Progress Report 2008: Essay DBS DeLong
The 2008 Progress Report on Brain Research


February, 2008

by Mahlon R. DeLong, M.D., and Thomas Wichmann, M.D.
  
 Progress Report 2008, Mahlon R. DeLong, M.D. - FeatureProgress Report 2008, Thomas Wichmann, M.D. - Feature

Left: Mahlon R. Delong, M.D. (Courtesy of Mahlon R. Delong) Right: Thomas Wichmann M.D. (Courtesy of Thomas Wichmann)

 

Introduction

During the last century, largely due to the absence of effective medical treatments, neurosurgeons, concerned to help desperate patients with disabling Parkinson’s disease (PD), tremor, and other movement disorders, began to explore the effects of lesioning various brain structures. This practice reached a peak in the 1950s and 1960s, about the same time at which surgery for various psychiatric disorders and abnormal behavior was also peaking. After the introduction of levodopa replacement therapy for Parkinson’s in the 1960s, and in response to the strong public outcry against the excesses of psychosurgery, the use of neurosurgical interventions sharply declined during the following decades.

Against this backdrop, it may seem surprising that in the past decade there has been a virtual renaissance of neurosurgical treatments for both neurological and psychiatric disorders. The most fundamental factor accounting for the resurgence of neurosurgical interventions has been the remarkable progress in basic science research into the organization of the motor system and the neurobiology of disorders such as Parkinson’s disease. This research, carried out in primate models, has demonstrated that movement disorders such as Parkinson’s are the result of abnormal activity in discrete brain circuits, and that modulation of activity in these circuits through highly focused surgical interventions at several nodal points can effectively alleviate symptoms.1 

Momentum for the resurgence of neurosurgical approaches comes from several factors: the available medications are not effective in treating all of the patient’s symptoms in advanced stages of many of these chronic neuropsychiatric disorders or they have unacceptable side effects, public awareness of the burden of these disorders on patients and their caregivers has increased, and, especially with respect to psychiatric conditions, patient consent procedures and other protections of patient rights are now consistently used.

Most of the targets for functional neurosurgical procedures that are in use today involve a cluster of brain structures called the basal ganglia. These subcortical brain structures are viewed as components of a family of anatomically distinct brain circuits that also encompass the cerebral cortex and thalamus. These circuits subserve aspects of motor behavior (“motor circuit”), cognitive/behavioral function (“associative circuit”), and emotion and motivation (“limbic circuit”).

Broadly speaking, movement disorders such as Parkinson’s result from abnormal neuronal activity in the motor circuit, while abnormalities in limbic or associative circuits may underlie some of the symptoms and signs of neuropsychiatric conditions. Consequently, surgeries in movement disorder patients are generally aimed at targets within the motor circuit, while neuropsychiatric diseases are being treated with interventions aimed at the limbic or associative circuit.

In the new generation of surgical approaches, deep brain stimulation (DBS) stands out for its ability to spark changes in the activity of certain circuits. DBS was first explored for movement disorders in the late 1970s as a treatment for tremor and was later found to be also highly effective for Parkinson’s disease and other movement disorders as more suitable targets were identified. In contrast to the irreversible effects of lesioning approaches, the brain is not permanently altered by DBS but is modified by the local application of electrical current in a way that can be changed or even reversed.

During DBS surgery, stimulating electrodes with four different contacts are implanted into specific brain regions, and a programmable pulse generator is implanted under the skin below the collarbone, similar to a cardiac pacemaker. The pulse generator can be programmed to deliver continuous stimulation of the optimal frequency, amplitude, and pulse duration to the targeted brain region. Reversibility and adjustability of stimulation are major advantages of DBS, as is its focused application in the relevant targets, which reduces the adverse side effects seen with drugs that act widely in the brain.

Deep brain stimulation offers truly remarkable benefits to patients with advanced movement disorders and other conditions, but exactly why it works remains unclear. Scientists first believed it simply mimicked the effects of lesioning, but more recent studies of brain activity in animals and patients have suggested that DBS alters patterns of activity in the extended brain networks associated with the stimulated brain region by activating axons that leave or enter the stimulated region of the nucleus.

 Movement Disorders

The most common application of deep brain stimulation is for patients with advanced Parkinson’s disease, a progressive disorder characterized by slowness of movement, tremor, and muscular rigidity. The symptoms are caused by the loss of the neurotransmitter dopamine in the basal ganglia, which strongly affects the neuronal activity throughout the motor circuit.

While the early stages of Parkinson’s are amenable to medical therapy, the development of drug-induced involuntary movements called dyskinesias and the more rapid wearing off of medication limit the effectiveness of medication treatments in later stages of the disease. DBS within the motor portions of two basal ganglia nuclei, the subthalamic nucleus and the internal segment of the globus pallidus, reverses many of the motor problems of Parkinson’s, as well as the drug-induced complications.2,3 Major surgical complications are infrequent, occurring in 1 to 2 percent of patients, and the long-term benefits are substantial.

