Deep Brain Stimulation and L-DOPA Therapy: Concepts of Action and Clinical Applications in Parkinson’s Disease

Abstract

L-DOPA is still the most effective pharmacological therapy for the treatment of motor
symptoms in Parkinson’s disease (PD) almost four decades after it was first used. Deep
brain stimulation (DBS) is a safe and highly effective treatment option in patients with PD.
Even though a clear understanding of the mechanisms of both treatment methods is
yet to be obtained, the combination of both treatments is the most effective standard
evidenced-based therapy to date. Recent studies have demonstrated that DBS is a
therapy option even in the early course of the disease, when first complications arise
despite a rigorous adjustment of the pharmacological treatment. The unique feature of
this therapeutic approach is the ability to preferentially modulate specific brain networks
through the choice of stimulation site. The clinical effects have been unequivocally
confirmed in recent studies; however, the impact of DBS and the supplementary effect of
L-DOPA on the neuronal network are not yet fully understood. In this review, we present
emerging data on the presumable mechanisms of DBS in patients with PD and discuss
the pathophysiological similarities and differences in the effects of DBS in comparison
to dopaminergic medication. Targeted, selective modulation of brain networks by DBS
and pharmacodynamic effects of L-DOPA therapy on the central nervous system are
presented. Moreover, we outline the perioperative algorithms for PD patients before and
directly after the implantation of DBS electrodes and strategies for the reduction of side
effects and optimization of motor and non-motor symptoms.

Full text

REVIEW
published: 27 August 2018
doi: 10.3389/fneur.2018.00711
Frontiers in Neurology | www.frontiersin.org 1August 2018 | Volume 9 | Article 711
Edited by:
Pille Taba,
University of Tartu, Estonia
Reviewed by:
Matteo Bologna,
Sapienza Università di Roma, Italy
Pedro Ribeiro,
Universidade Federal do Rio de
Janeiro, Brazil
*Correspondence:
Muthuraman Muthuraman
mmuthura@uni-mainz.de
†Shared authorship
Specialty section:
This article was submitted to
Movement Disorders,
a section of the journal
Frontiers in Neurology
Received: 01 May 2018
Accepted: 06 August 2018
Published: 27 August 2018
Citation:
Muthuraman M, Koirala N, Ciolac D,
Pintea B, Glaser M, Groppa S,
Tamás G and Groppa S (2018) Deep
Brain Stimulation and L-DOPA
Therapy: Concepts of Action and
Clinical Applications in Parkinson’s
Disease. Front. Neurol. 9:711.
doi: 10.3389/fneur.2018.00711
Deep Brain Stimulation and L-DOPA
Therapy: Concepts of Action and
Clinical Applications in Parkinson’s
Disease
Muthuraman Muthuraman 1
*†, Nabin Koirala 1†, Dumitru Ciolac 2, 3, Bogdan Pintea 4,
Martin Glaser 5, Stanislav Groppa 2,3 , Gertrúd Tamás 6† and Ser giu Groppa 1†
1Movement Disorders and Neurostimulation, Biomedical Statistics and Multimodal Signal Processing Unit, Department of
Neurology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany, 2Department of Neurology,
Institute of Emergency Medicine, Chisinau, Moldova, 3Laboratory of Neurobiology and Medical Genetics, Nicolae
Testemi¸tanu State University of Medicine and Pharmacy, Chisinau, Moldova, 4Department of Neurosurgery, University
Hospital of Bonn, Bonn, Germany, 5Department of Neurosurgery, University Medical Center of the Johannes Gutenberg
University, Mainz, Germany, 6Department of Neurology, Semmelweis University, Budapest, Hungary
L-DOPA is still the most effective pharmacological therapy for the treatment of motor
symptoms in Parkinson’s disease (PD) almost four decades after it was first used. Deep
brain stimulation (DBS) is a safe and highly effective treatment option in patients with PD.
Even though a clear understanding of the mechanisms of both treatment methods is
yet to be obtained, the combination of both treatments is the most effective standard
evidenced-based therapy to date. Recent studies have demonstrated that DBS is a
therapy option even in the early course of the disease, when first complications arise
despite a rigorous adjustment of the pharmacological treatment. The unique feature of
this therapeutic approach is the ability to preferentially modulate specific brain networks
through the choice of stimulation site. The clinical effects have been unequivocally
confirmed in recent studies; however, the impact of DBS and the supplementary effect of
L-DOPA on the neuronal network are not yet fully understood. In this review, we present
emerging data on the presumable mechanisms of DBS in patients with PD and discuss
the pathophysiological similarities and differences in the effects of DBS in comparison
to dopaminergic medication. Targeted, selective modulation of brain networks by DBS
and pharmacodynamic effects of L-DOPA therapy on the central nervous system are
presented. Moreover, we outline the perioperative algorithms for PD patients before and
directly after the implantation of DBS electrodes and strategies for the reduction of side
effects and optimization of motor and non-motor symptoms.
Keywords: Parkinson’s disease, levodopa, deep brain stimulation (DBS), subthalamic nucleus (STN), globus
pallidus internus (GPi)
INTRODUCTION
The principal pathological characteristic of Parkinson’s disease (PD) is the progressive death of
the pigmented neurons of the substantia nigra pars compacta (SNc) diagnosed by symptoms
including bradykinesia/akinesia, rigidity, postural abnormalities and tremor (1). The discovery in
the 1960s that the degeneration of the dopamine (DA) neurons of the SNc cause parkinsonism

Muthuraman et al. DBS and L-Dopa Networks in PD
(2) prompted the development of pharmacological therapies for
PD using the DA precursor L-3,4-dihydroxypheylalanine (L-
DOPA or levodopa) to enhance synaptic DA transmission (3).
