Neurophysiology of Deep Brain Stimulation

CHAPTER THREE
Neurophysiology of Deep Brain

Stimulation
Manuela Rosa*, Gaia Giannicola*, Sara Marceglia*,†,
Manuela Fumagalli*, Sergio Barbieri‡, Alberto Priori*,},1
*Centro Clinico per la Neurostimolazione, le Neurotecnologie ed i Disordini del Movimento, Fondazione
IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
†
Dipartimento di Bioingegneria, Politecnico di Milano, Milan, Italy
‡
Unità Operativa di Neurofisiopatologia Clinica, Fondazione IRCCS Ca’ Granda Ospedale Maggiore
Policlinico, Milan, Italy
}
Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Milan,
Italy
1
Corresponding author: e-mail address: alberto.priori@unimi.it
Contents
1. Electric Field and Charge Distribution 25
2. A Tool for Understanding the Functions of Human Deep Brain Structures 27
3. Neurophysiology 29
3.1 Single-unit 29
3.2 Local field potentials 33
3.3 Evoked potentials 36
3.4 Autonomic tests 37
3.5 Other neurophysiological variables 38
3.6 Synaptic plasticity 40
4. Behavioral Neurophysiology 41
5. Neurochemistry 42
6. Future Perspectives: Development of New Adaptive Deep Brain Stimulation (aDBS)
Systems 43
References 46
Abstract
We review the data concerning the neurophysiology of deep brain stimulation (DBS) in
humans, especially in reference to Parkinson's disease. The electric field generated by
DBS interacts with the brain in complex ways, and several variables could influence
the DBS-induced biophysical and clinical effects. The neurophysiology of DBS comprises
the DBS-induced effects per se as well as neurophysiological studies designed to record
electrical activity directly from the basal ganglia (single-unit or local field potential)
through the electrodes implanted for DBS. In the subthalamic nucleus, DBS locally
excites and concurrently inhibits at single-unit level, synchronizes low-frequency activ-
ity, and desynchronizes beta activity and also induces neurochemical changes in cyclic
guanosine monophosphate (cGMP) and GABA concentrations. DBS-induced effects at
International Review of Neurobiology, Volume 107 # 2012 Elsevier Inc. 23

ISSN 0074-7742 All rights reserved.
http://dx.doi.org/10.1016/B978-0-12-404706-8.00004-8
24 Manuela Rosa et al.
system level can be studied through evoked potentials, autonomic tests, spinal cord
segmental system, motor cortical and brainstem excitability, gait, and decision-making
tasks. All these variables are influenced by DBS, suggesting also distant effects on non-
motor structures of the brain. Last, advances in understanding the neurophysiological
mechanisms underlying DBS led researchers to develop a new adaptive DBS technol-
ogy designed to adapt stimulation settings to the individual patient's clinical condition
through a closed-loop system controlled by signals from the basal ganglia.
Even though deep brain stimulation (DBS) is an effective treatment in several

disorders (Benabid et al., 1991; Gubellini, Salin, Kerkerian-Le Goff, & Baunez,
2009; Hamani, Andrade, Hodaie, Wennberg, & Lozano, 2009; Kahane &
Depaulis, 2010; Krauss, Yianni, Loher, & Aziz, 2004; Kringelbach,
Jenkinson, Owen, & Aziz, 2007; Moro et al., 2010; Perlmutter & Mink,
2006; Pizzolato & Mandat, 2012; Volkmann, 2004), the neurophysiological
mechanisms underlying its therapeutic action remain debatable. Starting
from the concept that functional inactivation can produce a lesion-like effect
(Benazzouz, Gross, Feger, Boraud, & Bioulac, 1993; Benazzouz & Hallett,
2000; Beurrier, Bioulac, Audin, & Hammond, 2001; Magarinos-Ascone,
Pazo, Macadar, & Buno, 2002), clear evidence now shows that DBS
generates various effects at local and system levels (Carlson, Cleary, Cetas,
Heinricher, & Burchiel, 2010; Dostrovsky & Lozano, 2002; Gubellini et al.,
2009; Hammond, Ammari, Bioulac, & Garcia, 2008; McIntyre, Grill,
Sherman, & Thakor, 2004; McIntyre & Hahn, 2010; Montgomery & Gale,
2008; Xu, Russo, Hashimoto, Zhang, & Vitek, 2008).
In this chapter, we first examine DBS as a tool for understanding the neu-
rophysiology of the basal ganglia and other DBS target areas. Second, to
understand how DBS acts, we examine DBS-induced neurophysiological
modulations at different levels. DBS-induced neurophysiological changes
can be assessed by recording neural activity directly from a target structure
or by investigating quantitative measures such as evoked potentials (EPs),
autonomic and clinical neurophysiological tests, biochemical measures, and
behavioral data focusing our attention on human experiments. This background
information provides the rationale for possible future developments of DBS.
In the past years, encouraging data obtained in patients with severe de-
pression, obsessive compulsive disorders, and Gilles de la Tourette syndrome
have extended DBS therapeutic applications to neuropsychiatric disorders
(Aouizerate et al., 2009; Goodman & Alterman, 2012; Greenberg,
Rauch, & Haber, 2010; Mallet et al., 2008; Porta et al., 2009; Ward,
Hwynn, & Okun, 2010) and not only to movement disorders such as
Parkinson’s disease (PD) (Pizzolato & Mandat, 2012; Volkmann, 2004).
Neurophysiology of Deep Brain Stimulation 25
In general, these neuropsychiatric disorders are less well understood than

PD, and the DBS procedures for treating them are poorly standardized.
Accordingly, progress in understanding the neurophysiological
mechanism(s) underlying the therapeutic action of DBS relies mainly on
information from PD, a movement disorder whose pathophysiology is
relatively better known and for which we have experimental data from
DBS recordings and quantitative measures in humans. Hence, our review
focus mainly on DBS for PD.
1. ELECTRIC FIELD AND CHARGE DISTRIBUTION

In DBS, a low-impedance electrode is implanted into specific deep brain
structures to stimulate the neurons electrically. The electrode location depends
on the type of neurological or neuropsychiatric disorder treated and the pa-
tient’s predominant symptoms. The electrode is connected to a subcutaneous
stimulation device (pulse generator) placed in the subclavicular region.
When the DBS device is turned on, an electric pulse lasting between 60 and
180 ms, with a frequency ranging from low- (15–30 Hz) to high-frequency
(100–180 Hz) is delivered to the neuronal tissue in the selected target. The de-
livered electric pulse is usually biphasic with a waveform composed by a neg-
ative phase and a positive phase. If the two phases are balanced, the resulting net
charge delivered to the tissue is null; conversely, if they are unbalanced, the net
charge delivered may produce a polarization in the tissue. DBS can be either
voltage- or current-controlled. DBS devices delivering voltage-controlled
stimulation keep constant the applied electrical potential difference and mea-
sure the stimulation strength in volts (V). Conversely, current-controlled
DBS devices maintain costant the current intensity delivered to the tissue
(the electrical charge exchanged in time) and measure stimulation strength
in milliamps (mA). In the past 20 years, DBS is widely administered
with voltage-controlled devices, in which current is variable (Cheung &
Tagliati, 2010). Current-controlled stimulation might provide a more accurate
control of the spread of the electrical field than do voltage-controlled devices,
because adjustments can be made to account for the potential heterogeneity in
tissue impedance. A recent study showed that current-controlled DBS is safe
and efficacious for the treatment of PD (Okun et al., 2012).
DBS induces an electric charge exchange between the stimulating elec-
trode and the surrounding tissue. This charge exchange affects activation
properties in neurons surrounding the electrode, thus inducing therapeutic
effects (Yousif, Bayford, Wang, & Liu, 2008). Even though DBS is clinically
effective, we still know too little about DBS-induced changes at neuronal