In addition to the subthalamic nucleus and globus pallidus, several alternative DBS targets are currently being explored, for instance the pedunculopontine nucleus, which shows some promise for severe cases of Parkinson’s disease with treatment-resistant gait and balance problems. DBS is also being used successfully in patients with movement disorders other than tremor and Parkinson’s. For example, stimulation is now being tested in a variety of forms of dystonia, a highly variable movement disorder characterized by generalized or focal involuntary twisting movements and abnormal postures, bringing new hope to individuals who respond poorly to currently available treatments.4 

Neuropsychiatric Disorders

Because of the remarkable success of deep brain stimulation for Parkinson’s disease and other movement disorders and the insight that several common neuropsychiatric conditions may be caused by similarly abnormal activity patterns in neuronal networks, neurosurgeons are now beginning to cautiously explore the use of DBS for several such conditions. At present, these procedures remain strictly experimental.

One promising area is the treatment of obsessive-compulsive disorder (OCD), a condition characterized by the presence of intrusive thoughts and compulsive behaviors. Neurosurgical lesioning treatments for OCD have traditionally been aimed at empirical targets, such as the anterior limb of the internal capsule. It has recently been reported that DBS at the same target5 or in the nearby ventral striatum may also be beneficial.

Tourette’s syndrome, in which involuntary rapid, stereotyped movements and vocalizations (motor and vocal tics) are often associated with OCD, attention-deficit/hyperactivity disorder, depression, and psychosocial difficulties may also be treatable with DBS.6 Because symptoms often remit after adolescence, treatment is reserved for severe cases that have not improved spontaneously. Based on earlier empirical lesion studies and consideration of the relevant limbic circuit anatomy, DBS at several surgical targets has been tested in these patients, including the midline intralaminar thalamic nuclei or the motor and limbic portions of the globus pallidus. The preliminary studies have demonstrated substantial symptomatic benefits in some cases.

Several studies are also now under way to evaluate the potential of DBS in patients with severe depression that is unresponsive to conventional therapies. Following imaging studies suggesting that the cortical subgenual cingulate region, also called area 25, may be a key structure in depression, a recent study reported that DBS in this area produces significant clinical benefits in patients with depression.7 With prolonged stimulation (for six months) a significant and sustained improvement was reported in two thirds of the subjects, all of whom had failed multiple treatment trials. Needed now are follow-up studies and larger, well-controlled trials to try to confirm these findings and to gather data on other targets, such as the ventral striatum.

Conclusions

Deep brain stimulation has become the neurosurgical procedure of choice for patients with disabling movement disorders and is currently also being explored for patients with a variety of severe neuropsychiatric disorders. Although the neurobiological bases of disorders such as OCD, Tourette’s syndrome, and depression are less well understood than those of movement disorders, a common element between these conditions seems to be that they are associated with brain circuit dysfunction, for which DBS may prove to be effective in patients with treatment-resistant symptoms.

Notes

1. Wichmann T and Delong MR. Deep brain stimulation for neurologic and neuropsychiatric disorders. Neuron 2006 52(1):197–204.

2. Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schafer H, Botzel K, Daniels C, Deutschlander A, Dillmann U, Eisner W, Gruber D, Hamel W, Herzog J, Hilker R, Klebe S, Kloss M, Koy J, Krause M, Kupsch A, Lorenz D, Lorenzl S, Mehdorn HM, Moringlane JR, Oertel W, Pinsker MO, Reichmann H, Reuss A, Schneider GH, Schnitzler A, Steude U, Sturm V, Timmermann L, Tronnier V, Trottenberg T, Wojtecki L, Wolf E, Poewe W, and Voges J. A randomized trial of deep-brain stimulation for Parkinson's disease. New England Journal of Medicine 2006 355(9):896–908.

3. Benabid AL, Deuschl G, Lang AE, Lyons KE, and Rezai AR. Deep brain stimulation for Parkinson's disease: Surgical technique and perioperative management. Movement Disorders 2006 21 Suppl 14:S168–170.

4. Vidailhet M, Vercueil L, Houeto JL, Krystkowiak P, Benabid AL, Cornu P, Lagrange C, Tezenas du Montcel S, Dormont D, Grand S, Blond S, Detante O, Pillon B, Ardouin C, Agid Y, Destee A, and Pollak P. Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. New England Journal of Medicine 2005 352(5):459–467.

5. Greenberg BD, Malone DA, Friehs GM, Rezai AR, Kubu CS, Malloy PF, Salloway SP, Okun MS, Goodman WK, and Rasmussen SA. Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder. Neuropsychopharmacology 2006 31(11):2394.

6. Visser-Vandewalle V, Ackermans L, van der Linden C, Temel Y, Tijssen MA, Schruers KR, Nederveen P, Kleijer M, Boon P, Weber W, and Cath D. Deep brain stimulation in Gilles de la Tourette's syndrome. Neurosurgery 2006 58(3):E590.

7. Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, and Kennedy SH. Deep brain stimulation for treatment-resistant depression. Neuron 2005 45(5):651–660.

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