Five decades after its introduction, L-DOPA is still the most
effective and widely used drug to alleviate the symptoms of PD
(4). In recent years, deep brain stimulation (DBS) has become a
standard evidence-based therapy for severe movement disorders
such as PD (5), tremor (6) and dystonia (7). Since the first
DBS surgery in Grenoble nearly 30 years ago (8), over 100,000
patients have undergone DBS implantations for neurologic and
neuropsychiatric conditions (9). Even though DBS has been
investigated for more than 20 different clinical indications and
40 distinct targeted areas (10), the mechanisms through which
DBS modulates the underlying brain networks and the effects of
local stimulation on brain functioning are still poorly understood
(11–13). Whether DBS suppresses or activates local neuronal
elements, interrupts or modulates the information flow within
the cerebral networks (14–16) or improves the signal-to-noise
ratio in a stochastic system (17) is still a matter of debate.
Medically intractable motor fluctuations and tremor are
independent indications for DBS in PD, in which the electrodes
are most commonly implanted in the subthalamic nucleus
(STN) or globus pallidus internus (GPi) (5). Bilateral STN-DBS
effectively improves the motor fluctuations, bradykinesia and
tremor (18). Bilateral GPi stimulation has analogous effects on
these symptoms (19), except that comparable tremor relief is
less likely to be achieved with this implantation site (20). DBS
of the thalamic ventral intermediate nucleus (VIM) is a less
common alternative target in patients with tremor-dominant
PD, refractory to medication (21). In this review, we outline
the similarities and differences in dopaminergic treatment and
DBS on neurophysiological, anatomical and clinical levels. Based
on this, we discuss how these therapies should be efficiently
superimposed in the long-term to achieve an optimal clinical
outcome.
MOLECULAR MECHANISMS OF L-DOPA
Parkinsonian symptoms appear when brain levels of dopamine
are reduced by 70–80% (22). Dopamine itself has low
bioavailability and does not cross the blood-brain barrier (BBB),
hence its precursor L-DOPA is used clinically; it is readily
transported into the central nervous system (CNS) and is
converted into dopamine in the brain by the enzyme DOPA
decarboxylase (Figure 1). Only a small quantity of systemically
administered L-DOPA enters into the brain; however, this
quantity is enough to restore the nigrostriatal dopaminergic
neurotransmission. Although conversion into dopamine is the
basic mechanism of levodopa’s pharmacological effect, it also
possesses a direct neuromodulatory action and contributes to the
therapeutic efficiency.
L-DOPA is given with carbidopa or benserazide, drugs which
do not cross the BBB but inhibit DOPA decarboxylase in
peripheral tissues (23). This association of L-DOPA with DOPA
decarboxylase inhibitors minimizes it’s peripheral degradation,
thus extending its half-life (and increasing the availability to the
brain) and thereby prolonging the duration of its symptomatic
effect (24). Additionally, this reduction in peripheral conversion
to dopamine also minimizes the predominant side effects of
circulating dopamine like nausea, vomiting and hypotension
(25). Another method for improving the bioavailability of L-
DOPA is to inhibit its peripheral metabolism via the catechol-
O-methyltransferase (COMT) pathway. Inhibition of COMT by
tolcapone, entacapone (26) or by a newly available opicapone
(27) leads to decreased plasma concentration of 3-O-methyldopa,
increased uptake of levodopa, and increased concentrations of
dopamine in the brain.
EFFECTS OF DOPAMINE ON BRAIN
NETWORKS
Dopamine is produced in the ventral tegmental area and pars
compacta of SN and acts through anatomically segregated
but functionally connected pathways (28). The mesocortical,
mesolimbic and nigrostriatal dopaminergic systems play a
key role in cognition, reward and motor control functions,
respectively; their close interaction results in goal-directed
behaviors (29).
The midbrain dopaminergic systems project mainly to the
striatum and the cortex but also to the thalamus, amygdala,
hippocampus and globus pallidus (GP). Its afferent innervation
arrives from the striatum and the pedunculopontine nucleus (28).
Two subclasses of dopaminergic receptors have been identified
in the brain: the D1-like receptor (D1R and D5R) and the D2-
like receptor (D2R, D3R and D4R). D1R and D2R are expressed
on the GABAergic medium spiny neurons in the dorsal striatum.
The D1R contributes to the information flow of the direct
pathway, while the D2R contributes to the indirect pathways
(30). Their reorganization in the basal ganglia such as increased
D2R and decreased D1R expression (31) together with the loss
of presynaptic D2R leads to the primary symptoms of PD (30).
The highest densities of both D1R and D2R were found in areas
that receive a dense dopaminergic innervation such as in nucleus
caudatus, GP and putamen in the human brain (32). The SN
contains a higher concentration of D1R than D2R. Both receptor
types are also expressed in the hippocampus, but only D1R is
expressed in amygdala and the neocortex (33). Furthermore,
D3R was found in the hypothalamus, in addition to the SN,
ventral pallidum/substantia innominata, ventral striatum, GP
and thalamus, showing the clear involvement of basal ganglia
dopamine circuit (34). In addition, D1, D2 and D3 receptors were
identified in the STN and were shown to mediate the effect of
dopamine on STN neuronal activities (35).
The combination of different dopaminergic drugs is beneficial,
considering their diverse receptor affinity profiles. While
dopamine has the highest affinity to D1R, dopamine agonists
target mainly D2R. Dopamine agonists can be subdivided into
ergoline and non-ergoline derivatives (36). Among the ergoline
dopamine agonists, apomorphine is a combined D1R and D2R
agonist with more affinity to D2R/D3R than to D1R. In the
non-ergoline group, pramipexole, ropinirole and rontigotine
are the most widely used dopamine agonists. Pramipexole and
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Muthuraman et al. DBS and L-Dopa Networks in PD
FIGURE 1 | Illustration of the molecular mechanism of L-DOPA.
ropinirole are known to have a higher affinity to D3R than to
D2R, whereas rotigotine is considered to have affinity at several
dopamine receptors with a predilection to D1R, D2R and D3R
in comparison to D4R and D5R (37). The rare but severe side
effects of the ergot-derived dopamine agonists such as fibrosis of
the cardiac valves, pleuropulmonary and retroperitoneal fibrosis
have limited their use in the clinical practice (38). It has
been shown that dopamine is a neurotransmitter that acts not
only through synaptic transmission but also by non-synaptic
communication (39). In the latter case, dopamine diffuses into
the extracellular space and exerts its effect on high-affinity
receptors, which are as well-targeted by various drugs (e.g.,
imipramine).
