During the past decades focal high frequency electrical stimulation of the human brain has been used in order to treat the symptoms of several neurological disorders, including Parkinson's disease, essential tremor, dystonia, epilepsy and Tourette's syndrome. In the human brain neuronal circuitries have been detected which are responsible for motor control, others enable reception of information from the different sense organs (vision, hearing, sensation, taste, smell), still others are responsible for emotion, sexual behaviour, intelligence, memory etc. These circuitries do not simply exist in parallel to one another. Rather, there exist important connections in between them. Transmission of information runs via action potentials within one neuron and via neurotransmitters being released at the synapses in between neurons. Action potentials are transient electrical depolarisations of the cell membrane which propagate the signal from one place to another in the cell. Technically, it is possible to intervene with the electrical activity of a neuron by simply administering in the neighbourhood of that neuron an electrical field, which changes over time at a frequency in clinical practice usually between about 50 to 180 Hz (figure 4.1). In patients, this treatment is performed by means of implanting an electrode in a certain area of the brain. The electrode can be connected to an extension cable and an external current source. The extension cable and current source may be externalised in order to test the effectiveness of the treatment. Once short term efficacy of the treatment is proven, the stimulation system may be internalised. In many centres, the external phase is bypassed because of the risk of infection and because a high number of patients proceed to internalisation anyway.
Typically, the neurostimulator is implanted subcutaneously in the chest or in the abdomen and the extension cable runs below the skin passing behind the ear, connecting electrode and neurostimulator. There are new stimulators, currently under development (but not yet on the market), which are much smaller in size and which may be implanted subcuta-
19 The principal author of this chapter, B. N., would like to thank Prof. Paul Cosyns, Dr. Loes Gabriels, Dr. Kris van Kuyck, Mr. John Das, Mrs. Marleen Welkenhuysen, Dr. Herwig Neefs, Prof. Jan Gybels, the members of the international obsessive-compulsive-disorder-deep-brain-stimulation-collaborative-group, the members of the commission for neurosurgery for psychiatric disorders, the patients, their families and their psychiatrists for their collaboration.
The Research Council of the KU Leuven (project nr OT-98-31, project OT-03-57 and project VIS-02-007), the FWO (project nr G. 0273.97.N) and the SBO (project nr 50151, 2005) provided financial support. Medtronic Inc., QUEST program (L1170) provided the stimulating devices.
| Amplitude Time (milliseconds )
Figure 4.1: Current Applied via a DBS Electrode over Time
Above: the current changes over time. Sometimes instead of the current the potential difference (expressed in voltage) is used, but in this case the impedance should be known.
Below: illustration of a quadripolar electrode, which is implanted inside the brain.
neously on the cranium itself. Interaction with the stimulator becomes feasible through an external device which communicates with the implanted stimulator by means of a wireless connection. Thereby it is possible to vary different stimulation parameters (frequency, amplitude, pulse width etc.), to change the separate electrical contacts into anode, cathode or neutral and to obtain the history of the stimulation and the battery life. Radio-frequency systems, which obviate the need to replace the stimulator once the battery is empty, also exist, but are no longer frequently used because with this system an antenna is stuck to the skin on top of the implanted stimulator. This antenna is connected to an external stimulator via a wire. The patient can then only receive stimulation when carrying the external stimulator, wire and antenna, meaning that stimulation cannot be continued, for example, when bathing or swimming. It may also lead to skin irritation above the implanted stimulator. Rechargeable implantable systems for deep brain stimulation (DBS) are not yet available on the market, but the system is already used in spinal cord stimulation to treat chronic neuropathic pain.
Electrical brain stimulation was primarily used to treat pain and spastic-ity. The application of electrical brain stimulation for the symptomatic treatment of Parkinson's disease, which is best known to the public, came only later. Parkinson's disease is a disorder characterised by akinesia (the inability to start a movement), rigidity (an increased tone due to a lesion in the basal ganglia), tremor and postural instability. Many of those patients also have other symptoms such as problems with speech, writing, cognition, etc. The underlying basis is a degeneration of dopaminergic neurons in the
substantia nigra. The first treatment of Parkinson's disease is antiparkinson medication. Dyskinesia and on-off fluctuations are the most common side effects of the treatment, which usually arise after three to five years of using such drugs. If tremor is the main symptom and the side effects become too severe or if the medication does not help sufficiently, then a lesion can be produced in a specific brain region and in a controlled manner by thermocoagulation in order to diminish the tremor. This is done by stereotactic insertion of an electrode in the ventral intermediate nucleus of the thalamus (Vim). The temperature of the tip of that electrode is subsequently increased (usually to 80°C) for a certain amount of time (usually one minute). The consequence of this procedure is a burn lesion in the thalamus or thalamo-tomy. The advantage of such lesion surgery is that, after surgery, the signs and symptoms are gone and no further continuing administration of current is necessary. However, in case of side effects (e.g. ataxia, dysarthria, paresis) one can only hope that those side effects diminish with time due to a healing process, but occasionally the side effects remain. It sometimes also happens that the effect of the lesion vanishes, which then calls for an iterative surgery.
