Electrical Neuromodulation
Maxime Guye, M.D., Ph.D.,
Centre for Magnetic Resonance in Biomedicine (CRMBM), CNRS UMR 6612,
& Department of Clinical Neurophysiology, University Hospital La Timone,
Aix- Marseille University, Medical School, Marseille, FR
Introduction
Direct electrical neuromodulation is one of the oldest diagnostic and therapeutic
methods used in Neuroscience. Cerebral electrostimulation is useful not only to define
cortical functions and functional connectivity but also to treat several severe
neurological and psychiatric diseases.
Concerning functional mapping, electrical neuromodulation is still considered as the
“gold standard” method. However, despite the experience and a fairly good
knowledge of the electrostimulation effects at the cellular level, the exact local and
remote effects on cortical and subcortical areas are still imperfectly understood. In
addition, discordant effects have been evidenced in the literature (1). This is due to the
fact that several parameters, sometimes difficult to control, influence the actual
impact of the stimulation on the complex and highly interconnected cerebral tissue.
That is why the combination of not only simultaneous electrophysiological recordings
but also fMRI and diffusion-tractography MRI, is particularly useful to better
understand the effects of stimulation at the structure and system levels. In the same
way, functional and effective connectivity quantification assessed by fMRI as well as
structural connectivity quantification assessed by diffusion-tractography MRI are of
particular interest to assist electrical stimulations and better define the complex neural
system connectivity. Obviously, without MRI, therapeutic use of deep brain and
cortical stimulations could not be achieved with the same precision and safety.
The purposes of this course will be: first, reviewing the history and the basic
principles of brain electromodulation; second, reviewing its contribution to the body
of knowledge in Neuroscience and its usefulness in the clinic (with concrete examples
of stimulations with video and electrophysiological recordings); and third, showing
the adding value of combined electromodulation and advanced MRI techniques in the
perspective of a comprehensive assessment of brain function and connectivity.
I. Historical overview
Direct electrical stimulation of the brain to elucidate cortical and subcortical areas
functions began in the nineteenth century (2). The first series of experiments
conducted in animals and considered as the precursor of the “modern” era of cortical
stimulation have been conducted in 1870 by Fritsch and Hitzig in dogs on a dressing
table (3). They localized the cortical areas responsible for contralateral forepaw
stimulation and confirmed their results by the ablation of these areas. The first studies
in Monkey were published in 1873 by Ferrier by using better defined current
characteristics. He established the first cortical mapping of sensorimotor areas and
extrapolated the first human sensorimotor map. After these pioneering works,
numerous studies have led to the complex mapping of monkey cerebral cortex (2).
The first cortical stimulations in human have been performed by Bartholow in 1874
by inserting 2 electrodes along the cortex of a patient exposed by an infiltrating basal
cell carcinoma. He obtained muscular contractions after stimulating the motor cortex
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and a generalized tonic-clonic seizure with focal onset in the hand when he stimulated
at higher intensity. The patient had then several recurrent seizures and died presenting
with an extensive thrombosis of longitudinal sinus and pus over the hemisphere. After
the controversy following this case, human cerebral cortex stimulation slowly
regained interests and acceptance in the medical community in patients with
intractable epilepsy for epilepsy surgery. Several major works had then been
published (including Horsley’s (1887), Sherrington’s (1889), Cushing’s (1909),
Krause and Schum’s (1931), Foerster’s (1936) works and others) leading to the wellknown sensory and motor homunculus described by Penfield in 1937. This
description was followed by a series of articles and books dedicated to the cortical
function mapping of many brain areas which are still of great interest today (4,5).
Several other teams involved in epilepsy surgery have then contributed to the body of
knowledge in this field using either cortical or depth electrodes (6-9). In addition,
stimulations have been used to test the excitability of the cortex helping to delineate
the epileptogenic areas (10,11). Today, electrical stimulation is also used for cerebral
tumor excision in cortical areas susceptible to be involved in language and motor
functions (12).