level. Information is lacking also on the interaction between the electric field
generated by DBS and the underlying neuronal tissue, mainly because
DBS–neuronal tissue interactions are difficult to model (Butson &
McIntyre, 2005; Yousif et al., 2008).
The current density distribution on the electrode surface is estimated
through computational modeling techniques (Butson & McIntyre, 2005;
McIntyre & Grill, 1999, 2001, 2002; Wei & Grill, 2005). Considering an
idealized electrolytic medium, the current density over the electrode surface
increases toward the edges of the electrode, and multiple edges make the
current density profile less uniform (Wei & Grill, 2005). Besides current
density distribution on the electrode surface, DBS-induced changes in
neuronal tissue depend also on the interface between the electrode and the
surrounding neuronal tissue. Computational techniques used to model this
interface focus on three compartments: the implanted DBS electrode, the
neuronal tissue, and the peri-electrode space. The peri-electrode space varies
in composition over time: immediately after DBS electrode implant (acute
stage), the peri-electrode space is filled with extracellular fluid (Thoma et al.,
1987). Conversely, in the chronic stage, the extracellular fluid is replaced by
giant cell growth (Moss, Ryder, Aziz, Graeber, & Bain, 2004) or microglia
(Griffith & Humphrey, 2006). This change takes place approximately
6–8 weeks after electrode implant (Yousif et al., 2008). The evolving
electrode–brain interface affects the neuronal tissue volume activated and the
stimulation intensity needed to obtain a clinically beneficial therapeutic
effect. In a simulation study, Yousif et al. (2008) compared the potential
distribution around the activated electrode contact during DBS when the
peri-electrode space was filled with extracellular fluid with the potential
distribution obtained after the electrode was encapsulated with giant cells.
They showed that because the low-conductivity giant cells in chronic stage
restricted current spread they produced a magnitude of the potential at a
given distance consistently less that in acute stage when the peri-electrode
space was filled with extracellular fluid. Hence, to maintain stimulation
levels constant in the acute and chronic stages, DBS intensity should be
increased, thus partially explaining why DBS settings are adjusted for the first
time after DBS begins (Yousif et al., 2008).
Other modeling studies showed that tissue volume activated depends not
only on the electrode interface voltage drop but also on electrode and tissue
capacitance (the ability of the tissue to store an electrical charge), on the
tissue electrode encapsulation, and on tissue heterogeneity (anisotropy)
(Chaturvedi, Butson, Lempka, Cooper, & McIntyre, 2010). During

voltage-controlled stimulation, the electric field transmitted to the tissue
depends on electrode capacitance, whereas during current-controlled stim-
ulation, it depends on tissue capacitance (Butson & McIntyre, 2005). During
current-controlled stimulation, electrode capacitance can be ignored
because, whatever the stimulus waveform, the entire stimulus current passes
through the tissue, and electrode capacitance is discharged because the
applied waveform is biphasic and charge-balanced. Conversely, during
voltage-controlled stimulation, voltage drops across capacitances. DBS elec-
trode capacitance is about two orders of magnitude greater than tissue capac-
itance and can therefore be ignored (Butson & McIntyre, 2005). This
explains why, whereas the electric field generated by voltage-controlled
stimulation changes according to variations in the tissue impedance, that
generated by current-controlled stimulation is stable in size.
In conclusion, because DBS-induced changes in the electrical field in the
surrounding nervous systems are highly complex, computational models
should take into account the various properties pertaining to the stimulating
electrode and the electrode–tissue interface.
2. A TOOL FOR UNDERSTANDING THE FUNCTIONS