Administration of L-DOPA increases the functional
connectivity within the motor network comprising the putamen,
anterior cerebellum and ventral brainstem and ameliorates the
motor performance in both healthy (40) and PD populations
(41). At the same time, it also decreases the connectivity of the
STN-thalamo-cortical motor network (42). The modulatory
effects of L-DOPA on motor networks differ among PD patients
with different motor subtypes: L-DOPA increases the effective
connectivity between posterior putamen and distributed motor
network during a tapping task in tremor-dominant PD but not
in the postural instability/gait difficulty subtype (43). L-DOPA
also increases the coupling between the prefrontal cortex and
supplementary motor area (SMA) during a simple motor
task (such as finger tapping) but not during tasks requiring
higher motor control, hinting at the effect of dopaminergic
medication on selective motor control and partial effects on
bradykinesia (44,45). Another study showed that acute levodopa
administration significantly enhances the spontaneous functional
connectivity in the sensorimotor network in drug-naive patients
with PD (46). Taken together, these studies indicate the selective
improvement of hypokinetic and bradykinetic movement
abnormalities in PD with L-DOPA administration. L-DOPA
increases the functional connectivity between the regions related
to the cognitive network–the inferior ventral striatum and
ventrolateral prefrontal cortex in healthy subjects (40) and
in parkinsonian patients (47), in whom maintenance of the
working memory performance requires recruitment of the right
fronto-parietal network which is as well-boosted by L-DOPA
intake (48).
The effect of L-DOPA on cortical networks has been
studied considering the modulatory effects of dopamine in basal
ganglia. The abnormalities in M1 excitability and plasticity have
been demonstrated by several transcranial magnetic stimulation
(TMS) based neurophysiological studies (49,50). Even though
there are inconsistencies among studies regarding the findings
in altered motor cortical plasticity, almost all of them agree
that those abnormalities are improved following L-DOPA
administration (51–53). There are also conflicting findings in
the PD studies using the paired associative stimulation (PAS)
technique revealing abnormalities in M1 long-term plasticity.
PAS involves pairing a stimulus to the median nerve (at
the wrist) with a TMS pulse given some milliseconds later
over M1 (54). Some of these studies demonstrated decreased
responses to PAS in patients off treatment, with a partially
restored response when on treatment (55). Others showed either
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Muthuraman et al. DBS and L-Dopa Networks in PD
no effect of L-DOPA on PAS (56) or an increased response
to PAS in PD patients off therapy and restored responses
when they were on therapy (57). These differences might be
explained by the asymmetric motor symptoms and hemispheric
difference in the PAS-induced plasticity (58). Investigation of
the mechanism of action of L-DOPA by means of various
neurophysiological approaches has revealed that L-DOPA does
not restore movement abnormalities, such as the sequence
effect or facial bradykinesia but inhibits abnormal neuronal
oscillations in basal ganglia, improves reduced discriminative
capacities of the sensory system and partially normalizes motor
cortex excitability (59,60). Studies that integrate sensory
temporal processing and movement execution for observing the
effect of L-DOPA on plasticity and connectivity between the
primary motor area and other non-motor cortical areas are still
needed.
MECHANISMS OF DBS ACTION
Even though the exact underlying physiological mechanism
of DBS remains unclear, the therapeutic benefits of DBS
seem to be frequency-dependent and can modulate cortical
activities. Several animal studies have shown support for the
hypothesis of direct cortical activation during STN-DBS (61,62).
These studies have provided evidence of the occurrence of
antidromic spikes in M1 during the DBS paradigm which
coincides with the optimal effect of STN-DBS. Whether a similar
antidromic activation of the known cortex-GPi projection
(63) contributes to the therapeutic effect of GPi-DBS remains
to be studied. Non-invasive brain stimulation studies using
TMS have shown abnormal motor cortical plasticity in PD
which has been investigated further for understanding the
mechanism of DBS. It has been shown that paired associative
cortical plasticity could be induced by repeated STN and M1
stimulations at specific intervals, signifying that STN-DBS can
modulate cortical plasticity (64). Moreover, STN stimulation
with clinical efficacy increased the excitability of the motor
cortex at specific short and medium latencies, suggesting that
cortical activation could be one of the mechanisms mediating
the clinical effects of STN-DBS in PD (65). It has been further
suggested that enhancement of inhibitory synaptic plasticity,
non-specific synaptic depletion and frequency-dependent
potentiation might be complementary mechanisms of DBS action
(66,67).
Several hypotheses exist regarding how DBS acts on neural
elements (Figure 2). These hypotheses can broadly be divided
into three main categories. The most prevalent is the suppression
hypothesis in which DBS is supposed to suppress the activity
in local neuronal cells and modulate the pathways connecting
subcortical and cortical structures, thus having a similar effect as
lesioning (68,69). Inhibition of the neural action potential during
stimulation was recorded around the stimulation sites of STN-
DBS in patients (70,71), as well as in monkeys with induced
parkinsonism (72,73). In addition, the complete blockage
of neuro-axonal transmission of some STN neurons and the
residual neuronal activity of the remaining STN neurons was
shown to support the hypothesis of an inhibitory influence of
STN-DBS on neuronal activity in STN (74).
The second hypothesis is the activation of local neuronal
elements. STN-DBS increased neural activity in the
interconnected structures such as GPi and substantia nigra
(SN) neurons in parkinsonian monkeys (75). In rats, low
intensity STN-DBS induced GABAergic suppression in SN
through activation of the globus pallidus externus (GPe)
neurons, while high intensity STN-DBS induced glutamatergic
excitation in the SN (76,77). Furthermore, it has been shown
in rats that STN-DBS induces an increase in activity in motor
cortex neurons (62,78,79). Another study using optogenetics
additionally showed that selective stimulation of cortico-
STN afferent axons without activation of STN efferent axons
ameliorated the symptoms of parkinsonian mice (61).
