Medicine Meets Millennium World Congress on Medicine and Health 21 July - 31 August 2000 Future strategies to restore brain functions Alim Louis Benabid Department of Neurosciences University Joseph Fourier of Grenoble France Advantages and drawbacks of currently available methods in functional neurosurgery Neurosurgery along his history experiences periods of fame and periods of darkness. This results from the major interplay between needs and available satisfactory solutions. Movement disorders surgery is one of the most demonstrative examples. After being during the first half of the century, the only available treatment for movement disorders, essentially tremor but also rigidity and akinesia, and also dystonia, its use almost disappeared when levodopa came, with its wide spectrum of effects on almost, although unequally, all the components of Parkinson’s Disease (PD). The adaptability of the doses, and indirectly the reversibility of the side effects were not competitive for surgery which, once performed, could not be modulated and when it was plagued with side effects, namely sensory motor or cognitive deficits, they could not be corrected and were definitely deleterious for the patient. The occurrence of side effects specific to the medical treatment, such as the levodopa induced dyskinesias (LIDs), called for a specific treatment and it happened that the most effective, so far, was surgical, represented by pallidotomy. It is interesting to note that pallidotomy was invented in the mid-century and abandoned because of its insufficient effects. Its rebirth is due to the unexpected efficiency on this new iatrogenic disease which did not exist when it was invented and then forgotten. Pharmacology has the advantage of targeting specifically the receptors of the neurotransmitter system which is being considered. As a drawback, drugs interact with these receptors wherever they are ( fulfilling the principle of ubiquitous efficiency) ) but the receptors are involved in a large variety of systems, sometimes totally different from the first one to be considered (strange tendency of nature to make savings?). The pharmacological effects may in fact overpass the area of interest and administration of drugs, even when they fulfil the therapeutic goal of this administration, induce in these extended areas additional effects, most often unwanted and then prevent the full adequate use of the drugs. NMDA antagonists provide a demonstrative example of this as the inhibition of glutamate activity in the basal ganglia (BG) is counterbalanced by the widespread effects of inhibition of glutamate activity in the rest of the body where it is necessary. Here surgery comes back with its ability to focus very precisely the site of application of the therapy. This precision of application has been recently dramatically improved with the advent of image guided surgery, itself a combined consequence of the progresses made simultaneously in the fields of brain imaging (CT, MRI, PET and SPECT, MEG), of computer science and of robotics, providing neurosurgeons with the theoretical possibility to introduce a probe in every place of the human brain. Then how to reconcile the precision of targeting, allowing the specificity of action, and the usual irreversibility of surgical actions, based on destruction of structures? A possibility was offered through neural grafts, which gathered the advantages of specific action (competent cells to deliver a given biochemical compound) and precise targeting (graft where the deliverable compound was missing) with the lack of irreversible additional damage made by a lesion. Besides the difficulties of neuronal growth, absence of host rejection and functional activity which have been practically solved during the last decade, it appeared recently that in these patients in whom the graft successfully grew up an unexpected complication happens: dyskinesias, similar to levodopa induced abnormal movements and probably due to over secretion of dopamine in the striatum, develop and become permanent, intense and uncontrollable, inducing a severe disability in these patients, similar to the motor fluctuations observed in long term levodopa treated patients. The solution to this drawback could be found in encapsulated cells as proposed by Aebischer: they offer the possibility to remove cells, change their number and type, add growth factors or inhibitors and therefore control the functional output of these implanted cells. Similarly, local administration through pumps and implanted catheters in functional targets could control the activity of neurons in the implanted target. Technical problems such as tissue reaction to the drug, solubility of chemical compounds, permeability of catheters, reliability of pumps are not yet totally solved. Therefore, deep brain electrical stimulation seems to be the current best candidate as a method to manipulate neural functions and help restoring them. Electrical Neuromodulation: principles and developing concepts Electrical