OF HUMAN DEEP BRAIN STRUCTURES
Despite enormous progress achieved by experimental studies and
functional models (Wichmann & DeLong, 1996), little is known about
the signals controlling information processing and integration in the human
basal ganglia, “the dark basement of the brain” (Wilson, 1925). From a
scientific viewpoint, DBS provides a unique window into the human basal
ganglia thus helping to understand the neurophysiological mechanisms
underlying not only motor functions but also cognitive and behavioral
information processing.
During DBS surgery, high-impedance exploratory microelectrodes are
used to record the activity in single neurons in the target deep brain structure
to optimize the electrode localization electrophysiologically before the final
electrodes are definitively implanted. Besides serving clinical purposes,
single-unit (SU) recordings also provide a powerful research tool to correlate
anatomical, functional, and electrophysiological information (Levy,
Hutchison, Lozano, & Dostrovsky, 2000; Levy et al., 2001; Romanelli
et al., 2004; Stefani et al., 2002).
During the few days after DBS surgery and before the electrode leads are
connected to the subcutaneous electrical pulse generator, electrodes are
accessible for electrophysiological recordings from the target structure.
Because the final DBS electrodes have low-impedance, they are unsuitable
for recording single neuron activity during surgery but are ideal for record-
ing local field potentials (LFPs). LFPs reflect the synchronous presynaptic
and postsynaptic activity in large neuronal populations and can detect net-
work rhythms that are not necessarily observable in single neurons or neuron
pairs (Brown & Williams, 2005; Kuhn et al., 2004, 2008; Levy et al., 2002;
Marceglia, Fumagalli, & Priori, 2011; Priori et al., 2004; Rosa et al., 2011,
2012; Zaidel, Arkadir, Israel, & Bergman, 2009). LFP recordings show that
oscillatory activity in the deep brain structures ranges from the classic
electroencephalographic (EEG) frequencies (<50 Hz) to frequencies as
high as 300 Hz, and recordings in patients with PD have consistently
shown prominent oscillations between 8 and 30 Hz (beta band) (Kuhn
et al., 2004, 2008; Rosa et al., 2011; Zaidel et al., 2009) Excessive beta-
band synchronization is considered a feature common to the whole basal-
ganglia-cortical loop in PD with increased beta-band oscillations in the
subthalamic nucleus (STN), globus pallidus, and cerebral cortex (Brown &
Williams, 2005).
Many LFP studies in humans revealed in the past 10 years unknown
functions of basal ganglia in PD patients during the execution of motor, cog-
nitive, and behavioral task showing the existence of a “code” in LFP oscil-
lations corresponding to the clinical condition of patient (Marceglia et al.,
2007). LFP oscillatory patterns in patients with PD change in response to
antiparkinsonian drugs (Brown & Williams, 2005; Foffani et al., 2003;
Giannicola et al., 2010; Giannicola, Rosa, & Marceglia, 2012; Marceglia
et al., 2006; Priori et al., 2004) and are dependent on patients’ clinical
and motor conditions (Brown & Williams, 2005; Kuhn et al., 2004,
2008; Priori et al., 2004). Changes in LFP activity also provide evidence
that the human basal ganglia and thalamus intervene in all movement
phases (Foffani, Bianchi, Baselli, & Priori, 2005; Foffani & Priori, 2004;
Levy et al., 2002). More recent studies demonstrated that specific
oscillations in the STN are involved also in action representation
(Marceglia et al., 2009), cognitive information related to decision-making
(Fumagalli et al., 2011), and emotional information (Brucke et al., 2007;
Kuhn et al., 2005). The multiple rhythms recorded and differentially
modulated by movement and drugs consistently confirm that pathological
oscillations in the low-frequency power band (Giannicola, Rosa, &
Marceglia, 2012; Priori et al., 2006), beta band (Eusebio et al., 2011;
Giannicola et al., 2010; Kuhn et al., 2004, 2008; Rosa et al., 2011;
Zaidel et al., 2009), gamma band (Brown & Williams, 2005), and high-
frequency band (Brown & Williams, 2005; Foffani et al., 2003, 2006;
Ozkurt et al., 2011) are involved in the pathophysiology of movement
disorders and are crucial for understanding the neurophysiological
mechanisms underlying DBS clinical effects (Giannicola & Priori, 2012).
Direct methods of assessing neuronal activity as SU and LFP recordings
provided unique information at high temporal and spatial resolution about
fine structure of rates and patterns not investigated with other indirect im-
aging methods such as fMRI or other functional neuroimaging techniques.
3. NEUROPHYSIOLOGY
DBS-induced changes in human brain function are difficult to study.
Local DBS-induced effects assessed by recording SU activity and LFPs
directly from the target structure needed special technological approaches
for removing stimulus artifact. Chronically after surgery experiments
designed to investigate DBS can describe its effects on functions of distant
systems through quantitative measures such as EPs, autonomic variables,
and clinical neurophysiological tests. Neuroimaging experiments are dealt
with elsewhere in the book.
3.1. Single-unit
Studies using intraoperative multiple electrodes simultaneously stimulating
and recording from the same structure have examined how stimulation
affects adjacent neuronal activity (Carlson et al., 2010; Filali, Hutchison,
Palter, Lozano, & Dostrovsky, 2004; Maltete et al., 2007; Welter et al.,
2004). A major problem in such experiments is the large stimulus artifact
due to the stimulating electrodes in close proximity and the high
electrode impedance. To avoid this problem, early studies analyzed the
DBS-induced effects on the neural activity at very low intensity or
immediately after stimulation ceases—two important limiting factors.
Several studies showed that high-frequency DBS inhibits neuronal cell
bodies (somas) in the stimulated nucleus (Dostrovsky & Lozano, 2002;
Dostrovsky et al., 2000; Filali et al., 2004; Welter et al., 2004). By
activating the predominant presynaptic inhibitory neurons, DBS reduces
somatic spikes in local neurons close to high-frequency stimulus sites in
the target nucleus. In a study investigating the effects of STN stimulation
on the neuronal activity from STN neurons in patients with PD, Welter
et al. (2004) showed that during stimulation at clinical settings and
intensities, the mean firing rate in STN cells decreased by 77% and more
than 75% of the neurons maintained persistent activity. Another study
showed that intraoperative high-frequency STN DBS inhibited ipsilateral
firing in 42% of neurons tested (Filali et al., 2004). These results agreed
with similar experimental studies conducted on the human thalamus
(Dostrovsky & Lozano, 2002) and globus pallidus internus (GPi)
(Dostrovsky et al., 2000). Conversely, Carlson et al. (2010) reported that
high-frequency STN DBS left the mean firing rate in the recorded STN
neurons unchanged, suggesting that STN DBS might provide a null
signal to the basal ganglia corticothalamic circuit. The contradictory result
reported by Carlson and colleagues could depend on different current
density and distribution resulting from DBS delivered through a
definitive implanted macroelectrode (Butson & McIntyre, 2006) instead
of the intraoperative microelectrode used in previous studies.
Using a time-domain algorithm for artifact removal (Hashimoto, Elder,
& Vitek, 2002), Toleikis et al. (2012) acquired SU recordings also during
stimulation at effective voltage and showed that both ipsilateral and contra-
lateral high-frequency STN DBS at therapeutic intensities and settings
resulted in reversible STN firing rate suppression (Fig. 3.1A).
Numerous mechanisms have been proposed to explain how DBS
reduces neuronal activity within the stimulated target. These included a
depolarization block hypothesis, suggesting that repetitive cell stimulation
sufficiently depolarized the cell membrane to inactivate sodium channels
and to prevent cell firing (Beurrier et al., 2001). Another possible mechanism
is synaptic inhibition hypothesizing that DBS preferentially activates STN
afferents rather than neurons (Dostrovsky et al., 2000). Because most of these
afferents are inhibitory, DBS would ultimately reduce neuronal activity
within the stimulated target.
Conversely, several studies conducted during stimulation, including SU
recording in downstream structures, suggest an excitatory hypothesis (Galati
et al., 2006; Montgomery, 2006; Pralong et al., 2003; Reese et al., 2008).
They showed changes in neuronal activity suggesting that DBS activates
efferent axons in the stimulated nucleus. In a patient with dystonia,
Montgomery (2006) demonstrated predominant decreases in ventral
lateral (VL) thalamus activity after GPi stimulation implying that GPi
DBS activates the inhibitory projections from GPi to VL. Studying GPi
DBS-induced changes by recording neuronal activity in the ventralis
A
0.5 f=128 Hz l pt 1
Signal (mV)
80 l pt 2
l pt 3
c pt 3
c pt 4
c pt 5
0 70 c pt 6
Firing rate (spikes/s)

60
Raw
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60 0.1 sp/s 24.1 sp/s
Firing rate (spikes/s)
50 40
40 30
Post-stim control
Per-stim control
30
20
20
10 10
0 0
0 20 40 60 80 100 10 30 60 130 185
Time (s) Stimulus Frequency (Hz)
B C
GPi
Thalamus
45 s
D E
60
Splkes per second
GPe 40 GPi
Thalamus
GPi
20
0 STN
Pre Post Pre Post
Gpe Gpi
Figure 3.1 Effects of deep brain stimulation on single-unit activity. (A) Left-top: sample
spike waveforms before (gray, raw) and after (black, processed) stimulus artifact removal
during prestimulation and 128 Hz ipsilateral subthalamic nucleus (STN) stimulation
epochs. The processed signal overlaps the raw signal during nonstimulation epochs.
The large stimulus artifacts present in the raw signal are so closely spaced, they appear
as a solid gray area. Randomly selected spike waveforms are plotted above the signal
trace to illustrate continuity in single neuron spiking throughout the recording. Left-
bottom: histogram of activity during the nonstimulation (black) and stimulation (dark
gray) epochs, obtained using 1-s bins. Suppression of the average firing rate by deep
brain stimulation (DBS) is over 99.6%. sp, spikes; s, second. Right: graph showing the
effect of both ipsilateral (continuous lines) and contralateral (dashed lines) STN stimu-
lation frequency on the average single-unit firing rate during stimulation compared
with the rates during the prestimulation (leftmost points) and poststimulation control
(rightmost points) epochs. Note that ipsilateral and contralateral STN DBS suppressed
STN firing rates. (B) Effects of globus pallidus internus (GPI) DBS on the spontaneous
activity from ventralis oralis anterior (VOA) neuron in a patient with dystonia.
oralis anterior (VOA) nucleus of thalamus, Pralong et al. (2003) showed that
pallidal DBS inhibits a motor thalamic cell subpopulation (Fig. 3.1B). In
these studies, the reduced firing rate recorded in the thalamic nucleus, an
inhibitory GPi axonal target, suggested that DBS activates GPi efferent
fibers (Liu, Postupna, Falkenberg, & Anderson, 2008) (Fig. 3.1C). Similar
data came from Reese et al. (2008) who proposed that DBS excited the
output axons, because during STN DBS GPi neuron firing rates
increased (Fig. 3.1D). The increased GPi firing rate, confirmed by an
animal study (Hashimoto, Elder, Okun, Patrick, & Vitek, 2003), implies
that DBS activates excitatory projections from STN to GPi (Liu et al.,
2008) (Fig. 3.1E). Data recorded from substantia nigra pars reticulata
(SNr) during STN DBS in Parkinsonian patients provided convincing
evidence that STN stimulation produces its therapeutic effects by exciting
the STN output and driving the downstream basal ganglia output
neurons (Galati et al., 2006).
The results obtained by recording activity from SUs appear contradictory.
How can DBS excite yet at the same time inhibit a neuron? To understand
Extracellular recording of a neuronal activity located 3 mm anterodorsal from the target