The third hypothesis is the interruption hypothesis in which
the abnormal information flow through the STN is disturbed
by STN-DBS. The reciprocal GPi-STN connection produces
abnormal synchronized neuronal activity patterns in PD, and
this interruption of information flow through the STN reduces
these patterns (14,76). In addition, due to loss of dopaminergic
modulation, reduced activity in the striato-GPi direct pathway
and hyperactivity along the hyperdirect and striato-GPe indirect
pathways is observed in PD. The STN-DBS may disrupt this
neuonal activity in STN on the direct and indirect pathways
and subsequently reduces such pathological activity (80). Hence,
overall STN-DBS might effectively alter the rhythmic interaction
by modulating or suppressing the pathological excitability
without clearly inhibiting or activating the neural elements (81).
NETWORK EFFECTS OF DBS
A network perspective on brain structure and function,
accounting for the interaction and anatomical connections
between regions, offers a potentially valuable framework for the
study of physiological brain functioning and for identification
of relevant pathological abnormalities at the systemic level. The
involvement of STN and GPi in multiple circuits connecting
the basal ganglia and cortical regions that mainly regulate the
motor, limbic and associative functions is well-established (82–
86). This involvement of STN and GPi in various circuits has
motivated network-based exploration using various methods for
understanding the DBS modulation mechanisms (Figure 3).
Functional Network Effects
A considerable number of positron emission tomography (PET)
studies have analyzed the functions of the motor system in
PD and its relation to DBS treatment. Both resting state
and motor task paradigms were investigated using regional
cerebral blood flow (rCBF) measurements (87,88) or by
quantifying glucose metabolism (89,90). These studies showed
a decreased activation during STN stimulation at resting state in
comparison to no stimulation state in premotor cortex (PMC),
dorsolateral prefrontal cortex (DLPFC), SMA and anterior
cingulate cortex (ACC) and increased metabolism during task
in DLPFC, rostral SMA and ACC (88). Additionally, during
the comparison of STN-DBS ON vs. OFF state, increased
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Muthuraman et al. DBS and L-Dopa Networks in PD
FIGURE 2 | The basal ganglia circuits modulated by deep brain stimulation (DBS) and L-DOPA. The colors represent the activation by L-DOPA (green), excitatory
neuronal pathways (blue) and inhibitory neuronal pathways (red). The thickness of the lines between the regions represents the strength of signaling. GPi, globus
pallidus internus; GPe, globus pallidus externus.
rCBF was found in midbrain regions (including STN), GP and
thalamus (91). Furthermore, several studies addressed cerebral
metabolic dynamics during DBS while performing various
cognitive tasks. Irrespective of task (motor imagery of gait
or stance), during the STN-DBS stimulation OFF condition
the activity in sensorimotor cortex, SMA and cerebellum is
increased, while during the stimulation ON condition, bilateral
STN, precuneus, inferior parietal cortex and cerebellum are
activated (92). During both STN-DBS conditions, imagery of
gait increased the neural activity in SMA and superior parietal
lobule (93). The improvement of imagined gait during the
STN-DBS ON condition was linked to the increase in rCBF
in the pedunculopontine nucleus/mesencephalic locomotor
region without significant modulation of cortical and cerebellar
locomotor areas (92). Although the neural correlates of GPi
stimulation in PD have been less investigated, some studies
have shown an increase in ACC and SMA activation during
a motor task (94,95). These findings were similar to SMA
activity modulation during STN-DBS, however in contrast to
GPi-DBS there was no increase in DLPFC activation which could
be explained by different pathways affected by stimulating each
target (96). Furthermore, Fluorodeoxyglucose-positron emission
tomography (FDG-PET) measuring resting regional cerebral
glucose utilization during ON and OFF phases of stimulation
in GPi has shown a reduction in regional metabolic patterns
(largely in primary motor cortex) during ON phase which was
significantly correlated with the clinical improvement (97,98).
Studies in STN-DBS patients using functional MRI (fMRI)
are limited because of safety concerns and imaging artifacts
(99,100). Nonetheless, recent MR studies performed under
specific experimental conditions with resting state and task-based
fMRI have shown interesting results. In primates, a recent study
provided evidence that STN-DBS significantly increased blood
oxygenation level-dependent (BOLD) activation in sensorimotor
cortex, SMA, caudate nucleus, pedunculopontine nucleus,
cingulate, insular cortex and cerebellum (101). Similarly, a study
in rats also found increased BOLD responses in ipsilateral
cortical regions, including motor cortex, somatosensory cortex
and cingulate cortex during STN- and GPi-DBS (102). No clear
patterns of BOLD signal modulation have been tracked during
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Muthuraman et al. DBS and L-Dopa Networks in PD
FIGURE 3 | Network effect of DBS. The figure shows the functional network (with PET, fMRI, and EEG) and structural network with tractography. STN, subthalamic
nucleus; SN, substantia nigra; CN, caudate nucleus, SMA, supplementary motor area; SPCT, Subthalamo-ponto-cerebellar tract; DTT, Dentate-thalamic tract.
STN-DBS in humans (103), while several common regions have
been identified with distinct activation patterns in most of
these studies—encompassing ipsilateral thalamic nuclei, SMA,
DLPFC, lateral premotor cortex and ACC–corresponding to the
networks obtained in animal models and PET studies (104–
106). In a study to trace DBS-induced global neuronal network
activation in an animal model using fMRI, GPi-DBS activated
a larger area of the motor network in comparison to STN-
DBS (107). Although STN and GPi stimulation showed common
sensorimotor network activation, each was found to activate a
distinctive neural network.
Structural Network Effects
Even though the target for DBS consists of gray matter
structures, DBS predominantly activates the axons rather than
cell bodies (108,109). Hence, study of white matter tracts near
the deep nuclei is of great relevance. The measures of white
matter microstructural properties and their alterations in various
regions of the brain have shed light on important aspects of PD-
related pathological process using diffusion imaging (110–112).