Parallel to the development of these diagnostic tools, stimulations were developed in
order to modulate specific system dysfunction in a therapeutic perspective in the
second half of the twentieth century. The first applications were in coma,
schizophrenia, pain and epilepsy with targets focused on deep brain structures such as
basal ganglia, thalamus, hypothalamus and cerebellum. Indications and targets of
brain stimulation have increased significantly after the first successful report of
significant long-term effect on Parkinson disease in the late 1900s (13).
II. Basic principles
Basic principles of electrical stimulations have been studied quantitatively for the first
time by Weiss in 1901 and Lapicque in 1907 (14). This was almost 40 years after the
first experiments in which scientists controlled current intensity by testing the
stimulation on their tongue. Weiss and Lapicque defined the first parameters and laws
of electrostimulation that depend on the timing of delivery, the strength and the
temporal structure of the current applied. After first demonstration, strength–duration
relationship has been largely demonstrated. The current pulse required to induce a
neuronal response declines to an asymptotic level as the stimulus duration increases.
Lapicque defined this current intensity has the ‘rheobase’ that is inversely related to
pulse duration. Then he defined the ‘chronaxie’ as the duration of current pulse that
corresponds to the excitation threshold with an intensity of twice the rheobase. Thus,
the relationship between these parameters can be defined by the following equation: I
= R + RC/t (where I is the threshold current, R is the rheobase current (in Ampère, A),
C is the chronaxie (in second, s), and t is the pulse duration (in s)).
The current density conditions the potential cerebral damage of stimulation. The
current density is the amount of electric charge (in Coulomb, C) delivered by surface
or volume during a period of time. Thus, in addition to intensity, time and waveform
of the current pulse, the surface of the tip delivering the charge is also important to
determine the intensity and time of current application. Thus, macroelectrodes allow
higher intensity and time of pulse compared to microelectrodes.
In addition, the current applied locally is inversely proportional to the square of the
distance between the neurons and the electrode tip Therefore, size, shape and area of
the electrode can affect the spatial distribution of the current density on the electrode
Proc. Intl. Soc. Mag. Reson. Med. 20 (2012)
surface and the electric field generated within the brain. An electrode designed with a
low diameter and a high height maximizes the volume of tissue that can be activated.
In practice, micro or macroelectrodes can be used in animals and in humans;
stimulations can be mono or bipolar; pulses can be monophasic or biphasic.
The complexity of brain stimulation is also due to the anisotropic nature of the tissue
surrounding the electrodes. Thus, not only the electrodes configuration but also their
placements in the stimulated structures are critical for determining their effects
(orientation of the current flow (electrodes) and the axon). The heterogeneous
electrophysiological properties of the stimulated elements at cellular and/or structure
level are parameters to be considered. Indeed, different neuronal elements have
different chronaxies. At the cellular level, it is now accepted that stimulation
mostly/primarily affects the axons rather than the dendrites or cell bodies resulting
mainly in a local inhibition but a neuron firing. Locally there is a brief activation at
the structure level followed by a large inhibition. The effects on remote areas through
mono or polysynaptic pathways are also very complex and recent combinations of
electrostimulation and fMRI have brought valuable information on this point (cf. IV).
Cortical excitability must also been taken into account. Cortical areas behave
differently and stimulation parameters must be adapted to the type of cortex
stimulated. This is particularly the case during pathological conditions such as
epilepsy in which the cortex is highly excitable in regions involved in seizure
generation (this can be used to map epileptogenic regions).
For all the previous reasons, the control of all the parameters is highly difficult and it
is very complex to determine precisely the effect of the stimulation based on
behavioral consequences only. Stimulation evokes a complex sum effect in a
relatively large stimulated volume and can lead locally to either an increase
(activation) or a decrease (inhibition) neural activity. In addition, stimulation can
involve the recruitment of remote areas through current spread along fiber pathways
rather than passive current spread only. Simultaneous recordings are therefore
required to guide our interpretation primarily based on behavior. As these recordings
suffer from a spatial sampling issue, neuroimaging is of particular interest.
III. Cortical mapping and connectivity studies
Despite these limitations, electromodulation is still a ‘cornerstone’ in Neuroscience
and Neurosurgery.