in the VOA. Before GPI stimulation, the mean firing rate was 17 Hz. DBS (130 Hz) applied
to the GPI for 10 s reversibly inhibited this neuronal activity and 20 s after GPI stimula-
tion ended VOA neuronal activity recovered. Note that GPI stimulation inhibited activity
in a motor thalamic cell subpopulation. (C) Action potential produced by GPi stimula-
tion: stimulation decreases activity (downward arrows) in GPi neuronal somata, but in-
creases (upward arrow) activity in their inhibitory output axons. , inhibitory neurons.
(D) Effect of high-frequency STN DBS on pallidal neuronal activity in a patient with
Parkinson's disease. On the left, neuronal recording sites in a sagittal projection onto
the Schaltenbrand Wahren atlas at laterality of 22 mm. After high-frequency STN
DBS, mean GPi and globus pallidus externus (GPe) firing rates increase. On the right
box, plots show median (line within the box) as well as 10th, 25th, 75th, and 90th per-
centiles. The superimposed black dots represent the firing rate for each recorded neu-
ron and the change before and after high-frequency STN DBS (line). (E) Action potential
produced by STN stimulation: stimulation decreases discharges (downward arrows) in
STN neuronal somata but increases (upward arrow) activity in their excitatory output
axons, increases (upward arrows) GPi neuron excitation, and increases inhibition (de-
creases discharge rate, downward arrows) at the thalamus as in C. , inhibitory neurons;
þ, excitatory neurons. (A) Reprinted from Toleikis et al. (2012), Copyright (2012), with per-
mission from JNS Publishing Group; (B) Reprinted from Pralong et al. (2003), Copyright
(2003), with permission from Elsevier Masson SAS; (C) Reprinted from Liu, Postupna,
Falkenberg, and Anderson (2008), Copyright (2008), with permission from Elsevier; (D) From
Reese et al. (2008), Copyright (2008, Movement Disorders). This material is reproduced with
permission of John & Sons, Inc.; (E) Reprinted from Liu et al. (2008), Copyright (2008), with
permission from Elsevier.
the mechanisms through which DBS acts, rather than investigating increased
or decreased inhibition or excitation, we need to study the two effects com-
bined. These apparently mutually exclusive findings might be reconciled by
data from a modeling study conducted by McIntryre, Grill, Sherman, and
Thakor (2004) indicating that DBS both inhibits and excites the target nu-
cleus. During extracellular stimulation, the action potential begins in the axon.
While DBS inhibits neuronal cell bodies in the stimulated nucleus, it simul-
taneously excites neuronal cell axons (McIntyre et al., 2004). Given the low
probability that microelectrodes record axonal activity, SU recordings within
the stimulated nucleus disclose somatic inhibition suggesting that DBS inhibits
target neurons (Dostrovsky et al., 2000), whereas SU recordings in down-
stream nuclei reveal axonal excitation in the stimulated nucleus
(Hashimoto et al., 2003). Stimulation applied to the GPI would decrease
GPi activity and increase inhibitory output from basal ganglia, whereas stim-
ulation applied to the STN would decrease STN activity, increase excitatory
axons from STN to GPi, in turn, increase GPi activity, and, consequently,
increase inhibitory output from basal ganglia (Fig. 3.1C and E).
Although DBS-induced changes in activity assessed through SU record-
ings have provided important neurophysiological evidence, LFP recordings
are a more suitable tool for understanding the complex mechanisms of action
underlying DBS, which go beyond simple neuronal activation/inhibition.
3.2. Local field potentials

Another way to study the neurophysiological effects induced by DBS is to
record LFP activity directly from the target structure. The interest in LFPs
arose also, thanks to several studies showing that basal ganglia functional pro-
cesses are mediated not only by firing rates but also, and mainly, by firing pat-
terns (Bevan, Magill, Terman, Bolam, & Wilson, 2002; Terman, Rubin,
Yew, & Wilson, 2002), oscillatory phenomena (Gatev, Darbin, &
Wichmann, 2006; Uhlhaas & Singer, 2006; Wilke, Logothetis, & Leopold,
2006), and wave propagation (Rubino, Robbins, & Hatsopoulos, 2006).
Unlike SUs, basal ganglia LFPs can be recorded within days after DBS
surgery before the implanted macroelectrodes are connected to the
subcutaneous pulse generator. Another advantage is that because patients
are typically free to move during these experimental recordings they can
engage in more complex and ecological tasks than during DBS surgery.
Studies conducted before our group introduced FilterDBS, a new tech-
nology allowing LFP recording during DBS from the same electrode used
for stimulating (Rossi et al., 2007), reported contradictory results about
how DBS affects LFP activity. Whereas some suggested that in patients with
PD beta oscillations (8–30 Hz) decrease after STN DBS (Bronte-Stewart
et al., 2009; Brown et al., 2004; Kuhn et al., 2008), others failed to
confirm this observation (Foffani et al., 2006) and reported that low-
frequency oscillations (2–7 Hz) increased (Priori et al., 2006). The use of
FilterDBS-like amplifiers prompted new research and helped to study
DBS-induced changes in STN LFP oscillations. Studies using therapy
with levodopa and DBS combined show that the levodopa-induced
effect predominates (Giannicola et al., 2010; Rossi et al., 2008)
(Fig. 3.2A). One study compared the effect of DBS and antiparkinsonian
drugs, showing that whereas levodopa invariably disrupted beta
oscillations, DBS induced changes in beta oscillations only in patients
whose LFP recordings already showed wide beta activity before DBS
(Giannicola et al., 2010). Another study using a similar methodology
showed that DBS suppressed global beta oscillations in all nuclei selected
(Eusebio et al., 2011) (Fig. 3.2B). Eusebio and colleagues selected only
nuclei that showed significant high beta peak. Data from this study
confirmed the findings reported by Giannicola et al. (2010). Other
studies also established that the low-frequency band increase starts during
ongoing DBS and is consistent across patients (Giannicola, Rosa,
Marceglia, et al., 2012; Rossi et al., 2008) (Fig. 3.2C). This observation
agrees with the STN DBS-induced low-frequency band increase that lasts
several minutes after DBS is turned off and also corresponds with the
persistent STN DBS-induced improvement in the patients’ clinical state
(Giannicola, Rosa, Marceglia, et al., 2012; Priori et al., 2006; Rossi et al.,
2008). Hence, even though the exact mechanisms remain controversial,
ample evidence shows that DBS specifically modulates LFP oscillations in
patients with PD.
Evidence on the correlation between LFP oscillations and clinical state
and DBS-induced changes in LFPs suffers nevertheless from a major draw-
back, namely, that all experimental sessions took place within days after brain
surgery when a lesion effect and local brain edema remain. To date, only two
studies have investigated how DBS influences LFPs recorded more than
1 week after DBS surgery (Giannicola, Rosa, Servello, et al., 2012; Rosa
et al., 2011). In a study conducted in our laboratory comparing STN
LFPs recorded in PD patients immediately after and 30 days after DBS
surgery (Rosa et al., 2011), we reported that weeks after DBS electrode
implant STN LFPs remain stable and that in a subgroup of patients
whose recordings showed a strong beta activity at baseline, LFP beta
A B
On DBS On levodopa Off DBS
20
930
18 3.5 (s)
Time
Log -3
Frequency (Hz)
16 3
power -5 0
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10 1.5 -4
Fr
20
e qu
8 -4.5
Log power (a.u.)
en
0 5 10 15 20 25 30 35 40 45 50 30
cy
-5
(H
Time (min)
z)
20 20
Frequency (Hz) -5.5
Frequency (Hz)
18 18 40
-6
16 16
4
Voltage (V)
14 14 -6.5 3
12 12 2
-7
10 10 0 10 20 30 40 1
0
Frequency (Hz)
C Grand average (16 nuclei)