stimulation of neural elements has been considered so far as excitatory and all the current concepts of neurophysiology rely on this principle. Achieved at low (1 to 60 Hz usually) frequency, this excitatory stimulation has been achieved with some success in various fields, essentially pain and applied at various levels suggested by physiological knowledge: peripheral nerves, posterior horn of the spinal cord, thalamus, even motor cortex. These excitatory applications have been based on the neuroaugmentive concept, stating that increase in activity of some structures acting as gates could block the transmission of unwanted messages, such as nociceptive messages arising from the periphery or abnormally generated by disturbances of the normal sensory system, the most typical example being the phantom pain generated in stumps. However , all functions cannot be blocked by neuroaugmentation of pre-existing suppressing mechanisms. Interruption of pathways or disruption of networks may be necessary and this is what has been achieved by ablative neurosurgery. However, ablation is irreversible, non sizable and the risk of side effects is non negligible, even more if bilateral procedures are performed. In order to find a replacement method for ablative surgery, we have developed an inhibitory procedure based upon electrical stimulation of neural elements at high frequency (HF higher than 100Hz) which happens to mimic destructive lesions of brain targets but in a reversible and adaptable manner. This effect was discovered empirically when during thalamotomies, stimulation at various frequencies was used to explore the target to be destroyed and its vicinity. Its was quickly clear that low frequency stimulation (LFS) consistently reproduced the functional effect of the excited target i.e., dysesthesias in the sensory structures and motor contractions in the pyramidal tract) while the HF stimulation (HFS) mimicked the effects of ablation of these structures when they were cellular nuclei (i.e. thalamic of pallidal nuclei) and not when they were bundles which were excited at all frequencies (such as visual flashes in the optic tract or eye deviation in the IIIrd nerve fibres). The mechanisms of action are not fully understood. It is quite easy to understand the effects of LFS as they correspond to the widely accepted classical concept of activation of excitable neural elements by electrical currents, which tends to replicate or elicit or enhance the known function of a given brain structure. This has been often used to determine the physiological normal function of these structures and the concept is easily applied and accepted when the therapeutical effect is based on the increased activity of this structure. It is more difficult to accept the concept and understand the basic mechanisms underlying the ablative-like effects of HFS. Deep brain stimulation (DBS) at HF has been proven to be inhibitory in various nuclei, such as the thalamic Vim (ventral intermedius), or CM-Pf (centrum medianum-parafascicularis), the subthalamic nucleus (STN), the internal Pallidum (GPi) and the ventro-medial nucleus of the hypothalamus (VMH). This inhibitory effect was primarily established from the intraoperative observation that HFS of Vim induced immediate and reversible suppression of the parkinsonian and essential tremors, as thalamotomy does. In the other structures HFS also induces similar effects than destruction . Experiments in rats showed that HFS-STN induces prolonged inhibition of the neural activity in STN, EP (entopeduncular nucleus), SNr (substantia nigra reticulata) and in rTh (reticularis thalami), and an increased activity in GP (globus pallidus), VL (ventrolateral thalamus) and in SNc (substantia nigra compacta). These data are in agreement with the expectations from the current model of parallel processing in the basal ganglia (BG) and with intraoperative and chronic applications of HF-DBS in patients with movement disorders. However, HFS of SNr in humans fails to produce the clinical improvement expected from the model as well as SNr neurons do not present any evoked responses to usual stimuli influencing Vim, STN and GPi, suggesting that the role and place of SNr in the diagram of the organization of the BG in man should be revisited. It seems that the SNr responds preferentially to ocular movements and this could be related to the projection of SNr onto the superior colliculus (SC) which in rodents plays an important role in the motor behaviour of the prey versus the predator. The basic mechanism of action of HF-DBS is still unknown. The effect of Vim-HFS on tremor suggests the jamming of an oscillatory feedback, but this does not apply to non oscillatory symptoms such as akinesia and rigidity alleviated by HFS of STN and EP, the backfiring of GP could suggest that GP is retrogradely activated and inhibits in turn STN and EP by its GABAergic output, but destruction of GP does not suppress the effects of STN-HFS. The preferential excitation by HFS of large myelinated