The 1960s broke open a new treatment for PD and largely dismissed the surgical era. Scientists established that the malady arises from insufficient quantities of the neurotransmitter dopamine in an area of the brain that controls movement, the basal ganglia. By the end of the decade, the late George Cotzias (Lasker Clinical Medical Research Award, 1969) had reported dramatic improvements in PD patients who received a carefully tuned regimen of oral L-dopa, the metabolic precursor of dopamine. The medication honeymoon, however, can wear off. After long-term administration, the drug induces severe involuntary movements in some individuals. Only small windows of the day remain in which patients experience neither PD symptoms nor these disturbing effects.
When DeLong began his research, in the late 1960s, the basal ganglia had been implicated in movement, particularly because defects there were associated with illnesses such as PD in which motor disturbances feature prominently. Little was known, however, about how exactly the basal ganglia contribute to movement. To find out, DeLong inserted microelectrodes into monkeys’ brains and measured the activity of specific neurons in the basal ganglia while the animals performed trained actions. He thus matched neurons with tasks; some influenced, for instance, the direction, size, or speed of arm, leg, or facial movements. In this way, he mapped out the organization of the so-called motor circuit.
Based on his own work and that of others as well as existing anatomical information, DeLong proposed a model in which basal ganglia neurons operate in separate circuits. Multiple pathways originate from distinct centers in the cerebral cortex, run through the basal ganglia, and wind up back where they started; the circuits work alongside one another and allow parallel processing of emotions, thoughts, and motor functions.
This work provided insights into the well-established observation that cognitive and emotional problems accompany many motor disorders that stem from basal ganglia failings. Furthermore, the findings supplied a new framework for exploring how basal ganglia components malfunction in various illnesses, including PD. Although dopamine loss clearly causes the disease’s motor perturbations, the associated changes in basal ganglia activities were unclear. DeLong’s model — which included detailed maps of stimulatory and inhibitory signals through the basal ganglia — offered ideas. For example, the final stop in the motor circuit of the basal ganglia is a structure that sends restraining orders onward, thereby suppressing other parts of the motor system. Anything that causes superfluous activity at that site might generate the symptoms that characterize PD.
From addicts to insights
In the early 1980s, sporadic outbreaks of a syndrome that mimics PD started occurring among drug addicts, and scientists traced it to a chemical, MPTP, that was contaminating some batches of “synthetic heroin.” Administration of the compound to monkeys reproduced the key clinical and pathological features of PD, and thus offered a powerful new tool for studying the illness.
DeLong seized upon the opportunity. A part of the basal ganglia called the subthalamic nucleus drives the inhibitory output signal, and in 1987, DeLong reported that MPTP triggers neurons in the subthalamic nucleus of monkeys to fire excessively. Perhaps, DeLong reasoned, the overexuberant signals quash motor activity in PD. If so, inactivating the subthalamic nucleus might ameliorate some of the illness’s worst symptoms.
Next, he did an experiment that would transform PD treatment. He administered MPTP to two monkeys; as usual, they gradually slowed down until they sat motionless, their muscles stiffened, and they developed tremors. DeLong then injected a second toxic chemical that inactivated the subthalamic nucleus. Within one minute, the animals began to move. Gradually, their muscles loosened and the tremors ceased. These findings strongly supported the hypothesis that hyperactivity in the subthalamic nucleus underlies PD symptoms.
High frequency, high hopes
Across the Atlantic, Benabid had also been tackling neurological disorders, and he was frustrated. In a throwback to the pre-L-dopa era, the trickiest patients — those who did poorly with long-term pharmaceutical treatment — would wind up in the operating room. Benabid craved a new tool — something safer that would quiet the most disabling symptoms of PD.
One day in 1987, he was about to create a lesion in a person with essential tremor, a condition that causes trembling in various parts of the body. He was targeting a component of the thalamus that contributes to tremors. As usual, the patient was awake so Benabid could test whether he had located the right tissue; he inserted a probe into the spot that he intended to lesion and sent an electrical pulse to ensure that perturbing this site did not generate undesired effects.
Usually he delivered 50 Hz, but he decided to find out what would happen if he increased the frequency. Just below 100 Hz, something unexpected occurred: The tremor stopped. The patient became so still, Benabid thought that he had caused unintended muscle contraction. He switched off the stimulation and apologized for his mistake. The patient told him not to apologize, as it was the first time in many years that his hand hadn’t shaken.
Benabid repeated the procedure, with the same outcome. Furthermore, when he withdrew the current, the tremor recurred. The effect, therefore, was reversible.
Benabid realized he was onto something exciting. Deep brain stimulation had been used for more than two decades to treat pain, but no one had dialed up the frequency. Later that year, he tried the same approach for PD patients. In addition, he implanted a device that was on the market for pain relief and delivers constant stimulation. Some of the individuals benefited from the procedure, and no complications occurred.
In 1991, Benabid reported that high-frequency stimulation could be deployed bilaterally in people with essential tremor and PD; this strategy reduced tremor on both sides of the body. The gains were long lasting, and adverse effects were mild; furthermore, any undesired outcomes could be reversed by reducing stimulation.