Human
Epilepsy surgery has been the first clinical indication of intracerebral and/or
intracranial recordings and stimulations. It is still the main indication.
Macroelectrodes are more widely used in clinical practice. For recordings during
presurgical assessment of drug-resistant epilepsy, two kinds of approaches are used:
depth electrodes (Stereo-Electroencephalography, SEEG) or cortical electrodes
(Electro-corticography, ECoG) (10-11). Recording electrodes may be used for
stimulation in order to map functional areas. Depending on the characteristics of the
stimulation, ‘excitability’, functional and/or connectivity mappings can be achieved.
‘Excitability’ mapping is obtained by recording paroxystic post-discharges and/or
seizures in regions responsible for seizure generation (i.e. regions that should be
removed to cure the patient), by using either single pulses or train pulses with various
frequencies and time. Functional mapping is based on the behavioral consequences of
the same kind of stimulations with different parameters (these parameters must be
adapted to the type of cortex stimulated). Connectivity studies are based on recordings
Proc. Intl. Soc. Mag. Reson. Med. 20 (2012)
of evoked potentials in areas connected to the area stimulated usually using single
pulses. During the course, practical examples will be shown using video-SEEG in
patients with epilepsy.
Functional mapping is now also widely used in Neurosurgery of brain gliomas. Again,
practical examples of cortical mapping with simultaneous recordings during awaked
surgery in patients will be shown.
These particular clinical situations have led to cognitive studies using either the above
setting or using association of microelectrodes. The advantage of microelectrodes is
obviously the capacity of being more precise in the spatial localization of the
stimulation. Particularly, specific cortical layers can be stimulated.
Animals
These microelectrodes are more widely used in animal models, especially in Monkeys
(15). A vast literature of Monkeys studies has brought a considerable knowledge on
primate brain cortical specializations and brain functional connectivity. Several
examples will be given during the course.
III Electrotherapy using deep brain stimulation
Parkinson’s disease and movement disorders
The modern era of therapeutic brain stimulation has begun after the successful reports
of significant long-term effect on Parkinson disease (PD) in the late 1900s (11). Highfrequency stimulations (HFS) are used in order to mimic a ‘lesion’ of the structures
stimulated (16). The first target in PD was the HFS of the ventral intermediate nucleus
of the thalamus (VIM) with a significant effect on tremor. Essential tremor can now
also be treated by HSF of the VIM. Improvement of the cardinal motor symptoms of
PD has now been demonstrated after HFS of the subthalamic nucleus (STN) or the
internal segment of the globus pallidus (GPi). Deep brain stimulation is now well
recognized and approved in PD. Dystonia and Huntignton’s disease have also justified
evaluation studies of deep brain stimulations.
Epilepsy
Deep brain stimulation for epilepsy is still under evaluation (17). Significant results
have been recently obtained in refractory partial epilepsies using indirect stimulation
via the anterior thalami stimulations. Other indirect targets have been evaluated with
not enough significant results (centromedian nucleus, STN and cerebellum). It is also
the case for direct stimulation of hippocampus in temporal lobe epilepsy that have led
to contradictory results and which is not fully approved yet.
Psychiatric disorders
Deep brain stimulation has also been proposed in depression, obsessive-compulsive
disorders, motivational dysregulation and addiction, and Tourette syndrome.
IV. Combining electromodulation, electrophysiological recordings, fMRI and
Diffusion-tractography MRI
What are the exact effects of stimulation on neuronal mass overtime?
How does stimulation-elicited signal really initiate and propagate?
How comparable are physiological and electrical stimulations?
All these questions are crucial but are still imperfectly answered. Since the last few
years, the availability of advanced MRI methods to study brain connectivity (18) has
dramatically improved the body of knowledge in this area (10). Even more recently,
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the use of different modalities acquired simultaneously in animals have led to major
findings (19-21).