In the case of PD patients, two tracts, namely the subthalamo-
ponto-cerebellar tract (SPCT) and the dentate-thalamic tract
(DTT) were identified using probabilistic tractography and
showed that active contact positions in proximity to DTT are
associated with tremor improvement during the stimulation
(113). It has been recently shown using probabilistic tractography
that from STN the areas which are frequently connected with
the clinically effective contacts included thalamus, SN, brainstem
and superior frontal gyrus; the strength of connectivity to
the superior frontal gyrus and thalamus correlated with the
clinical effectiveness (114). In addition, the modulation of the
hyperdirect pathway between the STN and cortical regions was
postulated (115). A recent study using diffusion MRI-based
tractography (both deterministic and probabilistic) showed
that the connections from ipsilateral motor cortex primarily
terminated in the dorsolateral STN, further highlighting a key
role of hyperdirect pathways in mediating the effects of DBS
(116). A diffusion tensor imaging (DTI) analysis investigating the
connectivity map of GPi revealed the anterior part to be mainly
connected to the prefrontal cortex, the middle section to the
brainstem and GPe and the dorsal GPi mainly to the thalamus
and GPe (117). In addition, the postero-ventro-lateral part of
the GPi, shown to have the most effective clinical outcomes
for PD (118), was found to be connected to the thalamus via
the pallidothalamic tract. This is further supported by previous
findings of the functional perception of the pallidothalamic
tracts as the main sensorimotor GPi efference tract (119). One
of our recent works pointed out the role of the properties
of the targeted network, its connectivity profile and relation
to clinical response (86). The topological properties (derived
from probabilistic tractography of preoperative MRIs) of the
network, involving frontal, prefrontal cortex and cingulate gyrus
were directly associated with the post-operative clinical outcome.
Particularly, eccentricity (a network measure of the extent of
cerebral regions’ embeddedness in relation to distant areas)
inversely correlated with the DBS stimulation voltage at the active
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Muthuraman et al. DBS and L-Dopa Networks in PD
electrode for an optimal clinical response (86). Thus, we could
show that the connectivity pattern and topological organization
of the DBS-targeted network are important and independent
predictors of the post-DBS therapeutic efficiency.
EFFECTS OF DOPAMINE AND DBS ON
BRAIN OSCILLATIONS IN PD
Oscillations at multiple frequencies may reflect information
processing in the neural networks (120). It has already been
demonstrated that movement-related spectral changes in the
activity of the SMA, primary sensorimotor cortex and the
basal ganglia indicate a different kinetic state in the patient. In
the sensorimotor cortex, elevated synchronization in the beta
frequency (15–30 Hz) band was associated with the slowing of
voluntary finger movement in healthy subjects (121). Local field
potentials (LFPs) of STN in parkinsonian patients undergoing
DBS surgery exhibited increased beta activity in the basal
ganglia and cortical regions, and correlated with the OFF
phase symptoms (122), except tremor (123). This beta activity
was found to be decreased after levodopa intake (124). Beta
activity in the STN of PD patients is not permanently increased
but occurs rather in so-called beta bursts; the amplitude
of beta bursts (as the indicator of degree of local neural
synchronization) is progressively enhanced with the duration of
bursts (125). During the levodopa ON condition, beta bursts
become shorter with lower amplitude that correlates with the
motor improvement. However, long duration beta bursts are
associated with an increase not only in local synchronization
but also in interhemispheric synchronization that compromises
the patterns of motor processing (125) and is reversed by
levodopa treatment. Beta activity is differentially modulated
by adaptive and conventional DBS techniques (126). Adaptive
DBS elicits a shift from long beta bursts with high amplitude
toward shorter bursts with lower amplitude (due to precocious
cancelation of long beta bursts by triggered DBS stimulation),
while conventional DBS only suppresses beta activity on a global
level, without altering the frequency and duration of beta bursts.
The increased frequency of short duration beta bursts by adaptive
DBS partly explains the mechanisms by which adaptive DBS
induces the improvement of motor performance (126).
An excessive synchronization in beta band was identified
between the basal ganglia and the motor cortex in PD patients
(127,128). In addition, STN spiking has also been shown
to be synchronized with cortical broadband gamma, which
occurs in a phase-modulated pattern and begins prior to the
occurrence of STN spikes (129). The gamma frequency band
(>30 Hz) synchronization in the motor cortex areas and STN
of PD patients is thought to represent a prokinetic state which
promotes movement-related processing (130,131). Another
physiological phenomenon on the scalp level, the beta band
cortico-muscular coherence, seems to be also disturbed in PD
with its frequency shifted to the lower ranges in the OFF state
and is reversed after levodopa intake (132). It has become evident
that oscillatory activity across multiple circuits and frequency
bands may be important in the pathophysiology of PD (133,
134). This is perhaps best exemplified by recent simultaneous
magnetoencephalography (MEG) and STN-LFP measurements
in patients undergoing DBS surgery that demonstrated the
existence of multiple regions, which are spatially and spectrally
segregated in the STN-cortical oscillatory networks. At rest, a
beta band network exists between the STN and motor/premotor
areas in addition to a diffuse alpha band network between the
STN and temporoparietal regions as well as the brainstem (135).
A gamma band network between the STN and motor/premotor
cortical areas also intensifies around the time of movement,
particularly with dopaminergic therapy (136,137). With regard
to the identified network, it is interesting to note that activities
in this frequency band have been linked to orienting attention
at a cortical level (138) and also the directionality of this
network is predominantly from the cortex toward the STN (136).
Although formal confirmation of a putative role for the STN-
cortico-brainstem network in orienting attention is still needed,
it is worth mentioning that movement-related reductions in
coherence in this network (on and off levodopa) correlate with
clinical motor improvement (131). Given the above findings,
we might speculate that the coupling changes within the STN-
cortico-brainstem network in PD may be related to attentional
deficits to motor impairment. This hypothesis is supported by
previous correlations between attentional deficits in PD and signs
of motor impairment such as gait freezing and falls (139,140). It
is intriguing that the levodopa dependence on frequency changes
with the reactivity of STN-cortical coupling during voluntary
movement, which triggers the bursts of cortical multiunit activity
at beta rhythms driving the STN-LFP oscillations (131,141).