D
Grand average (n = 6)
On Off
40 t-30d
t-0h
Frequency (Hz)
20
7
10-1.2 10-1.2
PSD [AU]
PSD [AU]
0
2 4 6 8 10 12
Time (minutes)
-1.7 -1.7
Power (au)
0 0
10
Power (au)
10 10 10
-2 0 2 -2 0 2
Frequency (Hz) Frequency (Hz)
-2 -2
10 10
Baseline DBS on DBS off

0 10 20 30 40 0 10 20 30 40
Frequency (Hz) Frequency (Hz)
Figure 3.2 Effects of deep brain stimulation on local field potentials. (A) Time
course of subthalamic nucleus local field potentials (STN LFP) in a representative
patient with Parkinson's disease (PD). STN LFP time varying power spectrum in
the beta band (8–20 Hz). Top: time–frequency plot over the entire experimental
session (50 min total time, 42 min deep brain stimulation-DBS); the black dotted
lines, from the left, correspond to turning DBS on, the clinical effect of levodopa,
and turning DBS off. Bottom: transient states when DBS was turned on (left panel)
and off (right panel). Note that levodopa and DBS both reduced beta oscillations
but that the levodopa-induced effect predominates. (B) Effect of DBS on STN LFP in
a representative patient with PD. On the left, power autospectrum of LFP recorded
without stimulation. On the right, time–frequency log power LFP spectrum. Bars
along the time axis denote ongoing DBS at 2.0–3.0 V. Note that DBS at 2.0 V
suppressed the spectral peak, stimulation at 1.5 V transiently increased power
peak, and stimulation at 3.0 V delayed its return after stimulation ended. (C) STN
LFP power spectrum changes during DBS in patients with PD (grand average, 16
nuclei). Top: time course of LFP power spectrum changes over 12 min (DBS for
8 min). DBS begins at the vertical black dashed line on the left and ends at the ver-
tical black dashed line on the right. Bottom: instantaneous power spectra before
DBS (baseline) on the left and 4 min after DBS began on the right. Black lines:
the average spectrum; gray lines spectra of individual nuclei. Note that during
STN DBS the low-frequency power increases. (D) STN LFPs recorded immediately
(t-0h) and 30 days (t-30d) after DBS surgery in patients with PD: grand average for
nuclei showing significant beta-band (n ¼ 6 nuclei) power spectral density (PSD)
in the three experimental conditions: prestimulation (baseline: black, solid line),
activity recorded during DBS decreased immediately after and 30 days after
DBS surgery (Fig. 3.2D). Another study (Giannicola, Rosa, Servello et al.,
2012) showed that the STN LFP pattern recorded at baseline without DBS
and without medication a few days after DBS electrode implant remained
unchanged after 7 years of chronic DBS. We also found that DBS-
induced changes persist years after DBS electrode implantation and
chronic stimulation: whereas in a subgroup of patients, whose LFP
recordings showed strong beta activity at baseline, beta activity decreased,
low-frequency activity invariably increased.
Evidence that high-frequency DBS acts by modulating pathological
parkinsonian oscillatory activity toward a pattern, that the basal–
ganglia–cortical system finds more physiological receives strong support
from several studies (Giannicola, Rosa, Servello, et al., 2012; Rosa et al.,
2011; Silberstein et al., 2005). STN DBS acts not only by modulating
pathological STN activity but also by projecting modulated activity to
GPi and SNr (Hammond, Bergman, & Brown, 2007), the output
structures in the basal ganglia. The new STN DBS-driven output might
normalize basal-ganglia-cortical loops supporting the hypothesis that DBS
shifts overall activity patterns toward a more physiological pattern
(Kopell, Rezai, Chang, & Vitek, 2006).
3.3. Evoked potentials

Some effects induced by DBS ultimately involve DBS-induced changes in
cortical activity observed through scalp EEG recordings. DBS applied to
the STN with single pulses or trains produces potentials that can be detected
with stimulus-triggered average EEG signals in the frontocentral cortex. Sev-
eral studies have described cortical EPs during low-frequency STN stimula-
tion in patients with PD (Ashby et al., 2001; Baker, Montgomery, Rezai,
during stimulation (DBS on: gray, dashed line), and after stimulation (DBS off: light
gray, dashed line). Note that beta-band power decreases in the on DBS condition both
in t-0h and t-30d for nuclei with significant beta-band power. (A) Reprinted from
Giannicola et al. (2010), Copyright (2010), with permission from Elsevier; (B) Reproduced
from Eusebio et al. (2011), copyright notice 2011 with permission from BMJ Publishing
Group Ltd.; (C) Reprinted from Rossi et al. (2008), Copyright (2008), with permission from
Elsevier; (D) Reprinted from Rosa et al. (2011), Copyright (2011), with permission
from Karger.
Burgess, & Luders, 2002; Kuriakose et al., 2009; MacKinnon et al., 2005).
These cortical EPs comprise multiple components whose latencies differ.
Short-latency (3–8 ms) and long-latency responses (18–25 ms) correspond
to conduction from the STN stimulation site to the cortical recording
location via antidromic and orthodromic pathways. Few studies have
investigated cortical EPs evoked by STN DBS at clinically used frequencies
(80–130 Hz) because the interstimulus interval is shorter than the latency
for long-latency EPs. Rather than being DBS-related epiphenomena,
cortical EPs may reflect the temporal progression of changes in cortical
excitability related to clinical DBS therapeutic effects in patients with PD
(Devergnas & Wichmann, 2011). More detailed information is needed on
the correlation between the clinical effects of DBS and EPs.
Other researchers investigated DBS-induced changes in cortical activity
by studying auditory- and somatosensory-evoked potentials (AEPs and
SEPs). In an early study, Pierantozzi et al. (1999) showed that GPi and
STN DBS both selectively increase frontal SEP amplitude probably improv-
ing functional activity in the supplementary motor area and leaving the
parietal component unchanged. In a further study, parietal SEP amplitudes,
evaluated in a larger sample size, increased when DBS was turned off (Priori
et al., 2001). Others subsequently reported that somatosensory P60
responses tended to increase when DBS was on, whereas auditory N100
responses in right hemisphere enhanced during ipsilateral STN DBS
(Airaksinen et al., 2011). Changes in AEPs and SEPs suggest that DBS
modulates thalamocortical pathways or cortical processing or both.
Although the changes induced by DBS on late EPs suggest that DBS exerts
its therapeutic effects partly at cortical level, the precise mechanisms through
which it does so remain conjectural.
3.4. Autonomic tests