In the 1980s researchers in Grenoble conducted extensive studies into the possibility of continuous high frequency electrical stimulation of the Vim (Benabid et al. 1991). Although the mechanism through which electrical brain stimulation acts is not entirely known, several possible mechanisms have been proposed (Benabid et al. 2005). Whilst the current is being administered to the brain tissue, the symptom tremor disappears. However, as soon as the current supply is switched off, the tremor reappears. The disadvantage of this system is the continuous need for current supply and the subsequent need for the replacement of batteries when they are depleted. By contrast, the main advantages of this system are the reversibility and adaptability of stimulation parameters in case of side effects, or in case of evolution of the disease and an aggravation of the symptoms. In these cases, the stimulation parameters, and in particular the amplitude, can be increased. If unwanted side effects arise, the stimulation parameters may be altered and, in the worst case, the whole stimulation system can be removed.
Besides the treatment of parkinsonian tremor, Vim stimulation is also beneficial for the treatment of essential tremor, tremor in the case of multiple sclerosis and posttraumatic tremor. For all these conditions, both the lesioning procedure and electrical stimulation of the Vim induce similar beneficial effects.
In addition, many symptoms of Parkinson's disease can be abolished by performing a pallidotomy (a lesion in the internal part of the globus pal-lidus, GPi) or electrical stimulation of the GPi. However, the beneficial effects of the electrical stimulation of the subthalamic nucleus (STN) on most of those symptoms seem to be superior to the effects induced by pal-lidal stimulation. STN stimulation is now the most frequently performed surgical intervention in patients suffering from Parkinson's disease. The Vim, GPi and STN are all nuclei that are connected with each other as parts of one motor circuitry, which also explains why electrical stimulation of these different structures may produce similar effects in terms of symptom relief. Very recently, another target, the pedunculo-pontine nucleus (PPN), has been addressed (Plaha and Gill 2005; Mazzone et al. 2005), which seems to improve symptoms such as freezing during the ON period and gait problems, which are not alleviated by STN stimulation. The striking aspect of this new target is that, according to the physiological data provided by animal experiments, the improvement is obtained at low frequency, therefore meaning that the nucleus has to be excited, instead of being inhibited. In clinical practice this may mean that four electrodes are implanted in a patient suffering from Parkinson's disease with freezing in the ON period: two in the STN driven at high frequency, and two in PPN stimulated at low frequency.
For the treatment of dystonia, both pallidotomy and electrical stimulation of the GPi have been performed with moderate to good results. Preliminary data have been reported on the clinical application of high frequency stimulation of the STN, and the old thalamic target used by Irving Cooper in the fifties is now being reconsidered. At present, most neurosurgeons believe that, in general, electrical stimulation is the way to proceed because of the reversibility and adaptability of the treatment. There are some observations pointing in the direction of an increased risk of suicide resulting from STN stimulation (although there is no real proof of a causal link between STN stimulation and suicide at this moment). Recent data would tend to support the hypothesis that suicidal tendencies result from a multiplicity of factors, from the strong withdrawal effects caused by the decreases in drug dosage, which are facilitated by STN stimulation, to societal changes secondary to the major, and rather sudden, improvement experienced by the patients, without ruling out a possible involvement of the limbic part of STN. In line with the role of societal factors, one might mention that suicides have been reported in the case of other highly successful surgeries, such as temporal lobectomies to treat intractable epilepsy, as well as in cardiac bypass surgery. The neurosurgi-cal team in Leuven had one STN stimulated Parkinson's disease patient with suicidal thoughts, which decreased upon changing the stimulation parameters.
Technological innovations in brain stimulation are currently under development in various research projects, but are not, as yet, ready for clinical application. These include the miniaturisation of electrodes and stimulators, the use of nanotechnology, telemonitoring, telemedicine and telecontrol. In the case of telecontrol, the development of safety requirements is crucial to counter the risk of unwanted manipulation of stimulation parameters by unauthorised people.
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