The modulation of the amplitude of the cortical broad gamma
oscillations is involved in phase amplitude coupling (PAC), which
is decreased by DBS, correlating with the motor improvements
after DBS (142). In addition, new studies have shown that
DBS not only suppresses the elevated resting broadband gamma
activity present in PD (143) but that an adaptive DBS could
also focus on narrowband gamma oscillations for the reduction
of dyskinesia. It has been further proposed that the striatal
mechanisms of levodopa-induced dyskinesia (144) might have
some links with the gamma oscillations (145).
The resting tremor in PD is thought to be driven by certain
oscillators in the brain (146–148). But the neural basis of
these tremor oscillations is not very clear as the hand tremor
displays a marked spatiotemporal pattern which makes the
tremor activities of different limbs almost never coherent (149–
151). MEG and electroencephalography (EEG) studies have
allowed the characterization of brain regions coherent with
parkinsonian resting and postural tremor, hence, revealing the
functional tremor networks. These studies have demonstrated
the presence of strong electromyogram (EMG) coupling with the
signal of the contralateral primary motor cortex (M1) and also
cortico-cortical coupling between M1 and other premotor, SMA,
somatosensory areas, diencephalic and cerebellar sites (151–
153). On the subcortical level, oscillatory peaks at the tremor
frequency and its harmonics were revealed within the STN, GPi
and thalamus (154–156) in addition to coherence between these
sites and the EMG activity (157,158). Recent work has shown
that in the distinct group of brain regions acting synchronously,
segregated tremor clusters may relate to tremor activity in specific
muscle groups, pointing to multiple tremor-related subloops
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Muthuraman et al. DBS and L-Dopa Networks in PD
within subcortical structures (158), which suggests the possible
existence of multiple tremor oscillators within the basal ganglia-
thalamo-cortical circuits.
CLINICAL ASPECTS OF DOPAMINERGIC
THERAPY
The clinical benefit of levodopa has not been doubted since
its description (159) and is still the most effective symptomatic
drug for PD (160). Current therapeutic approaches rely upon
levodopa and dopamine agonists. Levodopa, the precursor
of dopamine moves across the BBB and combines with the
peripherally-acting decarboxylase inhibitors such as benserazid
and carbidopa to ensure its bioavailability in the CNS and
thereby its clinical effectiveness in patients (161). However, it
does not relieve other disabling symptoms of PD possibly derived
from alterations in other neurotransmitter systems, such as
cholinergic, noradrenergic, and serotonergic systems (162,163).
Furthermore, several classifications of PD subtypes (164) were
created with the need of an individual and/or combined strategy
to pharmacotherapy during the course of the disease.
The optimal time for starting levodopa therapy in the clinical
practice is still a matter of debate. Its short-term effect and
long-term complications should be taken into consideration
when planning the therapeutic strategies. Previous studies have
shown that the choreiform dyskinesias occur in 17–45% patients
and end-of-dose-wearing off in 37–57% patients in 2–5 years
after the onset of levodopa therapy (165,166). Even though
the pharmacokinetic profile of levodopa is often blamed as
the source of these complications, the exact cause is still far
from understood (167). With conventional formulation of L-
DOPA, irregular absorption and rapid catabolism are the basis of
these long-term complications, which triggered the development
of various other techniques including sustained-release oral
formulations (161). Even though the correlation between L-
DOPA therapy and the occurrence of long-term side effects
was apparently stated as essential in many studies, the recent
view considers the clinical phenotype and the individualized
course as an even more important factor (168). A possible toxic
nature of dopamine by accelerating the loss of dopamine neurons
emerged earlier and could not be excluded appropriately (169).
Thus, the lowest dosage providing satisfactory effect should
be applied for the optimal output. In advanced stages of PD,
there are evidence-based recommendations of strategies for
providing more continuous dopaminergic stimulation or to offer
DBS to the patients (170). However, drug adjustment is often
considered based on the phenotype and clinical complications
of the individual patient before addressing the indications for
DBS. Recently, additional therapeutic options like fluid L-DOPA
formulation or amantadine, safinamide and opicapone have been
introduced (171–173).
CLINICAL ASPECTS OF DBS SURGERY
Preoperative Management
DBS is an aggregate and interdisciplinary decision between
patients, their families, neurologists, neurosurgeons, psychiatrists
and neuropsychologists. All those involved in the process
including patients themselves need to have realistic expectations
after surgery. Patients should be made fully aware that DBS is not
able to cure the disease but it is able to optimize mainly the motor
symptoms, henceforth, the quality of life.
A detailed initial evaluation is needed in a movement disorder
center to determine whether the patient will benefit from
DBS. For this purpose, an experienced team of neurologists
specialized in movement disorders and in particular in DBS,
functional neurosurgeons, psychiatrists and psychologists with
experience in movement disorders needs to be homogenized.
As the first step, the diagnosis of idiopathic PD should
be confirmed as other Parkinson syndromes usually do not
respond to DBS (174). Furthermore, patient’s current and past
antiparkinsonian medication as well as the dosing schedule
should be carefully reviewed. Subsequently, the response to
dopaminergic medication (levodopa) should be (re)tested as the
improvement of motor symptoms after the L-DOPA challenge
is one of the very few known predictors of the clinical
outcome after DBS (175). There is still an imperative need for
the development of an objective and investigator-independent
paradigm that can accurately denote the symptoms that could
be targeted by DBS and the approximate improvement after
the surgery (176). Several further clinical parameters have been
analyzed as possible predictors of the post-operative clinical
outcome of DBS-STN but until now dopaminergic response has
been the strongest prognostic factor of post-operative outcome
(177). Recently, the newly developed network and cortical
morphometric parameters have also shown some promising
results for the prediction of clinical outcome after the STN-DBS
(86,176).