Evidence that DBS influences the human autonomic nervous system comes
from a study showing that DBS improves the sympathetic skin response
(Priori et al., 2001). In the same study, DBS-induced changes in cardiovas-
cular variables were assessed with plasma renin activity assay and the upright
tilt test. When DBS was turned off, plasma renin increased but arterial blood
pressure remained unchanged. These findings suggested that STN DBS im-
proved sympathetic and cardiovascular reactivity probably by interfering
with nonmotor functions in the basal ganglia and stimulus spread to nearby
structures (Priori et al., 2001).
In a study designed to assess STN DBS-induced changes in cardiovascu-

lar function during DBS surgery, Sauleau et al. (2005) directly monitored
autonomic side effects in patients undergoing STN DBS for PD: in 88%
of the patients, tachycardia arose within seconds after stimulation began,
whereas hypertension arose within about a minute.
In two prospective studies assessed to evaluate STN DBS-induced
changes in urinary function in patients with PD, Finazzi-Agro et al.
(2003) reported significantly increased bladder capacity and reflex volume
and Seif et al. (2004) found a reduced voiding desire.
3.5. Other neurophysiological variables

DBS modifies certain clinical neurophysiological abnormalities that may not
have a direct clinical correlate with movement disorder symptoms (Hallett,
1998; Rossini, Filippi, & Vernieri, 1998; Valls-Sole & Valldeoriola, 2002).
Ample evidence describes STN or GPi DBS-induced changes in motor
cortex excitability (Chen, Garg, Lozano, & Lang, 2001; Cunic et al., 2002;
Kuhn et al., 2003). For example, Chen et al. (2001) reported the effects of
GPi DBS on motor threshold, motor evoked potentials (MEP) recruitment
curve, silent period (SP) duration, short-interval intracortical inhibition
(SICI), long-interval intracortical inhibition, and intracortical facilitation in
patients with PD. No significant differences were found, except a reduced
cortical SP duration. When they switched GPi stimulation off, however,
motor threshold increased, and the size of contralateral responses in the
stimulus-response curves in relaxed muscles diminished. Similarly, in
patients with dystonia, Kuhn et al. (2003) reported that GPi DBS decreased
motor cortex excitability, as reflected by an increase in motor thresholds,
and no GPi DBS-related changes in spinal excitability were found.
Conversely, when they examined whether STN DBS affected motor
cortical excitability in parkinsonian patients, Cunic et al. (2002) reported
results that opposed those of GPi DBS on motor cortex excitability: STN
DBS induced no changes in SP duration, motor threshold, or MEP
recruitment curve. In experiments investigating the effects of STN and GPi
DBS on resting SICI, Pierantozzi et al. (2002) found that SICI increased
during either bilateral STN or GPi DBS at an interstimulus interval of 3 ms
and during bilateral STN DBS at interstimulus intervals of 2 ms, suggesting
that SICI may improve because DBS restores thalamocortical motor
pathway function. In another study testing the blink reflex in patients
with primary torsion dystonia, Tisch, Limousin, Rothwell, Asselman,
Quinn et al. (2006) measured changes in blink reflex excitability after GPi DBS
and showed that GPi DBS results in a functional reorganization in the nervous
system and long-term increase in brainstem inhibition. Others documented
reduced blink reflex inhibition after a prepulse stimulus (prepulse inhibition)
(Schicatano, Peshori, Gopalaswamy, Sahay, & Evinger, 2000; Valls-Sole,
Munoz, & Valldeoriola, 2004). In a study designed to investigate whether a
single electrical STN DBS pulse induced prepulse effects on the blink reflex
and how they compared with the effects induced by single auditory and
somatosensory stimuli, Costa, Valls-Sole, Valldeoriola, Pech, and Rumia
(2006) found that a single STN DBS pulse induced significant prepulse blink
reflex inhibition in all PD patients, who have abnormally reduced auditory
and somatosensory prepulse effects. They proposed that the abnormal
reduction in prepulse inhibition lies at a point before the circuit reaches the
structures activated by STN DBS or that DBS causes the prepulse through a
circuit other than that for auditory and somatosensory stimuli.
Others reported DBS-induced changes in spinal cord circuitry (Potter,
Illert, Wenzelburger, Deuschl, & Volkmann, 2004; Tisch, Limousin,
Rothwell, Asselman, Zrinzo, et al., 2006). In a study testing the H-reflex re-
ciprocal inhibition and clinical outcome in eight patients with primary torsion
dystonia, Tisch, Limousin, Rothwell, Asselman, Zrinzo, et al. (2006) reported a
progressive improvement in the reciprocal inhibitory effect induced by a radial-
nerve stimulus on the median nerve H-reflex, at 1, 3, and 6 months during GPi
DBS, and suggested that DBS causes a functional nervous system reorganization
that includes the spinal machinery. When they investigated the effect of high-
frequency STN DBS on autogenic inhibition in PD, Potter et al. (2004)
reported an increase in soleus H-reflex autogenic inhibition, a spinal inhibitory
phenomenon that is abnormal in PD (Delwaide, Pepin, & Maertens de
Noordhout, 1991). They measured the soleus H-reflex alone or conditioned
by previous gastrocnemius nerve stimulation at a 2–10-ms interstimulus inter-
val in patients with PD. STN DBS increased the conditioning stimulus inhibi-
tion and the increase correlated significantly with patients’ clinical
improvement in gait and posture.
Several studies investigated DBS-induced changes in gait and postural
stability in patients with PD and described motor function improvements
(Ferrarin et al., 2005; Johnsen, Mogensen, Sunde, & Ostergaard, 2009;
Joundi et al., 2012; St George et al., 2012). To investigate how STN and
GPI DBS affected autonomic postural responses, St George et al. (2012)
tested patients with PD before and 6 months after surgery and reported
that DBS improved automatic postural response stability for both STN
and GPi sites. Similar results came from Johnsen et al. (2009), who found
that STN DBS facilitated symmetric gait and thereby improved balance
during gait. Another study analyzed full body gait during overground
walking in patients with PD and reported a significantly increased gait
speed after DBS surgery, stride length, and lower limb joint range of
motion during DBS than in the DBS off condition (Ferrarin et al., 2005).
During STN DBS, Joundi et al. (2012) tested parkinsonian patients by
capturing simple ballistic movements across four joints using kinematic
motion analysis. They observed that velocity significantly improved
during DBS thus showing that STN DBS can enhance performance of
ballistic movements.
3.6. Synaptic plasticity

Several researchers tried to explain why the time course of clinical benefit
differs in patients with PD or dystonia treated with GPi DBS, by investigat-
ing how DBS influences synaptic plasticity. Instance, Ruge, Tisch, et al.
(2011) measured TMS-paired associative plasticity (a test of long-term
potentiation-like synaptic plasticity abnormal in patients with dystonia)
(Quartarone et al., 2008; Schwingenschuh et al., 2010; Weise et al.,
2006), after DBS surgery. Changes in synaptic plasticity were absent
1 month after surgery and then over the following months increased
toward levels observed in healthy individuals. When DBS is turned on, it
disrupts abnormal basal ganglia signals, reducing abnormal synaptic
plasticity but the clinical benefit is delayed because “memory” for
abnormal movement persists. In another study, Ruge, Cif, et al. (2011)
showed no change in physiological or clinical status when DBS was
turned off for 2 days, suggesting that synaptic plasticity may also drive the
long-term therapeutic effects induced by DBS in dystonia although
considerable variation between patients exists. Patients who had higher
synaptic plasticity levels during DBS retained clinical benefit when DBS
was stopped and vice versa. These findings suggested that shaping DBS in
the individual patient might maximize the beneficial neurophysiological
patterns that influence clinical status.
Although no study has investigated DBS-induced changes in synaptic plas-
ticity in human PD, one study investigated it in rat STN (Shen, Zhu, Munhall,
& Johnson, 2003). High-frequency DBS in the STN from a rat slice prepa-
ration induces three forms of synaptic plasticity at cortico-STN synapses:
short-term potentiation (STP), long-term potentiation (LTP), and long-term
depression (LTD) in excitatory synaptic potentials. DBS-induced STP and
LTD have paired-pulse characteristics consistent with changes in presynaptic