fibres such as the GABAergic terminals present in Vim, STN, EP has been proposed as a mechanism of intrinsic inhibition. This mechanism could be a satisfactory explanation, as it would induce the inhibition of the local neurons, compatible with the loss of their function induced by their destruction in thalamotomy, pallidotomy or sub-thalamotomy. However, this would be the case also at LF, which however does not induce inhibition and even excites the stimulated neurons such as in VMH, or in Vim. A mechanism involving more closely the membrane and cellular properties of the neurons such as inhibition of ion channels, depolarisation block or hyperpolarization could be also involved and several preliminary results are currently reported. Besides the mechanism of inhibition, the changes in neuronal activity induced in the BG is also a matter of investigation and then of controversies. The basic assumption is that, following the dopaminergic denervation induced by the neurodegenerescence of the dopaminergic neurons of the SNc is that the firing rates are modified, namely that they are increased in STN, SNr and GPi and decreased in Gpe and in the thalamus. Experimental data as well as recording in human parkinsonian patients tend to suggest that increased firing rate might be less important and deleterious that the pattern of firing. All available data show that the essential feature of these abnormal firings is the high percentage of bursts. It could be possible that this pattern generates functional disturbances in a way similar to periodic firing in the thalamus could induce tremor. Therefore, the system might behave better without activity than with abnormal activity. This might reconcile the fact that ablation of a nucleus could have the same effect than its inhibition by HFS. One may also consider the analogy between bursting activity and periodicity of kinaesthetic cells: this could allow to understand that HFS plays the role of a blank noise “filling up the zeroes” between the bursts, either spontaneous or synchronous to tremor. The neuronal message looses its significance and cannot trigger the system. The jamming hypothesis could be applied to explain neuroinhibition even in the absence of tremor. The continuous interplay and back and forth process between clinical effects observed during the functional surgery of movement disorders and experimental research currently provides elements allowing the progression of the knowledge about BG and motor control as well as new concepts in neurophysiology, those in turn leading to efficient therapeutic applications. Present and Future Clinical Applications HFS has been used by our group to treat movement disorders since 1987, first in Vim as a treatment of tremor of various origins over the last ten years and since 1992 in GPi for levodopa induced dyskinesias and in STN for tremor, akinesia and rigidity. STN appears to be a target of major interest, able to control the three cardinal symptoms and to allow the decrease or suppression of levodopa treatment, which then suppresses also LIDs. The stereotactic determination of the target uses ventriculography, MRI and electrophysiology, with both single neuron microrecording and microstimulation inducing symptom suppression or side effects. Chronic electrodes are placed bilaterally at the best physiologically defined location and connected to implantable stimulators, operated at 130-185. There was no operative mortality and permanent morbidity was observed in 3 patients. All cardinal symptoms are alleviated from tremor to akinesia and rigidity. This strong improvement allows to decrease the drug dosage to approximately 30% of the preoperative level, which suppresses the levodopa induced dyskinesias. The off period dystonias, freezings and falls are also suppressed. The effects remain stable over more than 5 years and in the same period the off stimulation-off medication UPDRS remains stable and does not increase at the usual rate The low rate of permanent complications, the minor side effects and their immediate reversibility, the possibility of bilateral implantation in one session and the long-term persistence of symptom relief are strong arguments which support chronic HFS of STN as the method of choice when a surgical procedure is indicated for the treatment of Parkinson's disease and even more when a bilateral procedure is necessary. Based on the efficiency of pallidotomy on dystonias, HFS of GPi has been used successfully as a treatment of this type of movement disorders. The well tolerated bilateral procedure has made available this treatment for generalized dystonias in children. Results are impressive and provide a significant improvement of the general motor function of these patients. This improvement is progressive, seems to depend on different parameters than those inducing the almost immediate effects observed in other movement disorders such as Parkinson’s disease or essential tremor, as pulse width and voltage which are higher, while the required