In everyday clinical practice, the Unified Parkinson’s Disease
Rating Scale (UPDRS) score of a patient is assessed in the
morning after overnight (approximately 12 h) withdrawal of
levodopa and 20–60 min after the patient has ingested 1.5 times
their normal morning levodopa dose. The best possible ON time
is rated as ascertained by the patient and the examiner. Different
dopamine agonists have different criteria to be paused before
testing as mentioned in Table 1. Although there is no fixed limit
of improvement required after the dopaminergic challenge for
a DBS candidate (177), motor improvement of at least 30% is
an objective response criterion (175). Conventionally, DBS is
only offered to the patients who fulfill this response criterion
because only those symptoms which are improved by levodopa
are expected to be improved by DBS.
There is no clear consent on the influence of age and disease
duration on the post-operative outcome. In some studies, it has
been shown that age and disease duration are not predictive
for the post-operative motor outcome (177), while in others,
it was shown that younger patients had more benefit from the
DBS (178). Even though the reason why younger patients have
better motor outcomes after DBS is not entirely clear, it might
be that the older patients may have more comorbidities and
less capacity for neuroplasticity. Similar outcomes have been
shown in recent studies that included patients with early motor
complications or with therapy refractory symptoms (179). A
further important clinical criterion for a positive DBS response
is the cognitive status of the patient. The presence of significant
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Muthuraman et al. DBS and L-Dopa Networks in PD
TABLE 1 | Medication reduction scheme before L-DOPA challenge.
Withdrawal scheme Medication
Overnight withdrawal (12 h) Levodopa/Benserazide
Levodopa/Carbidopa
Levodopa/Carbidopa/Entacapone
Entacapone
Amantadine
Safinamide
Selegeline, Rasagiline
Withdrawal >24 h Opicapone
Withdrawal >48 h Pramipexole, Ropinirole, Rotigotine
Withdrawal >72 h Cabergoline
cognitive impairment is considered a contraindication for STN-
DBS (180). A recent study using MRI demonstrated that cortical
thickness of the frontal lobe (paracentral area and superior
frontal gyrus) predicted the clinical improvement after STN-
DBS. Moreover, in patients with cortical atrophy of these areas,
a higher stimulation voltage was needed for an optimal clinical
response (176). It has also been shown that bilateral STN-
DBS is likely to have a negative impact on various aspects
of frontal executive functioning (181). An exact preoperative
assessment of the cognitive status by a neuropsychologist with
experience in movement disorders should identify psychiatric
symptoms such as psychosis, apathy, depression and anxiety
and treat them optimally before considering or denying the
DBS treatment. The possible cognitive and psychiatric side
effects of medications (cholinergic agents, dopamine agonists,
overdosed dopaminergic drugs) should be ruled out. For the
cognitive assessment one of the following tests are conventionally
used—Mini Mental State Examination (MMSE), Montreal
Cognitive Assessment (MoCA), DemTect (182), Parkinson
Neuropsychometric Dementia Assessment (PANDA) or Mini
Mental Parkinson (MMP).
Perioperative Management
From the surgical point of view, eligible candidates for the
DBS procedure should be in a satisfactory general and cognitive
condition. Even though there is no difference in motor function
outcomes for performing the surgery awake or under general
anesthesia (183), most of the surgeries are realized with
patients awake in order to perform intraoperative neurological
tasks. In PD patients, concomitant disorders concerning blood
clotting abnormalities, cardiovascular diseases and immune
deficiencies should be evaluated. As a variety of disorders
need anticoagulation therapy, patients should discuss with
their general practitioners to determine the best perioperative
bridging. Cardiovascular risks are discussed with the neuro-
anesthesiologists and the immunological state of the patient
should also be carefully considered, as post-surgical infection
may lead to the ex-plantation of the DBS system.
Concerning the implantation of the DBS system itself,
accuracy and safety are the most important factors to ensure
a good patient outcome. Meticulous trajectory planning to
avoid sulci, vessels, and ventricular walls is mandatory to
minimize the risk of intracerebral hemorrhage. For the precise
implantation, optimized imaging protocols with preoperative
3T magnetization-prepared rapid gradient-echo (MP-RAGE)
MRI with low degree of distortion, use of contrast media for
vessel visualization and modified T2-weighted sequences are
used (184). Frame positioning, computed tomography (CT)
scanning with the localizer and image fusion of the CT with the
preoperative MRI may also influence electrode targeting. One of
the issues unfavorably affecting the accuracy is the low rigidity of
the implanted permanent electrode itself. Hence, intraoperative
microrecording and macrostimulation is performed in many
centers (most commonly in Europe) to confirm the optimal
location of the electrode, and to overcome the brain shift problem
due to liquor loss after opening the dura mater (185,186).
Implantation of the impulse generator on the same day or
a few days after electrode implantation is the preference of
the implanting center. After the surgery, a post-operative CT
or MRI under safety recommendations of the manufactures is
performed; monitoring in an intensive care unit is only required
in case of intraoperative irregularities or post-operative delirium.
Mobilization of the patients starts the day after the surgery.
Regular wound inspection is necessary and patients are taught to
leave all dressings in place and not to manipulate the wounds. The
stiches are removed 10–12 days after the surgery. Intraoperative
and post-operative scanning/imaging is performed to exclude
electrode malpositioning and surgical complications (especially
intracranial hemorrhage). Dopamine is given as soon as possible
after the operation (if necessary over a gastric tube), with an
approximately 25–50% reduction in the preoperative dosage due
to a microlesioning effect (might be unstable) in the initial weeks.
Some patients develop post-operative confusion, which in
most cases needs a supportive therapy with parenteral fluid
therapy and reduced antiparkinsonian medication. In case
of prolonged confusion, atypical antipsychotic agents, e.g.,
quetiapine, clozapine are used.
Post-operative Long-Term Care
Management
There is no consensus for starting the DBS programing but
beginning the programming sessions a few weeks after the
implantation allows time for reducing the microlesioning effect
(187). As of late, stimulation based on constant current are
applied in severe cases, as it makes the stimulation intensity
independent of the impedance (188).
To start the stimulation, the neurologist performs a primary
testing, checking the clinical effects and the therapeutic window
(threshold determination for the clinical effects and the threshold
for the side-effects) for each of the contacts and the range
causing no side effects at each electrode contact, keeping the
pulse width and frequency constant. The contact with the best
clinical benefit/side effects ratio is then activated on both sides.
