STN should improve MPTP-induced parkinsonism. The DeLong team injected ibotenic acid into the STN of 2 African green monkeys and noted a remarkable finding: within minutes, both monkeys moved their contralateral extremities, purposeful movements ensued, and the tremors disappeared.2 The effect of STN lesions on the tremor was quite unexpected and suggested that this symptom results from basal ganglia circuit dysfunction. Nevertheless, lesioning the STN in humans did not appear to be a reasonable therapeutic approach because of the STN’s small size, and this is where Benabid’s contribution comes into play.
Benabid: High-Frequency Stimulations in the Brain Alim-Louis Benabid, both a neurosurgeon and a physicist, earned his medical degree in 1970 and his physics doctorate in 1978 at Université Joseph Fourier. As a staff neurosurgeon there, Benabid used electrical stimulation during stereotaxic surgery to identify the precise sites for lesioning. For instance, patients with severe, treatment-resistant tremors could be treated via thalamotomy of the thalamic nucleus ventralis intermedius, an irreversible procedure with many possible adverse effects. Benabid noticed that, upon using electrical stimu-
(Reprinted) JAMA Neurology March 2015 Volume 72, Number 3
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 05/19/2015
259
Opinion Viewpoint
Figure. Neural Circuits Affected in Parkinson Disease A Health
B
Parkinson disease after inactivation of STN
Cortex
Cortex
Cortex
Putamen
Putamen
Putamen
SNC
SNC
SNC
GPe
VL thalamus
STN
GPe
VL thalamus
STN GPi
GPe
VL thalamus
STN GPi
GPi
Schematic depicting direct and indirect pathways of the basal ganglia thalamocortical circuit (A), the effect of its disruption in Parkinson disease via loss of substantia nigra pars compacta (SNC) cells (B), and the rectifying effect of inhibiting the subthalamic nucleus using deep brain stimulation (C). The blue arrows represent excitatory connections, and the orange block lines represent inhibitory connections. Line thickness represents strength of neural
connectivity (with thicker lines representing stronger connectivity), and the dashed lines represent disruption of connectivity. GPe indicates external segment of the globus pallidus; GPi, internal segment of the globus pallidus; STN, subthalamic nucleus; and VL, ventrolateral (adapted from Bergman et al2 and Zoghbi3 and published with permission from Elsevier).
lation to locate this thalamic target in the patient, it could halt the tremor even before lesioning. Through a systematic approach, he found that stimulation of the ventralis intermedius nucleus at 100 Hz consistently suppressed tremors.4 A larger scale study of patients with both PD and essential tremor demonstrated a high rate of complete relief from the tremor, reliable safety, and reversibility (in case of mild adverse effects), making thalamic stimulation superior to thalamotomy.5 The next logical step was exploring this approach beyond the thalamus. If lesions of the STN proved to reverse parkinsonism in DeLong’s MPTP-treated monkeys, could bilateral STN stimulation benefit human patients? Indeed, Benabid performed a key study6 that demonstrated the benefits of STN stimulation for 24 patients with advanced PD; 20 of these patients were followed over the course of a year. This approach was remarkably successful, reducing gait difficulties, rigidity, tremor, and akinesia and allowing the dose of dopaminergic medication to be halved. This study6 not only validated DeLong’s predictions that were made almost a decade before but proved the relative safety, reliability, and efficacy of this adjunct therapy for patients with advanced PD. Indeed, longitudinal follow-up of treated patients revealed improved motor function over
5 years, particularly for those who were not receiving dopamine replacement therapy.7
ARTICLE INFORMATION Published Online: January 5, 2015. doi:10.1001/jamaneurol.2014.4109. Conflict of Interest Disclosures: None reported. REFERENCES 1. Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 1986;9:357-381.
260
C
Parkinson disease
Deep Brain Stimulation: Beyond PD Since US Food and Drug Administration approval in 2002, deep brain stimulation is now widely performed, particularly for patients who no longer respond to levodopa. By implanting electrode leads and precisely mapping the stimulation target, together with using a subcutaneous pulse generator, DeLong and Benabid found that patients can get much needed relief. More than 100 000 patients with PD have undergone deep brain stimulation of the STN, and several clinical trials comparing deep brain stimulation in conjunction with medication with medication alone have established that deep brain stimulation significantly improves motor symptoms, functionality, and quality of life. The collective work from these seminal studies—recognized by this award—leaves the neurology, psychiatry, and neurobiology communitieswith2gifts.First,thetransitionfromablationtodeepbrainstimulation has revived functional neurosurgery for several neuropsychiatric disorders. Second, the power of deep brain stimulation lies not only in its use as an effective therapy for altering neurological symptoms but also in its potential to probe neural circuits.
2. Bergman H, Wichmann T, DeLong MR. Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science. 1990;249(4975): 1436-1438.
5. Benabid AL, Pollak P, Gervason C, et al. Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet. 1991;337(8738):403-406.
3. Zoghbi HY. From anatomy to electrophysiology: clinical Lasker goes deep. Cell. 2014;158(6):1225-1229.
6. Limousin P, Krack P, Pollak P, et al. Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med. 1998;339(16):1105-1111.
4. Benabid AL, Pollak P, Louveau A, Henry S, de Rougemont J. Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease. Appl Neurophysiol. 1987;50(1-6):344-346.
7. Krack P, Batir A, Van Blercom N, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med. 2003;349(20):1925-1934.
JAMA Neurology March 2015 Volume 72, Number 3 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 05/19/2015
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