Combining Electromodulation with simultaneous electrophysiological recordings
A major prerequisite for interpreting the impact on the stimulated cortical structures is
the simultaneous recording of the electrical signals after stimulation by intracerebral
or intracranial EEG. The simultaneous recordings also allow recordings of evoked
potentials informing on the areas connected to the cortical target (22). This is true in
animals as well as in humans and can be done with macro+/-microelectrodes.
Combining macromodulation with electrophysiological recordings, task-related
fMRI, resting-state fMRI and tractography data in human
In clinical practice (especially surgery for refractory partial epilepsy and low grade
glioma), direct cortical and subcortical stimulations (+/- electrophysiological
recordings) are increasingly used in conjunction with data provided by task-related
fMRI (particularly language and/or motor fMRI) as well as tractography by using
image fusion via neuronavigation. FMRI activations during task-related fMRI give
valuable information on the cortical areas to be stimulated. Reciprocally, cortical
stimulations have helped defining the specificity and sensitivity of fMRI.
Identification of specific tracts by diffusion-tratography MRI adds important
information on the potential spread of the current effect via pathways and help to
define the specific neural networks sustaining a given function.
Resting-state fMRI is also increasingly recognized as a useful tool for inferring
underlying functional connectivity by measuring the correlations of spontaneous
BOLD signal fluctuations at rest within a functional network. Unpublished data
obtained by combining functional connectivity measured: i. by stimulation during
SEEG recordings, and ii. by resting-state fMRI, in patients with intractable epilepsy
will be presented.
Combining micromodulation with simultaneous electrophysiological recordings
and fMRI in animals
A series of studies dedicated to the simultaneous recording of electrophysiology and
fMRI during electrostimulation by microelectrodes, have led to major findings
concerning the effect of brain electrical stimulation.
Among others, Logothetis’ group in Tuebingen, has demonstrated that
microstimulation in the visual system elicits an increased BOLD signal in the direct
(mono-synaptic) efferent regions (19). However, the BOLD signal is suppressed in
the next trans-synaptic regions (20). For example, a stimulation of the lateral
geniculate nucleus (direct afferent structure of the primary visual cortex V1) elicited
an increased BOLD signal in V1 but suppressed it in the efferent retinotopically
matched structures of V1 (i.e. the extra-striate associative visual cortex). These effects
were found at sufficiently high frequency stimulation (approximately from 50Hz) and
increased linearly from 50 to 200 Hz (note that stimulations inferior to 50Hz elicited
decreased BOLD signal both in V1 and extrastriate cortex). Interestingly, after
microinjections of GABA antagonists in V1, lateral geniculate nucleus stimulation
induced increased BOLD signals in all of the cortical areas. This trans-synaptic
inhibition is therefore probably mediated by GABA and possibly due to the inhibitory
interneuron activation. An electrical stimulation could be seen as a brief activation
followed by a long-lasting inhibition in the structures stimulated as well as in
monosynaptic efferent cortical areas. In addition electrical stimulation disrupts
cortico-cortical signal propagation by inhibiting trans-synaptic signal transmissions
(20). The authors also found different local effects depending on the cortical layers
Proc. Intl. Soc. Mag. Reson. Med. 20 (2012)
considered. Thus, it is obvious that microstimulation and macrostimulation are not
easily comparable.
A recent study has also compared functional connectivity measured by resting-state
fMRI correlation maps and functional connectivity measured by cortical stimulationelicited fMRI activation maps in sensorimotor systems. Interestingly, they found
congruent intrahemispheric correspondences but consistent interhemispheric
differences (21).
Conclusion
Multimodality is probably the next step in order to bring further evidence in cortical
function and connectivity mapping. Electromodulation is an outstanding tool in
Neuroscience and Neurosurgery but the complex effects of such stimulations locally
and on remote connected areas should be better controlled. It is now clearly
demonstrated that the behavioral consequences of stimulations are not the gold
standard and should be assisted, at the best, by electrophysiological recordings, taskrelated and resting-state fMRI, and diffusion-tractography MRI.
In this field, modeling studies are also required to better predict these effects at the
microscopic and macroscopic scale in order to better understand what kinds of
neuronal populations are really stimulated and how.
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