The medication therapy is then adapted to the stimulation, the
most common being the first levodopa monotherapy (189). The
reduction of the L-DOPA needs a cautious approach to reach
the threshold for best motor outcome with no troublesome
dyskinesia. If the levodopa dose is insufficiently reduced,
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Muthuraman et al. DBS and L-Dopa Networks in PD
patients might develop side effects like dyskinesia or choreiform
hyperkinetic movements, impulsivity and mania but on the
other hand, reducing levodopa too much and too quickly might
lead to apathy, depression or anhedonia (85). Moreover, it
has been shown that decreased levodopa dose is a risk factor
for developing restless leg syndrome (190). The efficacy of
both DBS and dopaminergic therapy depends upon various
factors such as the DBS target and dose of the medications.
However, various cognitive symptoms such as the phonological
and semantic verbal fluency, visuomotor processing or mood
disorders (apathy, depression, anxiety) and other non-motor
symptoms do not respond well to either therapies (DBS and L-
DOPA) in a majority of patients (191). By adjusting the combined
therapy, the neurologist should pay attention to the above-
mentioned synergistic and diverse effects of the two therapies
and the individual needs of the patients. Further decisions on
medication therapy should be made according to evidence-based
recommendations (170).
In addition, patients need specialized neuro-rehabilitation
after DBS implantation (5). Before selecting a proper setting
of post-surgical rehabilitation, the individual needs and goals
for rehabilitation have to be defined for each DBS patient
individually. The goal-specific therapy could be physiotherapy,
Lee Silverman Voice Treatment (LSVT-BIG) therapy, speech
therapy, occupational therapy, talk therapy, cognitive therapy or
behavioral therapy depending upon the patient’s need for best
long-term clinical outcome (5).
DISCUSSION AND CONCLUSION
L-DOPA and DBS are now standard evidenced-based treatments
for PD. Both improve motor symptoms in similar magnitudes,
but show differential effects on dyskinesia, non-motor outcomes
and activities of daily living. After an initial so called
“honeymoon” period of L-DOPA, several limitations become
apparent including postural abnormalities, freezing episodes,
speech impairment, autonomic dysfunction, mood and cognitive
impairment. Additionally, drug-related side effects especially
psychosis, motor fluctuations, and dyskinesia are also observed
in the long term (4,192,193). Similarly, DBS also fails to
drastically improve the non-motor symptoms that significantly
impact the quality of life of the patients (194,195). A
recent meta-analysis demonstrated that while there was similar
individual efficacy of STN-DBS and L-DOPA, their combined
effect on motor severity was additive within and beyond 5
years of follow-up (196). In support of the currently prevalent
paradigm of reducing the dopaminergic tone during post-
surgical management, it has been also shown that a lower
reduction in dopaminergic medications might also result in a
lower incidence of apathy and depression (197). Hence, the
combination of both therapies irrespective of their differential
mechanisms and outcomes might be the best approach until
there is a clear understanding of the pathophysiology. However,
a few recent studies have shown promising preliminary results
in offering carefully selected PD patients earlier DBS treatment
and delaying the severely disabling L-DOPA adverse effects (179,
198). Therefore, the time point of application of DBS is still
a matter of debate and hence the subject of future studies to
prolong the long-term benefits and to modify the natural disease
course.
With the development of advanced imaging techniques and
the availability of up to 7T MRI scanners, it will become possible
for more accurate DBS. Moreover, new methods such as DTI
will enable visualization of the white matter tracts that are close
to the active DBS contact, and likely will provide a deeper
insight into DBS mechanisms (199,200). Furthermore, with the
closed loop and adaptive stimulation techniques being developed,
the dynamic conditions of stimulations might significantly
reduce side effects of DBS (201,202). Similar advancements
in dopaminergic therapy include the improvement of a pump
device for infusing L-DOPA in the jejunal cavity (203), approval
of long-acting (5- to 6-h duration of action) L-DOPA (204),
the new reversible MAO B-inhibitor safinamide to enhance
the action of L-DOPA (205) and an extended-release (24-h
long-acting) formulation of amantadine to markedly reduce the
severity and extent of L-DOPA-induced dyskinesia (206). These
developments will not only enhance the quality of life of the
patients but also will aid in understanding the mode of action.
Dopaminergic drugs act on receptors not only in the
nigrostriatal but also in the mesocortical and mesolimbic systems.
This characteristic distribution of different receptors ensures its
general effect on brain networks and explains its side effects.
The advantage of DBS over dopaminergic therapy is that it
acts on selective anatomical networks. The neuroanatomical
selectivity of DBS warrants less possibility of stimulation-
evoked side effects, especially with the recently implemented
directional stimulation through segmented electrodes. However,
even though the neuroanatomical selectivity of DBS is a huge
benefit, medication therapy and–even more so–the combination
of both is still of utmost importance for the best clinical outcome
for a multisystem disorder like PD. Detailed exploration of
STN and GPi connections and their somatotopy, which is still
missing in humans, would further enhance the outcome of
dopaminergic and neurostimulation treatments. A meticulous
pre-, peri-, and post-operative management is crucial for the best
clinical outcome.
AUTHOR CONTRIBUTIONS
MM and NK did the literature review and wrote the manuscript.
DC and StG contributed for the review of clinical aspects of
L-DOPA. BP and MG reviewed the clinical aspects of DBS
surgery. GT and SeG contributed with the critical review of the
article. All authors discussed the manuscript and agreed to the
final version.
FUNDING
The study was supported by the German Research Council
SFB 1193, SFB-TR-128 and Medtronic GmbH (study
080958/2015/OTIG).
ACKNOWLEDGMENTS
The authors thank Cheryl Ernest for proofreading and editing the
manuscript.
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Muthuraman et al. DBS and L-Dopa Networks in PD
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Conflict of Interest Statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Copyright © 2018 Muthuraman, Koirala, Ciolac, Pintea, Glaser, Groppa, Tamás and
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