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.

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