action, whereas LTP has features more consistent with a postsynaptic action. If
synaptic plasticity, especially long-term plasticity, is among the mechanisms by
which high-frequency DBS changes symptoms in PD, the effect should persist
for an appropriate time after the stimulator is turned off. This interesting pos-
sibility merits confirmation in a study designed to analyze in detail the
poststimulation symptom time course in humans.
4. BEHAVIORAL NEUROPHYSIOLOGY
Despite the increasing interest in nonmotor functions of deep brain
structures, in particular, in cognitive functions and behavior, only three studies
investigated the neurophysiological correlate from the STN during decision-
making processes in PD (Cavanagh et al., 2011; Fumagalli et al., 2011;
Fumagalli & Priori, 2012; Zaghloul et al., 2012). Fumagalli et al. (2011)
showed that STN LFP changes during decision-making related specifically
to moral conflict. In a similar study, Cavanagh et al. (2011) tested EEG and
LFP changes during a choice conflict task on and off STN DBS and
suggested that in high-conflict decisions the prefrontal-STN network
increases the decision threshold thus delaying the response. Another
neurophysiological study investigated the role of the STN in decision-
making by analyzing microelectrode recordings. When participants engaged
in a high-conflict decision-making task, STN single-unit activity increased
(Zaghloul et al., 2012). These neurophysiological studies provided direct
evidence for the basal ganglia’s role in decision-making, suggesting that
basal ganglia DBS might modulate cognitive functions and behavior.
In the past years, scientific literature investigated the behavioral effect of
STN DBS on decision-making in patients with PD (Balaz, Bockova,
Rektorova, & Rektor, 2011; Marceglia et al., 2011) thus providing useful
information that helps to explain the mechanisms underlying DBS. The
first study evaluated patients with PD undergoing bilateral STN DBS
during a stimulus reward learning task and a gambling task. The results
showed that STN stimulation had no influence on reward learning and
economic decisions (Czernecki et al., 2005). Using a computational model
of the cortico-basal-thalamocortical network (Frank, 2006), Frank,
Samanta, Moustafa, and Sherman (2007) tested a group of mildly
medicated PD patients with a reward-based probabilistic learning task,
during DBS, and compared their performance with a control group.
Patients were slower than controls in learning probabilistic reinforcements
and STN DBS-induced impulsive responses specifically in high-conflict
decisions (Frank et al., 2007). To study STN DBS effects on reward-based

decision-learning, a group of patients with PD bilaterally implanted with
STN DBS did a probabilistic learning task while on and off stimulation.
STN stimulation improved the action-oriented learning functions, enabling
patients to use feedback more effectively during STN DBS and
consequently to respond optimally to a situation requiring a decision (van
Wouwe et al., 2011). In a study aiming to clarify the specific effects of
STN DBS on gambling behavior, parkinsonian patients with chronically
implanted STN electrodes for DBS executed a loss-chasing game during
DBS. The task required them to choose between gambling to recover a
loss or quitting. The results indicated that STN DBS left the tendency to
chase losses unchanged but increased the value of losses that patients are
willing to pay (Rogers, 2011). To assess acute effects of STN DBS on
decision-making, PD patients did the Iowa Gambling Task before bilateral
STN DBS surgery, and 2–4 weeks post surgery in on and off stimulation
conditions. Although no significant differences emerged in their task
performance before surgery, on stimulation and off stimulation, patients
performed worse in the on condition than in the off condition only in the
last block of the task. The investigators concluded that STN DBS may
affect decision-making in the acute postoperative stage (Oyama et al., 2011).
The conflicting results reported in the aforementioned studies probably
depend on methodological differences (task used, time after surgery, dopa-
minergic medication). Although the mechanisms through which STN DBS
influences decision-making are still unclear, two studies provided interesting
insights in this field through a neuro-computational model in which the
STN provides a self-adaptive dynamic “hold-your-horses” signal that func-
tions as a brake that temporarily prevents subjects from responding to high-
conflict decisions and allows them more time to integrate all the necessary
information and settle on the optimal choice (Cavanagh et al., 2011; Frank
et al., 2007; Oyama et al., 2011). According to this model, the STN relays a
global NoGo signal via excitatory projections to the pallidum, thereby
inhibiting thalamocortical activity. STN DBS reduces the NoGo signal
thus impulsively speeding high-conflictual decisions (Frank et al., 2007).
5. NEUROCHEMISTRY
The various mechanisms through which DBS exerts its therapeutic
actions, including its ability to modulate pathological activity (Hammond
et al., 2007) and induce a depolarization blockade (Beurrier et al., 2001),
may in part depend on altered neurotransmitter levels in the basal ganglia.
In an intracerebral microdialysis study in rats, Windels et al. (2000) found

that high-frequency STN DBS significantly increases extracellular glutamate
levels in GPi and SNr. These results were confirmed in human parkinsonian
disease in intraoperative microdialysis studies in GPi (Stefani et al., 2005)
and SNr (Galati et al., 2006). Stefani et al. (2005) found elevated cyclic gua-
nosine monophosphate (cGMP) extracellular concentrations in GPi during
STN DBS indicating increased glutamatergic transmission or increased
glutamate effectiveness on GPi. Again confirming the importance of neuro-
chemical changes during DBS in parkinsonian patients, Galati et al. (2006)
showed that STN DBS increased cGMP levels in SNr suggesting increased
excitation resulting from overactivity in glutamatergic afferent fibers to the
SNr from the STN (Fig. 3.3A). In parkinsonian patients, Stefani et al. (2011)
studied the biochemical effect of STN DBS on GPi and basal ganglia output
to the motor thalamus, the crucial structure conveying motor information to
cortex. Effective STN DBS increased GPi cGMP levels and reduced
extracellular GABA concentrations in ventral anterior nucleus (VA)
supporting thalamic disinhibition, in turn, reestablishing more physiological
thalamocortical transmission, thereby improving motor symptoms
(Fig. 3.3B). Equally important, they indirectly suggest refreshing the stan-
dard basal ganglia model. The dogma indicating a hyperactive indirect path-
way as a crucial hallmark of hypokinetic signs in PD probably needs
rethinking because DBS relieves akinesia and rigidity even in the absence
of reduced GPi excitability. Clinical improvement nevertheless requires fast
changes in thalamic GABA, confirming the standard basal ganglia model, in
which the core player in determining thalamocortical transmission is VA
(Stefani et al., 2011).
Because evidence in animals shows the involvement of neurotransmitters
such as GABA during cognitive processes and behavior (Martins, Shahrokh,
& Powell, 2011; Mora, Segovia, & Del Arco, 2008; Skirzewski et al., 2011),
altered basal ganglia GABA levels during DBS might explain DBS-induced
effects on motor function and also on cognitive functions and behavior.
6. FUTURE PERSPECTIVES: DEVELOPMENT OF NEW

ADAPTIVE DEEP BRAIN STIMULATION (aDBS)
SYSTEMS
Despite its widespread acceptance and therapeutic effectiveness,
DBS suffers a major limitation, namely, it is delivered with constant stimulation
settings, adjusted only during control visits. Neurological and neuropsychiatric
disease treated with DBS, especially PD, the main indication for DBS, typically
A
STN-DBS
cGMP concentration (fmol/50 ml)