Although the technique quelled tremors, Benabid knew that this symptom was not the one that most debilitated people with PD. Perhaps high-frequency stimulation of brain areas other than the thalamus (i.e., the subthalamic nucleus) would alleviate the more troublesome aspects of the illness such as slowness of movement and rigidity, he reasoned.
In this state of mind, Benabid read DeLong’s report that damage to the subthalamic nucleus wipes out multiple symptoms of PD in animals. This site was not an attractive target: Lesioning procedures and spontaneous lesions had established decades earlier that, when things went wrong, violent flailing could result. By that time, however, Benabid had performed high-frequency stimulation of the thalamus and other brain regions’ in more than 150 patients. He was confident that he would cause no harm in the subthalamic nucleus; if necessary, he could remove the electrode.
In 1995, Benabid reported results from the first humans who received bilateral, high-frequency stimulation of the subthalamic nucleus — three people with severe PD. The treatment suppressed slowness of movement and muscle rigidity.
Eight years later, he confirmed and extended these results in a study of individuals who had undergone the procedure five years earlier. The surgery restored motor skills, suppressed tremor, and improved the ability to conduct normal activities of daily living. Furthermore, people were able to slash their dosage of L-dopa and related medications, which reduced associated complications.
In 2002, the US Food and Drug Administration (FDA) approved high-frequency stimulation of the subthalamic nucleus for treating advanced Parkinson’s disease. The method is not a cure, and it does not reverse all aspects of the malady. In particular, speech and cognition continue to decline.
Many questions remain about the mechanism of this intervention. It might jam or replace inappropriate circuit activity. Regardless how it works, surgeons are using high-frequency deep brain stimulation to combat an ever-growing number of sites and diseases: essential tremor, dystonia — a condition of involuntary muscle contractions — and even psychiatric illnesses. The FDA approved its use for obsessive-compulsive disorder in 2009, and scientists are investigating applications for drug-resistant depression and Tourette syndrome.
Through their open-minded explorations and willingness to challenge dogma, Benabid and DeLong have delivered extraordinary medical innovations to humankind. By reaching deep into the brain, they have soothed some of the most troubling conditions that corrupt it.
by Evelyn Strauss
Key publications of Alim Louis Benabid
Benabid, A.L., Pollak, P., Louveau, A., Henry, S., and de Rougemont, J. (1987). Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease. Appl. Neurophysiol. 50, 344-346.
Benabid, A.L., Pollak, P., Gervason, C., Hoffmann, D., Gao, D., Hommel, M., Perret, J.E., and de Rougemont, J. (1991). Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet. 337, 403-406.
Limousin, P., Pollak, P., Benazzouz, A., Hoffmann, D., Le Bas, J.F., Broussole, E., Perret, J.E., and Benabid, A.L. (1995). Effect on parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet. 345, 91-95.
Limousin, P., Krack, P., Pollak, P., Benazzouz, A., Ardouin, C., Hoffmann, D., and Benabid, A.L. (1998). Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N. Engl. J. Med. 339, 1105-1111.
Krack, P., Batir, A., Van Blercom, N., Chabardes, S., Fraix, V., Ardouin, C., Koudsie, A., Dowsey-Limousin, P., Benazzouz, A., Le Bas, J.F., Benabid, A.L., and Pollak, P. (2003). Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N. Engl. J. Med. 349, 1925-1934.
Mallet, L., Polosan, M., Jaafari, N., Baup, N., Welter, M.L., Fontaine, D., du Montcel, S.T., Yelnik, J., Chéreau, I., Arbus, C., Raoul, S., Aouizerate, B., Damier, P., Chabardès, S., Czernecki, V., Ardouin, C., Krebs, M.O., Bardinet, E., Chaynes, P., Burbaud, P., Cornu, P., Derost, P., Bougerol, T., Bataille, B., Mattei, V., Dormont, D., Devaux, B., Vérin, M., Houeto, J.L., Pollak, P., Benabid, A.L., Agid, Y., Krack, P., Millet, B., and Pelissolo, A. (2008). Subthalamic nucleus stimulation in severe obsessive-compulsive disorder. N. Engl. J. Med. 359, 2121-2134.
Key publications of Mahlon R. DeLong
Alexander, G.E., DeLong, M.R., and Strick, P.L. (1986). Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Ann. Rev. Neurosci. 9, 357-381.
Miller, W.C. and DeLong, M.R. (1987). Altered tonic activity of neurons in the globus pallidus and subthalamic nucleus in the primate MPTP model of parkinsonism. In: Advances of Behavioral Biology. M.B. Carpenter and A. Jayaraman (eds.), Plenum Publishing Corp., 32, 415-427, New York.
DeLong, M.R. (1990). Primate models of movement disorders of basal ganglia origin. Trends Neurosci. 13, 281-285.
Bergman, H., Wichmann, T. and DeLong, M.R. (1990). Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science. 249, 1436-1438.
Bergman, H.G., Wichmann, T., and DeLong, M.R. (1994). The primate subthalamic nucleus: II. Neural activity in the subthalamic nucleus and pallidum in the MPTP model of parkinsonism. J. Neurophysiol. 72, 507-520.
DeLong, M.R. and Wichmann, T. (2007). Circuits and circuit disorders of the basal ganglia. Arch. Neurol. 64, 20-24.