frequency remains high as in PD or ET. Based on the effect of STN HFS on off period dystonia, we have started to explore the potential role of STN stimulation in dystonias. Preliminary results tend to suggest that stimulation of STN at LF (about 10 Hz) would be in some cases as efficient as in GPi at HF. This would be coherent with the known occurrence of low firing rate in STN in choreas and dystonias which would require an excitation provided by LFS rather than an inhibition provided by HFS or by ablative methods. If this is proven to be true, it would have important consequences on the cost of the method, the stimulator being firing at much lower rate, as well as on the understanding of the pathophysiology of these disorders. This would also demonstrate the wide potentialities of DBS from low to HF, providing large range of modulation of neural activities. Based on the previous knowledge that SNr and the nigro-striatal system could play an inhibitory action on the mechanism of some forms of epilepsies, we have proven in experimental animals that STN HFS could control seizures? This has allowed us to investigate this potential effect in non operable pharmacoresistant epilepsies. Three cases have been operated with various follow-ups (2 cortical dysplasias, 6 and 18 months and 1 severe myoclonic epilepsy, 12 months) bilaterally except the first one which was a focal dysplasia of Taylor in the motor strip. The preliminary results are satisfactory with significant reduction of the seizures and recovery of motor function as well as improvement of the social and cognitive functions. The type of epilepsies and the optimal parameters are under evaluation, in particular the effect of intermittent stimulation rather than continuous and the necessity to trigger stimulation by the onset of the EEG abnormalities. The comparative efficiencies of STN stimulation and of the other targets (anterior thalamus, CM-Pf, vagus nerve) are still to be evaluated by clinical studies. The question of the optimal target , STN or SNr, is also to be precisely investigated, both in experimental and clinical situations. Problems and Perspectives Other experimental avenues are being investigated. In order to prove the differential effects between low and HF, we have studied in rats the effects of stimulation at these two regimens of the ventromedial and lateral nuclei of the hypothalamus, two targets known to have opposite effect one to the other and also within the same target whether they are excited at LF or inhibited by stereotactic lesions. This study confirmed that HFS mimics the effects of ablation while LF does excites the targets. In particular HFS of VMH will induce an hyperphagia in already fed rats while LFS of the same nucleus will refrain hungry rats from eating. This has a possible clinical application in food intake disorders such as malignant obesity or anorexia mentosa, which could be treated by chronic stimulation of the hypothalamic area. Obviously, clinical applications of these experimental findings require additional experimental investigations as well as careful ethical consideration. Similarly, one might consider that other applications, such as psychosurgery in OCD or other psychiatric disorders should be extensively investigated experimentally and carefully applied in clinical situations. At the difference with movement disorders and epilepsy, psychiatric disorders are poorly understood at the level of pathophysiology and animal model are extremely difficult to create. During the last decade, we have witnessed the rebirth of functional neurosurgery, in relation to several events and technical breakthroughs, as well as to advances in knowledge in basic neuroscience. Neurostimulation has been reintroduced through the inhibitory effects of HFS which paradoxically may redefine the field of applications of the classical excitatory LFS. A new concept has been created which opens its own field of research, as actually little is known about the mechanism of action, the effects of continuous stimulation and the physiology of long term HFS. A closed loop is being created from the methodology of HFS to its basic science which in turn opens on new indications which will call for new technological developments.A totally new area has appeared from which it is difficult to predict what will be the limits. 1. Benabid AL, et al. Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet 337:403-406, 1991. 2. Benazzouz A, et al. Responses of substantial nigra reticulata and globus pallidus complex to high frequency stimulation of the subthalamic nucleus in rats: electrophysiological data. Neuroscience Lett; 189:77-80, 1995. 3. Limousin P, et al. Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 339:1105-1111, 1998. 4. Piallat B, et al. Subthalamic nucleus lesion in rat prevents dopaminergic nigral neuron degeneration after striatal 6-OHDA injection : behavioral and immunohistochemical studies. Eur J Neurosci 8:1408-1414, 1996. 5. 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