14 10
UPDRS lll (selected items)

12
8
10
8 6
6 4
4
2
2
0 0
10 20 30 40 50 60 70 80 90
Time (min)
B
STN-DBS
VA Clinical
Worsening
5 10
GABA (pmol/50 ml)
4 8
UPDRS
3 6
2 4
1 2
0 0
1 2 3 4 5 1 2 3 4 5 6 1 2 3 4 5 6
Fractions
GPi Clinical
Worsening
10 10
cGMP (fmol/50 ml)
8 8
UPDRS
6 6
4 4
2 2
0 0
1 2 3 4 5 1 2 3 4 5 6 1 2 3 4 5 6
Fractions
Figure 3.3 Effects of deep brain stimulation on neurotransmitters. (A) Microdialysis data
from substantia nigra pars reticulata (SNr) 30 min before, during and after subthalamic
nucleus deep brain stimulation (STN DBS) in patients with Parkinson's disease (PD).
Cyclic guanosine monophosphate (cGMP) levels are reported every 10 min. The first
three fractions (white bars) were used for baseline evaluation. Monopolar STN DBS
was then switched on (black bars). After 30 min, STN DBS was discontinued and
10 min fractions were collected for an additional 30 min. Bars represent mean standard
deviation. Note a significant cGMP increase during STN DBS at P <0.01 versus
T10–T20–T30–T40–T80–T90. The clinical scores validate the effectiveness of STN DBS
(dotted line, selected items from the Unified Parkinson's disease rating scale-UPDRS:
fluctuates over time. The constant stimulation strategy therefore leaves symp-
toms partly uncontrolled (Deuschl et al., 2006; Krack et al., 2003; Romito &
Albanese, 2011). DBS could achieve an even better clinical result by adapting
moment-by-moment to the patient’s clinical condition. Another concern
arises from increasing evidence attributing several cognitive and behavioral
adverse effects, observed years after DBS therapy started, to the amount of
stimulation delivered (Bronstein et al., 2011; Romito & Albanese, 2011).
DBS therapy could be optimized to control fluctuations and adverse ef-
fects better by “fine-tuning” DBS settings (including frequency, amplitude,
pulse width, and waveform) in a short time-window. A possible solution
would be an “intelligent” DBS system, able to change stimulation settings
and variables when it detects fluctuations and adverse effects as well as more
subtle pathophysiological changes, without patients waiting until the next
clinic visit for reprogramming (Burgess et al., 2010; Marceglia et al.,
2007; Priori, Foffani, & Rossi, 2005a, 2005b; Rosin et al., 2011;
Santaniello, Fiengo, Glielmo, & Grill, 2011; Winestone, Zaidel,
Bergman, & Israel, 2012). This strategy is known as “closed-loop” or
“adaptive” DBS (aDBS). aDBS consists of a simple closed-loop model
designed to measure and analyze a control variable reflecting the patient’s
clinical condition to elaborate new stimulation device settings and send
them to an intelligent stimulator implanted in the chest.
The closed-loop concept works on the principle that a physiological var-
iable measurable in patients undergoing DBS, possibly without burdening
patients with implants other than those they already carry (electrodes, exten-
sions, and pulse generator), is able to reflect changes in the patient’s condi-
tion. Research conducted over the past 10 years suggests as a possible control
variable neuronal oscillations, measured through LFPs from DBS target
rigidity 0–4; finger tapping 0–4; hand movement 0–4; 0 corresponds to “normal”; 12 is the
maximum score). The scale is given on the right y axis. In all patients, rigidity and akinesia
in the upper contralateral arm improved by >30% without side effects within the first
10 min after stimulation began. (B) Microdialysis data from ventral anterior nucleus (VA)
and globus pallidus internus (GPi), and clinical evaluation before, during, and after STN
DBS in patients with PD. Clinically effective STN DBS significantly reduced GABA in VA
and clearly increased cGMP in the GPi. Dotted lines represent the clinical changes as in A.
The data are expressed as the mean standard deviation. (A) Reproduced from Galati
et al. (2006) with permission from John Wiley & Sons Ltd.; (B) Reprinted from Stefani et al.
(2011) with permission (http://creativecommons.org/licenses/by-nc-nd/3.0/).
LFP-based control signal

40
Frequency (Hz)
3.5
30 3
2.5
20 2 New parameters
1.5
10 1
0.5
0 Parameters
0 20 40 60 80 100 120
Time (s) adjustment
FilterDBS 0 1
LFPs
Figure 3.4 The concept of closed-loop adaptive Deep Brain Stimulation (aDBS). DBS is
delivered through implanted electrodes represented in the radiography. A control
variable (local field potentials, LFPs) is measured automatically from the implanted
electrodes and analyzed. FilterDBS provides artifact-free LFP. A LFP-based controlling
system evaluates the results of the analysis and provides new parameters to be deliv-
ered by the implanted pulse generator. Reprinted from Marceglia et al. (2007) with per-
mission from Expert Reviews Ltd.
structure (Priori, Foffani, Rossi, & Marceglia, 2012) (Fig. 3.4). This choice
receives support from the following observations: LFPs are recordable without
additional implants, correlate with the patient’s clinical condition (Brown &
Williams, 2005; Kuhn et al., 2004, 2008; Priori et al., 2004), and are easy to
capture and process also during DBS on, without artifacts (Rossi et al., 2007).
Another advantage is that LFPs recorded over time after electrode implant
(Rosa et al., 2010) show DBS-induced modulations similar to those
recorded a few days after electrode implant (Rosa et al., 2011).
Hence, even though the new aDBS approaches based on LFP recordings
now seem feasible, before aDBS systems can be applied in patients, further
research is needed to define the control variables that best reflect the patient’s
clinical state, refine feedback algorithms, develop a prototype device for use
in patients, and conduct a clinical study to compare the new aDBS system
with the current “reference-standard,” open-loop STN DBS.
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Neurophysiology of Deep Brain Stimulation

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Neurophysiology of Deep Brain Stimulation

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CHAPTER THREE

Neurophysiology of Deep Brain

International Review of Neurobiology, Volume 107 # 2012 Elsevier Inc. 23

Even though deep brain stimulation (DBS) is an effective treatment in several

In general, these neuropsychiatric disorders are less well understood than

1. ELECTRIC FIELD AND CHARGE DISTRIBUTION

effective, we still know too little about DBS-induced changes at neuronal

(Chaturvedi, Butson, Lempka, Cooper, & McIntyre, 2010). During

2. A TOOL FOR UNDERSTANDING THE FUNCTIONS

Firing rate (spikes/s)

Extracellular recording of a neuronal activity located 3 mm anterodorsal from the target

3.2. Local field potentials

Log power (a.u.)

C Grand average (16 nuclei)

Baseline DBS on DBS off

3.3. Evoked potentials

3.4. Autonomic tests

In a study designed to assess STN DBS-induced changes in cardiovascu-

3.5. Other neurophysiological variables

3.6. Synaptic plasticity

LTD have paired-pulse characteristics consistent with changes in presynaptic

decisions (Frank et al., 2007). To study STN DBS effects on reward-based

In an intracerebral microdialysis study in rats, Windels et al. (2000) found

6. FUTURE PERSPECTIVES: DEVELOPMENT OF NEW

cGMP concentration (fmol/50 ml)

UPDRS lll (selected items)

LFP-based control signal

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